Fasting Endogenous Glucose Production Research Articles

β-Cell Function, Incretin Effect, and Glucose Kinetics in Response to a Mixed Meal in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin.

To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion. Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m2) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity. At day 3, fasting and mean MMTT glucose levels were lower with SAXA+DAPA (-31.1 ± 1.6 and -91.5 ± 12.4 mg/dL) than with SAXA (-7.1 ± 2.1 and -53 ± 10.5 mg/dL) or DAPA (-17.0 ± 1.1 and -42.6 ± 10.0 mg/dL, respectively; P < 0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA +3%) and insulin sensitivity (+2.2 ± 1.7, +0.4 ± 0.7, and +0.4 ± 0.4 mg ⋅ kg-1⋅ min-1, respectively) improved with SAXA+DAPA (P < 0.007). Mean glucagon-like peptide 1 (GLP-1) was higher with SAXA+DAPA than with SAXA or DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting endogenous glucose production (EGP) increased with SAXA+DAPA and DAPA. During MMTT, EGP suppression was greater (48%) with SAXA+DAPA (vs. SAXA 44%; P = 0.02 or DAPA 34%; P = 0.2). Metabolic clearance rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, β-cell glucose sensitivity, and insulin sensitivity had further increased in the SAXA+DAPA group (P = 0.02), with no additional changes in GLP-1, glucagon, fasting or MMTT EGP, or MCRglu. SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA, with improved β-cell function, insulin sensitivity, GLP-1 availability, and glucose clearance.

Labeled breath tests in patients with NASH: Octanoate oxidation relates best to measures of glucose metabolism.

In vivo methods to estimate human liver mitochondrial activity are lacking and this project's goal was to use a non-invasive breath test to quantify complete mitochondrial fat oxidation and determine how test results changed when liver disease state was altered over time. Patients with suspected non-alcoholic fatty liver disease (NAFLD; 9 men, 16 women, 47 ± 10years, 113 ± 23kg) underwent a diagnostic liver biopsy and liver tissue was histologically scored by a pathologist using the NAFLD activity score (0-8). To assess liver oxidation activity, a labeled medium chain fatty acid was consumed orally (23.4mg 13C4-octanoate) and breath samples collected over 135min. Total CO2 production rates were measured using breath 13CO2 analysis by isotope ratio mass spectrometry. Fasting endogenous glucose production (EGP) was measured using an IV infusion of 13C6-glucose. At baseline, subjects oxidized 23.4 ± 3.9% (14.9%-31.5%) of the octanoate dose and octanoate oxidation (OctOx) was negatively correlated with fasting plasma glucose (r = -0.474, p = 0.017) and EGP (r = -0.441, p = 0.028). Twenty-two subjects returned for repeat tests 10.2 ± 1.0months later, following lifestyle treatment or standardized care. OctOx (% dose/kg) was significantly greater across all subjects (p = 0.044), negatively related to reductions in EGP (r = -0.401, p = 0.064), and tended to correlate with reduced fasting glucose (r = -0.371, p = 0.090). Subjects exhibited reductions in steatosis (p = 0.007) which tended to correlate with increased OctOx (% of dose/kg, r = -0.411, p = 0.058). Based on our findings, the use of an 13C-octanoate breath test may be an indicator of hepatic steatosis and glucose metabolism, but these relationships require verification through larger studies in NAFLD populations.

1325-P: Modulation of Overnight Free Fatty Acid and Glucose Concentrations and Their Effect on Postprandial Islet Function and Glucose Metabolism

