Acarbose Add-on Therapy in Patients with Type 2 Diabetes Mellitus with Metformin and Sitagliptin Failure: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

BACKGROUND: We evaluated the efficacy and safety of acarbose add-on therapy in Korean patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled with metformin and sitagliptin. METHODS: A total of 165 subjects were randomized to metformin and sitagliptin (Met+Sita, n=65), metformin, sitagliptin, and acarbose (Met+Sita+Acarb, n=66) and sitagliptin and acarbose (Sita+Acarb, exploratory assessment, n=34) therapy in five institutions in Korea. After 16 weeks of acarbose add-on or metformin-switch therapy, a triple combination therapy was maintained from week 16 to 24. RESULTS: The add-on of acarbose (Met+Sita+Acarb group) demonstrated a 0.44%±0.08% (P<0.001 vs. baseline) decrease in glycosylated hemoglobin (HbA1c) at week 16, while changes in HbA1c were insignificant in the Met+Sita group (−0.09%±0.10%, P=0.113). After 8 weeks of triple combination therapy, HbA1c levels were comparable between Met+Sita and Met+Sita+Acarb group (7.66%±0.13% vs. 7.47%±0.12%, P=0.321). Acarbose add-on therapy demonstrated suppressed glucagon secretion (area under the curve of glucagon, 4,726.17±415.80 ng·min/L vs. 3,314.38±191.63 ng·min/L, P=0.004) in the absence of excess insulin secretion during the meal tolerance tests at week 16 versus baseline. The incidence of adverse or serious adverse events was similar between two groups. CONCLUSION: In conclusion, a 16-week acarbose add-on therapy to metformin and sitagliptin, effectively lowered HbA1c without significant adverse events. Acarbose might be a good choice as a third-line therapy in addition to metformin and sitagliptin in Korean subjects with T2DM who have predominant postprandial hyperglycemia and a high carbohydrate intake.

Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation

BACKGROUND: Emerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB). METHODS: We examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels. RESULTS: Lack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends. CONCLUSION: Altogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.

Effects of Adding omega-3 Fatty Acids to Simvastatin on Lipids, Lipoprotein Size and Subspecies in Type 2 Diabetes Mellitus with Hypertriglyceridemia / 당뇨병

BACKGROUND: omega-3 fatty acids are known to improve lipid profiles, the distribution of lipoprotein subclasses, and secondary prevention against post-myocardial infarction. Rare reports have emerged of synergistic results of omega-3 fatty acids with simvastatin in cases of type 2 diabetes mellitus with hypertriglyceridemia. The purpose of this study was to determine the combined relationship of omega-3 fatty acids plus simvastatin on lipid, lipoprotein size and the types of subspecies. METHODS: This randomized, multi-center, comparison study evaluated eight weeks of combination therapy (omega-3 fatty acids (Omacor) 4 g/day plus simvastatin 20 mg/day) or monotherapy (simvastatin 20 mg/day) for at least six weeks in 62 diabetic patients. Subjects with a triglyceride concentration of more than 200 mg/dL were eligible for inclusion. RESULTS: No significant differences for omega-3 fatty acids + simvastatin versus simvastatin alone were observed for triglycerides (-22.7% vs. -14.3%, P = 0.292), HDL peak particle size (+2.8% vs. -0.4%, P = 0.076), LDL mean particle size (+0.4% vs -0.1%, P = 0.376) or LDL subspecies types, although the combination therapy showed a tendency toward lower triglycerides, larger HDL, and LDL particle sizes than did the monotherapy. There were no significant differences between the two groups in regard to HDL-C, LDL-C, or HbA1c levels. There were no serious adverse events and no abnormalities in the laboratory values associated with this study. CONCLUSION: omega-3 fatty acids were a safeform of treatment in hypertriglyceridemic patients with type 2 diabetes mellitus. But, regarding efficacy, a much larger sample size and longer-term follow-up may be needed to distinguish between the effects of combination therapy and monotherapy.

The Effects of C161-->T Polymorphisms in Exon 6 of Peroxisome Proliferator-Activated Receptor- Gene on Bone Mineral Metabolism and Serum Osteoprotegerin Levels in Healthy Korean Middle-aged Men / 대한내분비학회지

BACKGROUND: The peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor family known to be involved in adipocyte differentiation. Recent studies have revealed the inhibitory role of PPAR in osteoblastogenesis, which suggests its possibility as a candidate gene for osteoporosis. The frequency of C161-->T substitution in exon 6 of PPAR was observed in Korean men and the association of different genotypes with bone turnover markers, bone mineral density (BMD) and serum osteoprotegerin (OPG), which play inhibitory roles in osteoclastogenesis, examined. METHODS: In 72 healthy Korean men (mean age 54.5 6.4 yrs; range 42~69 yrs), anthropometric measurements, and lumbar spine and femoral neck BMD, and bone turnover markers, such as alkaline phosphatase (ALP), serum calcium, phosphorus, osteocalcin and cross-linked C-telopeptides of type I collagen (ICTP) measurements were performed. The levels of serum testosterone, estradiol and insulin-like growth factor (IGF-I), and those of serum OPG levels, were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) method. The DNAs were extracted from the samples, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the sequencing of the products were performed to confirm the substitution. RESULTS: The allele frequencies were 0.799 and 0.201 for the C and T allele, respectively, which were in Hardy-Weinberg equilibrium (p=0.80). Subjects with the CT genotype were older and those with the T allele showed higher blood pressure levels and lower body mass indices (p0.05). The levels of serum testosterone, estradiol, IGF-I and OPG were not different among the different genotype groups (p>0.05). The lumbar, femoral neck BMD (g/cm2) and T scores were significantly lower in subjects with T alleles, and those with CT genotypes showed the lowest BMD values (pT substitution in exon 6 of the PPAR gene in Korean men were similar to those observed in other races, and those with the T alleles showed significantly lower BMD values. These data imply the PPAR gene might be a candidate gene for the pathogenesis of osteoporosis