Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study

Objective: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. Research Design and Methods: Glucagon was measured in three randomized, parallel, clinical studies: (1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; (2) 267 adults studied at the same timepoints and treated with MET, G/M, liraglutide plus metformin (L+M) or placebo (PLAC); and (3) 88 adults studied at baseline, and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs). Results: No change in fasting glucagon, steady-state glucagon or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all p≤0.005), which was maintained three months after treatment withdrawal (all p<0.01). LB in adults also reduced fasting glucagon, steady-state glucagon and AGR at 12 and 24 months (p<0.05 for all, except AGR at 12 months [p=0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. Conclusions: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributed to weight loss in both interventions.

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Association of postprandial and fasting triglycerides with traits of the metabolic syndrome in the Metabolic Intervention Cohort Kiel

Acta Endocrinologica ◽

10.1530/eje-09-0446 ◽

2010 ◽

Vol 162 (4) ◽

pp. 719-727 ◽

Cited By ~ 10

Author(s):

Diana Rubin ◽

Ulf Helwig ◽

Michael Nothnagel ◽

Ulrich R Fölsch ◽

Stefan Schreiber ◽

...

Keyword(s):

Metabolic Syndrome ◽

Lipid Metabolism ◽

Cell Function ◽

International Diabetes Federation ◽

Tolerance Test ◽

Oral Glucose ◽

Middle Aged ◽

The Metabolic Syndrome ◽

Β Cell Function ◽

Design And Methods

ObjectivePostprandial (pp) lipid metabolism is associated with insulin resistance and type 2 diabetes. In young men, pp triglycerides (TGs) are more strongly associated with traits of metabolic syndrome (MS) than fasting TGs. We established a cohort of middle-aged men selected for traits of MS and pp lipid metabolism to determine if fasting TGs or pp TGs are more closely related to MS.Research design and methodsA total of 1558 men were characterized for MS. A total of 755 men underwent an oral metabolic tolerance test consisting of a standardized high-fat meal and an oral glucose tolerance test. Blood samples were drawn in the fasting state and hourly until 9 h to determine pp TGs and free fatty acids. Glucose and insulin were analyzed until 5 h pp.ResultsIn the overall cohort, 329 subjects (21.1%) had a complete MS based on the Adult Treatment Panel III criteria, and 650 subjects (41.7%) had a complete MS based on the International Diabetes Federation criteria. The association of pp TGs with MS parameters was not stronger than the association of fasting TGs with them. Pp TGs were independently associated with β-cell function.ConclusionsPp TGs did not show a higher correlation with MS traits than fasting TGs. This finding is probably due to the high incidence of overweight subjects in this middle-aged cohort.

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Diminished glucagon suppression after β-cell reduction is due to impaired α-cell function rather than an expansion of α-cell mass

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00315.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. E717-E723 ◽

Cited By ~ 24

Author(s):

Juris J. Meier ◽

Sandra Ueberberg ◽

Simone Korbas ◽

Stephan Schneider

Keyword(s):

