Rate Of Glucose Appearance Research Articles

The time lag prior to the rise in glucose requirements to maintain stable glycaemia during moderate exercise in a fasted insulinaemic state is of short duration and unaffected by the level at which glycaemia is maintained in Type 1 diabetes.

To determine the duration of the low hypoglycaemia risk period after the start of moderate-intensity exercise performed under basal insulinaemic conditions and whether this period is affected by the level at which glycaemia is maintained under these conditions. This was a prospective, randomized counterbalanced study. Eight participants with Type 1 diabetes (mean ± sd age 21.5 ± 4.0 years) underwent either a euglycaemic (5-6 mmol/l) or hyperglycaemic clamp (9-10 mmol/l) on separate days and were infused with insulin at basal rates and [6,6-2 H]glucose while cycling for 40 min at 50% maximum oxygen consumption rate. The main outcome measures were the glucose infusion rates required to maintain stable glycaemia and glucoregulatory hormone levels, and rates of glucose appearance and disappearance. During the first 20 min of exercise, the glucose infusion rate did not increase significantly, irrespective of the level at which glycaemia was maintained, but increased acutely between 20 and 25 min under both conditions. Maintaining higher glycaemia resulted in higher glucose infusion rate during, but not early post-exercise. With the exception of epinephrine, the glucoregulatory hormone levels and rates of glucose appearance and disappearance were similar between conditions. Irrespective of the levels at which glycaemia is maintained, there is a 20-min low exogenous glucose demand period during which the exogenous glucose requirements to maintain stable glycaemia do not increase during moderate exercise performed at basal insulin level.

The Hyperinsulinemic Isoglycemic Hyperlactemic Clamp

The Cori Cycle (glucose-lactate interchange) dominates carbohydrate fluxes. Glucose-to-lactate flux follows peripheral disposal; lactate-to-glucose occurs during gluconeogenesis. As glucose flux can be assessed by the change in an exogenous glucose infusion rate (GIR) required to maintain a constant concentration (glucose clamp), so too can lactate flux be assessed from an exogenous lactate infusion rate (LIR) required to maintain isolactemia. Simultaneous assessment of both fluxes will enable estimation of lactate-derived gluconeogenesis (GNG), and its contribution to the rate of glucose appearance (Ra) without using radiolabeled tracers, the mainstay of flux measurement. Anesthetized Sprague-Dawley rats were intubated, catheterized via artery and vein, and partially pancreatectomized to eliminate endogenous glucagon secretion. Establishment of a hyperinsulinemic (100mU/kg/h), hyperglycemic (7mM) clamp was followed by a hyperlactemic (4mM) clamp via independent variable infusions of glucose/Na-lactate in response to 5-min measures of plasma concentrations (YSI 2950D Analyzer with glucose/lactate electrodes). Hyperlactemia (∼10x resting) rendered it the dominant gluconeogenic substrate. After at least 30 min of isolactemia, glucagon was infused for 60 min (0, 1, 3, 10 or 50 µg/kg/h) to enable dose/concentration response analysis. Glucagon administration dose-dependently reduced the GIR and increased the LIR necessary to maintain isoglycemia/isolactemia (respective ED50’s 1.33, 0.98 µg/kg/h). δ-GIR of up to -12.2 mmol/kg/h potentially represented increased glucose Ra. δ-LIR of up to +8.6 mmol/kg/h potentially represented GNG. Since 2 lactate moieties are required per glucosyl, GNG contributed ∼35% of glucagon-stimulated glucose Ra (∼65% being glycogenolysis). In conclusion, the hyperinsulinemic isoglycemic hyperlactemic clamp enables a quantitative assessment of hepatic processes, complementing that of peripheral processes revealed with the glucose clamp. Disclosure D. Zaretsky: Employee; Self; Intarcia Therapeutics, Inc. A.A. Young: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; GlaxoSmithKline plc..

