The fat mass and obesity-associated (FTO) gene allele rs9939609 and glucose tolerance, hepatic and total insulin sensitivity, in adults with obesity

The objective of the study was to assess associations of the rs9939609 FTO allele to glucose tolerance, hepatic and total insulin sensitivity (IS) in individuals with obesity. From a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer, hepatic IS was assessed by rates of basal and suppressed glucose appearance (Ra), a measure of endogenous glucose production (EGP), and the hepatic insulin resistance index (HIR). Total IS was assessed by rates of glucose infusion (GIR), disappearance (Rd), and metabolic clearance (MCR). From a meal test we assessed IS by the Matsuda index and glucose tolerance by glucose and insulin measurements in the fasted state and postprandially for 2.5 h. The meal test was performed in 97 healthy individuals with BMI ≥35 in similar-sized risk-allele groups (n = 32 T/T, 31 A/T, and 34 A/A), and 79 of them performed the clamp. We analyzed outcomes separately for males and females, and adjusted glucose Ra, Rd, MCR, GIR, and HIR for fat mass. We did not find genotype effects on EGP. Among males, genotype A/A was associated with a significantly lower glucose Rd, MCR, and Matsuda index score relative to genotype T/T. Glucose tolerance was significantly lower in males with genotype A/T vs. T/T and A/A. For females, there were no genotype effects on hepatic or total IS, or on glucose tolerance. Independently of genotypes, females displayed a significantly better hepatic and total IS, and better glucose tolerance than males. We conclude that in subjects with similar obesity we did not register any FTO risk-allele effect on hepatic IS. A FTO risk-allele effect on total IS was registered in males only, findings which need to be reproduced in further studies. Results confirm marked differences in IS between the biological sexes and extend present knowledge by demonstrating a lower endogenous glucose production in females vs. males in uniformly obese individuals.

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Insulin sensitivity and body composition in cirrhosis: changes after TIPS

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00375.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. G486-G493 ◽

Cited By ~ 12

Author(s):

Peter Holland-Fischer ◽

Michael Festersen Nielsen ◽

Hendrik Vilstrup ◽

Dennis Tønner-Nielsen ◽

Anette Mengel ◽

...

Keyword(s):

Liver Cirrhosis ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Cell Mass ◽

Area Under The Curve ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Endogenous Glucose

Insertion of a transjugular intrahepatic porto-systemic shunt (TIPS) increases body cell mass (BCM) in patients with liver cirrhosis. The responsible mechanism is unidentified, but may involve changes in insulin sensitivity and glucose metabolism. Eleven patients with liver cirrhosis were examined before and 6 mo after a TIPS procedure with bioimpedance analyses, 2-h oral glucose tolerance tests, and two-step hyperinsulinemic euglycemic clamp with tracer-determined endogenous glucose production. After TIPS, BCM increased by 4.8 kg [confidence interval (CI): 2.7–7.3]. Fasting (f)-insulin increased from 123 ± 81 to 193 ± 124 pmol/l ( P = 0.03), whereas f-glucose was unchanged (6.0 ± 0.8 vs. 6.2 ± 1.0 mmol/l). Glucose and insulin oral glucose tolerance test area under the curve increased by 14% (CI: 7–22%) and 53% (CI: 14–90%), respectively, P < 0.05. The C-peptide-to-insulin ratio decreased by 21% (CI: 8-35%, P = 0.01). Insulin sensitivity based on glucose infusion rate (4.69 ± 1.82 vs. 4.85 ± 2.37 mg·kg−1·min−1) and glucose tracer-based rate of disappearance were unchanged (5.01 ± 1.61 vs. 4.97 ± 2.13 mg·kg−1·min−1). Despite a further increase in peripheral hyperinsulinemia, f-endogenous glucose production did not change between study days (2.01 ± 0.42 vs. 2.42 ± 0.58 mg·kg−1·min−1) and was suppressed equally by insulin (1.1 ± 0.1 vs. 1.0 ± 0.1 mg·kg−1·min−1). Insulin clearance, growth hormone, cortisol, and glucagon levels were unchanged. BCM improvement did not correlate with the measured variables. After TIPS, BCM rose, despite enhanced hyperinsulinemia and aggravated glucose intolerance, but unchanged peripheral and hepatic insulin sensitivity. This apparent discrepancy may be ascribed to shunt-related decreased insulin exposure to the liver cells. However, the anabolic effect of TIPS seems not to be related to improvements in insulin sensitivity and remains mechanistically unexplained.

