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BACKGROUNDThe appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin, and a reduction of β cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifesting β cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of β cell mass, on the subsequent development of hyperglycemia.METHODSTo pursue this aim, nondiabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamp (HC) procedures, followed by arginine stimulation before and after surgery. Based on postsurgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal glucose tolerance (post-NGT), impaired glucose tolerance (post-IGT), or having diabetes mellitus (post-DM).RESULTSAt baseline, the 3 groups showed similar fasting glucose and insulin levels; however, examining the various parameters, we found that reduced first-phase insulin secretion, reduced glucose sensitivity, and rate sensitivity were predictors of eventual postsurgery development of IGT and diabetes.CONCLUSIONDespite comparable functional mass and fasting glucose and insulin levels at baseline and the very same 50% mass reduction, only reduced first-phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM).TRIAL REGISTRATIONClinicalTrials.gov NCT02175459.FUNDINGUniversità Cattolica del Sacro Cuore; Italian Ministry of Education, University and Research; European Foundation for the Study of Diabetes.

It is known that for a given insulin level glucose clearance depends on glucose concentration. However, a quantitative representation of the concomitant effects of hyperinsulinemia and hyperglycemia on glucose clearance, necessary to describe heterogeneous tests such as euglycemic and hyperglycemic clamps and oral tests, is lacking. Data from five studies (123 subjects) using a glucose tracer and including all the above tests in normal and diabetic subjects were collected. A mathematical model was developed in which glucose utilization was represented as a Michaelis-Menten function of glucose with constant Km and insulin-controlled Vmax, consistently with the basic notions of glucose transport. Individual values for the model parameters were estimated using a population approach. Tracer data were accurately fitted in all tests. The estimated Km was 3.88 (2.83-5.32) mmol/l [median (interquartile range)]. Median model-derived glucose clearance at 600 pmol/l insulin was reduced from 246 to 158 ml·min(-1)·m(-2) when glucose was raised from 5 to 10 mmol/l. The model reproduced the characteristic lack of increase in glucose clearance when moderate hyperinsulinemia was accompanied by hyperglycemia. In all tests, insulin sensitivity was inversely correlated with BMI, as expected (R(2) = 0.234, P = 0.0001). In conclusion, glucose clearance in euglycemic and hyperglycemic clamps and oral tests can be described with a unifying model, consistent with the notions of glucose transport and able to reproduce the suppression of glucose clearance due to hyperglycemia observed in previous studies. The model may be important for the design of reliable glucose homeostasis simulators., (Copyright © 2016 the American Physiological Society.)

Context: Diabetes remission is frequent after biliopancreatic diversion (BPD) in morbidly obese patients with type 2 diabetes (T2D). Data, mechanisms, and clinical indications in nonobese T2D patients are scanty., Objective: The objective of the study was to assess remission and investigate insulin sensitivity and β-cell function after BPD in nonobese patients with long-standing T2D., Design, Setting, and Patients: This was a clinical research study comparing 15 T2D patients (aged 55 ± 1 years, duration of 16 ± 2 years, body mass index of 28.3 ± 0.6 kg/m², glycosylated hemoglobin 8.6% ± 1.3%) with 15 gender-, age-, and body mass index-matched nondiabetic controls. Before surgery and 2 months and 1 year later, a 3-hour oral glucose tolerance test, a 5-hour mixed-meal test, and a 3-hour euglycemic clamp were performed., Intervention: The intervention included a BPD (distal gastrectomy, proximal ileum anastomosed to remaining stomach, biliopancreatic limb anastomosed to ileum 50 cm from the ileocecal valve)., Results: Glycemia improved in all patients, but remission (glycosylated hemoglobin < 6.5% and normal oral glucose tolerance test) occurred in 6 of 15 patients. Insulin resistance (19.8 ± 0.8 μmol · min⁻¹ · kg(ffm)⁻¹, P < .001 vs 40.9 ± 5.3 of controls) resolved already at 2 months (34.2 ± 2.8) and was sustained at 1 year (34.7 ± 1.6), although insulin-mediated suppression of endogenous glucose production remained impaired. In contrast, β-cell glucose sensitivity (19 [12] pmol · min⁻¹ · m⁻² · mM⁻¹ vs 96 [73] of controls, P < .0001) rose (P = .02) only to 31 [26] at 1 year and was lower in nonremitters (16 [18]) than remitters (46 [33])., Conclusions: In nonobese patients with long-standing T2D, BPD improves metabolic control but induces remission in only approximately 40% of patients. Peripheral insulin sensitivity is restored early after surgery and similarly in remitters and nonremitters, indicating a weight-independent effect of the operation. The initial extent of β-cell incompetence is the main predictor of the metabolic outcome.

