scholarly journals Short-Term Calorie Restriction Maintains Plasma Insulin Concentrations along with a Reduction in Hepatic Insulin-Degrading Enzyme Levels in db/db Mice

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1190
Author(s):  
Yudai Nonaka ◽  
Reo Takeda ◽  
Yutaka Kano ◽  
Daisuke Hoshino
Keyword(s):  
Glucose Tolerance ◽  
Calorie Restriction ◽  
Late Stage ◽  
Area Under The Curve ◽  
Whole Body ◽  
Fasting Insulin ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Insulin Levels ◽  
Blood Insulin

Maintaining blood insulin levels is important for patients with diabetes because insulin secretion capacity declines with the development of the disease. Calorie restriction (CR) is effective for the improvement of glucose tolerance, but it is not clear whether CR can maintain insulin levels in the late stage of diabetes. We examined the effect of CR on whole-body glucose tolerance and fasting blood insulin concentrations in the late stage of diabetes. Male db/db mice were subjected to either a standard laboratory diet ad libitum for 3 weeks (dbdb group) or 40% CR (dbdb+CR group). CR significantly decreased body mass and epididymal fat weight. Glucose tolerance and fasting glucose levels were significantly improved with 3-week CR. Fasting insulin concentrations were decreased in the dbdb group but were maintained in the dbdb+CR group. CR significantly reduced insulin-degrading enzyme (IDE) levels in the liver, and hepatic IDE levels were significantly positively and negatively correlated with plasma glucose concentrations (area under the curve) after glucose administration and after fasting insulin concentrations, respectively. Therefore, 3-week CR maintained blood insulin levels and improved glucose tolerance with decreased hepatic IDE levels in an animal model of late-stage diabetes.

scholarly journals Reduced insulin clearance and lower insulin-degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein-restricted mice

2014 ◽  
Vol 112 (6) ◽  
pp. 900-907 ◽  
Author(s):  
Luiz F. Rezende ◽  
Rafael L. Camargo ◽  
Renato C. S. Branco ◽  
Ana P. G. Cappelli ◽  
Antonio C. Boschero ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Insulin Clearance ◽  
Protein Diet ◽  
Restricted Diet ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Thrifty Phenotype

Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of insulin clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on insulin clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and insulinaemia, increased glucose tolerance and altered insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in insulin sensitivity through the phosphorylation of the insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in insulin dynamics could be attributed to reduced insulin secretion coupled with reduced insulin clearance and lower insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less insulin, but also remove and degrade less insulin. This phenomenon has the double benefit of sparing insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.

scholarly journals Plasma Metabolomics to Identify and Stratify Patients With Impaired Glucose Tolerance

2019 ◽  
Vol 104 (12) ◽  
pp. 6357-6370 ◽  
Author(s):  
Charlotte Wildberg ◽  
Annette Masuch ◽  
Kathrin Budde ◽  
Gabi Kastenmüller ◽  
Anna Artati ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Proton Nuclear Magnetic Resonance ◽  
Oral Glucose ◽  
Resonance Spectroscopy ◽  
Insulin Levels ◽  
Model Combining ◽  
Branched Chain

Abstract Objective Impaired glucose tolerance (IGT) is one of the presymptomatic states of type 2 diabetes mellitus and requires an oral glucose tolerance test (OGTT) for diagnosis. Our aims were twofold: (i) characterize signatures of small molecules predicting the OGTT response and (ii) identify metabolic subgroups of participants with IGT. Methods Plasma samples from 827 participants of the Study of Health in Pomerania free of diabetes were measured using mass spectrometry and proton-nuclear magnetic resonance spectroscopy. Linear regression analyses were used to screen for metabolites significantly associated with the OGTT response after 2 hours, adjusting for baseline glucose and insulin levels as well as important confounders. A signature predictive for IGT was established using regularized logistic regression. All cases with IGT (N = 159) were selected and subjected to unsupervised clustering using a k-means approach. Results and Conclusion In total, 99 metabolites and 22 lipoprotein measures were significantly associated with either 2-hour glucose or 2-hour insulin levels. Those comprised variations in baseline concentrations of branched-chain amino ketoacids, acylcarnitines, lysophospholipids, or phosphatidylcholines, largely confirming previous studies. By the use of these metabolites, subjects with IGT segregated into two distinct groups. Our IGT prediction model combining both clinical and metabolomics traits achieved an area under the curve of 0.84, slightly improving the prediction based on established clinical measures. The present metabolomics approach revealed molecular signatures associated directly to the response of the OGTT and to IGT in line with previous studies. However, clustering of subjects with IGT revealed distinct metabolic signatures of otherwise similar individuals, pointing toward the possibility of metabolomics for patient stratification.

scholarly journals Role of the foregut in the early improvement in glucose tolerance and insulin sensitivity following Roux-en-Y gastric bypass surgery

