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Increased proinsulin secretion, which characterizes type 2 diabetes and insulin resistance, may be due to an intrinsic, primitive defect in proinsulin processing or be secondary to increased demand on β-cells (hyperinsulinemia secondary to insulin resistance). An alternative way to investigate the relation between relative hyperproinsulinemia and increased secretory demand is to study the dynamic changes in the proinsulin-to-insulin ratio after partial pancreatectomy, a model of acute increased β-cell workload on the remaining pancreas. To pursue this aim, patients without diabetes, scheduled for partial pancreatectomy, underwent 4-h mixed-meal tests and hyperinsulinemic-euglycemic clamps before and after surgery. After acute β-cell mass reduction, no changes were observed in the fasting proinsulin-to-insulin ratio, whereas the fold change in the proinsulin-to-insulin ratio significantly increased over time after the meal. Further, our data demonstrate that whole-body insulin resistance is associated with underlying defects in proinsulin secretion, which become detectable only in the presence of increased insulin secretion demand., (© 2018 by the American Diabetes Association.)

In vivo studies have investigated the role of β-cell dysfunction in type 2 diabetes (T2D), whereas in vitro research on islets has elucidated key mechanisms that control the insulin secretion rate. However, the relevance of the cellular mechanisms identified in vitro (i.e., the triggering and amplifying pathways) has not been established in vivo. Furthermore, the mechanisms underpinning β-cell dysfunction in T2D remain undetermined. We propose a unifying explanation of several characteristic features of insulin secretion both in vitro and in vivo by using a mathematical model. The model describes the triggering and amplifying pathways and reproduces a variety of in vitro and in vivo tests in subjects with and without T2D, identifies the mechanisms modulating first-phase insulin secretion rate in response to basal hyperglycemia or insulin resistance, and shows that β-cell dysfunction in T2D can be explained by an impaired amplifying pathway with no need to postulate defects in intracellular calcium handling., (© 2017 by the American Diabetes Association.)

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A , IGF2BP2 , KCNQ1 , HNF1B , VPS13C/C2CD4A , FAF1 , PTPRD , AP3S2 , KCNK16 , MAEA , LPP, WFS1 , and TMPRSS6 loci. The fasting glucose-raising allele near PDX1 , a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits., (© 2017 by the American Diabetes Association.)

A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 × 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 × 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 × 10(-3); n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 × 10(-9); n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m(2); P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR)., Research Design and Methods: Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at isoglycemia (IISR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and β-cell glucose sensitivity (β-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study., Results: In NGT, IISR was related to both insulin sensitivity and antecedent insulin exposure; GISR was related to insulin exposure. IISR was positively, if weakly, related to β-GS (r= 0.16, P < 0.0001). Both IISR (-23 [39] vs. -9 [2]%, median [interquartile range], P < 0.03) and β-GS (69 [47] vs. 118 [83] pmol ⋅ min(-1) ⋅ m(-2) ⋅ mmol(-1) ⋅ L, P < 0.0001) were decreased in IGR compared with NGT. Insulin sensitivity and β-GS were the major determinants of mean OGTT glucose in both NGT and IGR, with a minor role for IISR. In a multivariate logistic model, IGR was predicted by β-GS (odds ratio 4.84 [95% CI 2.89-8.09]) and insulin sensitivity (3.06 [2.19-4.27]) but not by IISR (1.11 [0.77-1.61])., Conclusions: Pre-exposure to physiological hyperinsulinemia stimulates insulin secretion to a degree that depends on insulin sensitivity. However, this phenomenon has limited impact on β-cell dysfunction and dysglycemia.

Objective: Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes., Research Design and Methods: In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19-44 kg/m(2), 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and β-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose)., Results: Insulin sensitivity was similar in weight gainers (top 20% of the distribution of BMI changes), weight losers (bottom 20%), and weight stable subjects across quartiles of baseline BMI. By multiple logistic or linear regression analyses controlling for center, age, sex, and baseline BMI, neither insulin sensitivity nor any β-cell function parameter showed an independent association with weight gain; this was true in normal glucose tolerance, impaired glucose tolerance, and whether subjects progressed to dysglycemia or not. Baseline BMI was significantly higher in gainers (26.1 ± 4.1 kg/m(2)) and losers (26.6 ± 3.7 kg/m(2)) than in weight stable subjects (24.8 ± 3.8 kg/m(2), P<0.0001 for both gainers and losers). Baseline waist circumference (or equivalently, BMI or weight) was a positive, independent predictor of both weight gain and weight loss (odds ratio 1.48 [95% CI 1.12-1.97]) in men and (1.67 [1.28-2.12]) in women. In men only, better insulin sensitivity was an additional independent predictor of weight loss., Conclusions: Neither insulin sensitivity nor insulin secretion predicts spontaneous weight gain. Individuals who have attained a higher weight are prone to either gaining or losing weight regardless of their glucose tolerance., (© 2011 by the American Diabetes Association.)

