Liquid Mixed Meal Tolerance Test Research Articles

Beyond Restrictive: Sleeve Gastrectomy to Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy as a Spectrum of One Single Procedure

Introduction: Single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) is a restrictive/hypoabsorptive procedure recommended for patients with obesity class 3. For safety reasons, SADI-S can be split into a two-step procedure by performing a sleeve gastrectomy (SG) first. This stepwise approach also provides an unprecedented opportunity to disentangle the weight loss mechanisms triggered by each component. The objective was to compare weight trajectories and post-prandial endocrine and metabolic responses of patients with obesity class 3 submitted to SADI-S or SG as the first step of SADI-S. Methods: Subjects submitted to SADI-S (n = 7) or SG (n = 7) at a tertiary referral public academic hospital underwent anthropometric evaluation and a liquid mixed meal tolerance test (MMTT) pre-operatively and at 3, 6, and 12 months post-operatively. Results: Anthropometric parameters, as well as metabolic and micronutrient profiles, were not significantly different between groups, neither before nor after surgery. There were no significant differences in fasting or post-prandial glucose, insulin, C-peptide, ghrelin, insulin secretion rate, and insulin clearance during the MMTT between subjects submitted to SADI-S and SG. There was no lost to follow-up. Conclusions: The restrictive component seems to be the main driver for weight loss and metabolic adaptations observed during the first 12 months after SADI-S, given that the weight trajectories and metabolic profiles do not differ from SG. These data provide support for surgeons’ choice of a two-step SADI-S without jeopardizing the weight loss outcomes.

1545-P: Characterization of Metabolic Defects in Pancreatic Cancer–Related Diabetes and Type 2 Diabetes in the DETECT Study

Diabetes due to pancreatic ductal adenocarcinoma (PDAC-D) is often difficult to clinically distinguish from type 2 diabetes (T2D) and both insulin resistance and reduced insulin secretion have been implicated in its pathophysiology. Although these metabolic defects are similar to those seen in T2D, the degree to which they relatively contribute to hyperglycemia in PDAC-D has not been established. Additionally, there is a lack of understanding of alpha cell function in PDAC-D. We sought to address these gaps in the DETECT study (NCT03460769). Adults with PDAC-D (n=28) or T2D (n=99) (diabetes diagnosis <3 years) underwent a standardized liquid mixed-meal tolerance test with serum glucose, insulin, and glucagon measurements. Insulin sensitivity was assessed by the Matsuda index, insulin secretion by the insulinogenic index, and beta cell function by the oral disposition index. The mean duration of diabetes was 10.8 months in PDAC-D and 12.5 months in T2D (P=0.51). HbA1c was higher in PDAC-D (7.27% vs 6.58%, P=0.03). The area under the curve (AUC) of the glucose response was similar in PDAC-D vs T2D (232 vs. 238 mg.min/ml, P=0.08). Insulin sensitivity was 2.5x higher in PDAC-D than in T2D (3.65 vs 1.45, P<0.001). In contrast, insulin secretion was 81% lower in PDAC-D (18 vs 95 μU/mg, P<0.001), and the oral disposition index was 40% lower (0.80 vs. 1.32, P<0.001). Fasting glucagon was similar in PDAC-D and T2D (21.1 vs 17.7 pM, P=0.09). In both groups, glucagon rose after the meal, but the incremental AUC was 57% higher in PDAC-D (581 vs. 370 pM.min, P=0.01). These results suggest that impaired insulin secretion is considerably more important than insulin resistance in the etiology of hyperglycemia of PDAC-D and that post-prandial alpha-cell dysregulation is likely to play a greater role than previously recognized. Collectively, these data also suggest that targeting insulin and glucagon levels, rather than insulin resistance, may be a more effective strategy to treat PDAC-D. Disclosure F.G.S.Toledo: Research Support; Dompé. R.V.Considine: Research Support; Lilly Diabetes. S.T.Chari: Advisory Panel; Nestlé Health Science, Guardant, Bluestar genomics. S.C.Graham: None. D.K.Andersen: None. J.Rinaudo: None. J.Serrano: None. M.O.Goodarzi: Advisory Panel; Nestlé Health Science, Other Relationship; Nestlé Health Science. P.Hart: Consultant; Sagent Pharmaceuticals. On behalf of the cpdpc: n/a. Y.Li: Stock/Shareholder; Agenus, Inc. F.Wang: None. D.Yadav: None. M.Bellin: Consultant; Insulet Corporation, Vertex Pharmaceuticals Incorporated, Research Support; Dexcom, Inc., ViaCyte, Inc. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. W.E.Fisher: None. Y.C.Kudva: Advisory Panel; Novo Nordisk, Research Support; Dexcom, Inc. W.Park: Advisory Panel; AbbVie Inc., Ariel Medicine, Nestlé Health Science, Consultant; Arctx Medical, Craif, Research Support; AbbVie Inc., Stock/Shareholder; Arctx Medical. Funding National Institutes of Health (U01DK108306, U01DK108288, U01DK108320, U01DK108323, U01DK108326, U01DK108327, U01DK108328, U01DK108300, U01DK108314, U01DK126300)

Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial

Diet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose–response relationship (P > 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).

370 Epicardial adipose tissue and cardiometabolic health in youth-onset type 2 diabetes undergoing vertical sleeve gastrectomy

OBJECTIVES/GOALS: The goal of this study is to investigate the potential independent relationship between epicardial adipose tissue (EAT) and cardiometabolic health in youth-onset type 2 diabetes (T2D) and explore changes in EAT as a potential mediator of changes in cardiometabolic health in response to vertical sleeve gastrectomy (VSG). METHODS/STUDY POPULATION: We will assess glycemic control, insulin sensitivity and secretion in youth with T2D before and 3 months after VSG. Fasting labs, anthropometrics, and a 4-hour, frequently sampled liquid mixed meal tolerance test (45g carbohydrates, 14g fat, and 14g protein) were performed. Calculations included glucose, insulin, and GLP-1 area under the curve (AUC), Matsuda Index, HOMA-IR, and oral disposition index (DI). These cardiometabolic outcomes will then be assessed for associations between total EAT volume, measured from cardiac MRI. RESULTS/ANTICIPATED RESULTS: Previous studies have shown that individuals with obesity have higher EAT than lean controls, and adults with T2D have even higher EAT than obese controls. Therefore, we anticipate that our participants will have higher volume of EAT than what has been reported in the literature and that they will have worsening cardiometabolic outcomes without MBS. Our anticipated results will include: Weight and BMI, hemoglobin A1c, diabetes medications, Matsuda Index, HOMA-IR, DI, and glucose and insulin AUC during an MMTT. Cardiac MRI's are being analyzed and will give total EAT volume and will be analyzed for correlations with the cardiometabolic outcomes of body composition, aortic stiffness, blood pressure, cardiac structure and function, as well as lipid panel and insulin sensitivity. DISCUSSION/SIGNIFICANCE: This study is the first to specifically assess EAT in adolescents with T2D. The assessment of EAT will be done with gold-standard MRI and correlated with cardiometabolic health assessed by gold-standard methods. Together, the results will give insight into EAT as a potential independent cardiometabolic risk factor in adolescents undergoing VSG.

Proinsulin to C-Peptide Ratio in the First Year After Diagnosis of Type 1 Diabetes.

The proinsulin to C-peptide (PI:C) ratio is reputedly a biomarker of β-cell endoplasmic reticulum (ER) stress. This study examined the natural history of the PI:C ratio and its correlation with residual β-cell function in childhood new-onset type 1 diabetes (T1D). Over the first year of T1D, the temporal trend in fasting and nutrient-stimulated PI data is limited. PI was a secondary pre-planned analysis of our 1-year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4 to 18 years, 30 were placebo. This study only involved the 30 placebo patients; all were enrolled within 5 weeks of T1D diagnosis. A liquid mixed meal tolerance test was administered at baseline and 5 and 12 months for determination of C-peptide, PI, glucose, and hemoglobin A1C. Both the fasting (P = 0.0003) and stimulated (P = 0.00008) PI:C ratios increased from baseline to 12 months, indicating escalating β-cell ER stress. The baseline fasting PI correlated with the fasting change in C-peptide at 12 months (P = 0.004) with a higher PI correlating with greater decline in C-peptide. Patients with an insulin-adjusted A1C >9% (hence, not in remission) had higher fasting PI:C ratios. Younger age at diagnosis correlated with a higher PI:C ratio (P = 0.04). Children with new-onset T1D undergo progressive β-cell ER stress and aberrant proinsulin processing, as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects more aggressive β-cell onslaught with younger age, as well as diminished glycemic control.