Individuals with prediabetes can be classified by fasting and glucose tolerance status. Previously we observed that elevated fasting Free Fatty Acids (FFA) are associated with Impaired Glucose Tolerance (IGT) and decreased β-cell function (quantified as Disposition Index (DI)) . Impaired Fasting glucose (IFG) is associated with further decreases in DI. To examine how changes in fasting FFA and glucose alter islet function, we studied subjects with Normal Fasting Glucose (NFG) and Normal Glucose Tolerance (NGT) on 2 occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG / IGT. In addition, we studied 7 subjects with IFG / IGT on 2 occasions. On one occasion insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG / NGT. The 2 groups were matched for Body Mass Index (BMI: 32±3 vs. 31±2 kg/m2, NFG / NGT vs. IFG / IGT respectively, p = 0.87) . The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and β-cell function. Elevation of overnight fasting FFA and glucose in NFG / NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 hrs, Saline vs. Intralipid / glucose, p = 0.55) . In people with IFG / IGT, insulin also did not alter peak and integrated glucose concentrations (2.5 ± 0.1 vs. 2.5 ± 0.2 Mol per 5 hrs, Saline vs. Insulin, p = 0.39) . Changing overnight concentrations of glucose and FFA did not alter postprandial concentrations of insulin and C-peptide in either group. While fasting Endogenous Glucose Production (EGP) differed between groups (14 ± 1 vs. 18 ± 1 μmol/kg/min, NFG / NGT vs. IFG / IGT, p &amp;lt; 0.01) , intervention did not change fasting and nadir EGP. Peak and integrated meal appearance and DI were also unchanged by intervention in either group. We conclude that acute, overnight changes in FFA and glucose concentrations do not alter islet function or glucose metabolism in prediabetes. Disclosure A.A.Welch: None. D.Schembri wismayer: None. A.M.Egan: None. R.A.Farahani: None. M.C.Laurenti: None. C.Cobelli: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk. Funding NIH DK 078646

Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial.

SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes. The underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24-h energy metabolism and insulin sensitivity in patients with type 2 diabetes. There were 26 patients with type 2 diabetes randomized to a 5-week double-blind, crossover study with a 6- to 8-week washout. Indirect calorimetry was used to measure 24-h energy metabolism and the respiratory exchange ratio (RER), both by whole-room calorimetry and by ventilated hood during a two-step euglycemic-hyperinsulinemic clamp. Results are presented as the differences in least squares mean (95% CI) between treatments. Evaluable patients (n = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m2, and HbA1c of 6.9% (0.7) (51.7 [6.8] mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, whereas fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 [1.39, 3.14] μmol/kg/min, P < 0.0001). Insulin-induced suppression of EGP (-1.71 [-2.75, -0.63] μmol/kg/min, P = 0.0036) and plasma free fatty acids (-21.93% [-39.31, -4.54], P = 0.016) was greater with dapagliflozin. Twenty-four-hour energy expenditure (-0.11 [-0.24, 0.03] MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced the RER during daytime and nighttime, resulting in an increased day-to-nighttime difference in the RER (-0.010 [-0.017, -0.002], P = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (-20.51 [-27.90, -13.12] g/day). Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction, increased fat oxidation, improved hepatic and adipose insulin sensitivity, and improved 24-h energy metabolism.

313-OR: Diurnal Pattern of Meal Tolerance in Type 2 Diabetes

The existence of a diurnal pattern of post prandial glucose tolerance is relevant for management of patients with type 2 diabetes (T2D). We studied 10 healthy (4M) and 9 T2D (6M) subjects matched for age (56±3 vs. 58±3 yrs) and BMI (29±2 vs. 32±2 kg/m2). OGTT was done in healthy subjects to rule out diabetes. Identical mixed meals (8 kcal/kg/meal; 75 gm carb) were ingested during breakfast (B), lunch (L), and dinner (D) at 0700, 1300, and 1900 h in randomized latin square order with one labeled test meal/day on 3 consecutive days. Physical activity was kept same. Postprandial glucose turnover was measured utilizing the triple tracer technique modified with all stable isotopes ([1-13C] Glucose, [2-13C] Glucose and [6, 6-2H2] Glucose). Results shown in Fig 1. Fasting and post-meal glucose were higher while fasting and post-meal insulin and C-peptide concentrations lower in T2D for all three meals compared to healthy. Although meal glucose appearance did not differ between meals in either group, fasting endogenous glucose production (EGP) was higher, percent suppression of EGP lower in T2D and glucose disappearance (corrected for urine glucose loss) lower in T2D than healthy for all meals consumed. This data correlates with lower insulin sensitivity, B-cell responsivity to glucose and disposition index in T2D than healthy throughout the day. Our results suggest an emerging diurnal pattern to glucose tolerance and fluxes in humans, and that the pattern is different in T2D. Disclosure Y.R. Yadav: None. D. Romeres: None. F. Ruchi: None. S. Sawleh: None. R. Carter: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

1861-P: Short-Term Overfeeding with Dairy Fat Impairs Insulin Sensitivity in Muscle and Liver but Increases Adipose Tissue Insulin Sensitivity and Suppresses Postprandial Glucose Rise in Healthy Nonobese Men

