Abstract
This review focuses on how insulin signals to metabolic processes in health, why this signaling is frequently deranged in Western/Westernized societies, how these derangements lead to, or abet development of, insulin-resistant states of obesity, the metabolic syndrome and type 2 diabetes mellitus, and what our options are for restoring insulin signaling, and glucose/lipid homeostasis. A central theme in this review is that excessive hepatic activity of an archetypal protein kinase enzyme, “atypical” protein kinase C (aPKC), plays a critically important role in the development of impaired glucose metabolism, systemic insulin resistance, and excessive hepatic production of glucose, lipids and proinflammatory factors that underlie clinical problems of glucose intolerance, obesity, hepatosteatosis, hyperlipidemia, and, ultimately, type 2 diabetes. The review suggests that normally inherited genes, in particular, the aPKC isoforms, that were important for survival and longevity in times of food scarcity are now liabilities in times of over-nutrition. Fortunately, new knowledge of insulin signaling mechanisms and how an aberration of excessive hepatic aPKC activation is induced by over-nutrition puts us in a position to target this aberration by diet and/or by specific inhibitors of hepatic aPKC.
Highlights
As to why muscle insulin receptor substrates (IRSs)-1/PI3K is downregulated in obesity will be discussed below in greater detail, but we recently found in early phases of experimental obesity induced by high fat feeding, that an abnormality in hepatic glucose production appears to be more primary than, and seems to account for, impairments in insulin signaling in muscle
We found that hepatic Akt activity is increased, presumably by hyperinsulinemia owing to increased hepatic gluconeogenesis and resultant glucose intolerance, and hepatic atypical” protein kinase C (aPKC) activity is increased, apparently owing to both hyperinsulinemia and dietary lipid-induced increases in hepatic ceramides that directly activate aPKC [13,18]
In the first phase of insulin resistance, as seen in mouse models of diet-dependent obesity that are produced either by a moderate increase in dietary fat or carbohydrate intake, or by hyperphagia secondary to genetic leptin deficiency, hepatic aPKC activity is inordinately increased, and, presumably because of co-localization of aPKC, Akt and FoxO1on the same ProF platform [13,38,39], and because of the ability of aPKC to bind, phosphorylate and inhibit Akt [40,41,42], the effects of Akt on FoxO1 phosphorylation are selectively diminished [13]. This selective impairment in FoxO1 phosphorylation leads to increased expression of gluconeogenic enzymes, glucose intolerance, hyperinsulinemia, further activation of hepatic aPKC and
Summary
Insulin-resistant syndromes of obesity, the metabolic syndrome and type 2 diabetes mellitus have reached pandemic levels in Western/Westernized societies. The increased activity of hepatic aPKC leads to excessive increases in transcription of a large array of lipogenic enzymes, and activation of factors that increase production of multiple proinflammatory cytokines These liver-derived lipids and proinflammatory cytokines can enter the circulation and are most likely major contributors to the subsequent impairment of insulin signaling to both Akt and aPKC in muscle, which in turn leads to diminished glucose transport, subsequent decreases in whole-body glucose disposal, and a further impairment in glucose tolerance. As will be discussed in greater detail below, with diet-induced excessive activation of hepatic aPKC, there is at first (presumably reflecting an early phase of obesity), an impairment in the ability of Akt to regulate (phosphorylate) downstream factors that diminish gluconeogenesis, and subsequent development of glucose intolerance, insulin resistance, hyperinsulinemia and increases in hepatic production of lipids and proinflammatory factors. Later, when pancreatic insulin secretion is less able or can no longer compensate for impairments in glucose homeostasis, Akt activation diminishes even further and type 2 diabetes worsens
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