Type 2 Diabetes: Etiology and Reversibility

Roy Taylor, MD, FRCP

Disclosures

Diabetes Care. 2013;36(4):1047-1055. 

In This Article

New Perspectives on the β-cell Defect

Chronic exposure of β-cells to triacylglycerol or fatty acids either in vitro or in vivo decreases β-cell capacity to respond to an acute increase in glucose levels.[57,58] This concept is far from new,[59,60] but the observations of what happens during reversal of diabetes provide a new perspective. β-Cells avidly import fatty acids through the CD36 transporter[24,61] and respond to increased fatty acid supply by storing the excess as triacylglycerol.[62] The cellular process of insulin secretion in response to an increase in glucose supply depends on ATP generation by glucose oxidation. However, in the context of an oversupply of fatty acids, such chronic nutrient surfeit prevents further increases in ATP production. Increased fatty acid availability inhibits both pyruvate cycling, which is normally increased during an acute increase in glucose availability, and pyruvate dehydrogenase activity, the major rate-limiting enzyme of glucose oxidation.[63] Fatty acids have been shown to inhibit β-cell proliferation in vitro by induction of the cell cycle inhibitors p16 and p18, and this effect is magnified by increased glucose concentration.[64] This antiproliferative effect is specifically prevented by small interfering RNA knockdown of the inhibitors. In the Zucker diabetic fatty rat, a genetic model of spontaneous type 2 diabetes, the onset of hyperglycemia is preceded by a rapid increase in pancreatic fat.[58] It is particularly noteworthy that the onset of diabetes in this genetic model is completely preventable by restriction of food intake,[65] illustrating the interaction between genetic susceptibility and environmental factors.

Clearly separate from the characteristic lack of acute insulin secretion in response to increase in glucose supply is the matter of total mass of β-cells. The former determines the immediate metabolic response to eating, whereas the latter places a long-term limitation on total possible insulin response. Histological studies of the pancreas in type 2 diabetes consistently show an ~50% reduction in number of β-cells compared with normal subjects.[66] β-Cell loss appears to increase as duration of diabetes increases.[67] The process is likely to be regulated by apoptosis, a mechanism known to be increased by chronic exposure to increased fatty acid metabolites.[68] Ceramides, which are synthesized directly from fatty acids, are likely mediators of the lipid effects on apoptosis.[10,69] In light of new knowledge about β-cell apoptosis and rates of turnover during adult life, it is conceivable that removal of adverse factors could result in restoration of normal β-cell number, even late in the disease.[66,70] Plasticity of lineage and transdifferentiation of human adult β-cells could also be relevant, and the evidence for this has recently been reviewed.[71] β-Cell number following reversal of type 2 diabetes remains to be examined, but overall, it is clear that at least a critical mass of β-cells is not permanently damaged but merely metabolically inhibited.

A wide scatter of absolute levels of pancreas triacylglycerol has been reported, with a tendency for higher levels in people with diabetes.[57] This large population study showed overlap between diabetic and weight-matched control groups. These findings were also observed in a more recent smaller study that used a more precise method.[21] Why would one person have normal β-cell function with a pancreas fat level of, for example, 8%, whereas another has type 2 diabetes with a pancreas fat level of 5%? There must be varying degrees of liposusceptibility of the metabolic organs, and this has been demonstrated in relation to ethnic differences.[72] If the fat is simply not available to the body, then the susceptibility of the pancreas will not be tested, whereas if the individual acquires excess fat stores, then β-cell failure may or may not develop depending on degree of liposusceptibility. In any group of people with type 2 diabetes, simple inspection reveals that diabetes develops in some with a body mass index (BMI) in the normal or overweight range, whereas others have a very high BMI. The pathophysiologic changes in insulin secretion and insulin sensitivity are not different in obese and normal weight people,[73] and the upswing in population rates of type 2 diabetes relates to a right shift in the whole BMI distribution. Hence, the person with a BMI of 24 and type 2 diabetes would in a previous era have had a BMI of 21 and no diabetes. It is clear that individual susceptibility factors determine the onset of the condition, and both genetic and epigenetic factors may contribute. Given that diabetes cannot occur without loss of acute insulin response to food, it can be postulated that this failure of acute insulin secretion could relate to both accumulation of fat and susceptibility to the adverse effect of excess fat in the pancreas.

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