Previous studies have demonstrated that saturated fat intake increases the risk of type 2 diabetes (T2DM) due to reduction of insulin sensitivity. On the other hand, the consumption of dairy fat that predominantly includes saturated fat is reported to be protective against T2DM. However, its underlying mechanism has not been fully understood. To address this, we recruited 21 healthy non-obese men and evaluated metabolic changes before and after 6-day high-calorie, high-fat diet (HCHFD) consisting of a regular diet plus 45% energy excess by supplementation with dairy fat. We measured intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) in tibialis anterior muscle by 1H-MRS and metabolic rate during sleeping by metabolic chamber. One day after the measurement, we performed meal test, and the next day, we measured tissue specific insulin sensitivity by 2-step hyperinsulinemic euglycemic clamp. After the HCHFD, body weight was increased by 0.4 kg, and IMCL and IHL were also increased by 47% and 200%, respectively. On the other hand, hepatic and muscle insulin sensitivity showed only a modest decrease by 8% and 4%, respectively. Consistently, fasting endogenous glucose production elevated by only 3% without altering insulin level; however, unexpectedly, fasting free fatty acid (FFA) greatly decreased by 43%, suggesting increased adipose tissue insulin sensitivity (ATIS), and total ketone body levels was decreased by 53% and glucose oxidation during sleeping was consistently increased. Further, post-prandial glucose rise during the meal test was suppressed after the HCHFD, although insulin secretion was lower during the test. In conclusion, short-term HCHFD by dairy fat supplementation increased ATIS and glucose oxidation, and suppressed post-prandial glucose rise with lowered insulin secretion. These metabolic changes by dairy fat may be beneficial to prevent T2DM. Disclosure D. Sugimoto: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. S. Kadowaki: None. Y. Someya: None. H. Kaga: None. R. Suzuki: None. S. Kakehi: None. N. Yamasaki: None. M. Sato: None. A. Kanazawa: Speaker’s Bureau; Self; Novartis Pharma K.K., Sanofi, Takeda Pharmaceutical Company Limited. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03196)

1143-P: A Single and Chronic SGLT2 Inhibitor Administration Did Not Alter Insulin Clearance in Type 2 Diabetes

Reduced insulin clearance (IC) and hyperinsulinemia are observed in obesity with insulin resistance and considered as compensatory change against insulin resistance. On the other hand, several animal models showed that enhanced IC by genetic modification suppressed high fat diet induced weight gain and insulin resistance. Recently we found that 3-day low carbohydrate diet increased IC, suggesting low glucose availability may acutely increase IC. Given that SGLT2 inhibitors decrease glucose availability by increasing urinary glucose excretion, we hypothesized that SGLT2 inhibitors may acutely increase IC, and then induce body weight reduction and improve metabolic disorders. To test this hypothesis, we recruited 12 Japanese men with type 2 diabetes mellitus. We evaluated IC and tissue specific insulin sensitivity by hyperinsulinemic euglycemic clamp (insulin infusion rate; 40 mU/m2·min) on baseline, immediately after a single administration (n=12) and after 8-week administration (n=9) of SGLT2 inhibitor (Tofogliflozin). We also measured ectopic fat in muscle and liver and abdominal fat areas by 1H-MRS and MRI, respectively. IC was not altered immediately after a single administration of Tofogliflozin (594.7±67.7ml/min/m2 to 608.3±90.9ml/min/m2, p=0.61). Also, 8 weeks administration of Tofogliflozin did not alter IC (582.5±67.3ml/min/m2 vs. 602.3±67.0ml/min/m2, p=0.41), while body weight and subcutaneous fat area were significantly decreased by 1.7% and 6.4%, respectively. In addition, 8 weeks administration of Tofogliflozin significantly decreased HbA1c and fasting plasma glucose levels and increased fasting endogenous glucose production, while insulin sensitivity and ectopic fat in muscle and liver were not changed. In conclusion, IC was not altered after a single and 8-week administration of Tofogliflozin. Decreased body weight and improved glycemic control by chronic administration of Tofogliflozin may occur independently of IC change. Disclosure M. Sato: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. H. Kaga: None. N. Yamasaki: None. M. Kiya: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. Y. Furukawa: None. T. Funayama: None. Y. Someya: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Kowa Company, Ltd.

