Schmitz-Peiffer
Skeletal muscle is one of the major insulin-responsive tissues involved in the regulation of blood glucose levels. Muscle becomes insulin resistant with increased fat availability and obesity, and this resistance is strongly linked to cardiovascular disease, hypertension and type 2 diabetes (the "Metabolic Syndrome"). The molecular mechanisms linking lipid oversupply to the inhibition of insulin action in muscle are, however, poorly understood. Our group uses animal and cell models of lipid-induced insulin resistance to investigate the role of lipid species and signalling pathways in the inhibition of insulin signal transduction, with particular emphasis on isoforms of the lipid-activated protein kinase C (PKC) family.
Lipid-Induced Insulin Resistance in Skeletal
Muscle
Using cultured skeletal muscle cells treated with fatty acids as a
model of obesity and insulin resistance, we have identified lipid
intermediates which inhibit insulin signal transduction. Further work
will investigate the activation of inhibitory pathways and gene
expression, which in turn act to block insulin signalling and normal
glucose metabolism.
The Role of PKC in Glucose Homeostasis
Our current studies using PKC knockout mice indicate that these kinases
contribute to glucose intolerance caused by lipid oversupply by
distinct actions in pancreatic islets and insulin target tissues. We
are now investigating these at both whole-body and mechanistic levels,
using tissue-specific knockout mice and cell models. A novel direction
is the investigation of the role of PKC in insulin receptor
internalization whihc regulates insulin clearance from the circulation
by the liver and thus determines the availability of the hormone to its
target tissues.
PKC Substrates and Regulatory Proteins
We are identifying proteins both up- and downstream of PKC isoforms
which play a role in the inhibitory signalling affecting both insluin
secretion and insulin action, employing molecular, biochemical and
proteomic techniques.
Staff
 PhD StudentDavid Pedersen |
 Research OfficerDr Katy Raddatz |
 Research OfficerDr Georgia Frangioudakis |
 Research AssistantMana Liao |
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