Moderate-intensity physical activity and fasting insulin levels in women: the Cross-Cultural...

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Are there DifferentEffects of Acarboseand Voglibose onSerum Levels ofDigoxin in a Diabetic PatientWith CongestiveHeart Failure?

�-Glucosidase inhibitors (�-GI),such as acarbose and voglibose, arewidely used in diabetic patients to

suppress postprandial hyperglycemia byinterfering with carbohydrate-digestingenzymes, thus delaying glucose absorption(1). Recently, acarbose and voglibose werereported to have different effects on theabsorption of digoxin; acarbose has beenshown to decrease the absorption of coad-ministered digoxin, whereas voglibose hasbeen demonstrated to have no such effect(2–5). We describe here a diabetic patientwith congestive heart failure whose serumdigoxin concentration responded differentlyto acarbose and voglibose.

An 82-year-old man with type 2 dia-betes and congestive heart failure wastreated with voglibose (0.9 mg/day) anddigoxin. The serum level of digoxinremained within the therapeutic range(0.8–2.0 ng/ml). However, we decided toadminister acarbose (300 mg/day) in placeof voglibose because of high levels ofHbA1c. The decision to switch from vogli-bose to acarbose was prompted by datafrom our earlier study, which demon-strated that acarbose (300 mg/day) has astronger effect than voglibose (0.9 mg/day)on suppressing postprandial hypergly-cemia (Y.N., T.H., unpublished data).Thereafter, the HbA1c level was improvedby acarbose without flatulence andabdominal distention. However, subthera-peutic levels of digoxin (0.2–0.4 ng/ml)were found without changing the digoxindosage. The patient showed no sign ofworsening congestive heart failure. Thepatient asserted that he was taking themedications regularly according to theinstructions, so compliance to the regimendid not appear to be the problem. We sus-pected the occurrence of a pharmacoki-netic drug-drug interaction between acar-bose and digoxin, a phenomenon previ-

ously described in earlier reports (2–4);therefore, we switched from acarbose backto voglibose (0.9 mg/day). Contrary to ourexpectations, the serum level of digoxin 1month after voglibose readministrationremained within the subtherapeutic range(0.3 ng/ml).

Miura et al. (3) reported that adminis-tering acarbose reduces the absorption ofdigoxin. In a report on two patients whoshowed subtherapeutic levels of digoxininduced by acarbose, Ben-Ami et al. (4)proposed the following mechanisms toexplain the phenomenon: 1) coadministra-tion with acarbose increases gastrointesti-nal motility, leading to decreased absorp-tion of digoxin, and 2) acarbose interfereswith the hydrolysis of digoxin before itsabsorption, thereby altering the release ofthe corresponding genine and affecting thereliability of the digoxin laboratory test.However, another type of �-GI voglibosewas shown not to reduce the level ofdigoxin (5), casting doubt on the hypothe-ses from Ben-Ami et al. The most interest-ing finding in our case is that the level ofdigoxin was essentially unchanged afterswitching back from acarbose to voglibose.We have no knowledge of the mechanismbehind this phenomenon; further studiesare needed to clarify it. Although the pre-cise mechanism of acarbose-inducedreduction of digoxin levels remainsunknown, voglibose should be recom-mended for diabetic patients with digoxincoadministration. If acarbose is needed,the dosage of digoxin and the timing of itsadministration should be considered.

YUKIHIRO NAGAI, MD, PHD

TETSUO HAYAKAWA, MD, PHD

TOSHIO ABE, MD, PHD

GAKUJI NOMURA, MD, PHD

From the Department of Internal Medicine,Kanazawa Municipal Hospital, Ishikawa, Japan.

Address correspondence to Yukihiro Nagai, MD,Department of Internal Medicine, KanazawaMunicipal Hospital, 3-7-3 Heiwa-machi, Kanazawa,Ishikawa, Japan 921-8105. E-mail: ynagai@p2223.nsk.ne.jp.

References1. Mooradian AD, Thurman JE: Drug ther-

apy of postprandial hyperglycemia. Drugs57:19–29, 1999

2. Serrano JS, Jimenez CM, Serrano MI, BalboaB: A possible interaction of potential clinicalinterest between digoxin and acarbose. ClinPharmacol Ther 60:589–592, 1996

3. Miura T, Ueno K, Tanaka K, Sugiura Y,Mizutani M, Takatsu F, Takano Y, Shiba-

kawa M: Impairment of absorption ofdigoxin by acarbose. J Clin Pharmacol 38:654–657, 1998

4. Ben-Ami H, Krivoy N, Nagachandran P,Roguin A, Edoute Y: An interactionbetween digoxin and acarbose (Letter).Diabetes Care 22:860–861, 1999

5. Kusumoto M, Ueno K, Fujimura Y,Kameda T, Mashimo K, Takeda K, TatamiR, Shibakawa M: Lack of kinetic interac-tion between digoxin and voglibose (Let-ter). Eur J Clin Pharmacol 55:79–80,1999

Effect of Chitosan on Plasma Lipoprotein Concentrations inType 2 Diabetic Subjects WithHypercholesterolemia

Hypercholesterolemia is a well-knownmajor cardiovascular risk factor inpatients with type 2 diabetes (1).

Step I of the National Cholesterol Educa-tional Program (2), the restriction of fatand cholesterol intake, is usually recom-mended as the initial treatment to lowerblood cholesterol. Therefore, dietary inter-vention is the first-line treatment, and, inaddition to traditional hypolipidemicagents, there is the emerging role of dietaryfiber in the hypolipidemic effect. Chi-tosan, the main component of crab andshrimp shells, is a polymer containing glu-cosamine units that have high positivecharge densities in acidic solutions. Thepositive charge of chitosan interacts withnegative surfaces, such as lipids. We stud-ied the effects of chitosan on the plasmalipoprotein concentrations in subjectswith type 2 diabetes who had hypercho-lesterolemia.

We recruited 40 subjects with type 2diabetes and hypercholesterolemia, ofwhich 33 completed the study. All subjectshad received oral hypoglycemic agents forat least 1 year and were in stable condi-tion. Glycemic control was kept constant,and the subjects maintained their routineeating habits throughout the course of thestudy. The inclusion criterion was having afasting plasma glucose level of �10mmol/l with hypercholesterolemia. Sub-jects were recruited if their LDL choles-terol level remained �3.36 mmol/l afterdietary control for 4–6 weeks. In experi-ment A, 19 subjects underwent a mixed

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1704 DIABETES CARE, VOLUME 23, NUMBER 11, NOVEMBER 2000

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meal test for 8 h. Patients received chi-tosan (Kio Tek, Hsin Chu, Taiwan), whichwas derived from shrimp shells with 97%deacetylate, in doses of 450 mg threetimes per day (n = 10) or placebo (n = 9).Blood samples were drawn hourly fordetermination of glucose and triglycerideconcentrations. In experiment B, 33 of 40subjects completed a randomized, double-blind, placebo-controlled, crossover clini-cal trial with a total duration of 16 weeks.Patients were randomly assigned to receiveeither 450 mg chitosan three times per dayor placebo and were crossed over to theother treatment after 8 weeks. The sub-jects visited our center once before the trialand at weeks 4, 8, 12, and 16. Their com-pliance was followed by counting theremaining capsules after each visit. Possi-ble adverse events were monitored byquestioning the subjects during each visit.

In experiment A, the ambient plasmaglucose and triglyceride concentrationsdid not differ significantly between thechitosan and placebo groups. In experi-ment B, the respective plasma total choles-terol (TC) and LDL cholesterol concentra-tions in the chitosan group were 4.4 ±1.8% (P = 0.039) and 6.5 ± 2.9% (P =0.045) lower than those in the placebogroup. There was no significant differencein triglycerides, HDL cholesterol, ratio ofTC to HDL cholesterol, HbA1c, and fastingglucose values.

Our results confirm the findings ofSharma et al. (3), Yihua and Binglin (4),and Wuolijoki et al. (5), who showed thatchitosan can specifically lower LDL cho-lesterol and does not affect the plasmatriglyceride concentration. Chitosan didnot affect triglyceride levels probablybecause triglyceride is an electrically neu-tral fat. The positive charge of chitosancannot interact with the triglycerides ofdiet and bile acid in the intestine.

The major sources of cholesterol in theintestinal lumen are dietary lipids and bile,which contain negatively charged surfacesof phospholipids and unesterified choles-terol. A possible mechanism is that chi-tosan is positively charged in gastric acid;thus, the positive charge of chitosan inter-acts strongly with negative surfaces of cho-lesterol and bile. The chitosan-cholesterolcomplex is transferred to the intestines (inan alkaline environment) and changes intoan insoluble gel form that cannot behydrolyzed by pancreatic or intestinalenzymes (6) and is excreted in the feces,thereby interrupting the cholesterol entero-

hepatic circulation and accelerating its lossin stools. The effects of chitosan on fecalsteroid excretion have been reported inanimal and human studies (7,8). Conse-quently, the absorption of cholesterol isdecreased, the hepatic bile acid pool isdepleted, and more hepatic cholesterol isdiverted to the production of bile acids. Ashepatic cholesterol demands increase,hepatic cholesterol synthesis increases andLDL receptor apolipoprotein (apo)B/Eactivity is stimulated. Stimulation of LDLreceptor apoB/E activity then increases thecatabolism of LDL cholesterol and reducesplasma LDL cholesterol levels (9). Thepresent study demonstrated that chitosancan effectively lower plasma cholesterol,possibly by binding dietary lipids, choles-terol, and cholesterol-containing bile acids.

In conclusion, our results suggest thatchitosan could effectively lower plasmatotal cholesterol and LDL cholesterol con-centrations without affecting plasmatriglyceride levels and blood glucose con-trol in subjects with type 2 diabetes whohave hypercholesterolemia. No seriousadverse events were reported.

TSAI-SUNG TAI, MD

WAYNE HUEY-HERNG SHEU, MD, PHD

WEN-JANE LEE, PHD

HSIEN-TSUNG YAO, MS

MENG-TSAN CHIANG, PHD

From the Division of Endocrinology and Metabo-lism (T.-S.T., W.H.-H.S., W.-J.L.), Department ofInternal Medicine, Taichung Veterans General Hos-pital; the Chung-Shan Medical and Dental College(W.-J.L.), Taichung; the National Yang-Ming Uni-versity and National Defense Medical Center (W.H.-H.S.), Taipei, Taiwan, Republic of China; and theDepartment of Food Science, National TaiwanOcean University (H.-T.Y., M.-T.C.), Kaelung, Tai-wan, Republic of China.

