Non-alcoholic fatty liver disease is an independent predictor for macroangiopathy in Japanese type 2 diabetic patients: a cross-sectional study.

OBJECTIVE: To clarify the clinical characteristics of type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD) and to assess whether NAFLD is related to angiopathy. METHODS: The study included 388 Japanese type 2 diabetic outpatients without viral hepatitis. The main outcome measures were angiopathy and NAFLD. RESULTS: The 388 subjects were divided into two subgroups based on alcohol consumption. Fatty liver was recognized in 36 of the 142 drinking patients (25%). There was no association of fatty liver disease with diabetic macro- or microangiopathy in these patients. Fatty liver disease (namely, NAFLD) was recognized in 77 of the 246 non-drinking patients (31%). Type 2 diabetic patients with NAFLD had a significantly younger age, higher body mass index level, higher levels of HbA1c, total cholesterol and triglyceride, lower HDL-C level, higher prevalence rates of hypercholesterolemia and obesity than counterparts without NAFLD. In addition, individuals in the elderly (≥65 years) non-drinking group with NAFLD had a significantly higher prevalence rates of diabetic macroangiopathy, coronary heart disease and thicker intima-media thickness level than their counterparts without NAFLD. The logistic regression analysis showed that NAFLD is an independent predictor of diabetic macroangiopathy. CONCLUSION: NAFLD was associated with an increased prevalence of diabetic macroangiopathy and coronary heart disease in elderly patients. In addition, NAFLD is an independent predictor for diabetic macroangiopathy. These findings suggest that type 2 diabetic patients with NAFLD should be considered as a high risk group for developing macroangiopathy, even if macroangiopathy is not clinically detected.

Hypertension resistant to antihypertensive agents commonly occurs with the progression of diabetic nephropathy in Japanese patients with type 2 diabetes mellitus: a prospective observational study.

BACKGROUND: We investigated 1) the frequency of hypertension in patients with type 2 diabetes graded by the new classification of chronic kidney disease (CKD) reported by the Kidney Disease: Improving Global Outcomes (KDIGO) and 2) the number of antihypertensive agents needed to achieve treatment goals using a prospective observational study. METHODS: A population of 2018 patients with type 2 diabetes mellitus was recruited for the study. The CKD stage was classified according to the eGFR and the urinary albumin excretion levels. RESULTS: Hypertension was found in 1420 (70%) of the patients, and the proportion of subjects showing a blood pressure<130/80 mmHg was 31% at the baseline. Although the mean blood pressure was approximately 130/75 mmHg, the rate of patients with a blood pressure of <130/80 mmHg became limited to 41-50% during the observation period. The number of antihypertensive agents required for treatment was significantly higher at the endpoint (2.0±1.3) than at the baseline (1.6±1.2). Furthermore, it increased with the progression of the CKD stage at both the baseline and the endpoint of the observation. However, the frequency of subjects who did not achieve the blood pressure target was found to increase in the group demonstrating the later stage of CKD. CONCLUSIONS: Hypertension resistant to antihypertensive agents was common in the patients with type 2 diabetes mellitus and increased with the progression of CKD. Although powerful combination therapy using antihypertensive agents is considered necessary for the strict control of blood pressure, this became difficult in individuals who were in advanced stages as graded based on the eGFR and the urinary albumin excretion levels.

The usefulness of the revised classification for chronic kidney disease by the KDIGO for determining the frequency of diabetic micro- and macroangiopathies in Japanese patients with type 2 diabetes mellitus.

