GLP-1 receptor agonist treatment improved fasting and postprandial lipidomic profile independently of diabetes and weight loss.

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduces liver steatosis and cardiometabolic risk (CMR). Only few data are available on lipid metabolism and no information on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a meal tolerance test (MTT) in adults with severe obesity without diabetes. Thirty individuals (26F/4M, 30-60 years old, BMI>40 kg/m2, HbA1c=5.76%) were assigned (1:1) to diet with exenatide treatment (EXE, n=15, 10 µg twice-daily) or without treatment as control (CT, n=15) for 3 months. Fasting and postprandial lipidomic profile (by LC/MS-QTOF) and fatty acid metabolism (following a 6-hour MTT/tracer study) and composition (by GC/MS) were evaluated before and after treatment. Both groups had slight weight loss (EXE: -5.5% vs CT: -1.9%, p=0.052). During fasting, exenatide, compared to CT, reduced some ceramides (CER) and lysophosphocholines (LPC) previously associated with CMR, while relatively increasing unsaturated phospholipid species (PC, LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MTT, both groups suppressed lipolysis equally to baseline, but EXE exenatide significantly lowered free fatty acid clearance and postprandial triacyclglycerols (TAG) concentrations, particularly saturated TAGs with 44-54 carbons. Exenatide also reduced some postprandial CERs, PCs, LPCs previously linked to cardiometabolic risk. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exenatide improved fasting and postprandial lipidomic profile associated with CMR mainly by reducing saturated postprandial TAGs and CERs, independently of weight loss and diabetes.

SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes.

Pancreatic ß-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in ß-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human ß-cells. Mice with ß-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

Effects of hypertriglyceridemia with or without NEFA elevation on ß-cell function and insulin clearance and sensitivity.

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 ß-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. ß-cell glucose sensitivity) and increased ß-cell potentiation, whereas I+H had neutral effects on these ß-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 ß-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.

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass.

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement. Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota. Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients. Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature.

Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD.

OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS: We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS: Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS: We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.

Differential effects of bariatric surgery on plasma levels of ANGPTL3 and ANGPTL4.

BACKGROUND AND AIM: Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are regulators of triglyceride storage and utilization. Bariatric surgery (BS) leads to profound changes in adipose tissue composition and energy metabolism. We evaluated the impact of BS on plasma levels of ANGPTL3 and ANGPTL4. METHODS AND RESULTS: Twenty-seven subjects affected by morbid obesity with or without type 2 diabetes (T2D) underwent Roux-en-Y gastric bypass (RYGB) and 18 patients with advanced T2D received Biliopancreatic Diversion (BPD). Fasting ANGPTL proteins levels, insulin sensitivity (evaluated by euglycemic hyperinsulinemic clamp), total bile acids (TBA) and free fatty acids (FFA) were measured at baseline and 1 year after surgery. Both surgical procedures resulted in the loss of fat mass, improved glucose control, and a ∼2-fold increase of insulin sensitivity. ANGPTL4 levels decreased significantly with both RYGB (26.6 ± 0.6 to 24.4 ± 0.3 ng/mL, p = 0.001) and BPD (27.9 ± 1.5 to 24.0 ± 0.5 ng/mL, p = 0.003). In contrast, ANGPTL3 concentrations did not change after RYGB but rose following BPD (225 ± 20 to 300 ± 15 ng/mL, p = 0.003). By multiple regression analysis, changes after BS in ANGPTL4 were independently associated with changes in blood glucose, (p = 0.0169) whereas changes in ANGPTL3 were associated with variations in FFA (p = 0.008) and insulin sensitivity (p = 0.043). CONCLUSION: Circulating ANGPTL4 is reduced by BS, probably due to the loss of fat mass and improved insulin sensitivity. Conversely, ANGPTL3 levels increased after BPD, but not after RYGB, presumably because of the metabolic changes induced by the malabsorptive effect of BPD.

Impaired Succinate Response to a Mixed Meal in Obesity and Type 2 Diabetes Is Normalized After Metabolic Surgery.

