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Drug Development Strategy for Type 2 Diabetes: Targeting Positive Energy Balances

[ Vol. 20 , Issue. 8 ]


Zhenqi Liu and Baichun Yang*   Pages 879 - 890 ( 12 )


Newer classes of medications have been proven useful in glycemic control in type 2 diabetes (T2D), but many do not appear capable to slow down the progressive loss of ß-cell function, or to improve population-level glycemic control. Positive energy balance, e.g. surplus energy intake over expenditure, is at the core for developing metabolic syndrome and T2D. Currently available glycemic control drugs come to the market based on their 1-2 years risk-benefit profiles, but most of them do not correct positive energy balance and lose efficacy in the long-term. This denouement is destined by a positive energy balance of T2D. There is continuous endeavor/investment in new drugs for T2D. In this review, we compared the effects of commonly used oral hypoglycemic agents on energy balance and discussed several novel therapeutic targets/approaches for T2D that could potentially correct positive energy balance: changing the composition of intestinal host-microbiota to alleviate excess caloric consumption, controlling chylomicron uptake into intestinal lacteals to reduce excessive caloric intake, and activating pyruvate kinase M2 (PKM2) to ameliorate glucose metabolism and increase energy expenditure. We further reviewed how nicotine affects body weight and ameliorates positive energy balance, and ways to encourage people to adopt a more healthy lifestyle by exercising more and/or decreasing caloric intake. These potential targets/approaches may hopefully correct positive energy balance, delay disease progression, reverse some pathophysiological changes, and eventually prevent and/or cure the disease. Drug development strategies applying new insights into T2D process and therapeutic index to correct positive energy balance need to be seriously considered.


Type 2 diabetes, positive energy balances, glycemic control, drug development strategy, intestinal microbiota, intestinal lacteal chylomicron, mitochondrial glycolytic flux.


Division of Endocrinology & Metabolism, Department of Medicine, University of Virginia School of Medicine, 450 Ray C. Hunt Dr. Charlottesville, VA 22903, Division of Cardiovascular and Renal Products, Office of New Drugs I, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993

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