Tsutomu Kanda

Effect of Troglitazene on Microalbuminuria in Patients With Incipient Diabetic Nephropathy

OBJECTIVE Although some studies have suggested a direct action of troglitazone on vascular cells, its effects on diabetic vascular diseases have not been reported. We therefore investigated the effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. RESEARCH DESIGN AND METHODS A total of 30 patients with type 2 diabetes associated with microalbuminuria (urinary albumin-to-creatinine ratio [ACR] [milligrams per gram creatinine] ranging from 30 to 300 mg/g creatinine) were studied. They were randomly divided into two groups: patients treated with metformin (500 mg/day, n = 13) or with troglitazone (400 mg/day, n = 17) for 12 weeks. ACR, lipid profile, blood pressure, glycated hemoglobin, and plasma glucose during meal-load tests were measured every 4 weeks. RESULTS Anthropometric indices (BMI and percent fat), lipid profile, and blood pressure did not change with either treatment. Fasting and postmeal glucose levels decreased similarly in the two groups. Decrements in glycated hemoglobin were greater in the metformin group at 4 and 8 weeks after the initiation of treatment (P < 0.05). Troglitazone reduced ACR (median [25–75th percentiles]) from 70 (49–195) to 40 (31–90) mg/g creatinine at 4 weeks (P = 0.021) and maintained these reduced levels throughout the treatment period (8 weeks: 35 [26–68], P = 0.007; 12 weeks: 43 [26–103], P = 0.047). Metformin did not change ACR throughout the 12 weeks. CONCLUSIONS Troglitazone ameliorated microalbuminuria in diabetic nephropathy. Furthermore, our findings suggest that troglitazone has some effects on vascular cells other than lowering plasma glucose levels. Troglitazone might be useful for diabetic angiopathy, including nephropathy and coronary artery disease.

Oral Glucose Tolerance Test Predicts Prognosis of Patients with Liver Cirrhosis

OBJECTIVE:The aim of this study was to evaluate whether oral glucose tolerance test (OGTT) was useful in evaluating the prognosis of patients with liver cirrhosis.METHODS:Fifty-six patients with liver cirrhosis were enrolled in a prospective cohort study. In all cases, glucose tolerance was diagnosed by a 75-g OGTT according to World Health Organization (WHO) criteria. The relationship of clinical variables to the cirrhosis-related prognosis was investigated using univariate and multivariate regression models.RESULTS:Diabetes mellitus (DM) was diagnosed in 21 subjects (38%), impaired glucose tolerance (IGT) in 13 subjects (23%), and normal glucose tolerance (NGT) in 22 subjects (39%) using OGTT. The cumulative survival rates of patients with liver cirrhosis and NGT were 94.7% at 5 yr; liver cirrhosis and IGT, 68.8% at 5 yr; liver cirrhosis and DM, 56.6% at 5 yr. The survival rates of patients with liver cirrhosis and DM significantly differed from those with NGT. Univariate analysis demonstrated that serum albumin, total bilirubin, prothrombin activity, Child-Pugh scores, and glucose intolerance were highly significant prognostic factors. Multiple regression analysis yielded albumin and DM as the most powerful independent negative predictors of survival.CONCLUSIONS:OGTT appears to be useful for evaluating the prognosis of cirrhotic patients.

Interferon induces insulin resistance in patients with chronic active hepatitis C

AIM/METHODS To elucidate the metabolic effect of interferon alpha, the following tests were performed on 14 patients with chronic active hepatitis C before and after interferon therapy (6 million units/day for 2 weeks): (1) oral glucose tolerance tests to measure insulin secretion; (2) euglycemic hyperinsulinemic clamp with oral glucose load to measure peripheral and hepatic insulin sensitivity (splanchnic glucose uptake); and (3) measurements of plasma levels of glucoregulatory hormones. RESULTS The oral glucose tolerance test showed that a 2-week treatment with interferon did not induce apparent change in plasma glucose and insulin profiles. Nevertheless, interferon therapy worsened insulin-mediated glucose uptake in the peripheral tissues by 17% from 44.4+/-3.2 to 37.3+/-3.0 micromol x kg(-1) x min(-1) (p<0.05). Furthermore, interferon therapy significantly decreased splanchnic glucose uptake by 38% from 47+/-2% to 29+/-3% (p<0.01). No changes were noted for plasma glucoregulatory hormones, such as epinephrine, norepinephrine, cortisol and growth hormone, after interferon therapy. CONCLUSIONS These results indicate that interferon therapy for 2 weeks induces insulin resistance in the splanchnic, as well as peripheral tissues, in patients with chronic active hepatitis C. Therefore, more careful observation may be needed during interferon therapy in subjects with impaired glucose tolerance.

Gastroesophageal reflux disease related to diabetes: Analysis of 241 cases with type 2 diabetes mellitus

Background and Aim:  We examined the incidence of symptomatic gastroesophageal reflux disease (GERD) in patients with type 2 diabetes mellitus (DM).

