Glucose Metabolism In Obese Subjects Research Articles

MON-115 Acute BAT Activation Improves Glucose Tolerance and Beta-Cell Secretion and Facilities Lipid over Glucose Utilization in Obese Metabolically Healthy Males

Background: Cold-activated brown adipose tissue (BAT) in humans is associated with improved insulin sensitivity and lipid metabolism, at least in lean individuals (1). Metabolic effects of acute cold-induced BAT activation in obese individuals are less characterized. Here, we studied the effects of acute cold-induced BAT activation on energy metabolism and aimed to identify underlying transcriptional mechanisms in obese males. Methods: Fourteen metabolically healthy obese subjects (age 25.3±0.8 years; BMI 32.6±0.92 kg/m2) participated in a cross-balanced within-subject study, with two experimental conditions. Using a water-perfused suit, subjects were exposed to thermoneutrality (25°C) and to moderate cold (16.07°C, shivering excluded) according to a protocol validated for BAT activation. Glucose and lipid metabolism as well as relevant hormones were measured. Glucose tolerance and insulin sensitivity were assessed by Botnia clamp. Moreover, the expression of 7 selected genes within lipolytic and β-oxidation pathways (i.e. PDK4, CPT1α and CPT1β, G0S2, FFAR4, SLC25A20 and PPARα) were determined from circulating blood cells. Major results: Upon moderate cold exposure, noradrenaline and dopamine markedly increased relative to thermoneutrality (p<0.001 and p=0.008, respectively), while fT4 decreased (p=0.012). Compared to thermoneutrality, fasting glucose was significantly decreased upon moderate cold exposure (p=0.03). The AUC of plasma glucose was reduced following the glucose challenge (total AUC p=0.009) and larger concentrations of serum insulin were found both during the first 30 minutes of the ivGTT and over its entire duration (AUC t0-t30 p=0.002, total AUC p<0.001). Circulating TG were increased upon exposure to moderate cold (p=0.034) but no changes were observed in total cholesterol, HDL or LDL (all p>0.442). Moderate cold increased relative expression levels of PDK4, CPT1α, SLC25A20 and G0S2 (p=0.006, p=0.017, p=0.041 and p=0.002, respectively) but no changes were observed for CPT1β, FFR4 and PPARα expressions (all p>0.065). Results interpretation and conclusion: Acute cold-induced BAT activation exerts beneficial effects on glucose metabolism in obese subjects although not on insulin sensitivity, as described in normal weight humans (2). Furthermore, here we showed that these effects might be fostered by a shift towards lipolysis and β-oxidation pathways. Reference: (1) Betz MJ et al., Diabetes. 2015;64(7):2352-60. (2) Iwen KA et al., JCEM. 2017;102(11):4226-4234 Sources of Research Support: Deutsche Forschungsgemeinschaft, project GRK1957 Adipocyte-Brain Crosstalk (grant to SMS)

γ-Glutamyltransferase Fractions in Obese Subjects with Type 2 Diabetes: Relation to Insulin Sensitivity and Effects of Bariatric Surgery.

Gamma-glutamyltranspeptidase (GGT) levels are an independent risk marker for the development of type 2 diabetes (T2DM). We investigated the relationship between the newly identified serum GGT fractions and glucose metabolism in obese subjects before and after bariatric surgery. Twenty-nine T2DM subjects, wait-listed for Roux-en-Y gastric bypass (RYGB; n = 21) or laparoscopic sleeve gastrectomy (LSG; n = 8), received a 5-h mixed meal test before (T0), 15days (T15), and 1year after surgery (T365). Insulin sensitivity was assessed by the OGIS index and β-cell function by C-peptide analysis; fractional GGT (b-, s-, m-, and f-GGT) analysis was performed by gel-filtration chromatography. At T15, total GGT activity decreased by 40% after LSG (p = 0.007) but remained unchanged after RYGB. At T365, all patients showed a reduction in total GGT, in particular b-GGT (≥ 60%) and m-GGT (≥ 50%). In patients with biopsy-proven steatohepatitis (n = 10), total, b-, s-, and m-GGT fractions at T0 were significantly higher than in patients with low-grade steatosis (p = 0.016, 0.0003, and 0.005, respectively); at T365, there was a significant fall in total GGT as well as in each fraction in both groups. In a multiple regression model, b-GGT was the only fraction related to insulin sensitivity (p = 0.016; β coeff. = - 14.0) independently of BMI, fasting glucose, and triglycerides. While GGT activity is generally associated with impaired glucose metabolism, fractional GGT analysis showed that the b-GGT fraction specifically and independently tracks with insulin resistance.