Objective: The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration., Research Design and Methods: We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals., Results: In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001)., Conclusions: In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes.

Objective: To study insulin sensitivity and perfusion in skeletal muscle together with the beta-cell function in subjects with the m.3243A>G mutation in mitochondrial DNA, the most common cause of mitochondrial diabetes., Research Design and Methods: We measured skeletal muscle glucose uptake and perfusion using positron emission tomography and 2-[18F]fluoro-2-deoxyglucose and [15O]H2O during euglycemic hyperinsulinemia in 15 patients with m.3243A>G. These patients included five subjects with no diabetes as defined by the oral glucose tolerance test (OGTT) (group 1), three with GHb <6.1% and newly found diabetes by OGTT (group 2), and seven with a previously diagnosed diabetes (group 3). Control subjects consisted of 13 healthy individuals who were similar to the carriers of m.3243A>G with respect to age and physical activity. Beta-cell function was assessed using the OGTT and subsequent mathematical modeling., Results: Skeletal muscle glucose uptake was significantly lower in groups 1, 2, and 3 than in the control subjects. The glucose sensitivity of beta-cells in group 1 patients was similar to that of the control subjects, whereas in group 2 and 3 patients, the glucose sensitivity was significantly lower. The insulin secretion parameters correlated strongly with the proportion of m.3243A>G mutation in muscle., Conclusions: Our findings show that subjects with m.3243A>G are insulin resistant in skeletal muscle even when beta-cell function is not markedly impaired or glucose control compromised. We suggest that both the skeletal muscle insulin sensitivity and the beta-cell function are affected before the onset of the mitochondrial diabetes caused by the m.3243A>G mutation.

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying beta-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14-15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol.min(-1).m(-2) was 11.7 +/- 1.1 vs. 7.2 +/- 0.7 mmol/l; P < 0.05), and decreased in slope (53 +/- 15 vs. 148 +/- 38 pmol.min(-1).m(-2).mmol(-1).l; P < 0.05) and the parameter of the dynamic control was decreased (220 +/- 67 vs. 908 +/- 276 pmol.m(-2).mmol(-1).l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 +/- 0.2 vs. 5.9 +/- 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 +/- 0.5 vs. 7.2 +/- 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of beta-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of beta-cell dysfunction.

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can modify beta-cell response by either inhibiting or potentiating both first- and second-phase insulin release. In normal subjects, the effect of acute hyperglycemia on insulin secretion is controversial. We measured (in 13 healthy volunteers) insulin secretion (by deconvolution of plasma C-peptide concentrations) during three consecutive 30-min hyperglycemic steps (2.8, 2.8, and 5.6 mmol/l), followed by an intravenous arginine bolus. First-phase insulin secretion in response to the first hyperglycemic step (456 +/- 83 pmol.min(-1).m(-2)) was significantly larger than that in response to the second step (311 +/- 37 pmol.min(-1).m(-2), P < 0.01); the subsequent increase in glycemia failed to stimulate first-phase secretion any further (377 +/- 60 pmol.min(-1).m(-2), NS vs. the previous value). This inhibition was also evident when insulin release rates were corrected for the respective increments (absolute or percentage) in plasma glucose levels and was not due to beta-cell exhaustion because the arginine bolus still elicited a large peak of insulin secretion (4,790 +/- 2,330 pmol.min(-1).m(-2)). In contrast, second-phase insulin secretion was related to the prevailing glucose levels across the three hyperglycemic steps in a direct quasilinear manner. We conclude that first-phase insulin secretion is inhibited by short-term modest hyperglycemia, whereas the second-phase insulin secretion increases linearly with hyperglycemia.

