Yoshito Oshiro

Evidence for a deficient pancreatic β-cell response in a rat model of hyperthyroidism

To clarify mechanism behind the abnormal glucose tolerance, observed in hyperthyroidism, we studied genomic and nongenomic effects of thyroid hormone on insulin secretion using a rat model of hyperthyroidism. Male Sprague-Dawley rats were intraperitoneally injected with vehicle, low (100 microg/kg) or high dose (600 microg/kg) of thyroxin (T(4)) for 2 weeks. Rats treated with high dose, but not low dose, of T(4), showed an increase in serum T(3) levels, and a decrease in body weight as compared to control rats. In rats treated with either dose of T(4), fasting blood glucose levels were increased, but serum insulin levels were similar to those of controls. After an oral glucose load, blood glucose levels were increased in rats treated with high dose, but not low dose, of T(4). Serum insulin levels after the oral glucose load were decreased in rats treated with either dose of T(4). After an intravenous glucose load, blood glucose levels were comparable among groups, but serum insulin levels tended to be low in T(4)-treated rats. Steady-state blood glucose levels were comparable among groups. The insulin secretory responses to high glucose (20mM) or arginine (10mM) of the isolated pancreas was decreased in rats treated with high dose, but not low dose, of T(4). Mean insulin secretory response to glucose and arginine were decreased by 40.1% and by 60.4% in high-dose-T(4)-treated rats. Addition of T(3) in the perfusion medium decreased glucose-induced insulin release. Ratios of proinsulin mRNA levels to beta-actin mRNA were decreased in the islets of T(4)-treated rats (0.45 +/- 0.07 vs control 0.61 +/- 0.03, p < 0.05). Levels of TR (thyroid hormone nuclear receptor) alpha1 + cErb Aalpha2 mRNA, but not TRbeta1, were decreased in the pancreatic islets of T(4)-treated rats. Calculated islet area was increased, but the number of beta-cells determined immunohistochemically was not increased in T(4)-treated rats, nor the volume density of insulin positive islets. We concluded that a deficient pancreatic beta-cell response to glucose, rather than insulin resistance, was responsible for abnormal glucose tolerance in this model of hyperthyroidism. Thyroid hormone causes a decrease in glucose-induced insulin secretion. We observed nongenomic and genomic effects of thyroid hormone on glucose-induced insulin secretion.

Impaired Glucose Tolerance, but Not Impaired Fasting Glucose, Underlies Left Ventricular Diastolic Dysfunction

OBJECTIVE Glucose intolerance is recognized as a predictor of congestive heart failure (CHF). However, the association of postprandial hyperglycemia or fasting hyperglycemia with CHF has not been clarified. We determined the impact of the total spectrum of glucose abnormalities on left ventricular (LV) geometry and diastolic function. RESEARCH DESIGN AND METHODS Two hundred and eighty-seven Japanese subjects who visited the university hospital to be checked for glucose intolerance or known type 2 diabetes were consecutively recruited. Participants underwent an oral glucose tolerance test if they had no history of diabetes, and LV geometry and LV systolic and diastolic function were analyzed by Doppler echocardiography. RESULTS The frequency of LV diastolic dysfunction in subjects with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), newly detected diabetes, and known diabetes were 13, 22, 50, 51, and 61%, respectively (χ2 = 54.2, P < 0.0001). IGT was a predictor for LV diastolic dysfunction after adjusting for age, sex, systolic blood pressure, and heart rate (odds ratio 3.43 [95% CI 1.09–11.2]), but IFG was not (0.49 [0.06–3.08]). IGT was a predictor after adjusting for established CHF risk factors but was no longer significant after adjusting for BMI and homeostasis model assessment of insulin resistance. CONCLUSIONS In this hospital-based registry of subjects without CHF, the prevalence of LV diastolic dysfunction was higher in subjects with IGT but not in those with IFG. Results suggest that IGT, as well as newly detected and known diabetes, could be linked to an increased risk of cardiovascular events, partly through LV diastolic dysfunction.

Cilazapril prevents cardiac hypertrophy and postischemic myocardial dysfunction in hyperthyroid rats.

