scholarly journals Loss of CHIP Expression Perturbs Glucose Homeostasis and Leads to Type II Diabetes through Defects in Microtubule Polymerization and Glucose Transporter Localization

2017 ◽  
Author(s):  
Holly McDonough ◽  
Kaitlin C. Lenhart ◽  
Sarah M. Ronnebaum ◽  
Chunlian Zhang ◽  
Jie An ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Protein Trafficking ◽  
Type Ii Diabetes ◽  
Glucose Transporter ◽  
Protein A ◽  
Whole Body ◽  
Type Ii ◽  
Interacting Protein ◽  
Microtubule Polymerization ◽  
Dependent Protein

ABSTRACTRecent evidence has implicated CHIP (carboxyl terminus of Hsc/Hsp70-interacting protein), a co-chaperone and ubiquitin ligase, in the functional support of several metabolism-related proteins, including AMPK and SirT6. In addition to previously reported aging and stress intolerance phenotypes, we find that CHIP -/- mice also demonstrate a Type II diabetes-like phenotype, including poor glucose tolerance, decreased sensitivity to insulin, and decreased insulin-stimulated glucose uptake in isolated skeletal muscle, characteristic of insulin resistance. In CHIP-deficient cells, glucose stimulation fails to induce translocation of Glut4 to the plasma membrane. This impairment in Glut4 translocation in CHIP-deficient cells is accompanied by decreased tubulin polymerization associated with decreased phosphorylation of stathmin, a microtubule-associated protein required for polymerization-dependent protein trafficking within the cell. Together, these data describe a novel role for CHIP in regulating microtubule polymerization that assists in glucose transporter translocation, promoting whole-body glucose homeostasis and sensitivity to insulin.

Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes

2005 ◽  
Vol 33 (2) ◽  
pp. 354-357 ◽  
Author(s):  
M. Björnholm ◽  
J.R. Zierath
Keyword(s):  
Skeletal Muscle ◽  
Type Ii Diabetes ◽  
Insulin Action ◽  
Glucose Transporter ◽  
Whole Body ◽  
Diabetic Patients ◽  
Type Ii ◽  
Peripheral Tissues ◽  
Glucose Homoeostasis ◽  
Insulin Receptor Signalling

Type II diabetes is characterized by defects in insulin action on peripheral tissues, such as skeletal muscle, adipose tissue and liver and pancreatic β-cell defects. Since the skeletal muscle accounts for approx. 75% of whole body insulin-stimulated glucose uptake, defects in this tissue play a major role in the impaired glucose homoeostasis in Type II diabetic patients. Thus identifying defective steps in this process may reveal attractive targets for drug development to combat insulin resistance and Type II diabetes. This review will describe the effects of insulin on glucose transport and other metabolic events in skeletal muscle that are mediated by intracellular signalling cascades. Evidence for impaired activation of the insulin receptor signalling cascade and defective glucose transporter 4 translocation in the skeletal muscle from Type II diabetic patients will be presented. Through the identification of the intracellular defects in insulin action that control glucose homoeostasis, a better understanding of the disease pathogenesis can be gained and strategies for intervention may be developed.

Insulin resistance: cross-talk between adipose tissue and skeletal muscle, through free fatty acids, liver X receptor, and peroxisome proliferator-activated receptor-α signaling

2013 ◽  
Vol 15 (3) ◽  
Author(s):  
Ann Louise Olson
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Glucose Transporter ◽  
Control Point ◽  
Nuclear Hormone Receptor ◽  
Whole Body ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

AbstractSkeletal muscle and adipose tissue play a major role in the regulation of whole-body glucose homeostasis. Much of the coordinated regulation of whole-body glucose homeostasis results from the regulation of lipid storage and release by adipose tissue and efficient switching between glucose oxidation and fatty acid oxidation in skeletal muscle. A control point for these biochemical actions center around the regulation of the insulin responsive glucose transporter, GLUT4. This review examines the regulation of GLUT4 in adipose tissue and skeletal muscle, in the context of the steroid nuclear hormone receptor signaling.

Glucose Transport and Glucose Homeostasis: New Insights From Transgenic Mice

Physiology ◽  
1995 ◽  
Vol 10 (1) ◽  
pp. 22-29 ◽  
Author(s):  
MM Mueckler
Keyword(s):  
Transgenic Mice ◽  
Glucose Transport ◽  
Glucose Homeostasis ◽  
Glucose Transporter ◽  
Whole Body ◽  
Genetic Enhancement ◽  
Glucose Disposal ◽  
Muscle Glucose Transport ◽  
Glucose Transporter Isoforms

Experiments with transgenic mice overexpressing glucose transporter isoforms demonstrate the preeminence of the transport step with respect to muscle glucose disposal and whole body glucose homeostasis. These studies suggest the feasibility of controlling diabetic hyperglycemia by pharmacological or genetic enhancement of muscle glucose transport.

Glycaemic instability is an underestimated problem in Type II diabetes

2006 ◽  
Vol 111 (2) ◽  
pp. 119-126 ◽  
Author(s):  
Stephan F. E. Praet ◽  
Ralph J. F. Manders ◽  
Ruth C. R. Meex ◽  
A. G. Lieverse ◽  
Coen D. A. Stehouwer ◽  
...  
Keyword(s):  
Physical Activity ◽  
Blood Glucose ◽  
Glycaemic Control ◽  
Glucose Tolerance ◽  
Type Ii Diabetes ◽  
Whole Body ◽  
Control Group ◽  
Oral Glucose ◽  
Type Ii ◽  
Oral Glucose Tolerance

The aim of the present study was to assess the level of glycaemic control by the measurement of 24 h blood glucose profiles and standard blood analyses under identical nutritional and physical activity conditions in patients with Type II diabetes and healthy normoglycaemic controls. A total of 11 male patients with Type II diabetes and 11 healthy matched controls participated in a 24 h CGMS (continuous subcutaneous glucose-monitoring system) assessment trial under strictly standardized dietary and physical activity conditions. In addition, fasting plasma glucose, insulin and HbA1c (glycated haemoglobin) concentrations were measured, and an OGTT (oral glucose tolerance test) was performed to calculate indices of whole-body insulin sensitivity, oral glucose tolerance and/or glycaemic control. In the healthy control group, hyperglycaemia (blood glucose concentration >10 mmol/l) was hardly present (2±1% or 0.4±0.2/24 h). However, in the patients with Type II diabetes, hyperglycaemia was experienced for as much as 55±7% of the time (13±2 h over 24 h) while using the same standardized diet. Breakfast-related hyperglycaemia contributed most (46±7%; P<0.01 as determined by ANOVA) to the total amount of hyperglycaemia and postprandial glycaemic instability. In the diabetes patients, blood HbA1c content correlated well with the duration of hyperglycaemia and the postprandial glucose responses (P<0.05). In conclusion, CGMS determinations show that standard measurements of glycaemic control underestimate the amount of hyperglycaemia prevalent during real-life conditions in Type II diabetes. Given the macro- and micro-vascular damage caused by postprandial hyperglycaemia, CGMS provides an excellent tool to evaluate alternative therapeutic strategies to reduce hyperglycaemic blood glucose excursions.

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