L-4 Malnutrition-related diabetes mellitus: Metabolic profile and morphogenesis

L-4 MALNUTRITION-RELATED DIABETES MELLITUS : METABOLIC PROFILE AND MORPHOGENESIS J.S. Bajaj Professor of Medicine, All-India Institute of Medical Sciences, New Delhi, India President, International Diabetes Federation Recent WHO classification of diabetes mellitus includes a class of malnutrition-related diabetes mellitus (MRDM), with its recognisable sub-categories of (i) protein-deficient (PDDM) and (ii) fibrocalculous pancreatic diabetes (FCPD), as originally proposed by us. FCPD is characterised by onset of pancreatic disease during childhood, with peak onset of symptoms of diabetes in the age group 15-35 years. Moderate to severe hyperglycaemia, requiring large doses of insulin for control, and associated with resistance to develop ketosis on insulin withdrawal, constitute the hallmark of metabolic profile. Pancreatic imaging provides evidence of calcification, due to presence of calculi in main pancreatic duct and its branches. Microscopic examination of pancreatic tissue shows diffuse parenchymal fibrosis, dilatation of ducts and ductules, and reduction in the number of acini and islets. Inflammatory changes are minimal or absent. As and ~ cells are equally affected, there is both hypoinsulinemia and hypoglucagonemia. This may provide metabolic basis for absence of ketosis. Epidemiological observations strongly suggest an interactive interdependence between dietary intake of cassave (tapioca) and protein undernutrition, and a possible causal relationship with FCPD. PDDM shares several clinical characteristics with FCPD. However, pancreatic calcification and exocrine pancreatic dysfunction are absent. In contrast to MODY, family history of diabetes is present in only less than ten percent of subjects with PDDM. Glucose stimulated insulin and C-peptide release indicate a significant, although subnormal, residual ~-cell function. Resistance to develop ketosis in PDDM may be due to both the presence of insulin in amounts adequate to inhibit lipolysis, as also a reduction in the number of adipocytes and their lack of response to lipolytic hormones. The causal relationship with protein deprivation in early childhood is suggested by the similarity of carbohydrate dysmetabolism and B-cell dysfunction in Kwashiorkor. The confirmatory evidence comes from studies in the sub-human primate experimental model (Macaca M ~ a ) wherein impaired glucose tolerance eoup£ed with impaired insulin release s in response to glucose challenge are demonstrable within 12 weeks of protein deprivation. A semiquantitative fit of experimental data has been obtained using a nonlinear mathematical model which incorporates both 8-cell kinetics and a glucose-insulin feedback system. The model predicts that it is the function and not the number of B-cells which is reduced in PDDM. Further delineation of MRDM and its descriptive sub-classes of FCPD and PDDM, may provide additional data and indicate possible heterogeneity due to interplay of several causative mechanisms. Intervention strategies for diabetes care and control in developing countries, based on sound epidemiological and demographic premises, must be planned urgently so as to facilitate primordial and primary prevention of diabetes affecting a large segment of young population in these countries.

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