We evaluated the effects of hyperthyroidism on cardiac structural changes and postischemic myocardial function, and also studied how an angiotensin-converting enzyme (ACE) inhibitor, cilazapril, can alter these changes. Hyperthyroidism was induced by daily intraperitoneal injection of thyroxine (T4) (600 microg/kg) with or without cilazapril (10 mg/kg per day, orally), and control rats were given by vehicle. After 2 weeks of treatment, T4-treated rats showed increases in blood pressure and heart weight to body weight ratio (HW:BW). Cilazapril decreased blood pressure to control values and reduced HW:BW. In the isolated working heart preparation, T4-treated rats showed a poor postischemic recovery of left ventricular pressure-rate product (14% of baseline at 30 minutes of reperfusion vs. vehicle 85%) and cardiac work (6% vs. 71%). Cilazapril recovered both values to 49% and 43%. Propranolol (500 mg/L in drinking water) decreased blood pressure to the same extent as cilazapril in hyperthyroid rats, but changed neither HW:BW nor the postischemic myocardial dysfunction. Percent recovery of cardiac work was inversely well correlated with HW:BW (R2 = 0.998, p < 0.001). Results indicate that T4-induced cardiac hypertrophy enhances postischemic cardiac dysfunction. Results also indicate renin-angiotensin system (RAS), but not sympathetic nerve activation, is involved in cardiac hypertrophy and postischemic myocardial dysfunction in hyperthyroid rats.

Diagnostic utility of brain-natriuretic peptide for left ventricular diastolic dysfunction in asymptomatic type 2 diabetic patients

Aim:  Left ventricular (LV) diastolic dysfunction has been reported to be prevalent in diabetic subjects, but this recognition could often be missed. We evaluated prevalence of LV diastolic dysfunction and diagnostic utility of brain‐natriuretic peptide (BNP) in asymptomatic patients with type 2 diabetes mellitus.

Triiodothyronine concomitantly inhibits calcium overload and postischemic myocardial stunning in diabetic rats

Acute effects of triiodothyronine (T3) on postischemic myocardial stunning and intracellular Ca2+ contents were studied in the isolated working hearts of streptozotocin-induced diabetic rats and age-matched controls. After two weeks of diabetes, serum T3 and T4 levels were decreased to 62.5% and 33.9% of control values. Basal preischemic cardiac performance did not differ between diabetic and control rats. In contrast, during reperfusion after 20-min ischemia, diabetic rats exhibited an impaired recovery of heart rate (at 30-min reperfusion 57.5% of baseline vs. control 88.5%), left ventricular (LV) systolic pressure (44.1% vs. 89.5%), and cardiac work (23.1% vs. 66.0%). When 1 and 100 nM T3 was added before ischemia, heart rate was recovered to 77.2% and 81.8% of baseline, LV systolic pressure to 68.3% and 81.9%, and cardiac work to 50.8% and 59.0%, respectively. Diabetic rat hearts showed a higher Ca2+ content in the basal state and a further increase after reperfusion (4.96+/-1.17 vs. control 3.78+/-0.48 micromol/g, p<0.01). In diabetic hearts, H+ release was decreased after reperfusion (5.24+/-2.21 vs. 8.70+/-1.41 mmol/min/g, p<0.05). T3 administration caused a decrease in the postischemic Ca2+ accumulation (lnM T3 4.66+/-0.41 and 100 nM T3 3.58+/-0.36) and recovered the H+ release (lnM T3 16.2+/-3.9 and 100 nM T3 11.6+/-0.9). T3 did not alter myocardial O2 consumption. Results suggest that diabetic rat hearts are vulnerable to postischemic stunning, and T3 protects the myocardial stunning possibly via inhibiting Ca2+ overload.

Eicosapentaenoic Acid Supplementation Changes Fatty Acid Composition and Corrects Endothelial Dysfunction in Hyperlipidemic Patients

We investigated the effects of purified eicosapentaenoic acid (EPA) on vascular endothelial function and free fatty acid composition in Japanese hyperlipidemic subjects. In subjects with hyperlipidemia (total cholesterol ≥220 mg/dL and/or triglycerides ≥150 mg/dL), lipid profile and forearm blood flow (FBF) during reactive hyperemia were determined before and 3 months after supplementation with 1800 mg/day EPA. Peak FBF during reactive hyperemia was lower in the hyperlipidemic group than the normolipidemic group. EPA supplementation did not change serum levels of total, HDL, or LDL cholesterol, apolipoproteins, remnant-like particle (RLP) cholesterol, RLP triglycerides, or malondialdehyde-modified LDL cholesterol. EPA supplementation did not change total free fatty acid levels in serum, but changed the fatty acid composition, with increased EPA and decreased linoleic acid, γ-linolenic acid, and dihomo-γ-linolenic acid. EPA supplementation recovered peak FBF after 3 months. Peak FBF recovery was correlated positively with EPA and EPA/arachidonic acid levels and correlated inversely with dihomo-γ-linolenic acid. EPA supplementation restores endothelium-dependent vasodilatation in hyperlipidemic patients despite having no effect on serum cholesterol and triglyceride patterns. These results suggest that EPA supplementation may improve vascular function at least partly via changes in fatty acid composition.