The contribution of defects in insulin signaling in skeletal muscle to insulin resistance and type 2 diabetes

2000 ◽  
pp. 41-64 ◽  
Author(s):  
Karen C. McCowen ◽  
E. Dale Abel
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Insulin Signaling

Mouse models of insulin resistance

2002 ◽  
Vol 282 (5) ◽  
pp. E977-E981 ◽  
Author(s):  
Marta Letizia Hribal ◽  
Francesco Oriente ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Impaired Insulin

The hallmarks of type 2 diabetes are impaired insulin action in peripheral tissues and decreased pancreatic β-cell function. Classically, the two defects have been viewed as separate entities, with insulin resistance arising primarily from impaired insulin-dependent glucose uptake in skeletal muscle, and β-cell dysfunction arising from impaired coupling of glucose sensing to insulin secretion. Targeted mutagenesis and transgenesis involving components of the insulin action pathway have changed our understanding of these phenomena. It appears that the role of insulin signaling in the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been overlooked in liver, pancreatic β-cells, and brain, which had been thought not to be primary insulin targets. We review recent progress and try to reconcile areas of apparent controversy surrounding insulin signaling in skeletal muscle and pancreatic β-cells.

scholarly journals Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1236
Author(s):  
Jesús Burillo ◽  
Patricia Marqués ◽  
Beatriz Jiménez ◽  
Carlos González-Blanco ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

scholarly journals Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats

2005 ◽  
Vol 34 (2) ◽  
pp. 299-315 ◽  
Author(s):  
Young Ho Suh ◽  
Younyoung Kim ◽  
Jeong Hyun Bang ◽  
Kyoung Suk Choi ◽  
June Woo Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

scholarly journals Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

2021 ◽  
Author(s):  
Qian Zhou ◽  
Wan-Wan Sun ◽  
Jia-Cong Chen ◽  
Huilu Zhang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Trna Synthetase ◽  
Blood Samples ◽  
Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

Abstract 209: Dimethylarginine Dimethylaminohydrolase 1 and Insulin Resistance

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sophie E Piper ◽  
James M Leiper
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Plasma Glucose ◽  
Knockout Mice ◽  
Physiological Role ◽  
Causal Link ◽  
Chow Diet ◽  
Dimethylarginine Dimethylaminohydrolase

Type 2 diabetes is a prevalent metabolic condition and is the result of an impaired response to insulin. Insulin resistance and type 2 diabetes are clearly associated with obesity and the secondary cardiovascular complications of this condition are serious and life threatening. Asymemetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases and increased levels are seen in multiple pathologies. Increased plasma levels of ADMA have been associated with patients with type 2 diabetes, insulin resistance and obesity, although a causal link between ADMA and diabetes has not been established. Dimethylarginine dimethylaminohydrolase (DDAH) is the enzyme that catalyses the metabolism of ADMA. There are two isoforms of the enzyme which are both involved in the control of ADMA and NO. The interplay of insulin with NO release is well established but the initial causes for the onset of insulin resistance are not well defined. Elevated levels of ADMA are linked to insulin resistance and transgenic mice that over-express ddah1 show increased insulin sensitivity. Of note is that metformin, an insulin sensitising drug that is widely used in the treatment of insulin resistance, reduces plasma glucose and ADMA concentrations. In order to elucidate the physiological role of DDAH1 in glucose homeostasis we investigated the glucose handling in a ddah1 global knockout model. Intra-peritoneal glucose tolerance tests in ddah1 global knockout mice demonstrate insulin resistance. Baseline plasma glucose levels were 25% higher in ddah1 knockouts and peak levels were 53% higher in ddah1 knockouts. The kinetics of plasma glucose accumulation and clearance in ddah1 knockout mice suggests dysfunction in both the liver and skeletal muscle. On a normal chow diet, hepatocyte specific ddah1 knockout mice and skeletal muscle specific ddah1 knockout mice show no insulin resistance. On a high fat diet however the hepatocyte specific ddah1 knockout mice show significant insulin resistance and lower metabolic rate than their fat fed wild-type counterparts. These studies demonstrate for the first time a causal link between ADMA accumulation and insulin resistance. Furthermore these data establish DDAH1 activity is a significant regulator of insulin resistance.

Insulin Signaling and Action in Fat Cells: Associations with Insulin Resistance and Type 2 Diabetes

1999 ◽  
Vol 892 (1 THE METABOLIC) ◽  
pp. 119-126 ◽  
Author(s):  
ULF SMITH ◽  
METTE AXELSEN ◽  
EUGENIA CARVALHO ◽  
BJORN ELIASSON ◽  
PER-ANDERS JANSSON ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Fat Cells

scholarly journals The Role of PGC-1α in the Development of Insulin Resistance in Skeletal Muscle - Revisited

2015 ◽  
Vol 37 (6) ◽  
pp. 2288-2296 ◽  
Author(s):  
Bartlomiej Łukaszuk ◽  
Krzysztof Kurek ◽  
Agnieszka Mikłosz ◽  
Małgorzata Żendzian-Piotrowska ◽  
Adrian Chabowski
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Medical Condition ◽  
Accumulation Rate ◽  
Common Denominator ◽  
Net Energy ◽  
Physically Active ◽  
Beneficial Effects

Currently, obesity is a predominant medical condition and an important risk factor for the development of several diseases, including type 2 diabetes mellitus. Importantly, most research has indicated lipid-induced insulin resistance in skeletal muscles is a key link between the aforementioned pathological conditions. PGC-1α is a prominent regulator of myocellular energy metabolism orchestrating gene transcription programming in response to numerous environmental stimuli. Moreover, it is widely acknowledged that mitochondrial metabolism (primary metabolic target of PGC-1α) disturbances are widely acknowledged contributors to type 2 diabetes development. Therefore, it seems surprising that the exact physiological contribution of PGC-1α in the development of insulin resistance in skeletal muscle remains poorly understood. This review aims to reconcile these allegedly different findings by looking for a common denominator in the role(s) of PGC-1α in respect to lipid-induced insulin resistance in skeletal muscle. Our scrutiny of the literature indicates that interventions at the level of PGC-1α may exert beneficial effects on myocytes in respect to lipid-induced insulin resistance. The latter takes place as a result of a positive net energy balance (fatty acids oxidation surpassing their accumulation rate). Moreover, the aforementioned effects may not necessarily be limited to physically active states. They seem to occur, however, only within a physiologically observed range in muscle cells (approximately 1-fold changes in PGC-1α protein expression).

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?

2017 ◽  
Vol 176 (2) ◽  
pp. R67-R78 ◽  
Author(s):  
Charlotte Brøns ◽  
Louise Groth Grunnet
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Cellular Localization ◽  
Future Research ◽  
Causal Mechanism ◽  
Increased Risk ◽  
Adipose Tissue Expandability

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.

Sign in / Sign up

Export Citation Format

Share Document