Objective: This study was conducted to characterize the effects of vildagliptin on beta-cell function in patients with type 2 diabetes and mild hyperglycemia., Design: A 52-wk double-blind, randomized, parallel-group study comparing vildagliptin (50 mg every day) and placebo was conducted in 306 patients with mild hyperglycemia (glycosylated hemoglobin of 6.2-7.5%). Plasma glucose and C-peptide levels were measured during standard meal tests performed at baseline, wk 24 and 52, and after 4-wk washout. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution, and beta-cell function was quantified with a mathematical model that describes ISR as a function of absolute glucose levels (insulin secretory tone and glucose sensitivity), the glucose rate of change (rate sensitivity), and a potentiation factor., Results: Vildagliptin significantly increased fasting insulin secretory tone [between-group difference in adjusted mean change from baseline to wk 52 (AM Delta) = +34.1 +/- 9.5 pmol.min(-1).m(-2), P < 0.001] glucose sensitivity (AM Delta = +20.7 +/- 5.2 pmol.min(-1).m(-2).mm(-1), P < 0.001), and rate sensitivity (AM Delta = +163.6 +/- 67.0 pmol.m(-2).mm(-1), P = 0.015), but total insulin secretion (ISR area under the curve at 0-2 h) and the potentiation factor excursion during meals were unchanged. These improvements in beta-cell function were accompanied by a decrease in the glucose area under the curve at 0-2 h (AM Delta = -1.7 +/- 0.5 mm/h, P = 0.002) and in glycosylated hemoglobin (AM Delta = -0.3 +/- 0.1%, P < 0.001). None of the effects of vildagliptin remained after 4-wk washout from study medication., Conclusions: Consistent with previous findings from shorter-term studies in patients with more severe hyperglycemia, in patients with mild hyperglycemia, improved beta-cell function is maintained throughout 52-wk treatment with vildagliptin and underlies a sustained improvement in glycemic control. However, no effects remain after washout.

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.

Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in glucokinase (GK, gene symbolGCK) and impaired glucose sensing. We investigated effects of dorzagliatin, a novel allosteric GK activator, on insulin secretion rates (ISR) and beta-cell glucose-sensitivity (βCGS) in GCK-MODY and recent-onset type 2 diabetes. In a double-blind, randomized cross-over study, eight participants with GCK-MODY and 10 with type 2 diabetes underwent 2-hour 12-mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Effects of dorzagliatin on wild-type and mutant GK enzyme activity were investigated using a nicotinamide adenine dinucleotide phosphate (NADP+) coupled assay with glucose-6-phosphate dehydrogenase (G6PD) in vitro. In GCK-MODY, dorzagliatin significantly increased absolute and incremental second-phase ISR versus placebo but not the acute insulin response. Dorzagliatin improved βCGS in GCK-MODY with a upward and leftward shift in ISR-glucose response. Dorzagliatin increased basal ISR in type 2 diabetes with smaller changes in second-phase ISR compared with GCK-MODY. In vitro, dorzagliatin directly reduced the glucose half saturation concentration (S0.5) of wild-type GK and selected GK mutants to varying degrees. Dorzagliatin directly restored enzyme activity of select GK mutants and enhanced wild-type GK activity, thereby correcting the primary defect of glucose sensing in GCK-MODY. [ABSTRACT FROM AUTHOR]

Context: Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear. Objective: To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach. Methods: PubMed, Scopus, and Web-of-Science were searched. Studies measuring IE by the gold-standard protocol employing an oral glucose tolerance test (OGTT) and an intravenous glucose infusion at matched glucose levels were selected. We extracted IE, sex, age, body mass index (BMI), and hemoglobin A1c, fasting values, and area under curve (AUC) of glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). In subjects with T2D, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications. Results: The IE weighted mean difference between subjects with T2D and those with normal glucose tolerance (NGT) was -27.3% (CI -36.5% to -18.1%; P < .001; I2 = 86.6%) and was affected by age (P < .005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (P < .05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (P < .0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI 9.2-13.2%; P < .0001; I2 = 28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose. Conclusion: The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in subjects with T2D only, the OGTT dose is a significant covariate. [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]

Objective: Glycemic control deteriorates more rapidly in youth vs adults. We compared model‐derived measures of β‐cell function between youth and adults with either impaired glucose tolerance (IGT) or type 2 diabetes to determine if a β‐cell defect differentiates these age groups. Methods: This is a cross‐sectional analysis of baseline data from the Restoring Insulin Secretion (RISE) Study. Youth (54 Y‐IGT, 33 Y‐D) and adults (250 A‐IGT, 104 A‐D) underwent 3‐hour oral glucose tolerance tests for modeling of insulin secretion rates (ISRs), glucose sensitivity, and rate sensitivity. Insulin sensitivity was quantified as the glucose infusion rate/insulin (M/I) from a hyperglycemic clamp. Results: Youth had lower insulin sensitivity despite similar body mass index. Analyses were adjusted for insulin sensitivity. Youth had higher basal ISRs (Y‐IGT 200 ± 161 vs A‐IGT 152 ± 74, P <.001; Y‐D 245 ± 2.5 vs A‐D 168 ± 115 pmol/min/m2, P =.007) and total ISRs (Y‐IGT 124 ± 86 vs A‐IGT 98 ± 39, P <.001; Y‐D 116 ± 110 vs A‐D 97 ± 62 nmol/m2, P =.002). Within IGT, glucose sensitivity (Y‐IGT 140 ± 153 vs A‐IGT 112 ± 70 pmol/min/m2/mM, P =.004) and rate sensitivity (median[interquartile range]:Y‐IGT 2271[1611, 3222] vs A‐IGT 1164[685, 1565] pmol/m2/mM, P <.001) were higher in youth, but not different by age group within diabetes. Conclusions: Model‐derived measures of β‐cell function provide additional insight into the pathophysiology of type 2 diabetes in youth with higher ISRs and β‐cell secretion more responsive to glucose in youth relative to adults even after adjusting for differences in insulin sensitivity. It is unknown whether these findings in youth reflect β‐cells that are healthier or whether this is a defect that contributes to more rapid loss of function. [ABSTRACT FROM AUTHOR]

Context: Elevated heart rate has been associated with insulin resistance and incident type 2 diabetes but its relationship with β-cell function is not known. Our aim was to investigate whether baseline heart rate is associated with β-cell function and hyperglycaemia. Methods: We used the prospective RISC cohort with 1005 non-diabetic individuals who had an oral glucose tolerance test (OGTT) at baseline and after 3 years. Impaired glucose regulation was defined as a fasting plasma glucose ≥6.1 mmol/l or a 2-h plasma glucose ≥7.8 mmol/l. Insulin sensitivity was assessed by the OGIS index and insulin secretion and β-cell glucose sensitivity at both baseline and 3 years. Results: Baseline heart rate was positively related to both fasting (P<0.0001) and 2 h glucose levels (P=0.02) at year 3 and predicted the presence of impaired glucose regulation at year 3 in a logistic regression model adjusting for insulin sensitivity at inclusion (OR/10 beats per min: 1.31; 95% CI (1.07-1.61); P=0.01). Baseline heart rate was associated with lower insulin sensitivity (β= -0.11; P<.0001), a decrease in both β-cell glucose sensitivity (β= -0.11; P=0.003) and basal insulin secretion rate (β= -0.11; P=0.002) at 3 years in an adjusted multivariable regression model. Baseline heart rate predicted the 3-year decrease in β-cell glucose sensitivity (β= -0.10; P=0.007) and basal insulin secretion (β= -0.12; P=0.007). Conclusions: Heart rate predicts β-cell function and impaired glucose regulation at 3 years in non-diabetic individuals, independently of the level of insulin sensitivity. These findings suggest a possible effect of the sympathetic nervous system on β-cell dysfunction, which deserves further investigation. [ABSTRACT FROM AUTHOR]

