Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose tolerance.

Proinsulin release is increased relative to insulin secretion in subjects with type 2 diabetes, indicative of islet dysfunction. However, it has not been conclusively shown whether there is an increased relative proinsulin release in subjects with impaired glucose tolerance (IGT), i.e. whether it precedes the development of diabetes. We therefore determined the proinsulin to insulin ratios in the fasting state and after acute stimulation of insulin secretion in 23 postmenopausal women, aged 61-62 yr (mean +/- SD, 61.7 +/- 0.5 yr). Ten women had normal glucose tolerance (NGT), and 13 had IGT. The groups were matched for insulin sensitivity and did not differ in body mass index. Proinsulin and insulin secretion were measured after arginine stimulation (5 g, i.v.) at three glucose levels (fasting, 14 mmol/L, and >25 mmol/L), and the acute insulin (AIR(arg)) and proinsulin responses (APIR(arg)) were calculated as the mean 2-5 min postload increase. At fasting glucose, levels of insulin, proinsulin, or the proinsulin/insulin ratio (13.6 +/- 5.0% vs. 11.1 +/- 2.7%; P = NS) did not differ between NGT and IGT. Although the AIR(arg) values were decreased in the IGT group at all glucose levels (P < 0.05), the absolute proinsulin levels and the APIRs(arg) were similar between IGT and NGT women. Therefore, the IGT women had higher proinsulin/insulin ratios at 14 mmol/L (10.7 +/- 4.4% vs. 6.4 +/- 1.8%; P = 0.006) and more than 25 mmol/L glucose (11.4 +/- 5.2% vs. 6.7 +/- 2.1%; P = 0.007). The IGT group had increased APIR(arg)/AIR(arg) at fasting (2.2 +/- 1.4% vs. 1.3 +/- 0.6%; P = 0.047) and more than 25 mmol/L glucose (3.5 +/- 1.6% vs. 2.3 +/- 0.7%; P = 0.037). We conclude that women with IGT exhibit increased relative proinsulin secretion, suggesting a defect in the intracellular proinsulin processing before diabetes develops.     

Proinsulin in pregnant women with normal glucose tolerance or mild gestational diabetes mellitus.

Pregnancy is characterized by peripheral insulin resistance, which is physiologically compensated by an increase in insulin secretion. Type 2 diabetes and impaired glucose tolerance (IGT) have been associated with an inappropriate increase in insulin precursors, namely proinsulin. The aim of this study was to determine levels of proinsulin (PI), specific insulin (SI) and the proinsulin-to-specific insulin (PI/SI) ratio in consecutive pregnant women (n = 209) with normal glucose tolerance (NGT), as assessed by a 2h oral glucose tolerance test, and with mild gestational diabetes (GDM), in comparison to 32 healthy, non-pregnant women. Furthermore, we related these variables to surrogate markers of insulin resistance and insulin secretion. We found no significant differences in the levels of PI and the PI/ SI ratio between pregnant and non-pregnant women (PI: 5.0 +/- 3.6 vs. 4.8 +/- 3.5 pmol/L, p = NS), and between pregnant women with mild GDM and NGT (PI: 5.4 +/- 2.4 vs. 4.9 +/- 3.9 pmol/L, p = NS). SI was elevated in women with mild GDM (112.2 +/- 47.3 vs. 94.8 +/- 43.0 pmol/L in NGT, p=0.02). PI was related to fasting glucose (r = 0.17, p < 0.02), but not post-load glucose levels, and to fasting insulin [specific insulin: r = 0.67, p = 0.0001; total immunoreactive insulin (IRI): r = 0.69, p = 0.0001], as well as post-load insulin levels (IRI at 120 min: r = 0.18, p < 0.03). The PI/SI ratio showed no association with fasting or post-load glucose or insulin levels. Pregnant women presented with a metabolic pattern suggestive of enhanced insulin resistance, namely increased fasting and post-load insulin levels. In women with mild GDM, fasting and post-load hyperglycemia, as well as an additional increase in insulin resistance was found. Group differences weakened when accounting for differences in body weight. The data of the present study suggest that in normal pregnancy as well as mild GDM metabolic alterations including enhanced insulin resistance and hyperglycemia do not result in an increase in circulating levels of proinsulin, both in absolute terms and relative to levels of specific insulin, as indicated by the proinsulin-to-specific insulin ratio.     

