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.

List of scientific papers

I. Steiler TL, Galuska D, Leng Y, Chibalin AV, Gilbert M, Zierath JR (2003). "Effect of hyperglycemia on signal transduction in skeletal muscle from diabetic Goto-Kakizaki rats." Endocrinology 144(12): 5259-67. Epub 2003 Aug 21
https://pubmed.ncbi.nlm.nih.gov/12960081

II. Leng Y, Steiler TL, Zierath JR (2004). "Effects of insulin, contraction, and phorbol esters on mitogen-activated protein kinase signaling in skeletal muscle from lean and ob/ob mice. " Diabetes 53(6): 1436-44
https://pubmed.ncbi.nlm.nih.gov/15161746

III. Barnes BR, Ryder JW, Steiler TL, Fryer LG, Carling D, Zierath JR (2002). "Isoform-specific regulation of 5 AMP-activated protein kinase in skeletal muscle from obese Zucker (fa/fa) rats in response to contraction. " Diabetes 51(9): 2703-8
https://pubmed.ncbi.nlm.nih.gov/12196462

IV. Barnes BR, Marklund S, Steiler TL, Walter M, Hjalm G, Amarger V, Mahlapuu M, Leng Y, Johansson C, Galuska D, Lindgren K, Abrink M, Stapleton D, Zierath JR, Andersson L (2004). "The 5-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. " J Biol Chem 279(37): 38441-7. Epub 2004 Jul 06
https://pubmed.ncbi.nlm.nih.gov/15247217