Impact of glucagon response on early postprandial glucose excursions irrespective of residual β-cell function in type 1 diabetes: A cross-sectional study using a mixed meal tolerance test.

Aims/IntroductionControlling postprandial glucose levels in patients with type 1 diabetes is challenging even under the adequate treatment of insulin injection. Recent studies showed that dysregulated glucagon secretion exacerbates hyperglycemia in type 2 diabetes patients, but little is known in type 1 diabetes patients. We investigated whether the glucagon response to a meal ingestion could influence the postprandial glucose excursion in patients with type 1 diabetes.Materials and MethodsWe enrolled 34 patients with type 1 diabetes and 23 patients with type 2 diabetes as controls. All patients underwent a liquid mixed meal tolerance test. We measured levels of plasma glucose, C‐peptide and glucagon at fasting (0 min), and 30, 60 and 120 min after meal ingestion. All type 1 diabetes patients received their usual basal insulin and two‐thirds of the necessary dose of the premeal bolus insulin.ResultsThe levels of plasma glucagon were elevated and peaked 30 min after the mixed meal ingestion in both type 1 diabetes and type 2 diabetes patients. The glucagon increments from fasting to each time point (30, 60 and 120 min) in type 1 diabetes patients were comparable to those in type 2 diabetes patients. Among the type 1 diabetes patients, the glucagon response showed no differences between the subgroups based on diabetes duration (<5 vs ≥5 years) and fasting C‐peptide levels (<0.10 vs ≥0.10 nmol/L). The changes in plasma glucose from fasting to 30 min were positively correlated with those in glucagon, but not C‐peptide, irrespective of diabetes duration and fasting C‐peptide levels in patients with type 1 diabetes.ConclusionsThe dysregulated glucagon likely contributes to postprandial hyperglycemia independent of the residual β‐cell functions during the progression of type 1 diabetes.

2098-P: The Accuracy of Meal Test to Diagnose Hypoglycemia after Gastric Bypass

Gastric bypass (GB) alters postprandial glucose pattern with a higher peak of glucose and lower glucose nadir. Glycemic effects of GB is exaggerated in patients suffering from postprandial hyperinsulinemic hypoglycemia. Diagnosis is complex and requires documentation of concurrent symptoms with low glucose that are relieved by carbohydrate (CHO) intake (Whipple’s triad). Mixed meal tolerance test (MTT) is often used to provoke hypoglycemia but glucose threshold to fulfill Whipple’s triad remains unknown. Here we measured accuracy of 350-kcal MTT (Ensure Plus®, 51 g CHO) to diagnose hypoglycemia in 95 GB subject (43 with prior documented hypoglycemia [H] and 52 asymptomatic [A]). In addition, measured outcomes were compared with those during isovolemic 250-kcal liquid MTT (Ensure®, 40 g CHO) in a separate cohort of 49 GB subjects (31 H vs. 18 A). Time and weight loss since surgery, BMI, and A1c were similar between H and A. The H subjects had lower fasting glucose (80±1 vs. 84±1 mg/dL, P&amp;lt;0.05) and nadir glucose levels (51±2 vs. 67±2 mg/dL, P&amp;lt;0.001). Nadir glucose values were associated with fasting glucose (r=0.6, P&amp;lt;0.001). Plotting true positive rate (sensitivity) against false positive rates (1-specificity) for nadir glucose during MTT yielded an area under the Receiver Operating Characteristics (ROC) curve of 0.80±0.05. A nadir blood glucose cut-off of 53 mg/dL produced the highest sum of sensitivity (65%) and specificity (88%) for detecting hypoglycemia. Lower CHO ingestion (40 g) did not significantly affect the accuracy of MTT to diagnose hypoglycemia (AUC ROC: 0.69±0.08). Our findings indicates that mixed meals containing 40-50 g of CHO have good discriminatory value to diagnose hypoglycemia after GB using blood glucose threshold of &amp;lt;54mg/dL. Disclosure H. Honka: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. M.E. Patti: Consultant; Self; Eiger BioPharmaceuticals. Research Support; Self; Dexcom, Inc., Janssen Pharmaceuticals, Inc., MedImmune, Xeris Pharmaceuticals, Inc. M. Salehi: None. Funding National Institutes of Health (DK105379, DK083554 to M.S.); National Center for Advancing Translational Sciences (8UL1TR000077); Finnish Cultural Foundation (00180071)

Biliopancreatic diversion with duodenal switch (BPD-DS) and single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) result in distinct post-prandial hormone profiles.