Stimulatory effect of increased non-esterified fatty acid concentrations on proinsulin processing in healthy humans

Aims/hypothesis. To assess the effect of increased concentrations of non-esterified fatty acids (NEFA) on proinsulin processing in healthy humans.¶Methods. We did a hyperglycaemic clamp (130 min duration, 8 mmol/l glucose, with a 5-g arginine bolus at min 120) before and after a 5-h infusion of Intralipid/heparin in 14 healthy subjects. Of the subjects eight underwent a saline control experiment. The proinsulin : insulin (PI:I) ratio immediately after the arginine bolus (122.5 to 125 min) was considered to provide an estimate for the conversion of proinsulin to insulin in the beta cell.¶Results. Concentrations of NEFA were 757 ± 86 μmol/l and 1669 ± 134 μmol/l (p < 0.001) after the 5-h infusion of saline or Intralipid, respectively. Insulin secretion rates were no different between the Intralipid and saline infusions (p = 0.73). There was no statistically significant difference for either the proinsulin concentration or the PI:I ratio during glucose stimulation alone (0 to 120 min). In response to arginine, in contrast, proinsulin remained unchanged during the saline infusion (from 31 ± 6 to 29 ± 7 pmol/l, p = 0.50) but decreased during 5 h of lipid infusion from (21 ± 3 to 15 ± 2 pmol/l, p = 0.02). The PI:I ratio in response to the arginine bolus was higher during the saline infusion (2.0 ± 0.2 % vs 1.7 ± 0.2 %, p = 0.04) but decreased during the Intralipid infusion (from 1.6 ± 0.2 % to 1.2 ± 0.1 %, p = 0.04).¶Conclusion/interpretation. The statistically significantly lower PI:I ratio in response to arginine during experimentally increased concentrations of NEFA suggests that NEFA increase the conversion of proinsulin to insulin in humans in vivo. [Diabetologia (2000) 43: 1368–1373]     

Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P <.001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P =.035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P <.001), but was not significantly different between the groups although there was a trend with lower extraction in IGT (P =.055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P =.036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response.     

Characterisation of beta-cell dysfunction of impaired glucose tolerance: Evidence for impairment of incretin-induced insulin secretion

Aims/hypothesis. Our studies were undertaken to characterise the defective insulin secretion of impaired glucose tolerance (IGT).¶Methods. We studied 13 normal glucose tolerant subjects (NGT) and 12 subjects with IGT carefully matched for age, sex, BMI and waist-to-hip ratio. A modified hyperglycaemic clamp (10 mmol/l) with a standard 2-h square-wave hyperglycaemia, an additional glucagon-like-peptide (GLP)-1 phase (1.5 pmol · kg^–1· min^–1 over 80 min) and a final arginine bolus (5 g) was used to assess various phases of insulin secretion rate.¶Results. Insulin sensitivity during the second phase of the hyperglycaemic clamp was low in both groups but not significantly different (0.12 ± 0.021 in NGT vs 0.11 ± 0.013 μmol · kg^–1· min^–1· pmol^–1 in IGT, p = 0.61). First-phase insulin secretion was lower in IGT (1467 ± 252 vs 3198 ± 527 pmol · min^–1, p = 0.008) whereas the second phase was not (677 ± 61 vs 878 ± 117 pmol · min^–1, p = 0.15). The acute insulin secretory peak in response to GLP-1 was absent in IGT subjects who only produced a late phase of GLP-1-induced insulin secretion rate which was lower (2228 ± 188 pmol · min^–1) than in NGT subjects (3056 ± 327 pmol · min^–1, p = 0.043). Insulin secretion in response to arginine was considerably although not significantly lower in IGT subjects. The relative impairment (per cent of the mean rate for NGT subjects) was greatest for the GLP-1 peak (19 ± 9 %).¶Conclusion/interpretation. In this Caucasian cohort a defective insulin secretion rate is essential for the development of IGT. The variable degrees of impairment of different phases of the insulin secretion rate indicate that several defects contribute to its abnormality in IGT. Defects in the incretin signalling pathway of the beta cell could contribute to the pathogenesis of beta-cell dysfunction of IGT and thus Type II (non-insulin-dependent) diabetes mellitus. [Diabetologia (2000) 43: 852–858]     

