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Aims: Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of non-esterified fatty acids (NEFAs). This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in non-diabetic subjects., Methods: Twenty-two healthy lean volunteers underwent two 5-h intravenous infusions of either saline or Intralipid, without (n=12) or with heparin (I+H; n=10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3h of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived β-cell function, and insulin clearance were measured after 2h of lipid infusion and during the OGTTs., Results: In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance, without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I+H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (i.e. β-cell glucose sensitivity) and increased β-cell potentiation, whereas I+H had neutral effects on these β-cell functions., Conclusion: In healthy non-obese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance, insulin sensitivity and clearance, and has selective and opposite effects on β-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.

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 (EIC ISR ) by mathematical modeling in nine different studies with insulin and glucose infusions ( N = 2,067). EIC ISR 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 EIC ISR , approximately four times more influential than insulin resistance-related hypersecretion. EIC ISR 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 EIC ISR , we posit the existence of two adaptive processes involving insulin clearance: the first reduces EIC ISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EIC ISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance., (© 2021 by the American Diabetes Association.)

We compared the effect of dapagliflozin versus glibenclamide on the ratio of lean-to total mass in patients with type 2 diabetes mellitus, carotid subclinical atherosclerosis, HbA1c 7.0-9.0% and 40-70 years-old. Ninety-eight patients (61% male; mean age 57 ± 7 years) were randomized into dapagliflozin 10 mg/day or glibenclamide 5 mg/day on top of metformin. Body composition was measured by Dual Energy X-Ray at randomization and after 12 weeks of treatment. Glycemic control was equivalent in both groups. Dapagliflozin decreased total body mass (-2741 g [95% CI: -3360 to 1945]; p < 0.001) and lean mass (-347 g [95% CI: -761 to -106]; p < 0.001), while glibenclamide increased total body mass (1060 g [95% CI: 140 to 1836]; p < 0.001) and lean mass (929 g [95% CI: 575 to 1283]; p < 0.001) for the differences between arms. The lean-to-total mass ratio increased by 1.2% in the dapagliflozin group and 0,018% in the glibenclamide group (p < 0.001). Dapagliflozin reduced the risk of a negative balance in the lean-to total mass ratio [OR: 0.16 (95% CI: 0.05 to 0.45); p < 0.001] even after adjustment for baseline lean-to total mass ratio, waist circumference, HOMAIR, HbA1c, mean of the two hands handgrip strength and gait speed [OR: 0.13 (95% CI: 0.03-0.57); p < 0.007]. In conclusion, under equivalent glycemic control, dapagliflozin reduced total body mass but increased the ratio of lean-to-total mass when compared with glibenclamide.

Background: Patients with type 2 diabetes mellitus (T2DM) remain at increased cardiovascular residual risk and endothelial dysfunction, even after optimizing metabolic control and treatment by sodium-glucose-2 transporter inhibitors (SGLT2-is). The present study was based on the hypothesis that proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9i) therapy may mitigate endothelial dysfunction in T2DM patients who are on regular treatment by SGLT2-i., Methods: The EXCEED-BHS3 is a prospective, single-center, investigator-blinded, open-label, randomized clinical trial. Participants ( n  = 110) will be randomized (1:1) to either empagliflozin 25 mg/day alone or empagliflozin 25 mg/day plus evolocumab 140 mg every 2 weeks in addition to optimal medical care. The primary endpoint was defined as the change in the 1-min flow-mediated dilation (FMD) after 16 weeks of treatment. The secondary endpoint is the FMD change after ischemia/reperfusion injury protocol (reserve FMD) after 16 weeks of treatment. Exploratory outcomes comprise the change in FMD and reserve FMD after 8 weeks of treatment and the change after 16 weeks of treatment in the following parameters: plasma levels of nitric oxide, vascular cell adhesion molecule-1 and isoprostane, high-density lipoprotein (HDL) and low-density lipoprotein subfractions profile, HDL function, blood pressure, body mass index, waist circumference and adipokines., Conclusion: This will be the first study to evaluate the add-on effect of PCSK9i on endothelial function of T2DM patients under regular use of empagliflozin., Trial Registration: ClinicalTrials.gov identifier: NCT03932721., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Objective: To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics., Research Design and Methods: Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected P < 0.05) was discerned through Ingenuity Pathway Analysis., Results: Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid-binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration., Conclusions: SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design., (© 2020 by the American Diabetes Association.)

Introduction: Insulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known., Methods: We applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination., Results: During saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kg FFM /min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion., Conclusions: Acute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin., Competing Interests: Competing interests: EF has participated in scientific advisory boards for Boehringer Ingelheim, Eli Lilly, and Sanofi; has been involved in ad hoc consulting for Janssen, AstraZeneca, and Mitsubishi Tanabe; has participated in occasional speaking engagements for AstraZeneca, Novo Nordisk, Sanofi, Mitsubishi Tanabe, Eli Lilly, Boehringer Ingelheim, and Merck Sharp & Dohme; and has received research grant support from Boehringer Ingelheim and AstraZeneca., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method . A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results . Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na + K + ATPase activity impacting on glucose transport. Conclusion . Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed., Competing Interests: The authors declare no conflict of interest regarding the publication of this paper., (Copyright © 2020 Ricardo Pereira-Moreira and Elza Muscelli.)

Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1 g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Incretin effect-the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route-is impaired in dysglycaemic states. Despite evidence from human islet studies that NEFA interfere with incretin function, little information is available about the effect in humans. We tested the impact of acute bidirectional NEFA manipulation on the incretin effect in humans., Methods: Thirteen individuals with type 2 diabetes and ten non-diabetic volunteers had a 3 h OGTT, and, a week later, an i.v. isoglycaemic glucose infusion (ISO; OGTT matched). Both pairs of studies were repeated during an exogenous lipid infusion in the non-diabetic volunteers, and following acipimox administration (to inhibit lipolysis) in people with diabetes. Mathematical modelling of insulin secretion dynamics assessed total insulin secretion (TIS), beta cell glucose sensitivity (β-GS), glucose-induced potentiation (P GLU ) and incretin-induced potentiation (P INCR ); the oral glucose sensitivity index was used to estimate insulin sensitivity., Results: Lipid infusion increased TIS (from 61 [interquartile range 26] to 78 [31] nmol/m 2 on OGTT and from 29 nmol/m 2 [26] to 57 nmol/m 2 [30] on ISO) and induced insulin resistance. P INCR decreased from 1.6 [1.1] to 1.3 [0.1] (p < 0.05). β-GS, P GLU and glucagon, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses were unaffected. Acipimox (lowering NEFA by ~55%) reduced plasma glucose and TIS and enhanced insulin sensitivity, but did not change β-GS, P INCR , P GLU or glucagon, GLP-1 or GIP responses. As the per cent difference, incretin effect was decreased in non-diabetic participants and unchanged in those with diabetes., Conclusions/interpretation: Raising NEFA selectively impairs incretin effect and insulin sensitivity in non-diabetic individuals, while acute NEFA reduction lowers plasma glucose and enhances insulin sensitivity in people with diabetes but does not correct the impaired incretin-induced potentiation.

Objective: Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes., Research Design and Methods: We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ≥60 mL · min -1 · 1.73 m -2 ) and in control subjects without diabetes at baseline and following empagliflozin treatment., Results: With chronic (4 weeks) sodium-glucose cotransporter 2 inhibition, baseline fractional glucose excretion (<2%) rose to 38 ± 12% and 46 ± 11% (fasting vs. postmeal, respectively; P < 0.0001) over a range of BMIs (range 23-41 kg/m 2 ) and creatinine clearance (65-168 mL · min -1 · m -2 ). Excretion of β-HB (median [interquartile range]: 0.08 [0.10] to 0.31 [0.43] µmol · min -1 ), lactate (0.06 [0.06] to 0.28 [0.25] µmol · min -1 ), and sodium (0.27 [0.22] to 0.36 [0.16] mEq · min -1 ) all increased ( P ≤ 0.001 for all) and were each positively related to glycosuria ( P ≤ 0.001). These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal pro-B-type natriuretic peptide levels were unaltered, plasma erythropoietin concentrations increased by 31 (64)% ( P = 0.0078)., Conclusions: We conclude that the sodium-glucose cotransporter 2 inhibitor-induced increase in β-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism., (© 2017 by the American Diabetes Association.)

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.)

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [(2)H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating β-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting β-hydroxybutyrate levels rose from 246 ± 288 to 561 ± 596 µmol/L (P < 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis., (© 2016 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.)

Aims/hypothesis: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes., Methods: A total of 32 TN and 34 patients on a stable dose of metformin, two subgroups of a study that we previously reported, received a mixed meal with double-tracer glucose administration and indirect calorimetry at baseline, after a single 25 mg dose of empagliflozin, and after 4 weeks of treatment with empagliflozin 25 mg/day., Results: At baseline, compared with the TN group, the Met group had higher fasting glycaemia (9.1 ± 1.7 vs 8.2 ± 1.3 mmol/l), lower fasting and postmeal insulin secretion, lower beta cell glucose sensitivity (37 [18] vs 58 [43] pmol min(-1) m(-2) [mmol/l](-1), median [interquartile range]) and insulin:glucagon ratio, and higher fasting EGP (15.9 [4.3] vs 12.1 [2.7] μmol kgFFM (-1) min(-1)). Change from baseline in fasting EGP after single dose and 4 weeks of treatment with empagliflozin was similar in the Met and TN groups (19.6 [4.2] and 19.0 [2.3] in Met vs 16.2 [3.6] and 15.5 [3.2] μmol kgFFM (-1) min(-1) in TN for acute and chronic dosing, respectively). Beta cell glucose sensitivity increased less in Met than TN patients, whereas substrate utilisation shifted from carbohydrate to fat more in Met than TN patients., Conclusions/interpretation: At baseline, Met patients with type 2 diabetes had more advanced disease than TN patients, featuring worse beta cell function and higher EGP. Empagliflozin induced similar glycosuria and metabolic and hormonal responses in Met and TN patients., Trial Registration: ClinicalTrials.gov NCT01248364; European Union Clinical Trials Register 2010-018708-99.

Aims: Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of α-hydroxybutyrate (α-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and α-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment., Methods: Forty-seven T2D patients [56 ± 7 years, body mass index (BMI) 29.9 ± 4.2 kg/m(2) ] were randomized to sitagliptin (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT)., Results: During a 5-h MTT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol/l · h over 2 h, median(interquartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol/l · h, p = 0.05]. Fasting α-HB was higher [7.5(2.7) vs. 5.9(1.3) µg/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. -41(86) µg/ml · h, p = 0.006]. Plasma non-esterified fatty acids (NEFA) declined during MTT, but their increments were greater in patients (53 ± 16 vs. 35 ± 10 mEq/l · h, p = 0.005). Compared to placebo, both BCAA [-6.4(21.1) vs. 0.0(48.0) mmol/l · h, p = 0.01] and α-HB increments [-114(250) vs. 114(428) µg/ml · h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and α-HB were reciprocally related to changes in insulin sensitivity (ρ = -0.37 and -0.43, p ≤ 0.01)., Conclusions: T2D is associated with a hyperaminoacidaemic response to MTT, which circulating α-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and α-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that α-HB is a readout of metabolic overload., (© 2014 John Wiley & Sons Ltd.)