Study of obesity associated proopiomelanocortin gene polymorphism: Relation to metabolic profile and eating habits in a sample of obese Egyptian children and adolescents

BackgroundMelanocortinergic system represents a known system involved in the central regulation of body weight with the central proopiomelanocortin (POMC) neurons forming a potent anorexigenic network. Polymorphisms in the POMC gene locus are associated with obesity phenotypes. AimTo assess the contribution of the POMC gene 9-bp insertional polymorphism in the susceptibility to obesity and its relation to body mass index (BMI) and adiposity-related co-morbidities in obese children and adolescents; as well as binge eating behavior. Patients and methodsFifty obese children and adolescents with simple obesity were screened for Binge Eating Disorder (BED) by The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), they were compared to 50 age, sex and pubertal stage-matched non obese controls. Anthropometric measurements, blood pressure, abdominal ultrasound for fatty liver, measurement of fasting lipid profile, fasting insulin, fasting blood glucose and assessment of POMC gene 9-bp insertional polymorphism were done. ResultsObese patients had significantly higher anthropometric measurements, blood pressure percentiles, fasting glucose, fasting insulin, homeostasis model assessment for insulin resistance (HOMA-IR) and fasting lipid profiles, and higher frequency of occurrence of non alcoholic fatty liver disease and BED. Allelic frequencies of POMC gene 9bp insertional polymorphism were comparable in patients and controls (p=0.956). Fasting insulin levels were significantly higher in the heterozygous cases having the polymorphism than in wild homozygous cases; whereas no difference was observed among the controls. ConclusionThis polymorphism was associated with higher fasting insulin levels in the obese patients only. These findings support the hypothesis that the melanocortin pathway may modulate glucose metabolism in obese subjects indicating a possible gene-environment interaction. POMC variant may be involved in the natural history of polygenic obesity, contributing to the link between type 2 diabetes and obesity.

Effects of Diet-Induced Moderate Weight Reduction on Intrahepatic and Intramyocellular Triglycerides and Glucose Metabolism in Obese Subjects

Although moderate weight reduction is recommended as primary therapy of metabolic syndrome, little information is known regarding metabolic changes associated with moderate weight reduction in nondiabetic obese subjects. The aim of this study was to determine the effects of a moderate weight reduction program on intracellular lipid and glucose metabolism in muscle and liver. Data for 13 nondiabetic obese subjects were evaluated. Subjects were put on a 3-month mildly hypocaloric diet therapy (approximately 35 kcal/kg of ideal body weight). Intrahepatic lipid (IHL) and intramyocellular lipid were measured by using (1)H magnetic resonance spectroscopy. Peripheral insulin sensitivity and splanchnic glucose uptake were evaluated by euglycemic-hyperinsulinemic clamp with oral glucose load. Diet therapy for 3 months resulted in 6% reduction in body weight (from 99.9 +/- 7.3 to 93.8 +/- 6.6 kg, P < 0.0001). This change was accompanied by reduction of plasma glucose and insulin excursions during 75-g oral glucose tolerance tests, decrease in diastolic blood pressure, glycated hemoglobin, serum low-density lipoprotein cholesterol, and triglyceride. These changes were also accompanied by a decrease in IHL (from 12.9 to 8.2%, P < 0.01) and increase in splanchnic glucose uptake (from 13.5 to 35.0%, P < 0.03). On the other hand, the diet program did not affect intramyocellular lipid or glucose infusion rate during euglycemic hyperinsulinemic clamp. Our results suggest that moderate weight reduction in obese subjects decreased IHL and augmented splanchnic glucose uptake. This mechanism is at least in part involved in improvement of glucose metabolism by moderate weight reduction in obese subjects.

An insertional polymorphism of the proopiomelanocortin gene is associated with fasting insulin levels in childhood obesity.

