Glucose Metabolism In Obese Patients Research Articles

2003-P: Triiodothyronine and Free Thyroxine Levels Combined with Thyroid-Stimulating Hormone Are Associated with Glucose Metabolism in Obese Patients with Euthyroid Function

Purpose: To present thyroid hormones (THs) cutoff values to assess the association of THs and glucose metabolism in obese patients with euthyroid function. Methods: This study investigated 445 obese patients (235 females and 210 males) with euthyroid function received treatment in the department of endocrinology of shanghai 10th people’s hospital from 2011 to 2019, with the median age of 29 years (interquartile range 22-35 years). The cut-offs for thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were 2mIU/L, 16mIU/L, and 5mIU/L, respectively. Results: Fasting blood glucose (FBG) and 2h-glucose (BG120) were significantly higher in low FT3 (P<0.05) and high FT4 patients (P<0.05). In patients with TSH under 2mIU/L, a low FT3 group was robustly associated with higher FBG and BG120 levels (P<0.05). In patients with TSH under 1.5mIU/L, additional association with lower fasting and 2h-insulin (P<0.05) could be found. FT3 had no predictive value in high TSH patients. In patients TSH over 1.5 or 2mIU/L, a high FT4 group was robustly associated with higher FBG and BG120 levels (P<0.05). FT4 had no predictive value in low TSH patients. Patients with TSH over 2mIU/L, high FT4 group had a crude odds ratio of 2.65(95% Confidence interval 1.40-5.03, P=0.003) for FBG compared with low FT4 and remained significant after adjustments for age, gender and body mass index. Similar results could be obtained in patients with TSH over 1.5mIU/L. Conclusions: A combination of TSH and FT4/FT3 instead of only one thyroid hormone indicator had predictive value of glucose metabolism in obese patients with euthyroid function. Disclosure J. Zhang: None. G. Li: None. X. Cheng: None. X. Wang: None. M. Jayachandran: None. Y. Huang: None. S. Qu: None. Funding National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677); Shanghai Pujiang Program (2019PJD040); Effect of ApoC3 High Expression on Islet Cells and Related Molecular Mechanism (03.05.18.002)

Effect of Dietary Macronutrients on Postprandial Glucagon and Insulin Release in Obese and Normal-Weight Women.

The aim of the study was to assess the effect of dietary macronutrients on circulating glucagon and insulin levels in obese and normal-weight women. Potentially, the impaired release of glucagon may proceed abnormal glucose metabolism in obese patients ahead of overt diabetes. In 20 insulin-sensitive women (11 obese and 9 normal-weight), plasma concentrations of insulin and glucagon levels were assessed before and after 3 different macronutrient test meals. AUCtotal insulin in the obese group was increased after protein and carbohydrates compared to fatty test meal consumption (3981 ± 2171 and 4869 ± 2784 vs. 2349 ± 1004 μIU∗h/m, p < 0.05, respectively), but without a difference between protein and carbohydrates ingestion. However, in the normal-weight group, AUCtotal insulin was increased after carbohydrates compared to fatty test meal ingestion (3929 ± 1719 vs. 2231 ± 509 μIU∗h/ml, p < 0.05) and similar after carbohydrate and protein as well as after fatty and protein test meals (3929 ± 1719 vs. 2231 ± 509 vs. 3046 ± 1406 μIU∗h/ml, respectively). However, AUCtotal insulin was significantly increased in obese compared to normal-weight women only after carbohydrate test meal ingestion (4869 ± 2784 vs. 3929 ± 1719 μIU∗h/ml, p < 0.05). AUCtotal glucagon was similar after carbohydrate, protein, and fatty test meals ingestion in obese and normal-weight women (921 ± 356 vs. 957 ± 368 vs. 926 ± 262 ng∗h/ml and 1196 ± 14 vs. 1360 ± 662 vs. 1792 ± 1176 ng∗h/ml, respectively). AUCtotal glucagon was significantly lower in obese than normal-weight women after a fatty meal (926 ± 262 vs. 1792 ± 1176 ng∗h/ml, p < 0.01). Postprandial glucagon secretion is not related to the macronutrient composition of the meal in normal-weight women since postprandial glucagon concentrations were stable and did not change after carbohydrate, protein, and fatty test meals. Lower glucagon secretion was observed in obese subjects after fatty meal consumption when compared to normal-weight subjects. Postprandial insulin profile was significantly higher after carbohydrate than fatty test meal intake in the obese group and did not differ between obese and normal-weight groups after carbohydrate, protein, and fatty test meals consumption. Impaired glucagon secretion after fatty meat suggests early pancreatic alpha-cell dysfunction, after a carbohydrate meal is a compensatory mechanism.