Aims/hypothesis: Oral glucose elicits a higher insulin secretory response than intravenous glucose at matched glucose concentrations. This potentiation, known as the incretin effect, is typically expressed as the difference between the total insulin response to oral vs intravenous glucose. This approach does not describe the dynamics of insulin secretion potentiation. We developed a model for the simultaneous analysis of oral and isoglycaemic intravenous glucose responses to dissect the impact of hyperglycaemia and incretin effect on insulin secretion and beta cell function., Methods: Fifty individuals (23 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT] and ten with type 2 diabetes) received an OGTT and an isoglycaemic test with measurement of plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Our model featured an incretin potentiation factor (PINCR) for the dose–response function relating insulin secretion to glucose concentration, and an effect on early secretion (rate sensitivity)., Results: In NGT, PINCR rapidly increased and remained sustained during the whole OGTT (mean PINCR>1, p<0.009). The increase was transient in IGT and virtually absent in diabetes. Mean PINCR was significantly but loosely correlated with GLP-1 AUC (r=0.49, p<0.006), while the relationship was not significant for GIP. An incretin effect on rate sensitivity was present in all groups (p<0.002)., Conclusions/interpretation: The onset of the incretin effect is rapid and sustained in NGT, transient in IGT and virtually absent in diabetes. The profiles of the incretin effect are poorly related to those of the incretin hormones.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes., Methods: We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry., Results: Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged., Conclusions: In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.

Gastric bypass surgery leads to marked improvements in glucose tolerance and insulin sensitivity in obese type 2 diabetes (T2D); the impact on glucose fluxes in response to a physiological stimulus, such as a mixed meal test (MTT), has not been determined. We administered an MTT to 12 obese T2D patients and 15 obese nondiabetic (ND) subjects before and 1 year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of β-cell function. In both groups postsurgery, tracer-derived appearance of oral glucose was biphasic, a rapid increase followed by a sharp drop, a pattern that was mirrored by postprandial glucose levels and insulin secretion. In diabetic patients, surgery lowered fasting and postprandial glucose levels, peripheral insulin sensitivity increased in proportion to weight loss (~30%), and β-cell glucose sensitivity doubled but did not normalize (compared with 21 nonsurgical obese and lean controls). Endogenous glucose production, however, was less suppressed during the MMT as the combined result of a relative hyperglucagonemia and the rapid fall in plasma glucose and insulin levels. We conclude that in T2D, bypass surgery changes the postprandial response to a dumping-like pattern and improves glucose tolerance, β-cell function, and peripheral insulin sensitivity but worsens endogenous glucose output in response to a physiological stimulus.

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.

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) lowers glucose levels by potentiating glucose-induced insulin secretion and inhibiting glucagon release. The question of whether GLP-1 exerts direct effects on the liver, independently of the hormonal changes, is controversial. We tested whether an exogenous GLP-1 infusion, designed to achieve physiological postprandial levels, directly affects endogenous glucose production (EGP) under conditions mimicking the fasting state in diabetes., Methods: In 14 healthy volunteers, we applied the pancreatic clamp technique, whereby plasma insulin and glucagon levels are clamped using somatostatin and hormone replacement. The clamp was applied in paired, 4 h experiments, during which saline (control) or GLP-1(7-37)amide (0.4 pmol min⁻¹ kg⁻¹) was infused., Results: During the control study, plasma insulin and glucagon were maintained at basal levels and plasma C-peptide was suppressed, such that plasma glucose rose to a plateau of ~10.5 mmol/l and tracer-determined EGP increased by ~60%. During GLP-1 infusion at matched plasma glucose levels, the rise of EGP from baseline was fully prevented. Lipolysis (as indexed by NEFA concentrations and tracer-determined glycerol rate of appearance) and substrate utilisation (by indirect calorimetry) were similar between control and GLP-1 infusion., Conclusions/interpretation: GLP-1 inhibits EGP under conditions where plasma insulin and glucagon are not allowed to change and glucose concentrations are matched, indicating either a direct effect on hepatocytes or neurally mediated inhibition.

Context: Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known., Objective: The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors., Design, Setting, and Patients: We administered a mixed meal with glucose tracers ([6,6-(2)H(2)]-glucose infused, [1-(2)H]-glucose ingested), and on a separate day, a glucose infusion matched the glucose responses to the meal (isoglycemic test) in 50 type 2 diabetes patients (hemoglobin A(1c) = 7.4 ± 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion., Intervention: We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg/d; n = 25) or placebo (n = 22)., Results: Relative to placebo, meal-induced changes in fasting glucose and glucose area under the curve (AUC) were greater with sitagliptin, in parallel with a lower appearance of oral glucose [difference (post-pre) AUC = -353 ± 915 vs. +146 ± 601 μmol · kg(-1) · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, β-cell glucose sensitivity improved (+19[29] vs. 5[21] pmol · min(-1) · m(-2) · mm(-1); median [interquartile range]) and glucagon AUC decreased (19.6 ± 7.5 to 17.3 ± 7.1 ng · ml(-1) · 5 h), whereas intact glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 AUC increased with sitagliptin vs. placebo. The incretin effect was unchanged because sitagliptin increased β-cell glucose sensitivity also during the isoglycemic test., Conclusions: Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and β-cell glucose sensing in response to both oral and iv glucose.

Objectives: The objective of this study was to define metabolic normality and to investigate the cardiometabolic profile of metabolically normal obese., Design: Cross-sectional study conducted at 21 research centers in Europe., Subjects: Normal body weight (nbw, n=382) and overweight or obese (ow/ob, n=185) subjects free from metabolic syndrome and with normal glucose tolerance, were selected among the Relationship between Insulin Sensitivity and Cardiovascular Disease study participants., Main Outcome Measures: Insulin sensitivity was assessed by the clamp technique. On the basis of quartiles in nbw subjects, the limits of normal insulin sensitivity and of normal fasting insulinemia were established. Subjects with normal insulin sensitivity and fasting insulin were defined as metabolically normal., Results: Among ow/ob subjects, 11% were metabolically normal vs 37% among nbw, P<0.0001. Ow/ob subjects showed increased fasting insulin (P=0.0009), low-density lipoprotein cholesterol (LDL-cholesterol) (P=0.004), systolic (P=0.0007) and diastolic (P=0.001) blood pressure, as compared with nbw. When evaluating the contribution of body mass index (BMI), hyperinsulinemia and insulin resistance, BMI showed an isolated effect on high-density lipoprotein (P=0.007), high-sensitivity C-reactive protein (P<0.0001), systolic (P=0.002) and diastolic (P=0.008) blood pressures. BMI shared its influence with insulinemia on total cholesterol (P=0.04 and 0.003, respectively), LDL-cholesterol (P=0.003 and 0.006, respectively) and triglycerides (P=0.02 and 0.001, respectively)., Conclusion: In obese subjects, fasting insulin should be taken into account in the definition of metabolic normality. Even when metabolically normal, obese subjects could be at increased risk for cardiometabolic diseases. Increased BMI, alone or with fasting insulin, is the major responsible for the less favorable cardio-metabolic profile.