Biliopancreatic diversion with duodenal switch (BPD-DS) is the most effective bariatric intervention to treat morbid obesity and related disorders. Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) is a new bariatric procedure devised with the purpose of simplifying the complexity of the BPD-DS technique while maintaining its efficacy. However, whether BPD-DS and SADI-S result in similar fasting and post-prandial hormone profiles has not yet been studied. Therefore, the purpose of this study was to assess and compare the hormone response to a standardized mixed meal in subjects operated with BPD-DS or SADI-S. Subjects submitted to BPD-DS (n = 9) or SADI-S (n = 9) 1.5 years earlier on average, with no past nor current diabetes diagnosis underwent a liquid mixed-meal tolerance test (MMTT) to assess the baseline and post-prandial profile of glucose, enteropancreatic hormones and total bile acids. Fasting glucose, enteropancreatic hormones and total bile acids levels after BPD-DS and SADI-S were similar. After the MMTT, the response of subjects who underwent SADI-S was characterized by higher glucose (t = 30 min: p < 0.05; iAUC: 156.1 ± 46.2 vs. 103.4 ± 35.8 mmol/L × min, p = 0.02), GLP-1 (t = 30 min: p < 0.05; iAUC: 5388 ± 3010 vs. 2959.0 ± 2146 pmol/L × min, p = 0.02), glucagon (t = 30 min: p < 0.05; iAUC: 678.7 ± 295.2 vs. 376.9 ± 215.7 pmol/L × min, p = 0.02), insulin (t = 30 and 45 min: p < 0.05); and C-peptide levels (t = 30 and 45 min: p < 0.05), when compared to BPD-DS. The post-prandial hormone secretion profile after SADI-S is characterized by increased GLP-1, glucagon and insulin secretion, when compared to BPD-DS, which suggests the existence of different endocrine driven mechanisms leading to weight loss and metabolic improvement after the two procedures.

Effects of MEDI0382 on Pancreatic and Incretin Hormones

MEDI0382, a GLP-1/glucagon dual receptor agonist, is being developed for the treatment of T2DM. GLP-1 receptor agonists promote glucose-dependent insulin release, suppress glucagon, and increase or have minimal effect on glucose-dependent insulinotropic polypeptide (GIP); knowledge of the effect on GLP-1 is limited. We characterized fasting and postprandial hormone profiles associated with MEDI0382 therapy. In a phase 2a study (NCT02548585), 51 subjects with T2DM and BMI 27-40 kg/m2 received MEDI0382 (uptitrated to 200 µg) or placebo (PBO) daily for 41 days. Glucose, insulin, glucagon, GIP, and GLP-1 were measured at baseline (day -1) and day 41 during a liquid mixed-meal tolerance test. MEDI0382 significantly reduced fasting glucose (-49.9 vs. -19.2 mg/dL for PBO; P &amp;lt; 0.0001) and glucose AUC0-4h (-32.8 vs. -10.2% for PBO; P &amp;lt; 0.0001) in association with increased fasting insulin (2.2 mU/L vs. -3.9 mU/L for PBO; P = 0.016), but postprandial insulin AUC was unchanged. In contrast, fasting and postprandial endogenous glucagon, GIP (Figure), and active and inactive GLP-1 were suppressed, and a delay in their kinetics was observed after MEDI0382 therapy. The results suggest that MEDI0382 is insulinotropic and might also cause delayed gastric emptying. The effects of MEDI0382 on GIP have not been observed with GLP-1 receptor mono-agonists and may represent a footprint of dual GLP-1/glucagon receptor agonism in this complex hormone signaling network. Disclosure V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.

Gut hormone release after gastric bypass depends on the length of the biliopancreatic limb.

