Insulin Secretion In Nondiabetic Subjects Research Articles

Plasma HDL-cholesterol and triglycerides, but not LDL-cholesterol, are associated with insulin secretion in non-diabetic subjects

ObjectiveExperimental data support the notion that lipoproteins might directly affect beta cell function, however clinical data are sparse and inconsistent. We aimed at verifying whether, independently of major confounders, serum lipids are associated with alterations in insulin secretion or clearance non-diabetic subjects. MethodsCross sectional and observational prospective (3.5yrs), multicentre study in which 1016 non-diabetic volunteers aged 30–60yrs. and with a wide range of BMI (20.0–39.9kg/m2) were recruited in a setting of University hospital ambulatory care (RISC study). Main outcome measures: baseline fasting lipids, fasting and OGTT-induced insulin secretion and clearance (measured by glucose and C-peptide modeling), peripheral insulin sensitivity (by the euglycemic clamp). Lipids and OGTT were repeated in 980 subjects after 3.5years. ResultsLDL-cholesterol did not show independent associations with fasting or stimulated insulin secretion or clearance. After accounting for potential confounders, HDL-cholesterol displayed negative and triglycerides positive independent associations with fasting and OGTT insulin secretion; neither with insulin clearance. Low HDL-cholesterol and high triglycerides were associated with an increase in glucose-dependent and a decrease in non-glucose-dependent insulin secretion. Over 3.5years both an HDL-cholesterol decline and a triglycerides rise were associated with an increase in fasting insulin secretion independent of changes in body weight or plasma glucose. ConclusionsLDL-cholesterol does not seem to influence any major determinant of insulin bioavailability while low HDL-cholesterol and high triglycerides might contribute to sustain the abnormalities in insulin secretion that characterize the pre-diabetic state.

Investigation of the relationship between hemoglobin and serum iron levels and early-phase insulin secretion in non-diabetic subjects.

Recent biological and epidemiological studies have found that insulin resistance is linked to iron overload. However, little is known about the association between hemoglobin and/or serum iron levels and pancreatic β-cell function. In this gender-separated cross-sectional study, we aimed to investigate the association of hemoglobin and serum iron levels with early-phase insulin secretion in non-diabetic subjects. A total of 804 non-diabetic Japanese subjects (482 males and 322 females) aged over 30years old were enrolled in the study. Early-phase insulin secretion was estimated using the insulinogenic index (IGI [ΔInsulin(30-0min)/ΔGlucose(30-0min)]) during a 75-g oral glucose tolerance test. Simple linear regression analysis showed that IGI negatively correlated with hemoglobin levels in male but not in female subjects. However, IGI did not correlate with serum iron levels in either gender. Multivariate linear regression analysis in male subjects revealed that hemoglobin levels were predictors of IGI, responsible for 3.0% of IGI variation (P=0.008). The association was independent of age, BMI, fasting glucose and insulin levels, and lipid profiles. In non-diabetic Japanese males, hemoglobin levels significantly and negatively correlated with early-phase insulin secretion. Our finding suggests that elevated hemoglobin levels may have a gender-specific impact on β-cell function and could be an independent predictor of β-cell dysfunction.

CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

BackgroundGenetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca2+ channel CaV2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes.Methodology/Principal FindingsIn 595 GAD-negative, drug naïve patients (mean±SD; age: 58.5±10.2 yrs; BMI: 29.9±5 kg/m2, HbA1c: 7.0±1.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering ∼93% of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p<0.05−0.01). Both major alleles of rs2184945 and rs3905011 were each (p<0.01 and p<0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p<0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p<0.05).Conclusions/SignificanceIn patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongly associated to beta cell function. Genotyping CACNA1E might be of help to infer the beta cell functional phenotype and to select a personalized treatment.