Cause of Hyperglycemia in Postmenopausal Underweight Women with Impaired Glucose Tolerance

Japanese women have substantially lower BMI than women in other developed countries and the prevalence of underweight (BMI<18.5 kg/m2) in them is currently 23.7%. Interestingly, Japanese underweight women showed ∼2 times higher risk for type 2 diabetes compared with normal weight (BMI18.5-22.9kg/m2). A previous study reported that the hyperglycemia in obese impaired glucose tolerance (IGT) subjects was primarily elicited by reduced suppression of endogenous glucose production (EGP); however, cause of hyperglycemia in underweight women with IGT has not been elucidated. To clarify the role of EGP, rate of glucose disappearance (Rd) and rate of glucose appearance of oral glucose load (Ra-Oral) on hyperglycemia in underweight women with IGT, we recruited postmenopausal underweight women with NGT (n=4) and IGT (n=9). Glucose kinetics was assessed by oral glucose tolerance test (OGTT) with double tracer (U-[13C]-glucose orally and 6,6-[2H2]-glucose intravenously). Age, BMI and percent body fat were comparable between NGT group and IGT group. IGT group showed lower area under the curve (AUC) of Rd compared with NGT group (1294±2vs. 1684±370 mg/kg fat-free mass (FFM), P<0.05) during the first 2 hours of OGTT. Consistently, amount of disappeared glucose during the first 2 hours, mainly reflecting muscle glucose uptake, was 17.6g lower in IGT group compared with NGT group (39.8±9.5 vs. 57.4±14.4 g, P<0.05). In contrast, AUC-EGP and AUC-Ra-Oral were comparable between the groups. AUC-insulin during OGTT was lower in IGT group compared with in NGT group (2.6±0.8 vs. 4.8±0.9 U·min/ml·103, P<0.01), and it was significantly correlated to AUC-Rd (r=0.70, P<0.01). In conclusion, the present study suggested that main cause of hyperglycemia in underweight women with IGT was decreased Rd. In addition, decreased insulin secretion may partly contribute to the decreased Rd in those IGT subjects. Disclosure R. Suzuki: None. Y. Tamura: None. Y. Someya: None. H. Kaga: None. D. Sugimoto: None. S. Kadowaki: None. S. Kakehi: None. K. Takeno: None. T. Funayama: None. Y. Furukawa: None. J. Sato: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Novartis Pharmaceuticals Corporation, Sanofi, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd.. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

BioChaperone Technology Enables the Development of Pramlintide-Prandial Insulin Combinations

Pramlintide (Symlin®) is currently used on top of mealtime insulin therapy by T1D or T2D patients to achieve a better control of post-prandial glucose excursion. Indeed, pramlintide affects the rate of postprandial glucose appearance by slowing down gastric emptying, reducing postprandial glucagon secretion and modulating satiety, which affects caloric intake. Nevertheless, the use of pramlintide is currently limited as it cannot be combined with prandial insulin due to formulation pH incompatibility and results in a high burden of the number of injections. BioChaperone (BC) technology stabilizes pramlintide in aqueous solution at neutral pH and enables a pramlintide - prandial insulin co-formulation. BC pramlintide-human insulin (BC Pram Ins) formulation is physically and chemically stable for at least 6 weeks at 30°C and 9 weeks at 25°C. Physical stability was evidenced by visual inspection and MFI analysis. Chemical stability (recovery measured by RP-HPLC and high molecular weight species measured by SE-HPLC) was similar to that of commercial Humulin® and Symlin®. Under simulated in-use pump conditions at 37°C, BC Pram Ins formulation shows excellent physical and chemical stability for at least 1 week, with insulin and pramlintide recoveries higher than 95% and a formulation essentially free of particles. The pharmacokinetics of pramlintide was evaluated following single subcutaneous administration (0.1875 U/kg insulin, 1.125 µg/kg pramlintide) of BC Pram Ins formulation and pramlintide co-injected with human insulin (separate injections) to fasted healthy pigs. BC Pram Ins shows a slower absorption of pramlintide (LSM ratio [95% CI] ΔAUCPram0-30min: 0.45 [0.20; 1.05]) while the late exposure to pramlintide is higher (ΔAUCPram60-180min: 2.65 [1.44; 4.90]) compared to the separate injections. In conclusion, the in-vitro and preclinical PD properties of BC Pram Ins support its clinical development to afford a better mealtime treatment for T1D and T2D patients. Disclosure G. Meiffren: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. A. Geissler: None. Y. Meyer: None. A. Ranson: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. C. Fortier: None. O. Soula: Board Member; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. R. Soula: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Board Member; Self; Cellnovo. B. Alluis: None. R. Charvet: None.

