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 enzy...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-03-01
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| Series: | MedComm |
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| Online Access: | https://doi.org/10.1002/mco2.54 |
| _version_ | 1829533445619974144 |
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| author | Mini P. Sajan Barbara C. Hansen Mildred Acevedo‐Duncan Mark S. Kindy Denise R. Cooper Robert V. Farese |
| author_facet | Mini P. Sajan Barbara C. Hansen Mildred Acevedo‐Duncan Mark S. Kindy Denise R. Cooper Robert V. Farese |
| author_sort | Mini P. Sajan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T18:57:13Z |
| format | Article |
| id | doaj.art-ec1d5d225cae4de1b000248920a5fece |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-12-16T18:57:13Z |
| publishDate | 2021-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj.art-ec1d5d225cae4de1b000248920a5fece2022-12-21T22:20:30ZengWileyMedComm2688-26632021-03-012131610.1002/mco2.54Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitusMini P. Sajan0Barbara C. Hansen1Mildred Acevedo‐Duncan2Mark S. Kindy3Denise R. Cooper4Robert V. Farese5Department of Internal Medicine University of South Florida College of Medicine Tampa Florida USADepartment of Internal Medicine University of South Florida College of Medicine Tampa Florida USADepartment of Chemistry College of Arts and Sciences University of South Florida Tampa Florida USAResearch Service James A Haley Veterans Administration Medical Center Tampa Florida USAResearch Service James A Haley Veterans Administration Medical Center Tampa Florida USADepartment of Internal Medicine University of South Florida College of Medicine Tampa Florida USAAbstract 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.https://doi.org/10.1002/mco2.54Alzheimer's diseaseatypical protein kinase CBACE1diabetes mellitushyperinsulinemiainsulin |
| spellingShingle | Mini P. Sajan Barbara C. Hansen Mildred Acevedo‐Duncan Mark S. Kindy Denise R. Cooper Robert V. Farese Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitus MedComm Alzheimer's disease atypical protein kinase C BACE1 diabetes mellitus hyperinsulinemia insulin |
| title | Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitus |
| title_full | Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitus |
| title_fullStr | Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitus |
| title_full_unstemmed | Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitus |
| title_short | Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitus |
| title_sort | roles of hepatic atypical protein kinase c hyperactivity and hyperinsulinemia in insulin resistant forms of obesity and type 2 diabetes mellitus |
| topic | Alzheimer's disease atypical protein kinase C BACE1 diabetes mellitus hyperinsulinemia insulin |
| url | https://doi.org/10.1002/mco2.54 |
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