Type 2 Diabetes: Etiology and Reversibility

Roy Taylor, MD, FRCP

Disclosures

Diabetes Care. 2013;36(4):1047-1055. 

In This Article

Introduction

Reversal of type 2 diabetes to normal metabolic control by either bariatric surgery or hypocaloric diet allows for the time sequence of underlying pathophysiologic mechanisms to be observed. In reverse order, the same mechanisms are likely to determine the events leading to the onset of hyperglycemia and permit insight into the etiology of type 2 diabetes. Within 7 days of instituting a substantial negative calorie balance by either dietary intervention or bariatric surgery, fasting plasma glucose levels can normalize. This rapid change relates to a substantial fall in liver fat content and return of normal hepatic insulin sensitivity. Over 8 weeks, first phase and maximal rates of insulin secretion steadily return to normal, and this change is in step with steadily decreasing pancreatic fat content. The difference in time course of these two processes is striking. Recent information on the intracellular effects of excess lipid intermediaries explains the likely biochemical basis, which simplifies both the basic understanding of the condition and the concepts used to determine appropriate management. Recent large, long-duration population studies on time course of plasma glucose and insulin secretion before the diagnosis of diabetes are consistent with this new understanding. Type 2 diabetes has long been regarded as inevitably progressive, requiring increasing numbers of oral hypoglycemic agents and eventually insulin, but it is now certain that the disease process can be halted with restoration of normal carbohydrate and fat metabolism. Type 2 diabetes can be understood as a potentially reversible metabolic state precipitated by the single cause of chronic excess intraorgan fat.

Type 2 diabetes has long been known to progress despite glucose-lowering treatment, with 50% of individuals requiring insulin therapy within 10 years.[1] This seemingly inexorable deterioration in control has been interpreted to mean that the condition is treatable but not curable. Clinical guidelines recognize this deterioration with algorithms of sequential addition of therapies. Insulin resistance and β-cell dysfunction are known to be the major pathophysiologic factors driving type 2 diabetes; however, these factors come into play with very different time courses. Insulin resistance in muscle is the earliest detectable abnormality of type 2 diabetes.[2] In contrast, changes in insulin secretion determine both the onset of hyperglycemia and the progression toward insulin therapy.[3,4] The etiology of each of these two major factors appears to be distinct. Insulin resistance may be caused by an insulin signaling defect,[5] glucose transporter defect,[6] or lipotoxicity,[7] and β-cell dysfunction is postulated to be caused by amyloid deposition in the islets,[8] oxidative stress,[9] excess fatty acid,[10] or lack of incretin effect.[11] The demonstration of reversibility of type 2 diabetes offers the opportunity to evaluate the time sequence of pathophysiologic events during return to normal glucose metabolism and, hence, to unraveling the etiology.

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