Venlafaxine HCl in the treatment of painful peripheral diabetic neuropathy

DIABETES CARE, VOLUME 23, NUMBER 5, MAY 2000 699

OBSERVATIONS

Venlafaxine HCl inthe Treatment ofPainful PeripheralDiabetic Neuropathy

In a recent letter by Davis and Smith (1),venlafaxine HCl was reported to beeffective in the symptomatic treatment

of patients with painful diabetic neuropa-thy. This observation is in accordance witha similar finding made by us.

We administered venlafaxine HCl in 8patients who had unremitting painfulperipheral diabetic neuropathy that did notrespond to conventional analgesia. Allpatients had type 2 diabetes and were ofGreek origin. The patients’ ages rangedfrom 49 to 80 years, and their duration ofdiabetes ranged from 6 to 21 years. Of thesepatients, 5 were men and 3 were women; 5of the patients were being treated with oralantidiabetic agents, and 3 were on treat-ment with insulin. The glycemic control ofeach patient was good (mean HbA1c value7.2 ± 1.2%).

Peripheral sensory neuropathy waspresent in all of them, and treatment withnonsteroidal anti-inflammatory drugs andacetaminophen was unsuccessful.

Symptoms of neuropathy includedsharp, stabbing, or burning pain on thefeet; numbness; and tingling. The symp-toms were unremitting with nocturnalexacerbation. The vibration sense, whichwas examined by use of a tuning fork, wasdecreased, and the ankle tendon reflexeswere absent in all of the patients. Otherfrequent causes of peripheral sensory neu-ropathy, such as uremia, myxedema, B12

deficiency, and alcoholism, were excluded.We tried several therapeutic regimens

for the management of this common anddifficult-to-treat problem. Administrationof carbamazepine resulted in some benefitwhen given to 2 of the patients, but thedrug was discontinued because of dizzi-ness in 1 patient and because of elevationof liver enzymes (aspartate aminotrans-ferase, alanine aminotransferase, andgamma-glutamyl-transpeptidase) in theother patient. Application of capsaicincream was temporarily effective in 2 otherpatients, but the symptoms were onlymildly to moderately alleviated. Adminis-tration of amitriptyline in a single dose of

25 mg, which was eventually increased to75 mg, at bedtime was effective whengiven to 4 patients. The degree of painrelief was significant, but the side effects in2 patients were intolerable. In 1 patient,amitriptyline caused sedation that inter-fered with the patient’s ability to drive acar; in the other patient, the drug causedpostural hypotension.

Finally, we administered venlafaxineHCl in a dose of 37.5 mg twice a day to allof the patients. The results were impres-sive, and none of the patients experiencedthe side effects associated with administra-tion of amitriptyline.

Well before experiencing the antide-pressant effect of the drug, the patientsexperienced a dramatic relief in the symp-toms associated with painful peripheralneuropathy within 2–8 days after initiat-ing treatment with venlafaxine HCl.

In 2 patients, administration of the drugresulted in nausea, but these episodes werenot severe enough to warrant the cessationof treatment. Resolution of venlafaxine-asso-ciated nausea occurred rapidly in bothpatients, and the treatment remained unin-terrupted. No serious side effects wereobserved. It is worth noting that venlafaxineHCl was especially effective in relieving thesymptoms of diabetic neuropathy in the 3insulin-treated diabetic patients. Thepatients began using insulin during only thelast months of the study, and, after experi-encing an improvement in glycemic control,they experienced an exacerbation of thesymptoms of neuropathy. This is a well-known phenomenon. Venlafaxine HCl wasdramatically effective in reducing the pain ofneuropathy in this group of patients.

The mode of action of venlafaxine HClis unknown. Venlafaxine HCl has beenshown to be effective in relieving thermalhyperalgesia in rats with experimentallyinduced neuropathic pain (2).

Venlafaxine HCl seems to have one ofthe most favorable drug interaction pro-files, and data indicate that it does notinhibit, or that it weakly inhibits, the activ-ity of isoenzymes CYP2C9, CYP2D6,CYP1A2, or CYP3A3/4 (3,4). This is animportant characteristic in view of the factthat type 2 diabetic patients are usuallyalready on treatment with oral antidiabeticagents or several other drugs.

Our observations, which are in agree-ment with those of Davis and Smith (1),reinforce their suggestion that venlafaxineHCl may be useful in the treatment ofpainful peripheral diabetic neuropathy.

JOHN A. KIAYIAS, MD

EUGENIA D. VLACHOU, RN, MSC

ELLI LAKKA-PAPADODIMA, MD

From the Department of Endocrinology and Metab-olism, Athens Polyclinic Hospital, Athens, Greece.

Address correspondence to John A. Kiayias, MD,Papadiamantopoylou 26 St., Athens, 11528 Greece.

References1. Davis JL, Smith RL: Painful peripheral dia-

betic neuropathy treated with venlafaxineHCl extended release capsules (Letter).Diabetes Care 22:1909–1910, 1999

2. Lang E, Hord AH, Denson D: VenlafaxineHCl (Effexor) relieves thermal hyperalge-sia in rats with an experimental mononeu-ropathy. Pain 68:151–155, 1996

3. Ereshefsky L: Drug-drug interactionsinvolving antidepressants: focus on ven-lafaxine. J Clin Psychopharmacol 16:37–50,1996

4. Rudolph RL, Derivan AT: The safety and tol-erability of venlafaxine HCl: analysis of theclinical trials database. J Clin Psychopharma-col 16:54–59, 1996

Bilateral DiabeticInfarction of theAnterior Tibial Muscle

Diabetic syndromes in which the mus-cles, rather than peripheral nerves,are the primary sites of pathology are

rare. Some studies have identified themuscles of the thigh (1–3) and a very fewstudies have identified the muscles of theleg (4–7) as sites of infarctions, each spar-ing the anterior tibial muscle, which ismore frequently involved in mechanicallyinduced compartment compression syn-dromes (8). We are reporting on a 71-year-old woman with poorly controlled type 2diabetes suffering from bilateral isolateddiabetic infarctions of the anterior tibialmuscles, occurring within an interval of 7months and confirmed by magnetic reso-nance imaging (MRI). Six weeks beforeadmission, she had suddenly experiencedpain, local tenderness, and hypesthesia ofthe right leg without any previous physicalexercise or trauma. There was no reportedfever, swelling of the leg, or associated localerythema, but there was some numbnessand paresthesia of the anterolateral part ofthe right leg. The pain worsened over thesubsequent 3 weeks. On examination, thepatient was afebrile but in pain. Muscle

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strength of the right lower limb was normalwith the exception of paretic dorsal exten-sion of the foot (grade 4 Medical ResearchCouncil [MRC]). She was unable to walk onher heels. Tendon reflexes were normal inthe arms and hyporeactive in the knees andankles. There was hyperpathia to tactilestimuli and paresthesia in the distal part ofthe anterolateral right leg. Pinprick and lighttouch sensation was attenuated in the samearea. All peripheral arterial pulses were nor-mal. There was no significant differencebetween the maximal circumferences of

both legs (�2 cm), but there was some mildbilateral ankle edema. The fasting blood glu-cose was 147 mg/dl, the HbA1c concentra-tion was 6.7% (normal �5.7%), and the C-peptide level was 1.43 mmol/l (normal�0.99 mmol/l). The white blood cell countwas 7,500 cells/mm3 with a normal differen-tial. The erythrocyte sedimentation rate was33 mm/h and the C-reactive protein 2.0mg/l (normal �2.0 mg/l). Repeated levels ofcreatine kinase, coagulation tests, and creati-nine levels were normal. Cerebrospinal fluidshowed normal protein content and cell

count. Standard motor nerve conductionand F-wave studies of bilateral deep per-oneal and tibial nerves were normal. Sen-sory nerve conduction studies of both suralnerves showed reduced action potentialamplitudes and normal nerve conductionvelocities. Concentric needle electromyog-raphy (EMG) of the right anterior tibialmuscle displayed severe fibrillations andpositive sharp waves (3� on a scale from 0to 4�). In contrast, there were only a fewquestionable fibrillations in the extensorhallucis longus muscle and posterior tibialmuscle, and no pathologic spontaneousactivity in the peronaeus longus, rectusfemoris, vastus medialis, gastrocnemius,gluteus medius, and adductor longus mus-cles. Motor unit potentials of the anteriortibial muscle were slightly enlarged. Thefollow-up EMG examination, 8 days later,did not show any significant change in thedistribution of the spontaneous activity,which was still very prominent in the ante-rior tibial muscle and at this time not pres-ent in the posterior tibial muscle. The plainX-ray of the leg showed no skeletal lesions.B-mode sonography of the anterolateral legmuscles and Doppler sonography andduplex scanning of the lower-limb arterieswere normal. The MRI of the lumbar spinewas normal. The MRI of the right legshowed high signal intensity of the anteriortibial muscle (Fig. 1C), while all other per-oneal muscles, as well as the gastrocnemiusmuscle appeared with normal signals in thelong T2-weighted images. No abnormali-ties could be detected in the other tissuessuch as nerves, bones, or soft tissues. InT1-weighted images, before and after con-trast enhancement, no significant signalabnormalities were present. Inversionrecovery MRI techniques were applied todifferentiate between the fat and water con-tents of the muscle structure by using delaytimes for the inversion pulse producing fatand water signal suppression. These imagesrevealed a normal fat distribution but anincreased net-water content of the anteriortibial muscle (Fig. 1A, 1B).

With analgesic therapy, the symptomsgradually improved until they completelyresolved after 7 weeks. However, 7 monthslater, the patient was readmitted because ofsimilar pain and tenderness of the antero-lateral left leg. On admission, she wasunable to walk on her heels, and dorsalextension of the foot was grade 3 MRC onthe left and 4� MRC on the right. Hyper-pathia to tactile stimuli and paresthesia ofthe anterolateral aspect of the left leg were

Figure 1—Sagittal MRI of the right and left lower leg (1A, 1D). Inversion recovery images with fatsignal suppression reveal high water content of the anterior tibial muscle (long arrows), suggestive ofsubacute infarction, while signal of the gastrocnemius muscle (arrowheads) is normal. The corre-sponding axial slices 10 cm below the knee demonstrate signal abnormality of the anterior tibial mus-cle (short arrows), while the muscles of the peroneal group and gastrocnemius appear normal (1B:inversion recovery MRI; 1C, 1E: long T2-weighted MRI).


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also found. The patient’s HbA1c was ele-vated to 7.9% (normal �5.7%), whereasother routine laboratory tests were normal.The EMG of the left anterior tibial muscledisplayed moderate fibrillations and posi-tive sharp waves (2� on a scale from 0 to4�), while there was no pathologic spon-taneous activity in neighboring muscles.Control EMG of the right anterior tibialmuscle showed enlarged polyphasic motorunit potentials with no signs of sponta-neous activity and a severely disruptedinterference pattern. This time, MRI scansof the left leg showed isolated high signalintensity changes of the left anterior tibialmuscle in the inversion recovery (Fig. 1D)and T2-weighted images (Fig. 1E).

In our patient with inadequately con-trolled diabetes, muscle infarction was atboth times suggested by the acute onset oflocalized pain in the anterolateral leg. Sev-eral weeks after onset, EMG revealed pro-fuse pathologic spontaneous activity con-fined to the anterior tibial muscles. Stan-dard motor conduction studies oflower-limb nerves were normal, so that amononeuropathy of the deep or commonperoneal nerve was unlikely, whereas sen-sory nerve conduction studies were sugges-tive of mild sensory polyneuropathy. Labo-ratory investigations of serum, includingcreatine-kinase and cerebrospinal fluid,gave no indication of ongoing inflamma-tion. In the absence of a history of previoustrauma or excessive exercise, a mechani-cally induced anterior compartment syn-drome of the leg with increased tissue pres-sure resulting in ischemia seemed unlikely.Also, typical features of anterior compart-ment syndrome, such as involvement of theanterior tibial muscle and the peronealmuscles, swelling of the leg and an electri-cally silent EMG (8), were absent in ourpatient. The MRI suggested an isolatedlesion of both anterior tibial muscles, 4 and6 weeks after onset of symptoms. Therewas increased signal intensity in longT2-weighted images and fat and water-sup-pression inversion-recovery sequences,thus indicating an increased net water con-tent of the anterior tibial muscle. Thesefindings were the morphological correlateof subacute infarction, i.e., the muscular tis-sue was beyond the stage of contrastenhancement but had not yet reached thechronic stage with formation of fatty streaksor scar tissue, as described in severalhistopathological studies (1,6). We did notsupplement the imaging results by musclebiopsy in order to limit focal muscular

damage in accordance with other authors(3). Clinical examination and ultrasound ofthe leg arteries failed to demonstrate largevessel occlusion. Usually, the anterior tibialmuscle is supplied by 3 or 4 branches of theanterior tibial artery (9) that do not regu-larly show up on angiography. We assumethat they must have been occluded in ourpatient, as in previous autopsy studies inpatients with diabetic muscle infarction,extensive atherosclerosis of small muscularand intramuscular arteries has beenreported (6). The sensory abnormalitieshad to be summarized under a mildperipheral sensory polyneuropathy as indi-cated by the bilaterally low tendon reflexactivity in the lower limbs and abnormali-ties of sensory nerve conduction.