Impaired splanchnic and peripheral glucose uptake in liver cirrhosis

BACKGROUND/AIM Patients with liver cirrhosis are insulin-resistant and frequently glucose-intolerant. Although peripheral glucose uptake has been shown to be impaired in liver cirrhosis, little is known about the significance of splanchnic (hepatic) glucose uptake after oral glucose load. METHODS/RESULTS We performed an oral glucose tolerance test and euglycemic hyperinsulinemic clamp with oral glucose load for eight patients with liver cirrhosis and eight patients with chronic active hepatitis. The patients with liver cirrhosis had higher plasma glucose levels 2 h after glucose load than those with chronic active hepatitis (228+/-22 mg/dl vs. 102+/-9 mg/dl, p<0.01). Using the euglycemic hyperinsulinemic clamp with oral glucose load, we simultaneously measured peripheral and splanchnic glucose uptake. Peripheral glucose uptake in liver cirrhosis was 6.1+/-0.7 mg x kg(-1) x min(-1), which was lower than that in healthy volunteers (10.5+/-0.9 mg x kg(-1) x min(-1), p<0.05) and in chronic active hepatitis (8.4+/-0.3 mg x kg(-1) x min(-1), p<0.05). Furthermore, splanchnic glucose uptake in liver cirrhosis was much lower (20.1+/-3.4%) than in healthy volunteers (36.0+/-4.0%, p<0.05) and in chronic active hepatitis (37.2+/-3.1%, p<0.05). CONCLUSION These results suggest that glucose intolerance in patients with liver cirrhosis is caused by a defect of the glucose uptake of both splanchnic and peripheral tissues.

Randomized comparative study of omeprazole and famotidine in reflux esophagitis.

Background: Although proton pump inhibitors (PPI) and H2‐receptor antagonists (H2‐RA) are routinely used in the treatment of reflux esophagitis (RE), no consensus has been reached yet as to whether the first‐choice drug should be PPI or H2‐RA. In this study, the effects of omeprazole (OMP) and famotidine (FAM) on RE have been examined in a randomized comparative study.

Monocyte chemoattractant protein-1 (MCP-1) gene polymorphism as a potential risk factor for diabetic retinopathy in Japanese patients with type 2 diabetes.

We examined the association between diabetic retinopathy and monocyte chemoattractant protein (MCP)-1 A-2518G polymorphism in 3802 Japanese type 2 diabetic subjects. The prevalence of diabetic retinopathy was higher as the number of G alleles increased, suggesting that the G allele of this polymorphism is a susceptibility allele for diabetic retinopathy.

Augmentation of Hepatic Glucose Uptake by a Positive Glucose Gradient Between Hepatoportal and Central Nervous Systems

To determine the role of the glucose gradient between the hepatoportal system (HPS) and the central nervous system (CNS) in regulating hepatic glucose uptake, experiments were conducted with seven conscious dogs using a hepatic venous catheterization technique. With the infusion of somatostatin (0.8 µg · kg−1 · min−1), glucagon (0.65 ng · kg−1 · min−1), and insulin (27 pmol · kg−1 · min−1), arterial glucose levels could be maintained at 8 mmol/l by adjusting the intravenous glucose infusion (Ginf) according to the following three periods: 1) peripheral glucose infusion period (PE), Ginf alone; 2) portal glucose infusion period (PO), Ginf plus constant glucose infusion into the portal vein (GIRPV, 55.6 μmol · kg−1 · min−1); 3) portal and brain glucose infusion period (PO+CNS), Ginf and GIRPV plus additional glucose infusion into the unilateral carotid and vertebral arteries to abolish the positive glucose gradient between HPS and CNS. Arterial plasma glucose levels were clamped during the three periods (8.1 ± 0.1, PE; 8.2 ± 0.1, PO; 8.2 ± 0.1 mmol/l, PO+CNS). During PO, when a positive glucose gradient was promoted between HPS and CNS, the net hepatic glucose balance (NHGB) determined by the difference between hepatic glucose inflow and outflow was significantly lower than that of PE (−41.5 ± 5.3, PO vs. −7.5 ± 3.4 µmol · kg−1 · min−1, PE; P < 0.01). However, this decrease in the NHGB significantly increased during PO+CNS, when the glucose gradient between HPS and CNS was minimized, compared with PO (−21.7 ± 3.2 µmol · kg−1 · min−1 , P < 0.05). We conclude that a positive glucose gradient between HPS and CNS is an important regulatory factor of hepatic glucose uptake, but other factors also play important roles because minimizing the glucose gradient between HPS and CNS diminished the net hepatic glucose uptake by 50%.

Bone changes and mineral metabolism disorders in rats with experimental liver cirrhosis.

Abstract  To investigate the pathogenesis of hepatic osteodystrophy (HOD) in parenchymal liver disease, we developed a laboratory model in animals using carbon tetrachloride (CCl4) and thioacetamide. Biochemical and histological parameters in the model were measured. In rats with both chronic non‐cirrhotic liver injury and CCl4‐induced cirrhosis, tibial bone volume was significantly lower than in controls. In CCl4‐treated cirrhotic rats, the osteoid volume decreased while the urinary calcium/creatinine ratio increased. In all CCl4‐treated rats, bone volume was significantly correlated with both the serum albumin concentration and the number of goblet cells reflecting intestinal villous atrophy. The serum concentration of vitamin D metabolites was not correlated with bone volume. Whole body retention of 47Ca was significantly lower in CCl4‐treated cirrhotic rats than in controls. Furthermore, the bone volume in thioacetamide‐treated cirrhotic rats was significantly lower than in controls. These data demonstrate that chronic parenchymal liver injury itself causes osteoporosis (i.e. HOD) due to a combination of low bone formation rates and high resorption rates, that HOD begins at the stage of chronic non‐cirrhotic liver injury, that bone volume in HOD parallels liver damage and that the principal pathogenesis of HOD seems to be intestinal Ca malabsorption due to lower serum albumin and villous atrophy, while serum levels of vitamin D metabolites have little influence on the pathogenesis of HOD.

Aldose reductase C-106T gene polymorphism is associated with diabetic retinopathy in Japanese patients with type 2 diabetes

It is likely that the C allele of the polymorphism at position -106 in the promoter of aldose reductase gene, which codes a rate-limiting enzyme of the polyol pathway, is a susceptibility allele for diabetic retinopathy in Japanese type 2 diabetic patients.