2011 ◽  
Vol 300 (5) ◽  
pp. G795-G802 ◽  
Author(s):  
Erik N. Hansen ◽  
Robyn A. Tamboli ◽  
James M. Isbell ◽  
Jabbar Saliba ◽  
Julia P. Dunn ◽  
...  
Keyword(s):  
Gastric Bypass ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Whole Body ◽  
Sensitivity Index ◽  
Mixed Meal ◽  
Early Improvement ◽  
Delivery Route ◽  
Over Time

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route × time interaction (all P ≥ 0.084). The glucose-dependent insulinotropic polypeptide (GIP) AUC was unchanged after RYGB ( P = 0.819); however, GIP levels peaked earlier after RYGB with jejunal delivery. The ratio of insulin AUC to GLP-1 and GIP AUC decreased after surgery ( P =.001 and 0.061, respectively) without an effect of delivery route over time (both P ≥ 0.646). Insulin sensitivity improved post-RYGB ( P = 0.001) with no difference between the gastric and jejunal delivery of the mixed meal over time ( P = 0.819). These data suggest that exclusion of nutrients from the foregut with RYGB does not improve glucose tolerance or insulin sensitivity. However, changes in the foregut response post-RYGB due to lack of nutrient exposure cannot be excluded. Our findings suggest that foregut bypass may alter the incretin response by enhanced nutrient delivery to the hindgut.

scholarly journals Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer’s disease: possible mechanisms of IDE in T2D and AD

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Huajie Li ◽  
Jian Wu ◽  
Linfeng Zhu ◽  
Luolin Sha ◽  
Song Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Glucose Tolerance ◽  
Spatial Learning ◽  
Expression Level ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Expression Levels

Insulin degrading enzyme (IDE) is believed to act as a junction point of Type 2 diabetes (T2D) and Alzheimer's disease (AD); however, the underlying mechanism was not completely clear yet. Transgenic APPSwe/PS1 mice were used as the AD model and were treated with streptozocin/streptozotocin (STZ) to develop a mixed mice model presenting both AD and T2D. Morris Water Maze (MWM) and recognition task were performed to trace the cognitive function. The detection of fasting plasma glucose (FPG) and plasma insulin concentration, and oral glucose tolerance test (OGTT) were used to trace the metabolism evolution. Aβ40 and Aβ42 were quantified by colorimetric ELISA kits. The mRNA or protein expression levels were determined by quantitative real-time RT-PCR and Western blotting analysis respectively. T2D contributes to the AD progress by accelerating and worsening spatial learning and recognition impairments. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The expression levels of IDE, PPARγ, and AMPK were down-regulated in mice with AD and T2D. PPARγ activator rosiglitazone (RSZ) or AMPK activator AICAR increased the expression level of IDE and decreased Aβ levels in mice with AD and T2D. RSZ or AICAR treatment also alleviated the spatial learning and recognition impairments in AD and T2D mice. Our results found that, in the mice with T2D and AD, the activators of PPARγ/AMPK signaling pathway significantly increased the expression level of IDE, and decreased the accumulation of Aβ40 and Aβ42, as well as alleviated the spatial learning and recognition impairments.

scholarly journals Western-style diet consumption impairs maternal insulin sensitivity and glucose metabolism during pregnancy in a Japanese macaque model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph M. Elsakr ◽  
Sifang Kathy Zhao ◽  
Valerie Ricciardi ◽  
Tyler A. Dean ◽  
Diana L. Takahashi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Maternal Obesity ◽  
Japanese Macaque ◽  
Area Under The Curve ◽  
The United States ◽  
Metabolic Effects ◽  
Intravenous Glucose ◽  
Insulin Levels ◽  
Macaque Model

AbstractThe prevalence of maternal obesity is increasing in the United States. Offspring born to women with obesity or poor glycemic control have greater odds of becoming obese and developing metabolic disease later in life. Our group has utilized a macaque model to study the metabolic effects of consumption of a calorically-dense, Western-style diet (WSD; 36.3% fat) during pregnancy. Here, our objective was to characterize the effects of WSD and obesity, alone and together, on maternal glucose tolerance and insulin levels in dams during each pregnancy. Recognizing the collinearity of maternal measures, we adjusted for confounding factors including maternal age and parity. Based on intravenous glucose tolerance tests, dams consuming a WSD showed lower glucose area under the curve during first study pregnancies despite increased body fat percentage and increased insulin area under the curve. However, with (1) prolonged WSD feeding, (2) multiple diet switches, and/or (3) increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. Our results suggest that prolonged or recurrent calorically-dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. These observations in a highly relevant species are likely of clinical and public health importance given the comparative ease of maternal dietary modifications relative to the low likelihood of successfully reversing obesity in the course of any given pregnancy.