In summary, from the clinical historyand examination, the electrodiagnosticfindings, and, in particular, the findings ofMRI, we concluded that our patient suf-fered from diabetic muscle infarction ofthe anterior tibial muscles. According tothe literature, a contralateral recurrence isnot rare (6). Recent articles includedpatients with diabetic muscle infarctionsof the legs and all involved the calves,directing attention from the thigh to othermuscular regions as potential sites ofinfarction (4–7). However, to the best ofour knowledge, this is the first report todescribe isolated bilateral diabetic infarc-tions of the anterior tibial muscles.

KONSTANTINOS SPENGOS, MD

JOHANNES C. WÖHRLE, MD

JOHANNES BINDER, MD

ANDREAS SCHWARTZ, MD

MICHAEL HENNERICI, MD

From the Department of Neurology, Universitäts-klinikum Mannheim, University of Heidelberg,Mannheim, Germany.

Address correspondence to Johannes C. Wöhrle,MD, the Department of Neurology, Universitäts-klinikum Mannheim, University of Heidelberg,Theodor Kutzer Ufer, D-68135 Mannheim, Ger-many. E-mail: [email protected].

References1. Barohn RJ, Kissel JT: Case-of-the-month:

painful thigh mass in a young woman: dia-betic muscle infarction. Muscle Nerve 15:850–855, 1992

2. Scully RE, Mark EJ, McNeely WF, EbelingSH, Phillips LD: Case records of the Mass-achusetts General Hospital: weekly clini-copathological exercises. Case 29-1997: a54-year-old diabetic woman with pain andswelling of the leg. N Engl J Med 337:839–845, 1997

3. Keller DR, Erpelding M, Grist T: Diabeticmuscular infarction: preventing morbidityby avoiding excisional biopsy. Arch InternMed 157:1611–1617, 1997

4. Umpierrez GE, Stiles RG, Kleinbart J,Krendel DA, Watts NB: Diabetic muscleinfarction. Am J Med 101:245–250, 1996

5. Van Slyke MA, Ostrov BE: MRI evaluationof diabetic muscle infarction. Magn ResonImaging 13:325–329, 1995

6. Chester CS, Banker MD: Focal infarction ofmuscle in diabetics. Diabetes Care 9:623–630, 1986

7. Nunez-Hoyo M, Gardner CL, Motta AO,Ashmead JW: Skeletal muscle infarction indiabetes: MR findings. J Comput AssistTomogr 17:986–988, 1993

8. Shields RW Jr, Root KE, Wilbourn AJ:Compartment syndromes and compres-sion neuropathies in coma. Neurology 36:1370–1374, 1986

9. Lang J, Wachsmuth W: Bein und Statik. InPraktische Anatomie. Bein und Statik. Berlin,Springer-Verlag, 1972, p. 311–313

Function of Pancreatic Islets Isolated From aType 1 DiabeticPatient

In type 1 diabetes, the progressiveautoimmune destruction of the pancre-atic �-cells leads to insulin deficiency,

with reduced or absent response to glucoseand nonglucose stimuli. An additional hor-monal defect involves glucagon secretion.This includes loss of glucose-induced sup-pression of glucagon secretion and exag-gerated increase of glucagon in response tostimuli such as arginine infusion and a pro-tein meal. It can be corrected by restorationof insulin levels. Not surprisingly, the infor-mation on insulin and glucagon secretionin human type 1 diabetes has beenobtained almost exclusively from in vivostudies. To our knowledge, only 1 articlehas been published on the function of iso-lated type 1 diabetic islets (1). In that case,pre-proinsulin mRNA and insulin content,as well as insulin response, were evaluatedfrom isolated islets at the clinical onset ofdisease. The authors found that, althoughmarkedly reduced, �-cells were still pres-ent, which showed a disproportionateimpairment of insulin release ability.

Our laboratories are involved in thepreparation and characterization of islets ofLangerhans from the pancreases of large


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mammals and people (2,3). We receivedthe pancreas of P.E., a young type 1 diabeticpatient, who was a multiorgan donor, andhad died accidentally, 8 months after thediagnosis of type 1 diabetes. This providedus the unique opportunity to study some ofthe functional properties of the islets iso-lated from a type 1 diabetes pancreas, at afew months from clinical onset of disease.

P.E. was a 14–year-old type 1 diabeticgirl. Eight months before the car accidentthat caused her death, she had beenadmitted to an emergency medicine clinicbecause of a coma of unknown origin, andthe diagnosis of diabetic ketoacidosis wassoon made. After a full recovery, she wasfollowed by a pediatric diabetologist, whoconfirmed the diagnosis of type 1 diabetesby demonstrating the presence of positiv-ity for HLA-DR3, high titer of islet cellantibody, anti-GAD, and anti-IA2 antibod-ies, and low levels of plasma C-peptide.Diabetes control was maintained fair(HbA1c levels �8%) by �0.4 U/kg bodywt of insulin, given daily through 3 sepa-rate injections. After the car accident, andafter brain death was confirmed, her par-ents agreed to organ donation.

The islets were prepared in the labora-tory in Pisa, Italy, by collagenase digestionand density gradient purification (2,4).Aliquots of the final preparation were sentto Brussels for the evaluation of insulinsynthesis and to perform perifusion exper-iments, as previously described (5). Theother studies were performed in Pisa andRome, according to previously reportedprocedures (2,4). The results were com-pared with those generated with the isletsprepared from the pancreas of a 25-year-old woman. Also in this case, the cause ofdeath had been a car accident, and we iso-lated the islets 2 days after the type 1 dia-betic pancreas processing. The methodsused were the same and the final puritywas �90%.

During the isolation process, the isletsfrom the type 1 diabetic patient appearedas discrete round or oval structures thatcould be identified by dithizone staining.At the end of the isolation and purifica-tion procedures, the purity of the islets, asroughly estimated by dithizone staining,was �60%.

After 5 days of isolation, the insulin syn-thetic activity was measured during a 2-hincubation at 10 mmol/l glucose. Whenexpressed as a function of correspondinginsulin content, the rate of glucose-inducedinsulin synthesis in �-cells from the dia-

betic pancreas was 76% of the values mea-sured in control cells (4.8 vs. 6.3%).

By the perifusion experiments, thefirst-phase insulin release was analyzedand the data were expressed as function ofinsulin content (Fig. 1). The basal insulindischarge from diabetic �-cells was com-parable to that from control preparations,whereas their glucose-stimulated activitywas markedly reduced. The diabetic isletsdid not respond to 5 mmol/l glucose,whereas control cells were stimulated4-fold; their secretory activity increased2- to 3-fold at 10 and 20 mmol/l glucose,but their maximal activity was still 4-foldlower than that of control values. Thisreduced glucose responsiveness could notbe corrected by the addition of arginine.

The static incubation experiments(mean ± SD of 4 to 5 determinations) wereperformed after 5 and 17 days of isolation,with the islets kept under standardized cul-ture conditions (2,4). Shortly after the isola-tion, insulin release (expressed as percent ofinsulin content) in response to 3.3 mmol/lglucose and 3.3 mmol/l glucose � 20mmol/l arginine was similar in control(respectively 1.0 ± 0.2 and 1.7 ± 0.4%) andtype 1 (respectively 1.2 ± 0.4 and 1.5 ±0.3%) islets, whereas the secretion of thehormone in response to 16.7 mmol/l glu-cose and 16.7 mmol/l glucose plus 1 mmol/l3-isobutyl-1-methylxanthine (IBMX) was

lower from type 1 islets (respectively 1.6 ±0.3 and 1.9 ± 0.2%) than from control cells(respectively 2.6 ± 0.6 and 3.0 ± 0.2%).After 17 days of culture, the difference athigh glucose was not observed (high glu-cose plus IBMX was not tested); insulinsecretion, normalized for insulin content,was 7.8 ± 1.2% from diabetic islets and 6.5± 0.5% from control islets.

The release of glucagon (pg/ml, mean ±SD of 4 to 5 determinations) from bothshortly prepared and cultured type 1 dia-betic islets was similar at 3.3 (respectively20.6 ± 1.2 and 20.3 ± 1.1) and 16.7 (19.9 ±1.6 and 20.9 ± 1.8) mmol/l glucose,whereas the control islets showed a reduc-tion of glucagon release (�20%) inresponse to high glucose (5-day culturedislets: 21.8 ± 1.4 at 3.3 mmol/l glucose and17.6 ± 1.5 at 16.7 mmol/l glucose; 17-daycultured islets: 22.4 ± 0.9 at 3.3 mmol/l glu-cose and 16.8 ± 0.2 at 16.7 mmol/l glucose).The addition of arginine to 3.3 mmol/l glu-cose caused a similar increase of glucagonrelease from both diabetic (25.2 ± 4.0 and31.6 ± 8.7, respectively, from 5- and17-day cultured cells), and control (33.1 ±6.2 and 26 ± 1.3, respectively, from 5- and17-day cultured cells) islets.

In the present study, the hormonalfunction of islets prepared from type 1diabetic patient a few months from theonset of disease is reported for the first

Figure 1—Insulin release from human islets isolated from diabetic (—) and control donors (•••).Preparations were perifused with 10-min pulses of varying glucose concentrations with or without 5mmol/l arginine.


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time. In these islets, 8 months after thediagnosis of diabetes, some residual cellscapable of insulin synthesis and secretionwere still present.

Our results confirm in vivo data show-ing that the defects of insulin release in thistype of diabetes are mainly quantitativeand involve a wide range of insulinotropicagents. Interestingly, we found that thecharacteristics of insulin release of type 1diabetic islets seemed to improve after aperiod of culture. This is in agreement withprevious data obtained with islets preparedfrom NOD mice, showing reversal of glu-cose-induced insulin release suppressionafter 7 days of culture (6). In that case,removal of intra-islet inflammatory cellswas considered as the factor leading to theimproved �-cell function. Our results sug-gest that some of the alterations observedwere due, at least in part, to the native type 1islet environment.

A loss of glucose-modulated glucagonsecretion and a maintained sensitivity toarginine have been observed in models ofboth type 1 and type 2 diabetes (7), sug-gesting that the defect of glucagon releaseis mainly due to the diminished insulinlevels. In our experiments, glucagonrelease from the diabetic islets was similarat 3.3 as 16.7 mmol/l glucose and thereduced suppression by high glucose didnot change upon culture. On the otherhand, in the presence of arginine, a similarincrease of glucagon secretion wasobserved from both diabetic and controlislets. Thus, the decreased insulin outputfrom our type 1 diabetes islets was paral-leled by minor derangements of glucagonrelease.

The persistence of some insulin syn-thetic and secretory function, even a fewmonths after the onset of diabetes, and theimprovement of insulin secretion character-istics after removal of the islets from theirnative environment support the search forstrategies aimed to allow the diagnosis andtreatment of type 1 diabetes as early as pos-sible in the natural history of the disease.

PIERO MARCHETTI, MD

FRANCESCO DOTTA, MD

ZHIDONG LING, PHD

ROBERTO LUPI, PHD

SILVIA DEL GUERRA, PHD

CARMELA SANTANGELO, PHD

MASSIMO REALACCI, PHD

LORELLA MARSELLI, MD

UMBERTO DI MARIO, MD

RENZO NAVALESI, MD

From the Department of Endocrinology and Metab-olism (P.M., R.L., S.D.G., L.M., R.N.), MetabolicUnit, University of Pisa, Pisa; the Department ofEndocrinology (F.D., C.S., M.R., U.D.M.), SecondMedical Clinic, “La Sapienza” University, Rome,Italy; and the Beta-Cell Transplant Unit (Z.L.), VrijeUniversiteit, Brussels, Belgium.

Address correspondence to Piero Marchetti,MD, Department of Endocrinology and Metabo-lism, Metabolic Unit, Ospedale Cisanello, Via Par-adisa 2, 56100 Pisa, Italy. E-mail: [email protected].

Acknowledgments — This work was sup-ported by grants from the Italian NationalResearch Council, Ministero Università eRicerca Scientifica e Tecnologica, RegioneToscana, the European Community (BMH1-CT92–0805, BMH4-CT95–1561), the Min-istry of Scientific Policy (CE-03–001), theFlemish Community (93/019), Biomed, andthe Juvenile Diabetes Foundation Interna-tional (DIRP 995004).

The authors thank Renè De Proft, LutgartHeylen, Gabriel Schoonjans, and Luc Bouwensfor technical assistance.