The effect of dapagliflozin on apolipoprotein B and glucose fluxes in patients with type 2 diabetes and well-controlled plasma LDL cholesterol.

AimTo dissect the effects of the sodium‐glucose linked transporter 2 inhibitor dapagliflozin on lipid metabolism and assess whether these effects could potentially offset cardiovascular benefit with this drug‐class.Materials and MethodsWe assessed the effect of dapagliflozin on lipid metabolism in 11 adults with uncomplicated type 2 diabetes. After 4 weeks of statin wash‐out and 4 weeks of rosuvastatin 10 mg treatment, participants were treated with dapagliflozin 10 mg once‐daily for 5 weeks. Before and after dapagliflozin, plasma lipids were measured and very low‐density lipoprotein (VLDL)‐1 and VLDL‐2 apolipoprotein (Apo)B fluxes were assessed using (5.5.5‐2H3)‐leucine tracer infusion. In addition, hepatic and peripheral insulin sensitivity as well as insulin‐mediated inhibition of peripheral lipolysis were measured during a two‐step hyperinsulinemic‐euglycaemic clamp using (6,6‐2H2)‐glucose and (1,1,2,3,3‐2H5)‐glycerol tracers.ResultsRosuvastatin decreased all plasma lipids significantly: total cholesterol from 4.5 (3.2–6.2) to 3.1 (2.5–3.8) mmol/L, LDL cholesterol from 2.6 (1.7–3.4) to 1.5 (1.1–2.2) mmol/L, HDL cholesterol from 1.34 (0.80–2.02) to 1.19 (0.74–1.89) mmol/L and triglycerides from 0.92 (0.31–3.91) to 0.79 (0.32–2.10) mmol/L. The addition of dapaglifozin to rosuvastatin did not raise either LDL cholesterol or total cholesterol, and only increased HDL cholesterol by 0.08 (−0.03–0.13) mmol/L (P = 0.03). In line with this, dapagliflozin did not affect VLDL‐1 or VLDL‐2 ApoB fluxes. Fasting endogenous glucose production tended to increase by 0.9 (−3.4–3.1) μmol kg−1 min−1 (P = 0.06), but no effect on hepatic and peripheral insulin sensitivity or on peripheral lipolysis was observed.ConclusionsDapagliflozin has no effect on plasma LDL‐cholesterol levels or VLDL‐apoB fluxes in the context of optimal lipid‐lowering treatment, which will thus not limit cardiovascular benefit when lipids are adequately controlled.

Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

Modest changes to glycemic regulation are sufficient to maintain glucose fluxes in healthy young men following overfeeding with a habitual macronutrient composition

Currently, it is unclear whether short-term overfeeding in healthy people significantly affects postprandial glucose regulation, as most human overfeeding studies have utilized induced experimental conditions such as the euglycemic-hyperinsulinemic clamp technique to assess glucoregulation. The aim of this study was to quantify glucose fluxes [rates of meal glucose appearance (Ra), disposal (Rd), and endogenous glucose production (EGP)] in response to 5 and 28 days of overfeeding (+45% energy) while maintaining habitual macronutrient composition (31.0 ± 1.9% fat, 48.6 ± 2.2% carbohydrate, 16.7 ± 1.4% protein) in healthy, lean young men. Meal tolerance testing was combined with the triple-stable isotope glucose tracer approach. Visceral adipose volume increased by ~15% with 5 days of overfeeding, while there was no further change at 28 days. In contrast, body mass (+1.6 kg) and fat mass (+1.3 kg) were significantly increased only after 28 days of overfeeding. Fasting EGP, Rd, and insulin were increased at 5 but unchanged after 28 days. Postprandial glucose and insulin responses were unaltered by 5 days of overfeeding but were modestly increased after 28 days (P < 0.05). However, meal Ra and glucose Rd were significantly increased after both 5 and 28 days of overfeeding (P < 0.05). Despite this, overfeeding did not lead to alterations to postprandial EGP suppression. Thus, in contrast to findings from euglycemic-hyperinsulinemic clamp studies, chronic overfeeding did not affect the ability to suppress EGP or stimulate Rd under postprandial conditions. Rather, glucose flux was appropriately maintained following 28 days of overfeeding through modest increases in postprandial glycemia and insulinemia.

