Diabetes and Insulin Resistance

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Adiponectin's involvement in CVD is likely multifactorial, but one of its main roles is likely in affecting traditional risk factors associated with coronary artery disease (CAD), particularly diabetes. As one of the diabetes susceptibility genes and the adiponectin gene both localize to 3q27, mutation at this locus has been associated with both type 2 diabetes and decreased adiponectin (41).

The majority of data for animal studies thus far suggest that adiponectin acts as an insulin-sensitizing hormone. Adiponectin-knockout mice develop insulin resistance either independently of diet or only after high-fat and high-sucrose diet, and treating these mice with adiponectin ameliorates their insulin resistance (35,42). The insulin resistance in adiponectin-deficient lipoatrophic and obese mice can partially be reversed via adiponectin administration and fully restored with both leptin and adiponectin supplementation (29). Furthermore, in a longitudinal study analyzing the progression of type 2 diabetes in obese monkeys, decrease in adiponectin closely parallels the observed reduction in insulin sensitivity, and the obese monkeys with greater plasma levels of adiponectin had less severe insulin resistance (43).

In humans, type 2 diabetes has been associated with decreased levels of adiponectin (14). In several studies, adiponectin has a negative correlation with fasting glucose, insulin, and insulin resistance and a positive association with insulin sensitivity, independent of BMI (9,14,44). One study demonstrated that adjusting for central obesity renders the negative correlation between adiponectin and insulin resistance no longer significant, suggesting that adiponectin may mediate the relationship between central obesity and insulin resistance (19). In studies involving Pima Indians, Japanese people, and Europeans, subjects with lower adiponectin were more likely to develop type 2 diabetes, independent of adiposity parameters (45-47). In contrast, type 1 diabetic patients have elevated adiponectin levels compared to nondiabetic individuals, and chronically administered insulin does not have an effect on adiponectin levels (48).

Although not entirely known, the cellular and molecular mechanisms linking adiponectin to improved insulin sensitivity are also likely multifactorial. In rodents, adiponectin administration enhances insulin-stimulated glucose uptake into fat and skeletal muscle cells (49-51). By increasing fatty acid oxidation, adiponectin can also lower circulating free fatty acids (FFAs), which may improve insulin action (51,52). Another important function of adiponectin is enhancement of insulin-induced suppression of hepatic glucose production (53,54). By generating nitric oxide (NO) formation, adiponectin may also augment vascular blood flow to promote glucose uptake (55). Taken together, all these effects could explain why giving adiponectin to mice on a high-fat and high-sucrose diet will induce weight loss and reduction in FFA, triglycerides, and glucose levels (56).

Adiponectin may also improve insulin sensitivity by promoting activation of the insulin-signaling system (58). The main enzyme implicated in adiponectin's action is adenosine monophosphate-activated protein kinase (AMPK) (49-51). A recent study demonstrates that binding of adiponectin to two distinct adiponectin receptors increases the levels of this enzyme (57). AMPK prevents activation of other enzymes involved in gluconeogenesis and may stimulate enzymes contributing to fatty acid oxidation (49,50,54,56).

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