Changes in gut hormone secretion are important for the anti-diabetic effects of bariatric surgery. Roux-en-Y gastric bypass (RYGB) with extended biliopancreatic limb (BPL) length may improve the metabolic outcomes when compared to the classical procedure. The purpose of this study was to compare the gut hormone responses to a liquid mixed meal after RYGB with one of two different BPL lengths. Non-diabetic weight-stable individuals previously submitted to classical RYGB (n = 9; BPL length: 87.8 ± 20.5 cm) or long BPL RYGB (n = 11; BPL length: 200 cm) underwent a liquid mixed-meal tolerance test (MMTT). Blood was sampled at baseline and 15, 30, 45, 60, 90 and 120 min later for measurement of plasma glucose, enteropancreatic hormones and total bile acids (TBA). Plasma glucose excursion curves were similar in the two groups. The long BPL RYGB group displayed significantly higher fasting and post-prandial GLP-1 (t = 0 min, p = 0.01 and t = 45 min, p < 0.05; tAUC: 11,205 ± 3399 vs 7889 ± 1686 pmol/L × min, p = 0.02) and neurotensin (t = 0 min, p = 0.02; t = 45 min, p < 0.05 and t = 60 min, p < 0.01; tAUC: 18,392 ± 7066 vs 11,437 ± 3658 pmol/L × min, p = 0.02) levels, while responses of GIP (t = 15 min, p < 0.01), insulin and C-peptide (t = 30 min, p < 0.001) were lower as compared to classical RYGB. There were no differences in glucagon, PP, PYY and TBA between the groups. RYGB with a longer BPL results in a distinctive post-prandial hormone profile with augmented GLP-1 and neurotensin responses that could be beneficial for the metabolic outcomes of the surgery.

The impact of acute bouts of interval and continuous walking on energy-intake and appetite regulation in subjects with type 2 diabetes.

In healthy subjects, it has been suggested that exercise may acutely suppress energy‐intake and appetite, with peak intensity being an important determinant for this effect. In subjects with type 2 diabetes (T2D), the effect of exercise on appetite‐related variables is, however, virtually unknown. We aimed to assess the effects of two exercise interventions, differing with regards to peak intensity, on energy‐intake, satiety and appetite‐related hormones in subjects with T2D. Thirteen subjects with T2D completed three 60‐min interventions with continuous measurement of oxygen consumption in a randomized and counterbalanced order: (1) Control, (2) Continuous walking (CW; intended 73% of VO 2peak), (3) Interval‐walking (IW; repeated cycles of 3 min slow [54% of VO 2peak] and 3 min fast walking [89% of VO 2peak]). Forty‐five minutes after completion of the intervention, a 3‐h liquid mixed meal tolerance test (MMTT, 450 kcal) with regular satiety assessments and blood samples for appetite‐related hormones commenced. An ad libitum meal was served after the MMTT, with subsequent calculation of energy‐intake. Moreover, free‐living diet records were completed for the following ~32 h. Exercise interventions were well‐matched for mean oxygen consumption (CW = 77 ± 2% of VO 2peak; IW = 76 ± 1% of VO 2peak, P > 0.05). No differences in appetite‐related hormones or energy‐intake were found (P > 0.05 for all comparisons). IW increased fullness compared to Control shortly after the intervention (P < 0.05) and tended to reduce hunger 2 h into the MMTT compared to CW and Control (P < 0.10). In conclusion, a single exercise session does not affect energy‐intake during the following ~4–36 h in subjects with T2D. However, satiety may be affected up to ~3 h after the exercise session, dependent on peak intensity.

The effects of interval- vs. continuous exercise on excess post-exercise oxygen consumption and substrate oxidation rates in subjects with type 2 diabetes

BackgroundFor unknown reasons, interval training often reduces body weight more than energy-expenditure matched continuous training. We compared the acute effects of time-duration and oxygen-consumption matched interval- vs. continuous exercise on excess post-exercise oxygen consumption (EPOC), substrate oxidation rates and lipid metabolism in the hours following exercise in subjects with type 2 diabetes (T2D). MethodsFollowing an overnight fast, ten T2D subjects (M/F: 7/3; age=60.3±2.3years; body mass index (BMI)=28.3±1.1kg/m2) completed three 60-min interventions in a counterbalanced, randomized order: 1) control (CON), 2) continuous walking (CW), 3) interval-walking (IW – repeated cycles of 3min of fast and 3min of slow walking). Indirect calorimetry was applied during each intervention and repeatedly for 30min per hour during the following 5h. A liquid mixed meal tolerance test (MMTT, 450kcal) was consumed by the subjects 45min after completion of the intervention with blood samples taken regularly. ResultsExercise interventions were successfully matched for total oxygen consumption (CW=1641±133mL/min; IW=1634±126mL/min, P>0.05). EPOC was higher after IW (8.4±1.3l) compared to CW (3.7±1.4l, P<0.05). Lipid oxidation rates were increased during the MMTT in IW (1.03±0.12mg/kg per min) and CW (0.87±0.04mg/kg per min) compared with CON (0.73±0.04mg/kg per min, P<0.01 and P<0.05, respectively), with no difference between IW and CW. Moreover, free fatty acids and glycerol concentrations, and glycerol kinetics were increased comparably during and after IW and CW compared to CON. ConclusionsInterval exercise results in greater EPOC than oxygen-consumption matched continuous exercise during a post-exercise MMTT in subjects with T2D, whereas effects on substrate oxidation and lipid metabolism are comparable.