Effects of the Novel Dual GLP-1R/GCGR Agonist SAR425899 on Postprandial Glucose Metabolism in Overweight/Obese Subjects with Type 2 Diabetes

SAR425899 (SAR) is a novel dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist. A randomized, double-blind, phase I multiple-ascending-dose study (NCT02411825) in 27 overweight/obese subjects with type 2 diabetes receiving SAR demonstrated decreased body weight with a safety profile comparable with GLP-1R agonists. Here, we report additional analyses of the effect of SAR on key processes in glucose metabolism. Subjects were randomized to receive daily subcutaneous administrations of low-dose SAR (30, 60, 90 µg) or high-dose SAR (60, 120, 180 µg) for 28 days; dose escalation occurred after Days 7 and 14. Mixed meal tests were conducted before treatment (Day −1) and on Days 1 and 28. Oral glucose and C-peptide minimal models were used to quantify metabolic indices of glucose absorption, insulin sensitivity, and β-cell responsiveness. Percent change in area under the curve for rate of meal glucose appearance between 0 and 120 min from Day −1 to Day 28 was −14% and −19% with low- and high-dose SAR, respectively. Change in insulin sensitivity was 104% and 262%, respectively. Change in β-cell function was 127% and 145%, respectively (Table). After 28 days of treatment, SAR improved postprandial glucose control by significantly reducing glucose absorption rate, increasing insulin sensitivity, and enhancing β-cell function. Disclosure B. Goebel: Employee; Self; Sanofi. M. Schiavon: None. R. Visentin: None. M. Riz: Employee; Self; Sanofi-Aventis Deutschland GmbH. C. Dalla Man: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc. T. Klabunde: Employee; Self; Sanofi.

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 (<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.

Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-μg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.

Unannounced Meals in the Artificial Pancreas: Detection Using Continuous Glucose Monitoring.

The artificial pancreas (AP) system is designed to regulate blood glucose in subjects with type 1 diabetes using a continuous glucose monitor informed controller that adjusts insulin infusion via an insulin pump. However, current AP developments are mainly hybrid closed-loop systems that include feed-forward actions triggered by the announcement of meals or exercise. The first step to fully closing the loop in the AP requires removing meal announcement, which is currently the most effective way to alleviate postprandial hyperglycemia due to the delay in insulin action. Here, a novel approach to meal detection in the AP is presented using a sliding window and computing the normalized cross-covariance between measured glucose and the forward difference of a disturbance term, estimated from an augmented minimal model using an Unscented Kalman Filter. Three different tunings were applied to the same meal detection algorithm: (1) a high sensitivity tuning, (2) a trade-off tuning that has a high amount of meals detected and a low amount of false positives (FP), and (3) a low FP tuning. For the three tunings sensitivities 99 ± 2%, 93 ± 5%, and 47 ± 12% were achieved, respectively. A sensitivity analysis was also performed and found that higher carbohydrate quantities and faster rates of glucose appearance result in favorable meal detection outcomes.

Sex-specific differences in insulin resistance in type 1 diabetes: The CACTI cohort

ObjectiveTo test the hypothesis that multitissue deficits in insulin sensitivity are greater among women than men with type 1 diabetes compared to respective controls. Research design and methodsThree-stage hyperinsulinemic-euglycemic clamps (4, 8, 40 mU/m2/min) were performed on 41 people with type 1 diabetes and 47 adults without diabetes (mean ± SD age 46 ± 8). Infusions of [1-13C]palmitate, [1,1,2,3,3-2H2]glycerol, and [6,6-2H2]glucose isotope tracers were used to determine free fatty acid (FFA), glycerol, and glucose kinetics in 52 of these participants (25 M and 27 W). ResultsThere was no difference in age or BMI by type 1 diabetes status in either sex. Free fatty acid rate of appearance (FFA Ra) was higher in both sexes with type 1 diabetes compared to those without diabetes during stages 1 and 2. The same was seen with glycerol for stages 1 and 2. During stage 3 glucose rate of disappearance (Rd) was lower in those with type 1 diabetes among both sexes. All had sex by type 1 diabetes interactions with greater deficits in insulin sensitivity in women. While there was no sex by diabetes interaction in regards to glucose rate of appearance (Ra), those with type 1 diabetes had a higher glucose Ra than those without diabetes. ConclusionsWe found that type 1 diabetes affected adipose and skeletal muscle insulin sensitivity to a greater extent in women than in men, perhaps contributing to the greater relative increase in cardiovascular risk in women with type 1 diabetes.