不同糖耐量水平人群血清真胰岛素和胰岛素原水平的临床意义

目的 探讨不同糖耐量者血清真胰岛素（ＴＩ）及胰岛素原（ＰＩ）水平的变化及临床意义。方法 用特异的单克隆抗体夹心放大酶联免疫分析法（ＢＡ－ＥＬＩＳＡ）检测１３５例正常糖耐量（ＮＧＴ）、８６例糖耐量低减（ＩＧＴ）及１０１例Ⅱ型糖尿病（ＤＭ）者口服葡萄糖耐量试验（ＯＧＴＴ）各点血清ＴＩ及ＰＩ水平。结果 ３组血清空腹ＴＩ差异无显著性（Ｐ〉０．０５）,免疫反应胰岛素（ＩＲＩ）Ⅱ型ＤＭ组明显升高（Ｐ〈０．０１     

Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin levels

Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited.     

Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy

OBJECTIVES: We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV-infected patients on highly active antiretroviral therapy (HAART). METHODS: Eighteen HIV-infected male patients (six lipodystrophic and 12 nonlipodystrophic) with normal glucose tolerance (NGT) were compared with 10 HIV-infected male patients (eight lipodystrophic and two nonlipodystrophic) with IGT. Plasma concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations. RESULTS: The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; P<0.05), whereas the incrAUC for GIP did not differ between the study groups (7689+/-1097 vs. 8041+/-998 pmol/L/180 min, respectively; not significant). In pooled study groups, the GIP incrAUC correlated positively with the ISR incrAUC without adjustment (r=0.38, P<0.05) and following adjustment for glucose incrAUC (r=0.49, P<0.01). CONCLUSIONS: Our data suggest: (1) that glucose-intolerant, HIV-infected male patients may display enhanced GLP-1 responses to oral glucose compared with normal glucose-tolerant HIV-infected male patients, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART.     

Association of proinsulin and insulin resistance with coronary artery disease in non-diabetic south Indian men.

AIMS: To evaluate the association of plasma proinsulin and insulin resistance (IR) with coronary artery disease (CAD) in non-diabetic subjects. METHODS: In this case control study, 41 normoglycaemic men with angiographic evidence of CAD were compared with 41 control men matched for age and glycaemia and with no history or evidence of cardiac diseases. Estimations of plasma glucose, lipids, fasting plasma specific insulin (SI) and proinsulin (PI) were performed. IR was calculated by the homeostasis model assessment (HOMA) method. Multiple logistic regression analysis was performed to test the association of the variables with the prevalence of CAD. RESULTS: Subjects with CAD had a higher body mass index (BMI) (25.4 +/- 4.3 vs. 22.9 +/- 3.2 kg/m2, P = 0.003) and waist to hip ratio (WHR) (0.95 +/- 0.05 vs. 0.89 +/- 0.09, P = 0.001) and a lower high-density lipoprotein (HDL) cholesterol level (0.97 +/- 0.2 vs. 1.1 +/- 0.2 mmol/l, P = 0.002). They also had higher mean SI values (107.5 vs. 62.3 pmol/l, P = 0.002), PI values (19.3 vs. 5.7 pmol/l, P < 0.0001), PI/SI ratios (21.4 vs. 10.3, P < 0.0001) and HOMA IR (4.2 vs. 2.4, P = 0.004) compared with non-CAD subjects. These variables were associated with CAD in the unadjusted multiple regression analysis. In the multiple regression with the forward entry of the variables, WHR and PI only showed independent association with CAD. CONCLUSIONS: Subjects with CAD had higher levels of obesity and WHR. CAD showed an association with low HDL cholesterol, circulating PI, PI/SI ratios and IR.     

