# NEONATAL INSULIN SENSITIVITY AND RESPONSIVENESS

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 1994 · $195,463

## Abstract

The overall goal of these investigations is to determine the mechanism(s)
responsible for insulin resistance among newborn dogs.  We and others have
demonstrated that the neonatal period is characterized by imprecise
regulation of glucose metabolism as manifested by fasting hypoglycemia and
alimented induced hyperglycemia.  Using the euglycemic hyperinsulinemic
clamp, we have demonstrated that neonatal insulin resistance in vivo is due
to a postreceptor defect as demonstrated by a reduced maximum rate of
insulin-mediated glucose uptake and by attenuated suppression of endogenous
glucose production.  These preliminary projects have led to further
testable hypotheses related to mechanisms of insulin action due to
immaturity, counterregulatory hormones, and FFA which may cause defects at
the level of the insulin receptor tyrosine kinase activity, and the
cellular uptake of glucose.  Presently there is a paucity of studies which
have simultaneously investigated the kinetic and postreceptor factors which
may be responsible for neonatal insulin resistance.  In addition to reduced
peripheral tissue glucose uptake the newborn demonstrated the attenuated
suppression of hepatic glucose production.  We will investigate the
relationship of this phenomenon with techniques to quantitate insulin's
effect on the suppression of gluconeogenesis.  This will be determined at
the substrate flux level in addition to the enzyme activity and mRNA
expression level.  We hypothesize that ongoing gluconeogenesis is
responsible for the poor suppression of hepatic glucose output in the
newborn mammal.  We also propose to employ the euglycemic hyperinsulinemic
clamp in newborn dogs, combined with specific perturbations which are
present during the neonatal period (e.g., epinephrine, FFA) and analyze
alterations of insulin-mediated glucose uptake.  In addition we will
determine the suppression of endogenous glucose production, receptor
binding characteristics, autophosphorylation of the insulin receptor, and
phosphorylation of receptor-associated proteins.  The insulin sensitive
adult dog will serve as the appropriate control.  It is anticipated that
the results of the proposed investigations will increase our understanding
of neonatal insulin resistance and further our knowledge about insulin
physiology in general.  The understanding of the relationship between
insulin and glucose in animal models of human metabolic problems will
enable more rational care for high-risk infants.

## Key facts

- **NIH application ID:** 2198105
- **Project number:** 5R01HD020851-08
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **SAM.gov UEI:** E8VWJXMMUQ67
- **Principal Investigator:** ROBERT M KLIEGMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $195,463
- **Award type:** 5
- **Project period:** 1985-12-01 → 1995-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2198105

## Citation

> US National Institutes of Health, RePORTER application 2198105, NEONATAL INSULIN SENSITIVITY AND RESPONSIVENESS (5R01HD020851-08). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2198105. Licensed CC0.

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