Insulin Treatment ◽

Cell Function ◽

Cell Mass ◽

Glucagon Secretion ◽

Pancreatic Tissue ◽

Oral Glucose ◽

Inverse Association ◽

Β Cell ◽

Glucose Ingestion ◽

Glucagon Suppression

Impaired suppression of glucagon levels after oral glucose or meal ingestion is a hallmark of type 2 diabetes. Whether hyperglucagonemia after a β-cell loss results from a functional upregulation of glucagon secretion or an increase in α-cell mass is yet unclear. CD-1 mice were treated with streptozotocin (STZ) or saline. Pancreatic tissue was collected after 14, 21, and 28 days and examined for α- and β-cell mass and turnover. Intraperitoneal (ip) glucose tolerance tests were performed at day 28 as well as after 12 days of subcutaneous insulin treatment, and glucose, insulin, and glucagon levels were determined. STZ treatment led to fasting and post-challenge hyperglycemia ( P < 0.001 vs. controls). Insulin levels increased after glucose injection in controls ( P < 0.001) but were unchanged in STZ mice ( P = 0.36). Intraperitoneal glucose elicited a 63.1 ± 4.1% glucagon suppression in control mice ( P < 0.001), whereas the glucagon suppression was absent in STZ mice ( P = 0.47). Insulin treatment failed to normalize glucagon levels. There was a significant inverse association between insulin and glucagon levels after ip glucose ingestion ( r2 = 0.99). β-Cell mass was reduced by ∼75% in STZ mice compared with controls ( P < 0.001), whereas α-cell mass remained unchanged ( P > 0.05). α-Cell apoptosis (TUNEL) and replication (Ki67) were rather infrequently noticed, with no significant differences between the groups. These studies underline the importance of endogenous insulin for the glucose-induced suppression of glucagon secretion and suggest that the insufficient decline in glucagon levels after glucose administration in diabetes is primarily due to a functional loss of intraislet inhibition of α-cell function rather than an expansion of α-cell mass.

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Role of the Gut in the Temporal Changes of β-Cell Function After Gastric Bypass in Individuals With and Without Diabetes Remission

10.2337/figshare.16989505 ◽

2021 ◽

Author(s):

Malini Prasad ◽

Victoria Mark ◽

Chanel Ligon ◽

Roxanne Dutia ◽

Nandini Nair ◽

...

Keyword(s):

Weight Loss ◽

Gastric Bypass ◽

Insulin Sensitivity ◽

Cell Function ◽

Diabetes Remission ◽

Oral Glucose ◽

Β Cell ◽

Remission Status ◽

Β Cell Function

Objective: The role of the gut in diabetes remission after gastric bypass (RYGB) is incompletely understood. We therefore assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. Research Design and Methods: Longitudinal, prospective measures of β-cell function after oral glucose and IV graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n=29), 12 (n=24) and 24 (n=20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center. Results: The decreases in body weight, fat mass, waist circumference and insulin resistance after surgery (all p<0.001 at 12 and 24 months), did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in β-cell glucose sensitivity after oral glucose differed by remission status (p=0.04): greater (6.5 fold, p<0.01) and sustained in full remitters, moderate and not sustained past 12 months in partial remitters (3.3 fold, p<0.001), minimal in non-remitters (2.7 fold, p=ns). The improvement in β-cell function after IV glucose was not apparent until 12 months, significant only in full remitters, and only ~1/3 of that observed after oral glucose. Pre-intervention β-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. Conclusion: Our data show the time course of changes in β-cell function after RYGB. The improvement in β-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.

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Impaired Glucose-Induced Glucagon Suppression after Partial Pancreatectomy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0826 ◽

2009 ◽

Vol 94 (8) ◽

pp. 2857-2863 ◽

Cited By ~ 16

Author(s):

Henning Schrader ◽

Bjoern A. Menge ◽

Thomas G. K. Breuer ◽

Peter R. Ritter ◽

Waldemar Uhl ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Plasma Concentrations ◽

Cell Mass ◽

Oral Glucose ◽

Partial Pancreatectomy ◽

C Peptide ◽

Glucose Ingestion ◽

Glucagon Suppression

Introduction: The glucose-induced decline in glucagon levels is often lost in patients with type 2 diabetes. It is unclear whether this is due to an independent defect in α-cell function or secondary to the impairment in insulin secretion. We examined whether a partial pancreatectomy in humans would also impair postchallenge glucagon concentrations and, if so, whether this could be attributed to the reduction in insulin levels. Patients and Methods: Thirty-six patients with pancreatic tumours or chronic pancreatitis were studied before and after approximately 50% pancreatectomy with a 240-min oral glucose challenge, and the plasma concentrations of glucose, insulin, C-peptide, and glucagon were determined. Results: Fasting and postchallenge insulin and C-peptide levels were significantly lower after partial pancreatectomy (P < 0.0001). Likewise, fasting glucagon concentrations tended to be lower after the intervention (P = 0.11). Oral glucose ingestion elicited a decline in glucagon concentrations before surgery (P < 0.0001), but this was lost after partial pancreatectomy (P < 0.01 vs. preoperative values). The loss of glucose-induced glucagon suppression was found after both pancreatic head (P < 0.001) and tail (P < 0.05) resection. The glucose-induced changes in glucagon levels were closely correlated to the respective increments in insulin and C-peptide concentrations (P < 0.01). Conclusions: The glucose-induced suppression in glucagon levels is lost after a 50% partial pancreatectomy in humans. This suggests that impaired α-cell function in patients with type 2 diabetes may also be secondary to reduced β-cell mass. Alterations in glucagon regulation should be considered as a potential side effect of partial pancreatectomies.

