Insulin resistance is a highly heritable trait and predisposes to both type 2 diabetes (T2D) and coronary heart disease (CHD). Whilst genome-wide association approaches have revealed multiple variants reproducibly associated with either T2D or CHD few of these variants are shared at a biological level. Additionally, there are no common variants yet reported to be reproducibly associated with biochemical measures of insulin resistance. Using serum adiponectin levels as a surrogate biomarker of insulin sensitivity, we aim to perform a meta-analysis of 3 genome-wide association studies and sought replication of our findings in 5 additional cohorts (including the ALSPAC children with non-fasting adiponectin levels measured at age 9).

Insulin resistance is a quantitative trait that predisposes to, and predicts independently, adverse metabolic and cardiovascular outcomes such as type 2 diabetes (T2D) and coronary heart disease (CHD)(1-3). Although factors such as obesity, diet and exercise importantly influence insulin resistance there is compelling evidence that it is strongly influenced by hereditary factors(4), yet few genetic determinants of insulin resistance have been described and none of these have been found to alter risk of T2D and CHD.

The precise mechanism through which insulin resistance has adverse impacts on metabolic and cardiovascular outcomes is as yet unclear and, indeed, may differ depending on the particular downstream pathology. Thus, while impaired insulin action per se may contribute directly to hyperglycemia, it has been suggested that the compensatory hyperinsulinemia that inevitably accompanies insulin resistance in the non-diabetic individual may have adverse consequences on the vasculature and liver that could predispose to athero-thrombosis(5, 6). However the precise quantification of insulin resistance in the epidemiological setting is challenging; "gold standard" measures of insulin resistance require technically demanding hyperinsulinemic clamp studies employing stable isotopes to dissect hepatic effects of insulin from those on muscle and fat, and such studies have consequently rarely been performed in populations large enough to generate meaningful information through genome wide association (GWA) studies(7).

We plan to undertake a large-scale meta-analysis of GWA studies (n = 14, 733) of circulating adiponectin levels in the hope that this will reveal common genetic variants that might at least in part explain the heritability of insulin resistance. Given the importance of insulin resistance as a precursor of both T2D and CHD, we anticipated that the identification of genetic variants associated with circulating adiponectin levels might be exerting their effects through an influence on insulin sensitivity/resistance and that such variants might therefore modulate the risk of T2D or CHD, or indeed both.

1. Chen, K.W., Boyko, E.J., Bergstrom, R.W., Leonetti, D.L., Newell-Morris, L., Wahl, P.W., and Fujimoto, W.Y. 1995. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-Year follow-up of initially nondiabetic Japanese-American men. Diabetes Care 18:747-753.

2. Beck-Nielsen, H., and Groop, L.C. 1994. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 94:1714-1721.

3. Meigs, J.B., Wilson, P.W., Fox, C.S., Vasan, R.S., Nathan, D.M., Sullivan, L.M., and D'Agostino, R.B. 2006. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 91:2906-2912.

4. Laws, A., Stefanick, M.L., and Reaven, G.M. 1989. Insulin resistance and hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 69:343-347.

5. Despres, J.P., Lamarche, B., Mauriege, P., Cantin, B., Dagenais, G.R., Moorjani, S., and Lupien, P.J. 1996. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952-957.

6. Semple, R.K., Sleigh, A., Murgatroyd, P.R., Adams, C.A., Bluck, L., Jackson, S., Vottero, A., Kanabar, D., Charlton-Menys, V., Durrington, P., et al. 2009. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest.

7. Howard, G., O'Leary, D.H., Zaccaro, D., Haffner, S., Rewers, M., Hamman, R., Selby, J.V., Saad, M.F., Savage, P., and Bergman, R. 1996. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation 93:1809-1817.