References1. Conget I, Fernadez-Alvarez J, Ferrer J,

Sarri Y, Novials A, Somoza N, Pujol-BorrelR, Casamitjana R, Gomis R: Human pan-creatic islet function at the onset of type 1(insulin-dependent) diabetes mellitus.Diabetologia 36:358–360, 1993

2. Marchetti P, Giannarelli R, Cosimi S,Masiello P, Coppelli A, Viacava P, NavalesiR: Massive isolation, morphological andfunctional characterization, and xeno-transplantation of bovine pancreatic islets.Diabetes 44:375–381, 1995

3. Keymeulen B, Ling Z, Gorus FK, DelvauxG, Bouwens L, Grupping A, HendrieckxC, Pipeleers-Marichal M, Van Schraven-dijk C, Salmela K, Pipeleers DG: Implanta-tion of standardized beta-cell graft in aliver segment of IDDM patients: graft andrecipient characteristics in two cases ofinsulin-independence under maintainanceimmunosuppression for prior kidneygraft. Diabetologia 41:452–459, 1998

4. Pupilli C, Giannini S, Marchetti P, Lupi R,Antonelli A, Malavasi F, Takasawa S,Okamoto H, Ferrannini E: Autoantibodiesto CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in Caucasian patientswith diabetes: effects on insulin releasefrom human islet cells. Diabetes 48:2309–2315, 1999

5. Ling Z, Pipeleers D: Prolonged exposure ofhuman beta-cells to elevated glucose levelsresults in sustained cellular activation witha loss of glucose regulation. J Clin Invest98:2805–2812, 1996

6. Strandell E, Eizirik DL, Sandler S: Reversalof beta-cell suppression in vitro in pancre-

atic islets isolated from NOD mice duringthe phase preceding insulin-dependentdiabetes mellitus. J Clin Invest 85:1944–1950, 1990

7. Ishida K, Mizuno A, Sano T, Shi K, ShimaK: Plasma glucagon responses to insulin-induced hypolgycemia and arginine inspontaneous non-insulin-dependent dia-betes mellitus rats, Otsuka Long EvansTokushima Fatty (OLEFT) strain. ActaEndocrinol (Copenh) 129:585–593, 1993

Circulating Levels ofCoagulation FactorXIII in Subjects WithType 2 Diabetes andin Their First-DegreeRelatives

Coagulation factor XIII (FXIII) circu-lates in plasma as an inactivetetramer of 2 A- (catalytic) and 2

B- (carrier) subunits. When activated bythrombin, it catalyzes the cross-linking offibrin chains and �2-antiplasmin to fibrin(1), thereby increasing the mechanicalstrength and fibrinolytic resistance of fib-rin clot. A functional role for FXIII inthrombotic disease is suggested by thefinding that the Leu allele at the commonVal34Leu polymorphism in the FXIIIA-subunit gene appears to protect againstboth myocardial infarction and venousthromboembolism (2,3).

We compared 173 subjects with type 2diabetes (48 treated with diet alone, 6treated with insulin, 21 treated with met-formin, 73 treated with sulfonylurea, and25 treated with combined sulfonylureaand metformin therapy) with a group of110 nondiabetic healthy control subjectsof similar age (mean age 63 years). Addi-tionally, 132 first-degree relatives (44 sib-lings, 77 children, and 4 parents) of sub-jects with type 2 diabetes were comparedwith a second control group of 151healthy subjects of similar age (mean ages45 and 47 years, respectively). All of thesubjects had been recruited for earlierhemostasis studies (4,5).

Circulating levels of FXIII were mea-sured in citrated plasma samples. FXIII A-and B-subunit antigen levels were mea-sured by use of a sandwich enzyme-linkedimmunosorbent assay method (6), andFXIII activity was measured by a sensitivemicrotiter assay using fibrinogen and5-(biotinamido)pentylamine (6). Geno-


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type at the FXIII codon34 (Val34Leu)polymorphism was determined by use of apreviously described method (3).

Mean (± SD) circulating levels of FXIIIA-subunit antigen and B-subunit antigenwere higher in diabetic subjects than incontrol subjects (117 ± 29 vs. 98 ± 27%and 125 ± 26 vs. 109 ± 26%, respectively),and these differences remained afteradjustments for age, sex, BMI, smokinghabit, and fibrinogen levels; the adjustedmean values were 120 vs. 96% for theA-subunit and 126 vs. 109% for theB-subunit (P � 0.0005 for each compari-son). In contrast, the levels of FXIII cross-linking activity were not different betweenthe type 2 diabetic subjects and the controlsubjects (104 ± 33 vs. 101 ± 37%). Levelsof FXIII in diabetic subjects were notaltered by exclusion of those subjects witha clinical history of coronary artery disease,cerebrovascular disease, peripheral vascu-lar disease, or diabetic retinopathy, and lev-els of FXIII showed no heterogeneity acrossantidiabetic treatment groups.

In relatives of subjects with type 2 dia-betes, mean levels of FXIII A-subunit werehigher than those in control subjects (116± 38 vs. 103 ± 29%, respectively, P �0.001), and this difference remained afteradjustment for age, sex, BMI, smokinghabit, and fibrinogen level (117 vs. 106%,respectively, P = 0.012). However, levels ofFXIII B-subunit (110 ± 29 vs. 108 ± 361%)and FXIII cross-linking activity (93 ± 37 vs.103 ± 41%) were not significantly differentbetween relatives and control subjects.

Levels of FXIII B-subunit antigenshowed a consistent pattern of correlationwith other recognized cardiovascular riskfactors (i.e., fibrinogen, factor VII coagulantactivity, cholesterol levels, triglyceride lev-els, and HbA1c levels [r � 0.16 and P �0.05 for each factor]). In the diabeticpatients and relative groups, there was alsoa significant correlation of levels of FXIIIB-subunit with insulin, homeostasis modelassessment insulin resistance (7), and PAI-1levels (r = 0.16, P �0.05). FXIII A-subunitantigen levels were correlated with levels offibrinogen only (r = 0.25, P = 0.001) in thediabetic patients and in the younger controlgroup (r = 0.23, P = 0.008).

Factor XIII activity levels rose as thenumber of Leu alleles increased at theFXIII codon34 (Val34Leu) polymorphismin each group. There was no consistentpattern of association of the Val34Leugenotype with levels of FXIII A- or B-sub-unit antigen across the groups.

These findings suggest that elevatedlevels of FXIII A-subunit may precede thedevelopment of diabetes and arise throughsome mechanism(s) shared with those thatcontribute to the familial predisposition totype 2 diabetes. It is not clear what thatmechanism may be. There was no associa-tion between the A-subunit level and thefasting glucose level, the HbA1c level, or anymeasured metabolic feature of diabetes, itsvascular complications, or its treatment.However, it is possible that raised FXIIIA-subunit levels may be an early marker ofsubclinical vascular damage.

FXIII A-subunits circulate only inFXIII tetramer, whereas B-subunits circu-late in both tetrameric and free dimericforms. This distinction and the differingsites of synthesis of the 2 subunits (8) mayaccount for the difference in findings forlevels of A- and B-subunits across thegroups studied. Furthermore, the consis-tency of the correlation between circulat-ing levels of FXIII B-subunit antigen andother cardiovascular risk markers raisesthe possibility of an underlying associa-tion with insulin resistance. However, ifthere is a functional significance ofincreased FXIII B-subunit levels, it has yetto be elucidated.

Despite the clear differences in levels ofFXIII subunit antigens, there was no differ-ence in the levels of FXIII activity betweendiabetic subjects or first-degree relativesand age-matched control subjects. It ispossible that the influence of genotype atthe Val34Leu polymorphism on FXIIIactivity levels (9,10) may have overridingimportance, because, even after adjust-ment for its influence, no difference wasfound between the subject groups. Fur-thermore, the extent to which in vitro mea-surements of FXIII activity reflect in vivophysiological FXIII function is unclear.

In conclusion, levels of FXIII A- andB-subunit antigen are elevated in subjectswith type 2 diabetes, and levels of FXIIIA-subunit antigen are elevated in relativesof subjects with type 2 diabetes. Levels ofFXIII B-subunit antigen show a consistentpattern of correlation with other vascularrisk markers, which supports the possibil-ity of an underlying association withinsulin resistance.

MICHAEL W. MANSFIELD, DM, MRCP

HANS P. KOHLER, MD

ROBERT A. S. ARIËNS, PHD

LYNN J. MCCORMACK, PHD

PETER J. GRANT, MD, FRCP

From the Academic Unit of Molecular VascularMedicine, University of Leeds, Leeds, U.K.

Address correspondence to Michael W. Mans-field, DM, MRCP, Academic Unit of Molecular Vas-cular Medicine, G-Floor, Martin Wing, GeneralInfirmary at Leeds, Leeds LS1 3EX, U.K. E-mail:[email protected].

Acknowledgments — This study was sup-ported by the British Heart Foundation.H.P.K. has received funds from the SwissFoundation for medical-biological grants.

References1. Greenberg CS, Birckbichler PJ, Rice RH:

Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues.FASEB J 5:3071–3077, 1991

2. Catto AJ, Kohler HP, Coore J, MansfieldMW, Stickland MH, Grant PJ: Associationof a common polymorphism in the factorXIII gene with venous thrombosis. Blood93:906–908, 1999

3. Kohler HP, Stickland MH, Ossei-GerningN, Carter A, Grant PJ: Association of acommon polymorphism in the factor XIIIgene with myocardial infarction. ThrombHaemost 79:8–13, 1998

4. Mansfield MW, Heywood DM, Grant PJ:Sex differences in coagulation and fibrinol-ysis in white subjects with non-insulin-dependent diabetes mellitus. ArteriosclerThromb Vasc Biol 16:160–164, 1996

5. Mansfield MW, Heywood D, Grant PJ: Cir-culating levels of factor VII, fibrinogen,and von Willebrand factor and features ofinsulin resistance in first-degree relativesof patients with NIDDM. Circulation 94:2171–2176, 1996

6. Ariëns RAS, Kohler HP, Mansfield MW,Grant PJ: Subunit antigen and activity lev-els of coagulation factor XIII in healthyindividuals: relationship to gender, age,smoking and hypertension. ArteriosclerThromb Vasc Biol 19:2012–2016, 1999

7. Matthews DR, Hosker JP, Rudenski AS,Naylor BA, Treacher DF, Turner RC:Homeostasis model assessment: insulinresistance and �-cell function from fastingplasma glucose and insulin concentrationsin man. Diabetologia 28:412–419, 1985

8. Schmeling A, Bockholdt B, Schroder H,Geserick G: Phenotype change in poly-morphic plasma proteins following livertransplantation. Exp Clin Immunogenet 13:78–83, 1996

9. Kangsadalampai S, Board PG: The Val34Leupolymorphism in the A subunit of coagu-lation factor XIII contributes to the largenormal range in activity and demonstratesthat the activation peptide plays a role incatalytic activity. Blood 92:2766–2770,1998

10. Kohler HP, Ariëns RAS, Whitaker P, Grant


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PJ: A common coding polymorphism inthe FXIII A-subunit gene (FXIIIVal34Leu)affects cross-linking activity (Letter).Thromb Haemost 80:704, 1998

Effect of AldoseReductase Inhibitoron Cutaneous NerveFiber Length in Diabetic Patients

For the treatment of diabetic neu-ropathy, how to evaluate the effi-cacy of given compounds is impor-

tant. Although the most reliable methodmay be a morphological examination,performing a nerve biopsy is not usuallyrecommended for diagnosing diabeticneuropathy because it may be harmful. Inthis context, skin biopsy is safe andreproducible. In addition, since the cuta-neous nerve is a terminal part of the sen-sory nerve where nerve fibers start todegenerate and readily regenerate in sen-sory neuropathies, examining cutaneousnerves may well be rationalized to evalu-ate the therapeutic effects of the drugs.Immunohistochemical analysis of dermalnerves using antibodies against proteingene product (PGP) 9.5, neuron specificpanaxonal marker, may be useful to eval-uate sensory neuropathies (1). Wereported that dermal nerve fiber length(NFL), which was obtained by measuringnerve fiber PGP 9.5, immunostained, andlabeled with streptavidin fluoresceinisothiocyanate under confocal laser scan-ning microscopy, was significantlyshorter in diabetic patients than in con-trol subjects (2).

Using this technique, we evaluatedthe therapeutic effect of aldose reductaseinhibitor (ARI) epalrestat in 32 type 2diabetic patients with neuropathy. Nine-teen patients were treated with epalrestat(50 mg) 3 times per day for �13 months(ARI group) and 12 patients served ascontrol subjects (control group). At thestart of the trial, there were no significantdifferences between the clinical back-grounds of the 2 groups. No significantchange in HbA1c was found in eithergroup during the trial. Since NFL washighly variable but reproducible for indi-vidual patients, the effect of epalrestat onNFL was evaluated by its percent changeduring the trial. The percent change of

epidermal NFL was not different betweenthe 2 groups, whereas the percent changeof dermal NFL was significantly greater inthe ARI group (249 ± 478%) than in thecontrol group (29 ± 40%). The numberof patients whose percent change of der-mal NFL exceeded its mean ± 2 SD(109%) in control group was significantlyhigher in the ARI group than in the con-trol group (P � 0.05, 8/19 vs. 1/12).Ultrastructurally, the fine fibers proliferat-ing in the upper dermis of the patientswith increased NFL proved to be com-posed of an increased number of axonswith incomplete Schwann cell coverage,a finding compatible with regeneratingnerve fibers.