A whole-grain diet reduces peripheral insulin resistance and improves glucose kinetics in obese adults: A randomized-controlled trial

BackgroundWhole-grain intake is associated with lower risk of type 2 diabetes but the mechanisms are unclear. PurposeWe tested the hypothesis that a WG diet reduces insulin resistance and improves glucose use in individuals at risk for type 2 diabetes compared with an isocaloric-matched refined-grain diet. MethodsA double-blind, randomized, controlled, crossover trial of 14 moderately obese adults (Age, 38 ± 2 y; BMI, 34.0 ± 1.1 kg/m2). Insulin resistance and glucose metabolism was assessed using an oral glucose tolerance test combined with isotopic tracers of [6,6-2H2]-glucose and [U-13C]-glucose, and indirect calorimetry. Peripheral and hepatic insulin resistance was assessed as 1/(rate of disposal/insulin), and endogenous glucose rates of appearance (Ra) iAUC60–240 × insulin iAUC60–240, respectively. Both diets met ADA nutritional guidelines and contained either whole-grain (50 g per 1000 kcal) or equivalent refined-grain. All food was provided for 8 wk. with an 8–10 wk. washout period between diets. ResultsPost-prandial glucose tolerance, peripheral insulin sensitivity, and metabolic flexibility (insulin-stimulated – fasting carbohydrate oxidation) improvements were greater after whole-grain compared to the refined-grain diet (P < 0.05). Compared to baseline, body fat (~2 kg) and hepatic Ra insulin resistance was reduced by both diets, while fasting glucose and exogenous glucose-meal were unchanged after both interventions. Changes in peripheral insulin resistance and metabolic flexibility correlated with improved glucose tolerance (P < 0.05). ConclusionWhole-grains reduced diabetes risk and the mechanisms appear to work through reduced post-prandial blood glucose and peripheral insulin resistance that were statistically linked to enhanced metabolic flexibility.

Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice

Pathologies including diabetes and conditions such as exercise place an unusual demand on liver energy metabolism, and this demand induces a state of energy discharge. Hepatic AMP-activated protein kinase (AMPK) has been proposed to inhibit anabolic processes such as gluconeogenesis in response to cellular energy stress. However, both AMPK activation and glucose release from the liver are increased during exercise. Here, we sought to test the role of hepatic AMPK in the regulation of in vivo glucose-producing and citric acid cycle-related fluxes during an acute bout of muscular work. We used 2H/13C metabolic flux analysis to quantify intermediary metabolism fluxes in both sedentary and treadmill-running mice. Additionally, liver-specific AMPK α1 and α2 subunit KO and WT mice were utilized. Exercise caused an increase in endogenous glucose production, glycogenolysis, and gluconeogenesis from phosphoenolpyruvate. Citric acid cycle fluxes, pyruvate cycling, anaplerosis, and cataplerosis were also elevated during this exercise. Sedentary nutrient fluxes in the postabsorptive state were comparable for the WT and KO mice. However, the increment in the endogenous rate of glucose appearance during exercise was blunted in the KO mice because of a diminished glycogenolytic flux. This lower rate of glycogenolysis was associated with lower hepatic glycogen content before the onset of exercise and prompted a reduction in arterial glucose during exercise. These results indicate that liver AMPKα1α2 is required for maintaining glucose homeostasis during an acute bout of exercise.