Soluble P-selectin and CD40L levels in subjects with prediabetes, diabetes mellitus, and metabolic syndrome--the Chennai Urban Rural Epidemiology Study

The aim of the study was to determine whether the levels of soluble P-selectin (sP-selectin) and soluble CD40L (sCD40L) are elevated in Asian Indian subjects with impaired glucose tolerance (IGT), diabetes, and metabolic syndrome (MS). Study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), an ongoing population-based study on a representative population of Chennai city in southern India, and were grouped as follows: group 1, normal glucose tolerance (NGT) (n = 60); group 2, IGT (n = 60); and group 3, type 2 diabetes mellitus (n = 60). Normal glucose tolerance, IGT, and diabetes were defined using World Health Organization consulting group criteria. The inclusion criteria were nonsmokers; normal resting 12-lead electrocardiogram; absence of angina, myocardial infarction, or history of any known vascular, infectious, or inflammatory diseases; and subjects not on statins or aspirin. Insulin resistance was calculated using the homeostasis assessment model using the formula: fasting insulin (microIU/mL) x fasting glucose (mmol/L)/22.5. Soluble P-selectin and sCD40L were estimated by enzyme-linked immunosorbent assay. Metabolic syndrome was defined using Adult Treatment Panel III guidelines. Subjects with diabetes and IGT were older (diabetes: 53 +/- 9 years, P < .01; IGT: 51 +/- 10 years, P < .05) compared with the NGT group (48 +/- 10 years). Subjects with diabetes and IGT had higher levels of sP-selectin (diabetes: 162 +/- 79 ng/mL, P < .001; IGT: 102 +/- 37 ng/mL, P < .001) compared with the NGT group (55 +/- 48 ng/mL). Soluble CD40L levels were also higher in those with diabetes and IGT (diabetes: 3.2 +/- 2.0 ng/mL, P < .001; IGT: 2.0 +/- 1.3 ng/mL, P < .001) compared with the NGT group (1.1 +/- 0.9 ng/mL). Subjects with MS had significantly higher levels of sP-selectin (with MS, 118 +/- 76 ng/mL; without MS, 95 +/- 66 ng/mL; P = .028) and sCD40L (with MS, 2.4 +/- 1.8 ng/mL; without MS, 1.9 +/- 1.5 ng/mL; P = .036) compared with subjects without MS. Among subjects with NGT and IGT, the mean levels of sP-selectin (tertile I, 65.0 ng/mL; tertile II, 80.0 ng/mL; tertile III, 91.0 ng/mL) and sCD40L levels (tertile I, 1.2 ng/mL; tertile II, 1.7 ng/mL; tertile III, 1.8 ng/mL) increased with increase in tertiles of homeostasis assessment model-insulin resistance, and the difference reached statistical significance in the last tertile compared with the first tertile (P < .05). This study demonstrates that increased levels of sP-selectin and sCD40L are seen in Asian Indian subjects with IGT, type 2 diabetes mellitus, MS, and insulin resistance.     

Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients

The relationship between basal serum tumor necrosis factor alpha (TNFalpha) levels and peripheral tissue (muscle) sensitivity to insulin was examined in 63 subjects with normal glucose tolerance (NGT), 18 subjects with impaired glucose tolerance (IGT), and 123 patients with type 2 diabetes mellitus (T2DM). The BMI was similar in NGT (28.8+/-0.7 kg/m(2)), IGT (31.1+/-1.0), and T2DM (30.0+/-0.4) groups. The fasting serum TNFalpha concentration in T2DM (4.4+/-0.2 pg/ml) was significantly higher than in NGT (3.1+/-0.2) and IGT (3.4+/-0.2; both P<0.05). In T2DM the fasting plasma glucose (FPG=183+/-5 mg/dl) and insulin (FPI=17+/-1 micro U/ml) concentrations were significantly higher than in NGT (FPG=95+/-1; FPI=10+/-1) and IGT (FPG=100+/-2; FPI=13+/-1; all P<0.01). The rate of total body insulin-mediated glucose disposal (Rd; 40 mU/m(2) min euglycemic insulin clamp in combination with (3)H-glucose) was reduced in T2DM (102+/-3 mg/m(2) min) compared with NGT (177+/-10) and IGT (151+/-14; both P<0.01). The serum TNFalpha concentration was inversely correlated with Rd (r=-0.47, P<0.0001) and positively correlated with both FPG (r=0.32, P=0.004) and FPI (r=0.32, P=0.004) in NGT plus IGT. No correlation was observed between serum TNFalpha and Rd (r=-0.02), FPG (r=0.15), or FPI (r=0.15) in T2DM. In stepwise multiple regression analysis using age, sex, BMI, FPG, FPI and serum TNFalpha concentration as independent variables, only BMI and serum TNFalpha concentration were significant and independent predictors of Rd (r(2)=0.29, P<0.0001) in the NGT plus IGT group, while FPG and FPI were significant and independent predictors of Rd (r(2)=0.13, P<0.0001) in T2DM. These results suggest that: (i) an increase in circulating TNFalpha concentration is associated with peripheral insulin resistance and increased plasma glucose and insulin levels prior to the onset of type 2 diabetes; and (ii) the further deterioration in peripheral insulin resistance in T2DM (compared with NGT and IGT) is unrelated to the increase in serum TNFalpha concentration.     

