ENDOCRINE PRACTICE Vol 21 No. 1 January 2015 1

Original Article

NORMOCALCEMIC HYPERPARATHYROIDISM AND INSULIN RESISTANCE

Sule Temizkan, MD1; Omer Kocak, MD2; Kadriye Aydin, MD1; Aysenur Ozderya, MD1; Gulgun Arslan, MD3; Nihal Yucel, MD4; Mehmet Sargin, MD2

Submitted for publication April 30, 2014Accepted for publication July 7, 2014From the Departments of 1Endocrinology and Metabolic Diseases, 2Family and Community Medicine, 3Internal Medicine, and 4Biochemistry, Kartal Dr. Lutfi Kirdar Training and Research Hospital, Istanbul, Turkey.Address correspondence to Dr. Sule Temizkan; Department of Endocrinology and Metabolic Diseases, Kartal Dr. Lutfi Kirdar Training and Research Hospital; 34890, Istanbul, Turkey.E-mail: suletemizkan@yahoo.comPublished as a Rapid Electronic Article in Press at http://www.endocrinepractice.org on August 6, 2014. DOI:10.4158/EP14195.ORTo purchase reprints of this article, please visit: www.aace.com/reprints.Copyright © 2015 AACE.

ABSTRACT

Objective: To determine whether insulin resistance (IR) accompanies normocalcemic primary hyperparathy-roidism (NCPHP). Methods: Twenty-five patients with NCPHP and 25 age-, sex-, and body mass index (BMI)-matched controls were included the study. Patients were diagnosed NCPHP if their serum calcium (Ca) concentrations and ionized serum Ca levels were in the normal range but parathyroid hormone (PTH) levels were inappropriately and persistently high. Subjects with 25-hydroxyvitamin D (25[OH]D) levels ≥20 ng/dL were included in the study. The upper limit of PTH was calculated using a nomogram for each subject. Patients and controls underwent a standard 75-gram oral glucose tolerance test (OGTT). IR was assessed by the homeosta-sis model assessment (HOMA-IR) and insulin sensitivity index (ISOGTT). Results: There were no differences between the demo-graphic features of patients with NCPHP and the control group. IR frequency was not different between groups (P = .14). HOMA-IR was higher and ISOGTT was lower in patients with NCPHP than the control group, but the differ-ences were not significant (P = .17 and P = .22, respec-tively). We did not find any correlation between PTH and

glucose metabolism markers (HOMA-IR, ISOGTT, glycated hemoglobin [HbA1c], and BMI) in either of the groups. Conclusion: The results of this study indicate that IR is not more common in patients with NCPHP, and PTH is not related to ISOGTT or HOMA-IR. (Endocr Pract. 2015;21:000-000)

Abbreviations:ALP = alkaline phosphatase; AUC = area under the curve; BMI = body mass index; Ca = calcium; CRP = C-reactive protein; HbA1c = glycated hemoglobin; HOMA-IR = homeostasis model assessment of insu-lin resistance; IR = insulin resistance; ISOGTT = insulin sensitivity index; NCPHP = normocalcemic primary hyperparathyroidism; OGTT = oral glucose tolerance test; 25(OH)D = 25-hydroxyvitamin D; PTH = para-thyroid hormone

INTRODUCTION

Normocalcemic hyperparathyroidism (NCPHP) is a relatively new clinical presentation of primary hyperpara-thyroidism that has been described in the past decade. It is characterized by normal total and ionized serum calcium (Ca) levels and persistently elevated parathyroid hormone (PTH) levels in the absence of secondary causes (1). The clinical importance of this early form of hyperparathyroid-ism is up for debate, and the entity remains incompletely described, particularly regarding its epidemiology, natu-ral history, and management. It is hypothesized that these patients may represent an early form of symptomatic rather than asymptomatic primary hyperparathyroidism (2). Now, as PTH measurement is more available, many patients with primary hyperparathyroidism are detected in this early stage. It is known that hyperparathyroidism is associated with an increased risk of cardiovascular morbidity and mortality. Many metabolic disturbances accompany the classic hypercalcemic form of hyperparathyroidism (3-5), including alterations in glucose metabolism (6-11). The

2 Parathyroid Hormone and Insulin Resistance, Endocr Pract. 2015;21(No. 1)

prevalence of diabetes mellitus in primary hyperparathy-roidism is 3-fold higher than the expected prevalence in general population (12). Obesity, vitamin D deficiency and biochemical abnormalities like hypercalcemia and hypophosphatemia associated with primary hyperparathy-roidism may affect glucose metabolism in these patients (3,13,14). In this study, we aimed to determine whether glucose metabolism abnormalities accompany this subclinical form of the disease and assess a possible association between PTH and insulin resistance in the absence of hypercalce-mia and vitamin D3 deficiency.