Address correspondence to Wayne Huey-HerngSheu, Division of Endocrinology and Metabolism,Taichung Veterans General Hospital, No. 160, Section3, Chung-Kang Road, Taichung, Taiwan 407, Repub-lic of China. E-mail: whhsheu@vghtc.vghtc.gov.tw.

References1. Laakso M, Lehto S: Epidemiology of

macrovascular disease in diabetes. DiabetesReviews 5:294–315, 1997

2. National Cholesterol Education Program:second report of the Expert Panel onDetection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults (AdultTreatment Panel II). Circulation 89:1333–1445, 1994

3. Sharma CP, Chandy T, Kumari TV, Paul W:Lipoprotein adsorption onto modified chi-tosan beads. Biomater Artif Cells Immobi-

lization Biotechnol 21:659–664, 19934. Yihua YU, Binglin HE: A new low density

lipoprotein (LDL) adsorbent. Artif CellsBlood Substit Immobil Biotechnol 25:445–450, 1997

5. Wuolijoki E, Hirvela T, Ylitalo P: Decreasein serum LDL cholesterol with microcrys-talline chitosan. Methods Find Exp ClinPharmacol 21:357–361, 1999

6. Kanauchi O, Deuchi K, Imasato Y,Shizukuishi M, Kobayashi E: Mechanismfor the inhibition of fat digestion by chi-tosan and for the synergistic effect of ascor-bate. Biosci Biotechnol Biochem 59:786–790,1995

7. Deuchi K, Kanauchi O, Imasato Y,Kobayashi E: Effect of the viscosity ordeacetylation degree of chitosan on fecal fatexcreted from rats fed on a high-fat diet.Biosci Biotechnol Biochem 59:781–785, 1995

8. Lengsfeld H, Fleury A, Nolte M, PiquerezJC, Hadvary P, Beglinger C: Effect of orlis-tat and chitosan on faecal fat excretion inyoung healthy volunteers (Abstract). ObesRes 7 (Suppl. 1):50S, 1999

9. Bilheimer DM: The lipoprotein receptorconcept. Drugs 36 (Suppl. 3):55–62, 1988

Prevalence of Diabetes in Canadian AdultsAged 40 Years or Older

The prevalence of diabetes, mainlytype 2 diabetes, in adults is believedto be higher in women than in men

(1,2). However, some population-basedstudies have recently demonstrated thatmen are as likely or more likely to have thedisease than women (3,4). These studiesmay suggest a changing pattern of sex-related distribution of type 2 diabetes inWestern countries.

This analysis was based on the datafrom the second cycle of the National Pop-ulation Health Survey conducted in1996–1997. The survey used multistagesampling techniques to select subjectsfrom all provinces of Canada (5). A total of39,021 adults, aged 40 years or older, whoanswered the question on diabetes wereincluded in this analysis. The subjectsconsidered to be diabetic were those whopositively answered the question of havingdiabetes diagnosed by a health profes-sional. Prevalence estimates were weightedto the Canadian population. A logisticregression was used to calculate adjustedodds ratios. The Rao-Wu bootstrap tech-

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nique was used to take the design effectinto consideration (6).

The overall prevalence (95% CI) was6.6% (5.8–7.5%) for men and 5.1%(4.6–5.7%) for women. The prevalenceincreased with increasing age in bothsexes, and leveled off for women aged 80years or older (Table 1). The odds ratio(95% CI) for men compared with womenwas 1.60 (1.33–1.91) after adjusting forcovariates. Men and women living in ruraland urban areas had similar prevalencesof diabetes.

In the last two decades, type 2 diabeteshad been profoundly studied in specificpopulations, especially aboriginal people,in Canada. This analysis was based on datafrom a representative sample of the Cana-dian population and demonstrated a differ-ence in distribution of diabetes betweenmen and women nationally. The reasonsfor the increased risk of diabetes in men arenot known. Obesity is one of the majorrisk factors for type 2 diabetes (1). Theprevalence of overweight (BMI �25 kg/m2)is higher in men than in women in Canada(60 vs. 40%) (7), which may be a partialexplanation. Men visited their dietitiansless frequently (8), and less than half ofmen compared with almost two-thirds ofwomen with a BMI �27 kg/m2 were tryingto lose weight (9). A similar prevalence inrural and urban areas may indicate there isnot much difference in determinants of thedisease between two areas.

The prevalence of diabetes has beensteadily increasing in Canada (10). Theprevalence of diabetes in aging men isincreasing more rapidly than that in agingwomen. This suggests that senior men

should be given more attention in terms ofdisease control and prevention.

MEI TANG, MD, MSC

YUE CHEN, MD, PHD

From the Department of Epidemiology and Com-munity Medicine, Faculty of Medicine, Universityof Ottawa, Ontario, Canada.

Address correspondence to Mei Tang, MD, Msc,Department of Epidemiology and CommunityHealth, Faculty of Medicine, University of Ottawa,451 Smyth Rd., Ottawa, Ontario K1H 8M5, Canada.E-mail: meitang@zeus.med.uottowa.ca.

Acknowledgments — This research was sup-ported by a National Health Research andDevelopment Program Grant (6606–06–1998/2640023).

We thank Ms. Colette Koeune of StatisticsCanada for her assistance in remote access tothe NPHS data.

References1. Myers AR: Medicine. 3rd ed. Baltimore, MD,

Williams & Wilkins, 1997, p. 475–4922. Harris MI: Non-insulin-dependent dia-

betes mellitus in black and white Ameri-cans. Diabetes Metab Rev 6:71–90, 1990

3. Harris MI, Goldstein DE, Flegal KM, LittleRR, Cowie CC, Wiedmeyer H, EberhardtMs, Byrd-Holt DD: Prevalence of diabetes,impaired fasting glucose, and impaired glu-cose tolerance in U.S. adults: the ThirdNational Health and Nutrition ExaminationSurvey. Diabetes Care 21:518–524, 1998

4. Connolly V, Unwin N, Sherriff P, Bilous R,Kelly W: Diabetes prevalence and socioeco-nomic status: a population based studyshowing increased prevalence of type 2 dia-betes mellitus in deprived areas. J EpidemiolCommunity Health 54:173–177, 2000

5. Statistics Canada: National PopulationHealth Survey 1996–97. Ottawa, Ontario,Canada, Health Statistics Division, 1997

6. Rao JNK, Wu CFJ, Yue K: Some recent workon resampling methods for complex sur-veys. Survey Methodology 18:209–227, 1992

7. Chen Y, Dales R, Krewski D: Increasedeffects of smoking and obesity on asthmaamong female Canadians: the NationalPopulation Health Survey (NPHS) 1994–1995. Am J Epidemiol 150:255–262, 1999

8. Lo R, MacLean D: A survey of people withdiabetes in northern New South Wales:problems with self-care. Int J Nurs Pract 2:11–20, 1996

9. Green KL, Cameron R, Polivy J, Cooper K,Liu L, Leiter L, Heatherton T: Weight dis-satisfaction and weight loss attemptsamong Canadian adults. CMAJ 157 (Suppl.1):S17–S25, 1997

10. King H, Aubert RE, Herman WH: Globalburden of diabetes, 1995–2025: preva-lence, numerical estimates, and projec-tions. Diabetes Care 21:1414–1424, 1998

Prevalence of GADAutoantibodies inWomen With Gestational Diabetes

A retrospective analysis

Autoantibodies to GAD (GADa) havebeen the source of considerableattention because of their association

with the development of type 1 diabetes.As a consequence, several groups havebeen interested in the relationship betweenGADa in women with gestational diabetesand the subsequent occurrence of perma-nent diabetes. Interestingly, publicationson this subject, emanating primarily fromEurope, have been notable for their lack ofunanimity concerning the rates of autoan-tibody positivity. These rates have rangedfrom 0% GADa positivity in gestationaldiabetic women from northern Italy (1) toa high of 10% in gestational diabeticwomen from a German multicenter study(2). A study in Denmark reported an inci-dence of 2.2% GADa positivity in sera fromgestational diabetic women (3). In all like-lihood, such discrepancies can be attrib-uted in whole or in part to distinct popula-tion characteristics and differences in labo-ratory methodology.

In view of the experience of the Euro-pean investigators vis-à-vis the aforemen-tioned rates of GADa positivity, wethought it would be of interest to deter-

Table 1—Prevalence and adjusted odds ratio for diabetes in relation to age and resident areaamong Canadian men and women

Men Women

Prevalence Adjusted* OR Prevalence Adjusted* ORn (95% CI) (95% CI) n (95% CI) (95% CI)

Age (years)40–49 6,067 2.2 (1.6–2.9) 1.0 6,232 2.4 (1.6–3.1) 1.050–59 4,433 6.6 (4.8–8.5) 2.9 (1.9–4.4) 4,947 3.7 (2.8–4.6) 1.2 (0.7–2.0)60–69 3,655 9.8 (7.9–11.8) 4.2 (2.5–6.9) 4,324 8.1 (6.4–9.7) 2.3 (1.3–3.8)70–79 2,613 13.1 (10.2–16.0) 5.5 (2.9–10.6) 3,889 9.7 (7.6–12.0) 2.5 (1.3–4.8)80� 962 14.4 (6.5–22.3) 6.0 (2.4–14.7) 1,899 7.2 (5.4–9.0) 1.8 (0.9–3.4)

Resident areaRural 13,421 6.5 (5.6–7.5) 1.0 16,674 5.08 (4.5–5.7) 1.0Urban 4,301 7.1 (5.2–9.0) 1.1 (0.8–1.5) 4,606 5.39 (4.4–6.4) 1.0 (0.8–1.3)Total 17,730 6.6 (5.8–7.5) — 21,291 5.13 (4.6–5.7) —

*Adjusted by income adequacy, education level, employment status, BMI, and physical activity. OR,odds ratio.

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mine the incidence of GADa in NorthAmerican women. To have a reasonablebasis for comparison, we elected to mea-sure GADa in women during the time oftheir pregnancy rather than postpartum.Therefore, we undertook a pilot retrospec-tive study in which GADa were assayed insera that had been collected from womenduring a defined period of pregnancy.

Since 1978, the Foundation for BloodResearch has routinely tested sera for�-fetoprotein between 15 and 18 weeks ofgestation from �60% of the pregnantwomen in Maine. Aliquots of sera wereretrieved from 100 women with gesta-tional diabetes and 100 matched nondia-betic control subjects. These sera had beencollected from 1990 to 1992 and stored inthe frozen state at �20°C. With the excep-tion of the diagnosis of gestational dia-betes, no information regarding treatmentwas available.

