Antidiabetogenic Effects of Chromium Mitigate Hyperinsulinemia-Induced Cellular Insulin Resistance via Correction of Plasma Membrane Cholesterol Imbalance

Horvath, E; Tackett, Lixuan; McCarthy, Alicia M.; Raman, Priya; Brozinick, Joseph T.; Elmendorf, Jeffrey S.

doi:10.1210/me.2007-0410

Cited by 40 publications

(20 citation statements)

References 62 publications

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“…Therefore, it is likely that increased RhoE GTPase per se may also play an important role in insulin resistance in type 2 diabetes in vivo. In this regard, studies with epitrochlearis muscles demonstrated that cortical F-actin was reduced in insulin-resistant obese Zucker rats compared with insulin-sensitive lean littermates, providing evidence that the abnormality of cytoskeletal reorganization could contribute to this insulin-resistant state (12). Future studies are needed to determine the physiological role of RhoE in the regulation of insulin sensitivity and glucose homeostasis.…”

Section: Resultsmentioning

confidence: 99%

In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes

Chun

Choi

Lee

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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To determine whether serine/threonine ROCK1 is activated by insulin in vivo in humans and whether impaired activation of ROCK1 could play a role in the pathogenesis of insulin resistance, we measured the activity of ROCK1 and the protein content of the Rho family in vastus lateralis muscle of lean, obese nondiabetic, and obese type 2 diabetic subjects. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic euglycemic clamp. Insulin-stimulated GDR was reduced 38% in obese nondiabetic subjects compared with lean, 62% in obese diabetic subjects compared with lean, and 39% in obese diabetic compared with obese nondiabetic subjects (all comparisons P < 0.001). Insulin-stimulated IRS-1 tyrosine phosphorylation is impaired 41-48% in diabetic subjects compared with lean or obese subjects. Basal activity of ROCK1 was similar in all groups. Insulin increased ROCK1 activity 2.1-fold in lean and 1.7-fold in obese nondiabetic subjects in muscle. However, ROCK1 activity did not increase in response to insulin in muscle of obese type 2 diabetic subjects without change in ROCK1 protein levels. Importantly, insulin-stimulated ROCK1 activity was positively correlated with insulin-mediated GDR in lean subjects (P < 0.01) but not in obese or type 2 diabetic subjects. Moreover, RhoE GTPase that inhibits the catalytic activity of ROCK1 by binding to the kinase domain of the enzyme is notably increased in obese type 2 diabetic subjects, accounting for defective ROCK1 activity. Thus, these data suggest that ROCK1 may play an important role in the pathogenesis of resistance to insulin action on glucose disposal in muscle of obese type 2 diabetic subjects.

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Section: Resultsmentioning

confidence: 99%

In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes

Chun

Choi

Lee

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Specifically, Sreejayan et al (19) reported that Cr treatment decreased liver triglyceride levels and lipid accumulation in animal models. Horvath et al (20) reported that Cr activates Glut-4 trafficking via a cholesterol-dependent mechanism and concluded that Cr 3+ supplementation may lower blood glucose by altering the plasma membrane composition of cholesterol in fat and muscle cells. However, there have been no reports assessing myocellular lipids in human studies evaluating Cr supplementation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus

et al. 2010

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OBJECTIVE To provide a comprehensive evaluation of chromium (Cr) supplementation on metabolic parameters in a cohort of Type 2 DM subjects representing a wide phenotype range and to evaluate changes in “responders” and “non-responders”. DESIGN After pre-intervention testing to assess glycemia, insulin sensitivity (assessed by euglycemic clamps), Cr status, body composition, subjects were randomized in a double-blind fashion to placebo or 1,000 μg Cr. A sub-study was performed to evaluate 24 hour energy balance/substrate oxidation and myocellular/intra-hepatic lipid content. RESULTS There was not a consistent effect of chromium supplementation to improve insulin action across all phenotypes. Insulin sensitivity was negatively correlated to soleus and tibialis muscle intramyocellular lipids and intra-hepatic lipid content. Myocellular lipids were significantly lower in subjects randomized to Cr. At pre-intervention, “responders”, defined as insulin sensitivity change from baseline > 10%, had significantly lower insulin sensitivity and higher fasting glucose and A1c when compared to placebo and “non-responders”, i.e. insulin sensitivity change from baseline < 10%. Clinical response was significantly correlated (p < 0.001) to the baseline insulin sensitivity, fasting glucose and A1c. There was no difference in Cr status between “responders”, and “non-responders”. CONCLUSIONS Clinical response to chromium is more likely in insulin resistant subjects who have more elevated fasting glucose and A1c levels. Cr may reduce myocellular lipids and enhance insulin sensitivity in subjects with type 2 DM independent of effects on weight or hepatic glucose production. Thus, modulation of lipid metabolism by Cr in peripheral tissues may represent a novel mechanism of action.

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“…135 One potential alternative is to use drugs that sequester plasma-membrane cholesterol, such as cyclodextrins, 24,136 which reduce intracellular cholesterol and inflammation 137 and increase insulin sensitivity in adipocytes in vitro . 138–140 Long-term studies of experimental treatment with hydroxy-propyl-β cyclodextrin (HPBCD) for compassionate use in Niemann–Pick disease are ongoing. 141 We reported a beneficial effect of HPBCD on DKD in the leptin-deficient BTBR ob/ob murine model of T2DM.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Lipid biology of the podocyte—new perspectives offer new opportunities

2014

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In the past 15 years, major advances have been made in understanding the role of lipids in podocyte biology. First, susceptibility to focal segmental glomerulosclerosis (FSGS) and glomerular disease is associated with an APOL1 sequence variant, is expressed in podocytes and encodes apolipoprotein L1, an important component of HDL. Second, acid sphingomyelinase-like phosphodiesterase 3b encoded by SMPDL3b has a role in the conversion of sphingomyelin to ceramide and its levels are reduced in renal biopsy samples from patients with recurrent FSGS. Furthermore, decreased SMPDL3b expression is associated with increased susceptibility of podocytes to injury after exposure to sera from these patients. Third, in many individuals with membranous nephropathy, autoantibodies against the phospholipase A2 (PLA2) receptor, which is expressed in podocytes, have been identified. Whether these autoantibodies affect the activity of PLA2, which liberates arachidonic acid from glycerophospholipids and modulates podocyte function, is unknown. Fourth, clinical and experimental evidence support a role for ATP-binding cassette sub-family A member 1-dependent cholesterol efflux, free fatty acids and glycerophospolipids in the pathogenesis of diabetic kidney disease. An improved understanding of lipid biology in podocytes might provide insights to develop therapeutic targets for primary and secondary glomerulopathies.

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Antidiabetogenic Effects of Chromium Mitigate Hyperinsulinemia-Induced Cellular Insulin Resistance via Correction of Plasma Membrane Cholesterol Imbalance

Cited by 40 publications

References 62 publications

In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes

In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes

Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus

Lipid biology of the podocyte—new perspectives offer new opportunities

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