METHODS

Subjects The study was conducted at the Endocrinology Outpatient Clinic in Kartal Dr. Lutfi Kirdar Training and Research Hospital between April 1, 2013 and December 31, 2013. Thirty patients were referred to the endocrinol-ogy clinic from other clinics with high PTH and normal serum Ca levels. Patients were evaluated and diagnosed with NCPHP if serum Ca concentrations and ionized serum Ca levels were in the normal range (1.12-1.32 mg/dL) but PTH levels were inappropriately and persistently high in the absence of secondary causes such as renal disease, vita-min D deficiency, hypercalciuria, medications and malab-sorption (15). Serum Ca and PTH were investigated on 2 occasions to rule out false values. Serum albumin levels were in the normal range in all participants. The upper limit of PTH was calculated using a nomo-gram (calculated maximum PTH = 120 - [6 × Ca (mg/dL)] - [½ × (25[OH]D) (ng/mL)] - [¼ × age]) to diagnose true NCPHP patients (16,17). By using this formula, we elimi-nated 5 patients with measured PTH less than the upper limit of normal PTH. The remaining 25 patients were included in the study. In all patients, the following secondary causes of hyperparathyroidism were excluded: (1) vitamin D3 defi-ciency (25[OH]D < 20 ng/mL) (17), (2) hypercalciuria (>400 mg/day), (3) decreased creatinine clearance (<60 mL/minute), (4) medications (lithium, phenytoin, thia-zide, and loop diuretics), and (5) gastrointestinal disorders (gastrointestinal symptoms or a history of malabsorption syndromes like gluten enteropathy or gastrointestinal surgery, and low urinary calcium [<50 mg/day]). Patients were not using any medication containing vitamin D3 or calcium. Patients’ daily calcium intake was not recorded. Twenty-five age-, sex-, weight-, body mass index (BMI)-, and vitamin D status-matched healthy controls were also included in the study. Healthy controls were recruited from Kartal Lutfi Kirdar Training and Research Hospital Family Medicine Policlinics. In the control group, the measured PTH values were less than the upper limit of

the normal range value (68 pg/mL), and measured PTH was less than the calculated maximum PTH, and 25-hydroxyvi-tamin D (25[OH]D) levels were ≥20 ng/dL. Subjects (both NCHPH patients and controls) with conditions that might affect glucose metabolism (e.g., chronic renal and hepatic failure, cancer, cardiovascular disease, malabsorption, abnormal thyroid function tests, thiazide, psychotropic drugs, glucocorticoids, oral contra-ceptives, antihyperlipidemics, and oral/parenteral antidia-betics), and a history of diabetes mellitus, were not includ-ed in the study. The study protocol was approved by the local ethi-cal committee and was performed in accordance with the Declaration of Helsinki. All subjects provided oral and written informed consent prior to the examination.

Methods All participants underwent a comprehensive medical evaluation including clinical history taking and a physi-cal examination. Blood pressure was measured in the right arm twice using an automated sphygmomanometer after 5 minutes resting. Weight (kg), height (m), and waist circumference (cm) were measured. BMI was calculated as weight divided by height squared. Study subjects underwent a standard 75-gram oral glucose tolerance test (OGTT) after an overnight fast. Blood samples were taken at 0, 30, 60, 90, and 120 minutes for the assessment of blood glucose and insulin concentra-tions. Insulin resistance (IR) was calculated by the homeo-stasis model assessment (HOMA-IR) and insulin sensitiv-ity index (ISOGTT) using the following formulas: HOMA-IR = (fasting plasma insulin [mIU/mL] × fasting plasma glucose [mg/dL])/405 and ISOGTT = (10,000/square root of [fasting glucose × fasting insulin] × [mean glucose × mean insulin during OGTT]) (19,20). Impaired fasting glucose and glucose tolerance were defined according to the current American Diabetes Association guidelines. Impaired fasting glucose was defined as a serum glucose level 100 to 125 mg/dL, and impaired glucose tolerance was defined as 2-hour glucose response to oral glucose loading between 140 and 199 mg/dL (21). HOMA-IR ≤2.5 was accepted as in the normal range for insulin resistance (22).