Elevated insulin levels following 7 days of increased sedentary time are due to lower hepatic extraction and not higher insulin secretion

2019 ◽  
Vol 44 (9) ◽  
pp. 1020-1023
Author(s):  
Richard Viskochil ◽  
Kate Lyden ◽  
John Staudenmayer ◽  
Sarah K. Keadle ◽  
Patty S. Freedson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Sedentary Behavior ◽  
Sedentary Time ◽  
Area Under The Curve ◽  
Normal Activity ◽  
Hepatic Extraction ◽  
Insulin Levels ◽  
Glucose Tolerance Tests ◽  
Hepatic Insulin Extraction

Higher insulin following sedentary behavior may be due to increased insulin secretion (IS), decreased hepatic insulin extraction (HIE), or a combination of both. Ten healthy adults completed glucose tolerance tests following 7 days of normal activity and 7 days of increased sitting. There were no differences in IS; however, HIE at 120 min after ingestion (85.4% ± 7.2% vs. 74.6% ± 6.6%, p < 0.05) and the area under the curve (73.6% ± 9.4% vs. 67.5% ± 11.3%, p < 0.05) were reduced following 7 days of increased sedentary time.

scholarly journals No difference in exogenous carbohydrate oxidation during exercise in children with and without impaired glucose tolerance

2016 ◽  
Vol 121 (3) ◽  
pp. 724-729 ◽  
Author(s):  
Lisa Chu ◽  
Katherine M. Morrison ◽  
Michael C. Riddell ◽  
Sandeep Raha ◽  
Brian W. Timmons
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Normal Glucose Tolerance ◽  
Whole Body ◽  
Oral Glucose ◽  
Insulin Resistant ◽  
Glucose Levels

The capacity to match carbohydrate (CHO) utilization with availability is impaired in insulin-resistant, obese adults at rest. Understanding exogenous carbohydrate (CHOexo) oxidation during exercise and its association to insulin resistance (IR) is important, especially in children at risk for type 2 diabetes. Our objective was to examine the oxidative efficiency of CHOexo during exercise in obese children with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Children attended two visits and were identified as NGT ( n = 22) or IGT ( n = 12) based on 2-h oral glucose tolerance test (OGTT) glucose levels of <7.8 mmol/l or ≥7.8 mmol/l, respectively. Anthropometry, body composition, and aerobic fitness (V̇o2max) were assessed. Insulin and glucose at baseline, 30, 60, 90, and 120 min during the OGTT were used to calculate measures of insulin sensitivity. On a separate day, a 13C-enriched CHO drink was ingested before exercise (3 × 20 min bouts) at 45% V̇o2max. Breath measurements were collected to calculate CHOexo oxidative efficiency. CHOexo oxidative efficiency during exercise was similar in IGT (17.0 ± 3.6%) compared with NGT (17.1 ± 4.4%) ( P = 0.90) despite lower whole body insulin sensitivity in IGT at rest ( P = 0.02). Area under the curve for insulin (AUCins) measured at rest during the OGTT was greater in IGT compared with NGT ( P = 0.04). The ability of skeletal muscle to utilize CHOexo was not impaired during exercise in children with IGT.

scholarly journals Insulin-Regulated Aminopeptidase Inhibition Ameliorates Metabolism in Obese Zucker Rats

2020 ◽  
Vol 7 ◽  
Author(s):  
Katarina Krskova ◽  
Lucia Balazova ◽  
Viktoria Dobrocsyova ◽  
Rafal Olszanecki ◽  
Maciej Suski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Signal Transduction Pathway ◽  
Whole Body ◽  
Zucker Rats ◽  
Epididymal Adipose Tissue ◽  
Markers Of Inflammation ◽  
Obese Zucker Rats

The aim of our study was to determine the influence of inhibition of insulin-regulated aminopeptidase/oxytocinase (IRAP) on glucose tolerance and metabolism of skeletal muscle and visceral adipose tissue in obese Zucker rats. Obese Zucker rats administered with IRAP inhibitor–HFI-419 at a dose of 29 μg/100 g BW/day by osmotic minipumps implanted subcutaneously for 2 weeks. Two-hour intraperitoneal glucose tolerance test (ipGTT) was performed in fasting rats. Plasma oxytocin levels were measured by enzyme immunoassay after plasma extraction. In the musculus quadriceps and epididymal adipose tissue, the expression of factors affecting tissue oxidative status and metabolism was determined by real-time qPCR and/or Western blot analysys. The plasma and tissue enzymatic activities were determined by colorimetric or fluorometric method. Circulated oxytocin levels in obese animals strongly tended to increase after HFI-419 administration. This was accompanied by significantly improved glucose utilization during ipGTT and decreased area under the curve (AUC) for glucose. In skeletal muscle IRAP inhibitor treatment up-regulated enzymes of antioxidant defense system – superoxide dismutase 1 and 2 and improved insulin signal transduction pathway. HFI-419 increased skeletal muscle aminopeptidase A expression and activity and normalized its plasma levels in obese animals. In epididymal adipose tissue, gene expression of markers of inflammation and adipocyte hypertrophy was down-regulated in obese rats after HFI-419 treatment. Our results demonstrate that IRAP inhibition improves whole-body glucose tolerance in insulin-resistant Zucker fatty rats and that this metabolic effect of HFI-419 involves ameliorated redox balance in skeletal muscle.

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