Insulin secretion is decreased in non‐diabetic individuals with hypomagnesaemia

Magnesium modulates insulin-mediated glucose uptake but data regarding its role in insulin secretion are scarce; therefore, in this study we determined whether decreased serum magnesium levels are associated with the impairment of insulin secretion in non-diabetic individuals. A total of 182 apparently healthy subjects, men and non-pregnant women, 18-65 years of age, were enrolled in a population-based cross-sectional study and allocated to groups with hypomagnesaemia and normomagnesaemia. The groups in the study were subsequently stratified according to glucose status: normal glucose tolerance, impaired fasting glucose, and impaired glucose tolerance. Insulin secretion was evaluated by the first and second phases of insulin secretion. The Spearman coefficient between serum magnesium and the first and second phases of insulin secretion showed a significant positive correlation in the overall (r = 0.265, p < 0.0005; r = 0.541, p < 0.0005), normal glucose tolerance (r = 0.369, p = 0.001; r = 0.618, p < 0.0005), impaired fasting glucose (r = 0.320, p = 0.02; r = 0.449, p = 0.001), and impaired glucose tolerance (r = 0.129, p = 0.37; r = 0.522, p < 0.0005) groups. The multivariate linear regression analysis showed a significant association between serum magnesium levels and the first and second phases of insulin secretion: for the entire groups [B = 75.2; 95% confidence interval (CI) 27.6-122.7; B = 25.4; 95% CI 16.4-34.3], normal glucose tolerance (B = 129.6, 95% CI 38.1-221.1; B = 40.3, 95% CI 23.7-56.8), impaired fasting glucose (B = 75.2, 95% CI 27.6-122.7; B = 15.1, 95% CI 4.2-30.2), and impaired glucose tolerance (B = 57.4, 95% CI 23.5-138.3; B = 25.4, 95% CI 16.4-34.3) groups. Our results show that hypomagnesaemia is associated with the decrease of the first and second phases of insulin secretion in non-diabetic subjects with hypomagnesaemia.

A model of GLP-1 action on insulin secretion in nondiabetic subjects

Glucagon-like peptide-1 (GLP-1)-based therapies for diabetes have aroused interest because of their effects on insulin secretion and glycemic control. However, a mechanistic model enabling quantitation of pancreatic response to GLP-1 has never been developed. To develop such a model we studied 88 healthy individuals (age 26.3 +/- 0.6 yr, BMI 24.9 +/- 0.4 kg/m(2)) by use of a hyperglycemic clamp. A variable infusion maintained glucose concentrations at 150 mg/dl for 240 min. At 120 min, an intravenous infusion of GLP-1 was started (0.75 pmol kg(-1) min(-1) from 120-180 min, 1.5 pmol kg(-1) min(-1) from 181-240 min). Consequently, plasma C-peptide concentration rose from 1,852.0 +/- 62.8 pmol/l at 120 min to 4,272.2 +/- 176.4 pmol/l at 180 min and to 6,995.8 +/- 323.5 pmol/l at 240 min. Four models of GLP-1 action on insulin secretion were considered. All models share the common assumption that insulin secretion is made up of two components, one proportional to glucose rate of change through dynamic responsivity, Phi(d), and one proportional to glucose through static responsivity, Phi(s), but differing by modality of GLP-1 control. The model that best fit C-peptide data assumes that above-basal insulin secretion depends linearly on GLP-1 concentration and its rate of change. An index (Pi) measuring the percentage increase of secretion due to GLP-1 is derived. Before GLP-1 infusion, Phi(d) = 245.7 +/- 15.6 10(-9) and Phi(s) = 25.2 +/- 1.4 10(-9) min(-1). Under GLP-1 stimulus, Pi = 12.6 +/- 0.71% per pmol/l, meaning that an increase of 5 pmol/l in peripheral GLP-1 concentrations induces an approximately 60% increase in over-basal insulin secretion.

