The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes

Abstract

Diabetes is currently of two types. Type I (insulin-dependent) diabetes mellitus is an autoimmune disorder of childhood, characterised by acute onset, ketoacidosis and insulin dependency. Type II diabetes is a metabolic disorder of middle-life, slow in onset and non-insulin-dependent.The definitions need urgent revision. More than half of the patients with Type I diabetes present in adulthood, when their onset is slow and many do not develop acidosis or require insulin for many years [1]. Type II diabetes occurs in teenagers [2], sometimes with keto-acidosis [3], and insulin-dependency frequently ensues given time. Clinically, there is little other than tempo to distinguish two types of diabetes. The HypothesisThe`Accelerator Hypothesis' argues that Type I and Type II diabetes are one and the same, distinguishable only by their rate of beta cell loss and the accelerators responsible. The first accelerator, a constitutionally (intrinsically) high rate of beta-cell apoptosis, is necessary for diabetes to develop but in itself rarely Diabetologia (2001) AbstractBlood glucose concentrations are controlled by a loop incorporating two components, the beta cells which secrete insulin and the insulin-sensitive tissues (liver, muscle, adipose) which respond to it. Loss of blood glucose control might result from failure of the beta cells to secrete insulin, resistance of the tissues to its action, or a combination of both. The distinctions between Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus are becoming increasingly blurred both clinically and aetiologically, where beta-cell insufficiency is the shared characteristic. The`Accelerator Hypothesis' identifies three processes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity.None of the accelerators leads to diabetes without excess weight gain, a trend which the`Accelerator Hypothesis' deems central to the rising incidence of both types of diabetes in the industrially developed world. Weight gain causes an increase in insulin resistance, which results in the weakening of glucose control. The rising blood glucose (glucotoxicity) accelerates beta-cell apoptosis directly in all and, by inducing beta-cell immunogens, further accelerates it in a subset genetically predisposed to autoimmunity. Rather than overlap between two types of diabetes, the`Accelerator Hypothesis' envisages overlay. Body mass is central to the development and rising incidence of all diabetes. Only tempo distinguishes the`types'. The control of weight gain, and with it insulin resistance, could be the means of minimising both.

Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis

“…More recently, Wilkins proposed similar ideas, with a focus on obesity and insulin resistance as the major accelerator [20]. This article argues that the accelerating effects are exerted by a number of risk factors which, acting together via a variety of mechanisms, may all lead to beta cell overload (Fig.…”

Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes?

“…Roles for impaired insulin action and increased insulin demand in the pathogenesis of autoimmune type 1 diabetes have been proposed [4,5]. There are consistent reports indicating that decreased insulin sensitivity leads to the earlier development of diabetes in islet autoantibody-positive relatives, particularly when they show a concomitant decrease in beta cell function [6][7][8].…”

Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions

“…In particular, the HLA DR4_DQB1*0302 haplotype, which is strongly associated with type 1 diabetes, was found to be associated with increased birthweight in the Swedish population [12]. Such relationships have fuelled interest and debate on a possible central role of nutrition and childhood weight status in the pathogenesis of type 1 and type 2 diabetes [14,15].…”