OBJECTIVE: To explore the meal response of circulating succinate in patients with obesity and type 2 diabetes undergoing bariatric surgery and to examine the role of gastrointestinal glucose sensing in succinate dynamics in healthy subjects. RESEARCH DESIGN AND METHODS: Cohort I comprised 45 patients with morbid obesity and type 2 diabetes (BMI 39.4 ± 1.9 kg/m2) undergoing metabolic surgery. Cohort II was a confirmatory cohort of 13 patients (BMI 39.3 ± 1.4 kg/m2) undergoing gastric bypass surgery. Cohort III comprised 15 healthy subjects (BMI 26.4 ± 0.5 kg/m2). Cohorts I and II completed a 2-h mixed-meal tolerance test (MTT) before the intervention and at 1 year of follow-up, and cohort II also completed a 3-h lipid test (LT). Cohort III underwent a 3-h oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) study. RESULTS: In cohort I, succinate response to MTT at follow-up was greater than before the intervention (P < 0.0001). This response was confirmed in cohort II with a greater increase after 1 year of surgery (P = 0.009). By contrast, LT did not elicit a succinate response. Changes in succinate response were associated with changes in the area under the curve of glucose (r = 0.417, P < 0.0001) and insulin (r = 0.204, P = 0.002). In cohort III, glycemia, per se, stimulated a plasma succinate response (P = 0.0004), but its response was greater in the OGTT (P = 0.02; OGTT versus IIGI). CONCLUSIONS: The meal-related response of circulating succinate in patients with obesity and type 2 diabetes is recovered after metabolic surgery.

Utility of Insulin Resistance in Estimating Cardiovascular Risk in Subjects with Type 1 Diabetes According to the Scores of the Steno Type 1 Risk Engine.

BACKGROUND: We sought to assess the potential of insulin resistance (IR) for estimating cardiovascular disease (CVD) risk in adults with type 1 diabetes (T1DM) according to the scores of the Steno Type 1 Risk Engine (ST1RE). METHODS: A total of 179 adults with T1DM (50.8% men, age 41.2 ± 13.1 years, duration of T1DM 16 (12-23) years) without established CVD were evaluated. IR was assessed by the estimation of insulin sensitivity (eIS) using two validated prediction equations: the estimated insulin sensitivity developed from the Pittsburgh Epidemiology of Diabetes Complications Study (eIS-EDC) and the estimated insulin sensitivity developed from Coronary Artery Calcification in T1DM Study (eIS-CACTI) ST1RE was used to estimate 10-year CVD risk and to classify subjects into three groups according to their risk: low (<10%; n = 105), moderate (10-20%; n = 53), and high (≥20%; n = 21). RESULTS: Both eIS-EDC and eIS-CACTI correlated negatively with ST1RE scores (eIS-EDC: r = -0.636, p < 0.001; eIS-CACTI: r = -0.291, p < 0.001). The C-statistic for predicting moderate/high risk and high risk was 0.816 (95% confidence interval (CI): 0.754-0.878) and 0.843 (95% CI: 0.772-0.913), respectively, for the eIS-EDC equation, and was 0.686 (95% CI: 0.609-0.763) and 0.646 (95% CI: 0.513-0.778), respectively, for the eIS-CACTI equation. The eIS-EDC equation had a significantly higher C-statistic both for moderate-/high-risk (p = 0.001) and high-risk (p = 0.007) subjects. Two cut-off points of eIS-EDC were identified for detecting moderate/high risk (8.52 mg·kg-1·min-1; sensitivity 74% and specificity 76%) and high risk (8.08 mg·kg-1·min-1; sensitivity 65% and specificity 95%) with potential applicability in clinical practice. CONCLUSIONS: eIS negatively correlates with the score of CVD risk in the ST1RE. Two cut-off points of eIS are reported with potential utility in clinical practice for detecting adults with T1DM with the highest CVD risk.

Preoperative Circulating Succinate Levels as a Biomarker for Diabetes Remission After Bariatric Surgery.

