Calorie restriction for long-term remission of type 2 diabetes

Abstract

Starting with a hypothesis which postulated a simple explanation arising from the basic cause of type 2 diabetes, a series of studies has introduced a paradigm shift in our understanding of the condition. Gradual accumulation of fat in the liver and pancreas leads eventually to beta cell dedifferentiation and loss of specialised function. The consequent hyperglycaemia can be returned to normal by removing the excess fat from liver and pancreas. At present this can be achieved only by substantial weight loss, and a simple practical and efficacious method for this has been developed and applied in a series of studies. For those people who used to have type 2 diabetes, the state of post-diabetes can be long term provided that weight regain is avoided. The implications for personal health and for national health economics are considerable.

Keywords: Type 2 diabetes; first phase insulin response; liver fat; pancreas fat; reversal of type 2 diabetes.

Fig 1.

The twin cycle hypothesis: during long-term intake of more calories than are expended each day, excess carbohydrate must undergo de novo lipogenesis, which particularly promotes fat accumulation in the liver. As insulin stimulates de novo lipogenesis, people with insulin resistance (determined by family or lifestyle factors) will accumulate liver fat more readily than others due to the higher plasma insulin levels. The increased liver fat will cause relative resistance to insulin-suppression of hepatic glucose production. Over many years a modest increase in fasting plasma glucose level will cause increased basal insulin secretion rates as a homeostatic response. The consequent hyperinsulinemia will increase further the conversion of excess calories into liver fat. A vicious cycle of hyperinsulinemia and inadequate suppression of hepatic glucose production becomes established. Fatty liver leads to increased export of very low density lipoprotein (VLDL) triacylglycerol which will increase fat delivery to all tissues including the islets. Excess fatty acid availability in the pancreatic islet impairs the acute insulin secretion in response to ingested food, and at a certain level of fatty acid exposure, dedifferentiation of the beta cell will occur with post-prandial hyperglycaemia. The hyperglycaemia will further increase insulin secretion rates, with secondary increase of hepatic lipogenesis, spinning the liver cycle faster and driving on the pancreas cycle. Eventually the fatty acid and glucose inhibitory effects on the islets reach a trigger level for dedifferentiation, leading to a relatively sudden onset of clinical diabetes. Figure adapted with permission from R Taylor.

Fig 2.

Data from Counterpoint showing (a) plasma glucose, (b) hepatic triglyceride content, (c) hepatic insulin sensitivity, (d) pancreas triglyceride content and (e) first phase insulin response. Data are shown as mean ±standard error, for diabetic subjects (filled circles) and measured at a single time point for a weight matched non-diabetic control group. Figures reproduced with permission from Lim et al.

Fig 3.

Data from DiRECT showing (a) hepatic triglyceride, (b) total plasma triglycerides, (c) hepatic VLDL1-TG production, (d) intrapancreatic triglyceride, (e) fasting plasma VLDL1-TG and (f) fasting plasma insulin. Time points are at baseline, post weight loss (5 months), and 12 months. Responders (those achieving non-diabetic glucose control; n=40) are shown as a solid line, and non-responders (those remaining in the diabetic range of HbA1c or plasma glucose) as a dotted mid green line. Those randomised to control (continuation of best practice by current guidelines) are shown as a dotted light green line. Figure reproduced with permission from Taylor et al. **p<0.01 vs. baseline, ***p<0.0001 vs. baseline (responders) ††p<0.01 vs. baseline, †††p<0.0001 vs. baseline (non-responders) #p<0.05 vs. 5 months (responders); ‡p<0.05 vs. 5 months (non-responders); ‡‡p<0.01 vs. 5 months (non-responders)