For the section about type 2 diabetes in youth we searched PubMed with the terms “obesity”, “type 2 diabetes”, “children and adolescents”, “youth”, “puberty”, “hepatic steatosis”, “visceral fat”, “fat partitioning”, “IMCL”, and “genes”, and selected publications that we judged to be original and relevant to the topic. Only English-language articles were assessed. For the section about latent autoimmune diabetes in adults (LADA), we searched PubMed and the Cochrane Library with the terms “LADA”
ReviewThe many faces of diabetes: a disease with increasing heterogeneity
Introduction
Diabetes is a disorder of chronic hyperglycaemia, and has traditionally been subdivided into type 1 diabetes (with autoimmune destruction of insulin-secreting β cells) and type 2 diabetes (with insulin resistance and features of metabolic syndrome). However, this subdivision is a gross oversimplification, and poorly describes the true range of diabetes. The notion of diabetes has widened in the past few decades with the realisation that several different overlapping mechanisms can lead to diabetes, and that these mechanisms and manifestations of the disease can be modified by genetic and environmental factors. Diabetes can result from destruction of pancreatic β cells as a result of autoimmune attack (advanced type 1 diabetes), resulting in total insulin deficiency (table 1). Less severe insulin deficiency occurs in patients with pancreatitis. The genetic characterisation of monogenic forms of diabetes (maturity-onset diabetes in the young [MODY]) implies the existence of another type of insulin deficiency, characterised by defective control of insulin secretion; β cells survive and produce insulin, but they respond poorly to increases in plasma concentrations of glucose.6 Mechanisms of defective control also operate in neonatal diabetes and mitochondrial diabetes. Although patients with type 2 diabetes often secrete large amounts of insulin, insulin sensitivity and secretion are imbalanced, and the increased concentration of insulin is not sufficient to meet the increased demands imposed by obesity and insulin resistance.7 Thereby, defective pancreatic β cells account for most, if not all, forms of diabetes.
In addition to these well established notions, many patients present with overlapping features. Indeed, if the processes leading to type 1 diabetes, type 2 diabetes, and MODY are thought to be separate, a proportion of the population might have features of two or more diabetes types. In this Review, we discuss some of the key factors contributing to this heterogeneity, including distorted age at onset for both type 1 and type 2 diabetes, different susceptibilities to obesity in different ethnic groups, and the role of genetic factors. We discuss changing notions rather than provide a complete overview of all diabetic subgroups. Although we discuss young-onset and adult-onset diabetes separately, they share similar aetiopathogenetic processes leading to diabetes. The group with highest heterogeneity and risk of misclassification is young adults (20–40 years of age), who are at the intersection of these two age groups.
Section snippets
Emergence of type 2 diabetes in pubertal and post-pubertal adolescents
Until three decades ago, all diabetic children and adolescents were assumed to have type 1 diabetes. In 1990–99, the age-adjusted incidence of type 1 diabetes per 100 000 children younger than 15 years per year in 114 populations varied from 0·51 in China to 40·9 in Finland;8, 9 the incidence has rapidly risen, particularly in white populations. Type 1 diabetes remains the most common form of diabetes in children.10 However, the accelerating yearly increase in new cases of type 1 diabetes seems
Diabetes with onset in adults
Classification of diabetes is mostly based on age at onset, together with the presence of either obesity and metabolic syndrome or insulin deficiency and autoantibodies; family history can assist with diagnosis. None of these criteria are clear cut. The cutoff for age at onset (35–40 years), traditionally used to distinguish between type 1 and type 2 diabetes, is of little clinical value nowadays. Classification can be particularly difficult in adults aged 20–50 years, during which not only
LADA is heterogeneous
Most patients with type 1 diabetes have pancreatic autoantibodies, which can react with non-specific cytoplasmic antigens in islet cells, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2, insulin, or zinc transporter 8. However, these antibodies have been reported in a subgroup of patients clinically diagnosed with type 2 diabetes, a subgroup that had been given various names (eg, type 1½ diabetes, autoimmune diabetes in adults,53, 54 or slow-onset diabetes in adults) before
Ketosis-prone diabetes in adults
Other hybrid forms of diabetes have features of both type 1 and type 2 diabetes without the autoimmune characteristics of LADA. A peculiar form of non-autoimmune ketosis-prone diabetes was described in African-American youths in the Flatbush suburb of Brooklyn, NY, USA.91, 92 This finding was followed by reports of similar forms of diabetes in patients of sub-Saharan-African descent.5 Although these patients presented with ketosis and severe insulin deficiency, 76% later achieved remission from
Changes in type 2 diabetes in Asia and China
The traditional form of type 2 diabetes is also changing in its presentation, particularly in Asia, where the population seems to be supersensitive to risk factors for type 2 diabetes. Of the Asian countries, China seems to be at highest risk, and its epidemic of type 2 diabetes will soon match that of the Middle East, which has the highest comparative prevalence of diabetes (11%) and health-care expenditures due to diabetes (2·3%).98
China has made astonishing advances in economic development
Conclusions
Diabetes is a much more heterogeneous disease than the present subdivision into type 1 and type 2 diabetes assumes. Both type 1 and type 2 diabetes seem to result from a collision between genes and environment. The rapid increase in incidence of both forms of diabetes suggests that many patients are genetically predisposed to both forms of diabetes. This epidemic also substantially affects and changes the age at onset of the disease. With the increasing possibilities to genetically and
Search strategy and selection criteria
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