OBJECTIVE: To determine the potential use of baseline circulating succinate to predict type 2 diabetes remission after bariatric surgery. RESEARCH DESIGN AND METHODS: Forty-five obese patients with diabetes were randomly assigned to Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or laparoscopic greater curvature plication. Anthropometric parameters were evaluated, and a complete biochemical analysis including circulating serum succinate concentrations was performed at baseline and 1 year after surgery. The results were externally validated in a second cohort including 88 obese patients with diabetes assigned to RYGB or SG based on clinical criteria. RESULTS: Succinate baseline concentrations were an independent predictor of diabetes remission after bariatric surgery. Patients achieving remission after 1 year had lower levels of baseline succinate (47.8 [37.6-64.6] µmol/L vs. 64.1 [52.5-82.9] µmol/L; P = 0.018). Moreover, succinate concentrations were significantly decreased 1 year after surgery (58.9 [46.4-82.4] µmol/L vs. 46.0 [35.8-65.3] µmol/L, P = 0.005). In multivariate analysis, the best logistic regression model showed that baseline succinate (odds ratio [OR] 11.3, P = 0.031) and the type of surgery (OR 26.4, P = 0.010) were independently associated with remission. The C-statistic for this model was 0.899 (95% CI 0.809-0.989) in the derivation cohort, which significantly improved the prediction of remission compared with current available scores, and 0.729 (95% CI 0.612-0.846) in the validation cohort. Interestingly, patients had a different response to the type of surgery according to baseline succinate, with significant differences in remission rates. CONCLUSIONS: Circulating succinate is reduced after bariatric surgery. Baseline succinate levels have predictive value for diabetes remission independently of previously described presurgical factors and improve upon the current available scores to predict remission.

Publisher Correction: Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery.

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Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes.

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 (ß-GS), glucose-induced potentiation (PGLU) and incretin-induced potentiation (PINCR); 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/m2 on OGTT and from 29 nmol/m2 [26] to 57 nmol/m2 [30] on ISO) and induced insulin resistance. PINCR decreased from 1.6 [1.1] to 1.3 [0.1] (p < 0.05). ß-GS, PGLU 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 ß-GS, PINCR, PGLU 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.

GLP-1 response to sequential mixed meals: influence of insulin resistance.

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; ß-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.

Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery.

Obesity is characterized by insulin-resistance (IR), enhanced lipolysis, and ectopic, inflamed fat. We related the histology of subcutaneous (SAT), visceral fat (VAT), and skeletal muscle to the metabolic abnormalities, and tested their mutual changes after bariatric surgery in type 2 diabetic (T2D) and weight-matched non-diabetic (ND) patients. We measured IR (insulin clamp), lipolysis (2H5-glycerol infusion), ß-cell glucose-sensitivity (ß-GS, mathematical modeling), and VAT, SAT, and rectus abdominis histology (light and electron microscopy). Presurgery, SAT and VAT showed signs of fibrosis/necrosis, small mitochondria, free interstitial lipids, thickened capillary basement membrane. Compared to ND, T2D had impaired ß-GS, intracapillary neutrophils and higher intramyocellular fat, adipocyte area in VAT, crown-like structures (CLS) in VAT and SAT with rare structures (cyst-like) ~10-fold larger than CLS. Fat expansion was associated with enhanced lipolysis and IR. VAT histology and intramyocellular fat were related to impaired ß-GS. Postsurgery, IR and lipolysis improved in all, ß-GS improved in T2D. Muscle fat infiltration was reduced, adipocytes were smaller and richer in mitochondria, and CLS density in SAT was reduced. In conclusion, IR improves proportionally to weight loss but remains subnormal, whilst SAT and muscle changes disappear. In T2D postsurgery, some VAT pathology persists and beta-cell dysfunction improves but is not normalized.

Renal Handling of Ketones in Response to Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes.

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, ß-hydroxybutyrate (ß-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/m2) and creatinine clearance (65-168 mL · min-1 · m-2). Excretion of ß-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 ß-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.

Effect of exenatide on postprandial glucose fluxes, lipolysis, and ß-cell function in non-diabetic, morbidly obese patients.

AIMS: To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions. MATERIALS AND METHODS: Patients were assigned to exenatide 10 µg twice daily (EXE, n = 15) or control (CT, n = 15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), ß-cell function, hepatic insulin resistance (HIR) and adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS). RESULTS: Post treatment, the EXE group showed a significant reduction in body weight ( P < .001). The postmeal time-course of glucose, insulin and ISR showed a lower peak between 60 and 180 minutes in phase with a reduction in RaO ( P < .01). After an initial similar suppression, EGP resumed at higher rates between 60 and 180 minutes ( P = .02) in EXE vs CT, while total RaO and EGP were similar throughout the MTT. In EXE, the postmeal glucagon, GLP1 and GIP responses were reduced ( P < .05). Fasting and postprandial lipolysis and ß-cell function were unaltered by active treatment. HIR, AT-IR and IS were all improved after exenatide treatment ( P < .05). CONCLUSIONS: In morbidly obese non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in ß-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement in hepatic, adipose tissue and whole-body IS with no influence on postprandial lipolysis.