Early Effects of Sleeve Gastrectomy (SG) on Systemic and Organ-Specific Dietary Fatty Acid Uptake, Postprandial Free Fatty Acids (FFA), and Glucose Metabolism in Type 2 Diabetes (T2D)

Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intolerance, with decreased FA storage in adipose tissues (AT) and increased FA uptake by the myocardium. These abnormalities are improved after 1 year of lifestyle-induced weight loss. Bariatric surgery leads to early metabolic improvements before weight loss, but the early effects on dietary FA metabolism and biodistribution have never been studied. 9 subjects with T2D underwent a 6-hour postprandial metabolic protocol before and 12 days after SG. A liquid meal containing [U-13C]-palmitate and [2H]-glucose was ingested at time 0, with an IV perfusion of [3H]-glucose and [7,7,8,8-2H]-palmitate, allowing quantification of glucose absorption, endogenous glucose production (EGP), lipolysis and dietary FA spillover. A capsule containing a positron-emitting long-chain FA analog (18FTHA) was taken with the meal for the quantification of organ-specific dietary FA uptake using PET/CT (n=6). Twelve days after SG, whole body and hepatic insulin sensitivity increased significantly whereas fasting and postprandial EGP decreased. Postprandial GLP-1, GIP, PYY and glucagon were higher after vs. before SG. Postprandial AUC of FFA (175 vs. 228 mmol/Lx min; p&amp;lt; 0.05) and total FA oxidation were higher (p&amp;lt; 0.02 from 180 min to 360 min), but dietary FA oxidation was reduced after SG (p&amp;lt; 0.002 from 180 min to 360 min). After SG, uptake of dietary FA 6 hours after the meal was reduced in the myocardium (mean SUV 2.07± 0.66 vs. 1.36± 0.44; p=0.06) and was increased in visceral AT (mean SUV 0.24± 0.2 vs. 0.42± 0.2; p=0.03), without changes in other organs. In conclusion, there is reduced myocardial and increased visceral AT uptake of dietary FA associated with reduced dietary FA oxidation and increased FFA mobilization and oxidation, concomitant with reduced EGP and insulin sensitization in patients with T2D early after SG. Disclosure A. Carreau: None. C. Noll: None. B. Guerin: None. L. Biertho: Advisory Panel; Self; Novo Nordisk Inc.. Consultant; Self; Johnson &amp; Johnson Services, Inc., Valeant Pharmaceuticals International, Inc.. E.E. Turcotte: None. A. Tchernof: Research Support; Self; Johnson &amp; Johnson Services, Inc., Medtronic. A. Carpentier: Consultant; Self; UniQure, Janssen Pharmaceuticals, Inc., Siemens. Research Support; Self; Caprion, Merck Sharp &amp; Dohme Corp., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, AstraZeneca, Bristol-Myers Squibb Company, Sanofi-Aventis, Pfizer Inc., Novo Nordisk Inc., Exelixis, Amgen Inc..

Elevated Glucose Concentrations 60 Minutes after an Oral Challenge in Subjects with Normal Glucose Tolerance Are Not Explained by the Rate of Meal-Derived Glucose Appearance

Glucose concentrations 60 minutes after an oral glucose tolerance test (OGTT) ≥155 mg/dL (8.6 mmol/L) identify an increased risk of progression to type 2 diabetes even in those with normal glucose tolerance (NGT). Recent data suggests that these differences can be explained by increased intestinal glucose absorption due to increased expression of the sodium/glucose cotransporter 1 (SGLT1) in the intestine. To examine the contribution of meal appearance to postprandial glucose concentrations we studied 36 subjects with NGT using a 75g OGTT, and a labelled mixed meal. Insulin secretion and action, endogenous glucose production (EGP), meal-derived glucose appearance (Meal Ra) and glucose disappearance (Rd) were subsequently calculated. Participants were grouped according to 60 minute glucose into HI (≥155 mg/dl) or LO (&amp;lt;155mg/dl). No differences in age (47±3 vs. 50±2 years, LO vs. HI respectively, p=0.59) or BMI (28±1 vs. 28±1 Kg/M2, p=0.95) were observed. Fasting (11.9±0.6 vs. 12.6±0.6 μmol/kg/min, p=0.44) and nadir (2.0±0.8 vs. 3.3±0.3 μmol/kg/min, p=0.21) EGP did not differ. Similarly, peak (86±10 vs. 92±6 μmol/kg/min, p=0.59) and integrated (9.8±1.3 vs. 10.6±1.1 mmol per 6 hour, p=0.69) Meal Ra did not differ between groups. On the other hand, when β-cell responsivity (ϕ) was expressed as a function of insulin action (Si), the resulting Disposition Index (DI) was lower in the HI group (1862±409 vs. 893±103 10-14 dl/kg/min2 per pmol/l, p=0.01). When analyzed as a continuous variable, 60 minute glucose was inversely related to DI (r = -0.37, p=0.02) but did not correlate with peak (r=0.03, p=0.96) and integrated (r=0.02, p=0.91) Meal Ra. Taken together, these data indicate that increased 60 minute glucose concentrations, even in subjects with NGT, are explained by decreased β-cell function not by an increased systemic rate of appearance of meal-derived glucose. Disclosure J. Adams: None. G. Treiber: None. M.D. Hurtado: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Dalla Man: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. R.A. Rizza: None. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG.