Whole-body propionate and glucose metabolism of multiparous dairy cows receiving folic acid and vitamin B12 supplements

This study was undertaken to evaluate the effect of supplementation of folic acid and vitamin B12 on glucose and propionate metabolism. Twenty-four multiparous cows were assigned according to a complete block design in a 2 × 2 factorial arrangement to one of the following treatments: (1) saline 0.9% NaCl, (2) 320 mg of folic acid, (3) 10 mg of vitamin B12, or (4) 320 mg of folic acid and 10 mg of vitamin B12. Intramuscular injections were given weekly from 3 wk before the expected calving date until 9 wk postpartum. At 63 d in milk, d-[6,6-2H2]-glucose (16.5 mmol/h; jugular vein) and [1-13C]-sodium propionate (13.9 mmol/h; ruminal vein) were simultaneously infused for 4 h; blood samples were collected from 2 to 4 h of the infusion period. Liver biopsies were carried out the following day. Supplements of folic acid and vitamin B12 respectively increased folate and vitamin B12 concentrations, both in milk and liver. Although dry matter intake was unaffected by treatments, milk and milk lactose yields tended to be lower by 5.0 and by 0.25 kg/d, respectively, for cows receiving the folic acid supplement. Plasma β-hydroxybutyrate concentration with the folic acid supplement followed the same tendency. Hepatic gene expression of methylmalonyl-CoA mutase and S-adenosylhomocysteine hydrolase was higher for cows receiving the combined folic acid and vitamin B12 supplement compared with cows receiving only the supplement of folic acid, whereas no treatment effect was noted for cows not receiving the folic acid supplement. Whole-body glucose rate of appearance and the proportion of whole-body glucose rate of appearance secreted in milk lactose decreased by 229 g/d and 5%, respectively, for animals receiving the folic acid supplement, concomitant with the lower milk lactose synthesis in these cows, indicating that supplementary folic acid may alter energy partitioning in cows. The absence of treatment effect on plasma concentrations of methylmalonic acid as well as on the proportion of glucose synthesized from propionate, averaging 60%, supports the fact that vitamin B12 supply was sufficient in control cows in the current study. Our results suggest that the folic acid supplement reduced glucose-derived lactose synthesis by redirecting glucose for other metabolic activity in the mammary gland or in other tissues.

Short term elevation in dietary protein intake does not worsen insulin resistance or lipids in older adults with metabolic syndrome: a randomized-controlled trial

BackgroundThere is a great deal of controversy as to whether higher protein intake improves or worsens insulin sensitivity in humans. The purpose of the study was to determine the influence of a short-term elevation in dietary protein on hepatic and peripheral insulin sensitivity in twelve older subjects (51–70 yrs) with metabolic syndrome.MethodsIndividuals were randomly assigned to one of the dietary groups: recommended protein intake (RPI, 10% of daily calorie intake) or elevated protein intake (EPI, 20% of daily calorie intake) for 4 weeks. Prior to and immediately following the dietary intervention, subjects were studied with primed continuous infusion of [6,6-2H2]glucose and [1-13C]glucose dissolved in drink during the dual tracer oral glucose tolerance test (DT OGTT) to determine hepatic and peripheral insulin sensitivity. Plasma lipids were measured pre- and post-dietary intervention.ResultsIn both intervention groups: 1) hepatic insulin sensitivity as assessed by the endogenous glucose rate of appearance (glucose Ra), 2) peripheral insulin sensitivity as assessed by the metabolic clearance rate of glucose normalized to plasma glucose concentration (MCR) and/or the rate of glucose utilization (Rd) or 3) glucose/insulin AUC were unaffected by the diets. Moreover, fasting lipid was not affected by RPI or EPI.ConclusionOur findings suggest that a short-term elevation in EPI with correspondingly higher branched chain amino acid (BCAA) contents has no detrimental impact on hepatic and peripheral insulin sensitivity or plasma lipid parameters in older adults with metabolic syndrome.Trial registrationClinicalTrials.gov Identifier: NCT02885935; This trial was registered retrospectively (Study start date, April 01, 2013, date of registration, August 26, 2016).

The Effect of a Breakfast Rich in Slowly Digestible Starch on Glucose Metabolism: A Statistical Meta-Analysis of Randomized Controlled Trials.

