Limits...
Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism.

Kain V, Kapadia B, Misra P, Saxena U - Sci Rep (2015)

Bottom Line: Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia.We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin.Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.

ABSTRACT
Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia. Recent clinical data suggest that chronic use of these drugs increases the frequency of new onset diabetes. Studies to define the risks of statin-induced diabetes and its underlying mechanisms are clearly necessary. We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin. Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway. These data may help design strategies for prevention of statin induced insulin resistance and diabetes in patients with hypercholesterolemia.

No MeSH data available.


Related in: MedlinePlus

(a) Mevalonate is unable to rescue Simvastatin induced inhibition of glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or Mevalonate (500 μM) for 48 h. DMSO (0.1%) treated cells served as internal control. Values are shown as mean±SD after normalizing with the corresponding protein content and expressed relative to basal of control cells which was set to 1; **p < 0.01, versus corresponding control cells , nsnon significant, ap < 0.01 versus corresponding Simvastatin treated cells (two way ANOVA). (b) Total Cholesterol levels were depleted upon Simvastatin treatment: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) or Mevalonate (500 μM). Post treatment lipid was extracted and total cholesterol was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01, ***p < 0.005 versus corresponding control (DMSO: 0.1%) cells, bp < 0.001 versus Simvastatin (1 μM) treated cells (two way ANOVA).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4561915&req=5

f2: (a) Mevalonate is unable to rescue Simvastatin induced inhibition of glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or Mevalonate (500 μM) for 48 h. DMSO (0.1%) treated cells served as internal control. Values are shown as mean±SD after normalizing with the corresponding protein content and expressed relative to basal of control cells which was set to 1; **p < 0.01, versus corresponding control cells , nsnon significant, ap < 0.01 versus corresponding Simvastatin treated cells (two way ANOVA). (b) Total Cholesterol levels were depleted upon Simvastatin treatment: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) or Mevalonate (500 μM). Post treatment lipid was extracted and total cholesterol was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01, ***p < 0.005 versus corresponding control (DMSO: 0.1%) cells, bp < 0.001 versus Simvastatin (1 μM) treated cells (two way ANOVA).

Mentions: We next explored if the inhibition of insulin mediated glucose uptake by simvastatin was related to the drug’s ability to inhibit intracellular cholesterol biosynthesis. It is known that the addition of excess mevalonate, a precursor for cholesterol biosynthesis, rescues the cells from statin’s cholesterol synthesis inhibitory effects. Therefore, we treated cells with simvastatin together with mevalonate and then examined the effect of simvastatin on insulin mediated glucose uptake for 5 min and 10 min. Incubation with mevalonate failed to rescue the cells from the inhibitory effect of simvastatin on insulin mediated glucose uptake (~50% reduction in glucose uptake with simvastatin alone and co-treatment with simvastatin and mevalonate) (Fig. 2a). To make sure that mevalonate treatment did increase cholesterol synthesis we also examined cholesterol content in the cells. As shown in Fig. 2b, simvastatin treatment alone as expected reduced cellular cholesterol content by about 50% relative to untreated cells, whereas when mevalonate was added together with simvastatin, the cholesterol content increased to slightly higher than that observed in control cells. Addition of mevalonate to control cells also increased cholesterol content. This suggests that the inhibitory effect of simvastatin on insulin stimulated glucose may be unrelated to its ability to block cellular cholesterol biosynthesis pathway.


Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism.

Kain V, Kapadia B, Misra P, Saxena U - Sci Rep (2015)

(a) Mevalonate is unable to rescue Simvastatin induced inhibition of glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or Mevalonate (500 μM) for 48 h. DMSO (0.1%) treated cells served as internal control. Values are shown as mean±SD after normalizing with the corresponding protein content and expressed relative to basal of control cells which was set to 1; **p < 0.01, versus corresponding control cells , nsnon significant, ap < 0.01 versus corresponding Simvastatin treated cells (two way ANOVA). (b) Total Cholesterol levels were depleted upon Simvastatin treatment: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) or Mevalonate (500 μM). Post treatment lipid was extracted and total cholesterol was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01, ***p < 0.005 versus corresponding control (DMSO: 0.1%) cells, bp < 0.001 versus Simvastatin (1 μM) treated cells (two way ANOVA).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561915&req=5

f2: (a) Mevalonate is unable to rescue Simvastatin induced inhibition of glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or Mevalonate (500 μM) for 48 h. DMSO (0.1%) treated cells served as internal control. Values are shown as mean±SD after normalizing with the corresponding protein content and expressed relative to basal of control cells which was set to 1; **p < 0.01, versus corresponding control cells , nsnon significant, ap < 0.01 versus corresponding Simvastatin treated cells (two way ANOVA). (b) Total Cholesterol levels were depleted upon Simvastatin treatment: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) or Mevalonate (500 μM). Post treatment lipid was extracted and total cholesterol was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01, ***p < 0.005 versus corresponding control (DMSO: 0.1%) cells, bp < 0.001 versus Simvastatin (1 μM) treated cells (two way ANOVA).
Mentions: We next explored if the inhibition of insulin mediated glucose uptake by simvastatin was related to the drug’s ability to inhibit intracellular cholesterol biosynthesis. It is known that the addition of excess mevalonate, a precursor for cholesterol biosynthesis, rescues the cells from statin’s cholesterol synthesis inhibitory effects. Therefore, we treated cells with simvastatin together with mevalonate and then examined the effect of simvastatin on insulin mediated glucose uptake for 5 min and 10 min. Incubation with mevalonate failed to rescue the cells from the inhibitory effect of simvastatin on insulin mediated glucose uptake (~50% reduction in glucose uptake with simvastatin alone and co-treatment with simvastatin and mevalonate) (Fig. 2a). To make sure that mevalonate treatment did increase cholesterol synthesis we also examined cholesterol content in the cells. As shown in Fig. 2b, simvastatin treatment alone as expected reduced cellular cholesterol content by about 50% relative to untreated cells, whereas when mevalonate was added together with simvastatin, the cholesterol content increased to slightly higher than that observed in control cells. Addition of mevalonate to control cells also increased cholesterol content. This suggests that the inhibitory effect of simvastatin on insulin stimulated glucose may be unrelated to its ability to block cellular cholesterol biosynthesis pathway.

Bottom Line: Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia.We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin.Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.

ABSTRACT
Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia. Recent clinical data suggest that chronic use of these drugs increases the frequency of new onset diabetes. Studies to define the risks of statin-induced diabetes and its underlying mechanisms are clearly necessary. We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin. Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway. These data may help design strategies for prevention of statin induced insulin resistance and diabetes in patients with hypercholesterolemia.

No MeSH data available.


Related in: MedlinePlus