Humoral factors and Insulin Resistance: Role of fetuin-A

Research in my lab is directed towards understanding the molecular mechanisms of INSULIN RESISTANCE, a hallmark of type 2 diabetes mellitus, which is characterized by an attenuated ability of peripheral target tissues to respond to insulin.

Humoral factors secreted by fat and the liver, including hormones and metabolites such as free fatty acids, leptin, adiponectin, resistin, klotho, and visfatin are implicated in regulation of insulin sensitivity. We have identified a novel liver-secreted physiological regulator of insulin action, Fetuin-A, also known as Alpha 2 Heremans Schmid Glycoprotein (Gene symbol: AHSG or FETUA).

Fetuin-A (AHSG) is a phosphorylated glycoprotein, secreted by the liver into circulation that inhibits insulin receptor autophosphorylation and tyrosine kinase activity. Rats fed a high-fat diet demonstrate increased AHSG gene expression levels. The human AHSG gene is localized on chromosome 3q27; a region that is strongly linked to metabolic syndrome and recently identified as a type 2 diabetes-susceptibility locus. In humans, fetuin-A levels are shown to be correlated with insulin resistance and the metabolic syndrome. In French Caucasians, a polymorphism of fetuin-A was shown to be associated with type 2 diabetes.

Recently, we have demonstrated that fetuin-A interacts with the activated insulin receptor. Mice lacking fetuin-A show improved insulin sensitivity and are resistant to weight gain induced by a high-fat diet.

Currently, our goal is to understand AHSG’s mechanism of action and examine the role of phosphorylation in insulin resistant conditions.

Beyond Calories to Cures: Functional Foods

           Functional foods, one of the most popular topics in nutrition and food science today, can be defined as foods that provide health benefits beyond basic nutrition. By this definition, functional foods can include whole foods, such as fruits and vegetables, as well as foods that have been modified to contain additional “bioactive components”. Some examples of bioactive components in functional foods include omega-3 fatty acids (from fatty fish) that reduces triglycerides, plant sterol and stanol esters to reduce total and LDL-cholesterol, ECGC (from green tea) for body-weight control, resveratrol (from grape juice or red wine) for reduced cardiovascular risk and improved general health. Further, numerous herbs and spices have been used for centuries in cultural medicine to treat illness, but there exists little clinical research to validate these health claims.

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       One compound of particular interest to our lab is curcumin, the physiologically active component of the curry spice, turmeric. Turmeric extract is derived from the rhizome (root) of the Curcuma longa plant, which is native to South and Southeast Asia where it is widely used for culinary purposes to add flavor and color to the native cuisine as well as for medicinal purposes to treat a number of health disorders. Previous research has demonstrated the strong anti-inflammatory and antioxidant properties of curcumin. Additionally, curcumin has been shown to be effective in normalizing blood glucose in diabetic rats.

           Currently, one aspect of our research is to understand the role of curcumin in modulating insulin action and glucose metabolism.