It was reported that the common −866G/A polymorphism in the promoter of the human uncoupling protein-2 (UCP2) gene, which enhances its trascriptional activity, is associated with increased mRNA levels in human adipocytes and reduced risk of obesity. Studies in knockout mice and β-cells indicate that UCP2 may play a role in β-cell function. In this study, we addressed the question of whether the common −866G/A polymorphism in UCP2 gene contributes to the variation of insulin secretion in humans by genotyping 301 nondiabetic subjects who underwent an oral glucose tolerance test. Glucose-stimulated insulin secretion estimated by several indexes of β-cell function was significantly lower in carriers of the −866A/A genotype compared with −866A/G or −866G/G according to the dosage of the A allele (P = 0.002–0.05). To investigate directly whether the UCP2 −866G/A polymorphism affects human islet function, pancreatic islets isolated from two −866G/G homozygous, seven −866G/A heterozygous, and one −866A/A homozygous nondiabetic donors were studied. Islets from −866A/A homozygous had lower insulin secretion in response to glucose stimulation as compared with −866G/G and −866G/A carriers. These results indicate that the common −866G/A polymorphism in the UCP2 gene may contribute to the biological variation of insulin secretion in humans.

The pathophysiology of type 2 diabetes includes two distinct defects: impaired insulin action in peripheral tissues and a failure of pancreatic β-cells to compensate for the enhanced insulin demand by increasing insulin secretion (1). The contribution of genetic factors to the development of both of these components has been known for many years. Evidence has been provided that impaired insulin action is an early metabolic feature of nondiabetic first-degree relatives of type 2 diabetic patients (2–4) and shows familial clustering in keeping with an underlying genetic predisposition (5). Nondiabetic first-degree relatives of type 2 diabetic patients also show various forms of pancreatic β-cell dysfunction (4,6). Although considerable effort has been devoted to identify genes that contribute to diabetes susceptibility, the genetic basis for β-cell dysfunction in common forms of type 2 diabetes, which is usually associated with obesity, has not yet been identified (7). Studies in knockout mice, pancreatic β-cell lines, and rat islets of Langerhans have indicated that an important role in the regulation of β-cell function may be played by uncoupling protein-2 (UCP2) (8–10). UCP2 is a member of the mitochondrial inner membrane carrier family that is highly expressed in adipose tissue and pancreatic islets (11,12). Like the homologous prototype UCP1, UCP2 mediates mitochondrial proton leak releasing energy stored within the proton motive force as heat that, ultimately, results in a decrease in ATP production. β-cells sense glucose through its oxidative metabolism and the resulting increase in the ATP/ADP ratio plays a central role in glucose-induced insulin secretion by causing closure of the membrane ATP-sensitive potassium channel, membrane depolarization, influx of calcium, and finally, insulin granule exocytosis. Uncoupling glucose metabolism from ATP generation would be expected to impair β-cell ability to secrete insulin in response to glucose. In support of this view, it has been shown that overexpression of UCP2 in pancreatic rat islets or clonal β-cell lines resulted in blunted glucose-stimulated insulin secretion associated with reduction in cellular ATP levels (8,9). In addition, UCP2 knockout mice exhibited higher islet ATP levels and increased glucose-stimulated insulin secretion both in vivo and in isolated pancreatic islets (10). Thus, an increased expression or activity of UCP2 in pancreatic β-cell may contribute to impair insulin secretion. Recently, an association of a common −866 G/A polymorphism in the promoter of the human UCP2 gene with obesity has been described (13). The A allele was associated with increased transcriptional activity, increased mRNA levels in human fat cells, and a reduced risk of obesity (13). More recently, it has been shown that the pancreatic transcription factor PAX6 was more effective in binding to and transactivating the A allele of UCP2 promoter (14).