Effects of alcohol abstinence on glucose metabolism in Japanese men with elevated fasting glucose: A pilot study

It has been demonstrated that moderate alcohol consumption provides protection against the development of type 2 diabetes. However, several other reports suggested that moderate alcohol intake may increase the risk of type 2 diabetes in non-obese Japanese. The aim of present study was to investigate the effect of 1-week alcohol abstinence on hepatic insulin sensitivity and fasting plasma glucose (FPG) in non-obese Japanese men. We recruited 8 non-obese Japanese men with mildly elevated FPG and drinking habits alcohol (mean frequency; 5.6 ± 2.5 times/week, mean alcohol consumption; 32.1 ± 20.0 g/day). Before and after the 1-week alcohol abstinence, we used the 2-step hyperinsulinemic-euglycemic clamp to measure endogenous glucose production (EGP) and insulin sensitivity (IS) in muscle and liver. One-week alcohol abstinence significantly reduced both FPG by 7% (from 105.5 ± 11.7 to 98.2 ± 7.8 mg/dl, P < 0.01) and fasting EGP by 6% (from 84.1 ± 4.2 to 77.6 ± 1.6 mg/m2 per min, P < 0.01), respectively. Two–step clamp study showed that alcohol abstinence significantly improved hepatic-IS, but not muscle-IS. In conclusion, one week alcohol abstinence improved hepatic IS and FPG in non-obese Japanese men with mildly elevated FPG and drinking habits alcohol.

Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance.

A common genetic variation in TCF7L2 is associated with type 2 diabetes. However, the mechanism by which this occurs remains elusive. In addition to affecting insulin secretion, genetic variation at the TCF7L2 locus may alter insulin action or directly modify hepatic glucose metabolism. We sought to determine whether the diabetes-associated variant in this locus (the T allele of rs7903146) increases fasting endogenous glucose production (EGP), and impairs insulin-induced suppression of EGP and insulin-stimulated glucose disappearance. To address this, we studied individuals who were either homozygous for the diabetes-associated allele (TT) at rs7903146 or were homozygous for the protective allele (CC). Subjects were matched for other anthropometric characteristics and were studied using a euglycemic clamp. EGP and glucose uptake were measured using the tracer dilution technique, and the relative contribution of gluconeogenesis to EGP was quantitated using deuterated water corrected for transaldolase exchange. We report that the diabetes-associated variation in TCF7L2 did not associate with fasting EGP, insulin-induced suppression of EGP, and insulin-induced stimulation of glucose uptake. There was no association with the contribution of gluconeogenesis and glycogenolysis to EGP. These data indicate that genetic variation at TCF7L2 does not predispose an individual to type 2 diabetes by altering either hepatic or extrahepatic insulin action.

Fish oil supplemented for 9 months does not improve glycaemic control or insulin sensitivity in subjects with impaired glucose regulation: a parallel randomised controlled trial.

