Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia
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REVIEW
Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia Nathalie Esser 1,2
&
Kristina M. Utzschneider 1,2
&
Steven E. Kahn 1,2
Received: 20 April 2020 / Accepted: 7 July 2020 / Published online: 31 August 2020 # This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020
Abstract Obesity and insulin resistance are associated with the development of type 2 diabetes. It is well accepted that beta cell dysfunction is required for hyperglycaemia to occur. The prevailing view is that, in the presence of insulin resistance, beta cell dysfunction that occurs early in the course of the disease process is the critical abnormality. An alternative model has been proposed in which primary beta cell overstimulation results in insulin hypersecretion that then leads to the development of obesity and insulin resistance, and ultimately to beta cell exhaustion. In this review, data from preclinical and clinical studies, including intervention studies, are discussed in the context of these models. The preponderance of the data supports the view that an early beta cell functional defect is the more likely mechanism underlying the pathogenesis of hyperglycaemia in the majority of individuals who develop type 2 diabetes.
Keywords Beta cell function . Hyperinsulinaemia . Insulin resistance . Obesity . Prediabetes . Review . Type 2 diabetes Abbreviations DPP-4 Dipeptidyl peptidase-4 GLP-1R Glucagon-like peptide-1 receptor HFD High-fat diet IFG Impaired fasting glucose IGT Impaired glucose tolerance
The beta cell in type 2 diabetes: history of the debate Type 2 diabetes is characterised by hyperglycaemia, typically due to the interaction of insulin resistance and impaired beta cell function [1]. The relative importance of these two critical factors has been extensively debated [2–8]. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-020-05245-x) contains a slideset of the figures for download, which is available to authorised users. * Steven E. Kahn [email protected] 1
Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), Seattle, WA 98108, USA
2
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Four decades ago, many felt insulin resistance was the primary abnormality in type 2 diabetes, with beta cell dysfunction being a later manifestation, when beta cells were no longer able to sustain sufficient insulin secretion to compensate and became ‘exhausted’ [2–5]. In contrast, others postulated that beta cell dysfunction was an early prerequisite for the development of dysglycaemia [6–8]. Currently, the predominantly accepted view is that beta cell dysfunction, manifest as impaired insulin secretion, is a primary independent abnormality that typically occurs early in the pathogenesis of dysglycaemia, on a background of insulin resistance (Fig. 1a). Recently, an alterna
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