GADa were measured using a highlysensitive radioimmunoassay kit for serum(Kronus, Boise, ID) according to the man-ufacturer’s instructions. Briefly, sera, cali-brators, and controls were incubated for�2 h with human recombinant 125I GAD65

in polystyrene tubes. Protein A was added,followed 1 h later by a wash solution. Thetubes were centrifuged, after which thesupernatants were discarded. Residualradioactivity was counted, and a standardcurve was automatically constructed byonline data reduction, which generatedvalues for the sera.

To account for systematic differencesamong assay runs, individual results weredivided by the median control value foreach run. The normalized results, expressedin multiples of the median (MoM), weretransformed logarithmically, thereby gener-ating a Gaussian distribution. Samples withantibody values above the geometric mean�3 SD (6.2 MoM) were considered posi-tive. None (0%) of the 100 control speci-mens was positive (the highest value was5.0 MoM). In contrast, six (6%) of the 100women with gestational diabetes wereautoantibody-positive (values ranged from6.3 to 31.0 MoM).

The GADa positivity of 6% in our ges-tational diabetic cohort essentially fallsmidway between the 0% reported fromnorthern Italy and the 10% prevalencefound in the German multicenter study. Asmentioned earlier, these discrepancies inthe rates of GADa positivity may be areflection of differences in both methodol-ogy and population characteristics. In

regard to the latter, the determination ofwhether our findings are unique to thewomen in Maine will have to await addi-tional retrospective or prospective studiesfrom other areas of North America.

The potential value for assaying GADain gestational diabetic women was demon-strated in the follow-up of patients in theGerman multicenter study. The data indi-cated that there was a significant correla-tion between the number of antibodies(among insulin antibody 2, islet cell anti-body, and GAD antibody) and the proba-bility of developing type 1 diabetes. Test-ing for GADa and other islet cell antibod-ies should prove useful in populationscreening when methods become availableto arrest or prevent type 1 diabetes.

MARVIN L. MITCHELL, MD

ROSALIE J. HERMOS, MPH

CECILIA A. LARSON, MD

GLENN E. PALOMAKI, BS

JAMES E. HADDOW, MD

From the New England Newborn Screening Pro-gram (M.L.M., R.J.H., C.A.L.), University of Massa-chusetts Medical School, Jamaica Plain, Massachu-setts; and the Foundation for Blood Research(G.E.P., J.E.H.), Scarborough, Maine.

Address correspondence to Marvin L. Mitchell,MD, New England Newborn Screening Program,State Laboratory Institute, 305 South St., JamaicaPlain, MA 02130-3597. E-mail: marvin.mitchell@state.ma.us.

M.L.M. received research support from Kronus.

References1. Dozio N, Beretta A, Belloni C, Castiglioni

M, Rosa S, Bosi E, Bonifacio E: Low preva-lence of islet autoantibodies in patientswith gestational diabetes. Diabetes Care 20:81–83, 1997

2. Fuchtenbusch M, Ferber K, Standl E,Ziegler A-G, participating centers: Predic-tion of type 1 diabetes mellitus by com-bined islet cell and autoantibody screen-ing: a prospective multicenter study. Dia-betes 46:1459–1467, 1997

3. Petersen JS, Dyrberg T, Damm P, Kuhl C,Molsted-Pedersen L, Buschard K: GAD65autoantibodies in women with gestationalor insulin-dependent diabetes mellitusdiagnosed during pregnancy. Diabetologia39:1329–1333, 1996

School Attendanceof Children WithType 1 Diabetes

Regular school attendance is impor-tant for a child’s academic achieve-ment, formation of peer relation-

ships, and self-esteem (1). Studies haveshown that children with chronic illnesseshave greater school absenteeism rates thantheir healthy peers (1–3). Although dia-betes is one of the most common chronicdisorders of childhood, most childrenwith the condition are otherwise healthy.To date, there has been very little focusspecifically on school attendance in chil-dren with diabetes (4).

In this pilot study, we recruited 56families from the diabetes clinic at the Hos-pital for Sick Children in Toronto, Canada.Parents who participated in the study werecontacted by telephone and asked to reportthe number of missed school days, asdetailed on their child’s report card. Absen-teeism data for the 1997–1998 academicyear was collected for both the diabeticchildren and each child’s closest sibling.The school absenteeism rate for the dia-betic children was compared with both thenondiabetic siblings’ records and pub-lished school attendance data of a controlgroup from the Toronto School Board (5).

Diabetic children were absent 6.1 moreschool days than their siblings (11.4 ± 10.9vs. 5.3 ± 5.8, respectively, P � 0.01). Whenschool absences caused by diabetes clinicappointments were subtracted from totalabsences, diabetic children were still foundto be absent 3.6 more school days than theirsiblings (8.9 ± 10.1 vs. 5.3 ± 5.8, P � 0.01).Although diabetic children also had higherabsenteeism rates than the control group,this difference was not statistically signifi-cant. There was a trend for young childrenwith diabetes (grades 1–3) to have higherrates of absenteeism than older childrenwith diabetes (P = 0.06); however, a similartrend was not found among the siblings.Neither metabolic control, as measured byHbA1c levels, nor the duration of diabetescorrelated with absenteeism. For children inthe same family, there was a highly signifi-cant correlation in absenteeism betweenthose with and those without diabetes (r =0.53, P � 0.01). Family unit function wasnot assessed quantitatively in this study;however, some interesting observationswere noted. It was our distinct impressionthat in families well adjusted to dealing withdiabetes, the children missed very littleschool. Similarly, in the families that hadsignificant difficulties coping with the prac-tical aspects of diabetes care, both the dia-betic children and their siblings appeared tohave much higher rates of absenteeism.

This pilot study showed that diabeticchildren miss, on average, a little more

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than 1 week per school year than theirnondiabetic siblings. The close correlationin absenteeism between diabetic childrenand their nondiabetic siblings suggeststhat family attitudes may be a major factorin determining school attendance. Factorscontributing to differences in schoolattendance may include parental overpro-tection, parental philosophy regardingacademics, and the quality of communi-cation between parents and teachers. Togain greater insight into this issue, a moreextensive study that attempts to quantifyfamily attitudes and family unit functionis needed.

JANE VETISKA, BSC

LAURA GLAAB, BNSC

KUSIEL PERLMAN, MD, FRCPC

DENIS DANEMAN, MB, BCH, FRCPC

From the Division of Endocrinology, the Hospitalfor Sick Children, Toronto, Ontario, Canada.

Address correspondence to Dr. Denis Daneman,Division of Endocrinology, Hospital for Sick Chil-dren, University of Toronto, 555 University Ave.,Toronto, Ontario M5G 1X8, Canada. E-mail: denis.daneman@sickkids.on.ca.

References1. Weitzman M: School absence rates as out-

come measures in studies of children withchronic illness. J Chronic Dis 39:799–808,1986

2. Weitzman M, Walker DK, Gortmaker S:Chronic illness, psychosocial problems,and school absences: results of a survey ofone county. Clin Pediatr 25:137–141, 1986

3. Cook BA, Schaller K, Krischer JP: Schoolabsence among children with chronic ill-ness. J Sch Health 55:265–267, 1985

4. Ryan C, Longstreet C, Morrow L: Theeffects of diabetes mellitus on the schoolattendance and school achievement ofadolescents. Child Care Health Dev 11:229–240, 1985

5. Brown R: More on secondary schoolabsenteeism. Research Review: The WeeklyCircular. 24 November 1995, p. 1–2

“Lady-like”

Is there a latent autoimmune diabetes in the young?

Latent autoimmune diabetes in adultsis often characterized by a mild mani-festation and a long period of pre-

served -cell function (1). In contrast,autoimmune diabetes in childhood is nor-mally seen as a rapid progressive disease

with immediate insulin deficiency at diag-nosis. Longer periods of remission afterinitial insulin therapy for up to severalyears have been described. In a series of747 children with newly diagnosed type 1diabetes (2), only 3.4% of the autoanti-body-positive children had clinical remis-sions 18 months after diagnosis (definedas a daily insulin dose �0.5 U kg�1 day). This statistic suggests that insulinindependence �1 year after initial diagno-sis of diabetes is a rather rare event in chil-dren with type 1 diabetes.

We have studied two newly diagnosedtype 1 diabetic children with multiple andhigh-titer autoantibodies and typical high-risk HLA haplotypes for autoimmune dia-betes. Nevertheless, the children havebeen insulin independent for up to oneyear. In both children, stable residual -cellfunction without insulin therapy was pre-served. The study of these patients ques-tions the concept of rapidly progressivetype 1 diabetes in autoimmune diabetesduring childhood and adds a point of cau-tion for the interpretation of ongoing trialsfor diabetes prevention in so-called high-risk prediabetic patients (3).

Patient 1, a girl aged 8 years 7 months,was diagnosed with diabetes in April 1999with a fasting blood glucose of 7 mmol/land an HbA1c level of 8.0% (upper limit inour laboratory 6.2%). She had no polyuriaor polydipsia and no weight loss at thistime. Furthermore, no ketonuria orketoacidosis was present. Basal C-peptidewas measured at 0.76 nmol/l and could bestimulated by 1 mg glucagon intra-venously to reach 1.47 nmol/l. Family his-tory revealed type 2 diabetes in bothgrandparents on the maternal side, whohad been diagnosed at 46 and 60 years,respectively, and treated by oral hypogly-cemic drugs. The girl herself was over-weight at diagnosis (BMI 28 kg/m2).Therefore, type 2 diabetes or maturity-onset diabetes of the young was suspectedat this time, and a calorie-reduced diet andphysical exercise were prescribed. Surpris-ingly, high-titer autoantibodies weredetected in the patient’s serum (ICA �40Juvenile Diabetes Foundation units [JDF-U], GADA 101 U, and IA2A 28 U) (meth-ods and workshop data of assays in [4]).In addition, the HLA type of the patientwas DRB1*0301/0401-DQB1*0201/0302.This represents the highest association forautoimmune type 1 diabetes. We found noother autoantibodies typical for polyen-docrine autoimmunity. In July 1999, the

girl had lost 6 kg of weight, her HbA1c hadnormalized to 5.9%, and all blood glucoselevels (fasting and postprandial) were inthe normal range. In August 1999, wemeasured a postprandial C-peptide levelof 2.86 nmol/l. This level suggests com-plete recovery of -cell function. In April2000, 12 months after initial diagnosis,the girl was still insulin-free with normalvalues for fasting blood glucose andHbA1c, but the 2-h blood glucose level ofthe oral glucose tolerance test (OGTT) was11.9 mmol/l, again in the diabetic range.The islet cell–specific autoantibodies wereconsistently positive (islet cell antibody,GAD, and IA2) throughout this period.