Preoperative Beta Cell Function Is Predictive of Diabetes Remission After Bariatric Surgery.

Bariatric surgery can improve glucose metabolism in obese patients with diabetes, but the factors that can predict diabetes remission are still under discussion. The present study aims to examine the impact of preoperative beta cell function on diabetes remission following surgery. We investigated a cohort of 363 obese diabetic patients who underwent bariatric surgery. The impact of several preoperative beta cell function indexes on diabetes remission was explored through bivariate logistic regression models. Postoperative diabetes remission was achieved in 39.9% of patients. Younger patients (p<0.001) and those with lower HbA1c (p=0.001) at the baseline evaluation had higher odds of diabetes remission. Use of oral anti-diabetics and insulin therapy did not reach statistical significance when they were adjusted for age and HbA1c. Among the evaluated indexes of beta cell function, higher values of insulinogenix index, Stumvoll first- and second-phase indexes, fasting C-peptide, C-peptide area under the curve (AUC), C-peptide/glucose AUC, ISR (insulin secretion rate) AUC, and ISR/glucose AUC predicted diabetes remission even after adjustment for age and HbA1c. Among them, C-peptide AUC had the higher discriminative power (AUC 0.76; p<0.001). Patients' age and preoperative HbA1c can forecast diabetes remission following surgery. Unlike other studies, our group found that the use of oral anti-diabetics and insulin therapy were not independent predictors of postoperative diabetes status. Preoperative beta cell function, mainly C-peptide AUC, is useful in predicting diabetes remission, and it should be assessed in all obese diabetic patients before bariatric or metabolic surgery.

Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients

Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

Effect of Low Calorie Diet and Controlled Fasting on Insulin Sensitivity and Glucose Metabolism in Obese Patients With Type 1 Diabetes Mellitus

Obesity in T1DM patients is associated with the components of metabolic syndrome. The influence of controlled fasting and low calorie diet (LCD) on insulin sensitivity and glucose metabolism was studied in 14 obese patients with type 1 diabetes mellitus (T1DM) (42.6+/-9.4 years, BMI 32.4+/-2.1 kg m(-2)). Insulin sensitivity in obese T1DM patients was measured using a hyperinsulinemic-euglycemic clamp before fasting, immediately after 7 days of fasting, and after 21 days of LCD. Glucose oxidation and non-oxidative glucose disposal were measured before and during the clamp by indirect calorimetry. In the control group of 13 of non-obese T1DM patients (36.9+/-13.9 years, BMI 22.6+/-2.1 kg m(-2)), only one hyperinsulinemic-euglycemic clamp was performed. Obese T1DM patients lost 6.1+/-1.1 kg after fasting and maintained reduction in body weight after 21 days of LCD. Fasting transiently reduced insulin-mediated glucose disposal in the clamp (from 9.69+/-1.48 to 6.78+/-1.21 mg min(-1) kg(-1), P<0.001). This was caused by reduced glucose oxidation after the fasting period (from 2.81+/-0.52 to 0.88+/-0.98 mg min(-1) kg(-1), P<0.001). We conclude that one week of fasting transiently decreased insulin-mediated glucose disposal in T1DM patients. This was caused by reduced glucose oxidation.

Alteration of JNK-1 Signaling in Skeletal Muscle Fails to Affect Glucose Homeostasis and Obesity-Associated Insulin Resistance in Mice

Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNKC). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNKC mice were crossed to Mck-Cre mice yielding JNKSM-C mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNKSM-C mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance.

Effect of laparoscopic Roux-en-Y gastric bypass on glucose metabolism in obese patients with type 2 diabetes mellitus

Effect of laparoscopic Roux-en-Y gastric bypass on glucose metabolism in obese patients with type 2 diabetes mellitus

Weight-Independent Changes in Blood Glucose Homeostasis After Gastric Bypass or Vertical Sleeve Gastrectomy in Rats

Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG. Rats underwent RYGB or VSG and were compared to sham-operated rats fed ad lib or pair-fed to animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function independent of incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance test was used to assess the effect of each surgery on postprandial release of glucagon-like peptide 1 (GLP-1)(7-36) and glucose tolerance, and was also performed in rats given GLP-1 receptor antagonist exendin(9-39). Following RYGB or VSG, glucose tolerance and insulin sensitivity improved in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7-36) and insulin were greatly and comparably increased in rats that received RYGB and VSG compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG. In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss.

A new life for bile acids

TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies invivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6alpha-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion invivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.