Introduction: Bariatric surgery in morbidly obese type 2 diabetic (T2DM) patients is associated with high rates of diabetes remission. We investigated the mechanisms of the anti-diabetic effect of the laparoscopic ileal interposition with sleeve gastrectomy (LII-SG) in normal weight (NW), overweight (OW) and obese (OB) T2DM patients., Methods: Ninety-four patients (aged 54 ± 8 years) with long-standing (median 10 years), treated diabetes (median HbA(1c) = 8.6%), who were NW (15), OW (64) or OB (15) based on BMI, underwent LII-SG. Insulin sensitivity and parameters of ß-cell function were measured from an Oral Glycaemic Tolerance Test pre- and post-operatively., Results: At a median of 13.4 months post-operatively, weight loss averaged 9.4 ± 1.3, 16.8 ± 0.8 and 23.2 ± 1.7 kg in NW, OW and OB subjects, respectively (p < 0.0001). Insulin sensitivity was fully restored (395 [108] vs 208 [99] ml min⁻¹ m⁻²), fasting insulin secretion rate decreased (68 [52] vs 146 [120] pmol min⁻¹ m⁻²) and total insulin output increased (52 [26] vs 39 [28] nmol m⁻², all p ≤ 0.001). ß-cell glucose sensitivity doubled (37 [33] vs 18 [24] mol min⁻¹ m⁻² mM⁻¹, p < 0.0001). The only parameter predicting remission of diabetes was a lower baseline insulin sensitivity (p = 0.005)., Conclusions: LII-SG induced changes on T2DM by mechanisms in part distinct from weight loss, principally involving restoration of insulin sensitivity and improvement of ß-cell function.

Aims/hypothesis: Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss., Methods: We studied 25 morbidly obese patients (BMI 51.7 ± 1.5 kg/m(2) [mean ± SEM]), 13 with non-insulin-treated type 2 diabetes (HbA(1c) 7.1 ± 0.5% [54 ± 5 mmol/mol]), before and at 2 weeks and 1 year after Roux-en-Y gastric bypass (RYGB). Lean (n = 8, BMI 23.0 ± 0.5 kg/m(2)) and obese (n = 14) volunteers who were BMI-matched (36.0 ± 1.2) to RYGB patients at 1 year after surgery served as controls. We measured insulin-stimulated glucose disposal (M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[(2)H(2)]glucose, lipolysis (rate of appearance of [(2)H(5)]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution)., Results: At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1 year post-RYGB (BMI 34.4 ± 1.1 kg/m(2)), all diabetic patients were off glucose-lowering treatment and mean HbA(1c) was 5.4 ± 0.14% (36 ± 2 mmol/mol) (p = 0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls., Conclusions/interpretation: In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term.

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.)

Aims/hypothesis: The natural history and physiological determinants of glucose intolerance in subjects living in Europe have not been investigated. The aim of this study was to increase our understanding of this area., Methods: We analysed the data from a population-based cohort of 1,048 non-diabetic, normotensive men and women (aged 30-60 years) in whom insulin sensitivity was measured by the glucose clamp technique (M/I index; average glucose infusion rate/steady-state insulin concentration) and beta cell function was estimated by mathematical modelling of the oral glucose tolerance test at baseline and 3 years later., Results: Seventy-seven per cent of the participants had normal glucose tolerance (NGT) and 5% were glucose intolerant both at baseline and follow up; glucose tolerance worsened in 13% (progressors) and improved in 6% (regressors). The metabolic phenotype of the latter three groups was similar (higher prevalence of familial diabetes, older age, higher waist-to-hip ratio, higher fasting and 2 h plasma glucose, higher fasting and 2 h plasma insulin, lower insulin sensitivity and reduced beta cell glucose sensitivity with increased absolute insulin secretion). Adjusting for these factors in a logistic model, progression was predicted by insulin resistance (bottom M/I quartile, OR 2.52 [95% CI 1.51-4.21]) and beta cell glucose insensitivity (bottom quartile, OR 2.39 [95% CI 1.6-3.93]) independently of waist-to-hip ratio (OR 1.44 [95% CI 1.13-1.84] for one SD). At follow up, insulin sensitivity and beta cell glucose sensitivity were unchanged in the stable NGT and stable non-NGT groups, worsened in progressors and improved in regressors., Conclusions/interpretation: Glucose tolerance deteriorates over time in young, healthy Europids. Progressors, regressors and glucose-intolerant participants share a common baseline phenotype. Insulin sensitivity and beta cell glucose sensitivity predict and track changes in glucose tolerance independently of sex, age and obesity.

