Elsevier

The Lancet

Volume 378, Issue 9786, 9–15 July 2011, Pages 169-181
The Lancet

Seminar
Type 2 diabetes across generations: from pathophysiology to prevention and management

https://doi.org/10.1016/S0140-6736(11)60614-4Get rights and content

Summary

Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.

Introduction

Type 2 diabetes mellitus is a metabolic disorder of fuel homoeostasis characterised by hyperglycaemia and altered lipid metabolism caused by islet β cells being unable to secrete adequate insulin in response to varying degrees of overnutrition, inactivity, consequential overweight or obesity, and insulin resistance. The burden of this disorder is enormous, owing to its rapidly increasing global prevalence, the devastating damage it can do to many organs of the body, and the direct and indirect costs. In this Seminar we discuss developments in the understanding of the pathogenesis of type 2 diabetes from epidemiology, genetics, epigenetics, and molecular cell biology, with emphasis on the emerging role of fetal and neonatal programming, and we underscore the need for a whole-of-life approach to prevention and management.

Section snippets

Epidemiology

A growing non-communicable disease epidemic

The estimated worldwide prevalence of diabetes among adults was 285 million (6·4%) in 2010, and this value is predicted to rise to around 439 million (7·7%) by 2030 (table 1).1 Type 2 diabetes is the predominant form and accounts for at least 90% of cases.2 The rise in prevalence is predicted to be much greater in developing than in developed countries (69% vs 20%).1 In developing countries people aged 40–60 years (ie, working age) are affected most,

Diagnosis

Recommendations for diagnostic strategies and criteria for hyperglycaemic disorders, including diabetes, in the general population as well as in pregnant women, have been revised and issued by WHO, the American Diabetes Association (ADA), and the IADPSG (table 2; for a more detailed discussion see webappendix p 1).11, 21, 22 Of particular note, WHO and ADA have both recommended that a glycated haemoglobin A1c (HbA1c) concentration of 6·5% or higher can be used to diagnose diabetes.21, 22 The

Pathophysiology

A brief overview of normal glucose homoeostasis is presented in figure 2.

Prevention and management

The pandemic of type 2 diabetes, along with its high human and economic costs, is showing no signs of abatement and, therefore, new approaches are urgently needed to prevent, slow the progression, and limit the consequences of this disease. Changes need to be based on knowledge of the pathophysiology and to take into account new insights from genetic and epigenetic studies. A whole-of-life approach is indicated, particularly for prevention.

Conclusions

To turn around the pandemic of type 2 diabetes and its effect on lives and economies worldwide is necessary, but is a major challenge for modern society. An improved understanding of the pathogenesis and natural history is crucial to focus efforts appropriately. Substantial evidence of safety and efficacy of candidate prevention and treatment strategies must be provided before they can be widely implemented. We propose that the whole of patients' lives need to be considered for effective

Search strategy and selection criteria

We searched PubMed with the terms “type 2 diabetes”, “prediabetes”, “gestational diabetes”, “obesity”, “insulin secretion”, “islet beta-cell dysfunction”, “beta-cell failure”, “insulin resistance”, “epidemiology”, “susceptibility genes”, “epigenetics”, “fetal origins of adult disease”, “diabetes complications”, “oral hypoglycaemic agents”, “incretin therapy”, “insulin therapy”, and combinations of these terms. We selected English language original and review articles mainly published between

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