Management of home blood pressure by amlodipine combined with angiotensin II receptor blocker in type 2 diabetes.

BACKGROUND: Angiotensin II receptor blocker (ARB) as a first-line drug for hypertension in diabetes often fails to control blood pressure adequately. The objective of the study was to evaluate the effect of amlodipine combined therapy on home blood pressure (HBP) useful for management of hypertension. METHODS AND RESULTS: A total of 263 type 2 diabetes with hypertension refractory to standard dose of ARB were randomized to increased ARB regimen (n=132) or amlodipine combination regimen (n=131). The primary endpoint was change in morning HBP at 1 year. The combination regimen significantly lowered morning HBP than the increased ARB regimen (158.2/82.5 mmHg in the combination regimen, 157.3/84.4 mmHg in the increased ARB regimen, at baseline; 142.7/76.3 vs. 155.0/83.1 mmHg, respectively, P<0.001 for both, at 8 weeks; 139.6/74.6 vs. 149.1/78.1 mmHg, respectively, P<0.001 for systolic and P=0.010 for diastolic, at 1 year). The combination regimen showed significantly higher rates of achieving target morning HBP at 8 weeks (11.3% vs. 2.7%, P=0.015). In the combination regimen, estimated glomerular filtration rate declined slower, and carotid intima-media thickness decreased in contrast to the increased ARB regimen. CONCLUSIONS: In type 2 diabetes patients with hypertension refractory to standard dose of ARB, the amlodipine combination regimen provides superior antihypertensive effect on HBP to the increased ARB regimen, and beneficial effects on reducing risks of cardiovascular events.

Comparison of effects of azelnidipine and trichlormethiazide in combination with olmesartan on blood pressure and metabolic parameters in hypertensive type 2 diabetic patients.

UNLABELLED: Aims/Introduction: Angiotensin II type 1 receptor blockers (ARB) are regarded as first-line treatment for type 2 diabetes with hypertension. However, lowering blood pressure to the target level often requires more than one antihypertensive agent as recommended by the guideline. In this open-label, prospective, crossover clinical trial, we compared the effects of combination treatment of ARB with a calcium channel blocker (CCB) or with a low-dose thiazide diuretic on blood pressure (BP) and various metabolic parameters in hypertensive patients with type 2 diabetes. MATERIALS AND METHODS: A total of 39 Japanese type 2 diabetics with hypertension treated with olmesartan (20 mg/day) for at least 8 weeks were recruited to this study. At study entry, treatment was switched to either olmesartan (20 mg/day)/azelnidipine (16 mg/day) or olmesartan (20 mg/day)/trichlormethiazide (1 mg/day) and continued for 12 weeks. Then, the drugs were switched and treatment was continued for another 12 weeks. We measured clinical blood pressure and various metabolic parameters before and at the end of each study arm. RESULTS: Compared with the olmesartan/trichlormethiazide treatment, treatment with olmesartan/azelnidipine achieved superior clinical blood pressure and pulse rate control. In contrast, the treatment with olmesartan/trichlormethiazide resulted in increased HbA1c, serum uric acid and worsening of estimated glomerular filtration rate, though there were no differences in other metabolic parameters including urine 8-hydroxy-2'-deoxyguanosine, C-reactive protein and adiponectin between the two treatments. CONCLUSIONS: Our results show that the combination of ARB with azelnidipine is more beneficial with regard to blood pressure control and metabolic outcome than the combination of olmesartan with low dose trichlormethiazide. This trial was registered with UMIN clinical trial registry (no. UMIN000005064). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00135.x, 2011).

Combined expression of transcription factors induces AR42J-B13 cells to differentiate into insulin-producing cells.

Neurogenin 3 (Ngn3) is a transcription factor that regulates an initial step of differentiation from uncommitted pancreatic progenitors into endocrine cells. Additional transcription factors are required for complete differentiation into mature pancreatic beta cells. In this study, we established an in vitro model system of beta-cell differentiation by adenovirus-mediated expression of several transcription factors in AR42J-B13 cells, a pancreatic progenitor-like cell line derived from exocrine pancreas. Exogenous expression of Ngn3 in AR42J-B13 cells induced expression of Nkx2.2, Pax4, and Pax6, which are all essential for beta-cell differentiation in mouse embryos. However, Ngn3 did not induce more downstream regulators of beta-cell differentiation, Nkx6.1 and Maf A. Coexpression of Nkx6.1 and Ngn3 induced endogenous expression of the insulin 2 gene, while coexpression of Maf A and Ngn3 induced both insulin 1 and 2 genes in AR42J-B13 cells. Our data demonstrated that Ngn3 expressed together with Nkx6.1 or MafA induces AR42J-B13 cells to differentiate into insulin-producing cells, supporting the use of these cells as a model system for studying beta-cell differentiation in vitro.

Nateglinide reduces carotid intima-media thickening in type 2 diabetic patients under good glycemic control.

