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Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.

ABSTRACT: Glucose metabolism is normally regulated by a feedback loop including islet ? cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of ?-cell response. If insulin resistance is present, ? cells maintain normal glucose tolerance by increasing insulin output. Only when ? cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although ?-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and ?-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of ?-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease.

SUBMITTER: Kahn SE

PROVIDER: S-EPMC4226760 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.

Kahn Steven E SE Cooper Mark E ME Del Prato Stefano S

Lancet (London, England) 20131203 9922

Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of β-cell response. If insulin resistance is present, β cells maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic component, environmental changes ...[more]

PMID: 24315620

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Project description:Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance given the global changes in lifestyle. Ten years have passed since the first round of genome-wide association studies for T2D and obesity. During this decade, we have witnessed remarkable developments in human genetics. We have graduated from the despair of candidate gene-based studies that generated few consistently replicated genotype-phenotype associations, to the excitement of an exponential harvest of loci robustly associated with medical outcomes through ever larger genome-wide association study meta-analyses. As well as discovering hundreds of loci, genome-wide association studies have provided transformative insights into the genetic architecture of T2D and other complex traits, highlighting the extent of polygenicity and the tiny effect sizes of many common risk alleles. Genome-wide association studies have also provided a critical starting point for discovering new biology relevant to these traits. Expectations are high that these discoveries will foster development of more effective strategies for intervention, through optimization of precision medicine approaches. In this article, we review current knowledge and provide suggestions for the next steps in genetic research for T2D and obesity. We focus on four areas relevant to precision medicine: genetic architecture, pharmacogenetics and other gene-environment interactions, mechanistic inference, and drug development. As we describe, the genetic architecture of complex traits has major implications for the prospects of precision medicine, rendering some anticipated approaches decidedly unrealistic. We highlight obstacles to the translation of human genetic findings into mechanism inference but are optimistic that, as these are overcome, there is untapped potential for novel drugs and more effective strategies for treating and preventing T2D and obesity.

Dataset Information

Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.

Publications

Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.

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