The effects of fish oil (FO) supplementation on glycaemic control are unclear, and positive effects may occur only when the phospholipid content of tissue membranes exceeds 14% as n-3 PUFA. Subjects (n 36, thirty-three completed) were paired based on metabolic parameters and allocated into a parallel double-blind randomised trial with one of each pair offered daily either 6 g of FO (3·9 g n-3 PUFA) or 6 g of maize oil (MO) for 9 months. Hyperinsulinaemic-euglycaemic-euaminoacidaemic (HIEGEAA) clamps (with [6,6 2H2 glucose]) were performed at the start and end of the intervention. Endogenous glucose production (EGP) and whole-body protein turnover (WBPT) were each measured after an overnight fast. The primary outcome involved the effect of oil type on insulin sensitivity related to glycaemic control. The secondary outcome involved the effect of oil type on WBPT. Subjects on FO (n 16) had increased erythrocyte n-3 PUFA concentrations >14%, whereas subjects on MO (n 17) had unaltered n-3 PUFA concentrations at 9%. Type of oil had no effect on fasting EGP, insulin sensitivity or total glucose disposal during the HIEGEAA clamp. In contrast, under insulin-stimulated conditions, total protein disposal (P=0·007) and endogenous WBPT (P=0·001) were both increased with FO. In an associated pilot study (n 4, three completed), although n-3 PUFA in erythrocyte membranes increased to >14% with the FO supplement, the enrichment in muscle membranes remained lower (8%; P<0·001). In conclusion, long-term supplementation with FO, at amounts near the safety limits set by regulatory authorities in Europe and the USA, did not alter glycaemic control but did have an impact on WBPT.

Six and 12 Weeks of Caloric Restriction Increases β Cell Function and Lowers Fasting and Postprandial Glucose Concentrations in People with Type 2 Diabetes1–3

Background: Caloric restriction alone has been shown to improve insulin action and fasting glucose metabolism; however, the mechanism by which this occurs remains uncertain.Objective: We sought to quantify the effect of caloric restriction on β cell function and glucose metabolism in people with type 2 diabetes.Methods: Nine subjects (2 men, 7 women) with type 2 diabetes [BMI (in kg/m2): 40.6 ± 1.4; age: 58 ± 3 y; glycated hemoglobin: 6.9% ± 0.2%] were studied using a triple-tracer mixed meal after withdrawal of oral diabetes therapy. The oral minimal model was used to measure β cell function. Caloric restriction limited subjects to a pureed diet (<900 kcal/d) for the 12 wk of study. The studies were repeated after 6 and 12 wk of caloric restriction.Results: Fasting glucose concentrations decreased significantly from baseline after 6 wk of caloric restriction with no further reduction after a further 6 wk of caloric restriction (9.8 ± 1.3, 5.9 ± 0.2, and 6.2 ± 0.3 mmol/L at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01) because of decreased fasting endogenous glucose production (EGP: 20.4 ± 1.1, 16.2 ± 0.8, and 17.4 ± 1.1 μmol · kg−1 · min−1 at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.03). These changes were accompanied by an improvement in β cell function measured by the disposition index (189 ± 51, 436 ± 68, and 449 ± 67 10−14 dL · kg−1 · min−2 · pmol−1 at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01).Conclusions: Six weeks of caloric restriction lowers fasting glucose and EGP with accompanying improvements in β cell function in people with type 2 diabetes. An additional 6 wk of caloric restriction maintained the improvement in glucose metabolism. This trial was registered at clinicaltrials.gov as NCT01094054.

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism.

A gene mutation of the Wnt/β-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/β-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and β-cell function. We performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. Sclerostin levels were higher in IGR compared with NGT (50.8 ± 2.4 vs. 38.7 ± 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = -0.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = -0.52 and r = -0.44, respectively; both P < 0.001). Sclerostin levels were not correlated with β-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r(2) associated with HOMA-IR (r(2) change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r(2) change: 0.059; F change: 4.938; P = 0.033). Sclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.

Effect of Global ATGL Knockout on Murine Fasting Glucose Kinetics.

Mice deficient in adipose triglyceride lipase (ATGL−/−) present elevated ectopic lipid levels but are paradoxically glucose-tolerant. Measurement of endogenous glucose production (EGP) and Cori cycle activity provide insights into the maintenance of glycemic control in these animals. These parameters were determined in 7 wild-type (ATGL+/−) and 6 ATGL−/− mice by a primed-infusion of [U-13C6]glucose followed by LC-MS/MS targeted mass-isotopomer analysis of blood glucose. EGP was quantified by isotope dilution of [U-13C6]glucose while Cori cycling was estimated by analysis of glucose triose 13C-isotopomers. Fasting plasma free fatty-acids were significantly lower in ATGL−/− versus control mice (0.43 ± 0.05 mM versus 0.73 ± 0.11 mM, P < 0.05). Six-hour fasting EGP rates were identical for both ATGL−/− and control mice (79 ± 11 versus 71 ± 7 μmol/kg/min, resp.). Peripheral glucose metabolism was dominated by Cori cycling (80 ± 2% and 82 ± 7% of glucose disposal for ATGL−/− and control mice, resp.) indicating that peripheral glucose oxidation was not significantly upregulated in ATGL−/− mice under these conditions. The glucose 13C-isotopomer distributions in both ATGL−/− and control mice were consistent with extensive hepatic pyruvate recycling. This suggests that gluconeogenic outflow from the Krebs cycle was also well compensated in ATGL−/− mice.