OBJECTIVE: Postprandial hyperglycemia observed in type 2 diabetes mellitus is a risk factor for atherosclerosis. The aim of this study was to investigate the effect of strict glycemic control by nateglinide on common carotid far wall intima-media thickness in type 2 diabetic patients who were already under good glycemic control. METHODS AND RESULTS: We performed an open labeled randomized prospective trial on 78 drug-naive type 2 diabetic patients whose HbA1c was less than 6.5%. Thirty-eight patients were randomly assigned to receive nateglinide (270 mg/dL) and 40 to control group (no treatment). After 12 months, a significant reduction in HbA1c was observed in the nateglinide group, whereas a significant increase of HbA1c was observed in the untreated group. The carotid intima-media thickness at the end of 1-year follow-up was significantly reduced in the nateglinide group compared with the untreated group (-0.017+/-0.054 mm/year versus 0.024+/-0.066 mm/year, P=0.0064). Whereas nateglinide treatment also reduced triglyceride, highly-sensitive C-reactive protein, and E-selectin, multiple regression analysis identified HbA1c as the only significant independent determinant of the change in carotid intima-media thickness. CONCLUSION: In type 2 diabetic patients with good glycemic control, further strict glycemic control by nateglinide results in regression of carotid intima-media thickness.

Protein kinase Cdelta plays a non-redundant role in insulin secretion in pancreatic beta cells.

Protein kinase C (PKC) is considered to modulate glucose-stimulated insulin secretion. Pancreatic beta cells express multiple isoforms of PKCs; however, the role of each isoform in glucose-stimulated insulin secretion remains controversial. In this study we investigated the role of PKCdelta, a major isoform expressed in pancreatic beta cells on beta cell function. Here, we showed that PKCdelta null mice manifested glucose intolerance with impaired insulin secretion. Insulin tolerance test showed no decrease in insulin sensitivity in PKCdelta null mice. Studies using islets isolated from these mice demonstrated decreased glucose- and KCl-stimulated insulin secretion. Perifusion studies indicated that mainly the second phase of insulin secretion was decreased. On the other hand, glucose-induced influx of Ca2+ into beta cells was not altered. Immunohistochemistry using total internal reflection fluorescence microscopy and electron microscopic analysis showed an increased number of insulin granules close to the plasma membrane in beta cells of PKCdelta null mice. Although PKC is thought to phosphorylate Munc18-1 and facilitate soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors complex formation, the phosphorylation of Munc18-1 by glucose stimulation was decreased in islets of PKCdelta null mice. We conclude that PKCdelta plays a non-redundant role in glucose-stimulated insulin secretion. The impaired insulin secretion in PKCdelta null mice is associated with reduced phosphorylation of Munc18-1.

Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients.

Insulin resistance is associated with the circulating free fatty acid (FFA) level and intracellular lipid content in muscle and liver. We investigated the effect of 2-wk diet and exercise therapy on total adiposity, circulating FFA, intracellular lipid content in muscle and liver, and peripheral insulin sensitivity. Type 2 diabetic patients were divided into a diet group (n = 7) and a diet plus exercise group (n = 7). We performed a hyperinsulinemic-euglycemic clamp study before and after treatment. Intramyocellular lipid (IMCL) in the tibialis anterior muscle and intrahepatic lipid (IHL) were evaluated by (1)H-magnetic resonance spectroscopy. Fasting FFA were not altered, and total body fat showed a slight, but significant, decrease in both groups after treatment. IMCL was decreased by 19%, and the glucose infusion rate was increased by 57% in the diet plus exercise group, whereas neither IMCL nor glucose infusion rate was significantly altered in the diet group. However, IHL showed a significant decrease in both groups. In summary, we found that 2 wk of diet and exercise decreased IMCL and increased muscle insulin-mediated glucose uptake, whereas diet with or without exercise decreased IHL. These effects were evident despite a small decrease in body fat and were observed independently of fasting FFA levels.

Reduction of insulin-stimulated glucose uptake by peroxynitrite is concurrent with tyrosine nitration of insulin receptor substrate-1.

Inducible nitric oxide synthetase plays an essential role in insulin resistance induced by a high-fat diet. The reaction of nitric oxide with superoxide leads to the formation of peroxynitrite (ONOO-), which can modify several proteins. In this study, we investigated whether peroxynitrite impairs insulin-signalling pathway. Our experiments showed that 3-(4-morpholinyl)sydnonimine hydrochloride (SIN-1), a constitutive producer of peroxynitrite, dose-dependently inhibited insulin-stimulated glucose uptake. While SIN-1 did not affect the insulin receptor protein level and tyrosine phosphorylation, it reduced the insulin receptor substrate-1 (IRS-1) protein level, and IRS-1 associated phosphatidylinositol-3 kinase (PI-3 kinase) activity. Although SIN-1 did not induce Ser307 phosphorylation of IRS-1, tyrosine nitration of IRS-1 was detected in SIN-1-treated-Rat1 fibroblasts expressing human insulin receptors. Mass spectrometry showed that peroxynitrite induced at least four nitrated tyrosine residues in rat IRS-1, including Tyr939, which is critical for association of IRS-1 with the p85 subunit of PI-3 kinase. Our results suggest that peroxynitrite reduces the IRS-1 protein level and decreases phosphorylation of IRS-1 concurrent with nitration of its tyrosine residues.