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The development of insulin resistance in Type 2 diabetes : insights from knockout studies

TLDR
By advancing the understanding of the complex molecular mechanisms underlying insulin resistance, these knock-out models may help to develop more effective treatments for Type 2 diabetes.
Abstract
Diabetes is a common endocrine disorder, primarily characterised by elevated plasma glucose levels. The disease affects all age groups worldwide. Most patients suffer from Type 2 diabetes, which is mainly due to insulin resistance. It is thought that changes in insulin signalling pathways underlie the development of insulin resistance. This article aims to review recent studies that have elucidated the role of individual proteins in these insulin signalling pathways. These studies have been undertaken using two strategies, one employing mice carrying a global null mutation of particular gene-encoding proteins by the homologous recombination method and another strategy using mice with tissue-specific insulin receptor and/or GLUT4 knockout by the Cre-loxP system. The various phenotypes of these knockout mice, and the light they shed on the etiology of insulin resistance, are discussed. By advancing our understanding of the complex molecular mechanisms underlying insulin resistance, these knock-out models may help us to develop more effective treatments for Type 2 diabetes.

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Citations
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Journal ArticleDOI

Sac3 Is an Insulin-regulated Phosphatidylinositol 3,5-Bisphosphate Phosphatase GAIN IN INSULIN RESPONSIVENESS THROUGH Sac3 DOWN-REGULATION IN ADIPOCYTES

TL;DR: Small interfering RNA-mediated knockdown of endogenous Sac3 by ∼60%, which resulted in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increased GLUT4 translocation and glucose entry in response to insulin is reported.
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Association between type two diabetes and non-alcoholic fatty liver disease in youth.

TL;DR: This work reviews the most recent epidemiological data on prevalence of both diseases in youth and their association and supports a close association between type 2 diabetes and fatty liver disease.
Journal ArticleDOI

Pathology of congenital generalized lipodystrophy in Agpat2-/- mice.

TL;DR: The absence of adipocytes in aged mice indicates that these cells must undergo necrosis/apoptosis at some point, and massive pancreatic islet hypertrophy in the face of chronic hyperglycemia suggests that glucotoxicity is insufficient by itself to cause β-cell loss and that adipocyte-derived factors help regulate total β- cell mass.
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Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

TL;DR: It is shown that I RTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production, and the administration of ectopic IRTKS can ameliorate the insulin resistance of IRT KS-def deficient and diabetic mice.
References
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Journal ArticleDOI

Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030

TL;DR: Findings indicate that the "diabetes epidemic" will continue even if levels of obesity remain constant, and given the increasing prevalence of obesity, it is likely that these figures provide an underestimate of future diabetes prevalence.
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Adipose Tissue as an Endocrine Organ

TL;DR: An overview of the endocrine functions of adipose tissue can be found in this paper, where the authors highlight the adverse metabolic consequences of both adipose excess and deficiency, and propose a more rational therapy for these increasingly prevalent disorders.
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Insulin signalling and the regulation of glucose and lipid metabolism

TL;DR: The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide, and tissues such as muscle, fat and liver become less responsive or resistant to insulin.
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Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.

TL;DR: In this article, the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP−1B+/+ littermates.
Journal ArticleDOI

Role of Brain Insulin Receptor in Control of Body Weight and Reproduction

TL;DR: Mice created with a neuron-specific disruption of the IR gene showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia.
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