Obesity-associated microvascular dysfunction (MVD) involves different body tissues, including skin, and concurs to increased cardiovascular risk in obese patients (Ob-P). Generalized improvement of MVD is an important goal in obesity treatment. Since skin MVD mirrors generalized systemic MVD, skin microvascular investigation in prospective studies in Ob-P may surrogate microvascular investigation in organs more important for cardiovascular risk of the studied patients. In this prospective study, we measured forearm skin post-occlusive reactive hyperaemia (PORH), as percentage flow increase from baseline, and skin vasomotion in 37 Ob-P before Roux-en-Y gastric bypass (RYGB), and in 24 of them about 1 year after RYGB, using laser Doppler flowmetry (LDF). The spectral contribution of skin LDF signal oscillations in the frequency intervals of 0.01-0.02 Hz, 0.02-0.06 Hz, and 0.06-0.2 Hz--corresponding to endothelial-, sympathetic-, and myogenic-dependent vasomotion, respectively, was measured by means of spectral Fourier analysis. The same measurements were also performed in 28 healthy, lean subjects (HLS). Before RYGB, Ob-P had a significant reduction in PORH and in the all vasomotion parameters investigated, compared with HLS. After RYGB, Ob-P who completed the follow-up, had a significant weight loss (∼40 kg on average), together with a full normalisation in PORH and in vasomotion parameters, regardless of diabetes status. Surgically induced sustained weight loss resulted in full normalisation of skin microvascolar function in Ob-P about 1 year after RYGB. This result suggests a beneficial effect of sustained weight loss on generalized MVD of the studied Ob-P.

Context: What defects in glucose metabolism are present in offspring of type 2 diabetic patients (FHD(+) with a positive family history of diabetes) and to what extent they depend on line of inheritance are uncertain., Objective: The objective of this study was to assess clinical phenotype, insulin sensitivity, and β-cell function in FHD(+) by line of inheritance., Subjects: The subjects included 1221 nondiabetic men and women aged 30-60 yr, of whom 343 were FHD(+), who participated to the Relationship between Insulin Sensitivity and Cardiovascular Disease Investigators study, a multicenter European collaboration., Main Outcome Measures: The main outcome measures included the following: insulin sensitivity by the euglycemic clamp; total insulin secretion, β-cell glucose sensitivity, rate sensitivity, and potentiation by C-peptide deconvolution and oral glucose tolerance test modeling; and acute insulin response to i.v. glucose., Results: Older age, increased adiposity, and dyslipidemia were the dominant features of FHD(+) clinical phenotype. FHD(+) subjects had a 13% reduction in insulin sensitivity [95% confidence interval (CI) of 6,19], which in males was more pronounced (17%, CI: 5,24 vs. 10%, CI: 2,20) and influenced by maternal inheritance (21%, CI: 5,38 vs. 14%, CI: 0,28 paternal). After adjusting for confounders, β-cell glucose sensitivity and rate sensitivity were reduced by 13% (CI: 3,20) and 18% (CI: 5,35), respectively (P < 0.01 for both); the former defect was more severe with maternal (16%, CI: 4,26) than paternal (9%, CI: -2,22) transmission. Independently of line of inheritance, both fasting and total oral glucose tolerance test insulin secretion were increased in proportion to the insulin resistance, whereas acute insulin response and rate sensitivity were not., Conclusions: Diabetic inheritance is expressed as a characteristic clinical phenotype associated with defects in insulin sensitivity and β-cell glucose sensitivity, which are accentuated along maternal inheritance. β-Cell rate sensitivity is reduced and β-cell dynamic responses to insulin resistance are lost independently of the line of inheritance.

Context: Type 2 diabetes mellitus (T2DM) and obesity are characterized by a low-grade inflammation, which might be related to the development of insulin resistance. Human leukocyte antigen-G (HLA-G) shows antiinflammatory and tolerogenic properties, including the modulation of CD8+ T-cell cytotoxicity and regulation of CD4+ T-lymphocyte function. These functions are partially shared with IL-10, whose levels are reduced in insulin-resistant states., Objective: The aim was to explore the relationship between HLA-G and the metabolic and inflammatory pattern of obesity or T2DM., Patients and Main Outcome Measures: Soluble HLA-G, IL-6, and IL-10 were measured and related with metabolic and biochemical parameters in 230 volunteers with normal glucose tolerance, impaired glucose tolerance, or T2DM by oral glucose tolerance test., Results: sHLA-G, detected in 144 subjects (sHLA-G positive), was more frequent in T2DM or impaired glucose tolerance subjects than in normal glucose tolerance (chi(2) =18.6; P < 0.0001), and its plasma levels increased progressively across the classes of glucose tolerance. sHLA-G-positive individuals had higher body mass index, systolic blood pressure, and cholesterol levels; a reduced degree of insulin sensitivity; and almost 2-fold higher levels of IL-6, a cytokine related to insulin sensitivity, whereas IL-10 was similar. In the sHLA-G-positive subgroup, by a multivariate regression model, sHLA-G was significantly related to 2-h glucose, the area under insulin curve, and IL-6 levels (multiple r(2) = 0.14; P < 0.001), independently of age, gender, and body mass index., Conclusions: A frequent expression of sHLA-G, linked to a typical biomarker of insulin resistance like IL-6, seems to characterize subjects with an impaired glucose metabolism.

Objective: We tested whether men and women in the European Society of Hypertension (ESH) high normal and normal blood pressure (BP) categories, all included in the the Seventh Joint National Committee (JNC 7) prehypertension group, share similar metabolic characteristics and whether they differ from men and women with optimal BP (<120/80 mmHg)., Methods: BP (multiple measurements with a standardized automatic device), insulin sensitivity (euglycaemic clamp), oral glucose tolerance test (OGTT), carotid intima-media-thickness (IMT, echo), family history (questionnaire), physical activity (accelerometer), and anthropometrics (bioimpedance) were evaluated in the 1384 healthy European individuals ranging from 30-60 years participating in the multicentre study Relationship between Insulin Sensitivity and Cardiovascular disease (RISC)., Results: BMI and waist-to-hip ratio were higher (both P < 0.05 adjusted for age and recruiting centre) in men and women with high normal (but not normal) BP with respect to optimal BP. Similarly, in women (after adjustment for study centre, age, physical activity, and waist), serum triglycerides and carotid IMT were higher in those with high normal (but not normal) BP; moreover, in this group there was a higher prevalence of glucose-intolerance (21.8 versus 9.7%, P = 0.02) and insulin sensitivity tended to be lower (P = 0.07). Insulin sensitivity and diastolic blood pressure were weakly related variables displaying a nonlinear association with a threshold below the normal BP values and no interaction with family history of hypertension., Conclusion: The JNC 7 category prehypertension identifies a dishomogeneous group of individuals whereas the ESH classification, particularly in women, was more accurate in identifying both the predisease and the healthy phenotype. Insulin resistance is not a major characteristic of the condition of prehypertension.