Patient 2 was a girl aged 8 years 5months who was diagnosed in January1999 with a blood glucose level of 17.6mmol/l from an OGTT and an HbA1c of6.4%. In the family history, the grand-mother on the paternal side had type 2 dia-betes. The girl was also overweight with aBMI of 22.1 kg/m2. She was treated withdiet and released from the hospital afterweight reduction without further therapy.Five months later, she was admitted to adiabetes rehabilitation clinic. There, shewas still insulin-free and was considerednot to have diabetes afterall. But after3 months, in September 1999, she wasagain admitted to the hospital with a fastingblood glucose level of 11.8 mmol/l. Herblood glucose level increased to 22.8mmol/l during an OGTT. The HbA1c levelwas then 8.6%. She had type 1diabetes–associated HLA haplotype DR3/4,DQ*0201/0302, and high-titer autoanti-bodies in her serum (ICA �40 JDF-U,GAD 7 U, and IA2 37 U). Therefore, thediagnosis of type 1 diabetes was madeaccording to the criteria of the AmericanDiabetes Association and the World HealthOrganization (5). The C-peptide level fromthe OGTT was basal 0.61 nmol/l andincreased to 0.76 nmol/l after glucose load.Therefore, insulin deficiency has been rec-ognized and insulin therapy started 9months after the first diagnosis with 0.15 U kg�1 day. Three months later, her HbA1c

was 6.5%, and insulin doses were reducedto 0.05 U kg�1 day.

Both cases demonstrate that theautoimmune destruction of islets can alsobe slowly progressive in childhood dia-betes. Even insulin independency may beobserved for up to 1 year. Others havereported nonprogression of subclinical -cell dysfunction in relatives of type 1 dia-betic patients and called this phenomen

Letters

“silent diabetes” (6). We found that evenovert diabetes in children may be seem-ingly reversible for some months. Further-more, being severely overweight may addsome kind of insulin resistance to thepathogenesis and suggests a combinationof type 1 and type 2 diabetes. This problemwill be seen more often in the futurebecause of the increasing frequency ofoverweight children in many countries andmay complicate diagnoses. These patientsshow how heterogeneous the natural his-tory of autoimmune diabetes may be in so-called high-risk prediabetic patients (mul-tiple autoantibodies of high-titer and HLAalleles associated with high risk for type 1diabetes) currently studied in diabetes pre-vention trials (3). We suggest allowing forsuch slow progression when case ratios arecalculated in prevention trials.

TOBIAS LOHMANN, MD

UTE NIETZSCHMANN, MD

WIELAND KIESS, MD

From the Department of Internal Medicine III (T.L.)and the Childrens Hospital (U.N., W.K.), Universityof Leipzig, Leipzig, Germany.

Address correspondence to Tobias Lohmann,MD, Department of Internal Medicine III, Univer-sity of Leipzig, Ph.-Rosenthal-Str. 27, 04103Leipzig, Germany.

References1. Tuomi T, Carlsson A, Li H, Miettinen A,

Nilsson A, Nissen M, Ehrnström B-O,Forsen B, Snickars B, Lahti K, Forsblom C,Saloranta C, Taskinen M-J, Groop LC:Clinical and genetic characteristics of type2 diabetes with and without GAD antibod-ies. Diabetes 48:150–157, 1999

2. Sabbah E, Savola K, Kulmala P, Veijola R,Vähäsola P, Karjalainen J, Akerblom HK,Knip M, and the Childhood Diabetes inFinland Study Group: Diabetes-associatedautoantibodies in relation to clinical char-acteristics and natural course in childrenwith newly diagnosed Type 1 diabetes. JClin Endocrinol Metab 84:1534–1539,1999

3. DPT-1 Study Group: The Diabetes Preven-tion Trial-Type 1 diabetes (DPT-1): imple-mentation of screening and staging of rela-tives. Transplant Proc 27:33–77, 1995

4. Lohmann T, Seissler J, Verlohren HJ,Schröder S, Rötger J, Dähn K, Morgen-thaler N, Scherbaum WA: Distinct geneticand immunological features in patientswith insulin-dependent diabetes belowand above age 40 at onset. Diabetes Care20:524–529, 1997

5. The Expert Committee on the Diagnosisand Classification of Diabetes Mellitus:

Report of the Expert Commitee on the diag-nosis and classification of diabetes mellitus.Diabetes Care 20:1183–1197, 1997

6. McCulloch DK, Klaff LJ, Kahn SE, Schoen-feld SL, Greenbau CJ, Mauseth RS, BensonEA, Nepom GT, Shewey L, Palmer JP:Nonprogression of subclinical -cell dys-function in first-degree relatives of IDDMpatients. Diabetes 39:549–556, 1990

Relevance of theTreatment Facilityfor Disease-RelatedKnowledge of Diabetic Patients

The treatment of diabetes is predomi-nantly a form of self-treatment car-ried out by patients. For this reason,

being sufficiently informed is consideredto be a prerequisite for a patient’s success-ful management of his or her blood glu-cose levels (1–3). It is a known fact thatstructured training courses can improvetreatment-related knowledge, at least inthe short term (4), whereas the physician’squalification and the quality of the physi-cian–patient relationship is more likely tobe of fundamental importance for the pro-curement of knowledge on the part of thepatient (5–7). However, the ultimate deci-sive factor is the amount of informationpatients have managed to acquire underroutine conditions. We examined whetherthe degree of specialization at the facilitywhere diabetic patients receive treatmenthas any relevance for patients’ level ofknowledge (8).

The present study examines a sam-pling of 625 diabetic patients. A total of174 patients were recruited from the dia-betes outpatient center at the Charité Uni-versity Polyclinic, 264 patients wererecruited from three specialist practices,and 187 patients were recruited from 28general practitioner practices. The threespecialist practices and 194 general practi-tioners were contacted randomly using theMedical Handbook for Berlin (9) until 3specialists and 30 general practitionerswere recruited in the Berlin metro area.Two general practitioners later refused totake part in the study. The record was com-piled consecutively over a period of 3months; the near-complete registration ofpatients treated at the polyclinic required aperiod of 9 months. Sociodemographicvariables (e.g., age, sex, and school educa-

tion) were equally distributed, except for aslight predominance among men in spe-cialized facilities. All patients were asked tofill out a standardized questionnaire to testtheir knowledge (10) while waiting to meetwith their physician. The 90-item ques-tionnaire is based on comparable Anglo-American questionnaires (11,12) andassesses knowledge in the following areas:causes/pathophysiology, insulin/effects ofinsulin, insulin injection/storage, nutrition,physical activity, personal control overmetabolic functions, hyperglycemia, hypo-glycemia, illnesses, insulin adaptation, andconsequential damages. Patients who didnot have insulin therapy were given anadapted version that excluded questionson insulin treatment.

In terms of treatment-related knowl-edge dependent on the facility where theyreceived treatment, the mean values, cor-rected for age, sex, and education,showed hardly any disparity between type1 diabetic patients and non–insulin-requiring type 2 diabetic patients, evenwhen the impact of structured trainingwas eliminated in the calculation (Table1). Conversely, insulin-dependent type 2diabetic patients treated in specializedfacilities had a significantly higher level ofknowledge (�16% more correct answers)than those treated by a general practi-tioner. This difference can be partiallyexplained by the fact that specialized facil-ities apply more intensified forms of ther-apy (intensified conventional insulintreatment and/or continuous subcuta-neous insulin infusion) and frequentstructured training programs; these twocharacteristics, independent of each other,were associated with a higher level ofknowledge. If these effects are excluded,differences still exist between treatmentfacilities, but they are not significant.

To summarize, in terms of acquiringextensive knowledge of diabetes, type 1and non–insulin-dependent type 2 dia-betic patients do not benefit from a degreeof specialization in the therapeutic facility.However, insulin-requiring type 2 diabeticpatients treated in specialized clinics havea much higher level of knowledge due tothe enhanced utilization of intensifiedforms of therapy and structured training.

MATTHIAS ROSE, MD

MARTIN HILDEBRANDT, MD

HERBERT FLIEGE, PHD

BÄRBEL SEIDLITZ, MD

LIVIA COTTA, MD

Letters

THEA SCHIROP, MD

BURGHARD F. KLAPP, MD

From the Department of Psychosomatic Medicineand Psychotherapy (M.R., M.H., H.F., B.S., B.F.K.),Diabetes Outpatient Clinic; the Department ofIntensive Care and Nephrology (T.S.), MedicalClinic and Polyclinic, Charité Campus-Virchow, Humboldt University, Berlin; and Thieme Publisher(L.C.), Stuttgart, Germany.

Address correspondence to Matthias Rose, MD,Department of Psychosomatic Medicine and Psy-chotherapy, Medical Clinic and Polyclinic, CharitéCampus-Virchow, Augustenburger Platz 1, 13353Berlin, Germany. E-mail: rose@charite.de.

References1. Glasgow RE, Fisher EB, Anderson BJ,

LaGreca A, Marrero D, Johnson SB, RubinRR, Cox DJ: Behavioral science in diabetes:contributions and opportunities. DiabetesCare 22:832–843, 1999

2. Fain JA, Nettles A, Funnell MM, CharronD: Diabetes patient education research: anintegrative literature review. Diabetes Educ25:7–15, 1999

3. Scorpiglione N, el-Shazly M, Abdel FM,Belfiglio M, Cavaliere D, Carinci F: Epi-demiology and determinants of blood glu-cose self-monitoring in clinical practice.Diabetes Res Clin Pract 34:115–125, 1996

4. Schiel R, Ulbrich S, Muller UA: Quality ofdiabetes care, diabetes knowledge and riskof severe hypoglycaemia one and fouryears after participation in a 5-day struc-tured treatment and teaching programmefor intensified insulin therapy. DiabetesMetab 24:509–514, 1998

5. Dalewitz J, Khan N, Hershey CO: Barriersto control of blood glucose in diabetesmellitus. Am J Med Qual 15:16–25, 2000

6. Kern RM, Penick JM, Hamby RD: Predic-

tion of diabetic adherence using theBASIS-A inventory. Diabetes Educ 22:367–373, 1996

7. Rose M, Burkert U, Scholler G, Schirop T,Danzer G, Klapp BF: Determinants of thequality of life of patients with diabetesunder intensified insulin therapy. DiabetesCare 21:1876–1885, 1998

8. Glasgow RE: Outcomes of and for diabeteseducation research. Diabetes Educ 25:74–88, 1999

9. Die Medizin in Berlin. Berlin, JoachimKugler Verlag, Postfach 370345, 1997

10. Roth R, Kulzer B, Teupe B, Borkenstein M:Diabetes-Wissens-Test: TYP-I. Goettingen,Germany, Hogrefe, 1996

11. Dunn SM, Bryson JM, Hoskins PL, AlfordJB, Handelsman DJ, Turtle JR: Develop-ment of the diabetes knowledge (DKN)scales: forms DKNA, DKNB, and DKNC.Diabetes Care 7:36–41, 1984

12. Hess GE, Davis WK: The validation of adiabetes patient knowledge test. DiabetesCare 6:591–596, 1983

The Met416 → ValVariant in theGlycogen SynthaseGene

The prevalence and the associationwith diabetes in a large number ofJapanese individuals

Muscle glycogen synthase (GYS1)is a key enzyme catalyzing glu-cose storage in skeletal muscles

during insulin stimulation (1) and seems

a promising candidate gene for type 2diabetes. The XbaI polymorphism of theGYS1 gene was shown to be associatedwith type 2 diabetes (2). Mutationalanalyses in the coding region of the GYS1gene detected four amino acid polymor-phisms (3–6). Among them, the allelefrequency of the Met416 (ATG) → Val(GTG) variant in exon 10 was muchhigher compared with three other muta-tions. In type 2 diabetic Japanese individ-uals, this variant was shown to be associ-ated with decreased insulin sensitivityevaluated by minimal model analysis (5),although the subsequent study in Finnishsubjects did not reach the same result (6).