Laboratory Analyses PTH, 25(OH)D, Ca, phosphorous (P), creatinine, alkaline phosphatase (ALP), uric acid, lipids, thyroid-stimulating hormone, and C-reactive protein (CRP) were evaluated in all subjects. Serum ionized Ca and 24-hour urinary Ca and creatinine clearance were studied to verify diagnosis only in patients with NCPHP. Blood samples were taken early in the morning (8:00 to 10:00 AM), after an overnight fast. Plasma intact PTH levels were measured by the immunoassay method (Abbott Diagnostics, Abbott Park, IL). The upper limit of normal PTH level was 68 pg/

Parathyroid Hormone and Insulin Resistance, Endocr Pract. 2015;21(No. 1) 3

mL. Serum insulin levels were measured with the same technique and equipment. 25(OH)D levels were measured by chromatograph using high-performance liquid chroma-tography (HPLC; Shimadzu Corporation, Kyoto, Japan). Serum total Ca, P, ALP, uric acid, 24-hour urinary Ca, and lipids were measured by calorimetric methods (Beckman Coulter, Brea, CA). Serum ionized Ca levels were measured in venous blood gas examination (Rapidlab, Siemens Healthcare Diagnostics Inc, Malvern, PA). HbA1c was also measured using HPLC (Bio-Rad, Hercules, CA). Plasma venous glucose was measured using the hexoki-nase method.

Statistical Analysis Data are presented as means ± SD for continuous vari-ables or median (25 and 75% interquartiles) for nonnor-mally distributed variables. Tests of significance used were independent sample t tests for normally distributed variables and Wilcoxon signed-rank test for nonnormally distributed variables, and c2 test for categorical variables. Areas under the curve (AUCs) for glucose and insulin during OGTT were calculated by the trapezoidal method. Correlation analysis was performed using the Spearman’s rank test. P<.05 was considered statistically significant. A posthoc power analysis was performed to detect a difference in HOMA-IR between patients and controls. On the basis of these sample data, to keep the power of the study at 80% with an a level of 0.05, a sample size of 196 patients in each group and a total of 392 participants were needed.

RESULTS

The demographic and clinical and laboratory char-acteristics of the 25 NCPHP and 25 control subjects are shown in Tables 1 and 2. There were no differences in demographic features between the 2 groups. All the patients were female. Patients with NCPHP were overweight/obese (mean BMI 30.3 ± 4.9 kg/m2). Nephrolithiasis was more common in patients with NCPHP, but the difference was not significant (P = .16). Serum ionized Ca levels and 24-hour urinary analysis were only measured in patients with NCPHP to verify the diagnosis. The mean serum ionized Ca levels was 1.19 ± 0.43 mg/dL, mean urinary Ca was 197 ± 141 mg/day, and mean creatinine clearance was 128 ± 25 mL/minute in patients with NCPHP (data not listed in the tables). Lipid parameters were similar in both groups (Table 2). Although ALP was within a normal range in both groups, it was significantly higher in patients with NCPHPT (P = .02, Table 2).

Insulin Sensitivity and Glucose Metabolism As shown in Table 3, IR frequencies were not different between groups (P = 0.14). Fasting glucose was higher in NCPHPT patients (97.9 ± 10.7 vs. 92.3 ± 9.0 mg/dL, P = .05). HOMA-IR and ISOGTT were higher and lower, respec-

tively in patients with NCPHP, but the difference was not significant (P = .17 and P = .22, respectively). We did not find any correlation between PTH and glucose metabolism markers (i.e., fasting glucose, HOMA-IR, ISOGTT, and HbA1c; P values of .24, .45, .61, and .23, respectively). There was a negative correlation between Ca and ISOGTT, but the correlation was not statistically signifi-cant (P = .06, Table 4). 25(OH)D was negatively correlated with HbA1c (P<.01, Table 4), and 25(OH)D was negatively correlated with CRP (P<.01, data is not given in the table).

DISCUSSION

This is the first study to evaluate both insulin sensitivity and HOMA-IR, in patients with NCHPH who were select-ed by a calculated maximum PTH nomogram adjusted for serum 25(OH)D, Ca levels, and age. The major findings of this study is that IR is not more common in patients with NCPHP and that PTH is not related to insulin sensitivity index or HOMA-IR. Our results are compatible with previ-ous studies. Cakır et al evaluated 18 patients with NCPHP and 18 age-, BMI,- and sex- matched controls with OGTT and found that IR and impaired glucose tolerance were not more common in patients with NCPHP (23). Hagström et al evaluated and followed 30 patients with NCHPH and 30 controls for 5 years. They found that HbA1c was similar in both groups, but fasting glucose and BMI were signifi-cantly higher in patients with NCPHP than controls (24). Unfortunately, the 25(OH)D levels of the participants were not evaluated, and the control group was not BMI matched in that study. We observed a negative correlation between Ca and ISOGTT, but the correlation was not significant (P = .06). Hagström et al showed that endogenous Ca might be

