BIOCHEMICAL MECHANISMS OF IN VIVO INSULIN RESISTANCE

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date8/1/945/31/10

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $451,360.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $455,437.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $451,304.00

ASJC

  • Endocrinology, Diabetes and Metabolism
  • Genetics
  • Medicine(all)
  • Biochemistry

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