In this study, we organized a multi-institutional study and investigated theprevalence and significance of the Met416

→ Val polymorphism in a large numberof Japanese individuals. All study sub-jects (1,529 diabetic and 901 controlsubjects) were unrelated, and they gavetheir written consent after beinginformed of the nature of the study. Thediagnosis of diabetes was based on thecriteria of the World Health Organiza-tion. The normal control subjects wereselected according to the following cri-teria: no past history of urinary sugar orglucose intolerance and having anHbA1c level �5.6%, an age of �60years, and no family history of diabetes.With the use of previously reportedpolymerase chain reaction–restrictionfragment-length polymorphism analysis(5), we determined the Met416 → Valvariant genotypes.

Table 1—Diabetes-specific knowledge of patients in different treatment facilities

% Correct answers Differences betweenPolyclinics Specialist clinics General practitioners providers [F (P)]

Type 1 diabetic patientsn 95 108 21Controlled and adjusted for age, sex, and education 65.9 ± 2.02 62.5 ± 2.09 65.7 ± 4.78 NS*Controlled and adjusted for age, sex, education and 64.3 ± 2.02 63.7 ± 2.08 67.9 ± 4.75 NS†use of training program, and type of therapy

Insulin-requiring type 2 diabetic patientsn 72 115 58Controlled and adjusted for age, sex, and education 49.3 ± 2.95 40.3 ± 2.19 33.0 ± 3.08 7.219 (0.001)‡Controlled and adjusted for age, sex, education and 44.6 ± 3.25 40.7 ± 2.12 37.2 ± 3.15 NS§use of training program, and type of therapy

Non–insulin-requiring type 2 diabetic patientsn 7 41 108Controlled and adjusted for age, sex, and education 58.7 ± 10.2 44.9 ± 3.48 47.6 ± 2.13 NS�Controlled and adjusted for age, sex, education and 58.1 ± 10.3 45.1 ± 3.50 47.5 ± 2.14 NS¶use of training program, and type of therapy

Data are means ± SEM unless otherwise indicated. Whole-corrected models: F (P) *9.03 (0.000); †8.47 (0.000); ‡5.66 (0.000); §7.56 (0.000); �2.91 (0.017); ¶2.25 (0.038).

Letters

The allele frequency of the Met416 →Val variant was 0.108 in diabetic subjects(Met/Met was 1,221, Met/Val was 285, andVal/Val was 23 of 1,529 subjects) and 0.102in control subjects (Met/Met was 723,Met/Val was 172, and Val/Val was 6 of 901subjects). There was no statistical differencein allele frequency of the Met416Val variantbetween the diabetic and control groups(the odds ratio for the association of the Valallele with type 2 diabetes was 1.1067[95% CI 0.882–1.291], P = 0.50233 vs.normal control group [�2 test]). In diabeticsubjects, there were no differences in age,sex, age at onset of diabetes, and the HbA1c,fasting plasma glucose, and serum lipid lev-els between the groups with or without theMet416 → Val substitution. Among the clin-ical parameters related to insulin resistance,BMI, maximum BMI, waist-to-hip ratio,and insulin resistance measured by thehomeostasis model assessment (HOMA-IR)(7) also showed no significant differences.

These results suggest that the Met416 →Val variant is not likely to be a single-nucleotide polymorphism associated withsusceptibility to type 2 diabetes. More-over, this polymorphism does not affectthe insulin sensitivity assessed by HOMA-IR in the present study, although the pre-vious study showed the associationbetween this variant and decreasedinsulin sensitivity evaluated by the mini-mal model analysis (5).

STUDY GROUP FOR THE IDENTIFICATION

OF TYPE 2 DIABETES GENES IN JAPANESE

The Study Group for the Identification of Type 2Diabetes Genes in Japanese consists of the followingconstituents: Hiroyuki Mori, Hiroshi Ikegami,Susumu Seino, Jun Takeda, Yutaka Seino, ToshiakiHanafusa, Takuya Awata, Takashi Kadowaki,Nobuhiro Yamada, Naoko Iwasaki, Tokio Sanke,Kishio Nanjo, Yoshitomo Oka, Eiichi Maeda, andMasato Kasuga.

Address correspondence to Masato Kasuga, Sec-ond Department of Internal Medicine, Kobe Uni-versity School of Medicine, 7-5-1 Kusunoki-cho,Chuo-ku, Kobe 650-0017, Japan. E-mail: kasuga@med.kobe-u.ac.jp.

Acknowledgments — The Study Group for theIdentification of Type 2 Diabetes Genes in Japaneseis supported by Health Sciences Research Grants(Research on Human Genome and Gene Therapy)from the Ministry of Health and Welfare in Japan.

References1. Shulman GI, Rothman DL, Jue T, Stein P,

DeFronzo RA, Shulman RG: Quantitationof muscle glycogen synthesis in normal

subjects and subjects with non-insulin-dependent diabetes by 13C nuclear mag-netic resonance spectroscopy. N Engl J Med322:223–228, 1990

2. Groop LC, Kankuri M, Schalin-Jantti C,Ekstrand A, Nikula-Ijas P, Widen E, Kuisma-nen E, Eriksson J, Franssila-Kallunki A, Salo-ranta C, Koskimies S: Association betweenpolymorphism of the glycogen synthasegene and non-insulin-dependent diabetesmellitus. N Engl J Med 328:10–14, 1993

3. Orho M, Nikula-Ijas P, Schalin-Jantti C, Per-mutt MA, Groop LC: Isolation and character-ization of the human muscle glycogen syn-thase gene. Diabetes 44:1099–1105, 1995

4. Bjorbaek C, Echwald SM, Hubricht P,Vestergaard H, Hansen T, Zierath J, PedersenO: Genetic variants in promoters and codingregions of the muscle glycogen synthase andthe insulin-responsive GLUT4 genes inNIDDM. Diabetes 43:976–983, 1994

5. Shimomura H, Sanke T, Ueda K,Hanabusa T, Sakagashira S, Nanjo K: Amissense mutation of the muscle glycogensynthase gene (M416V) is associated withinsulin resistance in the Japanese popula-tion. Diabetologia 40:947–952, 1997

6. Rissanen J, Pihlajamaki J, Heikkinen S,Kekalainen P, Mykkanen L, Kuusisto J,Kolle A, Laakso M: New variants in theglycogen synthase gene (Gln71His,Met416Val) in patients with NIDDM fromeastern Finland. Diabetologia 40:1313–1319, 1997

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 concentrationin man. Diabetologia 28:412–419, 1985

Venlafaxine inTreatment of SeverePainful PeripheralDiabetic Neuropathy

Venlafaxine is an antidepressant thatwas recently demonstrated to be aneffective remedy for painful diabetic

neuropathy (1). This report is on a 26-year-old woman who has had type 1 diabetessince the age of 13 years. She was a non-smoker and had no long-term diabetic com-plications. In association with bulimia andhigh blood glucose levels, she developedburning pains and pronounced tendernessin her legs and arms, particularly in the dis-tal part of her left leg. There was also distaledema in both legs, mostly on the left side.

The patient received the followingambulatory treatment at our department ofmedicine: paracetamol and dextropropox-

ifen for 7 months; amitriptylin, klonazepan,gabapentin, and diclofenak for 4 months;and tramadol and buprenorfin for 3months. She then had eight different anal-gesics at the upper level of the recom-mended doses, but they had no effect onher pains. She could only find relief whenshe put her legs in buckets of cold water formost of the night and day; otherwise, shewas bedridden. When she took her legs outof the buckets, the pain returned. After 7months, she developed pronounced ortho-statism and was entirely dependent on herfamily. During the period of severe pain, shedeveloped preproliferative retinopathy andmoderate signs of distal sensory, auto-nomic, and motor neuropathy.

Her pains increased despite taking theeight analgesics, and her health deterio-rated. The only pharmaceutical left to trywas mexiletinhydrochloride (2), but herpronounced orthostatism was a con-traindication. However, I had recentlyread the report on venlafaxine (1); whenher health further deteriorated, there wasno alternative, and a rapid decision wasnecessary. During her first week on ven-lafaxine depot at 75 mg/day (laterincreased to 3 � 75 mg/day), an improve-ment was noticed, including an improve-ment in her visual analogue scale tests.Now, 7 months later, her health is contin-uously better. She still has distal pains, butshe regards them as controllable. Therehave been some setbacks, such as whenshe walked too much and severe pain inthe feet returned for some days, or whenshe had bulimia for a short time. Thenumber of her analgesics could have beencontinuously reduced. However, we notedthat apart from venlafaxine, the only phar-maceutical that was not possible to reducewas gabapentin; the patient experienced areturn of pain both times it was reduced.

In conclusion, we found that, when noother analgesics helped in a diabetic patientwith severe distal painful neuropathy, ven-lafaxine had a good results from the start ofthe treatment and possibly in combinationwith gabapentin. In future studies, thesefactors associated with venlafaxine shouldbe validated.

FOLKE LITHNER, MD, PHD

From the Department of Medicine, Umeå Univer-sity Hospital, Umeå, Sweden.

Address correspondence to Folke Lithner, MD,PhD, Umeå University Hospital, Umeå S-901 85,Sweden. E-mail: folke.lithner@medicin.umu.se.