Starch digestibility may have an effect on the postprandial blood glucose profile. The aim of this meta-analysis was to analyze the relationship between Slowly Digestible Starch (SDS) levels and plasma glucose appearance and disappearance rates, as well as other parameters of glucose metabolism, after healthy subjects consumed cereal products that differed in SDS content. Three randomized controlled clinical trials that included a total of 79 subjects were identified. Using binary classification for the variables (high versus low levels, more than 12 g of SDS per portion, and less than 1 g of SDS per portion, respectively), we found that there was a 15-fold higher chance of having a low rate of appearance of exogenous glucose (RaE) after consumption of a high-SDS product. A high SDS content was also associated with a 12-fold and 4-fold higher chance of having a low rate of disappearance of exogenous glucose (RdE) and rate of disappearance of total plasma glucose (RdT), respectively. The RaE kinetics were further analyzed by modeling the contribution of SDS content to the different phases of the RaE response. We show that the higher the SDS content per portion of cereal product, the higher its contribution to the incremental area under the curve (iAUC) of the RaE response after 165 min. Using the association rule technique, we found that glycemic iAUC and insulinemic iAUC values vary in the same direction. In conclusion, this meta-analysis confirms the effect of the SDS level in cereal products on the metabolic response, and shows for the first time that the degree to which SDS affects the RaE response differs depending on the SDS content of the food product, as well as the phase of the postprandial period.

Decreased basal hepatic glucose uptake in impaired fasting glucose.

This research aimed to define the pathophysiological defects responsible for the elevated fasting plasma glucose (FPG) concentration and excessive rise in post-load plasma glucose observed in individuals with impaired fasting glucose (IFG). We used tracer techniques to quantify basal splanchnic (primarily hepatic) glucose uptake and glucose fluxes following glucose ingestion in individuals with normal glucose tolerance (NGT; n=10) and IFG (n=10). Individuals with IFG had a comparable basal rate of hepatic glucose production to those with NGT (15.2±0.2 vs 18.0±0.8μmolmin-1[kg lean body mass (LBM)]-1; p=0.09). However, they had a significantly reduced glucose clearance rate during the fasting state compared with NGT (2.64±0.11 vs 3.62±0.20ml min-1[kgLBM]-1; p<0.01). The difference between the basal rate of glucose appearance measured with [3-3H]glucose and [1-14C]glucose, which represent basal splanchnic glucose uptake, was significantly reduced in IFG compared with NGT (1.39±0.28 vs 3.16±0.44μmolmin-1[kgLBM]-1; p=0.02). Following glucose ingestion, the total amount of exogenous glucose that appeared in the systemic circulation was not significantly different between groups. However, suppression of endogenous glucose production (EGP) was markedly impaired in individuals with IFG. These results demonstrate that decreased tissue (liver) glucose uptake, not enhanced EGP, is the cause for elevated FPG concentration in individuals with IFG, while the excessive rise in plasma glucose concentration following a glucose load in these individuals is the result of impaired suppression of hepatic glucose production.

Berberine improves glucogenesis and lipid metabolism in nonalcoholic fatty liver disease

BackgroundNonalcoholic fatty liver disease (NAFLD) is considered a critical hepatic manifestation of metabolic syndrome. Berberine (BBR) exerts anti-hyperglycemic and anti-dyslipidemic effects and can also ameliorate NAFLD. Thus, BBR might exert its therapeutic effect on NAFLD by improving glucolipid metabolism. Here, we investigated the aspects and extent to which glucolipid metabolism were affected by BBR in rats with NAFLD.MethodsThree groups of Sprague–Dawley rats were studied: a control group (n = 6) fed a normal chow diet and a NAFLD group (n = 6) and a NAFLD + BBR group (n = 6) fed a high-fat diet. Normal saline and BBR (150 mg/kg body weight/day for 16 weeks) were administered by gavage. All rats were infused with isotope tracers. The rates of glucose appearance (Raglu), gluconeogenesis (GNG) and glycerol appearance (Ragly) were assessed with 2H and 13C tracers, whereas the rates of hepatic lipogenesis and fatty acid β oxidation were measured using the 3H tracer.ResultsWhen the NAFLD model was successfully induced by administering a high-fat diet, body weight, insulin resistance and dyslipidemia were significantly increased. After the BBR treatment, weight loss, decreased lipid profiles and HOMA-IR, and increased ISI were observed. Meanwhile, BBR reduced Raglu, GNG and hepatic lipogenesis, whereas the rate of fatty acid β oxidation in skeletal muscle showed an increasing trend. Ragly showed a decreasing trend. Based on the results of the histological analysis, BBR obviously attenuated the ectopic liver fat accumulation.ConclusionsBBR improved NAFLD by inhibiting glucogenesis and comprehensively regulating lipid metabolism, and its effect on inhibiting hepatic lipogenesis was much stronger. The improvement may be partly mediated by weight loss. Berberine might be a good choice for patients with NAFLD and glucose metabolic disorder. Future clinical trials need to be conducted to confirm these effects.

