The focus of this research is to use a new and exciting methodology of stable isotopomer analysis to determine the hormonal mechanisms controlling gluconeogenesis. In order to understand the regulation of gluconeogenesis, it will be necessary to quantitate and verify the movement of gluconeogenic precursors through the tricarboxylic (TCA) cycle. Research in the quantification of gluconeogenesis has been hampered by the inability to determine 1) the rate of TCA cycle flux (citrate synthase) and 2) the dilution of tracer that occurs at the pyruvate carboxylase, dehydrogenase and kinase steps. Since lactate is believed to be the major contributor to overall gluconeogenesis, this research proposal will administer U-13C lactate and other related isotopes and perform stable isotopomer analysis to quantitate gluconeogenesis by determining the dilutional parameters of the TCA cycle. It is our hypothesis that diabetic patients have a defect in pyruvate dehydrogenase and a secondary increase in pyruvate carboxylase and fasting gluconeogenesis. This may be a primary defect or a secondary effect due to altered hormonal regulation. In order to evaluate the hormonal regulation of hepatic pyruvate dehydrogenase and carboxylase, we will perform pituitary pancreatic euglycemic clamp studies in normal volunteers to evaluate hormonal effects on TCA cycle metabolism. Similar studies will be performed in diabetic patients to test our overall hypothesis and determine if a defect in pyruvate dehydrogenase activity is responsible for the abnormal glucose metabolism known to occur in diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002083-02
Application #
3081015
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1992-01-01
Project End
1996-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
City
Torrance
State
CA
Country
United States
Zip Code
90502
Cherukuri, Lavanya; Smith, Michael S; Tayek, John A (2018) The durability of oral diabetic medications: Time to A1c baseline and a review of common oral medications used by the primary care provider. Endocrinol Diabetes Metab J 2:
Ghanaat, Farhad; Tayek, John A (2005) Growth hormone administration increases glucose production by preventing the expected decrease in glycogenolysis seen with fasting in healthy volunteers. Metabolism 54:604-9
Manglik, Savita; Flores, Eugene; Lubarsky, Laura et al. (2003) Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial. Crit Care Med 31:1668-75
Apostol, Anthony T; Tayek, John A (2003) A decrease in glucose production is associated with an increase in plasma citrulline response to oral arginine in normal volunteers. Metabolism 52:1512-6
Huynh, Nhan T; Tayek, John A (2002) Oral arginine reduces systemic blood pressure in type 2 diabetes: its potential role in nitric oxide generation. J Am Coll Nutr 21:422-7
Richardson, Arthur P; Tayek, John A (2002) Type 2 diabetic patients may have a mild form of an injury response: a clinical research center study. Am J Physiol Endocrinol Metab 282:E1286-90
Khani, S; Tayek, J A (2001) Cortisol increases gluconeogenesis in humans: its role in the metabolic syndrome. Clin Sci (Lond) 101:739-47
Chhibber, V L; Soriano, C; Tayek, J A (2000) Effects of low-dose and high-dose glucagon on glucose production and gluconeogenesis in humans. Metabolism 49:39-46
Katz, J; Tayek, J A (1999) Recycling of glucose and determination of the Cori Cycle and gluconeogenesis. Am J Physiol 277:E401-7
Manglik, S; Cobanov, B; Flores, G et al. (1998) Serum insulin but not leptin is associated with spontaneous and growth hormone (GH)-releasing hormone-stimulated GH secretion in normal volunteers with and without weight loss. Metabolism 47:1127-33

Showing the most recent 10 out of 16 publications