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Hyperuricemia has been reported to be a risk factor for hypertension, but this association may be affected by alcohol consumption. This study aimed to investigate whether hyperuricemia remains a risk factor for hypertension after eliminating the effect of alcohol consumption. This study comprised 7848 participants (4247 men and 3601 women) aged 30-74 years without hypertension who had undergone a medical checkup between April 2008 and March 2009 at Saku Central Hospital, Nagano Prefecture, Japan. Hyperuricemia was defined as uric acid >7.0 mg/dl in men, ≥6.0 mg/dl in women, and/or receiving treatment for hyperuricemia or gout. The incidence of hypertension was defined as the first diagnoses of blood pressure ≥140/≥ 90 mmHg and/or initiations of antihypertensive drug treatment. Multivariable-adjusted hazard ratios (HRs) of hyperuricemia for the incidence of hypertension after adjustment for and classification by alcohol consumption were estimated using the Cox proportional hazard model. During a mean of 4.0 years of follow-up, 1679 individuals developed hypertension. After adjustment for alcohol consumption, the HRs (95% confidence interval) associated with hyperuricemia were 1.37 (1.19-1.58) in men and 1.54 (1.14-2.06) in women. Among nondrinkers, the HR was 1.29 (0.94-1.78) in men with hyperuricemia compared with men without, and the corresponding HR was 1.57 (1.11-2.22) in women. The corresponding HR was 1.88 (1.27-2.86) in all participants with baseline blood pressure <120/80 mmHg. The interactions between hyperuricemia and sex (P = 0.534) and between drinking and sex (P = 0.713) were not significant. In conclusion, hyperuricemia predicts the risk for developing hypertension independent of alcohol drinking status.

Exposure to maternal diabetes during pregnancy results in diabetes in offspring, but its underlying mechanisms are unclear. Here, we investigated the phenotype and molecular defects of the offspring of poorly controlled diabetic female mice generated by streptozotocin (STZ) administration. Offspring was exposed to maternal diabetes during pregnancy and lactation. The body weight of STZ offspring was lower than that of control offspring at birth and in adulthood, and glucose tolerance was impaired in adult STZ offspring. Interestingly, the phenotype was more pronounced in male offspring. We next investigated the morphology of islets and expression of β cell-related genes, but no significant changes were observed. However, transcriptome analysis of the liver revealed activation of the fork head box protein O1 (Foxo1) pathway in STZ male offspring. Notably, two key gluconeogenesis enzyme genes, glucose 6 phosphatase catalytic subunit (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1), were upregulated. Consistent with this finding, phosphorylation of Foxo1 was decreased in the liver of STZ male offspring. These changes were not obvious in female offspring. The activation of Foxo1 and gluconeogenesis in the liver may have contributed to the impaired glucose tolerance of STZ male offspring.

Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.

The aim was to investigate the risk of developing type 2 diabetes according to blood pressure (BP) levels and presence or absence of hypertensive treatment. This 5-year cohort study comprised 3508 Japanese adults aged 30-74 years without diabetes who had undergone a medical checkup including a 75-g oral glucose tolerance test (OGTT) between April 2008 and March 2009 at Saku Central Hospital. Participants receiving antihypertensive treatment were categorized into controlled hypertension ( < 140/90 mmHg) or uncontrolled hypertension ( ≥ 140/90 mmHg) groups. Participants not receiving antihypertensive treatment were categorized: optimal BP ( < 120/80 mmHg), normal BP (120-129/80-84 mmHg), high-normal BP (130-139/85-89 mmHg), grade I hypertension (140-159/90-99 mmHg), and grade II/III hypertension ( ≥ 160/100 mmHg). Hazard ratios and 95% confidence intervals for the incidence of type 2 diabetes as defined by the 75-g OGTT were estimated using multivariable-adjusted Cox proportional hazard models in reference to optimal BP. During an average of 4.4 years of follow-up, 295 participants developed type 2 diabetes. Those with high-normal BP, grade I hypertension, grade II/III hypertension, and uncontrolled hypertension were at significantly higher risk for developing type 2 diabetes, with hazard ratios (95% confidence intervals) of 1.53 (1.03-2.29), 1.53 (1.02-2.32), 2.19 (1.01-4.77), and 1.81 (1.10-2.99), respectively. In conclusion, compared with those with optimal BP, individuals with BP ≥ 130/85 mmHg not receiving antihypertensive treatment and uncontrolled hypertensives with BP ≥ 140/90 mmHg receiving antihypertensive treatment were at a significantly higher risk for developing type 2 diabetes.

Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.

To prevent cardiovascular events in patients with diabetes mellitus (DM), it is essential to reduce arterial pressure (AP). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) prevents cardiovascular events via the depressor response in patients with DM. In the present study, we examined whether SGLT2i ameliorates AP lability in DM rats. Ten-week-old male Sprague-Dawley rats were administered a single intravenous injection of streptozotocin (50 mg kg -1 ) and were divided into three groups treated with low-dose SGLT2i, vehicle (VEH) or subcutaneously implanted insulin pellets (SGLT2i, VEH and Insulin group, respectively) for 14 days. SGLT2i reduced blood glucose, but its effect was lower than that of insulin. The telemetered mean AP at the end of the experiment did not differ among the SGLT2i, Insulin and VEH groups (83±7 vs. 98±9 vs. 90±8 mm Hg, respectively, n=5 for each). The standard deviation of AP as the index of lability was significantly smaller during the active period in the SGLT2i group than in the VEH group (5.6±0.5 vs. 7.0±0.7 mm Hg, n=5 for each, P<0.05). Sympathetic nerve activity during the active period was significantly lower in the SGLT2i group than in the VEH group. Baroreflex sensitivity (BRS) was significantly higher in the SGLT2i group than in the VEH group. The standard deviation of AP and sympathoexcitation did not differ between the Insulin and VEH groups. In conclusion, SGLT2i at a non-depressor dose ameliorated the AP lability associated with sympathoinhibition during the active period and improved the BRS in streptozotocin-induced DM rats.