To address the question of whether the common −866 G/A polymorphism in the promoter of the human UCP2 gene contributes to variation of insulin secretion in humans, we genotyped 301 nondiabetic subjects who underwent an oral glucose tolerance test (OGTT). To estimate β-cell function, we used a number of validated indexes from insulin concentrations obtained during an OGTT. The clinical features of the study subjects are shown in Table 1. Of these subjects, 132 (43.9%) were −866G/G homozygous, 144 (47.8%) were −866G/A heterozygous, and the remainder (8.3%) were −866A/A homozygous. The genotype distribution was in the Hardy-Weinberg equilibrium. No significant differences in age, sex, BMI, waist-to-hip ratio, fasting and 2-h postload plasma glucose levels, fasting and 2-h postload plasma insulin concentrations, glycosylated hemoglobin (HbA1c) concentrations, triglycerides, and total and HDL cholesterol were observed among the three genotypes (Table 1). Insulin sensitivity estimated by six different indexes, including homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), insulin sensitivity index (ISI0), fasting insulin resistance index (FIRI), Matsuda, and fasting glucose to insulin ratio (FGIR) (15–20), did not differ among the three genotypes (Table 1). The indexes for insulin secretion adjusted for sex, age, and BMI, stratified according to genotype, are shown in Table 2. There was no significant difference in basal non-glucose-stimulated insulin secretion as estimated by β-cell HOMA (Table 2). By contrast, glucose-stimulated insulin secretion decreased according to the dosage of the A allele. Thus, carriers of the −866A/A genotype showed lower glucose-stimulated insulin secretion as compared with either −866A/G or −866G/G genotype (Table 2). As insulin secretion is dependent on actual insulin sensitivity, we compared the disposition index, calculated as the product of the Matsuda insulin sensitivity index and the first phase Stumvoll index, among genotype groups. After adjusting for sex, age, and BMI, carriers of the −866A/A genotype showed a significantly lower disposition index as compared with either −866G/G or −866A/G (71,533 ± 41,370, 91,616 ± 48,886, and 75,706 ± 48,569, respectively; P < 0.04). Although the employed insulin secretion indexes have been validated against “gold standard” hyperglycemic clamp or intravenous insulin tolerance test (15,19,21), they are not direct measurements of insulin secretion, and therefore, we cannot exclude that other factors such as changes in incretin effect, insulin metabolism, or hepatic clearance might account for the present results.

To investigate directly whether the UCP2 −866 G/A polymorphism affects human islet cells function, we took advantage of the opportunity to study a number of functional properties of pancreatic islets isolated from two −866G/G homozygous, seven −866G/A heterozygous, and one −866A/A homozygous nondiabetic donors. Table 3 shows clinical features of pancreas donors. Insulin secretion results in response to glucose, arginine, and glyburide are reported in Table 4. There were no significant differences among the three genotypes in basal insulin secretion as assessed at 3.3 mmol/l glucose concentrations. By contrast, carriers of the −866A/G genotype showed lower glucose-stimulated insulin secretion as compared with −866G/G homozygous islets (P < 0.02). The −866A/A homozygous islets showed a lower insulin release in response to glucose, glyburide, or arginine as compared with both −866G/A heterozygous and −866G/G homozygous islets. Although this analysis is limited by the small number of subjects studied, the results are suggestive for an association between the A allele and reduced glucose-stimulated insulin secretion. While this manuscript was in preparation, Krempler et al. (14) have reported a lower disposition index in subjects carrying the A allele in a group of 39 obese nondiabetic subjects. Those results are consistent with the present data and indicate that the common −866G/A polymorphism in the promoter of the human UCP2 gene may contribute to the biological variation of insulin secretion in humans. It is plausible that allele-specific enhancement of UCP2 expression in pancreatic β-cells would result in increased mitochondrial uncoupling, reduced ATP synthesis, and decrease insulin release in response to glucose stimulus. It is interesting to note that impairment of insulin secretion induced by the A allele was more prominent in the first-phase insulin secretion. Accordingly, the improvement caused by UCP2 deficiency in knockout mice was most relevant for defect in the first-phase insulin secretion (10). Because loss of first-phase insulin secretion is one the earliest abnormalities observed in subjects destined to develop type 2 diabetes, the present results may be of pathophysiological significance.

In conclusion, our results suggest that the common −866 G/A polymorphism in the promoter of UCP2 gene is associated with β-cell dysfunction in response to glucose in an Italian population of glucose-tolerant subjects. The finding that heterozygous carriers of the −866G/A polymorphism have intermediate glucose-stimulated insulin secretion pattern according to the dosage of the A allele indicates that UCP2 plays an important role in the control of the metabolic pathway governing insulin secretion. Similar gene dosage effects have been observed in knockout mice (10), further suggesting that relatively small changes in UCP2 activity are likely to have important effects on insulin secretion. However, we cannot exclude the possibility that the −866G/A polymorphism is not itself responsible for the association to impaired glucose-stimulated insulin secretion, but rather, is in linkage disequilibrium with other variants of UCP2 impairing gene function or expression. It is also possible that the casual polymorphism is located within a gene different from, but close to, the UCP2 gene.

Study subjects.

