Nonalcoholic Fatty Liver Disease and Hyperuricemia: A Close Relation with Hepatic Insulin Resistance after Nicotinic Acid Treatment?

Dear Editors,

Various randomized controlled trials have demonstrated that lipid-lowering therapies affect insulin sensibility and glucose control in type 2 diabetes patients [1] [2] [3]. This phenomenon seems linked to the close relation existing between lipid and glucose metabolism [3]. Extended-release nicotinic acid does not except to this rule. We reported that extended-release nicotinic acid beneficially affected the lipid profile of 20 nondiabetic dyslipidemic men with metabolic syndrome but induced liver insulin resistance [4]. Mechanisms explaining this closed relation remains unclear. Katsiki et al. challenged us about the mechanisms which may explain this relation reminding us that alteration of hepatic insulin sensitivity could be in partly explained by existence of nonalcoholic fatty liver disease frequently observed in patients with metabolic syndrome and by an increase in uric acid concentration [5].

Most adverse effects limiting the use of nicotinic acid (NA) have been reported as hyperglycemia, new onset of diabetes, hyperuricemia (incidence rate 14%), or liver enzyme and bilirubin elevation (incidence rate 0.2%) [6]. These side effects could be partly reduced with the use of extended release formulation of NA, taking medicine at bedtime, aspirin pretreatment, and gradual dose up-titration [6]. In our study [4], all patients presented an elevation in glycemia (5.4±0.5 vs. 5.9±0.6 mmol/l, p=0.003 – placebo vs. NA condition) and hyperinsulinemia (12.2±6.8 vs. 17.6±10.2 mIU/l, p=0.005 – placebo vs. NA condition) leading to an important increase in HOMA index (3.0±1.8 vs. 4.7±3.0, p=0.005 – placebo vs. NA condition) associated to a reduced inhibition of endogenous glucose production by insulin (0.7±0.4 vs. 1.0±0.5+mg/kg·min, p<0.05 – placebo vs. NA condition) and to a decrease in fasting hepatic insulin sensitivity index (4.8±1.8 vs. 3.2±1.6, p<0.05 – placebo vs. NA condition). No increase in asparate aminotransferase (AST), alanine aminotransferase (ALT), phosphatase alcaline (PAL), gamma-glutamyl transferase (GGT), and total bilirubin occurred significantly during the study suggesting that no significantly liver injury occurred during NA treatment (AST: 29±7 vs. 29±7 IU/l, p=1; ALT: 25±10 vs. 23±13 IU/l, p=0.332; PAL: 59±14 vs. 60±13 IU/l, p=0.759; GGT: 37±19 vs. 29±8 IU/l, p=0.123; bilirubin: 13±7 vs. 14±9 μmol/l, p=0.511 – placebo vs. NA condition). NA did not induce a more marked insulin resistance in patients with higher hepatic enzymes activities. We did not perform any measurements of intra-hepatic triglyceride content (IHTG) and ultrasound-diagnosis nor appreciate liver histology to score NAFLD, which did not allow us to conclude that NA did not increase the risk of NAFLD in patient with metabolic syndrome. However, extended release NA formulation has been rarely associated with hepatotoxicity appreciated by an elevation above 3 times the upper limit normal of ALT and AST [6]. A 16-week NA treatment in obese subjects with NAFLD did not affect IHTG content [7]. Of note, Ganji et al. demonstrated that high dose of crystalline NA in rats model could prevent and reduce hepatic steatosis induced by a high fat diet [8]. In this study, NA inhibit diacylglycerol acyltransferase 2 activity, protein expression and mRNA levels, a key enzyme of triglyceride synthesis inducing decrease in IHTG content, plasmatic triglyceride concentration, liver weight, and regression of preexisting hepatic steatosis [8].

As reminded by Katsiki et al. [5], the increase in serum uric acid is an independent risk factor of metabolic syndrome [9], cardiovascular diseases, obesity, dyslipidemia, NAFLD [10] [11], and insulin resistance [12] [13], even if the underlying mechanism has not been yet clarified. In our study, uric acid concentration increased slightly but not significantly after 8-weeks of extended-release NA (425±86 vs. 450±72 μmol/l, p=0.16 – placebo vs. NA condition). Three patients had uric acid concentration above the upper limit under placebo treatment vs. 6 patients under NA treatment, probably in relation to their metabolic syndrome and their insulin resistance state. Uric acid concentration was increased after NA treatment in 90% of our patients. The variation of uric acid concentration after placebo and NA treatment was not in relation with insulin resistance as assessed by variation of inhibition of endogenous production of glucose by insulin (r²=0.133, p=0.299), glucose utilization (r²=0.317, p=0.09) or fasting hepatic insulin sensitivity index (r²=0.135, p=0.296). Only one patient decreased drastically uric acid concentration after NA treatment (639 vs. 491 μmol/l, placebo vs. NA condition). Discarding this patient, uric acid was significantly increased after NA therapy (402±44 vs. 446±75 μmol/l, p=0.020 placebo vs. NA condition) and positive relation between variation of uric acid concentration and glucose utilization or between variation of uric acid concentration and fasting hepatic insulin sensitivity index occurred (respectively r²=0.787, p=0.001 and r²=0.560, p=0.020). Causal relation between hepatic insulin resistance and hyperuricemia induced by NA may need to be highlighted. Uric acid is known to be an antioxidant and a prooxidant agent. Elevation of uric acid is known to induce generation of mitochondrial oxidative stress inducing the drop in aconitase activity leading to an accumulation of its substrate, the citrate. Citrate could release to cytosol and acts as a substrate for lipogenic pathway by activation of fatty acid synthase, inducing an increase in lipogenic intermediates and NAFLD [14]. Increase in lipogenic intermediates as diacylglycerol could in return alter insulin signaling pathway [15]. More recently, Zhu et al. demonstrated that high uric acid directly inhibits insulin signaling by generation of oxidative stress, reducing Akt phospholrylation, and increasing IRS1 phosphorylation in a model of hepatic adenocarcinoma cell line [16].

NA is known to generate insulin resistance state and get an improvement of lipid profile, but molecular mechanisms explaining discrepancy between its beneficial effects on lipids metabolism and deleterious effects on glucose metabolism remain to be defined. Further studies are necessary to highlight its potential benefit in reducing NAFLD without worsening insulin-resistance state induced or to highlight the link between hyperuricemia and insulin-resistance observed with NA therapy.

• References

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