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Mechanisms Underlying the Pathogenesis of Isolated Impaired Glucose Tolerance in Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2016-1998 ◽

2016 ◽

Vol 101 (12) ◽

pp. 4816-4824 ◽

Cited By ~ 7

Author(s):

Ron T. Varghese ◽

Chiara Dalla Man ◽

Anu Sharma ◽

Ivan Viegas ◽

Cristina Barosa ◽

...

Keyword(s):

Glucose Tolerance ◽

Oral Glucose Tolerance Test ◽

Glucose Tolerance Test ◽

Fasting Glucose ◽

Glucose Production ◽

Tolerance Test ◽

Endogenous Glucose Production ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Endogenous Glucose

Context: Prediabetes is a heterogeneous disorder classified on the basis of fasting glucose concentrations and 2-hour glucose tolerance. Objective: We sought to determine the relative contributions of insulin secretion and action to the pathogenesis of isolated impaired glucose tolerance (IGT). Design: The study consisted of an oral glucose tolerance test and a euglycemic clamp performed in two cohorts matched for anthropometric characteristics and fasting glucose but discordant for glucose tolerance. Setting: An inpatient clinical research unit at an academic medical center. Patients or Other Participants: Twenty-five subjects who had normal fasting glucose (NFG) and normal glucose tolerance (NGT) and 19 NFG/IGT subjects participated in this study. Intervention(s): Subjects underwent a seven-sample oral glucose tolerance test and a 4-hour euglycemic, hyperinsulinemic clamp on separate occasions. Glucose turnover during the clamp was measured using tracers, and endogenous hormone secretion was inhibited by somatostatin. Main Outcome Measures: We sought to determine whether hepatic glucose metabolism, specifically the contribution of gluconeogenesis to endogenous glucose production, differed between subjects with NFG/NGT and those with NFG/IGT. Results: Endogenous glucose production did not differ between groups before or during the clamp. Insulin-stimulated glucose disappearance was lower in NFG/IGT (24.6 ± 2.2 vs 35.0 ± 3.6 μmol/kg/min; P = .03). The disposition index was decreased in NFG/IGT (681 ± 102 vs 2231 ± 413 × 10−14 dL/kg/min2 per pmol/L; P < .001). Conclusions: We conclude that innate defects in the regulation of glycogenolysis and gluconeogenesis do not contribute to NFG/IGT. However, insulin-stimulated glucose disposal is impaired, exacerbating defects in β-cell function.

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Improved tolerance to sequential glucose loading (Staub-Traugott effect): size and mechanisms

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00127.2009 ◽

2009 ◽

Vol 297 (2) ◽

pp. E532-E537 ◽

Cited By ~ 50

Author(s):

Sandra Bonuccelli ◽

Elza Muscelli ◽

Amalia Gastaldelli ◽

Elisabetta Barsotti ◽

Brenno D. Astiarraga ◽

...

Keyword(s):

Glucose Tolerance ◽

Plasma Glucose ◽

Cell Function ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Fat Free Mass ◽

Oral Glucose ◽

Glucose Response ◽

Glucose Loading ◽

Endogenous Glucose

Improved glucose tolerance to sequential glucose loading (Staub-Traugott effect) is an important determinant of day-to-day glycemic exposure. Its mechanisms have not been clearly established. We recruited 17 healthy volunteers to receive two sequential oral glucose tolerance tests (OGTTs), at time 0 min and 180 min ( Study I). The protocol was repeated on a separate day ( Study II) except that plasma glucose was clamped at 8.3 mmol/l between 60 and 180 min. β-Cell function was analyzed by mathematical modeling of C-peptide concentrations. In a subgroup, glucose kinetics were measured by a triple-tracer technique (infusion of [6,6-2H2]glucose and labeling of the 2 glucose loads with [1-2H]glucose and [U-13C]glucose). In both Studies I and II, the plasma glucose response to the second OGTT equaled 84 ± 2% ( P = 0.003) of the response to the first OGTT. Absolute insulin secretion was lower (37.8 ± 4.3 vs. 42.8 ± 5.1 nmol/m2, P = 0.02), but glucose potentiation (i.e., higher secretion at the same glycemia) was stronger (1.08 ± 0.02- vs. 0.92 ± 0.02-fold, P = 0.006), the increment being higher in Study II (+36 ± 5%) than Study I (+19 ± 6%, P < 0.05). In pooled data, a higher glucose area during the first OGTT was associated with a higher potentiation during the second OGTT (rho=0.60, P = 0.002). Neither insulin clearance nor glucose clearance differed between loads, and appearance of glucose over 3 h totalled 60 ± 6 g for the first load and 52 ± 5 g for the second load ( P = not significant). Fasting endogenous glucose production [13.3 ± 0.6 μmol·min−1·kg fat-free mass (FFM)−1] averaged 6.0 ± 3.8 μmol·min−1·kg FFM−1 between 0 and 180 min and 1.7 ± 2.6 between 180 and 360 min ( P < 0.03). Glucose potentiation and stronger suppression of endogenous glucose release are the main mechanisms underlying the Staub-Traugott effect.