Bariatric surgery results in notable weight loss and alleviates hyperglycemia in patients with type 2 diabetes (T2D). We aimed to characterize the vascular effects of a mixed meal and infusion of exogenous glucose-dependent insulinotropic polypeptide (GIP) in the splanchnic region in 10 obese patients with T2D before and after bariatric surgery and in 10 lean control subjects. The experiments were carried out on two separate days. Pancreatic and intestinal blood flow (BF) were measured at baseline, 20 min, and 50 min with 15O-water by using positron emission tomography and MRI. Before surgery, pancreatic and intestinal BF responses to a mixed meal did not differ between obese and lean control subjects. Compared with presurgery, the mixed meal induced a greater increase in plasma glucose, insulin, and GIP concentrations after surgery, which was accompanied by a marked augmentation of pancreatic and intestinal BF responses. GIP infusion decreased pancreatic but increased small intestinal BF similarly in all groups both before and after surgery. Taken together, these results demonstrate that bariatric surgery leads to enhanced splanchnic vascular responses as a likely consequence of rapid glucose appearance and GIP hypersecretion. [ABSTRACT FROM AUTHOR]

To characterize the defects in β-cell function in subjects with impaired fasting glucose (IFG) and compare the results to impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) subjects, β-cell glucose sensitivity and rate sensitivity during the oral glucose tolerance test were measured with the model by Mari in 172 Mexican Americans. A subgroup (n = 70) received a 2-h hyperglycemic clamp (+125 mg/dL), and first- and second-phase insulin secretion were quantitated. Compared with NGT, subjects with IFG and IGT manifested a decrease in b-cell glucose sensitivity; IFG subjects, but not IGT subjects, had decreased β-cell rate sensitivity. In IFG subjects, the defect in β-cell glucose sensitivity was time dependent, began to improve after 60 min, and was comparable to NGT after 90 min. The incremental area under the plasma C-peptide concentration curve during the first 12 min of the hyperglycemic clamp (ΔC-pep [AUC]0-12) was inversely related with the increase in FPG concentration (r = 236, r = 0.001), whereas ΔC-pep[AUC]15-120 positively correlated with FPG concentration (r = 0.29, r , 0.05). When adjusted for the prevailing level of insulin resistance, first-phase insulin secretion was markedly decreased in both IFG and IGT, whereas second-phase insulin secretion was decreased only in IGT. These results demonstrate distinct defects in β-cell function in IFG and IGT. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To study insulin sensitivity and perfusion in skeletal muscle together with the β-cell function in subjects with the m.3243A>G mutation in mitochondrial DNA, the most common cause of mitochondrial diabetes. RESEARCH DESIGN AND METHODS--We measured skeletal muscle glucose uptake and perfusion using positron emission tomography and 2-[[sup 18]F]fluoro-2-deoxyglucose and [[sup 15]O]H[sub 2]O during euglycemic hyperinsulinemia in 15 patients with m.3243A>G. These patients included five subjects with no diabetes as defined by the oral glucose tolerance test (OGTT) (group 1), three with GHb <6.1% and newly found diabetes by OGTT (group 2), and seven with a previously diagnosed diabetes (group 3). Control subjects consisted of 13 healthy individuals who were similar to the carriers of, m.3243A>G with respect to age and physical activity. β-Cell function was assessed using the OGTT and subsequent mathematical modeling. RESULTS--Skeletal muscle glucose uptake was significantly lower in groups 1, 2, and 3 than in the control subjects. The glucose sensitivity of β-cells in group 1 patients was similar to that of the control subjects, whereas in group 2 and 3 patients, the glucose sensitivity was significantly lower. The insulin secretion parameters correlated strongly with the proportion of m.3243A>G mutation in muscle. CONCLUSIONS---Our findings show that subjects with m.3243A >G are insulin resistant in skeletal muscle even when β-cell function is not markedly impaired or glucose control compromised. We suggest that both the skeletal muscle insulin sensitivity and the β-cell function are affected before the onset of the mitochondrial diabetes caused by the m.3243A>G mutation. Diabetes 58:543-549, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose). RESEARCH DESIGN AND METHODS--Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20-61 kg/m[sup 2]). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration doseresponse curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESULTS--The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P ≤ 0.05). The results were similar when subjects were stratified by BMI tertile (P ≤ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27-0.59, P ≤ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients. CONCLUSIONS--Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another. Diabetes 57:1340-1348, 2008 [ABSTRACT FROM AUTHOR]