Determinants of Exercise-induced Fat Oxidation in Obese Women and Men

Endurance training at an intensity eliciting maximal fat oxidation may have a beneficial effect on body weight and glucose metabolism in obese patients. However, the exercise intensity at which maximal fat oxidation occurs and the factors limiting fat oxidation are not well studied in this population. Obese, otherwise healthy men (n=38) and women (n=91) performed an incremental exercise test up to exhaustion on a cycle ergometer. Substrate oxidation was estimated using indirect calorimetry. Magnetic resonance tomography and spectroscopy were conducted to assess body fat distribution and intramyocellular fat content. We determined the exercise intensity at which maximal body fat oxidation occurs and assessed whether body composition, body fat distribution, intramyocellular fat content, or oxidative capacity predict exercise-induced fat oxidation. Maximal exercise-induced fat oxidation was 0.30+/-0.02 g/min in men and 0.23+/-0.01 g/min in women (p<0.05). Exercise intensity at the maximum fat oxidation was 42+/-2.2% VO (2 max) in men and 43+/-1.7% VO (2 max) in women. With multivariate analysis, exercise-induced fat oxidation was related to fat-free mass, percent fat mass, and oxidative capacity, but not to absolute fat mass, visceral fat, or intramyocellular fat content. We conclude that in obese subjects the capacity to oxidize fat during exercise appears to be limited by skeletal muscle mass and oxidative capacity rather than the availability of visceral or intramyocellular fat.

Neuroendocrine, metabolic and pharmacological control of feeding behaviour – closing in on antiobesity treatment

Neuroendocrine, metabolic and pharmacological control of feeding behaviour – closing in on antiobesity treatment

Bariatric surgery in obesity: Changes of glucose and lipid metabolism correlate with changes of fat mass

Background and Aim Bariatric surgery induces significant weight loss and improves glucose metabolism in obese patients (BMI > 35 kg/m 2). Our aim was to compare restrictive (LAGB, laparoscopic gastric banding) and malabsorptive approaches (BIBP, biliary-intestinal bypass) on the loss of fat-free mass (FFM), fat mass (FM), and on changes of glucose and lipid metabolism. Methods and Results Body composition (bio-impedance analysis, BIA), blood glucose (BG), insulin, triglycerides, total- and HDL-cholesterol, liver enzymes (AST and ALT) were measured at baseline and 1 year after surgery in patients undergoing LAGB, BIBP, and in diet-treated control patients. In the main study, with patients matched for initial BMI (43–55 kg/m 2, LAGB = 24, BIBP = 12, controls = 6), decreases of BMI, FM, BG and cholesterol were greater in patients with BIBP than with LAGB ( p < 0.01), while decreases of FFM, insulin, HOMA-IR and triglycerides were similar. No effects on BMI, FM, FFM, BG, insulin, HOMA-IR or cholesterol were observed in the control patients. Decreases of BG, insulin, HOMA-IR, cholesterol and triglycerides correlated with FM but not with FFM decrease. Similar results were obtained in an additional study in patients with a different initial BMI (LAGB = 25, BIBP = 6, controls = 24) and when considering all subjects together. A decrease of liver enzymes (ALT) was greater with LAGB than with BIBP, and HDL-cholesterol increased with LAGB and decreased with BIBP. Conclusion BMI, FM, BG and cholesterol decrease more with malabsorptive than with restrictive surgery, while FFM, insulin, HOMA-IR and triglycerides decrease in a similar way. FFM loss is of low entity. Changes of glucose and lipid metabolism are proportional to a decrease of fat mass but not of fat-free mass.

Cut-Off Fasting Plasma Glucose Level To Determine Impaired Glucose Metabolism In Obesity

Objective: Our aim was to find out which fasting glucose level should be the cut-off point for impaired glucose metabolism in obese patients. Subjects: 257 patients (195 females, 62 males) whose body mass indexes (BMI) were above 30kg/m² participated in this study. After all cases had underwent a 75gr oral glucose tolerance test (OGTT) the patients were divided into four groups according to their fasting plasma glucose values ( group 1:80-89mg/dl (4.4-4.9mmol/l), group 2:90-99mg/dl (5.0-5.5mmol/l), group 3:100-109mg/dl (5.6-6.0mmol/l), group 4 :110-125mg/dl (6.1-6.9mmol/l) ). According to OGTT results we defined patients as cases who were normal, who had impaired fasting glucose, and who had impaired glucose metabolism (diabetes mellitus and impaired glucose tolerance). Results: No difference was found between age, gender, BMI, systolic and diastolic blood pressure, and lipid profiles of the groups. The number of patients who were diagnosed as impaired glucose metabolism increased apparently in the third group (%50.7) (p<0.05). Mean fasting plasma glucose level of the third group was 104,16±2,73mg/dl (5.78±0,15mmol/l). Although there was no statistically difference between the groups, mean homeostasis model assessment (HOMA) values were above 4 in the third and fourth groups, in the patients who had impaired fasting glucose and impaired glucose metabolism. Conclusion: We think that it is necessary to apply a OGTT to obese patients whose fasting plasma glucose levels are above 104 mg/dl in order to reduce the mortality and morbidity of the cardiovascular diseases.