Background: Retinol-binding protein-4 (RBP4) is a novel adipokine able to modulate the action of insulin in several tissues. A variable degree of insulin resistance characterizes the vast majority of hypertensive (HYP) patients. The aim of this study was to evaluate the relationship between RBP4 and essential hypertension, exploring potential links between RBP4 and other adipokines with some proxies of early vascular damage in female naive HYP patients., Methods: Serum RBP4, leptin, adiponectin, and resistin levels were determined in 35 HYP and 35 normotensive lean women with normal glucose tolerance paired by age and body mass index (BMI) served as controls (CTL); carotid intima-media thickness (IMT) was also measured., Results: A striking difference was observed in RBP4 levels between HYP and CTL with significantly higher levels in the former than in the latter. No relationship was observed between glomerular filtration rate (GFR) and RBP4. Adiponectin levels were slightly but significantly lower in HYP than in CTL, whereas no differences were observed in resistin and leptin concentrations between the two groups of women. In the whole study group, a strong linear relationship was observed between IMT value and both RBP4 (rho = 0.321, P = 0.0076) and resistin (rho = 0.340, P = 0.0048); these two adipocytokines, together with cholesterol, were the only variables independently related to IMT (r(2) = 0.24; P = 0.004) by a stepwise analysis., Conclusions: RBP4 levels are increased in naive HYP women and correlated with the degree of IMT suggesting a participation of this adipocytokine in the modulation of the atherosclerotic process exerted by the adipose tissue as endocrine organ.

Improved glucose tolerance to sequential glucose loading (Staub-Traugott effect) is an important determinant of day-to-day glycemic exposure. Its mechanisms have not been clearly established. We recruited 17 healthy volunteers to receive two sequential oral glucose tolerance tests (OGTTs), at time 0 min and 180 min (Study I). The protocol was repeated on a separate day (Study II) except that plasma glucose was clamped at 8.3 mmol/l between 60 and 180 min. beta-Cell function was analyzed by mathematical modeling of C-peptide concentrations. In a subgroup, glucose kinetics were measured by a triple-tracer technique (infusion of [6,6-(2)H(2)]glucose and labeling of the 2 glucose loads with [1-(2)H]glucose and [U-(13)C]glucose). In both Studies I and II, the plasma glucose response to the second OGTT equaled 84 +/- 2% (P = 0.003) of the response to the first OGTT. Absolute insulin secretion was lower (37.8 +/- 4.3 vs. 42.8 +/- 5.1 nmol/m(2), P = 0.02), but glucose potentiation (i.e., higher secretion at the same glycemia) was stronger (1.08 +/- 0.02- vs. 0.92 +/- 0.02-fold, P = 0.006), the increment being higher in Study II (+36 +/- 5%) than Study I (+19 +/- 6%, P < 0.05). In pooled data, a higher glucose area during the first OGTT was associated with a higher potentiation during the second OGTT (rho=0.60, P = 0.002). Neither insulin clearance nor glucose clearance differed between loads, and appearance of glucose over 3 h totalled 60 +/- 6 g for the first load and 52 +/- 5 g for the second load (P = not significant). Fasting endogenous glucose production [13.3 +/- 0.6 micromol x min(-1) x kg fat-free mass (FFM)(-1)] averaged 6.0 +/- 3.8 micromol x min(-1) x kg FFM(-1) between 0 and 180 min and 1.7 +/- 2.6 between 180 and 360 min (P < 0.03). Glucose potentiation and stronger suppression of endogenous glucose release are the main mechanisms underlying the Staub-Traugott effect.

Some cytokines and proinflammatory mediators are considered markers of increased atherothrombotic risk. Few information is available on the effects of acute glucose and insulin variations on these markers of atherosclerosis. We assessed the acute effect of glucose and insulin on soluble CD40 ligand (sCD40L), IL-6, and P-selectin levels, evaluating their relationship with insulin sensitivity in normal glucose tolerance subjects (NGT). Twenty-four NGT subjects underwent a 3-h oral glucose tolerance test (OGTT) with measurements of sCD40L, IL-6, and P-selectin levels at 0, 90 and 180 min. Insulin sensitivity was assessed by the Oral Glucose Sensitivity Index (OGIS). To distinguish the role of glucose and insulin, eight subjects had the plasma glucose profile of the OGTT reproduced by a variable IV glucose infusion (ISO-G study) and nine underwent a euglycemic clamp. Lastly, a 3-h time-control (TC) study was performed in eleven subjects. A significant reduction of sCD40L was observed during OGTT and ISO-G study. This reduction was not due to time-related changes, since it was not observed in TC study. During the clamp, insulin induced a marked drop in sCD40L (from 4.89+/-1.34 to 1.60+/-0.29 ng/ml, p<0.05). In the pooled data from all studies, fasting sCD40L was indirectly related to LDL-cholesterol (r=-0.38; p=0.04), while IL-6 was directly related with BMI, fat mass, waist circumference, and P-selectin (p<0.05). sCD40L levels are downregulated during a short-term period of acute hyperinsulinemia, whether induced by oral or intravenous glucose administration or by insulin infusion, while it does not seem to affect P-selectin and IL-6.