Low plasma insulin-like growth factor-1 levels are associated with reduced insulin sensitivity and increased insulin secretion in nondiabetic subjects

Background and aim Weight gain is associated with a decline in insulin sensitivity and a compensatory increase in insulin secretion. IGF-1 is a plausible candidate to explain these divergent phenomena. In this cross-sectional study, we analyzed the relationship between IGF-1 levels, insulin sensitivity and secretion in 110 nondiabetic subjects with a wide range of BMI to verify this hypothesis. Methods and results Subjects underwent OGTT, IVGTT and euglycemic-hyperinsulinemic clamp. HOMA-beta, IVGTT-derived and OGTT-derived indexes for first-phase and second-phase insulin secretion were higher in obese as compared with overweight and normal-weight groups, while glucose disposal was lower. IGF-1 levels were negatively correlated with IVGTT-derived and OGTT-derived indexes first-phase and second-phase insulin secretion, and positively correlated with glucose disposal. These correlations were no longer significant after adjustment for BMI. In a multivariate analysis, the variables associated with glucose disposal were IGF-1, age, triglycerides, and 2-h post-load glucose accounting for 23.4% of its variation. When BMI was entered into the model, the variables associated with glucose disposal were triglycerides, 2-h post-load glucose and BMI accounting for 27.2% of variation. In a multivariate analysis, the only variable associated with IVGTT-derived first-phase and second-phase insulin secretion was IGF-1 accounting for 10.4% and 15.1% of variation, respectively. When BMI was entered into the model, it became the only variable associated with both first-phase and second-phase insulin secretion accounting for 25.7% and 37.6% of variation, respectively. Conclusion These data suggest that progressive reduction in IGF-1 levels may be involved in obesity-related changes in both insulin sensitivity and secretion.

Aryl hydrocarbon receptor nuclear translocator (ARNT) gene as a positional and functional candidate for type 2 diabetes and prediabetic intermediate traits: Mutation detection, case-control studies, and gene expression analysis.

BackgroundARNT, a member of the basic helix-loop-helix family of transcription factors, is located on human chromosome 1q21–q24, a region which showed well replicated linkage to type 2 diabetes. We hypothesized that common polymorphisms in the ARNT gene might increase the susceptibility to type 2 diabetes through impaired glucose-stimulated insulin secretion.MethodsWe selected 9 single nucleotide polymorphisms to tag common variation across the ARNT gene. Additionally we searched for novel variants in functional coding domains in European American and African American samples. Case-control studies were performed in 191 European American individuals with type 2 diabetes and 187 nondiabetic European American control individuals, and in 372 African American individuals with type 2 diabetes and 194 African American control individuals. Metabolic effects of ARNT variants were examined in 122 members of 26 European American families from Utah and in 225 unrelated individuals from Arkansas. Gene expression was tested in 8 sibling pairs discordant for type 2 diabetes.ResultsNo nonsynonymous variants or novel polymorphisms were identified. No SNP was associated with type 2 diabetes in either African Americans or European Americans, but among nondiabetic European American individuals, ARNT SNPs rs188970 and rs11204735 were associated with acute insulin response (AIRg; p =< 0.005). SNP rs2134688 interacted with body mass index to alter β-cell compensation to insulin resistance (disposition index; p = 0.004). No significant difference in ARNT mRNA levels was observed in transformed lymphocytes from sibling pairs discordant for type 2 diabetes.ConclusionCommon ARNT variants are unlikely to explain the linkage signal on chromosome 1q, but may alter insulin secretion in nondiabetic subjects. Our studies cannot exclude a role for rare variants or variants of small (< 1.6) effect size.

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes.

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

Association of serum phosphate levels with glucose tolerance, insulin sensitivity and insulin secretion in non-diabetic subjects