Diagnostic tools for post-gastric bypass hypoglycaemia.

In spite of its evident success, several late complications can occur after gastric bypass surgery. One of these is post-gastric bypass hypoglycaemia. No evidence-based guidelines exist in the literature on how to confirm the presence of this syndrome. This study aims to describe and compare the tests aimed at making a diagnosis of post-gastric bypass hypoglycaemia and to provide a diagnostic approach based upon the available evidence. A search was conducted in PubMed, Cochrane and Embase. A few questionnaires have been developed to measure the severity of symptoms in post-gastric bypass hypoglycaemia but none has been validated. The gold standard for provocation of a hypoglycaemic event is the oral glucose tolerance test or the liquid mixed meal tolerance test. Both show a high prevalence of hypoglycaemia in post-gastric bypass patients with and without hypoglycaemic complaints as well as in healthy volunteers. No uniformly established cut-off values for glucose concentrations are defined in the literature for the diagnosis of post-gastric bypass hypoglycaemia. For establishing an accurate diagnosis of post-gastric bypass hypoglycaemia, a validated questionnaire, in connection with the diagnostic performance of provocation tests, is the most important thing missing. Given these shortcomings, we provide recommendations based upon the current literature.

Ethnic differences in insulin sensitivity and beta-cell function among Asian men.

Background and objectives:Lean Asian Indians are less insulin sensitive compared with Chinese and Malays, but the pancreatic beta-cell function among these ethnic groups has yet to be studied in depth. We aimed to study beta-cell function in relation to insulin sensitivity among individuals of Chinese, Malay and Asian-Indian ethnicity living in Singapore.Subjects and methods:This is a sub-group analysis of 59 normoglycemic lean (body mass index (BMI) <23 kg m−2) adult males (14 Chinese, 21 Malays and 24 Asian Indians) from the Singapore Adults Metabolism Study. Insulin sensitivity was determined using fasting state indices (homeostatic model assessment—insulin resistance), the euglycemic-hyperinsulinemic clamp (ISI-clamp) and a liquid mixed-meal tolerance test (LMMTT) (Matsuda insulin sensitivity index (ISI-Mat)). Beta-cell function was assessed using fasting state indices (homeostatic model assessment—beta-cell function) and from the LMMTT (insulinogenic index and insulin secretion index). The oral disposition index (DI), a measure of beta-cell function relative to insulin sensitivity during the LMMTT, was calculated as a product of ISI-Mat and insulin secretion index.Results:Asian Indians had higher waist circumference and percent body fat than Chinese and Malays despite similar BMI. Overall, Asian Indians were the least insulin sensitive whereas the Chinese were most insulin sensitive. Asian Indians had higher beta-cell function compared with Chinese or Malays but these were not statistically different. Malays had the highest incremental area under the curve for glucose during LMMTT compared with Asian Indians and Chinese. However, there were no significant ethnic differences in the incremental insulin area under the curve. The oral DI was the lowest in Malays, followed by Asian Indians and Chinese.Conclusion:Among lean Asians, Chinese are the most insulin sensitive whereas Asian Indians are the least insulin sensitive. However, Malays demonstrate higher postprandial glucose excursion with lower beta-cell response compare with Chinese or Asian Indians. The paths leading to type 2 diabetes mellitus might differ between these Asian ethnic groups.

Post-meal β-cell function predicts the efficacy of glycemic control in patients with type 2 diabetes inadequately controlled by metformin monotherapy after addition of glibenclamide or acarbose.

