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In mice, DIO\/MetS\/T2DM initiation involves diet\u2010dependent 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\u2010to\u2010muscle 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 \u201cspare receptors\u201d to bypass receptor defects. Thus, in brain, hyperinsulinemia increases A\u03b2\u2010plaque precursors and Alzheimer risk; in kidney, hyperinsulinemia activates the renin\u2013angiotensin\u2013adrenal 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.<\/jats:p>","DOI":"10.1002\/mco2.54","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T06:56:42Z","timestamp":1614236202000},"page":"3-16","source":"Crossref","is-referenced-by-count":9,"title":["Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin\u2010resistant forms of obesity and type 2 diabetes mellitus"],"prefix":"10.1002","volume":"2","author":[{"given":"Mini P.","family":"Sajan","sequence":"first","affiliation":[{"name":"Department of Internal Medicine University of South Florida College of Medicine  Tampa Florida USA"},{"name":"Research Service James A Haley Veterans Administration Medical Center  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara 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