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Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

10.2337/figshare.13103027.v1 ◽

2020 ◽

Author(s):

Paola Lucidi ◽

Paola Candeloro ◽

Patrizia Cioli ◽

Anna Marinelli Andreoli ◽

Chiara Pascucci ◽

...

Keyword(s):

Type 1 Diabetes ◽

Steady State ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Glucagon Suppression ◽

Bolus Insulin ◽

Design And Methods ◽

Single Blind ◽

Randomized Crossover Study

OBJECTIVE To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m2], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg-1) and <a>Deg-100 </a>(0.26±0.06 U.Kg-1), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin. RESULTS At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR(0-24h)] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92). CONCLUSIONS In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.

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Stimulated Insulin Secretion Predicts Changes in Body Composition Following Weight Loss in Adults with High BMI

Journal of Nutrition ◽

10.1093/jn/nxab315 ◽

2021 ◽

Author(s):

Julia M W Wong ◽

Shui Yu ◽

Clement Ma ◽

Tapan Mehta ◽

Stephanie L Dickinson ◽

...

Keyword(s):

Weight Loss ◽

Body Composition ◽

Insulin Secretion ◽

Lean Mass ◽

Linear Models ◽

Obesity Treatment ◽

Oral Glucose ◽

Low Carbohydrate ◽

Composition Changes ◽

High Bmi

ABSTRACT Background The aim of obesity treatment is to promote loss of fat relative to lean mass. However, body composition changes with calorie restriction differ among individuals. Objectives The goal of this study was to test the hypothesis that insulin secretion predicts body composition changes among young and middle-age adults with high BMI (in kg/m2) following major weight loss. Methods Exploratory analyses were conducted with pre-randomization data from 2 large feeding trials: the Framingham, Boston, Bloomington, Birmingham, and Baylor study (FB4; n = 82, 43.9% women, BMI ≥27) and the Framingham State Food Study [(FS)2; n = 161, 69.6% women, BMI ≥25]. Participants in the 2 trials consumed calorie-restricted moderate-carbohydrate or very-low-carbohydrate diets to produce 12–18% weight loss in ∼14 wk or 10–14% in ∼10 wk, respectively. We determined insulin concentration 30 min after a 75-g oral glucose load (insulin-30) as a measure of insulin secretion and HOMA-IR as a measure of insulin resistance at baseline. Body composition was determined by DXA at baseline and post–weight loss. Associations were analyzed using general linear models with adjustment for covariates. Results In FB4, higher insulin-30 was associated with a smaller decrease in fat mass (0.441 kg per 100 μIU/mL increment in baseline insulin-30; P = 0.005; –1.20-kg mean difference between the first compared with the fifth group of insulin-30) and a larger decrease in lean mass (–0.465 kg per 100 μIU/mL; P = 0.004; 1.27-kg difference). Participants with higher insulin-30 lost a smaller proportion of weight loss as fat (–3.37% per 100 μIU/mL; P = 0.003; 9.20% difference). Greater HOMA-IR was also significantly associated with adverse body composition changes. Results from (FS)2 were qualitatively similar but of a smaller magnitude. Conclusions Baseline insulin dynamics predict substantial individual differences in body composition following weight loss. These findings may inform understanding of the pathophysiological basis for weight regain and the design of more effective obesity treatment. Registered at clinicaltrials.gov as NCT03394664 and NCT02068885.

