Abstract
Insulin resistance in type 2 diabetes is partly due to impaired glucose transport in skeletal muscle. Atypical protein kinase C (aPKC) and protein kinase B (PKB), operating downstream of phosphatidylinositol (PI) 3-kinase and its lipid product, PI-3,4,5-(PO(4))(3) (PIP(3)), apparently mediate insulin effects on glucose transport. We examined these signaling factors during hyperinsulinemic-euglycemic clamp studies in nondiabetic subjects, subjects with impaired glucose tolerance (IGT), and type 2 diabetic subjects. In nondiabetic control subjects, insulin provoked twofold increases in muscle aPKC activity. In both IGT and diabetes, aPKC activation was markedly (70-80%) diminished, most likely reflecting impaired activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase and decreased ability of PIP(3) to directly activate aPKCs; additionally, muscle PKC-zeta levels were diminished by 40%. PKB activation was diminished in patients with IGT but not significantly in diabetic patients. The insulin sensitizer rosiglitazone improved insulin-stimulated IRS-1-dependent PI 3-kinase and aPKC activation, as well as glucose disposal rates. Bicycle exercise, which activates aPKCs and stimulates glucose transport independently of PI 3-kinase, activated aPKCs comparably to insulin in nondiabetic subjects and better than insulin in diabetic patients. Defective aPKC activation contributes to skeletal muscle insulin resistance in IGT and type 2 diabetes, rosiglitazone improves insulin-stimulated aPKC activation, and exercise directly activates aPKCs in diabetic muscle.
Publication types
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Clinical Trial
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Controlled Clinical Trial
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Blood Glucose / metabolism
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / metabolism*
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Exercise / physiology
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Fatty Acids, Nonesterified / blood
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Female
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Glucose Intolerance / drug therapy
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Glucose Intolerance / metabolism
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Glucose Transporter Type 4
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Humans
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Hypoglycemic Agents / administration & dosage*
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Insulin / metabolism
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Insulin Receptor Substrate Proteins
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Insulin Resistance / physiology
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Isoenzymes / metabolism
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Male
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Middle Aged
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins*
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Muscle, Skeletal / enzymology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositol Phosphates / metabolism
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Kinase C / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins*
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Rosiglitazone
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Thiazoles / administration & dosage*
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Thiazolidinediones*
Substances
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Blood Glucose
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Fatty Acids, Nonesterified
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Glucose Transporter Type 4
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Hypoglycemic Agents
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IRS1 protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Isoenzymes
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Monosaccharide Transport Proteins
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Muscle Proteins
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Phosphatidylinositol Phosphates
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Phosphoproteins
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Proto-Oncogene Proteins
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SLC2A4 protein, human
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Thiazoles
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Thiazolidinediones
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phosphatidylinositol 3,4,5-triphosphate
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Rosiglitazone
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protein kinase C gamma
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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protein kinase C zeta
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Protein Kinase C
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protein kinase C lambda