Glucagon-like peptide-1 in the rat's hippocampus and β-amyloid protein-induced amnesia

Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG.Rats underwent RYGB or VSG and were compared to sham-operated rats fed ad lib or pair-fed to animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function independent of incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance test was used to assess the effect of each surgery on postprandial release of glucagon-like peptide 1 (GLP-1)(7-36) and glucose tolerance, and was also performed in rats given GLP-1 receptor antagonist exendin(9-39).Following RYGB or VSG, glucose tolerance and insulin sensitivity improved in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7-36) and insulin were greatly and comparably increased in rats that received RYGB and VSG compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG.In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss.

Whole‐body Glucose Metabolism in Obese Patients with Type 2 Diabetes Mellitus: the Impact of Hypertension and Strict Blood Glucose Control

We have examined the impact of hypertension and blood glucose control on insulin sensitivity in obese Type 2 (non-insulin-dependent) diabetic patients. Glucose metabolism in the basal state and in response to insulin was examined using the euglycaemic, hyperinsulinaemic (2 mU kg-1 min-1) clamp technique in combination with 3-[3H]-glucose infusion and indirect calorimetry in 60 obese Type 2 diabetic patients (30 normotensive patients and 30 hypertensive patients on antihypertensive treatment) and 10 obese normotensive control subjects. In the basal state and during hyperinsulinaemia, glucose disposal rates (total, oxidative, and nonoxidative) were similar in Type 2 diabetic patients with or without hypertension (230 +/- 83 vs 270 +/- 114 mg m-2 min-1 (NS), 83 +/- 28 vs 95 +/- 7 mg m-2 min-1 (NS), 148 +/- 70 vs 180 +/- 89 mg m-2 min-1 (NS), treated hypertensive vs normotensive subjects, respectively). However, compared to obese control subjects (403 +/- 65 mg m-2 min-1) both groups of diabetic patients had significantly decreased insulin-stimulated glucose disposal rates (p < 0.005). Even in a subset of Type 2 diabetic patients with long-term (> 6 months) near normal blood glucose control (HbA1c < 6.1%) significant defects were detectable in whole-body glucose and lipid metabolism when compared to control subjects. These results indicate that treated hypertension does not significantly aggravate the insulin insensitivity that is already present in Type 2 diabetes mellitus. Furthermore, Type 2 diabetic patients with long-term good metabolic control continue to demonstrate insulin insensitivity in peripheral tissues.

Intracellular defects in glucose metabolism in obese patients with NIDDM.

Skeletal muscle insulin resistance in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) is characterized by decreased glucose uptake. Although reduced glycogen synthesis is thought to be the predominant cause for this deficit, studies supporting this notion often have been conducted at supraphysiological insulin concentrations in which glucose storage is the overwhelming pathway of glucose disposal. However, at lower, more physiological insulin concentrations, decreased muscle glucose oxidation could play a significant role. This study was undertaken to determine whether, under euglycemic conditions, insulin resistance for leg muscle glucose uptake in NIDDM patients is due primarily to decreased glucose storage or to oxidation. The leg balance technique and leg indirect calorimetry were used under steady-state euglycemic conditions to estimate muscle glucose uptake, storage, and oxidation in eight moderately obese NIDDM patients and eight matched-control subjects. Leg muscle biopsies also were performed to determine whether alterations in muscle pyruvate dehydrogenase or glycogen synthase activities could explain defects in glucose oxidation or storage. At insulin concentrations of approximately 500-600 pM, leg glucose uptake, oxidation, and storage in the NIDDM group (2.03 +/- 0.42, 1.00 +/- 0.13, 0.66 +/- 0.36 mumol.min-1.100 ml-1) were significantly lower (P less than 0.05) than rates in control subjects (5.14 +/- 0.64, 1.92 +/- 0.17, 2.80 +/- 0.54). Pyruvate dehydrogenase and glycogen synthase activities were also decreased, consistent with the in vivo metabolic defects. The average deficit in leg glucose uptake in NIDDM was 3.11 +/- 0.42 mumol.min-1.100 ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular defects in glucose metabolism in obese patients with NIDDM

Intracellular defects in glucose metabolism in obese patients with NIDDM