Letters

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

betic neuropathy treated with venlafaxineHCL extended release capsules. DiabetesCare 22:1909–1910, 1999

2. Oskarsson P, Ljunggren J, Lins P, the Mex-iletine Study Group: Efficacy and safety ofmexiletine in the treatment of painful dia-betic neuropathy. Diabetes Care 20:1594–1597, 1997

Evaluating ClinicalAccuracy of Systemsfor Self-Monitoringof Blood Glucose byError Grid AnalysisComment on constructing the“upper A-line”

Error grid analysis for the evaluation ofsystems for the self-monitoring ofblood glucose (SMBG) was developed

in the late 1980s (1,2) and, since then, hasbeen applied by many scientists (3). Toconstruct an error grid plot for our ownpurposes (Fig. 1), we screened the respec-tive studies and were surprised to find thatthe upper A-line was often incorrectly con-structed (4,5). Whereas the correct upperA-line corresponds to a clinically acceptable�20% deviation of a SMBG from the refer-ence, those authors showed a line that cor-responds to a �25% deviation, resulting inan overoptimistic interpretation of SMBG.

The reason for this error might be thefollowing. Most authors use an error gridplot with an equally scaled x- and y-axisand start its construction by drawing thelower A-line (�20% deviation) using theformula y = 0.8 x. Thus, in Fig. 1, thelower A-line extends from the (x,y) pair(3.9,3.12) to (25,20). Then, one may betempted (because of the y-scale limitation)to construct the upper A-line by simplyreversing the x/y coordinates (4,5), whichwould result in the points (3.12,3.9) and(20,25) (represented by the bold brokenline in Fig. 1). However, this line representsa �25% deviation from the reference. Cor-rectly, one needs to calculate the respectivepoints with the formula x = y/1.2. Thus, inour case, the correct upper A-line extendsfrom (3.25, 3.9) to (20.83, 25) (representedby the full bold line in Fig. 1). A correctconstruction has been demonstrated previ-ously by Brunner et al. (6).

In view of this observation, we inves-tigated whether the original article by

Clarke et al. (1) would contain the sameerror (i.e., an upper A-line that representsa �25% deviation). To this purpose, wegraphically superimposed a self-con-structed analog of the Clarke et al. figurewith the original one and read the highestpoint of the upper A-line from the origi-nal (�[330,410] in original units [mil-ligrams per deciliter]; the correct pointshould be [330,396]). Both indicatedthat the original figure might be erro-neous. However, the quality of the graphin the original articles (1,2) made thereading of the point difficult. Definitiveproof of the erroneous upper A-line(coordinates of the upper point[330,412], which equal y = 1.25 x) wasfound in a more detailed figure publishedlater by the same group (7).

From the above, readers should beaware that error grid plots published inthe past may contain an erroneous upperA-line, and conclusions taken from suchgraphs should be interpreted with caution.

DIETMAR STÖCKL, PHD

KATY DEWITTE, PHARM

COLETTE FIERENS, PHARM

LINDA M. THIENPONT, PHD

From the Laboratorium voor Analytische Chemie,Faculteit Farmaceutische Wetenschappen, Univer-siteit Gent, Harelbekestraat 72, 9000 Gent, Belgium.

Address correspondence to Linda M. Thienpont,PhD, Laboratorium voor Analytische Chemie, Fac-ulteit Farmaceutische Wetenschappen, UniversiteitGent, Harelbekestraat 72, Gent 9000, Belgium.E-mail: linda.thienpont@rug.ac.be.

References1. Clarke WL, Cox D, Gonder-Frederick LA,

Carter W, Pohl SL: Evaluating clinicalaccuracy of systems for self-monitoring ofblood glucose. Diabetes Care 10:622–628,1987

2. Cox DJ, Richards FE, Gonder-FrederickLA, Julian DM, Carter WR, Clarke WL:Clarification of error-grid analysis. DiabetesCare 12:235–236, 1989

3. Cox DJ, Gonder-Frederick LA, KovatchevBP, Julian DM, Clarke WL: Understandingerror grid analysis. Diabetes Care 20:911–912, 1997

4. Trajanoski Z, Brunner GA, Schaupp L,Ellmerer M, Wach P, Pieber TR, Kotanko P,Skrabal F: Open-flow microperfusion ofsubcutaneous adipose tissue for online con-tinuous ex vivo measurement of glucoseconcentration. Diabetes Care 20:1114–1121, 1997

5. Weitgasser R, Gappmayer B, Pichler M:Newer portable glucose meters: analytical

Figure 1—Error grid analysis according to Clarke et al. (1). The original upper A-line is indicated by– – – and the correct upper A-line by ——. Detailed interpretations of the different zones (A–E) havebeen published previously (1–3).

Letters

improvement compared with previousgeneration devices? Clin Chem 45:1821–1825, 1999

6. Brunner GA, Ellmerer M, Sendlhofer G,Wutte A, Trajanoski Z, Schaupp L, Que-henberger F, Wach P, Krejs GJ, Pieber TR:Validation of home blood glucose meterswith respect to clinical and analyticalapproaches. Diabetes Care 21:585–590,1998

7. Gonder-Frederick LA, Snyder AL, ClarkeWL: Accuracy of blood glucose estimationby children with IDDM and their parents.Diabetes Care 14:565–570, 1991

Moderate-IntensityPhysical Activity andFasting Insulin Levels in Women

From a cross-sectional study, Irwin etal. (1) concluded that increasingmoderate-intensity physical activity

(PA) reduced fasting insulin levelsamong 142 African-American, NativeAmerican, and Caucasian women aged40–83 years. While interesting, thisstudy contains a perplexing statementand a paradoxical result.

The authors’ perplexing statement is“to encourage increased participation inmoderate-intensity PA, it is necessary tointervene on activities in which womenreport participating” (1). The authors didnot detail the singular contributions ofreported household, occupational, andparenting activities to the measures ofMET-min (the product of the minutes foreach activity times the MET intensity level)of both moderate and moderate/vigorousPA. (MET intensity is defined as the associ-ated metabolic rate for a specific activitydivided by a standard resting metabolicrate.) In a previous article, the authorsreported such contributions to moderateactivity for only African-American andNative American women (2). Unlike thecurrent study, those minority womenreported for three, rather than for two, 4-day periods. The authors also did notshow that each individual type of activityis significantly associated with fastinginsulin after adjusting for other activities.

The authors’ current study may lacksufficient statistical power to show suchassociations. After statistical adjustment,only the aggregate measure of moderate/vigorous PA was significantly associatedwith decreased fasting insulin for the fol-

lowing strata: ethnicity (except forAfrican-Americans), low cardiorespira-tory fitness, and central obesity (Table 5).For moderate PA alone, only low fitnessand central obesity were significantlyassociated with decreased fasting insulin.Stratifying the data further would proba-bly not support the implied activity-spe-cific associations.

Aside from problems of statisticalpower, the authors’ task would be diffi-cult because efforts to find significantassociations between household, occu-pational, and child care activities andcardiovascular risk factors have failed(3,4). Without knowing the individualcontribution of such activities to healthoutcomes, monitoring their occurrencein national surveillance systems is unjus-tifiable (5).

The MET-min measure the authorsuse implies that women who do more PAshould have better weight control. Para-doxically, this measure does not corre-spond well to the BMI values reported intheir study. Native American womenreported 15% more moderate activity(median 528 MET-min/day) than Cau-casian women (median 461 MET-min/day), but had a 13% greater meanBMI (28.6 vs. 25.2 kg/m2); Native Ameri-can women also reported 84% more mod-erate activity than African-Americanwomen (median 287 MET-min/day), butwere only 8% lighter than African-Ameri-can women (BMI 31.1 kg/m2).

Furthermore, the overlapping inter-quartile ranges of group MET-min/day(Table 2) indicate that group differences inactivity were negligible; yet, the authorsstate that “comparison of the PA levels byrace/ethnicity showed lower energy expen-ditures among African-Americans thanamong the other races/ethnicities” (1).More likely, the authors’ admittedly unrep-resentative samples (1) belie the cross-cul-tural scope of the study mentioned in thearticle’s title.

Even if household, occupational, andparenting activities were shown to havepotent biologic health benefits and wereworth monitoring, intervening on suchactivities may be problematic. Minoritywomen report as stressful the very activi-ties that distinguish the authors’ assess-ment method from those questionnairesemphasizing more enjoyable “traditionalsports and recreational activities” (6). Ifinstead the authors prefer to focus on thebenefits of brisk walking in preventing dia-

betes (1), as they note others have done inprospective studies (7,8), then they shouldaccordingly conduct specific analyses.

CARL J. CASPERSEN, PHD, MPH

MATTHEW M. ZACK, MD

JANET E. FULTON, PHD

From the Division of Diabetes Translation (C.J.C.),the Division of Adult and Community Health(M.M.Z.), and the Division of Nutrition and Physi-cal Activity (J.E.F.), the Centers for Disease Controland Prevention, Atlanta, Georgia.

Address correspondence to Carl J. Caspersen,PhD, MPH, Division of Diabetes Translation,National Center for Chronic Disease Prevention andHealth Promotion, Centers for Disease Control andPrevention, K-10, 4770 Buford Highway NE,Atlanta, GA 30341-3724. E-mail: cjc1@cdc.gov.

References1. Irwin M, Mayer-Davis E, Addy C, Pate R,

Durstine J, Stolarczyk L, Ainsworth B:Moderate-intensity physical activity andfasting insulin levels in women: the Cross-Cultural Activity Participation Study. Dia-betes Care 23:449–454, 2000

2. Ainsworth B, Irwin M, Addy C, Whitt M,Hootman J, Stolarczyk L: Moderate physi-cal activity patterns among minoritywomen: the Cross-Cultural Activity Partic-ipation Study. J Womens Health 8:805–813,1999

3. Sternfield B, Sidney S, Jacobs D,Ainsworth B: Household physical activityand cardiovascular risk factors in blackand white women: the CARDIA Study(Abstract). Med Sci Sports Exerc 28:S145,1995

4. Ainsworth B, Sternfield B, Benfield J,Criscoe S: Evaluation of the Health Physi-cal Activity Survey (Abstract). Med SciSports Exerc 28:S34, 1996

5. Caspersen C, Zack M: The prevalence ofphysical inactivity in the United States. InPhysical Activity and Cardiovascular Health:A National Consensus. Leon AS, Ed. Cham-paign, IL, Human Kinetics, 1997, p.32–39

6. Eyler A, Baker E, Cromer L, King A,Brownson R, Donatelle R: Physical activ-ity and minority women: a qualitativestudy. Health Educ Behavior 25:640–652,1998

7. Manson J, Rimm E, Stampfer J, ColditzG, Willett W, Kroleweski A, Rosner B,Hennekens L, Speizer F: Physical activityand incidence of non-insulin-dependentdiabetes mellitus. Lancet 338:774–778,1991

8. Hu F, Sigal R, Rich-Edwards J, Colditz G,Solomon C, Willett W, Speizer F, MansonJ: Walking compared with vigorousphysical activity and risk of type 2 dia-betes in women. JAMA 282:1433–1439,1999

Letters

Moderate-IntensityPhysical Activity andFasting Insulin Levels in Women

Response to Caspersen et al.