Table 1Patient Clinical Featuresa

NCPHP Control Pn (sex % F) 25 (100%) 25 (100%)Age (years) 48.1 ± 8.4 45.5 ± 7.2 ns

BMI (kg/m²) 30.3 ± 4.9 29.0 ± 4.5 nsWC (cm) 91 ± 12 96 ± 12 nsBP systolic (mm Hg) 124 ± 14 122 ± 16 nsBP diastolic (mm Hg) 84 ± 10 80 ± 8 nsNephrolithiasis n (%) 7 (28%) 3 (12%) nsAbbreviations: BMI = body mass index; BP = blood pressure; F = female; NCPHP = normocalcemic hyperparathyroidism; ns = not significant; WC = waist circumference.aData are n (%) or means ± SD for continuous variables. Differences were assessed with independent sample t tests for normally distributed variables and c2 tests for categorical variables.

4 Parathyroid Hormone and Insulin Resistance, Endocr Pract. 2015;21(No. 1)

Table 2Laboratory Analysesa

NCPHP (n = 25) Controls (n = 25) PPTH (pg/mL) 116 ± 39 45 ± 8.5 <.001Ca (mg/dL) 9.4 ± 0.4 9.2 ± 0.5 .09P (mg/dL) 3.0 ± 0.6 3.1 ± 0.5 .6725(OH)D (ng/mL) 30 (28-38) 35 (26-39) .46ALP (U/L) 75 (68-90) 65 (53-79) .02Creatinine (mg/dL) 0.63 (0.58-0.70) 0.55 (0.47-0.69) .08TSH (mIU/mL) 1.6 (0.8-2.0) 1.7 (0.9-2.3) .44CRP (mg/L) 3.0 (2-5) 3.0 (2-4) .51Uric acid (mg/dL) 4.8 (4.1-5.1) 4.9 (4.3-5.2) .46Total cholesterol (mg/dL) 203 ± 32 194 ± 36 .37Triglyceride (mg/dL) 126 (102-171) 115 ± 52 .09LDL-C (mg/dL) 115 ± 36 122 ± 32 .53HDL-C (mg/dL) 53 ± 13 49 ± 9.6 .22

Abbreviations: ALP = alkaline phosphatase; Ca = calcium; CRP = C-reactive protein; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NCPHP = normocalcemic hyperparathyroidism; P = phosphorus; PTH = parathyroid hormone; TSH = thyroid-stimulating hormone.aData are means ± SD for continuous variables or median (25 and 75% interquartiles) for nonnormally distributed variables. Differences were assessed with independent sample t tests for normally distributed variables and Wilcoxon signed-rank tests for nonnormally distributed variables.

Table 3Glucose Metabolism Assessments

NCPHP (n = 25) Controls (n = 25) PFasting glucose (mg/dL) 97.9 ± 10.7 92.3 ± 9.0 .052-hour glucose (mg/dL) 113.2 ± 28.8 106.6 ± 40.6 .51Insulin resistance

HOMA-IR 2.4 (1.7-3.1) 1.8 (1.2-3.0) .17Insulin sensitivity index

ISOGTT 4.0 (2.5-6.5) 5.0 (4-9.5) .22AUC (insulin) 6,285 (4,443-10,863) 5,775 (2,977-7,657) .33AUC (glucose) 16,578 ± 3,867 14,542 ± 4,120 .10HbA1c (%) 5.6 ± 0.6 5.4 ± 0.3 .15Impaired fasting glucose, n 10 8 .55Impaired glucose tolerance, n 3 6 .46

Insulin resistance (HOMA-IR >2.5), n

12 7 .14

Abbreviations: AUC = area under the curve during oral glucose tolerance test; HbA1c = glycated hemo-globin; HOMA-IR = homeostasis model assessment of insulin resistance; ISOGTT = insulin sensitivity index; NCPHP = normocalcemic hyperparathyroidism.Data are means ± SD for continuous variables or median (25 and 75% interquartiles) for nonnormally distributed variables. Differences were assessed with independent sample t tests for normally distributed variables and Wilcoxon signed-rank test for nonnormally distributed variables. Categorical variables were assessed with c2 and Fisher exact tests.

