Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin-resistant forms of obesity and type 2 diabetes mellitus

Abstract

Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using "spare receptors" to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ-plaque precursors and Alzheimer risk; in kidney, hyperinsulinemia activates the renin-angiotensin-adrenal axis, thus increasing vasoconstriction, sodium retention, and cardiovascular risk; and in liver, hyperinsulinemia increases lipogenesis, obesity, hepatosteatosis, hyperlipidemia, and cardiovascular risk. In summary, increases in hepatic aPKC are critically required for development of DIO/MetS/T2DM and its adverse sequelae, and therapeutic approaches that limit hepatic aPKC may be particularly effective.

Keywords: Alzheimer's disease; BACE1; atypical protein kinase C; diabetes mellitus; hyperinsulinemia; insulin; obesity.

FIGURE 1

PKC‐i in primates and its homologue, PKC‐l, in mice are the major 70 kDa aPKCs in liver, skeletal muscle, cardiac muscle, and brain and are activated by IRS‐1/PI3K in skeletal and cardiac muscle, but by IRS‐2/PI3K in liver (brain data on IRS are lacking). In muscle and liver, Akt is mainly activated by IRS‐1/PI3K, but, in heart, Akt is mainly and constitutively activated by IRS‐2/PI3K. In liver, Akt selectively phosphorylates FoxO1 and PGC‐1α on the WD40/ProF platform, shown by the shaded area, and, whereas both Akt and aPKC are used for insulin‐stimulated lipogenesis, Akt alone mediates insulin‐suppression of gluconeogenesis. Indeed, aPKC excess impairs the effect of Akt on FoxO1, PGC‐1a, and gluconeogenesis by displacing Akt from the WD40/ProF platform

FIGURE 2

Heat map of obesity (as per BMI) and T2DM‐dependent abnormalities in insulin signaling to phospho‐aPKC, phospho‐Akt, phospho‐FoxO1, and phospho‐PGC‐1α, and protein and/or mRNA levels of PKC‐i, IRS‐1, PGC‐1α, gluconeogenic enzymes (PEPCK/G6Pase), and lipogenic enzymes (SREBP‐1c, ACC, FAS) in human liver. (Data from Ref. ⁸ )

FIGURE 3

Time‐dependent development of aPKC‐dependent aberrations in postreceptor insulin signaling and appearance of alterations of gluconeogenic, lipogenic, and proinflammatory factors, in the mouse model of diet‐dependent, HFD‐induced obesity, the metabolic syndrome, and T2DM. Note (a) in phase I, the prominent role of SREBP‐1c, as activated by aPKC and Akt, for promoting increases in the activation of conventional and novel PKCs in muscle that, perhaps along with ceramide, lead to postreceptor impairments in insulin signaling via IRS‐1/PI3K in muscle; and (b), in phase 2, the blockade (red bar) of Akt entry to the WD40/ProF scaffold (shaded area), the subsequent impairment of insulin/Akt‐dependent phosphorylation of FoxO1 and PGC‐1α, and the resultant impairment of insulin‐suppression of PEPCK/G6Pase expression and gluconeogenesis. Not shown is the timing of onset for aPKC‐dependent decreases in insulin receptor levels, which is still unknown, but is clearly present at 2–3 months of HFD