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Metabolic abnormalities preceding non-insulin dependent diabetes

Gelding, Susan Valerie; (1995) Metabolic abnormalities preceding non-insulin dependent diabetes. Doctoral thesis (M.D), UCL (University College London). Green open access

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Abstract

Non-insulin dependent diabetes (NIDDM) is characterised by disturbances in insulin action and insulin secretion with hyperproinsulinaemia, but the primary defect remains unknown. The pathogenesis has a strong genetic component and first-degree relatives of patients with NIDDM constitute a population at-risk. Metabolic abnormalities identified in this predisposed group, whilst glucose tolerance is still normal, may represent the primary cause of NIDDM. With this aim this thesis has investigated insulin secretion and insulin sensitivity in glucose-tolerant first-degree relatives from three ethnic groups. In the progress of this work, three new methods for measuring insulin sensitivity were developed: the low dose short insulin tolerance test; glycerol turnover measured in response to low dose insulin using stable isotopic tracers and a glycerol clamp. Relatives of patients of Asian (Indian-subcontinent) origin had raised fasting circulating immunoreactive insulin and glycerol levels and impaired suppression of glycerol and non-esterified fatty acid concentrations following oral glucose. This suggested insulin resistance, which was confirmed using the short insulin tolerance test. Relatives of European patients possessed more subtle abnormalities; when glycerol turnover was measured isotopically in response to low dose insulin infusion, insulin-induced suppression of lipolysis was impaired; these relatives also demonstrated increased levels of 32, 33 split proinsulin following intravenous glucose, indicating a defect in insulin processing. Afro-Caribbean relatives exhibited disturbed pancreatic B cell processing as well with exaggerated intact and 32, 33 split proinsulin responses to intravenous glucose, but a coexistent defect in insulin sensitivity was also apparent. No abnormality in serum lipoprotein concentrations was identified in any ethnic group, suggesting that the dyslipidaemia of NIDDM is a secondary phenomenon. Insulin insensitivity to lipolysis was present in relatives of all ethnic groups despite normal glucose tolerance, suggesting that this is one of the earliest metabolic abnormalities in the pathogenesis of NIDDM. Insulin processing defects identified in European and Afro-Caribbean subjects may also be of aetiological significance.

Type: Thesis (Doctoral)
Qualification: M.D
Title: Metabolic abnormalities preceding non-insulin dependent diabetes
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10099756
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