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Insulin action and resistance in obesity and type 2 diabetes

Abstract

Nutritional excess is a major forerunner of type 2 diabetes. It enhances the secretion of insulin, but attenuates insulin's metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes, pointing to a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity seems to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletal muscle. These and other advances over the past 5 years offer exciting opportunities and daunting challenges for the development of new therapeutic strategies for the treatment of type 2 diabetes.

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Figure 1: A model for how HFD feeding and obesity induce insulin resistance, thereby resulting in hyperglycemia and hyperlipidemia.
Figure 2: Effect of a HFD and/or obesity on liver and adipose metabolism.
Figure 3: A model for how HFD feeding and obesity induce hyperinsulinemia and thereby result in insulin resistance, hyperglycemia and hyperlipidemia.
Figure 4: The effects of modulating insulin levels on energy expenditure, adipose browning glucose intolerance and the liver in mice on a high-fat diet.
Figure 5: Adipocyte pathways downstream of insulin signaling to Akt disrupted by HFD feeding and obesity (denoted by asterisks) may contribute to systemic insulin resistance in mice and humans.

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Acknowledgements

I thank M. Birnbaum (Pfizer), S. O'Rahilly (University of Cambridge), and S. Corvera, J. Virbasius, A. Guilherme and D. Pedersen (University of Massachusetts Medical School) for their critical reading of the manuscript and their helpful comments. I also thank our laboratory group members for stimulating discussions on these topics, and L. Smith (University of Massachusetts Medical School) for her contributions to the formatting and editing of the manuscript. The work cited from our laboratory was funded by US National Institutes of Health (NIH) grants DK 103047 and DK 030898, and the Isadore and Fannie Foxman endowed professorship in medical science.

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Czech, M. Insulin action and resistance in obesity and type 2 diabetes. Nat Med 23, 804–814 (2017). https://doi.org/10.1038/nm.4350

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