AIMS: A new classification of chronic kidney disease (CKD) was proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) in 2011. The major point of revision of this classification was the introduction of a two-dimensional staging of the CKD according to the level of albuminuria in addition to the GFR level. Furthermore, the previous CKD stage 3 was subdivided into two stages (G3a and G3b). We examined the prevalence of diabetic micro- and macroangiopathies in patients with type 2 diabetes mellitus based on the new classification. METHODS: A cross-sectional study was performed in 2018 patients with type 2 diabetes mellitus. RESULTS: All of the diabetic micro- and macroangiopathies significantly more common in the later stages of both the GFR and albuminuria. The proportion of subjects with diabetic retinopathy, neuropathy, cerebrovascular disease and coronary heart disease was significantly higher in the G3b group than in the G3a group. The brachial-ankle pulse wave velocity, which is one of the surrogate markers for atherosclerosis, was also significantly greater in the G3b group compared to the G3a group. CONCLUSION: The subdivision of the G3 stage in the revised classification proposed by the KDIGO is useful to evaluate the risk for diabetic vascular complications.

Hyperuricemia is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus.

AIMS: To investigate the relationship between hyperuricemia (HUA) and the clinical backgrounds in Japanese patients with type 2 diabetes mellitus. METHODS: After a cross-sectional study evaluating the association of HUA with the clinical characteristics in 1,213 patients with type 2 diabetes mellitus, the estimated glomerular filtration rate (eGFR) and the incidence of diabetic macroangiopathies was investigated in a prospective observational study in 1,073 patients during a 3.5 year period. HUA was defined by serum uric acid levels >327 µmol/L or as patients using allopurinol. RESULTS: The frequency of HUA was significantly higher in the diabetic patients (32% in men and 15% in women) than in the normal controls (14% in men and 1% in women). In total, HUA was found in 299 (25%) of the patients during the cross-sectional study. Even after adjusting for sex, drinking status, treatment for diabetes mellitus, body mass index, hypertension, use of diuretics, hyperlipidemia, HbA1c and/or the eGFR, the HUA was independently associated with some diabetic complications. The eGFR was significantly reduced in HUA patients compared to those with normouricemia in the 12 months after observation was started. HUA was also an independent risk factor for coronary heart disease even after adjustment in the Cox proportional hazard model. CONCLUSIONS: HUA is a associated with diabetic micro- and macroangiopathies. HUA is a predictor of coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. However, the influence of HUA is considered to be limited.

Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus.

BACKGROUND: We aimed to investigate the long-term effect of metformin on the blood glucose control in non-obese patients with type 2 diabetes mellitus. METHODS: A retrospective study was performed in 213 patients with type 2 diabetes mellitus under the administration of metformin for more than one year. The clinical parameters were investigated for 3 years. The obese and non-obese individuals were defined as a body mass index (BMI) of 25 kg/m2 or over (n = 105) and a BMI of less than 25 kg/m2 (n = 108), respectively. RESULTS: HbA1c levels were significantly decreased compared with those at the baseline time. The course of HbA1c was similar between the non-obese and the obese groups, while the dose of metformin required to control blood glucose was significantly lower in the non-obese group than in the obese group. The reductions in HbA1c were 1.2% and 1.1% at 12 months, 0.9% and 0.9% at 24 months, and 0.8% and 1.0% at 36 months in the non-obese and obese groups, respectively. BMI did not change during the observation periods. Approximately half of all patients required no additional antidiabetic agents or a reduction in other treatments after the initiation of metformin in either of the two groups. CONCLUSIONS: The present study demonstrated the long-term beneficial effect of metformin in non-obese (BMI < 25 kg/m2) diabetic patients. This effect appears to be maintained even after the observation period of this study, because metformin was limited to a relatively low dose in the non-obese group and the observed worsening in glycemic control over time can probably be attenuated by increasing the dose of metformin.

The estimated GFR, but not the stage of diabetic nephropathy graded by the urinary albumin excretion, is associated with the carotid intima-media thickness in patients with type 2 diabetes mellitus: a cross-sectional study.

