Banting Memorial lecture 2012: reversing the twin cycles of type 2 diabetes

Abstract

It has become widely accepted that Type 2 diabetes is inevitably life-long, with irreversible and progressive beta cell damage. However, the restoration of normal glucose metabolism within days after bariatric surgery in the majority of people with Type 2 diabetes disproves this concept. There is now no doubt that this reversal of diabetes depends upon the sudden and profound decrease in food intake, and does not relate to any direct surgical effect. The Counterpoint study demonstrated that normal glucose levels and normal beta cell function could be restored by a very low calorie diet alone. Novel magnetic resonance methods were applied to measure intra-organ fat. The results showed two different time courses: a) resolution of hepatic insulin sensitivity within days along with a rapid fall in liver fat and normalisation of fasting glucose levels; and b) return of normal beta cell insulin secretion over weeks in step with a fall in pancreas fat. Now that it has been possible to observe the pathophysiological events during reversal of Type 2 diabetes, the reverse time course of events which determine the onset of the condition can be identified. The twin cycle hypothesis postulates that chronic calorie excess leads to accumulation of liver fat with eventual spill over into the pancreas. These self-reinforcing cycles between liver and pancreas eventually cause metabolic inhibition of insulin secretion after meals and onset of hyperglycaemia. It is now clear that Type 2 diabetes is a reversible condition of intra-organ fat excess to which some people are more susceptible than others.

FIGURE 1

Change in fasting plasma glucose during the 13 years prior to onset of Type 2 diabetes. These data from the Whitehall II study demonstrate the elevation of plasma glucose within the normal range for many years, but a sudden breakdown of control mechanisms around 2 years prior to diagnosis. Data replotted from Tabak et al. (2009), with permission from Elsevier .

FIGURE 2

(a) Rates of insulin secretion by islets from pre-diabetic male Zucker diabetic fatty (ZDF) rats when in vitro glucose concentration is raised from 3 to 23 mmol/l and when arginine is added at 20 mmol/l. Pre-incubated at 3 mmol/l glucose only (black line); pre-incubated for 7 days with 2 mmol/l oleic and palmitic acid (grey line). In susceptible islets, excess provision of alternative fuel prevents ATP production from glucose or arginine, and this causes decreased insulin secretion. Data replotted from Lee et al. (1994) with permission from Dr Roger H. Unger [9]. (b, c) Exposure of human islet to fatty acid causes an increase in intra-islet fat storage (b) and a marker of apoptosis (c). Data replotted from Lalloyer et al. (2006) with permission from American Diabetes Association .

FIGURE 3

During the 18 months prior to diagnosis of Type 2 diabetes, serum ALT rises steadily (solid line). This is likely to reflect the steadily increasing burden of fat within hepatocytes. In any one individual, this change may go unnoticed as for most people it remains within the range of normal. Serum ALT is also shown for the larger group who did not develop diabetes (dotted line). Data replotted from Sattar et al. (2007) with permission from American Diabetes Association .

FIGURE 4

On the left is a standard image of the abdomen. As the atomic nuclei of protons in fat and water resonate at slightly different frequencies, it is possible to separate the signals from each. Separate images of fat (upper) and water (lower) can be derived. Then, for every single pixel the percentage of fat can be calculated and plotted as an image (right). This allows averaging of the percentage of fat for each pixel definitely within the pancreas and, as the pancreas is identified after acquisition of the image, this can be precisely determined. The same process can be applied to liver, avoiding major vessels.

FIGURE 5

Effect of a very low calorie diet in Type 2 diabetes on fasting plasma glucose (upper panel), basal rate of hepatic glucose production (HGP) (middle panel) and hepatic triacylglycerol (TG) content (lower panel). For comparison, data from a matched control group without diabetes are shown as open circles. Reproduced from Lim et al. (2011) .

FIGURE 6

After induction of sudden negative calorie balance, there was an immediate improvement in insulin sensitivity of liver (upper panel), in sharp contrast to no change in muscle (lower panel). Insulin sensitivity for liver is shown as the degree of suppression of hepatic glucose output (HGP) during an insulin clamp (insulin infusion rate 40 mU m⁻² min⁻¹) and for muscle as clamp glucose disposal rate. The dotted lines indicate the mean values for the normoglycaemic control group. Data replotted from Lim et al. (2011) .

FIGURE 7

The Stepped Insulin Secretion Test was carried out in test subjects and control subjects by stepwise elevation of plasma glucose, then administration of a bolus of arginine. (a) Achieved plasma glucose levels in each group. (b) Insulin section rates (ISR) in a matched control group. c) Diabetes group at baseline. (d) Diabetes group at 1 week of diet. (e) Diabetes group at 4 weeks. (f) Diabetes group at 8 weeks. It can be seen that both first-phase response and maximal (arginine-stimulated) rates of insulin secretion return to normal. Reproduced from Lim et al. (2011) .

FIGURE 8

During the 8 weeks of the hypocaloric diet there were steady and reciprocal changes in first-phase insulin secretion (upper panel) and pancreas fat content (lower panel). Values for the weight-matched control group without diabetes are shown as open circles. Reproduced from Lim et al. (2011) .

FIGURE 9

This bicycle is controlled by handlebars representing chronic, excess (XS) calorie intake in the presence of muscle insulin resistance. Raised plasma insulin levels will expedite chronic excess calorie storage from carbohydrate via de novo lipogenesis, and hence promote liver fat storage. This will cause the liver to become relatively resistant to insulin and a small increase in plasma glucose will occur. In turn, insulin secretion will increase to control plasma glucose down. The further increased insulin levels will bring about a self-reinforcing cycle. Excess fat will result in increased export of VLDL triglyceride from the liver, uptake by islets and inhibition of meal insulin secretion. At a personal threshold, the pancreas fat becomes too great a load and plasma glucose levels will then rise relatively rapidly. HGP, hepatic glucose production.