Insulin Resistance and Lipid Disorders

Roberto Miccoli; Cristina Bianchi; Giuseppe Penno; Stefano Del Prato

Disclosures

Future Lipidology. 2008;3(6):651-664. 

In This Article

Therapeutic Implications

Therapeutic strategies aiming at reducing (intracellular) lipid availability in insulin-sensitive tissues, such as skeletal muscle and liver, and pharmacological modulation of the signaling pathways activated by increased lipid stores and availability, represent targets for treatment of insulin resistance and prevention of its complications. Moderate increases in physical activity in overweight to obese subjects improves insulin sensitivity in conjunction with a reduction of abdominal fat, TG levels, increased plasma HDL-C concentrations and improved oxidative capacity in muscle.[93] Diet, both in quantitative and qualitative terms, is an obvious cornerstone in the treatment of metabolic diseases. The biochemical and molecular processes linking dietary fats to insulin resistance are not completely understood, but may relate to altered membrane phospholipid fatty acid composition and membrane fluidity and stability, changes in lipogenic gene transcription, the type of fatty acids within TG and direct interference with insulin signaling.[94] In subjects with insulin resistance, replacement of saturated with unsaturated fat lowers VLDL-TG, while the effects on HDL-C are less clear. Increased unsaturated fat intake is also associated with improvement in insulin sensitivity.[95] Trans fatty acids induce similar effects on plasma lipoprotein levels as those observed with saturated fat.[95] Long-chain ω-3 fatty acids are powerful in reducing TG levels, although no clear-cut effect on insulin sensitivity has been observed.[96] In subjects without T2DM, no difference in insulin response to meals rich in saturated, monounsaturated, or polyunsaturated (n-3 or n-6) fatty acids have been reported.[97] The available data support the idea that consumption of diets high in total carbohydrate does not adversely affect insulin sensitivity, while increased intake of dietary fiber appears to improve insulin action and may protect against the development of T2DM.[98]

Several pharmacologic interventions have been used to treat lipid abnormalities associated with insulin resistance in patients with T2DM, MS or obesity. A possible approach is to target insulin sensitivity and adiposity rather than dyslipidemia. Selective CB1-receptor blockade with rimonabant has been demonstrated to reduce body weight and waist circumference and improves, possibly independently of weight loss, the lipid profile in high-risk patients.[99] Only 1 year of treatment with rimonabant significantly reduced triglyceride and increased HDL-C levels, without significant effect on LDL or total cholesterol.[99] It is noteworthy that the European Medicine Agency (EMEA), by October 2008, has suspended the product license for rimonabant because the treatment benefits no longer outweigh it's risks (psychiatric side effects).

Metformin is widely used for T2DM treatment and its most likely mechanism of action is linked to energy sensing through AMP kinase.[100] The drug exerts its main effect on the liver by increasing insulin sensitivity and inhibiting gluconeogenesis and it may result in improvement of liver function tests, although no clear histological changes have been documented.[101] Some effect on lipid profile has been claimed with a 15% reduction in plasma TG concentration.[5]

A larger effect is usually obtained with TZDs. Rosiglitazone and pioglitazone are PPARγ agonists exerting an insulin-sensitizing and antihyperglycemic effect.[102] Many of the beneficial actions of TZDs have been explained on the basis of lipid redistribution from ectopic and visceral fat in subcutaneous fat.[103] Owing to this effect, as well as anti-inflammatory properties, TZDs may exert a beneficial effect on NASH.[104] In subjects with NASH, the administration of pioglitazone normalized liver enzymes, decreased hepatic fat content and increased hepatic insulin sensitivity and led to histologic improvement in steatosis, ballooning necrosis and inflammation.[105] Recent studies demonstrated that PPARγ agonists may protect β-cell function from lipotoxicity.[106] However, the effect of TZDs on plasma lipid profile remains debated, particularly since some difference exists between the two molecules.[107,108] While pioglitazone treatment lowers serum concentrations of LDL and TG, rosiglitazone does not appear to lower TG and may result in a modest increase in LDL-C, although associated with increased HDL-C. Improvement of lipid profile in insulin-resistant subjects is obviously finalized at improving the cardiovascular risk profile. Therefore, the recent perplexities raised with respect to uncertain effect on cardiovascular events should be taken into full account.[109]

Fibrates exert their hypolipidemic effect through activation of PPARα. Their use results in a decrease in plasma TG levels (∼25%) and in a moderate increase of HDL-C (∼7%). Several studies do not support beneficial effects of fibrates on carbohydrate metabolism[110,111]; however, changes in TG with fibrates have been associated with improvements of insulin action in both T2DM[112] and MS subjects.[113] Based on these effects, it has been argued that combined activation of PPARα and PPARγ may result in a complementary and synergistic action on lipid metabolism, insulin sensitivity and inflammation. Dual PPARα/γ agonists have, therefore, been developed. Unfortunately, development of the most advanced molecules (tesaglitazar and muraglitazar) have been stopped owing to a possible increase in cardiovascular risk.[114] New compounds are under development and even panPPAR (i.e., PPARα/γ/∂agonists) are under assessment. The expectation is to finally have the possibility to obtain a sustained and significant increase in HDL-cholesterol after the disappointment generated by the severe side effects that seem to accompany CETP inhibitors.[115] The association of fibrate with an antiobesity drug, such as orlistat, may improve atherogenic lipid profile and reverse MS.[116,117] A significant increase (10-25%) in HDL-C can be obtained with nicotinic acid. The drug probably exerts its effect by lowering hepatic VLDL ApoB production and increasing de novo synthesis of ApoA-1.[118] Its use was quite limited owing to accompanying flushing accounting for 25-40% treatment discontinuation. This limitation may be overcome with the combination of nicotinic acid with the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT).[119] Even in this case, the effect of the treatment on insulin sensitivity remains to be proven. Hyperglycemia and decreased glucose tolerance can occur in individuals with T2DM and is thought by some to result from insulin resistance consequent to the fatty acid rebound after niacin.[120]

Depsite the fact that elevated serum concentrations of LDL-C are not necessarily associated with insulin resistance, current guidelines recommend lowering LDL-C, followed by treating HDL-C when TG levels are increased, as a primary target to reduce cardiometabolic risk.[121] Statins stand up as first-line therapy for aggressive lipid-lowering intervention and this approach is substantiated by clinical trials.[122] The Comparative Study with Rosuvastatin in Subjects with Metabolic Syndrome (COMETS), examined the effects of rosuvastatin and atorvastatin versus placebo on insulin resistance in patients with MS. Both statins had a marked benefit on reducing atherogenic lipoproteins and improving the ApoB:ApoA-I ratio, although no effect was apparent on insulin sensitivity.[123] However, the effects of statins on glucose homeostasis are a matter of debate, since WOSCOPS[124] showed a beneficial effect, while in other statin trials no difference in the incidence of T2DM was noticed.[125,126] Clinical trials have demonstrated that in high-risk patients, such as T2DM patients, statins reduce overall cardiovascular events by 30-40%.[127] Furthermore, the degree to which a statin may lower TGs in hypertriglyceridemic patients is correlated with its ability to lower LDL-C. Statins with greater LDL-C-lowering efficacy, such as rosuvastatin, would be expected to produce equally substantial reductions in TG.[128] Therefore, since subjects with insulin resistance have high cardiovascular risk, the use of a statin should be carefully considered.

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