Hypophosphatemia is associated with impaired glucose tolerance and insulin resistance in primary hyperparathyroidism. However, little is known about the association between serum phosphate and glucose metabolism in healthy subjects. We measured fasting serum phosphate levels (SP, normal range 2.6-4.5 mg/dl) and serum calcium (S-Ca, normal range 2.1-2.6 mmol/l) in 881 non-diabetic subjects (341 male/540 female, age: 38+/-1 years, body mass index 25.9+/-0.2 kg/m(2) (mean+/-standard error of the mean). An oral glucose tolerance test (OGTT) with determination of glucose and insulin every 30 min was performed in all subjects. Insulin secretion and insulin sensitivity (IS) were estimated from the OGTT using validated indices. Furthermore, we tested whether serum phosphate predicts glucose tolerance in 115 subjects during a lifestyle intervention program (LIP). Serum phosphate was negatively correlated with 2-h blood glucose levels independent of age, gender and percent body fat (r=-0.13, P<0.0001). This association remained significant after additional adjustment for S-Ca, creatinine and parathyroid hormone. Serum phosphate was positively correlated with IS (r=0.10, P=0.0006), but not with insulin secretion. This was independent of age, gender, percent body fat, S-Ca and serum creatinine. In the subjects taking part in the LIP low serum phosphate levels at baseline were associated with higher postprandial glucose levels. In non-diabetic subjects, low serum phosphate levels are associated with high 2-h blood glucose levels and reduced IS. Whether low serum phosphate levels are a cause or a consequence of low IS and impairment of glucose tolerance needs to be tested in further studies.

A polymorphism in the promoter of UCP2 gene modulates lipid levels in patients with type 2 diabetes

A G/A single nucleotide polymorphism (SNP) in the position −866 of the UCP2 promoter modulates UCP2 expression in adipose tissue and pancreatic β-cell, and is associated with variations of body mass index (BMI) and insulin secretion in nondiabetic subjects. We investigated associations of this SNP with traits related to obesity, dyslipidemia, and hyperglycemia in patients with type 2 diabetes. The −866 G/A SNP in the UCP2 promoter was genotyped by PCR/RFLP in 681 type 2 diabetic patients. Increased triglyceride (⩾1.70 mM), total cholesterol (⩾6.0 mM) and LDL-cholesterol (⩾3.35 mM) levels were significantly less frequent in homozygous carriers of the G-allele than in homozygous carriers of the A-allele. Odds ratios for the risk of dyslipidemia in GG vs AA carriers were 0.45, 0.57, and 0.50, for triglyceride, total cholesterol and LDL-cholesterol, respectively (all p < 0.007). No genetic effects of this polymorphism on the BMI or on traits related to the severity of hyperglycemia were observed. In conclusion, a common polymorphism in the promoter region of the UCP2 gene modulates triglycerides and cholesterol levels in French Caucasian subjects with type 2 diabetes. The implications of this effect in the evolution of type 2 diabetes and its macrovascular complications deserve to be investigated.

A C-reactive protein promoter polymorphism is associated with type 2 diabetes mellitus in Pima Indians

Linkage analysis has identified a susceptibility locus for type 2 diabetes mellitus (T2DM) on chromosome 1q21–q23 in several populations. Results from recent prospective studies indicate that increased levels of C-reactive protein (CRP), a marker of immune system activation, are predictive of diabetes, independent of adiposity. Because CRP is located on 1q21, we considered it a potential positional candidate gene for T2DM. We therefore evaluated CRP and the nearby serum amyloid P-component, APCS, which is structurally similar to CRP, as candidate diabetes susceptibility genes. Approximately 10.9 kb of the CRP-APCS locus was screened for polymorphisms using denaturing high performance liquid chromatography and direct sequencing. We identified 27 informative polymorphisms, including 26 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion, which were divided into 7 linkage disequilibrium clusters. We genotyped representative SNPs in ∼1300 Pima samples and found a single variant in the CRP promoter (SNP 133552) that was associated with T2DM ( P=0.014), as well as a common haplotype (CGCG) that was associated with both T2DM ( P=0.029) and corrected insulin response, a surrogate measure of insulin secretion in non-diabetic subjects ( P=0.050). Linkage analyses that adjusted for the effect of these polymorphisms indicated that they do not in themselves account for the observed linkage with T2DM on chromosome 1q. However, these findings suggest that variation within the CRP locus may play a role in diabetes susceptibility in Pima Indians.

