During the post-absorptive period hepatic glucose production becomes the major source of new glucose production and the major determinant of hyperglycemia in the diabetic state. Evidence suggests that during this period hepatic glucose production (HGP) may be controlled by peripheral events. The major hypothesis to be tested is that a signalling mechanism exists between the periphery and the liver which may play an important role in post- absorptive hyperglycemia of diabetes. Peripheral signalling will be examined in two situations in which HGP may be controlled by peripheral events--during (1) sleep when HGP and peripheral metabolic events are synchronized and (2) following administration of insulin in quantities not increasing Rd or portal vein insulin levels. Peripheral signalling will be evaluated in terms of body composition (males, females, young, old thin obese, growth hormone deficient). The specific signal(s) involved will be assessed by replacement of any metabolites whose plasma concentration has fallen in conjunction with reduced HGP (free fatty acids, glycerol, lactate, alanine). The effect of these signals on qualitative aspects of HGP such as the proportion of HGP from gluconeogenesis vs glycogenolysis and the rate of futile cycling will also be evaluated. The association between android obesity, HGP, and carbohydrate metabolism will be explored by portal vein studies assessing the signal/substrate release from omental vs peripheral fat and the metabolic activity (lipolysis and re-esterification) of omental compared to peripheral fat. Finally, the signalling nature of peripherally derived metabolites will be examined in a well- defined hepatocyte culture system designed to examine carbon flux into glucose via either the direct pyruvate carboxylase or TCA pathway at the first branch point in gluconeogenesis. The putative signalling mechanism will be examined in non-obese, non-diabetic, obese, and diabetic subjects. The experiments are expected to indicate that signals (independent of substrate provision) from the periphery including omental fat stimulate gluconeogenesis, futile cycling, and HGP, but that the hyperinsulinemia of obesity restrains the latter two. Only in the diabetic state when insulin secretion has decreased are the increase in futile cycling and HGP observed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK018903-13
Application #
3226194
Study Section
Nutrition Study Section (NTN)
Project Start
1979-06-01
Project End
1993-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
13
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Clore, J N; Li, L; Rizzo, W B (2000) Effects of fructose and troglitazone on phospholipid fatty acid composition in rat skeletal muscle. Lipids 35:1281-7
Clore, J N; Harris, P A; Li, J et al. (2000) Changes in phosphatidylcholine fatty acid composition are associated with altered skeletal muscle insulin responsiveness in normal man. Metabolism 49:232-8
Blackard, W G; Li, J; Clore, J N et al. (1997) Phospholipid fatty acid composition in type I and type II rat muscle. Lipids 32:193-8
Nestler, J E (1995) Regulation of human dehydroepiandrosterone metabolism by insulin. Ann N Y Acad Sci 774:73-81
Blackard, W G; Clore, J N; Kellum, J M (1994) Amylin/insulin secretory ratios in morbidly obese man: inverse relationship with glucose disappearance rate. J Clin Endocrinol Metab 78:1257-60
Blackard, W G; Clore, J N; Glickman, P S et al. (1993) Insulin sensitivity of splanchnic and peripheral adipose tissue in vivo in morbidly obese man. Metabolism 42:1195-200
Clore, J N; Post, E P; Bailey, D J et al. (1992) Evidence for increased liver glycogen in patients with noninsulin-dependent diabetes mellitus after a 3-day fast. J Clin Endocrinol Metab 74:660-6
Clore, J N; Stillman, J S; Helm, S T et al. (1992) Evidence for dissociation of gluconeogenesis stimulated by non-esterified fatty acids and changes in fructose 2,6-bisphosphate in cultured rat hepatocytes. Biochem J 288 ( Pt 1):145-8
Nestler, J E; McClanahan, M A (1992) Diabetes and adrenal disease. Baillieres Clin Endocrinol Metab 6:829-47
Clore, J N; Glickman, P S; Nestler, J E et al. (1991) In vivo evidence for hepatic autoregulation during FFA-stimulated gluconeogenesis in normal humans. Am J Physiol 261:E425-9

Showing the most recent 10 out of 23 publications