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Type 2 diabetes (T2D) risk is lower in females than males. It has been reported that females have greater pancreatic 훽‐cell function than males, which may at least in part contribute to the T2D risk in females. 훽‐cell function is influenced by exercise training; however, previous trials comparing 훽‐cell function between the sexes have not included participants matched for training status. Furthermore, the acute effects of different modes of exercise on 훽‐cell function, and whether sex inherently influences these effects, are largely unexamined. Males and females (12/sex) completed a 120‐min oral glucose tolerance test (OGTT) at rest (CON) and following acute bouts of high‐intensity interval exercise (HIIE), moderate intensity continuous (MIC) exercise, and low‐load high‐repetition (LLHR) resistance exercise to assess whether sex inherently influences baseline and/or post‐exercise pancreatic function in the absence of pathology. We found no sex differences in basal pancreatic 훽‐cell function. Females had greater basal insulin clearance following MIC exercise compared to males (p = 0.01) and males tended to have a higher potentiation ratio following HIIE (p = 0.07). Females also had lower glucose sensitivity following MIC exercise compared to HIIE (p = 0.007) and LLHR (p = 0.003). Insulin clearance during the OGTT was greater following HIIE as compared with CON and MIC exercise (p = 0.02). 2‐H oral glucose insulin sensitivity was greater following LLHR compared to CON (p = 0.01). Acute bouts of different modes of exercise do not differentially influence 훽‐cell function but do influence insulin clearance and insulin sensitivity. Therefore, sex and exercise mode interact to differentially influence insulin clearance and glucose sensitivity. [ABSTRACT FROM AUTHOR]

Objective: Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors.Research Design and Methods: We estimated standardized EIC (EICISR) by mathematical modeling in nine different studies with insulin and glucose infusions (N = 2,067). EICISR association with various traits was analyzed by stepwise multivariable regression in studies with both euglycemic clamp and oral glucose tolerance test (OGTT) (N = 1,410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N = 1,555).Results: Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, approximately four times more influential than insulin resistance-related hypersecretion. EICISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ∼10% EIC reduction is necessary to explain the observed insulin concentration profiles.Conclusions: Based on EICISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EICISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EICISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM.Methods: Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration.Results: A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)].Conclusions/interpretation: Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia. [ABSTRACT FROM AUTHOR]

Background: Glucose is a natural ligand for sweet taste receptors (STRs) that are expressed on the tongue and in the gastrointestinal tract. Whether STRs directly contribute to the regulation of glucose homeostasis in response to glucose ingestion is unclear. Objective: We sought to determine the metabolic effects of the pharmacologic inhibition of STRs in response to an oral glucose load in healthy lean participants. Design: Ten healthy lean participants with a body mass index (in kg/m2) of 22.4 ± 0.8 were subjected to an oral-glucose-tolerance test (OGTT) on 4 separate days with the use of a randomized crossover design. Ten minutes before the 75-g OGTT, participants consumed a preload solution of either 300 parts per million (ppm) saccharin or water with or without the addition of 500 ppm lactisole, a humanspecific inhibitor of STRs. When present, lactisole was included in both the preload and OGTT solutions. We assessed plasma responses of glucose, insulin, C-peptide, glucagon, glucagon-like peptides 1 and 2, gastric inhibitory peptide, acetaminophen, and 3-O-methylglucose. With the use of mathematical modeling, we estimated gastric emptying, glucose absorption, β-cell function, insulin sensitivity and clearance, and the portal insulin:glucagon ratio. Results: The addition of lactisole to the OGTT caused increases in the plasma responses of insulin (P = 0.012), C-peptide (P = 0.004), and the insulin secretory rate (P = 0.020) compared with the control OGTT. The addition of lactisole also caused a slight reduction in the insulin sensitivity index independent of prior saccharin consumption (P < 0.025). The ingestion of saccharin before the OGTT did not alter any of the measured variables but eliminated the effects of lactisole on the OGTT. Conclusion: The pharmacologic inhibition of STRs in the gastrointestinal tract alters insulin responses during an oral glucose challenge in lean healthy participants. This trial was registered at clinicaltrials.gov as NCT02835859. [ABSTRACT FROM AUTHOR]

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated β-cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon-like peptide 1 ( GLP-1) and glucose-dependent insulinotropic polypeptide ( GIP) in augmenting insulin secretion, we examined β-cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance ( NGT), during a 2-h oral glucose tolerance test ( OGTT) with mathematical modeling of plasma glucose and C-peptide concentrations to assess β-cell glucose sensitivity ( βCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater βCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened β-cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in β-cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth. [ABSTRACT FROM AUTHOR]