The effect of ARI on the regenerativecapacity of myelinated nerve fibers hasalready been reported in clinical (3) andexperimental studies (4). The presentstudy shows that small nerve fibers,mainly composed of unmyelinated nervefibers of the sensory nerve terminal, couldalso regenerate or sprout with ARI. Thepossible mechanisms by which aldosereductase plays a role in the pathogenesisof diabetic neuropathy may also be rele-vant to the mechanisms by which ARIimproves dermal nerve regeneration. Inaddition, ARI improves decreased contentof nerve growth factor (NGF) in the sci-atic nerves of diabetic rats (5). NGF,which is essential for the development ofcollateral reinnervation from cutaneousC-fibers (6), depletes keratinocytes in theskin of diabetic patients (7) and may bereversed by ARI. Unlike dermal innerva-tion, epidermal innervation was notimproved with ARI. This finding maysuggest that regenerating or sproutingnerves of the dermis cannot easily enterthe epidermis in a diabetic state, ratherthan that epidermal nerves cannot regen-erate or sprout, since epidermal innerva-tion was very poor in most patients. Gly-cated basement membrane of the epider-mis may prevent reinnervation of dermalnerve fibers into the epidermis.

HITOSHI YASUDA, MD, PHD

AKINORI HIRAI, MD, PHD

MARI JOKO, MD, PHD

MASAHIKO TERADA, MD, PHD

TORU KAWABATA, MD, PHD

KENGO MAEDA, MD, PHD

MASAKAZU HANEDA, MD, PHD

ATSUNORI KASHIWAGI, MD, PHD

TOSHIHIRO MAEDA, MD, PHD

RYUICHI KIKKAWA, MD, PHD

From the Third Department of Medicine (H.Y.,A.H., J.M., M.T., T.K., K.M., M.H., A.K., R.K.) andthe Department of Anatomy (T.M.), Shiga Univer-sity of Medical Science, Otsu, Shiga, Japan.

Address correspondence to Hitoshi Yasuda, MD,PhD, Third Department of Medicine, Shiga Univer-sity of Medical Science, Otsu, Shiga 520-2192,Japan. E-mail: [email protected].

References1. McCarthy BG, Hsieth ST, Stocks A, Hauer

P, Macko C, Cornblath DR, Griffin JW,McArthur: Cutaneus innervation in sen-sory neuropathies: evaluation by skinbiopsy. Neurology 45:1848–1855, 1995

2. Hirai A, Yasuda H, Joko M, Maeda T,Kikkawa R: Evaluation of diabetic neu-ropathy through the quantitation of cuta-neous nerves. J Neurol Sci 172:55–62, 2000

3. Sima AA, Bril V, Nathaniel V, McEwen TA,Brown MB, Lattimer SA, Greene DA: Regen-eration and repair of myelinated fibers insural nerve biopsy specimens from patientswith diabetic neuropathy treated withsorbinil. N Engl J Med 319:548–555, 1988

4. Terada M, Yasuda H, Kikkawa R, Shigeta Y:Tolrestat improves nerve regeneration aftercrush injury in streptozocin-induced dia-betic rats. Metabolism 45:1189–1195, 1996

5. Ohi T, Saita K, Furukawa S, Ohta M,Hayashi K, Matsukura S: Therapeuticeffects of aldose reductase inhibitor onexperimental diabetic neuropathy throughsynthesis/secretion of nerve growth factor.Exp Neurol 151:215–220, 1998

6. Doubleday B, Robinson PP: The role ofnerve growth factor in collateral reinnerva-tion by cutaneous C-fibers in the rat. BrainRes 593:179–184, 1992

7. Anand P, Terenghi G, Warner G, Kopel-man P, Williams-Chestnut RE, SinicropiDV: The role of endogenous nerve growthfactor in human diabetic neuropathy. NatMed 2:703–707, 1996

Prevalence of Diabetes in AdultPatients WithDown’s SyndromeLiving in a Residential Home

Previous studies reported an increasedprevalence of diabetes in patientswith Down’s syndrome (1–3). These

studies, however, were limited to youngpeople with Down’s syndrome. Recently,mortality from Down’s syndrome hasdeclined, and life expectancy in Down’ssyndrome patients has improved (4,5). It is


Letters

important to examine the prevalence of dia-betes in adult patients with Down’s syn-drome to prevent diabetic complicationsand cardiovascular disease.

In this study, we examined the preva-lence of diabetes in adult patients withDown’s syndrome living in a residentialhome for adults with mental and physicalhandicaps. Data were collected for 40 adultpatients identified as having Down’s syn-drome by chromosome analysis (26patients with regular trisomy 21, 13patients with mosaic trisomy 21, and 1patient with trisomy 21 by translocation).Of the 40 subjects, 27 were men and 13were women. The mean ages of the menand women were 47.7 ± 5.8 years (range37–62) and 48.8 ± 6.6 years (38–62),respectively. The BMIs of the men andwomen were 22.0 ± 2.7 and 21.8 ± 2.1kg/m2, respectively. The mean fastingplasma glucose (FPG) levels for the menand women were 5.1 ± 0.4 mmol/l (92.1 ±7.6 mg/dl) and 5.1 ± 0.5 mmol/l (92.3 ±8.3 mg/dl), respectively. The FPG for thepatients was no more than 6.0 mmol/l(108 mg/dl). According to the new Ameri-can Diabetes Association criteria for dia-betes using FPG (6), none of the patientswere classified as having diabetes orimpaired fasting glucose (IFG). TheDECODE Study Group showed that 3,119subjects (10.7%) had IFG and 1,143 sub-jects (3.9%) had diabetic FPG among the29,108 people (mean age 53.3 years, meanBMI 26.1 kg/m2) without previously diag-nosed diabetes, according to the new fast-ing category (7). Another study reported that70.6% of men and 95.8% of women withDown’s syndrome living in the communitywere categorized as overweight (BMI�25.1 kg/m2) (8). In our study, 3 of themen (11.1%) and none of the women werecategorized as overweight. It seems that thevery low prevalence of diabetes in ourstudy results from the good control of bodyweight, which may be related to a stablelifestyle. This includes a proper diet (2,000kcal/day) and appropriate exercise (anhour of walking each day) for the patientsliving in their residential home. Greateremphasis should be given to the preven-tion of excessive weight gain throughproper diet and appropriate exercise toreduce the prevalence of diabetes in thegeneral population as well as in patientswith Down’s syndrome.

YOSHIO OHYAMA, MD

TOSHIHIRO UTSUGI, MD

TSUYOSHI UCHIYAMA, MD

TAKUJI HANAOKA, MD

SHOICHI TOMONO, MD

MASAHIKO KURABAYASHI, MD

From the Second Department of Internal Medicine(Y.O., T.Ut., T.Uc., M.K.), the Health ScienceGunma University School of Medicine (S.T.),Gunma; and the Association for the Welfare of theMentally and Physically Handicapped (T.H.),Gunma, Japan.

Address correspondence to Yoshio Ohyama,MD, the Second Department of Internal Medicine,Gunma University School of Medicine, 3-39-22,Showa, Maebashi, Gunma, 371-8511, Japan. E-mail:[email protected].

References1. Farquhar JW: Diabetic children in Scot-

land and the need for care. Scot Med J 7:119–123, 1962

2. Milunsky A, Neurath PW: Diabetes melli-tus in Down’s syndrome. Arch EnvironHealth 17:372–376, 1968

3. Jeremiah DE, Leyshon GE, Rose T, FrancisHWS, Elliott RW: Down’s syndrome anddiabetes. Psychol Med 3:455–457, 1973

4. Declining mortality from Down syndrome:no cause for complacency (Editorial).Lancet 335:888–889, 1990

5. Baird PA, Sadovnick AD: Life expectancyin Down syndrome. J Pediatr 110:849–854, 1987

6. Expert Committee on the Diagnosis andClassification of Diabetes Mellitus: Reportof the Expert Committee on the Diagnosisand Classification of Diabetes Mellitus.Diabetes Care 20:1183–1197, 1997

7. The DECODE Study Group on behalf ofthe European Diabetes EpidemiologyGroup: Is fasting glucose sufficient todefine diabetes? Epidemiological datafrom 20 European studies. Diabetologia 42:647–654, 1999

8. Bell AJ, Bhate MS: Prevalence of over-weight and obesity in Down’s syndromeand other mentally handicapped adultsliving in the community. J Intellect DisabilRes 36:359–364, 1992

Effect of Data Management on aCentral Server onHbA1c Levels inInsulin-RequiringPatients

Self-monitoring of blood glucose(SMBG) is critically important toadjust insulin doses appropriately.

Given the general level of poor control of

HbA1c concentrations in insulin-requir-ing patients (1,2), it is obvious thatSMBG is not being used effectively. Barri-ers to its effective use rest with bothpatients (inconvenience, pain, and cost)and physicians (lack of time for analysisand communication with the patientsand, in some cases, lack of expertise foranalysis). A major problem for somepatients is also a lack of time for appro-priate communication with the physicianor the health care provider responsiblefor insulin dose adjustments. We studiedthe effect of removing the impediments oflack of time and expertise in analysis ofHbA1c concentrations in insulin-requir-ing patients.

We recruited 29 patients takinginsulin for the study (12 men, 17women; 10 with type 1 diabetes, 19 withtype 2 diabetes). Of the 29 patients, 15were on a mixed/split regimen, 4 on apreprandial regular or lispro plus bed-time NPH regimen, and 10 on a bedtimeNPH, daytime sulfonylurea agent regi-men. Although 23 of them were per-forming SMBG at the beginning of thestudy, most could communicate onlysporadically with the educator (whoadjusted insulin doses in my practice)because of conflicts in both of their busyschedules.

All of the patients were given a One-Touch Profile meter (LifeScan, Milpitas,CA) at the onset of the study (pretest),and communication with the educator forthe following 4 weeks was stressed. Atthat point (baseline), patients wereinstructed in the use of a reporter (adevice that connected the meter to theirphone), which transferred the data via amodem to a central server. The data wereanalyzed by an algorithm developed byone of the authors (M.B.D.). The resultswere faxed to the educator and mailed tothe patient.

HbA1c concentrations were measuredat pretest (in most patients), baseline, and10 and 20 weeks later. The mean value forthe pretest and baseline measurementswas 8.4%, falling to 7.9% at 10 weeks and7.7% at 20 weeks. Sixteen of the patientshad mean initial values �8.0% and wereanalyzed separately, because the AmericanDiabetes Association’s guidelines requireaction at this point. In these patients athigh risk for the microvascular complica-tions of diabetes, the mean value for thepretest and baseline measurements was9.1%, falling to 8.5% at 10 weeks and


Letters

8.3% at 20 weeks. Data management bythe central server significantly loweredthe 10- and 20-week HbA1c concentra-tions in both groups (P � 0.001 by analy-sis of variance).

The (nonsignificant) differencebetween the baseline and pretest HbA1c

concentrations in the whole cohort was0.4%, and in the high-risk patients,0.3%. Since 50% of the changes in HbA1c

concentrations occur in the first month(3,4), the similarity of the pretest andbaseline values shows the absence of theHawthorne effect.

Convenience and efficient use of timefor both the patient and educator (it took�1 min for the educator to decide oninsulin dose adjustments after reviewingthe information provided by the centralserver) were important factors in the suc-cess of central data management of SMBGvalues in this small study. Wider applica-tion of this technology should improvediabetes control in populations of insulin-requiring patients.

MAYER B. DAVIDSON, MD

GWYNETH LEWIS, MAOM

From the Clinical Trials Unit (M.B.D.), Charles R.Drew University, Los Angeles; and City of HopeNational Medical Center (G.L.), Duarte, California.

Address correspondence to Mayer B. Davidson,MD, Clinical Trials Unit (MP 30), Charles R. DrewUniversity, 1731 E. 120th St., Los Angeles, CA.E-mail: [email protected].

Acknowledgments — Dr. Davidson is sup-ported by National Institutes of Health Grant#5U01-DKS54047.

We thank Mary Pearce and Barbara Wise-hart, who also helped manage some of thesepatients.

References1. Davidson MB: Diabetes care in health

maintenance organisation and fee-for-ser-vice settings. Dis Manage Health Outcomes2:189–197, 1997

2. Hayward RA, Manning WG, Kaplan SH,Wagner EH, Greenfield S: Starting insulintherapy in patients with type 2 diabetes:effectiveness, complications, and resourceutilization. JAMA 278:1663–1669, 1997

3. Tahara Y, Shima K: The response of GHbto stepwise plasma glucose change overtime in diabetic patients. Diabetes Care 16:1313–1314, 1993

4. Tahara Y, Shima K: Kinetics of HbA1c, gly-cated albumin, and fructosamine andanalysis of their weight functions againstpreceding plasma glucose level. DiabetesCare 18:440–447, 1995

Prevalence of Diabetes, ImpairedGlucose Tolerance,and Impaired Fasting Glucose in aRural Population ofKorea, According to1997 AmericanDiabetes Associationand 1985 WorldHealth OrganizationCriteria

In 1997, the American Diabetes Associa-tion (ADA) proposed new criteria fordefining diabetes based on fasting

plasma glucose (FPG) (1). A new diagnos-tic entity, impaired fasting glucose (IFG),was also introduced. However, conse-quent studies have pointed out severallimitations of the new ADA criteria, suchas a significant difference in the preva-lence of diabetes according to the WorldHealth Organization (WHO) criteria andADA criteria (2). There is also consider-able discordance between IFG andimpaired glucose tolerance (IGT) and alower sensitivity of IFG for predicting theprogression to diabetes (3) or develop-ment of cardiovascular disease (4).