Parathyroid Hormone and Insulin Resistance, Endocr Pract. 2015;21(No. 1) 5

involved early in the pathogenesis diabetes, and they found that this effect was primarily mediated through effects on insulin sensitivity rather than defective insulin secre-tion (14). High serum Ca levels can cause IR by raising intracellular free Ca concentration in hyperparathyroidism (12). Elevated levels of Ca can impair insulin-stimulated glucose uptake and induce impairment at the postbinding steps of insulin action (25). This alteration can increase the requirement for insulin, and if IR progresses, impaired glucose tolerance and diabetes mellitus would result. This may explain the increased prevalence of diabetes in patients with hypercalcemic primary hyperparathyroidism, but this mechanism is not suitable for NCPHP. Although our study subjects’ serum 25(OH)D levels were over 20 ng/dL, we found a significant negative corre-lation between 25(OH)D levels and HbA1c (P<.01), but there were no correlations between 25(OH)D levels and fasting glucose, AUC(gluc), AUC(ins), ISOGTT, or HOMA-IR. In the Trompso study with 8,643 participants, there was a significant inverse association between 25(OH)D and HbA1c after adjustment for confounders (BMI, age, sex, season, Ca, hemoglobin, etc.). In our study, 25(OH)D had a significantly negative correlation with HbA1c but not with fasting glucose, AUC(gluc), AUC(ins), ISOGTT, or HOMA-IR; this is probably due to the participants’ serum 25(OH)D levels (≥20 ng/dL). Most cross-sectional stud-ies have found significant inverse associations between 25(OH)D and IR; however, some of them reported no asso-ciation (26-36). 25(OH)D may play a role in insulin action by stimulating the expression of insulin receptor, thereby enhancing insulin responsiveness for glucose transport

(37). Vitamin D has a modulating effect on the immune system (38). Poor vitamin D status may induce a higher inflammatory response, which is associated with IR (39). In our study, 25(OH)D had significantly negative correla-tions with CRP (P<.01). Increased BMI may contribute to the reported asso-ciation between primary hyperparathyroidism and glucose metabolism. In a meta-analysis, patients with primary hyperparathyroidism were heavier (3). Although the pathogenesis is not fully elucidated, obesity may establish a basis for hyperparathyroidism as it promotes decreased bioavailability of vitamin D, which is sequestered in body fat, and increased leptin levels in obesity may have an endocrine or paracrine effect on PTH (40). In our study, patients with NCPHP were also overweight/obese (mean BMI 30.3 ± 4.9 kg/m2), so we selected overweight/obese controls so ensure no differences in IR parameters between the 2 groups. Although NCPHP is thought to be an early stage of the disease, bone metabolism is already affected in these patients (2,19). In our study, ALP was in the normal range, but it was statistically higher in patients with NCPHP than controls (P = .02). This suggested accelerated bone turn-over in this stage of the disease. The small sample size is among the limitations of our study. Additionally, the cross-sectional design makes it difficult to establish a causal relationship. We did not use the euglycemic hyperinsulinemic clamp technique, which is considered the gold standard for evaluating IR. Another limitation is that all the recruited patients with NCPHP were female. A far as we know, NCPHP is more common

Table 4Correlation Tablea,b

FG HOMA-IR ISOGTT HbA1crP

rP

rP

rP

PTH (pg/mL) 0.17.24

0.11.45

–0.08.61

0.17.23

Ca (mg/dL) 0.15.30

0.22.14

–0.27.06

–0.07.64

P (mg/dL) –0.09.49

–0.12.40

0.20.17

–0.15.30

25(OH)D (ng/mL) –0.09.50

–0.02.91

–0.01.94

–0.39<.01

Abbreviations: Ca = calcium; FG = fasting glucose; HbA1c = glycated hemoglobin; HOMA-IR = homeostasis model assessment of insulin resistance; ISOGTT = insulin sensitivity index; 25(OH)D = 25-hydroxyvitamin D; P = phosphorous; PTH = para-thyroid hormone.a Including all study participantsb Spearman’s correlation (2-tailed)

6 Parathyroid Hormone and Insulin Resistance, Endocr Pract. 2015;21(No. 1)

among females; estrogen may have a masking effect on hypercalcemia by protecting against the bone-resorbing effects of PTH (41), and this might be an explanation for the selection bias of female patients. Finally, none of the patients with NCPHP underwent parathyroidectomy, so the diagnosis was not confirmed pathologically.

CONCLUSION

In conclusion, the results of this study indicate that IR is not more common in patients with NCPHP, and PTH is not related to HOMA-IR and ISOGTT; however, further stud-ies with more subjects are warranted to clarify the associa-tion between PTH and insulin resistance and the natural course of patients with NCPHP.

DISCLOSURE

The authors have no multiplicity of interest to disclose.

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