Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients

doi:10.1053/meta.2001.21028

Metabolism

Volume 50, Issue 4, April 2001, Pages 477-480

https://doi.org/10.1053/meta.2001.21028 Get rights and content

Abstract

The aim of the present study was to investigate the effect of bezafibrate on insulin sensitivity and insulin secretion in 30 non-obese Japanese type 2 diabetic patients with hypertriglyceridemia (serum triglycerides > 150 mg/dL). Insulin sensitivity was measured with homeostasis model assessment insulin resistance (HOMA-IR) proposed by Matthews et al. HOMA-B-cell function, proposed by Matthews et al validated against minimal model-derived insulin secretion, was used to assess pancreatic insulin function. Twenty-two patients were treated with glibenclimide and the rest were treated with diet alone. All patients were treated with bezafibrate (400 mg/d) for 3 months. There were no changes in diet and the dose of any medications used throughout the study. Fasting glucose, insulin, triglycerides, HDL cholesterol, and total cholesterol levels were measured before and after treatment of bezafibrate. After treatment of bezafibrate for 3 months, serum triglyceride levels significantly decreased from 277 ± 30 to 139 ± 9 mg/dL (P < .001) and serum HDL cholesterol levels increased significantly from 45 ± 2 to 52 ± 2 mg/dL (P = .003). Serum cholesterol level was unchanged during the study (198 ± 7 v 201 ± 7 mg/dL, P = .383). Fasting glucose (163 ± 8 v 139 ± 6 mg/dL, P = .006) significantly decreased after the treatment with bezafibrate. HbA1c levels decreased, although not statistically significant (7.50 ± 0.25 v 7.17% ± 0.19%, P = .147). On the other hand, fasting insulin (9.3 ± 0.7 v 7.3 ± 0.5 μU/mL, P = .010) and HOMA-IR (3.61 ± 0.24 to 2.53 ± 0.20, P < .001) levels decreased significantly after the treatment with bezafibrate. In contrast, HOMA-B-cell function did not change during the study (41.4 ± 5.5 v 41.8 ± 4.7, P = .478). There was no significant difference in body mass index (BMI) levels before and after the therapy (23.0 ± 0.4 v 23.1 ± 0.4 kg/m², P = .483). From these results, it can be concluded that bezafibrate reduces serum tiglycerides, insulin resistance, and fasting blood glucose levels in non-obese Japanese type 2 diabetic patients.

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Probably, reducing the chronic secretory demands for pancreatic beta-cell by improving of insulin sensitivity and direct reducing of triglycerides accumulation in pancreatic islets can explain preservation of BCF in patients with T2DM by bezafibrate. Previous observations have shown beneficial effects of bezafibrate on glucose and insulin metabolism and prevention of T2DM [8,10,41–43]. The issue whether these findings influence the hard cardiovascular end-points was partially answered in patients with metabolic syndrome [44]: significant lower cardiovascular risk for these patients treated by bezafibrate was observed.
Development of insulin resistance (IR) and the progressive failure of the pancreatic beta-cell function (BCF) may be important in the pathogenesis of type 2 diabetes. Influence of peroxisome proliferator-activated receptors ligand bezafibrate on BCF and IR in patients with diabetes is unknown. The present study was aimed to investigate the long-term effect of bezafibrate on these parameters in diabetic patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study.
Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from 351 diabetic patients (168 treated by bezafibrate and 183 by placebo) who completed a 2-year of randomized, double-blind, placebo-controlled study period. The homeostatic indexes of BCF (HOMA-BCF) and IR (HOMA-IR) were calculated according to the homeostasis model of assessment.
Both groups displayed similar baseline characteristics. During follow-up, in the placebo group there was 28% rise of HOMA-IR (p < 0.001). In contrast, HOMA-IR in patients in the bezafibrate group did not change (p = 0.99). The intergroup differences in HOMA-IR percentage changes were in favor of bezafibrate (p = 0.01). HOMA-BCF values have significantly decreased by 13.9% (p = 0.04) in patients of placebo group, whereas in patients of bezafibrate group HOMA-BCF was stable during follow-up and its alterations (−2.9%) were non-significant (p = 0.59).
Diabetic patients from the placebo group demonstrated a progressive declining of BCF and an increasing of IR over 2 years of follow-up. These longitudinal changes were attenuated when patients used bezafibrate.
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This result that showed serum triglycerides but not BMI is associated with insulin resistance in the patients with a BMI less than 27.0 kg/m2 has been confirmed in two of our studies [13,14]. Treatment of bezafibrate for 3 months significantly decreased serum triglyceride (277 ± 30 to 139 ± 9 mg/dl, P < 0.001), fasting glucose (163 ± 8 to 139 ± 6 mg/dl, P = 0.006), and HOMA-IR (3.61 ± 0.24 to 2.53 ± 0.20, P < 0.001), but had no effect on BMI (23.0 ± 0.4 to 23.1 ± 0.4 kg/m2, P = 0.483) [13]. Short-term (7 days) low-intensity physical exercise combined with hospital diet significantly reduced serum triglyceride (149 ± 5 to 113 ± 7 mg/dl, P = 0.004), fasting glucose (153 ± 7 to 131 ± 6 mg/dl, P = 0.014), and HOMA-IR (2.36 ± 0.17 to 1.58 ± 0.10, P = 0.001), but had no effect on BMI (23.1 ± 0.4 to 22.8 ± 0.4 kg/m2, P = 0.343) [14].
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Japanese type 2 diabetic patients with insulin resistance had significantly higher concentrations of triglyceride, remnant-like particle cholesterol, subcutaneous and visceral abdominal fat areas, leptin, high sensitive C-reactive protein (hs-CRP), and soluble E-selectin and lower concentration of adiponectin when compared to those with normal insulin sensitivity. There were, however, no significant difference in tumor necrosis factor (TNF)-α and soluble TNF receptors between the two groups. Serum triglyceride was positively correlated to visceral abdominal fat area, while serum leptin was positively correlated with subcutaneous abdominal fat area. In contrast, serum adiponectin was negatively correlated to visceral abdominal fat area. High sensitive CRP was positively correlated to BMI, triglyceride, and leptin, but was negatively correlated to adiponectin. Tumor necrosis factor-α and soluble TNF receptors, however, were not associated with any of these factors.
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