To examine the prevalence of differentcategories of glucose tolerance in a ruralpopulation of Korea using the 1997 ADAand the 1985 WHO criteria, 1,108 sub-jects (aged 40–99 years) living in the

Chongup area of Korea were subjected to a2-h oral glucose tolerance test. The preva-lence of glucose tolerance categories wasobtained using the WHO criteria and theADA fasting plasma glucose criteria.Anthropometric and metabolic characteris-tics of the subjects with different categorieswere compared.

The prevalence of known diabetes inthis population was 3.4%. The preva-lence of unknown diabetes by WHO cri-teria and ADA criteria was 4.7% (95% CI3.5–5.9%) and 4.5% (3.3–5.7%), respec-tively. When the data were adjusted tothe standard world population of Segi(5), the prevalence of diabetes was 7.1%by WHO criteria and 7.7% by ADA crite-ria. Among elderly subjects aged �65,the prevalence of unknown diabetes byADA criteria was slightly, but not signifi-cantly, less (3.3%; 95% CI 1.5–5.1%)than the prevalence by WHO criteria(4.5%; 2.5–6.5%).

On the other hand, the prevalence ofIGT by WHO criteria (12.4%; 95% CI10.5–14.3%) was significantly higherthan that of IFG by ADA criteria (6.3%;4.9–7.7, P � 0.01). Of the 137 subjectswith IGT by WHO criteria, 104 (75.9%)were classified as normoglycemic byADA criteria. The level of agreementbetween the 2 criteria was low ( = 0.42,P � 0.001).

To compare clinical characteristics ofthe subjects with IGT and IFG accordingto WHO and ADA diagnostic criteria, weclassified nondiabetic subjects by bothcriteria into 4 categories (Table 1). Theconcordant IGT/IFG group showedhigher BMI and waist-to-hip ratio, systolic

Table 1—Comparison of clinical and metabolic characteristics of patients in the various cate-gories of glucose tolerance by 1997 ADA and 1985 WHO classifications

NGT/NFG IGT/NFG NGT/IFG IGT/IFG

n 841 104 34 29Age (years) 60.3 ± 9.4 65.4 ± 10.4* 61.5 ± 10.8 64.2 ± 9.4*BMI (kg/m2) 23.6 ± 2.9 23.7 ± 3.5 24.1 ± 3.7 25.5 ± 2.8*Waist-to-hip ratio 0.88 ± 0.06 0.88 ± 0.06 0.90 ± 0.06 0.91 ± 0.06*FPG (mmol/l) 4.8 ± 0.6 5.2 ± 0.5* 6.4 ± 0.3*† 6.5 ± 0.3*†2-h Plasma glucose (mmol/l) 6.0 ± 0.8 8.8 ± 0.8*‡ 6.7 ± 0.8* 9.0 ± 0.9*‡Systolic blood pressure (mmHg) 131.5 ± 22.6 134.8 ± 23.2 136.2 ± 23.6 151.1 ± 25.6*Diastolic blood pressure (mmHg) 85.2 ± 11.8 85.4 ± 12.4 86.5 ± 14.4 90.6 ± 12.1Total cholesterol (mmol/l) 5.2 ± 0.9 5.4 ± 0.9 5.5 ± 0.9 5.2 ± 0.9Triglyceride (mmol/l) 1.8 ± 1.1 2.3 ± 1.5* 1.9 ± 0.7 2.6 ± 1.7*HDL cholesterol (mmol/l) 1.2 ± 0.3 1.2 ± 0.3 1.2 ± 0.3 1.1 ± 0.3

Data are n or means ± SD. *P � 0.05 vs. NGT/NFG; †P � 0.05 vs. IGT/NFG; ‡P � 0.05 vs. NGT/IFG.


Letters

blood pressure, FPG and 2-h plasma glu-cose (PP2), and plasma triglyceride levelsthan concordant normal subjects. Bothnormal glucose tolerance (NGT)/IFG andIGT/NFG groups had higher FPG andPP2 than concordant normal subjects.The IGT/NFG group also showed higherages and plasma triglyceride levels thanthe concordant normal group. Asexpected, the NGT/IFG group exhibitedsignificantly higher FPG and lower PP2values than the IGT/NFG group. How-ever, there was no significant difference inall other variables between the 2 groups.

The present study found that theprevalence of diabetes among Koreans inthe rural area by ADA and WHO criteriawas similar: 8.1% by WHO criteria and7.9% by ADA criteria. However, the preva-lence of diabetes by ADA criteria was,although statistically not significant, 1.2%lower than that by WHO criteria in theelderly subjects age �65. In addition,although FPG was not related to age, 2-hglucose levels were significantly correlatedwith age (r = 0.27, P � 0.05). These obser-vations suggest that ADA criteria mayunderestimate the prevalence of diabetes,especially in the elderly subjects, becauseof the increased sensitivity of the 2-h glu-cose values to aging.

In agreement with most previousstudies (2,6), the prevalence of IGT byWHO criteria was almost 2-fold higherthan that of IFG by ADA criteria. In addi-tion, the concordance between subjectswith IFG and IGT was not high. Thus, the2 tests appear to diagnose 2 different pop-ulations of subjects with disturbed glu-cose metabolism. Accordingly, Gimeno etal. (6) reported that the subjects with IGThad higher blood pressure and triglyceridelevels and lower HDL cholesterol levelsthan the subjects with IFG. On the otherhand, the present study and the study byLarsson et al. (7) showed that the subjectswith IGT and the subjects with IFG arecomparable in terms of BMI, blood pres-sure, and plasma lipids. However, consider-ing higher cardiovascular events in the sub-jects with IGT (4), it is quite possible thatfactors other than ordinary coronary riskfactors (8) may be different in the 2 diag-nostic groups.

JOONG-YEOL PARK, MD

YOUNG I. KIM, MD

CHEOL S. CHOI, MD

YUN E. CHUNG, MD

SANG-WOOK KIM, MD

MOO-SONG LEE, MD

SANG I. LEE, MD

SUNG K. HONG, MD

KI-UP LEE, MD

From the Departments of Internal Medicine ( J.-Y.P.,Y.I.K., C.S.C, Y.E.C., S.-W.K., S.K.H., K.-U.L.) andPreventive Medicine (M.-S.L., S.I.L.), University ofUlsan College of Medicine, Seoul, Korea.

Address correspondence to Ki-Up Lee, MD, theDepartment of Internal Medicine, University ofUlsan College of Medicine, 388-1 Poong-NapDong, Song-Pa Ku, Seoul 138-736, Korea. E-mail:[email protected].

References1. The Expert Committee on the Diagnosis

and Classification of Diabetes Mellitus:Report of the Expert Committee on theDiagnosis and Classification of DiabetesMellitus. Diabetes Care 20:1183–1197,1997

2. Wahl PW, Savage PJ, Psaty BM, OrchardTJ, Robbins JA, Tracy RP: Diabetes in olderadults: comparison of 1997 American Dia-betes Association classification of diabetesmellitus with 1985 WHO classification.Lancet 352:1012–1015, 1998

3. Shaw JE, Zimmet PZ, de Courten M,Dowse GK, Chitson P, Gareeboo H, Hem-raj F, Fareed D, Tuomilehto J, Alberti KG:Impaired fasting glucose or impaired glu-cose tolerance: what best predicts futurediabetes in Mauritius? Diabetes Care 22:399–402, 1999

4. Tominaga M, Eguchi H, Manaka H,Igarashi K, Kato T, Sekikawa A: Impairedglucose tolerance is a risk factor for cardio-vascular disease, but not impaired fastingglucose: the Funagata Diabetes Study. Dia-betes Care 22:920–924, 1999

5. King H, Rewers M: Global estimates forprevalence of diabetes mellitus andimpaired glucose tolerance in adults.WHO Ad Hoc Diabetes Reporting Group.Diabetes Care 16:157–177, 1993

6. Gimeno SGA, Ferreira SRG, Franco LJ,Iunes M, the Japanese-Brazilian DiabetesStudy Group: Comparison of glucose tol-erance categories according to WorldHealth Organization and American Dia-betes Association diagnostic criteria in apopulation-based study in Brazil. DiabetesCare 21:1889–1892, 1998

7. Larsson H, Berglund G, Lindgarde F,Ahren B: Comparison of ADA and WHOcriteria for diagnosis of diabetes and glu-cose intolerance. Diabetologia 41:1124–1125, 1998

8. Harjai KJ: Potential new cardiovascularrisk factors: left ventricular hypertrophy,homocysteine, lipoprotein(a), triglyc-erides, oxidative stress, and fibrinogen.Ann Intern Med 131:376–386, 1999

Rapid Remission ofNephrotic-RangeProteinuria in aCase of HistologicallyProven DiabeticNephropathyTreated With an ACE Inhibitor

In the past, a relentless decline in renalfunction was considered inevitable indiabetic nephropathy with nephrotic-

range proteinuria (1). Some recent studies,however, have demonstrated that the useof ACE inhibitors can maintain stablerenal function and reduce proteinuria inrelatively young type 1 diabetic patientswith nephrotic-range proteinuria (2–4). Inthese studies, nephrotic-range proteinuriaremitted within a few years after com-mencing treatment with an ACE inhibitor.We discuss here an elderly type 2 diabeticwoman who presented with nephroticsyndrome due to biopsy-proven diabeticnephropathy. Treatment with an ACEinhibitor, temocapril, resulted in anextremely rapid decrease of proteinuria on2 separate occasions.

A 69-year-old Japanese woman wasadmitted to our hospital in March 1998with abdominal pain and constipation. Hermedical and family histories were unre-markable and the patient had not under-gone a health check-up in the past. Shewas 150 cm tall and weighed 46 kg. Herblood pressure was 153/80 mmHg and nopretibial edema was present. Laboratorystudies revealed a fasting plasma glucose(FPG) level of 14.2 µmol/l, an HbA1c con-centration of 8.8% (normal range4.2–5.5%), a serum creatinine level of 44.2µmol/l, a serum albumin level of 26 g/l,and a serum cholesterol level of 5.35µmol/l. Urinalysis showed 3� proteinuriawith normal sediment. The 24-h urinaryprotein excretion was 7.2 g and creatinineclearance was 1.59 ml/s. She was treatedconservatively, under the diagnosis ofintestinal pseudo-obstruction, and herabdominal symptoms improved rapidly. Inaddition to protein and salt restriction (30g/day and 3 g/day, respectively), temocapril(Acecol) (2 mg/day) together with gli-clazide (20 mg/day) and voglibose (0.6mg/day) were started in the hospital. The


Letters

patient’s 24-h urinary protein excretiondeclined markedly to 0.5 g within 2 weeks(Fig. 1). Blood pressure and serum albu-min levels also improved to 130/70 mmHgand 37 g/l, respectively. The patient wasfollowed at the outpatient clinic after dis-charge from the hospital. However, in May1998, she stopped coming to the clinic anddiscontinued all of her medications.

The patient, however, apparentlyremained well until December 1998 whenshe developed leg edema in associationwith an increase in body weight from 45 to48 kg within a month. She was subse-quently seen again at our hospital. Herblood pressure was 171/89 mmHg and uri-nalysis revealed 3� proteinuria. Her chestX-ray revealed mild pleural effusions. Anattempt to control her edema with adiuretic (furosemide 20 mg/day) as an out-patient was unsuccessful, and she began toexperience dyspnea on exertion. She was,therefore, admitted to our hospital in Janu-ary 1999. Her body weight was 52 kg andblood pressure was 160/83 mmHg onadmission. Examination of the ocular fundirevealed microaneurysms and dot hemor-rhages without exudates. There were signsof diabetic neuropathy, including decreased

vibratory sensation and an orthostatic dropof blood pressure. Laboratory studiesrevealed a postprandial plasma glucoselevel of 15.3 µmol/l, an HbA1c concentra-tion of 6.2%, a serum creatinine level of44.2 µmol/l, a serum albumin level of 24g/l, and a serum cholesterol level of 4.89µmol/l. The 24-h urinary excretion was 6.2 gand creatinine clearance was 1.07 ml/s.Chest X-rays showed moderate pleuraleffusions. Renal biopsy was performed inthe hospital to clarify the etiology ofrepeated nephrotic-range proteinuria, withwritten informed consent from the patient.The specimen for light microscopy con-tained 9 glomeruli, of which 1 was globallysclerotic and the rest showed diffuse inter-capillary glomerulosclerosis without cellu-lar proliferation. More than half of theglomeruli contained lamellated argyrophilmesangial nodules. Occasional afferentarterioles showed hyalinosis, and mildtubular atrophy and interstitial fibrosis werepresent. Immunofluorescence revealed lin-ear localization of IgG along the glomeru-lar capillary walls. Electron microscopyshowed a marked increase in the mesangialmatrix in association with thickening ofcapillary basement membrane. Electron-

dense deposits were absent. The histologi-cal diagnosis based on these findings wasdiffuse and nodular diabetic glomeruloscle-rosis. Temocapril (2 mg/day) was re-startedand the dose of furosemide was increasedto 40 mg a day after renal biopsy. Efonidip-ine (Landel), 40 mg/day was added a fewdays later. Insulin therapy (4U with NPHinsulin at breakfast) was used to controlhyperglycemia for a week, and laterreplaced with gliclazide (40 mg/day). The24-h urinary protein excretion declinedagain markedly to 1.6 g within a monthafter starting temocapril (Fig. 1). Pleuraleffusions and edema disappeared and herbody weight decreased to 41 kg. Bloodpressure and serum albumin levels alsoimproved to 120/70 mmHg and 28 g/l,respectively. A month after admission, shewas asymptomatic and was dischargedfrom the hospital.