Background: The mechanisms by which menopause may influence the systemic subclinical atherosclerosis are unexplained. The aim of this cross-sectional study was to evaluate the associations between early menopause, established cardiovascular (c-v) risk factors, metabolic parameters (insulin secretion and sensitivity, plasma adiponectin), and carotid intima-media thickness (IMT) in healthy women., Methods: In 74 menopausal women (mean age = 51 +/- 3 years, mean duration of menopause = 2.9 +/- 1.2 years) and in 74 nonmenopausal women comparable for age and body mass index (BMI), common carotid artery (CCA) luminal diameter, and IMT in different carotid segments were measured in digitized ultrasound images. Insulin sensitivity and secretion were assessed using the euglycemic hyperinsulinemic clamp technique and oral glucose tolerance test (OGTT). Insulin secretion was reconstructed by mathematical modeling., Results: CCA diameter (5.55 +/- 0.46 vs. 5.21+/- 0.51 mm, P < 0.001), CCA IMT (608 +/- 78 vs. 576 +/- 74 microm, P < 0.01) and systolic blood pressure (BP) (117 +/- 12 vs. 113 +/- 11 mm Hg, P < 0.05) were higher in menopausal women, whereas CCA IMT/diameter ratio and IMT in other carotid segments did not differ between the groups. By multivariate models, independent predictors of CCA diameter were menopause and body weight (cumulative R2 = 0.37) and independent correlates of CCA IMT were luminal diameter, systolic BP and low-density lipoprotein (LDL) cholesterol (cumulative R2 = 0.48). Fasting insulin, insulin secretion, and sensitivity and plasma adiponectin were similar in the two groups and were not related to carotid IMT., Conclusions: Early menopause is associated with CCA remodeling, characterized by a proportional increase in luminal diameter and wall thickness, independent of atherosclerotic risk factors and metabolic variables.

Background: It has been proposed that there is improvement in glucose and insulin metabolism after weight loss in patients who underwent diet restriction and bariatric surgery., Methods: Eleven normal glucose tolerant (NGT) morbidly obese patients [body mass index (BMI), 46.1+/-2.27 g/m2] and eight abnormal glucose metabolism (AGM) obese patients (BMI, 51.20 kg/m2) were submitted to diet-restriction and bariatric surgery. Prospective study on weight loss changes, over the glucose, insulin metabolism, glucagon-like peptide-1 (GLP-1), and adiponectin levels were evaluated by oral glucose tolerance test during three periods: T1 (first evaluation), T2 (pre-surgery), and T3 (9 months after surgery)., Results: Insulin levels improved after surgery. T1 was 131.1+/-17.60 pmol/l in the NGT group and 197.57+/-57.94 pmol/l in the AGM group, and T3 was 72.48+/-3.67 pmol/l in the NGT group and 61.2+/-9.33 pmol/l in the AGM group. The major reduction was at the first hour of the glucose load as well as fasting levels. At 9 months after surgery (T3), GLP-1 levels at 30 and 60 min had significantly increased in both groups. It was observed that the AGM group had higher levels of GLP-1 at 30 min (34.06+/-6.18 pmol/l) when compared to the NGT group (22.69+/-4.04 pmol/l). Homeostasis model assessment of insulin resistance from the NGT and AGM groups had a significant reduction at periods T3 in relation to T1 and T2. Adiponectin levels had increased concentration in both groups before and after surgical weight loss. However, it did not have any statistical difference between periods T1 vs. T2., Conclusions: Weight loss by surgery leads to improvement in the metabolism of carbohydrates in relation to sensitivity to the insulin, contributing to the reduction of type 2 diabetes incidence. This improvement also was expressed by the improvement of the levels of adiponectin and GLP-1.

Objective: To assess the relationship between adiponectin and metabolic parameters in severely obese women during surgical-induced weight loss., Methods: Nineteen lean (CT - BMI:21.2 +/- 0.3 kg.m(2)), 14 overweight/class II obese (OB/OW - BMI: 29.7 +/- 0.7 kg/m(2)) and 8 morbidly obese (OBIII - BMI: 56.4 +/- 3.6 kg/m(2)) were evaluated by hyperinsulinemic-euglycemic clamp, adiponectin, and lipids. OBIII were evaluated at 5th and 16th month post-operatively., Results: Compared to lean, obese groups had lower adiponectin (OB/OW: 9.4 +/- 0.9, OBIII: 7.1 +/- 1.3 versus 12.2 +/- 0.9 ng/dL; p < 0.01), lower HDL-cholesterol (OB/OW:1.05 +/- 0.05, OBIII: 0.88 +/- 0.04 versus 1.22 +/- 0.07 mmol/L; p < 0.01) and insulin resistance-IR (glucose uptake, M-value - OB/OW: 43.6 +/- 2.7, OBIII: 32.4 +/- 3.2 versus 20.0 +/- 1.8 umol/kgFFM.min; p < 0.001). Considering all subjects, adiponectin levels were inversely correlated to BMI and waist circumference, and directly to M-value and HDL-cholesterol (p < 0.01). During weight loss, improvements in IR (Study III: 36.1 +/- 3.9 umol/kg/FFM.min, p < 0.0001), adiponectin (11.8 +/- 1.4 ng/dL, p = 0.006) and HDL-cholesterol were observed (1.10 +/- 0.04 mmol/L, p = 0.007). Moreover, HDL-cholesterol improvement was significantly and independently related to variations of adiponectin and BMI (r(2) = 0.86; p < 0.0002)., Conclusions: The improvements of IR and adiponectin were related to surgical-induced weight loss, suggesting an important role of adiponectin in HDL-cholesterol regulation.

