Bezafibrate improves insulin resistance evaluated using the glucose clamp technique in patients with type 2 diabetes mellitus: a small-scale clinical study.

BACKGROUND: Bezafibrate is mainly used to treat hypertriglyceridemia. Studies have reported that bezafibrate also improves type 2 diabetes mellitus, but the mechanism has not been fully elucidated. We performed euglycemic hyperinsulinemic clamps (glucose clamp) and meal tolerance tests (MTT) to examine the effects of bezafibrate on insulin resistance in patients with type 2 diabetes mellitus. METHODS: Twelve Japanese patients with type 2 diabetes mellitus and dyslipidemia (mean age: 59.5 years; fasting plasma glucose: 7.95 mmol/L; hemoglobin A1c [HbA1c]: 7.3%; body mass index: 26.5 kg/m(2)) underwent a glucose clamp and MTT before and after 12 weeks of treatment with 400 mg/day bezafibrate. The glucose infusion rate was measured during the glucose clamp. The patients took a test meal (460 kcal) in the MTT. Plasma glucose and immunoreactive insulin levels were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity, serum lipids, and liver function markers were also measured during the MTT. RESULTS: Bezafibrate significantly increased the mean glucose infusion rate from 5.78 ± 1.94 to 6.78 ± 2.52 mg/kg/min (p < 0.05). HbA1c improved from 7.30 ± 0.55% to 7.02 ± 0.52% (p < 0.05). In the MTT, fasting plasma glucose decreased from 7.95 ± 1.15 to 6.98 ± 1.07 mmol/L (p < 0.05). The area under the plasma glucose curve from 0 to 180 min decreased significantly from 29.48 ± 5.07 to 27.12 ± 3.98 mmol/h/L (p < 0.05), whereas immunoreactive insulin was unchanged. Furthermore, bezafibrate also significantly improved serum lipids, with decreases in triglyceride levels from 1.84 ± 0.88 to 1.14 ± 0.41 mmol/L (p < 0.05), low-density lipoprotein cholesterol levels from 3.56 ± 0.83 to 2.92 ± 0.55 mmol/L (p < 0.05), and remnant-like particle cholesterol levels decreased from 0.25 ± 0.16 to 0.14 ± 0.06 mmol/L (p < 0.05), and increases in high-density lipoprotein cholesterol levels from 1.50 ± 0.24 to 1.66 ± 0.29 mmol/L (p < 0.05). CONCLUSIONS: Bezafibrate improved glucose intolerance and peripheral insulin resistance in these Japanese patients with type 2 diabetes mellitus and dyslipidemia. Therefore, bezafibrate could be used to treat insulin resistance in patients with type 2 diabetes mellitus and dyslipidemia. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000012462.

Low serum galectin-3 concentrations are associated with insulin resistance in patients with type 2 diabetes mellitus.

BACKGROUND: Galectin-3 is a family of soluble beta-galactoside-binding lectins that play many important regulatory roles in inflammation. Galectin-3-deficient mice have been shown to exhibit excess adiposity, hyperglycemia, insulin resistance and systemic inflammation. We investigated the association between serum galectin-3 and insulin resistance in patients with type 2 diabetes using a glucose clamp method. METHODS: This was a cross-sectional study. Twenty patients (mean fasting plasma glucose 7.6 mmol/L, HbA1c 7.2%, BMI 28.1 kg/m(2)) underwent a meal tolerance test and glucose clamp test. Participants were given a test meal and plasma glucose and insulin were measured at 0, 30, 60, 120 and 180 min. The glucose disposal rate was measured during hyperinsulinemic-euglycemic glucose clamps. Serum galectin-3 levels were measured using the enzyme-linked immunosorbent assay method. RESULTS: The mean serum galectin-3 level was 5103 pg/ml. Galectin-3 levels correlated significantly with the glucose disposal rate (R = 0.71, P < 0.001), fasting insulin (R = -0.56, P < 0.01), homeostasis model assessment for insulin resistance (R = -0.52, P < 0.05), and the insulin sensitivity index (R = 0.62, P < 0.005). Galectin-3 levels also positively correlated with the serum adiponectin level (R = 0.61, P < 0.05), but not with the high-sensitive C-reactive protein and interleukin-6 and -10. CONCLUSIONS: These results suggest that low levels of serum galectin-3 are associated with insulin resistance in patients with type 2 diabetes.

Sitagliptin Improves the Impaired Acute Insulin Response during a Meal Tolerance Test in Japanese Patients with Type 2 Diabetes Mellitus: A Small-Scale Real-World Study.

INTRODUCTION: Several studies have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors improve insulin secretion during oral glucose tolerance tests. However, the effects of DPP-4 inhibitors on impaired acute insulin responses in the postprandial state in real-world settings are unknown. Therefore, we evaluated the effects of sitagliptin on the acute insulin responses in Japanese patients with type 2 diabetes mellitus (T2DM) using meal tolerance tests. METHODS: Twenty-one patients with T2DM were given a test meal (460 kcal), and plasma glucose and insulin were measured at 0, 30, 60, 120, and 180 min after the meal. The insulinogenic index of all of these patients was below 43.2. The postprandial profiles were assessed at baseline and after 3 months of treatment with 50 mg/day sitagliptin after a meal (n = 11) or were untreated (control group; n = 10). This study was a prospective, open-label, non-blinded, non-randomized, clinical study. RESULTS: Sitagliptin significantly decreased the plasma glucose levels at 60, 120, and 180 min, and significantly increased the plasma insulin levels at 0 and 30 min. There were no significant changes in glucose or insulin in the control group. The insulinogenic index increased significantly in the sitagliptin group compared with the control group (+16.7 vs. +0.1, P < 0.005). However, homeostasis model assessment of insulin resistance and the insulin sensitivity index were not significant different between the two groups. CONCLUSION: Administration of sitagliptin at 50 mg/day after a meal improved the impaired acute insulin response and suppressed postprandial hyperglycemia. Whereas the study is rather small and the design is suboptimal as it is not randomized and not blinded, these results suggest that sitagliptin is effective in Japanese patients with T2DM, many of whom display impaired acute insulin responses after a meal.

