McNamara, Catherine Mary; (1999) Early metabolic predictors for the development of Type 2 diabetes in 1st degree relatives. Results of a 10-year follow-up study (1984-1994), together with cross-sectional analyses in 1994. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The relative contributions of reduced insulin sensitivity and beta-cell dysfunction to the pathogenesis of Type 2 diabetes are unknown. In addition, the influence of islet amyloid polypeptide (IAPP) and proinsulin secretion upon disease expression have not been fully characterised. In 1994 a 10 year-follow-up study of 96 previously non-diabetic, 1st degree relatives of Type 2 diabetic subjects was undertaken, with a physiological test-CIGMA(Continuous infusion of glucose with model assessment). The aims were to determine the conversion rate to diabetes, together with the most sensitive baseline predictors for disease progression. Results showed a cumulative prevalence for diabetes of 29% in the case of the siblings by mean age 60(10)y with an additional 8% having Impaired Fasting Glucose (fasting plasma glucose 6.1mmol/1 (IFG), and in the offspring, 10% by mean age 44(8)y with an additional 5% having IFG. The major predictor for conversion to diabetes was the degree of fasting glycaemia at baseline. Neither beta cell function nor insulin sensitivity were predictive. In a separate study, cross-sectional analyses of plasma IAPP and proinsulin concentrations in 58 non-diabetic relatives, 19 control subjects and 39 Type 2 diabetic patients, showed both peptides increased proportionally to C-peptide from normoglycaemia (FPG<5.5mmol/l) to IFG. Once diabetes was established, disproportionate hyperproinsulinaemia occurred, particularly in relation to the lower C-peptide concentrations in the insulin treated diabetics. IAPP levels were highest in relatives with IFG and in the diet and tablet treated diabetics and, like the C-peptide levels were significantly reduced in the insulin treated group. In summary, this study confirms the high prevalence and incidence of Type 2 diabetes in 1st degree relatives of white Caucasian diabetic patients. Raised fasting plasma glucose was the most sensitive predictor of diabetes. It is unlikely that routine assessment of beta-cell function or insulin sensitivity will give clinically useful information indicating which patients with IFG are at greater risk of developing diabetes. Disproportionate secretion of proinsulin did not occur until diabetes was established and is likely to be a secondary phenomenon.

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