It has long been thought that theappearance of persistent proteinuria her-alds a progressive decline of renal functionduring the natural history of diabeticnephropathy, and that nephrotic-rangeproteinuria, in particular, points toward apoor renal prognosis (1). Meanwhile,many recent studies have demonstratedthat antihypertensive therapy can slow therate of decline of renal function in diabeticnephropathy. Furthermore, it was sug-gested in more recent studies that ACEinhibitors reduce proteinuria and protectrenal function in patients with diabeticnephropathy more effectively than otherantihypertensive agents, and that thisrenoprotective effect of ACE inhibitors isindependent of changes in blood pressure(5). Some studies have shown that type 1diabetic patients with nephrotic-rangeproteinuria can maintain stable renal func-tion with a marked reduction of protein-uria on ACE inhibitors (2–4). Herbert etal. (2) reported that 7 of 42 (16.7%) type 1diabetic patients with nephrotic-rangeproteinuria treated with captopril achievedremission of proteinuria and maintainedstable renal function over a mean follow-up period of 3.4 years. Meanwhile, only 1of 66 (1.5%) in the placebo group had acomparable clinical course. Gault and Fer-nandez (3) reported a type 1 diabeticpatient in whom enalapril, started after 10years of nephrotic-range proteinuria,resulted in stable renal function and disap-pearance of proteinuria. McGregor andBailey (4) reported that treatment withcaptopril or enalapril in 2 type 1 diabeticpatients with nephropathy resulted in sta-

Figure 1—Clinical course of the patient.


Letters

ble renal function and remission ofnephrotic-range proteinuria for over 11years. In these 3 reports, nephrotic-rangeproteinuria disappeared gradually over afew years on ACE inhibitors. Moreover,these were all type 1 diabetic patients ofrelatively young age (�30 years old), incontrast to our patient.

We documented a 69-year-old type 2diabetic woman with histologically provendiabetic nephropathy in whom rapidremission of nephrotic-range proteinuriawas observed within a month on an ACEinhibitor, temocapril, on 2 separate occa-sions. As shown in Fig. 1, the reduction ofproteinuria occurred in association with adecrease in creatinine clearance, althoughthe magnitude of the former by farexceeded that of the latter. The mechanismof the reduction of glomerular proteinuriaby ACE inhibitors is still disputed. Imanishiet al. (6) suggested that ACE inhibitorsreduce albuminuria in diabetic nephropa-thy by decreasing the glomerular capillarypressure and improving hyperfiltration viaefferent arteriolar dilatation. Meanwhile,other investigators have suggestedimprovement of size selectivity of theglomerular capillary membrane by ACEinhibitors (7). Whatever the mechanisminvolved, reduction of proteinuria by ACEinhibitors in patients with diabeticnephropathy is expected to have a benefi-cial effect on renal prognosis, since protein-uria itself is considered nephrotoxic and tobe a promoter of progressive renal dysfunc-tion (8). Our report, for the first time,demonstrated that an ACE inhibitor couldexert a rapid beneficial effect on nephroticsyndrome due to diabetic nephropathy inan elderly patient with type 2 diabetes.Although the experience is limited to a sin-gle patient, it is should be worth attemptingto treat such patients with ACE inhibitors.

RYUJI SUZUKI, MD

AKIRA SHIMADA, MD

KONOSUKE KONISHI, MD

TAKAO SARUTA, MD

From the Department of Internal Medicine, KeioUniversity School of Medicine, Tokyo, Japan.

Address correspondence to Akira Shimada, MD,Department of Internal Medicine, Keio Univer-sity School of Medicine, 35 Shinanomachi, Shin-juku-ku, Tokyo 160-8582, Japan. E-mail: [email protected].

References1. Austin SM, Lieberman JS, Newton LD,

Mejia M, Peters WA, Myers BD: Slope of

serial glomerular filtration rate and theprogression of diabetic glomerular disease.J Am Soc Nephrol 3:1358–1370, 1993

2. Herbert LA, Bain RP, Verme D, Cattran D,Whittier FC, Tolchin N, Rohde RD, LewisEJ: Remission of nephrotic range protein-uria in type 1 diabetes. Kidney Int 46:1688–1693, 1994

3. Gault HM, Fernandez D: Stable renalfunction in insulin-dependent diabetesmellitus 10 years after nephrotic rangeproteinuria. Nephron 72:86–92, 1996

4. McGregor D, Bailey RR: Over 11 years ofstable renal function after remission ofnephrotic-range proteinuria in type 1 dia-betics treated with an ACE inhibitor.Nephron 76:270–275, 1997

5. Lewis EJ, Hunsicker LG, Bain RP, RohdeRD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropa-thy: the Collaborative Study Group. N EnglJ Med 329:1456–1462, 1993

6. Imanishi M, Yoshioka K, Okumura M,Konishi Y, Tanaka S, Fujii S, Kimura G:Mechanism of decreased albuminuriacaused by angiotensin converting enzymeinhibitor in early diabetic nephropathy.Kidney Int 52 (Suppl. 63):198–200, 1997

7. Rumuzzi A, Ruggenenti P, Mosconi L, PataV, Viberti G, Remuzzi G: Effect of low-doseenalapril on glomerular size-selectivity inhuman diabetic nephropathy. J Nephrol 6:36–43, 1993

8. Remizzi G, Bertani T: Is glomerulosclerosisa consequence of altered glomerular per-meability to macromolecules? Kidney Int38:384–394, 1990

Interesting InsulinResponse to OralGlucose Load inYoung JapaneseSubjects WithImpaired GlucoseTolerance

We recently reported that the degreeof insulin response in Japanesesubjects with impaired glucose

tolerance (IGT) and diabetes to 75-g oralglucose load (1) is much lower than that inCaucasian subjects (2,3). Japanese-Ameri-can IGT or diabetic subjects in Hawaii andSeattle, Washington, however, showedmuch higher insulin resistance and com-pensatory hyper-response to insulin secre-tion than native Japanese subjects. Thissuggests that environmental factors oflifestyle, such as a high-fat and high-pro-tein diet and/or less exercise, may deterio-

rate insulin sensitivity and strengthen thepotency of insulin secretion even in thosewith the same genetic background (4,5). InJapan, the increase in personal cars andtraffic networks has mushroomed since thelate 1960s. Transportation and a Western-ized diet, including high fat and animalprotein, have combined to affect the entirepopulation of Japan. Younger Japanese,born during or after the 1960s, grew upwith a Westernized lifestyle, and wehypothesize that continuous exposure tosuch environmental factors during growthmay strengthen the potency of insulinsecretion and promote compensatoryhyperinsulin secretion in an insulin-resis-tant state after maturity. To certify ourhypothesis, we compared the insulinresponse to an oral glucose load in youngerJapanese adult IGT subjects (20–39 years)with that of subjects �40 years in a 75-goral glucose tolerance test (OGTT).

A series of 2,142 Japanese subjects,1,361 men and 781 women aged 20–82years (mean: 56 years), suspected of havingdiabetes, underwent a 75-g OGTT (0–3 h)for diagnosis at Tokyo Saiseikai CentralHospital and Juntendo University Hospitalfrom January 1996 to December 1998.They were divided into 3 groups using cur-rent World Health Organization criteria,and 831 subjects were diagnosed with IGT.The IGT subjects aged 56 ± 0.4 (mean ±SEM, M/F 521/310) were divided into 5groups by age (�39, 40–49, 50–59,60–69, and �70 years) and compared with3 insulin sensitivity and secretion parame-ters among age-groups. The homeostasismodel assessment of insulin resistance(HOMA-IR), a marker of insulin resistance,was calculated as fasting plasma glucose(mg/dl) fasting plasma insulin(µU/ml)/405 converted from the originalformula (6). The insulinogenic index (IsIx),a marker of early insulin secretion, wasdefined as �insulin/�PG, or (Insulin30–Insulin0)/(PG30–PG0) (7). The area underthe insulin curve (AUCins), a marker of totalinsulin secretion, was calculated as the totalarea under the insulin response curve dur-ing the 3-h OGTT.

Surprisingly, HOMA-IR, IsIx, andAUCins, in the youngest age-group (�39years), are all significantly and notablyhigher than in the other age-groups (Fig. 1).Although our study groups are not largeand other clinical characteristics, such asfamily history of diabetes, BMI, lipid pro-files, or blood pressure, were not evalu-ated, the result supports our hypothesis,

https://www.researchgate.net/publication/13823692_Mechanism_of_decreased_albuminuria_caused_by_angiotensin_converting_enzyme_inhibitor_in_early_diabetic_nephropathy?el=1_x_8&enrichId=rgreq-a6335a458742043dc61792567d06a7d7-XXX&enrichSource=Y292ZXJQYWdlOzEyNDg0NjE2O0FTOjEwNDAzNDk1MDE4OTA2M0AxNDAxODE1MjczNDM0






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https://www.researchgate.net/publication/14786765_The_Effect_of_Angiotensin-Converting-Enzyme_Inhibition_on_Diabetic_Nephropathy_The_Collaborative_Study_Group?el=1_x_8&enrichId=rgreq-a6335a458742043dc61792567d06a7d7-XXX&enrichSource=Y292ZXJQYWdlOzEyNDg0NjE2O0FTOjEwNDAzNDk1MDE4OTA2M0AxNDAxODE1MjczNDM0





https://www.researchgate.net/publication/13993839_Over_11_Years_of_Stable_Renal_Function_after_Remission_of_Nephrotic-Range_Proteinuria_in_Type_I_Diabetics_Treated_with_an_ACE_Inhibitor?el=1_x_8&enrichId=rgreq-a6335a458742043dc61792567d06a7d7-XXX&enrichSource=Y292ZXJQYWdlOzEyNDg0NjE2O0FTOjEwNDAzNDk1MDE4OTA2M0AxNDAxODE1MjczNDM0





https://www.researchgate.net/publication/257307176_Effect_of_low-dose_Enalapril_on_glomerular_size-selectivity_in_human_diabetic_nephropathy?el=1_x_8&enrichId=rgreq-a6335a458742043dc61792567d06a7d7-XXX&enrichSource=Y292ZXJQYWdlOzEyNDg0NjE2O0FTOjEwNDAzNDk1MDE4OTA2M0AxNDAxODE1MjczNDM0





https://www.researchgate.net/publication/20922553_Is_glomerulosclerosis_a_consequence_of_altered_glomerular_permeability_to_macromolecules_Kidney_Int_38_384-394?el=1_x_8&enrichId=rgreq-a6335a458742043dc61792567d06a7d7-XXX&enrichSource=Y292ZXJQYWdlOzEyNDg0NjE2O0FTOjEwNDAzNDk1MDE4OTA2M0AxNDAxODE1MjczNDM0




https://www.researchgate.net/publication/245837875_Remission_of_nephrotic_range_proteinuria_in_type_I_diabetes?el=1_x_8&enrichId=rgreq-a6335a458742043dc61792567d06a7d7-XXX&enrichSource=Y292ZXJQYWdlOzEyNDg0NjE2O0FTOjEwNDAzNDk1MDE4OTA2M0AxNDAxODE1MjczNDM0






Letters

namely that the generation of JapaneseIGT subjects �39 years of age, as com-pared with older subjects, have a strongpotential of insulin secretion under aninsulin-resistant state. It has been assumedthat Japanese subjects develop overt dia-betes from IGT much earlier than Cau-casian subjects because of exposure to fac-tors causing insulin resistance, such asobesity, less exercise, or excessive stress.This may be the result of Japanese subjectshaving weaker potency of insulin secretionand maximal compensatory hypersecre-tion of insulin that are less than those of

Caucasians and Japanese-Americans.Although the present study is preliminary,results suggest that the number of Japan-ese IGT subjects retaining long-term IGTthrough strong insulin secretion willincrease. The results further suggest thatthe development of insulin resistance andcompensatory hyperinsulinemia-relatedatherosclerotic disease, observed in syn-drome X (8) or insulin resistance syn-drome (9) of Caucasians, will also increasein Japan in the near future. We must,therefore, start further large-scale epidemi-ological studies focusing on the develop-

ment of both diabetes and atherosclerosisfrom IGT in young subjects. It should beof great interest to determine whether andhow the Westernized lifestyle duringgrowth may upregulate pancreatic �-cellgrowth or function and affect the potencyof insulin secretion in adults. We view thisas a very important research direction inthe etiology of diabetes and atherosclerosisin Japan and other rapidly developing andWesternized countries.

YASUSHI TANAKA, MD

YOSHIHITO ATSUMI, MD

KENPEI MATSUOKA, MD

TOMIO ONUMA, MD

RYUZO KAWAMORI, MD

From the Department of Medicine (Y.T., T.O., R.K.),Metabolism and Endocrinology, School of Medi-cine, Juntendo University; and the Department ofMedicine (Y.A., K.M.), Tokyo Saiseikai Central Hos-pital, Tokyo, Japan.