BackgroundThis study aimed to explore parameters which will predict good control of HbA1c after adding a second anti-diabetic drug in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy.MethodsFifty-one patients (M/F: 25/26, mean age: 53.7 ± 8.2 years, mean glycated hemoglobin [HbA1c] 8.4 ± 1.2%) with T2DM inadequately controlled with metformin were randomized to add-on glibenclamide or acarbose for 16 weeks. Before and after combination therapy, the subjects underwent a 2-hour liquid mixed meal tolerance test to determine insulin secretion (HOMA-β, insulinogenic index, and disposition index [DI]) and insulin sensitivity (HOMA-IR and Matsuda insulin sensitivity index).ResultsAt baseline, there was a significant inverse relationship between DI120 and HbA1c (p = 0.001) in all subjects. The addition of glibenclamide and acarbose improved HbA1c significantly from 8.6 ± 1.6% to 7.4 ± 1.2% (p < 0.001), and from 8.2 ± 0.8% to 7.5 ± 0.8% (p < 0.001), respectively. In the glibenclamide group, DI120 significantly increased from 51.2 ± 24.2 to 74.9 ± 41.9 (p < 0.05), and in the acarbose group, from 62.5 ± 31.4 to 91.7 ± 36.2 (p < 0.05), respectively. Multiple regression analyses showed that both baseline HbA1c and DI120 independently predicted reduction of HbA1c as well as final HbA1c after combination therapy.ConclusionsIn patients with T2DM inadequately controlled with metformin, add-on oral anti-diabetic agent with glibenclamide or acarbose resulted in the significant HbA1c reduction and improvement of β-cell function. Subjects with greater baseline β-cell function reserve displayed better glycemic response in the combination therapy of metformin with glibenclamide or acarbose.Trial registrationThis study was registered in the ClinicalTrials.gov with registration number of NCT00417729.

The effect of vitamin D supplementation on peripheral regulatory T cells and β cell function in healthy humans: a randomized controlled trial

Increasing evidence supports the role of vitamin D (vitD) in modifying the risk to develop type 1 diabetes (T1D) and other autoimmune diseases. VitD3 might stimulate regulatory T cells (Tregs), a central player in the maintenance of self-tolerance. In addition, direct effects of vitD on β-cell function are postulated. The aim of our study was to evaluate the effect of a high dose vitD supplementation on Tregs frequency (%Tregs) and β-cell function assessed by a mixed meal tolerance test (MMTT) in healthy humans. A double-blind, placebo controlled trial was performed in 59 healthy adult subjects (49% females). Subjects received oral vitD3 (140,000 IU monthly) or placebo for 3 months. %Tregs within 20,000 CD4+ T cells of peripheral blood was determined by multi-parametric FACS-analysis. A liquid MMTT was carried out before and after treatment. %Tregs increased significantly in the vitD group, but remained unchanged in the placebo group. Fasting C-peptide concentrations did not change significantly in either group. Similarly, the mean AUC for C-peptide after 3 months and the change in mean values from baseline to the end of the treatment were comparable in both groups. A short time high dose vitD3 supplementation significantly increased the frequency of Tregs, but did not further improve β-cell function in apparently healthy subjects. The immunomodulatory potential of vitD might be an important mechanistic link for the association of vitD and T1D.

The Case for Intravenous Arginine Stimulation In Lieu of Mixed-Meal Tolerance Tests as Outcome Measure for Intervention Studies in Recent-Onset Type 1 Diabetes

Residual β-cell function in patients with type 1 diabetes has been generally determined by C-peptide response to stimulation by a liquid mixed-meal tolerance test (MMTT) or intravenous glucagon (1). Early trials assessed benefits of therapy by frequency and duration of the clinical remission phase in which minimal or no exogenous insulin was needed to maintain euglycemia (reviewed in 2). What is now needed is the most sensitive, and not necessarily the most physiologic measure, so that any improvement in β-cell function during a clinical trial can be detected. Both the MMTT and the intravenous glucagon test have practical limitations. The MMTT takes 2–4 h to complete, and the stimulus is subject to variations in gastrointestinal absorption, while the intravenous glucagon test often invokes nausea. In contrast, the use of intravenous arginine to stimulate and measure β-cell secretion takes only a few minutes to perform, circumvents gastrointestinal variation, and is clinically well tolerated. In addition, responses to this nonglucose secretagogue have been demonstrated to persist after the diagnosis of diabetes at a time when responses to glucose are gone (3–6). Our goal was to determine whether arginine-stimulated C-peptide could be used in lieu of MMTT as an outcome measure for intervention studies in recent-onset type 1 diabetes. Institutional review board approval and informed consent were obtained before the study began. Nineteen subjects between 7–42 and 1–24 …