In an interesting paper the question is asked what if the history of the development of our understanding of diabetes has it wrong? The paper (J. Denis McGarry. What If Minkowski Had Been Ageusic? An Alternative Angle on Diabetes. Science, Vol. 258, No. 5083 (Oct. 30, 1992), pp. 766-770).
Despite decades of intensive investigation, the basic pathophysiological mechanisms responsible for the metabolic derangements associated with diabetes mellitus have remained elusive. Explored here is the possibility that traditional concepts in this area might have carried the wrong emphasis. It is suggested that the phenomena of insulin resistanceand hyperglycemia might be more readily understood if viewed in the context of underlying abnormalities of lipid metabolism.
The author considers the possibility that the hyperinsulinemia of early non-insulin—dependent diabetes is coincident with hyperamylinemia, since insulin and amylin are cosecreted. Amylin would cause an increase in plasma lactate (Cori cycle); and lactate, a better precursor than glucose for fatty acid synthesis, would indirectly promote the production of very-low-density lipoproteins (VLDL). There would follow an increased flux of triglycerides from liver to muscle (and adipose tissue) and, as proposed and elaborated on, an increase in insulin resistance and production of many of the metabolic disturbances occurring in diabetes.
The Randle cycle is a biochemical mechanism involving the competition between glucose and fatty acids for their oxidation and uptake in muscle and adipose tissue. The cycle controls fuel selection and adapts the substrate supply and demand in normal tissues. This cycle adds a nutrient-mediated fine tuning on top of the more coarse hormonal control on fuel metabolism. This adaptation to nutrient availability applies to the interaction between adipose tissue and muscle. Hormones that control adipose tissue lipolysis affect circulating concentrations of fatty acids, these in turn control the fuel selection in muscle. Mechanisms involved in the Randle Cycle include allosteric control, reversible phosphorylation and the expression of key enzymes. The energy balance from meals composed of differing macronutrient composition is identical, but the glucose and fat balances that contribute to the overall energy balance change reciprocally with meal composition.
Fatty acids may act directly upon the pancreatic β-cell to regulate glucose-stimulated insulin secretion. This effect is biphasic. Initially fatty acids potentiate the effects of glucose. After prolonged exposure to high fatty acid concentrations this changes to an inhibition. Randle suggested that the term fatty acid syndrome would be appropriate to apply to the biochemical syndrome resulting from the high concentration of fatty acids and the relationship to abnormalities of carbohydrate metabolism, including starvation, diabetes and Cushing’s syndrome.