We appreciate Caspersen et al.’s (1)interest in our article (2), and wevalue their perspective. We feel,

however, that they took what was meant ascommentary for potential applicationsand/or future directions and discussed it ina manner, relative to our analyses, that wewould not have anticipated. By doing so,we feel that they overlooked the main find-ing of our work: namely, that evidence wasprovided for an association between moder-ate-intensity physical activity (PA) and fast-ing insulin levels.

Specifically, we found that an increaseof 30 min of moderate-intensity PA perday was associated with a 5.2% lower fast-ing insulin level after adjusting for ethnic-ity, age, educational attainment, centralobesity, BMI, fitness, fasting glucose levels,and site (P � 0.05). We then concludedthat moderate-intensity PA is beneficialand that future research should focus ontrying to elucidate ways to increase partic-ipation in moderate-intensity activities.Our suggestion was “to intervene on activ-ities in which women report participating”(1). This was meant as a commonsensicalapproach of intervening on activities inwhich women already participate, whichmight be more effective than introducingunfamiliar activities in hopes of long-termadoption of these new activities (3).

Furthermore, although we did not lookat the singular contributions of specific activ-ities, the majority of moderate-intensityactivities reported by the participants in ourstudy were household, gardening, child care,walking, and occupational activities. Of theactivities recorded by participants in theirPhysical Activity Records, �1% were sportsand conditioning activities. Other studieshave confirmed our finding that householdactivities, gardening, and walking arereported as common activities amongwomen and are significantly associated withreduced chronic disease morbidity (4,5).

It is true that “the sample size wassmall and may not be representative of theparticipants’ respective ethnic groups (1).”The small sample size did not allow us tohave enough power to observe significant

associations between PA and insulin bysubgroups (ethnicity, fitness, and centralobesity). However, the differences in fast-ing insulin levels observed by subgroupwas of sufficient interest to reviewers towarrant a table in the letter.

Lastly, our PA MET-min measure (theproduct of the minutes for each activitytimes the MET intensity level, with METintensity defined as the associated meta-bolic rate for a specific activity divided bya standard resting metabolic rate) wasused to examine differences in insulin lev-els for the sample as a whole and by sub-groups of ethnicity, fitness, and obesity.We were not examining the associationbetween PA and BMI by certain sub-groups. However, we recognize the meritof their comment that the inclusion ofindividuals who may not have representedthe activity habits of the underlying popu-lation most likely resulted in the inconsis-tent findings of higher BMIs among eth-nicities with higher PA and lower BMIsamong ethnicities with lower PA. It isextremely important to note that, althoughthe lack of external generalizability withregard to activity patterns likely exists, thiswould not inherently lead to compromisesin the internal validity of the study. Thebiologic effect of activity on insulin levelswould not be expected to differ betweenindividuals included in and thoseexcluded from the study population.

In conclusion, our study found asignificant association between moderate-intensity PA, at levels recommended by theCenters for Disease Control and AmericanCollege of Sports Medicine, and fastinginsulin levels. Future studies with largersample sizes from diverse populations needto examine the association between types ofspecific moderate-intensity activities (suchas household activities, gardening, andwalking) and chronic disease morbidityand mortality outcomes. Such analyses mayalso need to consider whether energyexpended was in aerobic or isometric activ-ities, because the reason for the expenditureof energy (work or play) would not itselfmake a difference in biologic effects. How-ever, the type of activity could be critical interms of identifying activities in which par-ticipants could be successfully encouragedto increase overall PA.

MELINDA L. IRWIN, PHD

ELIZABETH J. MAYER-DAVIS, PHD

CHERYL L. ADDY, PHD

RUSSELL R. PATE, PHD

J. LARRY DURSTINE, PHD

LISA M. STOLARCZYK, PHD

BARBARA E. AINSWORTH, PHD, MPH

From the Fred Hutchinson Cancer Research Center(M.L.I.), Seattle, Washington; the Departments ofEpidemiology and Biostatistics (E.J.M.-D., C.L.A.,B.E.A.) and Exercise Science (R.R.P., J.L.D.), Schoolof Public Health, University of South Carolina,Columbia, South Carolina; and the Center for Exer-cise and Applied Human Physiology (L.M.S.,B.E.A.), University of New Mexico, Albuquerque,New Mexico.

Address correspondence to Melinda L. Irwin,PhD, Fred Hutchinson Cancer Research Center,1100 Fairview Ave. North, MP-900, Seattle, WA98109-1024. E-mail: mirwin@fhcrc.org.

References1. Caspersen CJ, Zack MM, Fulton JE: Mod-

erate-intensity physical activity and fastinginsulin levels in women (Letter). DiabetesCare 23:1712, 2000

2. Irwin M, Mayer-Davis E, Addy C, Pate R,Durstine J, Stolarczyk L, Ainsworth B:Moderate-intensity physical activity andfasting insulin levels in women: the Cross-Cultural Activity Participation Study. Dia-betes Care 23:449–454, 2000

3. Dunn A, Marcus B, Kampert J, Garcia M,Kohl H, Blair S: Comparison of lifestyleand structured interventions to increasephysical activity and cardiorespiratory fit-ness. JAMA 281:327–334, 1999

4. Weller I, Corey P: The impact of excludingnon-leisure energy expenditure on therelationship of physical activity and mor-tality in women. Epidemiology 9:632–635,1998

5. Hu F, Sigal R, Rich-Edwards J, Colditz G,Solomon C, Willett W, Speizer F, MansonJ: Walking compared with vigorous physi-cal activity and risk of type 2 diabetes inwomen. JAMA 282:1433–1439, 1999

Are Tumor NecrosisFactor-� Receptor 2Levels AssociatedWith Age?

We read with great interest the arti-cle by Fernandez-Real et al. (1).They concluded in their study

that tumor necrosis factor-� receptor 2(TNFR2) levels positively correlate withage (1). However, a potential bias mayhave been introduced by the unequaldistribution of type 2 diabetes preva-lence and BMI ranges in the differentage-groups. As shown in Tables 2 and 3in the article, patients with diabetes weresignificantly older than healthy controlsubjects, and the older subjects had a

Letters

higher mean BMI. Numerous data sup-port the relationship between bothtumor necrosis factor-� (TNF-�) (2–4)and TNFR2 (5,6) and obesity-relatedinsulin resistance. Therefore, one wouldexpect to find elevated TNF-� andTNFR2 levels in type 2 diabetic patients,especially if such patients are of an olderage-group. Thus, a multivariate analysisthat would take into account BMI, age,insulin resistance status, and the pres-ence of the TNFR2 A2 allele should beconducted. The results of such an analy-sis would be of special interest to us,because we could not detect an associa-tion between age and TNF-� levels innondiabetic obese children (2).

WAEL TAHA, MD

IDO PAZ-PRIEL, MD

HENRY ANHALT, DO

From the Division of Pediatric Endocrinology,Department of Pediatrics, Maimonides Medical Cen-ter, Brooklyn, New York.

Address correspondence to Henry Anhalt, DO,977 48th St., Brooklyn, NY 11219.

References1. Fernandez-Real JM, Vendrell J, Ricart W,

Broch M, Gutierrez C, Casamitjana R, Ori-ola J, Richart C: Polymorphism of thetumor necrosis factor-� receptor 2 gene isassociated with obesity, leptin levels, andinsulin resistance in young subjects anddiet-treated type 2 diabetic patients. Dia-betes Care 23:831–837, 2000

2. Paz-Priel I, Khan N, Taha W, Lashiker L,Chin D, Anhalt H: The relationshipbetween serum tumor necrosis factoralpha levels and anthropometric measure-ment in morbidly obese children. PediatrRes 47:135A, 2000

3. Hotamisligil GS, Shargill NS, SpiegelmanBM: Adipose expression of tumor necrosisfactor alpha: direct role in obesity-linkedinsulin resistance. Science 259:87–91,1993

4. Uysal KT, Weisbrock, Marino MW, Hotamis-ligil GS: Protection from obesity-inducedinsulin resistance in mice lacking TNF alphafunction. Nature 389:610–614, 1997

5. Fernandez-Real JM, Molina A, Broch M,Ricart W, Gutierrez C, Casamitjana R, Ven-drell J, Soler J, Gómez-Sáez JM: Tumornecrosis factor system activity is associatedwith insulin resistance and dyslipidemia inmyotonic dystrophy. Diabetes 48:1108–1112, 1999

6. Hotamisligil GS, Arner P, Atkinson RL,Spiegelman BM: Differential regulation ofthe p80 tumor necrosis factor receptor inhuman obesity and insulin resistance. Dia-betes 46:451–455, 1997

Plasma TumorNecrosis Factor-�Receptor 2 LevelsAre Associated WithAge

Response to Taha, Paz-Priel, andAnhalt

Taha, Paz-Priel, and Anhalt wonderwhether the relationship betweenplasma levels of the soluble fraction

of tumor necrosis factor-� receptor 2(sTNFR2) and age was merely due to anunequal distribution of the subjectsamong groups. In our previous article (1),we reported that 50% of the subjects werecontrol subjects and 50% were type 2 dia-betic subjects. The relationship betweensTNFR2 and age was similar in bothgroups and remained so after excludingthe diabetic patients. To clarify such a rela-tionship, we have further evaluated 261control subjects with BMIs �40 kg/m2,

normal glucose levels, no medication, andno acute illness in the previous month. Inthese subjects, sTNFR2 significantly corre-lated with age (r = 0.27, P � 0.0001) (Fig.1), and this relationship was even strongerin women (107 subjects, r = 0.34, P �0.0001). A similar correlation coefficientbetween sTNFR2 levels and age has beendescribed in a recent article (2).

The results reported in the abstract byTaha, Paz-Priel, and Anhalt (3) are in sharpcontrast with the findings of Paolisso et al.(4), who found a correlation betweenplasma TNF-� and age (r = 0.64, P �0.001) that was independent of sex andbody fat. These differences may be attrib-uted to the pediatric age of the patients eval-uated and to the inclusion of morbidlyobese children in Taha, Paz-Priel, andAnhalt’s study. In fact, adipose tissue expres-sion of TNF-� is paradoxically decreased inadult subjects with morbid obesity (5).

JOSÉ-MANUEL FERNÁNDEZ-REAL, MD, PHD

JOAN VENDRELL, MD, PHD

WIFREDO RICART, MD

Figure 1—Correlation between plasma sTNFR2 levels and age. r = 0.27; P � 0.0001.