A total of 301 unrelated normal glucose-tolerant subjects were recruited in the Lazio region of Italy. All subjects were Caucasian and were consecutively recruited from the Department of Internal Medicine of the University of Rome-Tor Vergata to participate in this study. Inclusion criteria were absence of diabetes or impaired glucose tolerance (fasting plasma glucose <110 mg/dl and 2-h plasma glucose <140 mg/dl) (22) and absence of diseases able to modify glucose metabolism. Insulin sensitivity was estimated by using the HOMA index (15), FGIR (16), the QUICKI (17), the Matsuda index (18), the ISI0 (19), and FIRI (20). Insulin secretion was estimated by the HOMA index (15), the Stumvoll index for estimated first phase and second phase (21), the corrected insulin response (CIR30) (19), the insulin ratio (I30/I0) (19), the 30-min insulin-to-glucose ratio (I30/G30) (19), and the insulinogenic indexes estimated as I30-I0/G30 or I30-I0/G30-G0 (ΔI30/ΔG30) (19). The study was approved by an institutional ethics committee, and informed consent was obtained from each subject in accordance with principles of the Declaration of Helsinki.

DNA analysis.

Genomic DNA was isolated from peripheral blood according to standard procedures. The −866A/G polymorphism in the promoter of human UCP2 gene was determined by digesting PCR products with restriction enzyme MluI (Invitrogen) as previously described (13). The primers used were 5′-CAC GCT GCT TCT GCC AGG AC-3′ as upstream primer and 5′-AGG CGT CAG GAG ATG GAC CG-3′ as downstream primer.

Human islet studies.

The pancreata were procured through the local organ procurement agency, within the framework of a project aiming to clinical islet allotransplantion into diabetic patients, approved by the Ethics Committee of the University of Pisa. Procedures for islet preparation have been reported in detail previously (23–25). Briefly, the pancreatic duct was cannulated and the digestion solution (Collagenase P, Roche Diagnostics, 1.5–2 mg/ml, dissolved in 200 ml Hanks’ balanced salt solution [HBSS]) was slowly injected to distend the tissue. After distension, the gland was loaded into a shaking water bath at 37°C for 10 min, and the digestate was filtered through 300- and 90-μm mesh stainless steel filters, in sequence. The tissue remaining in the 90-μm filter was washed with HBSS and 2% human albumin. The same procedure of filtration, washing, and settling in HBSS solution was repeated at 8–10 intervals up to 40–50 min. For purification, 3 ml of tissue was loaded into 220-ml plastic conicals and resuspended in 60 ml of 80% Histopaque (Sigma) 1.077 in HBSS, topped with 40 ml of HBSS. After centrifugation at 800g for 5 min at 4°C, islets were recovered at the interface between the two layers, washed with HBSS, 2% human albumin, resuspended in M199 culture medium, and cultured at 37°C in a CO2 incubator for 5–6 days. Islet secretory function was evaluated as previously described (19–21). After a 30-min preincubation period at 37°C in Krebs-Ringer bicarbonate solution, 0.5% albumin, pH 7.4, containing 3.3 mmol/l glucose, aliquots of 30 hand-picked islets were incubated for 45 min in the Krebs-Ringer with 3.3 mmol/l glucose, 16.7 mmol/l glucose, or 3.3 mmol/l glucose plus 20 mmol/l arginine or 100 μmol/l glyburide. At the end of the incubation time, aliquots of the incubation medium were taken for insulin (Medgenix Diagnostics, Fleurs, Belgium; no cross-reactivity with human proinsulin).

Statistical analysis.

Parametric data are expressed as means ± SD. Group differences of continuous variables were compared using ANOVA. Logarithmic transformations were made if equal variance and normality assumptions of ANOVA were rejected. All differences were also tested after adjusting for sex, age, or BMI by ANCOVA. The Bonferroni correction for multiple comparisons was applied. Categorical variables were compared by contingency χ2 test. The Hardy-Weinberg equilibrium among the genotypes was evaluated by χ2 test. Unpaired Student’s t test was performed to test differences between islets in response to glucose concentrations. For all analyses, a P value <0.05 was considered to be statistically significant. All analyses were performed using SPSS software program version 10.0 for Windows.

TABLE 1

Clinical and biochemical characteristics of the study population according to the UCP2 genotype