新疆汉、维民族糖调节受损人群胰岛素分泌功能和胰岛素作用功能的研究

目的 评估新疆汉、维民族在IFG,IGT及IGR阶段的胰岛素分泌功能和胰岛素作用功能。 方法 采用多中心研究进行横断面调查,行OGTT试验。用胰岛素抵抗指数（HOMA-IR）评估IR,胰岛β细胞功能指数（HOMA-β）评估基础胰岛素分泌;ΔI30/ΔG30评价胰岛素早相分泌,ΔI30/ΔG30/HOMA-IR评估葡萄糖处置指数（DI）。 结果 WC、BMI、血脂、FIns、2 hIns在汉、维民族不同糖代谢组差异有统计学意义。IFG组与NGT、IGT组比较,汉、维族人群的HOMA-IR差异有统计学意义。在汉族中NGT组与IGT、IGR组比较,HOMA-β差异有统计学意义（P=0.030、0.044）,而在维族只有IFG组与NGT组比较差异有统计学意义（P=0.001）。ΔI30/ΔG30、DI在两民族不同糖代谢组差异均无统计学意义。 结论 汉族人群IR在IFG阶段,胰岛素分泌功能在IGT阶段起主要作用。IR和胰岛素分泌功能在维族人群IFG阶段起重要作用。胰岛素早相分泌及葡萄糖处置功能在糖调节受损阶段作用不显著。     

Relationship between insulin resistance and left ventricular diastolic dysfunction in patients with impaired glucose tolerance and type 2 diabetes

AIM: The aim of this study was to explore the relationship between insulin resistance (IR) and the left ventricular diastolic function in patients with type 2 diabetes and subjects with impaired glucose tolerance (IGT). METHODS: The study included 119 subjects who underwent oral glucose tolerance test (OGTT). IR was assessed using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI). Left ventricular diastolic function was assessed using trans-thoracic Doppler echocardiography. RESULTS: Based on the OGTT results, 29 subjects had normal glucose tolerance (NGT), 20 subjects had impaired glucose tolerance (IGT), and 70 patients had type 2 diabetes. There were significant differences among the patients in groups with NGT, IGT and diabetes regarding HOMA-IR (4.20 +/- 1.20 vs. 6.45 +/- 3.83 vs. 8.70 +/- 6.26; P < 0.001) and QUICKI (0.54 +/- 0.11 vs. 0.49 +/- 0.08 vs. 0.47 +/- 0.08; P < 0.001). In subjects with NGT, IGT and patients with diabetes, the pulsed Doppler transmitral variables were: E-wave (0.72 +/- 0.16 cm/s vs. 0.62 +/- 0.13 cm/s vs. 0.58 +/- 0.17 cm/s; P < 0.001), A-wave (0.61 +/- 0.13 cm/s vs. 0.62 +/- 0.11 cm/s vs. 0.71+/- 0.14 cm/s; P = 0.006) and E/A ratio (1.22 +/- 0.33 vs. 1.02 +/- 0.24 vs. 0.85 +/- 0.26; p < 0.001). The proportion of subjects with an E/A ratio <1 was 27.6% in the group with NGT, 55% in the group with IGT and 75.7% in the group with diabetes (P < 0.001). The E/A ratio correlated with HOMA-IR (r = -0.30, p = 0.001) and QUICKI (r = 0.37, p < 0.0001). Multiple linear regression model showed that IR (assessed by QUICKI) was an independent correlate of diastolic dysfunction (P = 0.034). CONCLUSIONS: In subjects with impaired glucose tolerance and patients with type 2 diabetes, insulin resistance is associated with impaired diastolic function of the left ventricle.     

