Susceptibility to insulin resistance in indigenous Australians may be down stream of resistin

Objective: Obesity is thought to be a major risk factor for the development of insulin resistance and type 2 diabetes mellitus. However, not all obese or insulin resistant individuals develop T2DM suggesting additional factors are required to cause disease. In order to identify additional mechanisms leading to insulin resistance and T2DM, we measured plasma adipokines as well as established biochemical risk factors for developing T2DM in a large indigenous Australian family. Results: We found T2DM individuals had higher insulin resistance (as measured by HOMA-IR) (p< 0.001), triglyceride (p= 0.003), cholesterol (p=0.02) and TNFα (p=0.03) levels than normoglycaemic controls, independent of age, gender and BMI. The alterations in insulin resistance could not be attributed to TNFα, as we did not find a correlation between TNFα and HOMA- IR in either normoglycaemic or T2DM individuals. In contrast, resistin correlated strongly to HOMA-IR in T2DM (p<0.001) but not normoglycaemic individuals despite the lack of significant differences in circulating levels. We also showed obese T2DM individuals had significantly lower leptin levels (p<0.001) and ß cell function (as measured by HOMA-%B) (p<0.001) compared to obese normoglycaemic family members. Conclusion: These results suggest that events downstream of resistin signalling warrant further investigation to identify the cause for increased susceptibility to insulin resistance in this family. The lower leptin levels in obese T2DM individuals may be explained by a reduced ß cell function. Longitudinal studies are required to assess the utility of TNFα and leptin levels in relation to BMI as risk factors for T2DM.