Lines of evidence show a role of the melanocortinergic system in the regulation of glucose metabolism in obese subjects. The aim of this study was to investigate the influence of proopiomelanocortin (POMC) in the variability of insulin levels in early-onset obesity. To address this issue, an association study using a 9-bp insertional polymorphism, AGC AGC GGC, between nucleotides 6979 and 6998 of the POMC gene, was performed in 380 (185 girls) Italian obese children and adolescents. Allelic frequencies were comparable in our patients (0.053) and in 300 lean controls of Mediterranean descent (0.045). Interestingly, we showed that this polymorphism, in the obese patients, was associated with differences in fasting insulin levels; this finding persisted after correction for age, sex, and pubertal stage. Heterozygotes had 24% higher mean insulin levels than those homozygous for the wild allele and showed a stronger correlation between insulin and body mass index (P < 0.001). These findings support the hypothesis that the melanocortin pathway may modulate glucose metabolism in obese subjects and suggest that this common POMC variant may be involved in the natural history of polygenic obesity in late adolescence and adulthood, contributing to the link between type 2 diabetes and obesity.

The effect of starvation on leucine, alanine and glucose metabolism in obese subjects

The relationship between changes in ketone concentrations and leucine metabolism (seven obese subjects), glucose and alanine metabolism (seven obese subjects) was investigated using radioisotopic techniques after 12 h, 60 h and 2 weeks starvation. Leucine metabolism was also measured in five lean subjects after 12 h and 60 h starvation. In the obese subjects leucine concentration increased after 60 h starvation and leucine metabolic clearance rate, glucose and alanine concentration decreased (P < 0.05). Glucose and alanine production rate (Ra) decreased after 2 weeks (P < 0.05) but there was no change in leucine Ra after 60 h or 2 weeks. In the lean subjects leucine concentration, production rate and oxidation rate were increased after 60 h (P < 0.005, P < 0.05, P < 0.05). Ketone concentration was inversely related to alanine Ra (r = -0.51, P < 0.02) but was not related to measurements of protein metabolism in the obese subjects. This study demonstrates that the effect of short-term starvation on protein metabolism differs in lean and obese subjects. The decrease in glucose Ra during long-term starvation may be in part due to a decreased supply of alanine for gluconeogenesis.

Augmented effect of short-term pulsatile versus continuous insulin delivery on lipid metabolism but similar effect on whole-body glucose metabolism in obese subjects

The present study was designed to examine the effect of pulsatile versus continuous insulin delivery on glucose and lipid metabolism in insulin-resistant subjects. Six obese women (body mass index, 40.0 ± 2.8 kg/m 2) underwent a euglycemic glucose clamp (plasma glucose, 90 mg/dL) twice. In random order, insulin was infused intravenously for 375 minutes either at a constant rate (0.4 mU/kg/min) or in a pulsatile manner (2.4 mU/kg/min for 2 minutes followed by an off interval of 10 minutes). Endogenous insulin release was suppressed by infusion of somatostatin (250 μg/h). Mean circulating insulin concentrations were similar during the two protocols (pulsatile v continuous infusion, 60 ± 10 v 56 ± 9 mU/L), but pulsatile infusion was accompanied by oscillations with an amplitude of 120 mU/L. After 6 hours of pulsatile versus continuous insulin, isotopically determined total glucose disposal (3- 3H-glucose) and hepatic glucose production (HGP) were comparable (pulsatile v continuous, 2.80 ± 0.56 v 2.82 ± 0.51 and 0.37 ± 0.14 v 0.32 ± 0.17 mg/kg/min). However, the rate of glucose oxidation (indirect calorimetry) was augmented ( P < .05), whereas lipid oxidation tended to be diminished (.10 > P > .05) following pulsatile infusion. In addition, blood glycerol was more suppressed with pulsatile (31 ± 9 nmol/L) than with continuous infusion (36 ± 10 nmol/L, P < .05), whereas blood lactate, alanine, and 3-hydroxybutyrate were similar in the two infusion protocols. Lipoprotein lipase (LPL) activity in abdominal adipose tissue (taken at 375 minutes) was significantly increased following pulsatile insulin delivery (pulsatile v continuous infusion, 707 ± 120 v 474 ± 87 nmol/nonesterified fatty acids [NEFA]/h/g, P < .05). Thus, in obese individuals pulsatile insulin exposure for approximately 6 hours has a greater impact on lipid metabolism than an equimolar amount of insulin infused at a constant rate. Both a greater suppression of lipolysis and activation of LPL occurred, implying presumably an increased rate of reesterification of NEFA. In contrast, whole-body insulin-stimulated glucose disposal and suppression of HGP were similar with pulsatile and constant insulin administration.