Effects of thorough mastication on postprandial plasma glucose concentrations in nonobese Japanese subjects

Thorough mastication has the potential to affect postprandial plasma glucose concentrations by improving digestibility and absorption of nutrients. To evaluate the effects of mastication on postprandial plasma glucose concentration, we compared usual and thorough mastication in subjects with normal glucose tolerance (NGT group, n = 16) and subjects predisposed to type 2 diabetes (first-degree relatives of type 2 diabetic patients, subjects with impaired glucose tolerance, and type 2 diabetic patients) (predisposed group, n = 10) in a crossover trial of 52 test meals. Plasma glucose and serum insulin concentrations were measured for 3 hours postprandially, and the insulinogenic index (the ratio of incremental serum insulin to plasma glucose concentration during the first 30 minutes after meal) was calculated. In the NGT group, thorough mastication reduced the postprandial plasma glucose concentration at 90 minutes (5.8 +/- 0.3 vs 6.5 +/- 0.4 mmol/L, P < .05) and 120 minutes (5.4 +/- 0.2 vs 6.3 +/- 0.4 mmol/L, P < .05) and the area under the curve (AUC) from -15 to 180 minutes (19.1 +/- 0.6 vs 20.6 +/- 0.8 [mmol . L]/h, P < .05) without an increase in the AUC for insulin. In the predisposed group, thorough mastication significantly augmented plasma glucose and serum insulin concentrations and the AUCs compared with usual mastication. Thorough mastication elicited a significantly higher insulinogenic index than usual mastication in the NGT group (205.0 +/- 27.6 vs 145.6 +/- 17.7 pmol/mmol, P < .05), whereas the predisposed group showed significantly less early-phase insulin secretion than the NGT group. In the NGT group the postprandial plasma glucose concentration upon thorough mastication of meal was significantly lower, most probably because of the potentiation of early-phase insulin secretion. In the subjects predisposed to type 2 diabetes, thorough mastication did not potentiate early-phase insulin secretion and elicited a higher postprandial plasma glucose concentration.     

A DIRECT ASSAY FOR PROINSULIN IN PLASMA AND ITS APPLICATIONS IN HYPOGLYCAEMIA

A direct radioimmunoassay in unextracted plasma is described. The assay has a sensitivity of 4 pmol/l (2 standard deviation from zero). The proinsulin antiserum was immuno-adsorbed against human C-peptide and insulin coupled to glass beads. Cross-reactivity of the antiserum was assessed and shown to be less than 0.01% with both peptides. In normal healthy fasting subjects the plasma proinsulin level was 6.7 +/- 1.7 pmol/l (n = 17) (mean +/- SD). Fasting proinsulin levels in non-insulin dependent diabetics were significantly elevated compared with non diabetics (14.2 +/- 2 pmol/l (n = 11) vs 6.7 +/- 1.7 (n = 17) P less than 0.005). The insulin/proinsulin ratio was 3.4:1 in the non-insulin dependent diabetic compared with 6:1 in non-diabetics. Samples from 21 insulinoma patients were assayed and mean fasting plasma proinsulin level was 255 pmol/l +/- 479 when the patients were hypoglycaemic. The range in pro-insulin levels was large (30-2300 pmol/l). Mean fasting proinsulin level in three hypoglycaemic subjects due to sulphonylurea overdose was 15.7 +/- 2.3 pmol/l. The molar ratio of proinsulin to insulin was 1:6 in healthy subjects, 1:1 in insulinoma patients and 10:1 in sulphonylurea induced hypoglycaemic patients.     