Address correspondence to Yasushi Tanaka, MD,Department of Medicine, Metabolism andEndocrinology, School of Medicine, Juntendo Uni-versity, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421,Japan. E-mail: [email protected].

References1. Tanaka Y, Atsumi Y, Asahina T, Hosokawa

K, Matsuoka K, Kinoshita J, Onuma T,Kawamori R: Usefulness of revised fastingplasma glucose criterion and characteristicsof the insulin response to an oral glucoseload in newly diagnosed Japanese diabeticsubjects. Diabetes Care 21:1133–1137,1998

2. DeFronzo RA: The triumvirate: �-cell,muscle, liver: a collusion responsible forNIDDM. Diabetes 37:667–687, 1988

3. DeFronzo RA: Pathogenesis of type 2 (non-insulin dependent) diabetes: a balancedoverview. Diabetologia 35:389–397, 1992

4. Hara H, Egusa G, Yamakido M, Kawate R:The high prevalence of diabetes mellitusand hyperinsulinemia among Japanese-Americans living in Hawaii and Los Ange-les. Diabetes Res Clin Pract 24:S37–S42,1994

5. Fujimoto WY, Leonetti DL, Kinyoun JL,Newell-Morris L, Shuman WP, Stolov WC,Wahl PW: Prevalence of diabetes mellitusand impaired glucose tolerance among sec-ond-generation Japanese-American men.Diabetes 36:721–729, 1987

6. Matthews DR, Hosker JP, Rudenski AS,Naylor BA, Treacher DF, Turner RC:Homeostasis model assessment: insulinresistance and �-cell function from fastingplasma glucose and insulin concentrationsin man. Diabetologia 28:412–419, 1985

7. Kosaka K, Kuzuya T, Yoshinaga H, HaguraR: A prospective study of health check

Figure 1—Clinical markers for insulin sensitivity and secretion during the 75-g OGTT in 831 Japan-ese subjects with IGT. Values are expressed as means ± SEM. Numbers of subjects are shown in paren-theses. *P � 0.05 vs. the group aged 40–49 years; **P � 0.01 vs. the group aged �59 years; †P �0.01 vs. the group aged 60–69 years.


Letters

examinees for the development of non-insulin-dependent diabetes mellitus: rela-tionship of the incidence of diabetes withthe initial insulinogenic index and degreeof obesity. Diabet Med 13 (Suppl. 6):S120–S126, 1996

8. Reaven GM, Laws A: Insulin resistance,compensatory insulinemia, and coronaryheart disease. Diabetologia 37:948–952,1994

9. DeFronzo RA, Ferannini E: Insulin resis-tance: a multifocal syndrome responsiblefor NIDDM, obesity, hypertension, dyslipi-demia, and atherosclerotic cardiovasculardisease. Diabetes Care 14:173–194, 1991

COMMENTS ANDRESPONSES

An Equation forInsulin SensitivityIndex

Matsuda and DeFronzo (1) pre-sented a novel method of estimat-ing insulin sensitivity from data

obtained by an oral glucose tolerance test.They correlated the values thus obtainedwith values from the same subjects withthe euglycemic clamp technique. Theresults are significant, and the effort iscommendable. To stimulate further dis-cussion, I would like to proffer the follow-ing questions:

In the study, fasting plasma glucose(FPG) and glucose (G) are expressed inmg/dl, and fasting plasma insulin (FPI) andinsulin (I) are expressed in µl/ml. In a bio-logical system, the action of insulin on glu-cose proceeds at the molecular level. Willit, then, be more consistent to express FPGand G in M�3/l, and FPI and I in M�12/l?

The composite equation for theinsulin sensitivity index (ISI) states that

ISI = 10,000/√(FPG FPI) (–G

–I )

For simplicity, let us assume that–G ap-

proaches FPG and that –I approaches FPI.

The equation then simplifies to

ISI = 10,000/√(FPG2 FPI2)

10,000/(FPG FPI)

This means that the ISI is inversely pro-portional to FPG and to FPI. Are these

proportionalities linear, logarithmic, orotherwise? The study presupposes thatthey are linear. Is there any theoretical jus-tification for this supposition?

JOSE S. CHENG, MD

From the Department of Family and CommunityMedicine, Baylor College of Medicine, Houston,Texas.

Address correspondence to Jose S. Cheng, MD,3825 Tennyson St., Houston, TX 77005-2851. E-mail: [email protected].

References1. Matsuda M, DeFronzo R: Insulin sensitiv-

ity indices obtained from oral glucose tol-erance testing: comparison with the eugly-cemic insulin clamp. Diabetes Care 22:1462–1470, 1999

Response to Cheng

In response to Dr. Cheng (1), it shouldbe noted that expressing the units ofglucose and insulin as mmol/l and

pmol/l, respectively (instead of mg/dl andµU/ml), will not change any of theobserved correlations.

As we described (2), the simplifiedequation for the insulin sensitivity index(ISI) [ISI = 10,000/(FPG FPI)] cited inDr. Cheng’s letter is mathematically equiv-alent to the inverse of the reduced home-ostasis model assessment formula, inwhich k = 10,000.

We examined the relationship betweenour proposed ISI and the measurement ofinsulin sensitivity obtained from theeuglycemic insulin clamp by use of boththe log of the insulin concentration (r =0.69 and P � 0.0001) and the absoluteplasma insulin concentration (r = 0.73 andP � 0.0001). The correlation coefficientswere quite similar.

RALPH A. DEFRONZO, MD

From the Diabetes Division, Department of Medi-cine, University of Texas Health Science Center atSan Antonio, San Antonio, Texas.

Address correspondence to Ralph A. DeFronzo,MD, Professor of Medicine, University of TexasHealth Science Center at San Antonio, DiabetesDivison, Department of Medicine, 7703 Floyd CurlDr., San Antonio, TX 78284-7886. E-mail: [email protected].

References1. Cheng JS: An equation for insulin sensitiv-

ity index (Letter). Diabetes Care 23:712,

20002. Matsuda M, DeFronzo R: Insulin sensitivity

indices obtained from oral glucose toler-ance testing. Diabetes Care 22:1462–1470,1999

Effect of Gluten-FreeDiet on the Metabolic Control ofType 1 Diabetes inPatients With Diabetes and Celiac Disease

Previously (1), we described anincreased frequency of hypoglycemicepisodes with a reduction in insulin

requirement as a presenting sign of celiacdisease in children with type 1 diabetes. Ina study conducted at a different center inItaly, similar data were observed: 6 well-controlled patients (mean GHb value 8.7 ±2.2%) had significantly more hypoglycemicepisodes before diagnosis of celiac diseasewhen compared with 12 well-matched dia-betic patients without celiac disease (4.3 ±2.0 vs. 1.5 ± 2.4 episodes/week, respec-tively). This difference persisted up to6 months after initiation of a gluten-freediet (6.6 ± 6.2 vs. 1.8 ± 4.2 episodes/week)(F.C., personal communication).

In contrast, Kaukinen et al. (2) failed tofind an impact on metabolic control inadult patients with type 1 diabetes andceliac disease when a gluten-free diet wasinadequate. It is worth noting that the meanGHb value in these patients ranged from9.8 to 10% during the 3 years precedingthe diagnosis of celiac disease and remainedsubstantially unchanged (9.5–10.3%) dur-ing the year after the initiation of a gluten-free diet. Similarly, the average daily insulindosage (0.6 U/kg) remained unchangedafter the start of a gluten-free diet. In ourpatients, the mean GHb value was 7.1 ±1.1% at the time of diagnosis of celiac dis-ease; the mean insulin requirement was 0.6U/kg body weight. This requirement wasthe mean final result of a progressive reduc-tion of the dose ranging from �30 to�60% in individuals due to symptomaticand asymptomatic hypoglycemic episodes.

Thus, the lack of hypoglycemicepisodes at the clinical onset of celiac dis-eases in the patients described by Kauki-nen et al. (2) could be the result of ahigher mean blood glucose level as com-


Letters

pared with our patients who received anintensified therapy and had a better meta-bolic control (as determined by GHb val-ues). In patients maintained at a strictmetabolism (as our patients are), hypogly-cemic crisis and a reduction of insulinrequirement may more easily manifest assigns of celiac disease.

DARIO IAFUSCO, MD

FRANCESCO REA, MD, PH

FRANCESCO CHIARELLI, MD, PH

ANGELIKA MOHN, MD

FRANCESCO PRISCO, MD, PH

From the Department of Pediatrics (D.I., F.R., F.P.),Second University of Naples, Naples; and theDepartment of Pediatrics (F.C., A.M.), University ofChieti, Chieti, Italy.

Address correspondence to Dario Iafusco, MD,Department of Pediatrics, Second University ofNaples, Via S. Andrea delle Dame n. 4, 80138Naples, Italy. E-mail: [email protected].

References1. Iafusco D, Rea F, Prisco F: Hypoglycemia

and reduction of the insulin requirementas a sign of celiac disease in children withIDDM (Letter). Diabetes Care 21:1379–1380, 1998

2. Kaukinen K, Salmi J, Lahtela J, Siljamäki-Ojansuu U, Koivisto A-M, Oksa H, CollinP: No effect of gluten-free diet on themetabolic control of type 1 diabetes inpatients with diabetes and celiac disease(Letter). Diabetes Care 22:1747–1748,1999

Response to Iafusco et al.

Effect of gluten-free diet on themetabolic control of type 1 diabetes in patients with diabetesand celiac disease

The letter of Iafusco et al. (1) suggeststhat the lack of hypoglycemic epi-sodes in patients with celiac disease

and diabetes might be a consequence ofpoor glycemic control. Evidence showsthat the risk for hypoglycemia is increasedwhen the HbA1c percentage is low (2).This phenomenon may indeed explainwhy this complication was rarely observedin our series, in which the mean HbA1c

value of our patients varied from 8.5 to10%. However, we must also emphasizethat our untreated celiac disease patients

were generally in good condition; most ofthem had only vague, if any, symptoms ofceliac disease. More than likely, the risk ofhypoglycemia will be considerably greaterin patients suffering from a severe malab-sorption. The risk may further differbetween adults and children who haveboth celiac disease and diabetes.

The low frequency of hypoglycemicepisodes does not refute our conclusionthat a gluten-free diet has no influence onthe metabolic control of diabetes. Neverthe-less, we fully agree that, in some cases,hypoglycemia can be due to untreatedceliac disease. Celiac disease should be con-sidered in type 1 diabetes patients who fre-quently experience hypoglycemic events.Furthermore, whenever the metabolic con-trol is poor in patients with concomitantdiabetes and celiac disease, other autoim-mune conditions should be considered.The coexistence of celiac disease, type 1diabetes, and autoimmune thyroid diseaseor Addison’s disease is not uncommon (3).

On the other hand, it is worth notingthat in the series of Chiarelli (1), hypogly-cemic events were even more frequent inceliac patients who had maintained agluten-free diet for 6 months than theywere before the start of the diet (6.6 and4.3 episodes on average, respectively).This observation, we feel, supports ourconclusion that gluten-free diet has, byand large, little if any effect on the meta-bolic control of diabetes.

Restricting celiac screening to diabeticpatients who suffer from hypoglycemiccomplications means that most caseswould remain undetected. According toseveral reports, the prevalence of celiacdisease in type 1 diabetes is as high as2–7%. Endomysial (4) and tissue transg-lutaminase (5,6) antibody assays arehighly specific tests and are sensitiveenough to effectively screen for celiac dis-ease. Therefore, it is now feasible to screenall patients with type 1 diabetes for celiacdisease; this has been our practice formore than 10 years.

We have not carried out active screen-ing only to improve the metabolic controlof diabetes. We consider that our screen-ing policy is further justified for other rea-sons. First, the aim is to treat celiac diseasebefore overt malabsorption develops. Sec-ond, osteopenia is a problem in both dia-betes (7) and celiac disease (8). A lowbone mineral density can improve even inasymptomatic celiac patients when theyare placed on a gluten-free diet (9).

A gluten-free diet may be difficult tomaintain for diabetic patients. Prospectivestudies are warranted to evaluate the qual-ity of life before and after the treatment ofceliac disease in individuals with concomi-tant type 1 diabetes.

KATRI KAUKINEN, MD

JORMA SALMI, MD

JORMA LAHTELA, MD

HEIKKI OKSA, MD

PEKKA COLLIN, MD

From the Department of Internal Medicine, Tam-pere University Hospital and Medical School, Uni-versity of Tampere, Tampere, Finland.

Address correspondence to Pekka Collin, MD,Medical School, University of Tampere, P.O. Box607, FIN-33101 Tampere, Finland. E-mail:[email protected].