BACKGROUND: To study the relationship between the intima-media thickness (IMT) of the carotid artery and the stage of chronic kidney disease (CKD) based on the estimated glomerular filtration rate (eGFR) and diabetic nephropathy graded by the urinary albumin excretion (UAE) in the patients with type 2 diabetes mellitus. METHODS: A cross-sectional study was performed in 338 patients with type 2 diabetes mellitus. The carotid IMT was measured using an ultrasonographic examination. RESULTS: The mean carotid IMT was 1.06 +/- 0.27 mm, and 42% of the subjects showed IMT thickening (>or= 1.1 mm). Cerebrovascular disease and coronary heart disease were frequent in the patients with IMT thickening. The carotid IMT elevated significantly with the stage progression of CKD (0.87 +/- 0.19 mm in stage 1, 1.02 +/- 0.26 mm in stage 2, 1.11 +/- 0.26 mm in stage 3, and 1.11 +/- 0.27 mm in stage 4+5). However, the IMT was not significantly different among the various stages of diabetic nephropathy. The IMT was significantly greater in the diabetic patients with hypertension compared to those without hypertension. The IMT positively correlated with the age, the duration of diabetes mellitus, and the brachial-ankle pulse wave velocities (baPWV), and negatively correlated with the eGFR. In a stepwise multivariate regression analysis, the eGFR and the baPWV were independently associated with the carotid IMT. CONCLUSIONS: Our study is the first report showing a relationship between the carotid IMT and the renal parameters including eGFR and the stages of diabetic nephropathy with a confirmed association between the IMT and diabetic macroangiopathy. Our study further confirms the importance of intensive examinations for the early detection of atherosclerosis and positive treatments for hypertension, dyslipidaemia, obesity, as well as hyperglycaemia are necessary when a reduced eGFR is found in diabetic patients.

High frequencies of diabetic micro- and macroangiopathies in patients with type 2 diabetes mellitus with decreased estimated glomerular filtration rate and normoalbuminuria.

BACKGROUND: The clinical characteristics of diabetic patients presenting with normoalbuminuria with decreased kidney functions were investigated. METHODS: A cross-sectional study was performed in 1197 patients with type 2 diabetes mellitus. The estimated glomerular filtration rate (eGFR) was calculated using the formula recommended by the Japanese Society of Nephrology. RESULTS: The groups with normoalbuminuria, microalbuminuria, macroalbuminuria and renal failure consisted of 696 (58%), 229 (19%), 196 (16%) and 76 (6%) subjects, respectively. The frequencies of all diabetic micro- and macroangiopathies increased with progression of diabetic nephropathy stage. However, in the groups with chronic kidney disease (CKD) stage 3+4 (60 > eGFR > or = 15 mL/min/1.73 m(2)), the frequencies of diabetic neuropathy and macroangiopathies were not different among the groups staged by urinary albumin excretion. In the normoalbuminuria group, 223 (32%) cases showed CKD stage 3+4. Diabetic neuropathy and macroangiopathies were significantly more frequent in the groups presenting with normoalbuminuria with CKD stage 3+4 than in those with CKD stage 1+2 (eGFR > or = 60 mL/min/1.73 m(2)). The patients' age, duration of diabetes mellitus and frequency of hypertension were significantly higher in the groups presenting with normoalbuminuria with CKD stage 3+4. After adjustment by age, grade of albuminuria or both, CKD stage 3+4 was an independent risk factor for some diabetic complications. CONCLUSIONS: The combination of urinary albumin excretion and eGFR is useful for earlier detection of kidney and vascular damage in patients with diabetes mellitus. Evaluation of eGFR should be performed for all diabetic patients even if they show normoalbuminuria.

Mild anemia is frequent and associated with micro- and macroangiopathies in patients with type 2 diabetes mellitus.

