MECHANISMS OF INSULIN RESISTANCE IN MAN

  • Rizza, Robert Allan (PI)
  • Basu, Rita (PI)
  • Basu, Rita (CoPI)
  • Rizza, Robert Allan (CoPI)

Project: Research project

Project Details

Description

The goal of therapy of patients with diabetes mellitus is to prevent
acute and chronic complications. Until the causes of diabetic
complications are known, presumably therapy should attempt to normalize
glucose metabolism as well as glucose concentration. Diabetes is
associated with alterations in insulin action, insulin secretion, and
counterregulatory hormone concentrations. Furthermore, conventional
insulin therapy results in systemic rather than portal insulin delivery.
The relative contribution of these abnormalities to carbohydrate
intolerance in patients with diabetes mellitus is unknown. Since insulin
and glucose concentrations continuously change after food ingestion, the
rate of onset of insulin action likely is as important as the ultimate
response to a given insulin concentration. Initial experiments will
validate and use single and dual isotope methods to test the hypotheses
that in the presence of euglycemia, rates of insulin induced suppression
of hepatic glucose release and stimulation of glucose uptake are similar
in nondiabetic man with both being impaired in diabetic man. Efforts
also will be made to assess the contribution of gluconeogenesis to
persistent hepatic glucose release during hyperinsulinemia. Next, since
under physiologic conditions insulin concentrations virtually never
increase unless glucose also increases, and since glucose per se is a
powerful regulator of glucose metabolism, computerized infusion systems
will be used to produce glucose and insulin profiles that mimic those
observed in diabetic and nondiabetic patients following food ingestion.
The effects of "nondiabetic" and "diabetic" postprandial glucose profiles
will be assessed in diabetic and nondiabetic subjects to quantitate the
impact of impaired insulin secretion and insulin action on carbohydrate
metabolism and to test the hypotheses that following food ingestion, the
effects of glucose per se compensate for hepatic insulin resistance in
diabetes. In subsequent experiments the regulatory effects and
mechanisms by which physiologic changes in glucagon, growth hormone, and
cortisol influence postprandial glucose metabolism will be determined by
inhibiting and reproducing the normal postprandial suppression of
glucagon and nocturnal increases in growth hormone and cortisol.
Finally, the ability of systemic insulin delivery to normalize glucose
disposition will be examined by comparing postprandial glucose metabolism
and insulin action in patients with combined pancreas/kidney transplants
to that observed in nondiabetic kidney transplant patients taking the
same immunosuppressive agents as well as to that observed in healthy
nondiabetic volunteers. By providing a better understanding of the
interactions among changes in insulin action, insulin secretion, route
of insulin delivery, and the regulatory effects of glucagon, growth
hormone, cortisol and glucose per se on glucose metabolism, the proposed
experiments hopefully will lead to more rational and effective forms of
therapy for people with diabetes mellitus.
StatusFinished
Effective start/end date5/1/827/31/18

Funding

  • National Institutes of Health: $473,660.00
  • National Institutes of Health
  • National Institutes of Health: $78,163.00
  • National Institutes of Health: $522,027.00
  • National Institutes of Health: $522,996.00
  • National Institutes of Health: $516,250.00
  • National Institutes of Health: $575,505.00
  • National Institutes of Health: $651,329.00
  • National Institutes of Health: $523,266.00
  • National Institutes of Health
  • National Institutes of Health: $614,135.00
  • National Institutes of Health
  • National Institutes of Health: $527,583.00
  • National Institutes of Health
  • National Institutes of Health: $574,150.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $503,085.00
  • National Institutes of Health
  • National Institutes of Health: $614,135.00
  • National Institutes of Health: $627,850.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $351,045.00
  • National Institutes of Health
  • National Institutes of Health: $464,271.00
  • National Institutes of Health: $553,065.00
  • National Institutes of Health: $664,154.00
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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