Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

Abstract

Aims/hypothesis: Metformin is widely used for treating type 2 diabetes mellitus, but its actions are poorly understood. In addition to diminishing hepatic glucose output, metformin, in muscle, activates 5'-AMP-activated protein kinase (AMPK), which alone increases glucose uptake and glycolysis, diminishes lipid synthesis, and increases oxidation of fatty acids. Moreover, such lipid effects may improve insulin sensitivity and insulinstimulated glucose uptake. Nevertheless, the effects of metformin on insulin-sensitive signalling factors in human muscle have only been partly characterised to date. Interestingly, other substances that activate AMPK, e.g., aminoimidazole-4-carboxamide-1-β-D-riboside (AICAR), simultaneously activate atypical protein kinase C (aPKC), which appears to be required for the glucose transport effects of AICAR and insulin. Methods: Since aPKC activation is defective in type 2 diabetes, we evaluated effects of metformin therapy on aPKC activity in muscles of diabetic subjects during hyperinsulinaemic-euglycaemic clamp studies. Results: After metformin therapy for 1 month, basal aPKC activity increased in muscle, with little or no change in insulin-stimulated aPKC activity. Metformin therapy for 8 to 12 months improved insulinstimulated, as well as basal aPKC activity in muscle. In contrast, IRS-1-dependent phosphatidylinositol (PI) 3-kinase activity and Ser473 phosphorylation of protein kinase B were not altered by metformin therapy, whereas the responsiveness of muscle aPKC to PI-3,4,5-(PO 4 ) 3 , the lipid product of PI 3-kinase, was improved. Conclusions/ interpretation: These findings suggest that the activation of AMPK by metformin is accompanied by increases in aPKC activity and responsiveness in skeletal muscle, which may contribute to the therapeutic effects of metformin.

Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells

“…55 In type 2 diabetic patients, metformin increases PKC-activity, accompanied by increased AMPK activity. 56 We have also demonstrated that PKC-phosphorylates LKB1 at Ser428 in both in vitro assays and in cultured cells, including endothelial cells, pericytes, adipocytes, and cultured vascular smooth muscle cells. 36 Furthermore, inhibition of PKC-attenuates AMPK activation by other stimuli (Z.X., unpublished data, 2008).…”

PREP1 deficiency downregulates hepatic lipogenesis and attenuates steatohepatitis in mice

“…Indeed, PKCζ/LKB1 signalling was also induced in Prep1-deficient mouse liver. Work by Luna and co-workers has demonstrated that metformin-induced activation of AMPK is accompanied by induction of PKCζ [38]. Importantly, genetic ablation as well as pharmacologic inhibition of PKCζ prevent stimulation of both LKB1 and AMPK [29], indicating that PREP1 lipogenic signalling upstream of AMPK involves PKCζ upregulation.…”

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

“…Treatment with metformin increased insulin-induced Akt phosphorylation in cultured HepG2 cells [52] and HGL5 cells [53], as well as in vivo in rat heart [54]. In contrast, metformin reduced Akt phosphorylation stimulated by interleukin-1b or by high glucose [55], whereas Akt phosphorylation was unaltered by metformin treatment in H4IIE cells [56] and in vivo in diabetic muscle [57][58][59]. These mixed results with metformin indicate that context (i.e., cell type and stimulus) as well as possible multiple targets of metformin cause this diversity of effects on Akt phosphorylation.…”