Context: Adiponectin inhibits protein synthesis in cardiac myocytes, thereby opposing the effect of cardiac workload and trophic factors (in particular, insulin) on left ventricular (LV) mass and wall thickness (WT)., Objective: We tested whether adiponectin and its isoforms are related to LV mass, WT, and function independently of metabolic factors., Design: This was a cross-sectional study., Subjects: The study included 77 healthy volunteers (42 men) aged 30-59 yr with normal LV structure and function., Main Outcome Measures: Insulin response and insulin sensitivity were assessed by oral glucose tolerance test and euglycemic hyperinsulinemic clamp. LV mass, WT, stroke work, chamber function, and myocardial longitudinal function were evaluated by standard Doppler echocardiography and tissue Doppler imaging. Total and molecular isoforms of adiponectin were measured in plasma., Results: By multivariate analysis, independent factors affecting LV mass were sex, body mass index, stroke work, and current smoking (R(2) = 0.66). Independent correlates of LV WT were age, stroke work, and plasma adiponectin (standardized r = 0.28, 0.41, and -0.26, P at least < 0.005, R(2) = 0.48). LV longitudinal late diastolic velocity was independently related to age, body mass index, and adiponectin (standardized r = 0.20, 0.26, -0.33, P at least < 0.05, R(2) = 0.30). High-molecular-weight adiponectin (47% of total), but not lower molecular-weight isoforms, insulin sensitivity, or other metabolic factors, was inversely and independently related to WT (standardized r = -0.27, P < 0.01) and myocardial longitudinal late diastolic velocity (standardized r = -0.28, P < 0.05)., Conclusion: In healthy subjects, circulating total and high-molecular-weight adiponectin are related to LV WT and diastolic function, independently of age and metabolic factors.

Objective: To quantitate the separate impact of obesity and hyperglycemia on the incretin effect (i.e., the gain in beta-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(2)). C-peptide deconvolution was used to reconstruct insulin secretion rates, and beta-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response 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 beta-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P

Aims/hypothesis: Hyperglycaemia and hyperinsulinaemia have opposite effects on endothelium-dependent vasodilatation in microcirculation, but the net effect elicited by glucose ingestion and the separate influence of glucose tolerance are unknown., Methods: In participants with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or diabetic glucose tolerance, multiple plasma markers of both oxidative stress and endothelial activation, and forearm vascular responses (plethysmography) to intra-arterial acetylcholine (ACh) and sodium nitroprusside (SNP) infusions were measured before and after glucose ingestion. In another IGT group, we evaluated the time-course of the skin vascular responses (laser Doppler) to ACh and SNP (by iontophoresis) 1, 2 and 3 h into the OGTT; the plasma glucose profile was then reproduced by means of a variable intravenous glucose infusion and the vascular measurements repeated., Results: Following oral glucose, plasma antioxidants were reduced by 5% to 10% (p < 0.01) in all patient groups. The response to acetylcholine was not affected by glucose ingestion in any group, while the response to SNP was attenuated, particularly in the IGT group. The ACh:SNP ratio was slightly improved therefore in all groups, even in diabetic participants, in whom it was impaired basally. A time-dependent improvement in ACh:SNP ratio was also observed in skin microcirculation following oral glucose; this improvement was blunted when matched hyperglycaemia was coupled with lower hyperinsulinaemia (intravenous glucose)., Conclusions/interpretation: Regardless of glucose tolerance, oral glucose does not impair endothelium-dependent vasodilatation either in resistance arteries or in the microcirculation, despite causing increased oxidative stress; the endogenous insulin response is probably responsible for countering any inhibitory effect on vascular function.

Mild-to-moderate hypertension is often associated with insulin resistance and visceral adiposity. Whether these metabolic abnormalities have an independent impact on regional cardiac function is not known. The goal of this study was to investigate the effects of increased blood pressure, insulin resistance, and ectopic fat accumulation on the changes in peak systolic circumferential strain. Thirty-five male subjects (age: 47+/-1 years; body mass index: 28.4+/-0.6 kg m(-2); mean+/-SEM) included 13 with normal blood pressure (BP: 113+/-5/67+/-2 mm Hg), 13 with prehypertension (BP: 130+/-1/76+/-2 mm Hg), and 9 newly diagnosed with essential hypertension (BP: 150+/-2/94+/-2 mm Hg) who underwent cardiac magnetic resonance tissue tagging (MRI) and MRI quantitation of abdominal visceral and epicardial fat. Glucose tolerance, on oral glucose tolerance test, and insulin resistance were assessed along with the serum lipid profile. All of the subjects had normal glucose tolerance, left- and right-ventricular volumes, and ejection fraction. Across the BP groups, left ventricular mass tended to increase, and circumferential shortening was progressively reduced at basal, midheart, and apical segments (on average, from -17.0+/-0.5% in normal blood pressure to -15.2+/-0.7% in prehypertension to -13.6+/-0.8% in those newly diagnosed with essential hypertension; P=0.004). Reduced circumferential strain was significantly associated with raised BP independent of age (r=0.41; P=0.01) and with epicardial and visceral fat, serum triglycerides, and insulin resistance independent of age and BP. In conclusion, regional left ventricular function is already reduced at the early stages of hypertension despite the normal global cardiac function. Insulin resistance, dyslipidemia, and ectopic fat accumulation are associated with reduced regional systolic function.

Aims/hypothesis: Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals., Methods: We measured IR [by a euglycaemic-hyperinsulinaemic (240 pmol min(-1) m(-2)) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m(2) (range 18-44 kg/m(2))] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control., Results: In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was approximately 2 for both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001)., Conclusions/interpretation: Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets.

The mechanisms by which the enteroinsular axis influences beta-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate beta-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 +/- 0.18, P = 0.004] amounted to 18 +/- 2 nmol/m(2) (32 +/- 4% of oral response), and its time course matched that of total insulin secretion. The beta-cell glucose sensitivity (OGTT/IV ratio = 1.52 +/- 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 +/- 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, beta-cell glucose sensitivity (75 +/- 14 vs. 156 +/- 28 pmol.min(-1).m(-2).mM(-1) of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of beta-cell glucose sensitivity (OGTT/IV ratio = 1.73 +/- 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of beta-cell function, particularly beta-cell glucose sensitivity. In IGT, beta-cell function is inherently impaired, whereas the incretin effect is only partially affected.