UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Most often, the metabolic disorders of carbohydrate (CHO) and fat metabolism have been studied independently, and the importance of their mutual interaction has been overlooked. My interest in the inter-relationship between CHO and fat metabolism was triggered by the fact that, although individuals with insulin resistance and type 2 diabetes are identified and treated for their problems with CHO homeostasis, they often have equally important perturbations of fat homeostasis (dyslipidemia) and are more likely to die from cardiovascular diseases. For these reasons, I have concentrated my research efforts on whole body and hepatic fuel homeostasis with special attention to the inter-relationship between carbohydrate and fat metabolism.

I felt that studying simultaneously the interplay between hepatic de novo lipogenesis ( DNL), glucose production and gluconeogenesis (GNG) would lead to a better understanding of the pathophysiology at the origin of hypertriglyceridemia and hyperglycemia. Indeed, the pathway converting CHO to fat (DNL) shares precursors with the GNG pathway and is a biochemical bridge between CHO and fat metabolism. This latter fact and our preliminary studies led me to hypothesize that hepatic DNL was an important regulatory pathway diverting part of the GNG flux to better control GNG and glucose production.

We chose three main approaches to test this hypothesis in humans. One approach was to stimulate hepatic DNL by energy overfeeding with CHO or by feeding energy balanced high CHO diets and to monitor how this affects glucose production in healthy controls. The second approach was to utilize insulin resistant patients (such as obese and critically ill patients) who often have defects in glucose homeostasis and determine how these defects impact DNL. Finally, the third approach was to test if inhibition of hepatic DNL had an impact on GNG and glucose production.

Selected References

Schwarz J-M, Mulligan K, Lee J, Lo JC, Noor M, Wen M, Grunfeld C, Schambelan M. The effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 87(2): 942-945, 2002.

Schwarz J-M, Linfoot PA, Dare D, and Aghajanian K. Hepatic de novo lipogenesis in normo and hyperinsulinemic subjects consuming high-fat/low-carbohydrate and low-fat/high-carbohydrate isoenergetic diets Am J of Clin Nutr 77 (1): 43-50, 2003.

Faeh D, Minehira K, Schwarz J-M, Periasamy R, Park S, Tappy L. Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy males. Diabetes 54:1907-1913, 2005.

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