Glucagon-like peptide-1 (7-37) augments insulin-mediated glucose uptake in elderly patients with diabetes.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose-induced insulin secretion in patients with type 2 diabetes. It has also been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs because this hormone enhances insulin-mediated glucose disposal. However, interpretations of the studies have been controversial. This study determines the effect of GLP-1 on insulin-mediated glucose disposal in elderly patients with type 2 diabetes. METHODS: Studies were conducted on 8 elderly patients with type 2 diabetes (age range, 76 +/- 1 years; body mass index, 28 +/- 1 kg/m(2)). Each subject underwent two 180-minute euglycemic (insulin infusion rate, 40 mU/m(2)/min) insulin clamps in random order. Glucose production (Ra) and disposal (Rd) rates were measured using tritiated glucose methodology. In one study, glucose and insulin alone were infused. In the other study, a primed-continuous infusion of GLP-1 was administered at a final rate of 1.5 pmol x kg(-1) x min(-1) from 30 to 180 minutes. RESULTS: Glucose values were similar between the control and GLP-1 infusion studies. 120- to 180-minute insulin values appeared to be higher during the GLP-1 infusion study (control, 795 +/- 63 pmol/l; GLP-1, 1140 +/- 275 pmol/l; p = not significant [NS]). The higher insulin values were largely due to 2 subjects who had substantial insulin responses to GLP-1 despite euglycemia and hyperinsulinemia. The 120- to 180-minute insulin values were similar in the other 6 subjects (control, 746 +/- 35 pmol/l; GLP-1, 781 +/- 41 pmol/l; p = NS). Basal (control, 2.08 +/- 0.05 mg/kg/min; GLP-1, 2.13 +/- 0.04 mg/kg/min; p = NS) and 120- to 180-minute (control, 0.50 +/- 0.18 mg/kg/min; GLP-1, 0.45 +/- 0.14 mg/kg/min; p = NS) Ra was similar between studies. The 120- to 180-minute Rd values were higher during the GLP-1 infusion studies (control, 4.73 +/- 0.39 mg/kg/min; GLP-1, 5.52 +/- 0.43 mg/kg/min; p <.01). When the 2 subjects who had significant insulin responses to GLP-1 during the euglycemic clamp were excluded, the 120- to 180-minute Rd values were still higher in the GLP-1 infusion study (control, 5.22 +/- 0.32 mg/kg/min; GLP-1, 6.05 +/- 0.37 mg/kg/min; p <.05). CONCLUSIONS: We conclude that GLP-1 may enhance insulin sensitivity in elderly patients with diabetes.     

Disproportionately elevated proinsulin in Pima Indians with noninsulin-dependent diabetes mellitus

Fasting serum total immunoreactive insulin (IRI), true insulin, and true proinsulin (PI) were measured in 169 Pima Indians. The relationship of these variables to glucose tolerance, obesity, and parental diabetes was studied. Seventy-seven subjects had normal glucose tolerance, 46 had impaired glucose tolerance (IGT), and 46 had noninsulin-dependent diabetes mellitus (NIDDM) by WHO criteria. In subjects with normal glucose tolerance, the geometric mean ratio of PI to IRI (PI/IRI) was 10.8% (arithmetic mean, 12.5%), similar to that reported in other ethnic groups with lower prevalence rates of NIDDM. Parental diabetes had no effect on PI/IRI. Obese persons (body mass index, greater than or equal to 27 kg/m2) with normal glucose tolerance had PI/IRI of 9.3% compared with 16.3% for the nonobese (P less than 0.001), and PI/IRI was negatively correlated with body mass index (r = -0.34; P = 0.002). Proinsulin was disproportionately elevated in NIDDM (geometric mean PI/IRI, 19.9%; arithmetic mean, 23.6%), and the degree of elevation was related to the severity of hyperglycemia, but not the duration of diabetes. Subjects with IGT were more obese and had higher fasting plasma glucose (5.7 vs. 5.2 mmol/L; P = 0.025), true insulin (250 vs. 125 pmol/L; P less than 0.001), and PI concentrations (26 vs. 15 pmol/L; P less than 0.001) than those with normal glucose tolerance but similar mean PI/IRI (9.4 vs. 10.8%; P = 0.4). These findings indicate that Pima Indians with NIDDM have a disproportionate elevation of PI consistent with the hypothesis that beta-cell dysfunction associated with hyperglycemia leads to the release of proinsulin-rich immature granules.     

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.     

Basal insulin hypersecretion in insulin-resistant Zucker diabetic and Zucker fatty rats: role of enhanced fuel metabolism.

