Molecular mechanism of the insulin sensitizing adipokine vaspin

• Published in: Diabetologie und Stoffwechsel
• Main Authors: Heiker, JT, Klöting, N, Kovacs, P, Küttner, EB, Sträter, N, Schultz, S, Kern, M, Stumvoll, M, Blüher, M, Beck-Sickinger, AG
• Format: Conference Proceeding
• Language: English
• Published: 09.05.2011
• ISSN: 1861-9002; 1861-9010
• DOI: 10.1055/s-0031-1277364

Introduction: Obesity represents a fast growing health problem that is reaching epidemic proportions worldwide and is associated with an increased risk of premature death. Obesity significantly increases the risk of developing type 2 diabetes mellitus, hypertension, coronary heart disease, stroke, and several types of cancer. Vaspin (visceral adipose tissue-derived serpin) was identified as an adipokine with insulin-sensitizing effects, which is predominantly secreted from visceral adipose tissue in a rat model of type 2 diabetes (T2D). We recently reported that elevated vaspin serum concentrations are associated with obesity and impaired insulin sensitivity in humans. It has therefore been postulated that increased vaspin expression and secretion could represent a compensatory mechanism associated with obesity, severe insulin resistance, and type 2 diabetes. Although, antiprotease properties have been suggested as mechanism of vaspin action, until now a protease substrate of vaspin has not been identified. Methods and results: Here, we show that the crystal structure of vaspin confirms the typical serpin structure and suggests a protease target. We find that vaspin is expressed in pancreatic b-cells and inhibits a member of the kallikrein family with a high specificity via typical serpin mechanism in vitro. This is the first identified target of vaspin. Consistent with a potential insulin protective role of vaspin, plasma insulin concentrations in response to glucose are higher in mouse models treated with recombinant vaspin compared to controls explaining the glucose lowering effect of vaspin. Significantly lower kallikrein serum concentrations in patients with type 2 diabetes together with increased vaspin expression in obesity/T2D corroborate the vaspin-kallikrein system as a physiological compensation mechanism in the metabolically challenged state of insulin resistance. Conclusion: Our results suggest the vaspin-kallikrein system as a potential novel target for anti-diabetic treatment strategies.