Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause

Abstract

The metabolic abnormalities of type 2 diabetes can be reversed reproducibly by bariatric surgery. By quantifying the major pathophysiological abnormalities in insulin secretion and insulin action after surgery, the sequence of events leading to restoration of normal metabolism can be defined. Liver fat levels fall within days and normal hepatic insulin sensitivity is restored. Simultaneously, plasma glucose levels return towards normal. Insulin sensitivity of muscle remains abnormal, at least over the weeks and months after bariatric surgery. The effect of the surgery is explicable solely in terms of energy restriction. By combining this information with prospective observation of the changes immediately preceding the onset of type 2 diabetes, a clear picture emerges. Insulin resistance in muscle, caused by inherited and environmental factors, facilitates the development of fatty liver during positive energy balance. Once established, the increased insulin secretion required to maintain plasma glucose levels will further increase liver fat deposition. Fatty liver causes resistance to insulin suppression of hepatic glucose output as well as raised plasma triacylglycerol. Exposure of beta cells to increased levels of fatty acids, derived from circulating and locally deposited triacylglycerol, suppresses glucose-mediated insulin secretion. This is reversible initially, but eventually becomes permanent. The essential time sequence of the pathogenesis of type 2 diabetes is now evident. Muscle insulin resistance determines the rate at which fatty liver progresses, and ectopic fat deposition in liver and islet underlies the related dynamic defects of hepatic insulin resistance and beta cell dysfunction. These defects are capable of dramatic reversal under hypoenergetic feeding conditions, completely in early diabetes and to a worthwhile extent in more established disease.

Fatty liver index in polycystic ovary syndrome

“…Whether IR leads to hepatic steatosis or whether fat accumulation in the liver is the primary event leading to hepatic and consequently peripheral IR is not entirely clear (7). It has been proposed that a fatty liver and hepatic IR are key factors in and initiators of a twin vicious cycle underlying the pathophysiology of type 2 diabetes (29). NAFLD, as manifested by elevated ALT levels, predicts the future development of diabetes (30).…”

Targeting beta-cell preservation in the management of type 2 diabetes

“…Exposure of the beta-cells to excess fatty acids derived from circulating and locally deposited triacylglycerol suppresses glucose-mediated insulin secretion. 11 This decline in beta-cell function starts several years before the diagnosis of T2D; the Whitehall II study demonstrated gradually increasing fasting plasma glucose (FPG) levels for 10-12 years prior to diagnosis of T2D. 12 This trajectory changes dramatically two years before diagnosis, reflecting acute beta-cell decompensation ( Figure 1).…”

Dietary reversal of Type 2 diabetes motivated by research knowledge

“…The associated time course of decrease in liver volume is over days [10]. Conversely, the period before onset of Type 2 diabetes is characterized by accumulation of liver fat [11].…”