In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

/pdf/type-2-non-insulin-dependent-diabetes-mellitus-the-thrifty-wkzyogfl8p.pdf

Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

Glucose reacts nonenzymatically with the NH2-terminal amino acid of the beta chain of human hemoglobin by way of a ketoamine linkage, resulting in the formation of hemoglobin AIc. Other minor components appear to be adducts of glucose 6-phosphate and fructose 1,6-diphosphate. These hemoglobins are formed slowly and continuously throughout the 120-day life-span of the red cell. There is a two- to threefold increase in hemoglobin AIc in the red cells of patients with diabetes mellitus. By providing an integrated measurement of blood glucose, hemoglobin AIc is useful in assessing the degree of diabetic control. Furthermore, this hemoglobin is a useful model of nonenzymatic glycosylation of other proteins that may be involved in the long-term complications of the disease.

https://science.sciencemag.org/content/sci/200/4337/21.full.pdf

The glycosylation of hemoglobin: relevance to diabetes mellitus

Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis

A technique was devised for a more accurate measurement than has been heretofore possible of one of the factors responsible for hyperglycemia in the complex syndrome of diabetes. This factor is termed impedance and represents the tissues' insensitivity or resistance to insulin-mediated glucose uptake. It was measured by use of steady-state exogenous insulin and glucose infusions during a period of pharmacological suppression of endogenous insulin secretion. Endogenous new glucose production was also inhibited. Impedance as calculated is a direct function of steady-state glucose concentrations, since exogenous insulin concentrations were similar in all studies. Two groups of normal weight subjects were studied. One had maturity onset latent diabetes, and the other (matched for age, weight, and per cent adiposity) was normal. Impedance was closely reproducible in the same individual and remained relatively constant during prolonged infusions. The diabetics had average infusion glucose concentrations (and thus impedance) 68% higher than the normal group, and it is of note that their previously measured glucose intolerance differed by a similar degree; that is, the diabetic's intolerance (as defined by mean weighted plasma glucose response after oral glucose) was 52% greater than that of the normal individuals.

/pdf/comparison-of-impedance-to-insulin-mediated-glucose-uptake-1uzbk8dp8f.pdf

Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes

Even before the introduction of insulin therapy in 1922, retinopathy, neuropathy and proteinuria had all been described in association with diabetes mellitus. However, as the use of insulin has permitted long-term survival of young diabetic subjects, the full extent of the problems caused by these and other chronic complications (nephropathy, generalized microangiopathy and atherosclerosis) has become more apparent. Diabetes is one of the major causes of visual loss in the developed world; and premature death, now usually due to atherosclerosis or renal failure, is still all too common in the diabetic subject. In the continuing debate about the pathogenesis of diabetic complications, much speculation and controversy has focussed on the possible role of chronic hyperglycaemia. The long-term, evolutionary nature of the complications, the lack of reliable objective indices of glycaemic control, and the inability to achieve normal physiological glycaemic control with subcutaneous insulin therapy are among the factors that have prevented resolution of this basic controversy. Nevertheless, there is an increasing body of evidence, based on both clinical experience with patients [1, 2] and animal model studies [3], which indicates that chronic hyperglycaemia may be the major factor contributing to the long-term complications of diabetes. Detection of the minor haemoglobins, HbAlc and HbAl(a+b+o) [4] and their chemical characterization as non-enzymatically glycosylated derivatives of haemoglobin [5-7], has added new dimensions to the continuing debate on the role of hyperglycaemia in the complications of diabetes. Thus, measurement of glycosylated haemoglobin provides an objective, retrospective index of glycaemic control [8-12]. Serial measurements should provide a truer reflection than previously possible of long-term glycaemic control in prospective studies of the development of diabetic complications. In addition, it has become clear that haemoglobin is not unique, and that non-enzymatic glycosylation is in fact a common post-translational modification of many body proteins. Thus glycosylation results from a direct chemical reaction between glucose and amino groups on protein. The first stable product of the reaction is termed the ketoamine adduct to protein, but, from studies of protein-reducing sugar systems in vitro, the ketoamine is known to undergo further dehydration, rearrangement and cleavage reactions. The final products in vitro are highly crosslinked, insoluble, pigmented and fluorescent carbohydrate-protein polymers, called melanoidins (hence this is termed the browning reaction). Whether these products of the browning reaction are also formed in vivo is not yet known. However, since non-enzymatic glycosylation is enhanced during hyperglycaemia, it is not surprising that there has been much speculation concerning its role, and the role of the subsequent browning reactions in the pathogenesis of the complications of diabetes [13, 14]. The purpose of this article is to review and evaluate the existing evidence in support of this speculation. To this end, it is convenient to consider individual proteins or groups of proteins in turn.

/pdf/non-enzymatic-glycosylation-and-the-chronic-complications-of-32z7d9yd6u.pdf

Non-enzymatic glycosylation and the chronic complications of diabetes: an overview.

Evidence for proinsulin in human urine and serum

Immunosuppression in the treatment of insulin-dependent (type 1) diabetes

Spontaneous hypoglycaemia in congestive heart-failure.

Relation of renal growth to diabetic glomerulosclerosis

Acute effect of ascorbic acid infusion on carbohydrate tolerance.

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