The proinsulin/insulin (PI/I) ratio is reduced by postprandial targeting therapy in type 2 diabetes mellitus: a small-scale clinical study.

BACKGROUND: An elevated PI/I ratio is attributable to increased secretory demand on ß-cells. However, the effect of postprandial targeting therapy on proinsulin level is unknown. We evaluated the metabolic effect of glinide and sulfonylurea (SU) using the meal tolerance test (MTT). METHODS: MTT was applied to previously untreated Type 2 Diabetes Mellitus (T2DM) subjects. Twenty-two participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum proinsulin and C-peptide immunoreactivity (CPR) were measured at 0 and 120 min. Postprandial profile was assessed at baseline and following 3 months treatment with either mitiglinide or glimepiride. RESULTS: Plasma glucose level at 30, 60, 120, and 180 min was significantly improved by mitiglinide. Whereas, glimepiride showed a significant improve plasma glucose at 0, 180 min. Peak IRI shifted from 120 to 30 min by mitiglinide treatment. The pattern of insulin secretion was not changed by glimepiride treatment. Whereas mitiglinide did not affect the PI/I ratio, glimepiride tended to increase the PI/I ratio. Moreover, although mitiglinide did not affect PI/I ratio as a whole, marked reduction was noted in some patients treated by mitiglinide. PI/I ratio was reduced significantly in the responder group. The responder subgroup exhibited less insulin resistance and higher insulinogenic index at baseline than non-responders. Moreover, the triglyceride level of responders was significantly lower than that of non-responders. CONCLUSIONS: Mitiglinide improved postprandial insulin secretion pattern and thereby suppressed postprandial glucose spike. In T2DM patients with low insulin resistance and low triglyceride, mitiglinide recovered impaired ß-cell function from the viewpoint of the PI/I ratio. TRIAL REGISTRATION UMIN-CTR: UMIN000010467.

20/(fasting C-peptide × fasting plasma glucose) is a simple and effective index of insulin resistance in patients with type 2 diabetes mellitus: a preliminary report.

BACKGROUND: We developed a simple and new insulin resistance index derived from a glucose clamp and a meal tolerance test (MTT) in Japanese patients with type 2 diabetes mellitus. METHODS: Fifteen patients [mean age: 53 years, fasting plasma glucose (FPG) 7.7 mmol/L, HbA1c 7.1% (54 mmol/mol), body mass index 26.8 kg/m(2)] underwent a MTT and a glucose clamp. Participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity (CPR) was measured at 0 (fasting; F-CPR) and 120 min. Homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices (ISI) were calculated from the MTT results. The glucose infusion rate (GIR) was measured during hyperinsulinemic-euglycemic glucose clamps. RESULTS: The mean GIR in all patients was 5.8 mg·kg(-1)·min(-1). The index 20/(F-CPR × FPG) was correlated strongly with GIR (r = 0.83, P < 0.0005). HOMA-IR (r = -0.74, P < 0.005) and ISI (r = 0.66, P < 0.01) were also correlated with GIR. In 10 patients with mild insulin resistance (GIR 5.0-10.0 mg·kg(-1)·min(-1)), 20/(F-CPR × FPG) was very strongly correlated with GIR (r = 0.90, P < 0.0005), but not with HOMA-IR and ISI (r = -0.49, P = 0.15; r = 0.20, P = 0.56, respectively). In patients with mild insulin resistance, plasma adiponectin (r = 0.65, P < 0.05), but not BMI or waist circumstance, was correlated with GIR. CONCLUSIONS: 20/(F-CPR × FPG) is a simple and effective index of insulin resistance, and performs better than HOMA-IR and ISI in Japanese patients with type 2 diabetes mellitus. Our results suggest that 20/(F-CPR × FPG) is a more effective index than HOMA-IR in Japanese patients with mild insulin resistance.

[A case of AFP-producing gastric cancer responding to the combination of systemic chemotherapy, transcatheter arterial embolization and hepatic infusion chemotherapy].

We report a case of a 64-year-old male with a-fetoprotein(AFP)-producing gastric cancer accompanied by large liver metastases and multiple lymph node metastases. The patient's serum AFP level was 42,307 ng/mL and a biopsy specimen showed AFP-positive tumor cells immunohistochemically. Systemic chemotherapy by tegafur gimeracil oteracil potassium(S-1)and local therapy for the hepatic metastases consisting of transcatheter arterial embolization (TAE)and infusion of epirubicin(EPI)to the hepatic arteries decreased the serum AFP level and reduced the gastric cancer and metastases. Due to the increase of AFP and lymph node metastases, we had to successively change the regimen to paclitaxel(PTX), a combination of cisplatin(CDDP)/irinotecan(CPT-11)and S-1. Continuous systemic chemotherapy in combination with various drugs for gastric cancer treatment followed by TAE and hepatic infusion chemotherapy for hepatic metastases proved effective. The patient survived for 3 years and 2 months.