Background: Insulin secretion correlates inversely with insulin sensitivity, which may suggest the existence of a crosstalk between peripheral organs and pancreas. Such interaction might be mediated through glucose oxidation that may drive the release of circulating factors with action on insulin secretion. Aim: To evaluate the association between whole-body carbohydrate oxidation and circulating factors with insulin secretion to consecutive oral glucose loading in non-diabetic individuals. Methods: Carbohydrate oxidation was measured after an overnight fast and for 6 hours after two 3-h apart 75-g oral glucose tolerance tests (OGTT) in 53 participants (24/29 males/females; 34±9 y; 27±4 kg/m2). Insulin secretion was estimated by deconvolution of serum C-peptide concentration, β cell function by mathematical modelling and insulin sensitivity from an OGTT. Circulating lactate, free-fatty acids (FFA) and candidate chemokines were assessed before and after OGTT. The effect of recombinant RANTES (regulated on activation, normal T cell expressed and secreted) and IL8 (interleukin 8) on insulin secretion from isolated mice islets was also measured. Results: Carbohydrate oxidation assessed over the 6-h period did not relate with insulin secretion (r = -0.11; p = 0.45) or β cell function indexes. Circulating lactate and FFA showed no association with 6-h insulin secretion. Circulating chemokines concentration increased upon oral glucose stimulation. Insulin secretion associated with plasma IL6 (r = 0.35; p<0.05), RANTES (r = 0.30; p<0.05) and IL8 (r = 0.41; p<0.05) determined at 60 min OGTT. IL8 was independently associated with in vivo insulin secretion; however, it did not affect in vitro insulin secretion. Conclusion: Whole-body carbohydrate oxidation appears to have no influence on insulin secretion or putative circulating mediators. IL8 may be a potential factor influencing insulin secretion. [ABSTRACT FROM AUTHOR]

The incretin effect on insulin secretion was investigated in 8 subjects with type 2 diabetes (T2D) and 8 with normal glucose tolerance (NGT), using 25, 75, and 125 g oral glucose tolerance tests (OGTT) and isoglycemic intravenous glucose infusions (IIGI). The ß-cell response was evaluated using a model embedding a dose-response (slope = glucose sensitivity), an early response (rate sensitivity), and potentiation (time-related secretion increase). The incretin effect, as OGTT/IIGI ratio, was calculated for each parameter. In NGT, the incretin effect on total secretion increased with dose (1.3±0.1, 1.7±0.2, 2.2±0.2 fold of IIGI, P<0.0001), mediated by a dose-dependent increase of the incretin effect on glucose sensitivity (1.9±0.4, 2.4±0.4, 3.1±0.4, P = 0.005), and a dose-independent enhancement of the incretin effect on rate sensitivity (894 [1145], 454 [516], 783 [1259] pmol m−2 L mmol−1 above IIGI; median [interquartile range], P<0.0001). The incretin effect on potentiation also increased (0.97±0.06, 1.45±0.20, 1.24±0.16, P<0.0001). In T2D, the incretin effect on total secretion (1.0±0.1, 1.1±0.1, 1.3±0.1, P = 0.004) and glucose sensitivity (1.2±0.2, 1.3±0.2, 2.0±0.2, P = 0.005) were impaired vs NGT; however, the incretin effect on rate sensitivity increased already at 25 g (269 [169], 284 [301], 193 [465] pmol m−2 L mmol−1 above IIGI; negligible IIGI rate sensitivity in T2D prevented the calculation of the fold increment). OGTT did not stimulate potentiation above IIGI (0.94±0.04, 0.89±0.06, 1.06±0.09; P<0.01 vs NGT). In the whole group, the incretin effect was inversely associated with total secretion during IIGI, although systematically lower in T2D. In conclusion, 1) In NGT, glucose sensitivity and potentiation mediate the dose-dependent incretin effect increase; 2) In T2D, the incretin effect is blunted vs NGT, but rate sensitivity is enhanced at all loads; 3) Relatively lower incretin effect in NGT is associated with higher secretion during IIGI, suggesting that the reduced incretin effect does not result from ß-cell dysfunction. [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]

The article offers information on the results of a study on β-cell function among severely obese patients with type 2 diabetes. It says that the intravenous glucose tolerance test was utilized to determine the impact of bariatric surgery on β-cell function in diabetic subjects. It mentions that the bariatric surgery can improve insulin sensitivity.

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]