Trace glucose fluxes in individuals with prediabetes using stable isotopes

Background The glucose fluxes of individuals with prediabetes in Chinese population are not clear. This study was to determine whether the endogenous glucose production (EGP), oral glucose rate of appearance (Ra) and glucose rate of disappearance (Rd) were different in Chinese individuals with prediabetes under fasting conditions and following an oral glucose challenge. Methods Five subjects with type 2 diabetes, 5 subjects with prediabetes and 5 non-diabetic subjects matched for age, weight, fat free mass and body mass index underwent a 180 minute stable glucose isotope tracing ([6, 6-2H2] glucose, [1-13C] glucose, and [U-13C] glucose) study under fasting and after ingestion of a 75 g oral glucose load. Isotope glucose enrichment was measured by gas chromatography-mass spectrometry. Insulin sensitivity was estimated using the oral glucose tolerance test (OGTT)-derived insulin sensitivity index, β cell function was determined by the insulinogenic index (ΔI30/ΔG30). Results The insulin sensitivity index (P=0.043) and insulinogenic index (P=0.021) were decreased in subjects with prediabetes compared with non-diabetes. Fasting EGP was slightly higher (P=0.29) and postprandial EGP was comparable in subjects with prediabetes and non-diabetes during 120 minutes after glucose ingestion, but nadir EGP occurred later in prediabetic than non-diabetic subjects. Ra did not differ among the three groups. Rd was substantially lower in subjects with prediabetes than non-diabetes after glucose intake (P=0.013). Conclusion The mild hyperglycemia observed among individuals with prediabetes may result from decreased Rd during the postprandial state.

Effect of eplerenone on insulin action in essential hypertension: a randomised, controlled, crossover study.

An association exists between hyperaldosteronism, hypertension and impaired insulin action. Eplerenone is a selective mineralocorticoid receptor antagonist; however, little is known about its effects on insulin action. The aim of this study was to determine the effect of eplerenone on insulin action in hypertensive adults, using the hyperinsulinaemic euglycaemic clamp. A randomised, controlled, double-blind, crossover design was employed. After a 6-week washout period, hypertensive, non-diabetic patients were treated with either eplerenone 25 mg twice daily or doxazosin 2 mg twice daily for 12 weeks. After each treatment period, insulin action was assessed by a hyperinsulinaemic euglycaemic clamp, with isotope dilution methodology. After washout, treatment groups were crossed over. Fifteen patients completed the study. There were no differences in fasting glucose, or fasting insulin between treatment with eplerenone or doxazosin. The measure of overall insulin sensitivity, exogenous glucose infusion rates during the last 30 min of the clamp, was similar with both treatments; 23.4 (3.9) μmol kg(-1) min(-1) after eplerenone and 23.3 (3.6) μmol kg(-1) min(-1) after doxazosin (P=0.83). Isotopically determined fasting endogenous glucose production rates were similar after both treatments (eplerenone 9.4 (0.6) μmol kg(-1) min(-1) vs doxazosin 10.6 (0.7) μmol kg(-1) min(-1)). There was a trend for lower endogenous glucose production rates during hyperinsulinaemia following eplerenone compared with doxazosin (2.0 (0.8) μmol kg(-1) min(-1) vs 4.1 (0.9) μmol kg(-1) min(-1)). There was no difference in insulin stimulated peripheral glucose utilisation rates after treatment with eplerenone or doxazosin (25.4 (3.6) μmol kg(-1) min(-1) vs 27.0 (3.9) μmol kg(-1) min(-1)). This study gives reassuring evidence of the neutral effect of eplerenone on insulin action in hypertensive, non-diabetic patients.