UNLABELLED: Aims/Introduction: The present study investigated the frequency of mild anemia, which is not an indication of intensive therapy using drugs, in Japanese patients with type 2 diabetes mellitus and the association of mild anemia with diabetic complications. MATERIALS AND METHODS: This is a cross-sectional study of 1189 patients with type 2 diabetes mellitus. Anemia was defined as a hemoglobin level <13.5 g/dL in men and <12.0 g/dL in women. The patients with anemia were divided into two groups: (i) grade 1 anemia with a hemoglobin level ≥11.0 g/dL; and (ii) grade 2 anemia with a hemoglobin level <11.0 g/dL. RESULTS: The prevalence of anemia increased with the progression of the stage of diabetic nephropathy and chronic kidney disease. The frequencies of diabetic micro- and macroangiopathies increased with the progression of anemia among 798 patients without anemia, 300 with grade 1 anemia and 91 with grade 2 anemia. Both grade 1 and grade 2 anemia were associated with diabetic micro- and macroangiopathies. They remained independently associated with diabetic retinopathy, coronary heart disease and peripheral arterial disease after adjustment by age, sex, body mass index, use of angiotensin II receptor blocker, estimated glomerular filtration rate and stage of diabetic nephropathy. CONCLUSIONS: Mild anemia is frequent and associated with micro- and macroangiopathies in patients with type 2 diabetes mellitus. It is important to carry out intensive examinations for the detection of diabetic micro- and macroangiopathies in addition to evaluating the causes of anemia when mild anemia is found in patients with diabetes mellitus. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00060.x, 2010).

Insulin Autoimmune Syndrome possibly caused by alpha lipoic acid.

Insulin Autoimmune Syndrome (IAS) is a rare disease characterized by hypoglycemia and autoantibodies to insulin without prior insulin administration. Here, we report a case of IAS associated with alpha lipoic acid (ALA). The patient is a 55-year-old man. He began to complain of hypoglycemic symptoms after taking ALA. He lost consciousness in the late postprandial period and blood glucose was found to be 27 mg/dl. A high insulin level and high titers of insulin antibodies were detected. His HLA genotype contains DRB1* 0406. As ALA comes to be used widely, the incidence of IAS due to ALA might increase.

Angiotensin II regulates migration in mouse cultured mesangial cells: evidence for the presence of receptor subtype-specific regulation.

The biological effects of angiotensin II (AngII) are mediated by two major subtypes of AngII receptors, type 1 (AT1R) and type 2 (AT2R). In this study, we attempted to elucidate the role of AngII subtype receptor-specific regulation in migration and proliferation of mouse cultured mesangial (MSG) cells. We found that 100 nM AngII stimulated weak migration of MSG cells. Cell motility increased more in the presence of AT2R than in the presence of AT1R, and it was suppressed by guanylate cyclase inhibitors. On the other hand, the activation of AT1R resulted in increased cell numbers, while AT2R activation inhibited cell proliferation. Moreover, high concentrations of glucose (25 mM) stimulated the expression of AT2R but not AT1R. These results indicate that there are receptor subtype-specific roles in MSG cells, and it is therefore possible that the activation of AT2R stimulates repair of glomerular tissue defect, by regulation of migration and proliferation of MSG cells. Taken together, these results suggest that the relative concentrations of AT1R and AT2R are important factors in the regulation of AngII function in glomerular tissue, and alterations in the concentrations of these receptors may contribute to progression of or protection from diabetic nephropathy.

Vascular endothelial cell growth factor attenuates actions of transforming growth factor-beta in human endothelial cells.

Because vascular endothelial cell growth factor (VEGF) and transforming growth factor-beta (TGF-beta) are both involved in cellular growth and differentiation, we examined whether VEGF modifies TGF-beta signaling cascade in human umbilical cord vein endothelial cells (HUVEC). Production of plasminogen activator inhibitor-1 (PAI-1), which is under the specific control of TGF-beta, was strongly enhanced (3.5-fold) by TGF-beta treatment. Remarkably, physiological concentration of VEGF (30 nm) profoundly (by 60%) attenuated the TGF-beta stimulation of PAI-1 production without an effect on the basal PAI-1 production. In HUVECs transiently transfected with an expression construct containing a PAI-1 promoter fused to luciferase reporter gene, TGF-beta-stimulation of transcription of PAI-1 was clearly (by 60%) inhibited by VEGF. TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, was also suppressed by VEGF. VEGF attenuation of TGF-beta action was also demonstrated in two other endothelial cell lines. In conclusion, VEGF attenuates TGF-beta action in the human endothelial cell, specifically at the level of transcription of PAI-1 gene and Smad2/3 phosphorylation.