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia. [ABSTRACT FROM AUTHOR]

Objective: Anti-inflammatory glucocorticoid (GC) therapy often induces hyperglycemia due to insulin resistance and islet-cell dysfunction. Incretin-based therapies may preserve glucose tolerance and pancreatic islet-cell function. In this study, we hypothesized that concomitant administration of the dipeptidyl peptidase-4 inhibitor sitagliptin and prednisolone in men at high risk to develop type 2 diabetes could protect against the GC-induced diabetogenic effects. Design and methods: Men with the metabolic syndrome but without diabetes received prednisolone 30 mg once daily plus sitagliptin 100 mg once daily (n=14), prednisolone (n=12) or sitagliptin alone (n=14) or placebo (n=12) for 14 days in a double-blind 2×2 randomized-controlled study. Glucose, insulin, C-peptide, and glucagon were measured in the fasted state and following a standardized mixed-meal test. β-cell function parameters were assessed both from a hyperglycemic-arginine clamp procedure and from the meal test. Insulin sensitivity (M-value) was measured by euglycemic clamp. Results: Prednisolone increased postprandial area under the curve (AUC)-glucose by 17% (P<0.001 vs placebo) and postprandial AUC-glucagon by 50% (P<0.001). Prednisolone reduced 1st and 2nd phase glucose-stimulated-and combined hyperglycemia-arginine-stimulated C-peptide secretion (all P≤0.001). When sitagliptin was added, both clamp-measured β-cell function (P=NS for 1st and 2nd phase vs placebo) and postprandial hyperglucagonemia (P=NS vs placebo) remained unaffected. However, administration of sitagliptin could not prevent prednisolone-induced increment in postprandial glucose concentrations (P<0.001 vs placebo). M-value was not altered by any treatment. Conclusion: Fourteen-day treatment with high-dose prednisolone impaired postprandial glucose metabolism in subjects with the metabolic syndrome. Concomitant treatment with sitagliptin improved various aspects of pancreatic islet-cell function, but did not prevent deterioration of glucose tolerance by GC treatment. [ABSTRACT FROM AUTHOR]

Aim of this study was analyzing the time trajectories of the metabolic parameters in European women with former gestational diabetes (fGDM), and determining predictors of type 2 diabetes onset. A group of seventy-six fGDM women were studied at the outpatient department of the University Clinic of Vienna. They were evaluated yearly with a 3 h-oral glucose tolerance test (OGTT) up to 7-years from delivery. At baseline, women also underwent an intravenous glucose tolerance test (IVGTT). Insulin sensitivity and beta-cell function were assessed by both OGTT and IVGTT. Women were divided into progressors (PROG) to diabetes (n = 19) and non-progressors (n = 57). Time trajectories of glycemia and other parameters were analyzed after synchronization to time of diabetes onset or last OGTT. Then, Cox proportional hazard regression analysis was performed to assess the predictive power of studied variables for diabetes onset. We found that, in PROG, time trajectories of glycemia were flat until diabetes onset, when they showed a marked increase (P<0.0001). Insulin sensitivity showed similar marked decrease (P<0.0001) at diabetes onset, together with a tendency to continuous slow decline in the previous years. At contrast, beta-cell function showed only continuous slow decline. Major predictors of diabetes onset were glycemic levels, BMI, insulin resistance, and condition of impaired glucose tolerance. In conclusion, in fGDM, marked deterioration of insulin sensitivity is associated with diabetes onset. Prevention strategies aimed at opposing to the insulin sensitivity derangement may be particularly beneficial. [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]

We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive β-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of β-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese "prediabetic" ZDF rats with mild hyperglycemia, the FFA-induced decrease in 3-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired β-cell function. In conclusion, 1) the FFA-induced impairment in β-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the β-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing. [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]