Impact of a mild decrease in fasting plasma glucose on ß-cell function in healthy subjects and patients with type 2 diabetes.

Restoring euglycaemia for weeks or months improves insulin secretion in patients with type 2 diabetes (T2D). We tested whether mild decrements in fasting glucose (FPG) acutely affect ß-cell function and insulin sensitivity. Thirteen normotolerant (NGT) and 10 T2D patients volunteered in pairs. In an isoglycemic test (Iso), after 100 min of stabilization, an incremental glucose infusion over 3 h was applied to raise plasma glucose to >22 mmol/l, followed by an arginine challenge; in a subisoglycemic test (Sub), a glucose infusion matching the plasma glucose time course of Iso was preceded by an insulin infusion period (100 min) aimed at maintaining a mild FPG reduction while avoiding hypoglycaemia. ß-Cell function was assessed by mathematical modeling, whereas the acute insulin response (AIR) to arginine was determined from C-peptide levels. In the Sub, FPG was lowered by 17% in NGT and 31% in T2D patients. On the glucose ramp, total insulin release was lower in Sub than in Iso in both groups [from 106 (43) to 75 (39) nmol/m(-2) in NGT and from 71 (63) to 64 (41) nmol/m(-2) in T2D, P = 0.001]. In the Sub, ß-cell glucose sensitivity was significantly (P = 0.008) reduced in NGT [from 50 (31) to 43 (21) pmol·min(-1)·m(-2)·mM(-1)] but not in T2D [19 (20) to 20 (20) pmol·min(-1)·m(-2)·mM(-1)]. Likewise, AIR was lowered in NGT [8.9 (4.6) to 7.1 (4.4) nmol/l, P = 0.048] but not in T2D [4.7 (3.3) to 5.3 (3.2) nmol/l]. Insulin sensitivity improved in NGT but only marginally in T2D. Prestimulatory glucose levels acutely influence both ß-cell function and insulin sensitivity differentially in nondiabetic and type 2 diabetic individuals.

Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes.

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 ß-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 ß-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.

Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity.

CONTEXT: Alterations in bile acid (BA) synthesis and transport have the potential to affect multiple metabolic pathways in the pathophysiology of obesity. OBJECTIVE: The objective of the study was to investigate the effects of obesity on serum fluctuations of BAs and markers of BA synthesis. DESIGN: We measured BA fluctuations in 11 nonobese and 32 obese subjects and BA transporter expression in liver specimens from 42 individuals and specimens of duodenum, jejunum, ileum, colon, and pancreas from nine individuals. MAIN OUTCOME MEASURES: We analyzed serum BAs and markers of BA synthesis after overnight fasting, during a hyperinsulinemic-euglycemic clamp, or a mixed-meal tolerance test and the association of BA transporter expression with body mass index. RESULTS: BA synthesis markers were 2-fold higher (P < .01) and preferentially 12α-hydroxylated (P < .05) in obese subjects, and both measures were correlated with clamp-derived insulin sensitivity (r = -0.62, P < .0001, and r = -0.39, P = .01, respectively). Insulin infusion acutely reduced serum BAs in nonobese subjects, but this effect was blunted in obese subjects (δBAs -44.2% vs -4.2%, P < .05). The rise in serum BAs postprandially was also relatively blunted in obese subjects (δBAs +402% vs +133%, P < .01). Liver expression of the Na+-taurocholate cotransporting polypeptide and the bile salt export pump were negatively correlated with body mass index (r = -0.37, P = .02, and r = -0.48, P = .001, respectively). CONCLUSIONS: Obesity is associated with increased BA synthesis, preferential 12α-hydroxylation, and impaired serum BA fluctuations. The findings reveal new pathophysiological aspects of BA action in obesity that may lend themselves to therapeutic targeting in metabolic disease.