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

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. 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). 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). 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.

Insulin resistance of protein anabolism accompanies that of glucose metabolism in lean, glucose-tolerant offspring of persons with type 2 diabetes

ObjectiveTo test whether protein anabolic resistance is an early defect in type 2 diabetes (T2D).Research design and methodsSeven lean, normoglycemic T2D offspring (T2D-O) and eight matched participants without family history...

Effects of 13-Hour Hyperglucagonemia on Energy Expenditure and Hepatic Glucose Production in Humans.

Glucagon (GCG) acutely stimulates energy expenditure (EE) and hepatic glucose production (HGP) in humans, but whether these effects persist during hyperglucagonemia of longer duration is unclear. Using a prospective, randomized, single-blind, crossover study design, we therefore measured EE and rates of glucose appearance (glucose RA) during three separate infusion protocols in healthy lean males: A) 10-h overnight GCG infusion (6 ng/[kg × min]) followed by 3-h infusion of GCG, octreotide (OCT), and insulin (INS) for basal replacement; B) overnight saline (SAL) infusion followed by GCG/OCT/INS infusion; and C) overnight SAL infusion followed by SAL/OCT/INS infusion. Sleep EE, measured at 6 to 7 h of the overnight infusion, was increased 65-70 kcal/24 h in A compared with B and C. During the 3-h infusion, mean resting EE remained significantly increased in A versus C by ∼50 kcal/24 h; in B, resting EE increased with a statistical trend but was not significantly greater than in C. Glucose RA increased to comparable levels in A and B. We conclude that in healthy lean males, stimulation of EE and HGP is sustained during hyperglucagonemia of longer duration when insulin secretion is inhibited. The increase in EE at the present GCG dose was of marginal clinical significance.

Green tea extract does not affect exogenous glucose appearance but reduces insulinemia with glucose ingestion in exercise recovery.

We reported that supplementation with green tea extract (GTE) lowered the glycemic response to an oral glucose load following exercise, but via an unknown mechanism (Martin BJ, MacInnis MJ, Gillen JB, Skelly LE, Gibala MJ. Appl Physiol Nutr Metab 41: 1057-1063, 2016. Here we examined the effect of supplementation with GTE on plasma glucose kinetics on ingestion of a glucose beverage during exercise recovery. Eleven healthy, sedentary men (21 ± 2 yr old; body mass index = 23 ± 4 kg/m2, peak O2 uptake = 38 ± 7 ml·kg-1·min-1; means ± SD) ingested GTE (350 mg) or placebo (PLA) thrice daily for 7 days in a double-blind, crossover design. In the fasted state, a primed constant infusion of [U-13C6]glucose was started, and 1 h later, subjects performed a graded exercise test (25 W/3 min) on a cycle ergometer. Immediately postexercise, subjects ingested a 75-g glucose beverage containing 2 g of [6,6-2H2]glucose, and blood samples were collected every 10 min for 3 h of recovery. The rate of carbohydrate oxidation was lower during exercise after GTE vs. PLA (1.26 ± 0.34 vs. 1.48 ± 0.51 g/min, P = 0.04). Glucose area under the curve (AUC) was not different between treatments after drink ingestion (GTE = 1,067 ± 133 vs. PLA = 1,052 ± 91 mM/180 min, P = 0.91). Insulin AUC was lower after GTE vs. PLA (5,673 ± 2,153 vs. 7,039 ± 2,588 µIU/180 min, P = 0.05), despite similar rates of glucose appearance (GTE = 0.42 ± 0.16 vs. PLA = 0.43 ± 0.13 g/min, P = 0.74) and disappearance (GTE = 0.43 ± 0.14 vs. PLA = 0.44 ± 0.14 g/min, P = 0.57). We conclude that short-term GTE supplementation did not affect glucose kinetics following ingestion of an oral glucose load postexercise; however, GTE was associated with attenuated insulinemia. These findings suggest GTE lowers the insulin required for a given glucose load during postexercise recovery, which warrants further mechanistic studies in humans.