Insulin Self-Association and the Relationship to Pharmacokinetics and Pharmacodynamics

The treatment of type 1 diabetes requires multiple, daily injections of insulin. While many improvements involving formulation adjustments have been made in an attempt to optimize therapy, clinical experience indicates that the commercially available insulin preparations used for treatment have significant limitations. One principal deficiency relates to poor simulation of the physiological insulin secretion pattern, making achieving normalization of blood glucose concentrations difficult. Endogenous insulin secretion in nondiabetic subjects is characterized by a pulsatile profile that displays multiple, meal-stimulated phases and low basal concentrations between meals and overnight. Optimal diabetes therapy, therefore, requires insulin preparations that display a rapid onset of action with corresponding rapid clearance to provide for meal ingestion as well as preparations that can maintain a sustained, peakless profile for basal requirements. Recent efforts in pharmaceutical research have used the concept of rational-based design of the insulin molecule in an attempt to produce preparations that display more ideal pharmacological profiles. Using detailed structural information obtained from X-ray crystallographic studies to guide design strategies and exploit the nonrestrictive synthetic capabilities of recombinant DNA technology, researchers have prepared a number of insulin analogs that display a reduced propensity towards self-association. Clinical evaluations have shown that these so called "monomeric" analogs better mimic the meal-stimulated pharmacokinetics of insulin secretion observed in nondiabetics. Two monomeric insulin analog preparations have successfully obtained regulatory approval and are now commercially available. Efforts to produce optimized basal-acting insulin analogs have lagged behind. While some of these analogs have been engineered using recombinant DNA technology, design strategies in many cases exploit physicochemical properties of insulin other than self-association. One basal insulin analog has recently received regulatory approval. This paper reviews insulin self-association and its relationship to pharmacokinetics and pharmacodynamics. Particular emphasis is placed on the approaches used to manipulate self-assembly resulting in meal-time insulin analogs that display optimal pharmacological properties. Other design strategies used to develop improved basal insulin preparations are also considered.

Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects.

Elevated heart rate has been predictive of cardiovascular disease and has been proposed as a global index of the autonomic nervous system influence on the heart. Hyperinsulinism has been shown to trigger sympathetic activity experimentally; however, the clinical and epidemiological data on the association of heart rate with hyperinsulinism and insulin resistance are conflicting. Insulin sensitivity (S(I)) and the acute insulin response (AIR) to glucose were assessed by a frequently sampled intravenous glucose tolerance test and related to resting heart rate in the tri-ethnic nondiabetic population (n = 1,000) of the Insulin Resistance Atherosclerosis Study. Heart rate was related to fasting insulin (r = 0.20), intact proinsulin (r = 0.15), split proinsulin (r = 0.17), and AIR (r = 0.18), and an inverse relation was found between heart rate and S(I) (r = -0.19) (all P values <0.0001, adjusted for age, sex, ethnicity, glucose tolerance status, and smoking). In a multiple linear regression analysis (adjusting for age, sex, ethnicity, clinical center, glucose tolerance status, and smoking), heart rate was significantly and independently associated with AIR, proinsulin, and S(I). Proinsulin, acute insulin secretion, and S(I) are associated with heart rate in nondiabetic subjects.

Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.

Type 2 diabetes mellitus is a common disabling disease with onset in middle-aged individuals, caused by an imbalance between insulin production and action. Genetic studies point to major genetic components, but, with the exception of maturity-onset diabetes of the young (MODY), specific diabetes susceptibility genes remain to be identified. Recent studies showed that a dominant negative mutation in the insulin promoter factor-1 (IPF-1), a pancreatic beta-cell specific transcription factor, causes pancreatic agenesis and MODY. Thus, we investigated 192 French, non-MODY type 2 diabetic families for mutations in IPF-1. We identified 3 novel IPF-1 mutations, including 2 substitutions (Q59L and D76N) and an in-frame proline insertion (InsCCG243). Functional transactivation assays of these IPF-1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF-1 expression plasmids demonstrate a significant inhibition of basal insulin promoter activity (stronger with the InsCCG243 mutant). We find that the InsCCG243 mutation is linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion becomes progressively impaired. The lower penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin-secretion in nondiabetic subjects. We propose that IPF-1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes in humans.