Currently, there are no data in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of type 2 diabetes after bariatric surgery, which was reported as an additional benefit of the surgical treatment for morbid obesity. With this question in mind, insulin sensitivity, using euglycemic-hyperinsulinemic clamp, and insulin secretion, by the C-peptide deconvolution method after an oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines, have been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) to avoid the weight loss interference. Diabetes disappeared 1 week after BPD, while insulin sensitivity (32.96 ± 4.3 to 65.73 ± 3.22 µmol ⋅ kg fat-free mass-1 ⋅ min-1 at 1 week and to 64.73 ± 3.42 µmol ⋅ kg fat-free mass-1 ⋅ min-1 at 4 weeks; P < 0.0001) was fully normalized. Fasting insulin secretion rate (148.16 ± 20.07 to 70.0.2 ± 8.14 and 83.24 ± 8.28 pmol/min per m²; P < 0.01) and total insulin output (43.76 ± 4.07 to 25.48 ± 1.69 and 30.50 ± 4.71 nmol/m²; P < 0.05) dramatically decreased, while a significant improvement in β-cell glucose sensitivity was observed. Both fasting and glucose-stimulated gastrointestinal polypeptide (13.40 ± 1.99 to 6.58 ± 1.72 pmol/l at 1 week and 5.83 ± 0.80 pmol/l at 4 weeks) significantly (P < 0.001) decreased, while glucagon-like peptide 1 significantly increased (1.75 ± 0.16 to 3.42 ± 0.41 pmol/l at 1 week and 3.62 ± 0.21 pmol/l at 4 weeks; P < 0.001). BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and enhancing β-cell sensitivity to glucose, these changes occurring very early after the operation. This operation may affect the enteroinsular axis function by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum. Diabetes 55:2025-2031, 2006 [ABSTRACT FROM AUTHOR]

In nondiabetic subjects, obesity is associated with a modest expansion of β-cell mass, possibly amounting--according to the best available estimates--to 10-30% for each 10 kg of weight excess. Whether age of onset and duration of obesity, recent changes in body weight, and body fat distribution have any effect on β-cell mass in humans is unknown. Both fasting insulin secretion and the total insulin response to oral glucose have the following characteristics: 1) they increase with BMI in an approximately linear fashion, 2) both fat-free and fat mass are significant positive correlates, and 3) BMI exerts a positive effect separate from that of insulin resistance (i.e., obesity may be a state of primary insulin hypersecretion). The mechanisms are currently unknown, though chronic small increments in plasma glucose may play a role. In contrast, dynamic properties of β-cell function, such as glucose sensitivity (i.e., dose-response function), rate sensitivity, and potentiation, do not appear to be substantially altered by the presence of obesity, body fat distribution, or insulin resistance as long as glucose tolerance is maintained. Weight loss, by diet or restrictive bariatric surgery, is associated with consensual decrements in insulin resistance and insulin hypersecretion. The latter, however, seems to be more persistent, suggesting that the postobese state may reproduce the primary insulin hypersecretion of the obese state. Malabsorptive bariatric surgery, in contrast, normalizes insulin sensitivity and abolishes insulin hypersecretion even before achievement of ideal body weight. Lipid-triggered messages from the gastrointestinal tract to the insulin target tissues and endocrine pancreas are the subject of intense investigation. Diabetes 53 (Suppl. 3):S26-S33, 2004 [ABSTRACT FROM AUTHOR]

Gestational diabetes (GDM) carries a high risk of incident diabetes. We asked the question, whether prior GDM has any impact on B-cell function and insulin action in women who have normal glucose tolerance (NGT). Ninety-one NGT women (age 41±8 years, mean±SD) were studied (by mathematical modelling of a frequently-sampled OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 of them were GDM. Fasting (4.64±0.56 vs 4.97±0.46 mM) and 2-h plasma glucose (5.91±1.14 vs 5.914-1.21 mM) were similar in prior-GDM (age 41 ± 5 y, BMI 25.4±3.9 kg/m²) and non-prior-GDM women (age 41 ± 5 y, BMI 26.8±6.4 kg/m²). However, β-cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) (95 [71] vs 115 [79] pmol⋅min[sup -1] ⋅m[sup -2]⋅mM[sup -1], p=0.025 [Mann Whitney]) and insulin sensitivity (398 [77] vs 424 [98] ml⋅min[sup -1]⋅m[sup -2], p=0.025) were both reduced in prior-GDM women. At the time of the index pregnancy, GDM and non-GDM had similar age and BMI; however, insulin sensitivity was significantly lower (359 [93] vs 417 [92] ml⋅min[sup -1]⋅ m[sup -2], p=0.001) and the ratio of incremental insulin area/incremental glucose area (as an empirical index of β-cell function) was reduced (18 [13] vs 27 [26] µU/mmol, p=0.02) in GDM vs non-GDM women. Both at the index pregnancy and follow up, β-cell function and insulin sensitivity were idependent determinants of mean OGTT glucose levels (r²'s of 0.40 and 0.22, p<0.0001 for both) independently of age and BMI. We conclude that the impairment in B-cell function and insulin sensitivity that characterise GDM are carried over into the NGT status even years after a GDM pregnancy. [ABSTRACT FROM AUTHOR]

Demonstrates an approach for estimating insulin secretion based on the measurement of plasma C-peptide. Equality of systematic appearance of c-peptide and pancreatic release of insulin; Evaluation of 24 hour profiles of insulin secretion.

Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes (DM). We investigated the mechanisms by which risk progresses to disease. In 144 islet-cell autoantibody-positive, non-diabetic relatives from the close observation (control) group of the DPT-1 Parenteral Insulin Trial (73 female, age=12 [10] years (median [interquartile range]), BMI=18.3 [6.1] kg⋅m[sup -2], 42 IGT and 102 NGT). A frequently-sampled OGTT was performed at baseline and again 2.5 [2.8] years later, when 61 subjects (33 female/28 male, 28 from IGT, 33 from NGT) had developed DM. β-cell glucose sensitivity (β-GS, slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity (IS) were obtained by mathematical modelling of glucose/C-peptide responses to OGTT. Relatives progressing to DM had worse β-GS at follow up (18 [21] vs 62 [50] pmol⋅min[sub -1]⋅m[sub -2], p<0.0001 [Mann Whitney]) as well as at baseline (41 [30] vs 75 [68] pmol⋅min[sup -1]⋅m[sup -2]⋅mM[sup -1], p<0.0001). In contrast, IS was only marginally lower in progressors than non-progressors both at baseline (418 [79] vs 427 [61 ] ml⋅min[sup -1]⋅m[sup -2], p=0.77) and follow up (386 [66] vs 405 [64] ml⋅min[sup -1]⋅m[sup -2], p=0.12). By Kaplan-Meier modelling, DM-free survival was significantly (log-rank p<0.0001) worse in the bottom β-GS tertile (30 [21] pmol⋅min[sup -1]⋅m[sup -2]⋅mM[sup -1]) as compared to the middle (56 [13]) or top tertile (117 [53]). By proportional hazards analysis, incident DM was predicted (as relative risk, RR and [95% confidence interval] per 1 SD of the predictor) by baseline β-GS (RR=0.42 [0.32-0.56]), age (RR=0.27 [0.14-0.52]), female gender (RR=3.08 [1.73-5.45]), baseline IS (RR=0.66 [0.49-0.90]) and baseline BMI (RR=1.64 [0.98-2.73]), in that order of strength (χ²=36.9, 15.3, 14.8, 6.8 and 3.6, respectively). In this multivariate model, baseline glucose tolerance, fasting and 2-hour plasma glucose levels were not significant predictors. We conclude that, in high-risk relatives of type 1 patients progression to DM is mainly predicted by impaired β-cell glucose sensitivity, with younger age, female sex, reduced insulin sensitivity and higher BMI making additional contributions to DM risk. ADA-Funded Research [ABSTRACT FROM AUTHOR]

We studied whether parameters of beta cell function were similar during an oral glucose tolerance test (OGTT) and a -physiologically more relevant-mixed meal tolerance test (MTT) in different glucose tolerance groups. Individuals with normal glucose tolerance (NGT, n=150), intermediate hyperglycaemia (IH, n=19) and diabetes (DM, n=19) underwent an OGTT and an MTT, both containing 75g carbohydrates. The meal also contained 50g fat and 24g proteins. Plasma glucose, insulin and C-peptide were sampled before and 15, 30, 60, 90 and 120 minutes after OGTT and MTT. Insulin secretion rate (ISR) and beta cell function parameters were calculated from C-peptide using a mathematical model. These parameters included beta cell glucose sansitivity, i.e., the slope of the glucose concentration - ISR relationship and potentiation, which expresses a relative increase of ISR from the beginning to the end of the test. ANOVA and dependent t-tests with Bonferroni corrections were used to test for differences. Beta cell glucose sensitivity was higher during MTT than during OGTT in all groups (Table 1). Diabetic subjects had significantly lower beta cell glucose sensitivity than IH- and NGT-subjects. Potentiation was similar (NGT-or DM-subjects) or slightly higher (IH-subjects) during MTT. Beta cells were more sensitive to glucose (i.e. insulin secretion per glucose unit was higher) during a mixed meal load than during a glucose load while the ability to modulate this relationship (potentiation) was similar or slightly higher. Individuals with IH, unlike diabetic subjects, did not have lower beta cell sensitivity than NGT-individuals. We conclude that beta cell response is stronger after a mixed meal than after an OGTT with equal-carbohydrate quantity. [ABSTRACT FROM AUTHOR]