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Model-based assessment of insulin sensitivity of glucose disposal and endogenous glucose production from double-tracer oral glucose tolerance test

Computer Methods and Programs in Biomedicine ◽

10.1016/j.cmpb.2007.06.003 ◽

2008 ◽

Vol 89 (2) ◽

pp. 132-140 ◽

Cited By ~ 10

Author(s):

Karl Thomaseth ◽

Alessandra Pavan ◽

Rachele Berria ◽

Leonard Glass ◽

Ralph DeFronzo ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Tolerance Test ◽

Glucose Production ◽

Tolerance Test ◽

Endogenous Glucose Production ◽

Glucose Disposal ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Endogenous Glucose

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Impact of sleep restriction on metabolic outcomes induced by overfeeding: a randomized controlled trial in healthy individuals

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy215 ◽

2019 ◽

Vol 109 (1) ◽

pp. 17-28 ◽

Cited By ~ 2

Author(s):

Jérémy Cros ◽

Enea Pianezzi ◽

Robin Rosset ◽

Léonie Egli ◽

Philippe Schneiter ◽

...

Keyword(s):

Glucose Tolerance ◽

Glucose Tolerance Test ◽

Glucose Production ◽

Tolerance Test ◽

Endogenous Glucose Production ◽

Hepatic Insulin Resistance ◽

Sleep Restriction ◽

Oral Glucose ◽

Normal Sleep ◽

Endogenous Glucose

ABSTRACT Background Overconsumption of energy-dense foods and sleep restriction are both associated with the development of metabolic and cardiovascular diseases, but their combined effects remain poorly evaluated. Objective The aim of this study was to assess whether sleep restriction potentiates the effects of a short-term overfeeding on intrahepatocellular lipid (IHCL) concentrations and on glucose homeostasis. Design Ten healthy subjects were exposed to a 6-d overfeeding period (130% daily energy needs, with 15% extra energy as sucrose and 15% as fat), with normal sleep (8 h sleep opportunity time) or sleep restriction (4 h sleep opportunity time), according to a randomized, crossover design. At baseline and after intervention, IHCL concentrations were measured by proton magnetic resonance spectroscopy, and a dual intravenous [6,6-2H2]-, oral 13C-labeled glucose tolerance test and a polysomnographic recording were performed. Results Overfeeding significantly increased IHCL concentrations (Poverfeeding < 0.001; overfeeding + normal sleep: +53% ± 16%). During the oral glucose tolerance test, overfeeding significantly increased endogenous glucose production (Poverfeeding = 0.034) and the oxidation of 13C-labeled glucose load (Poverfeeding = 0.038). Sleep restriction significantly decreased total sleep time, and the duration of stages 1 and 2 and rapid eye movement sleep (all P < 0.001), whereas slow-wave sleep duration was preserved (Poverfeeding × sleep = 0.809). Compared with overfeeding, overfeeding + sleep restriction did not change IHCL concentrations (Poverfeeding × sleep = 0.541; +83% ± 33%), endogenous glucose production (Poverfeeding × sleep = 0.567), or exogenous glucose oxidation (Poverfeeding × sleep = 0.118). Sleep restriction did not significantly alter blood pressure, heart rate, or plasma cortisol concentrations (all Poverfeeding × sleep = NS). Conclusions Six days of a high-sucrose, high-fat overfeeding diet significantly increased IHCL concentrations and increased endogenous glucose production, suggesting hepatic insulin resistance. These effects of overfeeding were not altered by sleep restriction. This trial was registered at clinicaltrials.gov as NCT02075723. Other study ID numbers: SleepDep 02/14.

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