• Kirkland, James L (PI)
  • Must, Aviva (PI)
  • Grand, Richard (PI)
  • Corkey, Barbara E. (PI)
  • Roberts, Susan (PI)
  • Istfan, Nawfal (PI)
  • Miller, Donald (PI)
  • Chen, Kim (PI)
  • Kelly, Kathleen (PI)
  • Flier, Jeffrey (PI)
  • Dietz, William (PI)
  • Colditz, Graham (PI)
  • Kelly, Kathleen (PI)
  • Colditz, Graham (PI)
  • Hu, Frank (PI)
  • Lowell, Bradford (PI)
  • Roberts, Susan (PI)
  • Istfan, Nawfal (PI)
  • Chen, Kim (PI)
  • Flier, Jeffrey (PI)
  • Dietz, William (PI)
  • Corkey, Barbara E. (PI)
  • Fried, Susan (PI)
  • Miller, Donald (PI)
  • Rosen, Evan (PI)
  • Corkey, Barbara E. (PI)

Project: Research project

Project Details


This proposal will examine the hypothesis that the insulin resistance
associated with obesity is a consequence of increased diacylglycerol (DAG)
synthesis, with resultant elevation of protein kinase C (PKC) activity and
feedback inhibition of insulin targets, such as the insulin receptor
tyrosine kinase and glycogen synthase. The hypothesis is based on
preliminary findings of a paradoxical increase in insulin-stimulated DAG
synthesis and elevated PKC activity in two "insulin resistant" conditions,
hyperinsulinemia/hyperglycemia and denervation. The increases in DAG under
those conditions were glucose- and insulin-dependent, and occurred in a
metabolically species of DAG. The increase in DAG was correlated to
increased membrane-associated PKC activity. PKC has been reported to
inhibit insulin action at various levels including the stimulation of the
insulin-receptor tyrosine kinase, and glycogen synthase. Since DAG is an
important signalling molecule and a key intermediate in the conversion of
glucose to storage fat, its potential role as a link between obesity and
insulin resistance will be examined. Funding is requested to initiate the
proposed study to determine whether a lesion in enhanced DAG synthesis and
PKC activity, similar to that caused by hyperglycemia/hyperinsulinemia and
denervation, occurs in the adipose tissue of an obese animal model. The
ultimate aim is to extended the study to define the biochemistry of insulin
resistance in various forms of human obesity. The specific aims of this
study are as follows:
1) The synthesis of DAG and other lipids, and analysis of their molecular
subspecies, in adipocytes from obese animals will be compared with those
from their lean littermates. Parallel studies to assess insulin
sensitivity and action on insulin-receptor activity, glucose uptake and
glycogen synthesis will be carried out.
2) The amounts of total and membrane-associated PKC in tissues under
various test conditions will be measured by enzymatic and immunoblotting
techniques to assess PKC activity.
3) The relationship between PKC activity and a) the insulin receptor, b)
glucose transporters and c) glycogen synthesis and their activation by
insulin will then be studied by enzymatic, metabolic labelling and
immunoblotting techniques.

These studies should determine whether obesity is accompanied by an
alteration in the content and synthesis of specific pools of DAG and in PKC
signalling in the adipose tissue. If so, a common biochemical mechanism by
be responsible for insulin resistance of various peripheral tissues caused
by obesity and other pathological conditions, and novel means to counteract
the pathogenesis of NIDDM may be indicated.
Effective start/end date9/30/923/31/18


  • Medicine(all)