The biochemical mechanisms responsible for basal hyperinsulinemia in insulin-resistant states have not been fully defined. We therefore studied pancreatic beta-cell function in vitro to characterize the relative importance of fuel metabolism or secretion via a constitutive pathway in the maintenance of high basal insulin secretion in Zucker diabetic fatty (ZDF) and Zucker fatty (ZF) rats. Insulin secretion from ZF (10+/-1.8 v 5+/-0.6 pmol/ng DNA/h) and ZDF (30+/-4 v 7+/-0.8 pmol/ng DNA/h) islets at 2.8 mmol/L glucose was two to four times greater than secretion from islets of lean littermate control rats. In response to a decreasing glucose concentration (from 12 to 0 mmol/L), a paradoxical increase in insulin secretion was observed in perfused ZDF rat pancreas. Insulin secretion at 2.8 mmol/L glucose was suppressed approximately 70% to 80% in islets from ZDF and ZF rats following exposure to diazoxide, a K+-adenosine triphosphate (K(ATP)) channel opener that inhibits membrane depolarization, or rotenone and oligomycin, agents that inhibit ATP production, or by incubation at 23 degrees C. Inhibition of glycolysis with mannoheptulose, 2-deoxyglucose, and iodoacetate or fatty acid oxidation with a carnitine palmitoyltransferase I inhibitor also significantly inhibited basal insulin secretion in islets of ZDF and ZF rats but not their lean littermates. Furthermore, the glycolytic flux at 2.8 mmol/L glucose was significantly higher in ZDF islets versus ZDF lean littermate (ZLC) islets (2.2+/-0.1 v 3.7+/-0.3 pmol/ng DNA/2 h, P < .01) and was suppressed by mannoheptulose. In ZDF and ZF islets, high basal insulin secretion was maintained despite a 50% reduction in the rate of proinsulin/insulin biosynthesis at 2.8 mmol/L glucose. The rate of proinsulin to insulin conversion and the ratio of proinsulin to insulin secretion by islets of ZDF rats were similar to the values in the lean littermates. Thus, basal hypersecretion in these two insulin-resistant models appears to be related to enhanced fuel metabolism rather than the contribution of a constitutive pathway of secretion.     

Insulin secretion and anti-GAD65 antibodies in subjects with impaired glucose tolerance.

The study was designed to evaluate the pattern of insulin secretion and the presence of anti-GAD65 antibodies as beta-cell autoimmune marker in subjects with impaired glucose tolerance (IGT) and their impact on the further development of glucose intolerance. 29 subjects with IGT, of mean BMI 24.7 +/- 2.4 kg/m(2) and mean age 37.7 +/- 7.0 years were enrolled in the study. They were followed-up once yearly for three years. A group of 59 age- and weight-matched subjects with normal glucose tolerance (NGT) served as a control group. 42 newly-diagnosed diabetic patients, of mean BMI 24.4 +/- 2.7 kg/m(2) and mean age 37.2 +/- 6.9 years were also studied. According to their response during IVGTT the subjects with IGT were divided into two groups. The first group (n = 11)(IGT-I) showed reduced FPIS (34.0 +/- 8.9 mU/l vs 114.4 +/- 41.2, p < 0.001), SPIS being within normal values, and reduced AUC for total insulin secretion (1554.1 +/- 496.3 vs 2323.6 +/- 804.5 mU/l x 60 min, p < 0.001); the difference with type 1 diabetic patients being significant (p < 0.001), the pattern of insulin secretion being quite similar to that of type 2 diabetic patients. The other group (n = 18) (IGT-II) demonstrated normal insulin secretion (FPIS, SPIS, AUC for insulin secretion), not differing from that of the controls with NGT. Anti-GAD65 were present in 3.3% of subjects with NGT, in 73.7% of patients with type 1 diabetes and in none of type 2 diabetic patients. 18% from the group with IGT-I were anti-GAD65 positive, and 22% - from IGT-II. 5 of the subjects with IGT-I developed diabetes during the follow-up period - 2 at the 1st year, 1 at the 2nd year and 2 - at the third year. One of these patients was anti-GAD65 positive (having the highest anti-GAD65 level amongst the others with IGT - 15.2 U/ml), showing pattern of insulin secretion similar to that of type 1 diabetic patients. 3 of the subjects with IGT-II reverted to NGT within the first year and 2 - at the second year, none of them being anti-GAD65 positive. The anti-GAD65 positive patients from this group remained with IGT, and none progressed to diabetes mellitus. We consider that IVGTT allows precise assessment of the phases of insulin secretion and in combination with the study of anti-GAD65 antibodies helps to identify the subjects with IGT at risk of developing diabetes mellitus. As far as the decrease in the FPIS is considered it could be proposed that such subjects are assigned to certain protective measures - diet, physical activity and some drugs affecting postprandial glucose levels.