References1. Iafusco D, Rea F, Chiarelli F, Mohn A,

Prisco F: Effect of gluten-free diet on themetabolic control of type 1 diabetes inpatients with diabetes and celiac disease(Letter). Diabetes Care 23:712–713,2000

2. The Diabetes Control and ComplicationsTrial Research Group: Hypoglycemia inthe Diabetes Control and Complicationstrial. Diabetes 46:271–286, 1997

3. Kaukinen K, Collin P, Mykkänen A-H, Par-tanen J, Mäki M, Salmi J: Celiac diseaseand autoimmune endocrinologic disor-ders. Dig Dis Sci 44:1428–1433, 1999

4. Ladinser B, Rossipal E, Pittschieler K:Endomysium antibodies in coeliac disease:an improved method. Gut 35:776–778,1994

5. Dieterich W, Laag E, Schopper H, Volta U,Ferguson A, Gillett H, Riecken EO, Schup-pan D: Autoantibodies to tissue transgluta-minase as predictors of celiac disease. Gas-troenterology 115:1317–1321, 1998

6. Sulkanen S, Halttunen T, Laurila K, KolhoK-L, Korponay-Szabo I, Sarnesto A, Savi-lahti E, Collin P, Mäki M: Tissue transglut-aminase autoantibody enzyme-linkedimmunosorbent assay in detecting celiacdisease. Gastroenterology 115:1322–1328,1998

7. Selby PL: Osteopenia and diabetes. DiabetMed 5:423–428, 1988

8. Corazza GR, Di Sario A, Cecchetti L,Tarozzi C, Corrao G, Bernardi M, Gasbar-rini G: Bone mass and metabolism inpatients with celiac disease. Gastroenterol-ogy 109:122–128, 1995

9. Mustalahti K, Collin P, Sievänen H, SalmiJ, Mäki M: Osteopenia in patients withclinically silent coeliac disease warrantsscreening. Lancet 354:744–745, 1999


Letters

Prediction of Albumin ExcretionRate From Albumin-to-CreatinineRatio

Two recent articles in Diabetes Carehave continued the long-runningdebate about methods of screening

for albuminuria in diabetes (1,2). The cruxof this issue is whether the information thatcan be obtained from spot urine samples(either albumin concentration or the albu-min-to-creatinine ratio) can provide equiv-alent information to a timed albuminexcretion rate, on which our current defin-itions of albuminuria are based. Spot sam-ples have the huge advantage of not requir-ing accuracy of either timing or volumemeasurement, both of which are potentsources of patient dissatisfaction and errorin clinical practice.

Harvey et al. (1) and Bakker (2) haveestimated cutoff values for albumin-to-crea-tinine ratios that predict values for the albu-min excretion rate. Both have emphasizedthat values discriminating between normaland abnormal albuminuria are dependenton age and sex (1,2). Even though thisapproach is useful, it is worth rememberingan alternative method that was first sug-gested by Ginsberg et al. (3) in 1983. Thedaily urine creatinine excretion, which isrelatively constant, can be estimated fromthe Cockcroft-Gault formula, which takesinto account age, sex, and body size (4).The formula is as follows: creatinine excre-tion (mmol/day) = [(140�age) weight(kg)]/k, where k = 665 for men and 782 forwomen. The estimated urine creatininemultiplied by the albumin-to-creatinineratio gives an estimate of 24-h urine albu-min excretion.

In 1992, we published data on theagreement between the albumin excretionrate estimated in this way from spot sam-ples and the albumin excretion rate mea-sured by 24-h urine collections and on theagreement between repeated 24-h urinecollections (5). We demonstrated that theestimate gave numerically similar values tothe measured samples with a degree ofagreement similar to that found betweentimed collections. The errors inherent inthe estimates were trivial compared withthe day-to-day variability in albuminexcretion (5). This simple device deserveswider appreciation.

TIM CUNDY, MD

JOHN BAKER, MD

From the Department of Medicine, University ofAuckland, Auckland, New Zealand.

Address correspondence to Tim Cundy, MD,Department of Medicine, Auckland Hospital, Pri-vate Bag 92-019, Auckland 1, New Zealand. E-mail:[email protected].

References1. Harvey JN, Hook K, Platts JK, Devarjoo S,

Meadows PA: Prediction of albumin excre-tion rate from albumin-to-creatinine ratio(Letter). Diabetes Care 22:1597–1598, 1999

2. Bakker AJ: Detection of microalbuminuria:receiver operating characteristic curveanalysis favors albumin-to-creatinine ratioover albumin concentration. Diabetes Care22:307–313, 1999

3. Ginsberg JM, Chang BS, Matarese RA,Garella S: Use of single-voided urine sam-ples to estimate quantitative proteinuria.N Engl J Med 309:1543–1546, 1983

4. Cockcroft DW, Gault MH: Prediction ofcreatinine clearance from serum creati-nine. Nephron 16:31–41, 1976

5. Cundy TF, Nixon D, Berkahn L, Baker J:Measuring the albumin excretion rate:agreement between methods and biologi-cal variability. Diabet Med 9:138–143, 1992

Response to Cundyand Baker

The methodology recommended byCundy and Baker (2) is a usefulmeans of estimating 24-h urinary

albumin excretion rates from the albumin-to-creatinine ratio (ACR). Such a method-ology uses the Cockcroft-Gault equation tofactor age, sex, and body weight intoaccount (1,2). The diagnostic values of theACR, as it is commonly used in currentmethodologies, incorporate only the effectof sex. Cundy and Baker’s recommenda-tion is useful for the comparison of ACRvalues with 24-h urinary albumin values,but in Europe in recent years, we havemoved toward timed overnight collectionsas the gold standard in the assessment ofdiabetic proteinuria, because posture andactivity are controlled for and collection issimplified for the patient. The Cockcroft-Gault equation, as currently validated,does not allow calculation of the overnightalbumin excretion rate from the ACR (3).In general clinical practice, a decision onwhether the result indicates normal albu-min excretion, microalbuminuria, or estab-lished nephropathy is all that is required.

For this purpose, the cutoff values that wederived are satisfactory (4). They generallyprovide a clear distinction of microalbu-minuria from normal, because the diagnos-tic values are far removed from the normalpopulation mean (5).

We found that the ACR had lesswithin-subject variation than timed over-night measurements (4). For this reason,coupled with its simplicity, we feel that theuse of single samples with or without theconversion to 24-h albumin excretionrates, as advocated by Cundy and Baker, ispreferable for large surveys and routineclinical use.

JOHN N. HARVEY, MD

From the University of Wales College of Medicine,Wrexham Academic Unit, Wrexham, U.K.

Address correspondence to John N. Harvey, MD,Diabetes Unit, Gladstone Centre, Maelor Hospital,Croesnewydd Road, Wrexham Clwyd LL13 7TD,U.K. E-mail: [email protected].

References1. Cundy T, Nixon D, Berkahn L, Baker I:

Measuring the albumin excretion rate:agreement between methods and biologi-cal variability. Diabet Med 9:138–143,1992

2. Cundy T, Baker I: Prediction of albuminexcretion rate from albumin-to-creatinineratio (Letter). Diabetes Care 23:714, 2000

3. Cockcroft DS, Gault MH: Prediction ofcreatinine clearance from serum creati-nine. Nephron 16:31–41, 1976

4. Harvey JN, Hood K, Platts JK, DevarajooS, Meadows PA: Prediction of albuminexcretion rate from albumin-to-creatinineratio. Diabetes Care 22:1597–1598, 1999

5. Watts GF, Morris RW, Khan K, Polak A:Urinary albumin excretion in healthyadult subjects: reference values and somefactors affecting their interpretation. ClinChim Acta 172:191–198, 1988

Is There Any Use forthe Oral GlucoseTolerance Test?

In relation to the ongoing debate on thenew diagnostic criteria, we appreciatedthe balanced view of Dr. Perry (1),

expressed in a letter published in a recentissue of this journal. The author quite cor-rectly states that merits and limits are builtinto any screening method and warnsagainst sterile discussions about the needfor a compromise between the pragmatic


Letters

and the ideal. One should bear in mind thatthe main objective should be to ensure thatpeople with abnormal glucose homeostatsisare detected in the community. To serve thispurpose, the author suggests that the bestcompromise is a screening approach basedon the measurement of fasting glucosecombined with the oral glucose tolerancetest (OGTT) in those with abnormal fastingvalues. We largely share the view of a needfor a compromise, as the OGTT is littleused by clinicians and may be unfeasible inmany contexts as a screening test on a pop-ulation basis. However, we would like tocomment on the suggested approach.

In relation to the diagnosis of diabetes,there is mounting evidence that there is asizeable proportion of previously undiag-nosed diabetic people with a postload glu-cose �11.1 mmol/l (200 mg/dl) and fast-ing plasma glucose �7.0 mmol/l (126mg/dl). This proportion varies in differentpopulations and ranges from 32 to 72%(2–4). Furthermore, in a pooled analysis of20 studies conducted in different Euro-pean countries, as many as 31% of thosewho are diabetic, according to postchal-lenge plasma glucose, have normal fastingvalues (�6.1 mmol/l, 110 mg/dl) (4) and,therefore, would not be detected by ascreening procedure based essentially onfasting glucose measurements. In addition,fasting glucose is of little help in diagnosingimpaired glucose intolerance (IGT). Evi-dence is accumulating that most peoplewith IGT, from 54 to 67%, have fastingglucose in the normal range (�6.1 mmol/l,110 mg/dl) (4–6). It has also become clearthat isolated postload hyperglycemia is astrong predictor of mortality (2,7,8). Fur-thermore, we have shown that in Cau-casians, IGT is a strong predictor of pro-gression to diabetes (5), and similar datawere produced in other ethnic groups (6).

Moreover, the suggested 2-step approachhas been mimicked through the use ofpooled data from 20 studies conducted in

various European countries. These dataclearly show that a fasting glucose of 5.5mmol/l, a value well within the normalrange, is to be used as the threshold forproposing OGTT to detect 93% of all thosewith diabetes diagnosed on the basis ofpostload values. However, even with theuse of this low threshold, the ability for fast-ing glucose levels to identify IGT does notimprove substantially. Therefore, perform-ing OGTT on people with abnormal fastingglucose would discriminate between dia-betes and impaired fasting glucose, but willbe of little help in identifying IGT; this isnot of minor importance, because preven-tion of progression to overt diabetes in thisgroup seems to be possible.

To preliminarily explore alternativestrategies, we analyzed data relative to anoccupational group of employees of theItalian telephone company (n = 1,038)screened by OGTT in 1980, in whommajor cardiovascular risk factors were alsomeasured (9). Of the 68 participants withpostload glucose in the IGT range, 58 (i.e.,85%) clustered in the group of people withat least 1 among the following conditions:BMI �28, fasting triglycerides �180, bloodpressure �140/90, or on current treatmentfor hypertension or hypertriglyceridemia.We, therefore, suggest that as a possiblecompromise between the pragmatic andthe ideal, the OGTT could be used, irre-spective of fasting glucose levels, for selec-tive screenings of high-risk groups (i.e.,those with 1 or more of the features of themetabolic syndrome: hypertension, hyper-triglyceridemia, low HDL cholesterol, obe-sity/large waist circumference, and/or posi-tive first-degree family history of diabetes).

OLGA VACCARO, MD

GIANLUCA RUFFA, MD

GABRIELE RICCARDI, MD

From the Department of Clinical and ExperimentalMedicine, Federico II University, Naples, Italy.

Address correspondence to Olga Vaccaro, MD,Department of Clinical and Experimental Medicine,II Policlinico, via S. Pansini 5, 80131 Naples, Italy.E-mail: [email protected].

References1. Perry RC: Impaired fasting glucose and

cardiovascular disease (Letter). DiabetesCare 22:1919–1920, 1999

2. Barrett-Connor E, Ferrara A: Isolatedpostchallenge hyperglycemia and the riskof fatal cardiovascular disease in olderwomen and men: the Rancho BernardoStudy. Diabetes Care 21:1236–1239, 1998

3. Shaw JE, de Courten M, Boyko EJ, ZimmetPZ: Impact of new diagnostic criteria fordiabetes on different populations. DiabetesCare 22:762–766, 1999

4. The DECODE Study Group on behalf ofthe European Diabetes EpidemiologyGroup: Is fasting glucose sufficient todefine diabetes? Epidemiological datafrom 20 European studies. Diabetologia 42:647–654, 1999

5. Vaccaro O, Ruffa G, Imperatore G, IovinoV, Rivellese AA, Riccardi G: Risk of dia-betes in the new diagnostic category ofimpaired fasting glucose. Diabetes Care 22:1490–1493, 1999

6. Shaw JE, Zimmet PZ, De Couten M,Dowse GK, Chitson P, Gareboo H, HemrajF, Fareed D, Tuomilehto J, Alberti KG:Impaired fasting glucose or impaired glu-cose tolerance? Diabetes Care 22:399–402,1999

7. The DECODE Study Group on behalf ofthe European Diabetes EpidemiologyGroup: Glucose tolerance and mortality:comparison of WHO and American Dia-betes Association diagnostic criteria.Lancet 354:617–621, 1999

8. Shaw JE, Hodge AM, de Courten M, Chit-son P, Zimmet PZ: Isolated post-challengehyperglycemia confirmed as a risk factorfor mortality. Diabetologia 42:1050–1054,1999

9. Vaccaro O, Rivellese A, Riccardi G,Capaldo B, Tutino L, Annuzzi G, ManciniM: Impaired glucose tolerance and riskfactors for atherosclerosis. Arteriosclerosis4:592–597, 1984

Venlafaxine HCl in the treatment of painful peripheral diabetic neuropathy

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