−866G/G−866A/G−866A/AP
n (M/F) 41/92 46/98 11/14 0.42 
Age (years) 41.1 ± 13.2 43.7 ± 13.6 42.7 ± 13.4 0.15 
BMI (kg/m2) 29.5 ± 7.6 30.3 ± 7.1 29.9 ± 7.2 0.68 
Waist-to-hip ratio 0.85 ± 0.11 0.86 ± 0.08 0.85 ± 0.10 0.63 
Fasting glucose (mg/dl) 87 ± 10 89 ± 11 88 ± 11 0.36 
2-h glucose (mg/dl) 106 ± 32 112 ± 31 110 ± 31 0.35 
Fasting insulin (μU/ml) 11.3 ± 7.3 11.7 ± 6.1 10.6 ± 4.4 0.72 
2-h insulin (μU/ml) 65.5 ± 73.2 64.9 ± 45.8 56.3 ± 37.5 0.76 
HbA1c (%) 5.2 ± 0.6 5.2 ± 0.5 5.4 ± 0.9 0.25 
Total cholesterol (mg/dl) 205 ± 52 200 ± 42 197 ± 36 0.65 
HDL cholesterol (mg/dl) 53 ± 14 51 ± 14 49 ± 12 0.20 
Triglycerides (mg/dl) 121 ± 73 125 ± 68 116 ± 58 0.80 
HOMA 2.48 ± 1.73 2.59 ± 1.38 2.41 ± 1.21 0.78 
QUICKI 0.34 ± 0.03 0.34 ± 0.03 0.34 ± 0.03 0.40 
ISI 255 ± 148 232 ± 150 252 ± 175 0.44 
FIRI 2.23 ± 1.55 2.33 ± 1.25 2.17 ± 1.09 0.78 
Matsuda index 93 ± 52 82 ± 44 98 ± 59 0.21 
FGIR 10.3 ± 5.6 9.6 ± 5.1 10.3 ± 5.1 0.53 
−866G/G−866A/G−866A/AP
n (M/F) 41/92 46/98 11/14 0.42 
Age (years) 41.1 ± 13.2 43.7 ± 13.6 42.7 ± 13.4 0.15 
BMI (kg/m2) 29.5 ± 7.6 30.3 ± 7.1 29.9 ± 7.2 0.68 
Waist-to-hip ratio 0.85 ± 0.11 0.86 ± 0.08 0.85 ± 0.10 0.63 
Fasting glucose (mg/dl) 87 ± 10 89 ± 11 88 ± 11 0.36 
2-h glucose (mg/dl) 106 ± 32 112 ± 31 110 ± 31 0.35 
Fasting insulin (μU/ml) 11.3 ± 7.3 11.7 ± 6.1 10.6 ± 4.4 0.72 
2-h insulin (μU/ml) 65.5 ± 73.2 64.9 ± 45.8 56.3 ± 37.5 0.76 
HbA1c (%) 5.2 ± 0.6 5.2 ± 0.5 5.4 ± 0.9 0.25 
Total cholesterol (mg/dl) 205 ± 52 200 ± 42 197 ± 36 0.65 
HDL cholesterol (mg/dl) 53 ± 14 51 ± 14 49 ± 12 0.20 
Triglycerides (mg/dl) 121 ± 73 125 ± 68 116 ± 58 0.80 
HOMA 2.48 ± 1.73 2.59 ± 1.38 2.41 ± 1.21 0.78 
QUICKI 0.34 ± 0.03 0.34 ± 0.03 0.34 ± 0.03 0.40 
ISI 255 ± 148 232 ± 150 252 ± 175 0.44 
FIRI 2.23 ± 1.55 2.33 ± 1.25 2.17 ± 1.09 0.78 
Matsuda index 93 ± 52 82 ± 44 98 ± 59 0.21 
FGIR 10.3 ± 5.6 9.6 ± 5.1 10.3 ± 5.1 0.53 

Data are means ± SD. Group differences of continuous variables were compared using ANOVA; categorical variables were compared by χ2 test.

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TABLE 2

Indexes for insulin secretion of the study population according to the UCP2 genotype.

−866G/G−866A/G−866A/AP*
β-cell HOMA 205 ± 188 203 ± 192 172 ± 132 0.9 
Stumvoll 1st phase 1181 ± 613 1086 ± 494 893 ± 314* 0.03 
Stumvoll 2nd phase 304 ± 146 278 ± 125 238 ± 78* 0.04 
CIR30 0.0086 ± 0.007 0.0088 ± 0.0148† 0.0055 ± 0.0036* 0.04 
Insulin ratio (I30/I0) 7.1 ± 4.7‡ 6.1 ± 3.4† 4.5 ± 3.4§ 0.009 
Insulin/glucose ratio (I30/G30) 7.1 ± 4.8 6.1 ± 3.8† 4.1 ± 2.1§ 0.01 
I30-I0/G30 8.5 ± 5.3 7.5 ± 4.2† 5.4 ± 2.5§ 0.002 
ΔI30/ΔG30 21 ± 16 18 ± 12 12 ± 7* 0.05 
−866G/G−866A/G−866A/AP*
β-cell HOMA 205 ± 188 203 ± 192 172 ± 132 0.9 
Stumvoll 1st phase 1181 ± 613 1086 ± 494 893 ± 314* 0.03 
Stumvoll 2nd phase 304 ± 146 278 ± 125 238 ± 78* 0.04 
CIR30 0.0086 ± 0.007 0.0088 ± 0.0148† 0.0055 ± 0.0036* 0.04 
Insulin ratio (I30/I0) 7.1 ± 4.7‡ 6.1 ± 3.4† 4.5 ± 3.4§ 0.009 
Insulin/glucose ratio (I30/G30) 7.1 ± 4.8 6.1 ± 3.8† 4.1 ± 2.1§ 0.01 
I30-I0/G30 8.5 ± 5.3 7.5 ± 4.2† 5.4 ± 2.5§ 0.002 
ΔI30/ΔG30 21 ± 16 18 ± 12 12 ± 7* 0.05 

