Endocrine Abstracts (2011) 26 P667

Unacylated ghrelin improves insulin sensitivity in the early phase of obesity

P J D Delhanty1, M Huisman1, I van den Berge1, T Abribat2, A P N Themmen1 & A J van der Lely1

1Erasmus MC, Rotterdam, The Netherlands; 2Alizé Pharma, Lyon, France.

In Europe more than 50 million adults are diabetic. Of these, 90–95% have type 2 diabetes (T2D). It is also recognized that an even larger population is insulin resistant and it is thought that treatment at this early phase of the metabolic syndrome may prevent the occurrence of overt diabetes and associated pathologies. We are in the process of developing unacylated ghrelin (UAG) analogues as therapeutics for T2D. Towards this goal, we have used a mouse protocol in which we pretreat mice with the analogues, then initiate a short-term high fat diet (HFD) to induce insulin resistance but not diabetes. Twelve week old C57BL/6 mice (n=10) were fed either normal chow (12% kcal from fat), or a HFD consisting of 41% kcal from fat, for 2 weeks. We assessed animal weight, food intake, fat mass, fed and fasting plasma glucose concentrations, and glucose tolerance (glucose tolerance tests) during the study, then insulin sensitivity (insulin tolerance tests, ITT) at the end of the study. Body weight was significantly increased by the HFD during the study period, and fat mass was markedly increased by ~2.5-fold compared with animals on control diets. This occurred despite a decrease in food intake in this group. The animals on the HFD became glucose intolerant, and insulin resistant. Infusion of UAG and analogues had no consistent effects on glycemia or glucose tolerance in this short-term model. Importantly, though, insulin sensitivity was significantly improved, as assessed by ITT, in agreement with our preliminary data in obese diabetic ob/ob mice. UAG agonists may be of use as therapeutics in the treatment of insulin resistance in metabolic syndrome.

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