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Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

10.2337/figshare.13103027 ◽

2020 ◽

Author(s):

Paola Lucidi ◽

Paola Candeloro ◽

Patrizia Cioli ◽

Anna Marinelli Andreoli ◽

Chiara Pascucci ◽

...

Keyword(s):

Type 1 Diabetes ◽

Steady State ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Glucagon Suppression ◽

Bolus Insulin ◽

Design And Methods ◽

Single Blind ◽

Randomized Crossover Study

OBJECTIVE To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m2], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg-1) and <a>Deg-100 </a>(0.26±0.06 U.Kg-1), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin. RESULTS At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR(0-24h)] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92). CONCLUSIONS In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.

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Role of the Gut in the Temporal Changes of β-Cell Function After Gastric Bypass in Individuals With and Without Diabetes Remission

10.2337/figshare.16989505.v1 ◽

2021 ◽

Author(s):

Malini Prasad ◽

Victoria Mark ◽

Chanel Ligon ◽

Roxanne Dutia ◽

Nandini Nair ◽

...

Keyword(s):

Weight Loss ◽

Gastric Bypass ◽

Insulin Sensitivity ◽

Cell Function ◽

Diabetes Remission ◽

Oral Glucose ◽

Β Cell ◽

Remission Status ◽

Β Cell Function

Objective: The role of the gut in diabetes remission after gastric bypass (RYGB) is incompletely understood. We therefore assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. Research Design and Methods: Longitudinal, prospective measures of β-cell function after oral glucose and IV graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n=29), 12 (n=24) and 24 (n=20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center. Results: The decreases in body weight, fat mass, waist circumference and insulin resistance after surgery (all p<0.001 at 12 and 24 months), did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in β-cell glucose sensitivity after oral glucose differed by remission status (p=0.04): greater (6.5 fold, p<0.01) and sustained in full remitters, moderate and not sustained past 12 months in partial remitters (3.3 fold, p<0.001), minimal in non-remitters (2.7 fold, p=ns). The improvement in β-cell function after IV glucose was not apparent until 12 months, significant only in full remitters, and only ~1/3 of that observed after oral glucose. Pre-intervention β-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. Conclusion: Our data show the time course of changes in β-cell function after RYGB. The improvement in β-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.

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Prediction of Tire Tread Wear with FEM Steady State Rolling Contact Simulation

Tire Science and Technology ◽

10.2346/1.2135268 ◽

2003 ◽

Vol 31 (3) ◽

pp. 189-202 ◽

Cited By ~ 24

Author(s):

D. Zheng

Keyword(s):

Weight Loss ◽

Steady State ◽

Cross Section ◽

Rolling Contact ◽

Dynamic Simulations ◽

Element Analysis ◽

Vehicle Acceleration ◽

Steady State Rolling ◽

Driving Conditions ◽

Rate Profile

Abstract A procedure based on steady state rolling contact Finite Element Analysis (FEM) has been developed to predict tire cross section tread wear profile under specified vehicle driving conditions. This procedure not only considers the tire construction effects, it also includes the effects of materials, vehicle setup, test course, and driver's driving style. In this algorithm, the vehicle driving conditions are represented by the vehicle acceleration histogram. Vehicle dynamic simulations are done to transform the acceleration histogram into tire loading condition distributions for each tire position. Tire weight loss rates for different vehicle accelerations are generated based on a steady state rolling contact simulation algorithm. Combining the weight loss rate and the vehicle acceleration histogram, nine typical tire loading conditions are chosen with different weight factors to represent tire usage conditions. It is discovered that the tire tread wear rate profile is changing continuously as the tire is worn. Simulation of a new tire alone cannot be used to predict the tire cross-section tread wear profile. For this reason, an incremental tread wear simulation procedure is performed to predict the tire cross section tread wear profile. Compared with actual tire cross-section tread wear profiles, good results are obtained from the simulations.

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