3 research outputs found
Kinase cascades in the regulation of glucose homeostasis
Therapeutic strategies to treat Type 2 Diabetes Mellitus (T2DM) aim at
improving muscle insulin sensitivity by either directly modulating, or
bypassing defective insulin signaling. Insulin induces metabolic and gene
regulatory responses via PI 3-Kinase (PI3K) and Mitogen-Activated Protein
Kinase (MAPK) signaling pathways, respectively. MAPK signaling pathways
can also be activated by insulinindependent stimuli such as
exercise/contraction and stress/hypoxia. AMPactivated protein kinase
(AMPK) also transduces signals to glucose transport and gene regulatory
responses by insulinindependent stimuli. Identifying the molecular
mechanisms underlying insulin dependent and - independent signaling
pathways will reveal molecular targets for the pharmacological treatment
of insulin resistance.
Glucose induces insulin resistance in skeletal muscle. Glucose sensitive
targets in the P13K signaling pathway were identified in Wistar and
Goto-Kakizaki (GK) rats exposed to a 3-hr hyperglycemic infusion. In
skeletal muscle, glucose directly activates Phosphoinositide Dependent
Kinase 1 (PDK-1) and downstream Protein Kinase C (PKC) isoforms
(alpha/beta, 6 and zeta) through a mechanism that is independent of
changes in PI3K, Protein Kinase B (PK13) and Extracellular
signalRegulated protein Kinase (ERK) phosphorylation. This may account
for defects in insulin signaling in non-obese diabetic GK rats, whereby
PKCzeta was also activated by hyperglycemia. Thus, hyperglycemia acutely
modulates signal transduction and this may account for skeletal muscle
insulin resistance at the level of the P13 K pathway.
MAPK activation in skeletal muscle from insulin resistant ob/ob mice was
measured to determine if insulin-dependent and -independent induction of
MAPK signaling is intact in insulin resistant tissue. Insulin action on
MAPK was impaired in ob/ob mice, whereas contraction-mediated effects
were preserved. In addition Phorbol 12-Myristate- 13 -Acetate (PMA)
elicited divergent effects on MAPK signaling in ob/ob mice; c-Jun
NH2-terminal Kinase (JNK) and ERK phosphorylation were preserved, whereas
p38-MAPK phosphorylation was refractory. Thus appropriate MAPK response
can be elicited in insulin-resistant skeletal muscle via
insulin-independent mechanisms. Exercise and muscle contraction may
circumvent aberrant MAPK signaling in insulin-resistant skeletal muscle.
Exercise- and hypoxia-stimulated AMPK activity and glucose transport were
measured in skeletal muscle from insulin resistant obese Zucker fa/fa
rats. An isoform-specific defect in AMPK 1 activity in response to
contraction was observed, which was inconsequential to glucose transport.
Thus, AMPK signaling to glucose transport is unaffected by insulin
resistance.
Constitutive activation of AMPK can be achieved by AMPKgamma3 missense
mutation (R22SQ). Transgenic mice overexpressing the R225Q gamma3 mutant
form were challenged with a 55% fat diet. Transgenic mice have increased
lipid oxidation in the presence of lipid oversupply, which attenuates the
expected accumulation of intramuscular triglyceride content and protects
against skeletal muscle insulin resistance. In contrast, ablation of
AMPKgamma3 resulted in increased triglyceride content and impaired
insulin action. Thus, the muscle specific AMPKgamma3-subunit is a
putative target for pharmacological treatment of diet-induced skeletal
muscle insulin resistance.
In conclusion insulin signaling defects at the level of P13K and MAPK
pathways appear to contribute to skeletal muscle insulin resistance.
Insulin-independent pathways via MAPK and AMPK may prove valuable in the
treatment of insulin resistance in T2DM
Kinase cascades in the regulation of glucose homeostasis
PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF