Though """"""""insulin resistance"""""""" is likely to have multiple primary causes, the impairment in insulin's ability to promote skeletal muscle glucose transport and/or phosphorylation is a recurrent feature. A possible explanation for this observation is that a primary cause of either moderate glucose intolerance (ie, beta cell and/or hepatic defect) or a primary impairment in a major pathway of intracellular glucose disposal (ie, glycogen synthesis and/or glycolysis) may cause the full expression of the insulin resistance syndrome through a common biochemical pathway. Using primary cultures of adipose cells, Marshall and colleagues suggested that the desensitization of the glucose transport system in cells incubated with high levels of glucose and insulin required the metabolism of glucose in the hexosamine biosynthesis pathway. If such a regulatory pathway is operating in skeletal muscle in vivo and is capable of desensitizing the glucose transport system to insulin, it would represent an attractive unifying hypothesis for the presence of defective insulin action on glucose transport/phosphorylation in most insulin resistant states. In fact, increased routing of glucose carbons through the glucosamine pathway could result from a sustained elevation in intracellular fructose-6-phosphate concentrations due to either or both increased glucose availability, ie, chronic hyperglycemia/hyperinsulinemia, and decreased disposal through glycolysis and/or glycogen synthesis. Thus, the mechanism by which hyperglycemia begets impaired insulin action on glucose transport/phosphorylation may shed light on a more fundamental """"""""feed-back control system"""""""" which down- regulates cellular glucose uptake in response to a sustained increase in the intracellular availability of hexose-phosphates. Our proposal will attempt to identify the sequential appearance of metabolic defects in hepatic and skeletal muscle glucose metabolism in a diabetic model of chronic hyperglycemia and moderate hypoinsulinemia and the time-course of their reversal following correction of chronic hyperglycemia by phlorizin treatment. In particular, tracer methodologies recently developed in the conscious rat should allow us to clarify the role of defective glucose-induced suppression of hepatic gluconeogenesis/glycogenolysis and of impaired insulin-mediated inhibition of skeletal muscle glycogenolysis to the development of glucose-induced insulin resistance. We will also examine whether the metabolism of glucose through the glucosamine pathway has the important regulatory role in in vivo glucose-induced desensitization which was suggested in primary culture of adipose cells and whether such a desensitization can be induced through the impairment of intracellular glucose disposal even in the absence of sustained hyperglycemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK048321-05
Application #
2749519
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1998-08-05
Budget End
1999-07-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Lontchi-Yimagou, Eric; You, Jee Young; Carey, Michelle et al. (2018) Potential approaches to prevent hypoglycemia-associated autonomic failure. J Investig Med 66:641-647
Carey, Michelle; Gospin, Rebekah; Goyal, Akankasha et al. (2017) Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans. Diabetes 66:2764-2773
Parks, Elizabeth; Yki-Järvinen, Hannele; Hawkins, Meredith (2017) Out of the frying pan: dietary saturated fat influences nonalcoholic fatty liver disease. J Clin Invest 127:454-456
Esterson, Yonah B; Carey, Michelle; Boucai, Laura et al. (2016) Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes. Diabetes 65:2569-79
Esterson, Yonah B; Carey, Michelle; Piette, John D et al. (2014) A systematic review of innovative diabetes care models in low-and middle-income countries (LMICs). J Health Care Poor Underserved 25:72-93
Davis, Cecilia; Mudd, Jeremy; Hawkins, Meredith (2014) Neuroprotective effects of leptin in the context of obesity and metabolic disorders. Neurobiol Dis 72 Pt A:61-71
Koppaka, Sudha; Kehlenbrink, Sylvia; Carey, Michelle et al. (2013) Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans. Diabetes 62:1843-54
Har, Daniel; Carey, Michelle; Hawkins, Meredith (2013) Coordinated regulation of adipose tissue macrophages by cellular and nutritional signals. J Investig Med 61:937-41
Esterson, Yonah B; Zhang, Kehao; Koppaka, Sudha et al. (2013) Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients. J Investig Med 61:1152-60
Kishore, P; Kehlenbrink, S; Hu, M et al. (2012) Xylitol prevents NEFA-induced insulin resistance in rats. Diabetologia 55:1808-12

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