Letters

From the Unitat de Diabetes ( J.-M.F.-R., W.R.),Endocrinologia i Nutrició, University Hospital ofGirona, Dr. Josep Trueta; and the Unitat deEndocrinologia ( J.V.), Department de Medicina,University Hospital of Tarragona Joan XXIII, Uni-versitat Rovira i Virgili, Girona, Spain.

Address correspondence to José-Manuel Fernán-dez-Real, MD, PhD, Department of Endocrinology,Hospital de Girona, Ctra. França s/n, 17007 Girona,Spain. E-mail: endocrino@htrueta.scs.es.

References1. Fernández-Real JM, Vendrell J, Ricart W,

Broch M, Gutiérrez C, Casamitjana R, Ori-ola J, Richart C: Polymorphism of thetumor necrosis factor-� receptor 2 gene isassociated with obesity, leptin levels, andinsulin resistance in young subjects anddiet-treated type 2 diabetic patients. Dia-betes Care 23:831–837, 2000

2. Glenn CL, Wang WYS, Benjafield AV, Mor-ris BJ: Linkage and association of tumornecrosis factor receptor 2 locus withhypertension, hypercholesterolemia andplasma shed receptor. Hum Mol Genet 9:1943–1949, 2000

3. Paz-Priel I, Khan N, Taha W, Lashiker L,Chin D, Anhalt H: The relationshipbetween serum tumor necrosis factoralpha levels and anthropometric measure-ment in morbidly obese children. PediatrRes 47:135A, 2000

4. Paolisso G, Rizzo MR, Mazziotti G, Taglia-monte MR, Gambardella A, Rotondi M,Carella C, Giugliano D, Varicchio M,D’Onofrio F: Advancing age and insulinresistance: role of plasma tumor necrosisfactor-�. Am J Physiol 275 (Suppl. 2):E294–E299, 1998

5. Kern PA, Saghizadeh M, Ong JM, BoschRJ, Deem R, Simsolo RB: The expression oftumor necrosis factor in human adiposetissue: regulation by obesity, weight loss,and relationship to lipoprotein lipase. JClin Invest 95:2111–2119, 1995

Hypoglycemia,Seizures, and Pulmonary Edema

Ortega et al. (1) are to be congratu-lated for resuscitating the well-described but easily forgotten associ-

ation between severe hypoglycemia andnoncardiac pulmonary edema.

I suggest that the common denomi-nator in most of these cases is a grandmal seizure, which is a well-known com-plication of hypoglycemia. In 1975, we(2) described two patients with recurrentpostictal noncardiac pulmonary edema andfound 24 additional reported cases. Wenoted that these episodes could be unilat-

eral, recurrent, associated with fever andleucocytosis, and, especially when seen inisolation, typically mistaken for pneumoniaand aspiration. Prompted by Ortega et al.’s(1) observations, I quickly perused severalof their references. In the study by Nielsenet al. (3), one patient had initial unilateralpulmonary edema that later became bilat-eral, and another had what was describedas “violent torsion spasms” before the devel-opment of acute respiratory distress syn-drome (ARDS). Arem and Zoghebi (4)reported on two patients who developedpulmonary edema, both of whom weredescribed as having seizures before devel-oping ARDS. Baruh and Sherman’s (5)patient also had left-sided seizures beforedeveloping pulmonary edema.

In reviewing deaths caused by therapyin psychiatric patients, Maclay (6) does notcomment on seizures in patients treated forinsulin coma, although this complicationhas been described. In his listing of causesof death, Maclay (6) includes sevenpatients with pulmonary edema and onewith bronchopneumonia. Under the cate-gory of causes of death related to electro-convulsive therapy, he included three withpulmonary edema and four with pneumo-nia. Finally, Ortega et al.’s patient had agrand mal seizure before developing pul-monary edema.

I therefore suggest that, at least in themajority of patients with hypoglycemia-associated ARDS, the common pathway topulmonary edema is having one or moreseizures. This hypothesis strongly supportsthe possibility that a neurogenic mecha-nism is the major culprit in the develop-ment of hypoglycemia-associated ARDS.

ROBERT MATZ, MD

From the Mount Sinai School of Medicine, NewYork, New York.

Address correspondence to Robert Matz, MD, 32Buena Vista Dr., Hastings on Hudson, NY 10706-1104. E-mail: robertmatz@mountsinai.org.

References1. Ortega E, Wagner A, Caixas A, Barcons M,

Corcoy R: Hypoglycemia and pulmonaryedema: a forgotten association. DiabetesCare 23:1023–1024, 2000

2. Greene R, Platt R, Matz R: Postictal pul-monary edema. NYS J Med 75:1257–1261,1975

3. Nielsen JM, Ingham SD, Von Hagen DO:Pulmonary edema and embolism as com-plication of insulin shock in treatment ofschizophrenia. JAMA 3:2455–2458, 1938

4. Arem R, Zoghibi W: Insulin overdose ineight patients: insulin pharmacokineticsand review of the literature. Medicine 64:323–332, 1985

5. Baruh S, Sherman L: Hypoglycemia, acause of pulmonary edema: progressivefatal pulmonary edema complicating hypo-glycemia induced by alcohol and insulin. JNatl Med Assoc 67:200–204, 1975

6. Maclay WS: Death due to treatment. ProcRoy Soc Med 46:13–20, 1953

Can All Newly Diagnosed SubjectsWithout Type 1 Diabetes–AssociatedAutoimmune MarkersBe Classified as Type 1b DiabeticPatients?

Comparison among recent studiesshows variability in clinical and bio-logic features at the onset of type 1

diabetes among different ethnic popula-tions of origin (1–3).

We are reporting data from a cohort ofnewly diagnosed type 1 diabetic subjectswith a follow-up period of up to 1 year atour institution. We investigated the pres-ence of cytoplasmic islet cell antibodies(ICAs) and GAD65 antibodies (GADAs)and their relation to other clinical and bio-logic parameters in 68 type 1 diabetic sub-jects consecutively seen at diagnosis. Thestudy included 44 men and 24 women(mean age 22.5 ± 9.3 years). Antibodieswere determined as previously described(4). ICAs and GADAs were positive in 87and 66% of subjects at diagnosis, respec-tively. Only four patients (6%) were nega-tive for both antibodies. Antibody-nega-tive subjects did not differ from those pos-itive for one or two antibodies in terms ofclinical characteristics (i.e., age, BMI,hyperglycemic symptoms’ duration,insulin requirements, HbA1c, glycemia,proportion of ketoacidosis, and C-peptidelevels) at diagnosis and during the follow-up. Only GADA� patients, as comparedwith GADA� patients showed lowerinsulin requirements (units per kilogramper day) during follow-up: 3 months(0.24 ± 0.19 vs. 0.45 ± 0.23), 6 months(0.27 ± 0.2 vs. 0.46 ± 0.23), and 12months (0.37 ± 0.22 vs. 0.55 ± 0.2) afterdiagnosis (P � 0.01 for all comparisons).

Letters

We could not find any other differencesafter stratification of ICA or combinedICA/GADA status. Further analysisrevealed that the subgroup of patients withHbA1c value above the mean for the wholegroup (i.e., 10.7%) and with longer dura-tion of symptoms (�2 weeks) showedhigher insulin requirements and lower C-peptide levels at follow-up with no influ-ence of antibody status. The latter data areclearly discordant with recent findings in aJapanese study (3). Thus, no major differ-ences are found between antibody-posi-tive and antibody-negative subjects atonset in our cohort.

Our results are clearly concordant withrecent studies in which the proportion ofantibody-negative subjects at onset of type 1diabetes in Caucasian populations is verylow (3.5–7%) (1,2). This is at variance withrecent data in Japanese type 1 diabeticpatients for whom a novel subtype of fulmi-nant nonautoimmune diabetes is claimed toexist (3). This novel subtype of diabetesdoes not seem to exist in the Caucasian pop-ulation. Further, patients with type 1b dia-betes, as described in the American DiabetesAssociation classification (5), are hardlyidentified in European populations of Cau-casian origin. There seems to be no majordifferences in type 1 diabetic subjects atonset when autoimmune markers are taken

into account (1–3,6). Moreover, as recentlydemonstrated, markers of autoimmunitymay not be present at onset but may appearlater at follow-up or even may have beenpresent in the prediabetic period (2). Onthese grounds, the absence of humoralautoimmune markers at onset of type 1 dia-betes in Caucasian populations does notnecessarily preclude the existence of an on-going autoimmune process directed against-cells. This group of patients may not beclassified as type 1b diabetic subjects, assuggested by other investigators (2).

GEMMA CARRERAS, PHD

DIDAC MAURICIO, MD

ANTONIO PÉREZ, MD

ALBERTO DE LEIVA, MD

From the Department of Endocrinology (D.M., A.P.,A.d.L.) and the Department of Pediatrics (G.C.),Hospital Sant Pau, Autonomous University ofBarcelona, Barcelona, Spain.

Address correspondence to Gemma CarrerasGonzález, PhD, Department of Pediatrics, HospitalSant Pau, Autonomous University of Barcelona,Sant Antoni Mª Claret 167, 08025 Barcelona, Spain.E-mail: gcarreras@hsp.santpau.es.

References1. Decochez K, Tits J, Coolens JL, Van Gaal L,

Krzentowski G, Winnock F, Anckaert E,Weets E, Pipeleers DG, Gorus FK, the Bel-

gian Diabetes Registry: High frequency ofpersisting or increasing islet-specificautoantibody levels after diagnosis of type1 diabetes presenting before 40 years ofage. Diabetes Care 23:838–844, 2000

2. Tiberti C, Buzzetti R, Anastasi E, Dotta F,Vasta M, Petrone A, Cervoni M, Torresi P,Vecci E, Multari G, Di Mario U: Autoanti-body negative new onset type 1 diabeticpatients lacking high risk HLA alleles in aCaucasian population: are these type 1bdiabetes cases? Diabetes Metab Res Rev 16:8–14, 2000

3. Imagawa A, Hanafusa T, Miyagawa J, Mat-suzawa Y: A novel subtype of type 1 dia-betes mellitus characterized by rapid onsetand absence of diabetes-related antibodies.N Engl J Med 342:301–307, 2000

4. Mauricio D, Carreras G, Pérez A, Morales J,Puig-Domingo M, de Leiva A: Associationof islet-cell and glutamic-acid decarboxy-lase antibodies to -cell function after theonset of type 1 diabetes in adult subjects.Diabetes Nutr Metab 10:189–192, 1997

5. 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

6. Pozzilli P, Visalli N, Buzzetti R, Cavallo G,Marietti G, Hawa M, Leslie RDG, theIMDIAB Study Group: Metabolic andimmune parameters at clinical onset ofinsulin-dependent diabetes: a population-based study. Metabolism 47:1205–1210,1998

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