|ISSN No. 1606-7754 Vol.16 No.1 April 2008|
Susceptibility to insulin resistance in indigenous Australians may be down stream of resistin.
David A Good1, John Cardinal2, Robert S Ware3, Lisa Marks2, Janine B Kesting1, Lionel CK Chan1, Joanne TE Shaw1
Discipline of Medicine, The University of Queensland, The Prince Charles Hospital, Brisbane, Queensland 40321,Chemical Pathology, Queensland Health Pathology Service, Brisbane, Queensland 40292, School of Population Health, The University of Queensland, Brisbane, Queensland 40063, Australia
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.
Key words: Adipokines, Adiponectin, Diabetes, Leptin, Obesity, Resistin, TNFα
Type 2 diabetes mellitus (T2DM) is an increasingly common condition associated with reduced life expectancy and considerable morbidity. It may remain undetected for a number of years, and consequently, a significant proportion of people with newly diagnosed T2DM have established complications at the time of diagnosis.1
Obesity is thought to be a major risk factor for T2DM. A major complication of obesity is the development of insulin resistance. The mechanisms underlying insulin resistance are unclear. It has been suggested that increased adiposity induces a chronic inflammatory state characterized by elevated circulating levels of adipokines produced from adipocytes or macrophages infiltrating the fat pad.2-4 Many of these cytokines have been shown to antagonize insulin signalling in rodent models leading to an increased secretion of insulin by pancreatic beta cells. T2DM is thought to occur when the internal milieu governing glucose homeostasis is disrupted to such a degree that it overrides residual pancreatic beta cell function.5
Although obesity increases the risk of developing T2DM, not all obese or insulin resistant individuals develop T2DM. There is also a significant role for genetic differences in determining the level of insulin resistance and T2DM susceptibility. A previous study identified three distinct regions of genetic linkage to T2DM in a large indigenous Australian family with a high prevalence of T2DM and obesity.6 In this present study, we aim to better delineate the phenotype of individuals who are susceptible to insulin resistance and T2DM in this family. As adipokines have been implicated in the pathogenesis of diabetes, we measured plasma adipokine levels along with established biochemical risk factors for developing T2DM and compared these variables between individuals with and without T2DM.