Data are means ± SD. Group differences of continuous variables were compared using ANOVA. P values were adjusted for age, sex, and BMI.

*

P < 0.05 vs. −866G/G;

†

P < 0.05 vs. −866A/A;

‡

P < 0.05 vs. −866A/G;

§

P < 0.01 vs. − 866G/G genotype after Bonferroni correction. *P < 0.05 and §P < 0.01 vs. −866G/G, P < 0.05 vs. −866A/A, and ‡P < 0.05 vs. −866A/G genotype after Bonferroni correction.

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TABLE 3

Clinical characteristics of pancreas donors.

GenotypeAge (years)SexWeight (kg)Height (cm)Cause of death
−866G/G # 1 44 M 67 168 Trauma 
−866G/G # 2 39 F 54 160 Trauma 
−866A/G # 1 50 F 55 156 Cerebral hemorrhage 
−866A/G # 2 40 M 72 175 Trauma 
−866A/G # 3 57 F 60 160 Cerebral hemorrhage 
−866A/G # 4 22 M 65 173 Trauma 
−866A/G # 5 42 M 80 183 Cerebral hemorrhage 
−866A/G # 6 27 F 56 159 Trauma 
−866A/G # 7 71 M 78 175 Cerebral hemorrhage 
−866A/A # 1 30 M 77 176 Trauma 
GenotypeAge (years)SexWeight (kg)Height (cm)Cause of death
−866G/G # 1 44 M 67 168 Trauma 
−866G/G # 2 39 F 54 160 Trauma 
−866A/G # 1 50 F 55 156 Cerebral hemorrhage 
−866A/G # 2 40 M 72 175 Trauma 
−866A/G # 3 57 F 60 160 Cerebral hemorrhage 
−866A/G # 4 22 M 65 173 Trauma 
−866A/G # 5 42 M 80 183 Cerebral hemorrhage 
−866A/G # 6 27 F 56 159 Trauma 
−866A/G # 7 71 M 78 175 Cerebral hemorrhage 
−866A/A # 1 30 M 77 176 Trauma 
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TABLE 4

Insulin release (μU/ml) in islets from the three UCP2 genotypes in response to different stimuli.

Glucose
Glyburide 100 μmol/lArginine 20 mmol/l
3.3 mmol/l16.7 mmol/l
−866G/G 35 ± 8 89 ± 19* 96 ± 31 84 ± 24 
−866A/G 33 ± 9 50 ± 10 64 ± 8 81 ± 25 
−866A/A 37 39 41 34 
Glucose
Glyburide 100 μmol/lArginine 20 mmol/l
3.3 mmol/l16.7 mmol/l
−866G/G 35 ± 8 89 ± 19* 96 ± 31 84 ± 24 
−866A/G 33 ± 9 50 ± 10 64 ± 8 81 ± 25 
−866A/A 37 39 41 34 

Data are means ± SD.

*

P < 0.02 vs. −866A/G by two-tailed unpaired Student’s t test.

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This study was supported in part by grants from the European Community (QLG1-CT-1999-00674), Ministero della Sanità (G.S.), and PRIN-COFIN 2001 and 2002 from Ministero dell’Istruzione, Università e Ricerca (G.S. and R.L.).

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Address correspondence and reprint requests to Giorgio Sesti, MD, Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia, Via Tommaso Campanella, 115 88100 Catanzaro, Italy. E-mail: [email protected].

Received for publication 25 November 2002 and accepted in revised form 22 January 2003.

CIR, corrected insulin response; FGIR, fasting glucose to insulin ratio; FIRI, fasting insulin resistance index; HBSS, Hanks’ balanced salt solution; HOMA, homeostasis model assessment; OGTT, oral glucose tolerance test; QUICKI, quantitative insulin sensitivity check index; UCP2, uncoupling protein-2.

DIABETES
2003