The Role of Lipid Metabolism In Altered Insulin Sensitivity In Endocrine Disease

Abstract

Acromegaly and Cushing's disease are rare endocrine conditions. The lean phenotype of acromegaly is in stark contrast to that of Cushing's, where increased fat deposition is seen. Both conditions are associated with altered insulin sensitivity and lipid metabolism. Using Multi-slice whole body MRI and 1H Magnetic Resonance Spectroscopy, macro and microscopic fat distribution was observed. Using stable isotopes of glucose and glycerol, insulin sensitivity and rates of lipolysis were assessed in the basal and stimulated state. Using Acipimox (synthetic nicotinic acid) to block lipolysis, the impact of Free Fatty Acids (FFA) on insulin sensitivity in these conditions was observed.Acromegaly patients had reduced intrahepatic triglyceride, as measured by 1H MRS. This is a novel finding. Insulin sensitivity was improved by lipolysis inhibition in both the basal and stimulated state in acromegaly; in addition to improved tissue sensitivity, lipolysis blockade improved first phase insulin secretion indicating a possible role of Free Fatty Acids in β Cell toxicity.Cushing's disease was associated with higher visceral adipose tissue (VAT) and had higher intrahepatic triglyceride by 1H MRS, although the latter was not statistically significant. Blocking lipolysis had a more modest effect on basal insulin sensitivity in Cushing's.These results suggest that lipolysis is critical to the development of insulin resistance in acromegaly, and the low hepatic triglyceride suggests that FFA flux through the liver may be responsible for the hepatic insulin resistance seen. Anti-lipolysis has a more modest effect on insulin resistance in Cushing's, perhaps reflecting the differing pathophysiology involved.

Date of Award	31 Dec 2013
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Peter Trainer (Supervisor) & Tara Kearney (Supervisor)