Yoshinori Miyazaki

High plasma immunoreactive leptin level in essential hypertension.

Insulin resistance, the most important factor in metabolic syndrome X, has been considered to raise blood pressure. Recently it was reported that insulin resistance was related to an elevated plasma level of leptin, which is an adipocyte-specific ob gene product and which plays a role in food intake suppression, thermogenesis, and energy expenditure through the activation of the hypothalamus. However there are no reports that deal with the relationship of insulin resistance to plasma leptin and blood pressure. To evaluate the role of leptin in essential hypertensives, two groups of subjects who were carefully matched for body mass index (BMI) were studied; 22 normotensives (NT, age: 46.5 +/- 2.6 years, BMI: 23.9 +/- 0.4 kg/m2, male/female: 14/8) and 45 mild-to-moderate essential hypertensives (EHT, age: 51.9 +/- 2.0 years, BMI: 24.5 +/- 0.4 kg/m2, male/female: 21/24). We applied the euglycemic hyperinsulinemic glucose clamp technique to all subjects and insulin sensitivity was evaluated as the M value. EHT showed a significantly lower M value (160.2 +/- 7.4 v 184.3 +/- 7.3 mg/m2/min, P < .05) and higher basal plasma immunoreactive leptin level (7.6 +/- 0.8 v 5.0 +/- 0.8 ng/mL, P < .05) than NT, despite the fact that there was no significant difference between NT and EHT in age, gender, or BMI. The relationship between mean blood pressure and leptin showed a significant positive correlation in all of the subjects (r = 0.31, P < .05), suggesting that leptin may be related to a pathophysiology of essential hypertension.

Effects of angiotensin receptor antagonist and angiotensin converting enzyme inhibitor on insulin sensitivity in fructose-fed hypertensive rats and essential hypertensives

This study was designed to investigate the effects of angiotensin II (AII) receptor antagonist and angiotensin converting enzyme (ACE) inhibitor on insulin resistance, and the mechanism by which ACE inhibitor improves insulin-dependent glucose uptake (insulin sensitivity) in an insulin-resistant hypertensive rat model (fructose-fed rats, FFR) and in essential hypertensives (EHT). Male Sprague-Dawley rats were fed on fructose-rich or standard chow for 4 weeks and treated either with 10 mg/kg/day of delapril (n = 8), 1 mg/kg/day of TCV-116 (AII receptor antagonist; n = 13), or vehicle (n = 9) for the latter 2 weeks. Steady-state plasma glucose (SSPG) was measured with the subjects in the conscious state; simultaneously, we infused insulin (2.5 mU/kg/min) and glucose (8 mg/kg/min) to determine insulin sensitivity in each group. Thirteen EHT were hospitalized and the 2-h euglycemic hyperinsulinemic glucose clamp (GC) method was performed in a fasting condition before and after 2 weeks administration of TCV-116 (8 mg/day) in 7 EHT and of delapril (120 mg/day) in 6 EHT. Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Mean blood pressure (MBP) was higher in FFR (137.7 +/- 73.8 mm Hg, P < .05) compared to controls (120.8 +/- 2.7 mm Hg), and was lower in both the delapril (108.1 +/- 6.3 mm Hg, P < .05) and TCV-116 (112.8 +/- 4.3 mm Hg, P < .05) groups than in FFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of Muscle Fiber Composition Linking to Insulin Resistance and Hypertension in Fructose−Fed Rats

The aim of this study was to examine the role of muscle fiber composition in insulin resistance and the effect of a calcium channel antagonist on insulin sensitivity in fructose-induced insulin resistant and hypertensive rats. Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or fructose-rich diet (FFR). For the last 2 weeks of a 6-week period of either diet, the rats were treated, by gavage, with gum arabic solution (control or FFR) or a dihydropyridine calcium channel antagonist, benidipine hydrochloride (3 mg/kg/day: FFR + Ca), then the euglycemic hyperinsulinemic glucose clamp technique was performed to evaluate insulin sensitivity. Blood pressure was measured weekly for 6 weeks. At the end of the glucose clamp, the soleus muscle was dissected out for determination of muscle fiber composition by ATPase methods. Blood pressure was elevated at 2 weeks after the start of fructose-rich chow feeding and persisted thereafter throughout the study. Blood pressure at the glucose clamp in the FFR was significantly higher than that in the control group (142 +/- 2 v 155 +/- 2 mm Hg, P < .01) and the calcium antagonist significantly lowered blood pressure of FFR (136 +/- 6 mm Hg for FFR +/- Ca, P < .05). The average rate of glucose infusion during glucose clamp, as a measure of insulin sensitivity (M value), was significantly lower in the FFR than in the control (15.4 +/- 0.4 v 10.9 +/- 0.6 mg/kg/min, P < .01). The calcium channel antagonist partially improved the M value compared to that of FFR (13.4 +/- 0.7 mg/kg/min in FFR +/- Ca, P < .01 compared to FFR, P < .05 compared to control). The composite ratio of type I fiber in soleus muscle was significantly decreased in FFR compared to control (81.7 +/- 1.5% v 75.0 +/- 1.7%, P < .01), and the composite ratio of type I fiber in rats treated with the calcium channel antagonist (FFR +/- Ca) recovered to the control level (79.9 +/- 1.1%, P < .05 compared to FFR). The M value was significantly correlated with the compositions of type I and type II fibers (for type I fibers, r = 0.80, P < .01; for type II fibers, r = -0.81, P < .01). These results suggest that fiber composition of skeletal muscle links insulin resistance and that a calcium channel antagonist may modulate muscle fiber composition in hypertensive animal model, fructose-fed rats.

Low Adiponectin Level in Young Normotensive Men with a Family History of Essential Hypertension

Circulating level of adiponectin, an adipocyte-derived protein, is reduced in states of insulin resistance such as obesity and type 2 diabetes. We have previously shown that hypoadiponectinemia is related to insulin resistance in essential hypertension. Recent studies have shown that normotensive subjects with a positive family history of essential hypertension (FH+) have decreased insulin sensitivity compared to subjects with a negative family history of essential hypertension (FH-). We here examined the association between adiponectin concentration and insulin sensitivity in FH+ and FH-. Thirty young, non-obese and normotensive men without a family history of diabetes mellitus were enrolled. A total of 15 subjects were FH+, and the remaining 15 subjects were FH-. Insulin sensitivity index (ISI) was evaluated by the euglycemic hyperinsulinemic glucose clamp technique. Concentrations of adiponectin and other metabolic variables were measured. The FH+ group had significantly lower levels of ISI and adiponectin than did the FH- group. In all of the subjects, ISI was positively correlated with adiponectin concentration and high-density lipoprotein (HDL) cholesterol level and was negatively correlated with insulin level. Adiponectin concentration was the only independent determinant of ISI in a multiple regression analysis. Our results showed that adiponectin level was significantly decreased and that this was accompanied by reduced insulin sensitivity in young, non-obese and normotensive men with a family history of essential hypertension. Phenotype of reduced adiponectin level as an earlier penetrance may be especially useful in genetic analyses of insulin resistance and essential hypertension.

Effects of a calcium channel blocker, manidipine, on insulin sensitivity in essential hypertensives

This study was designed to investigate the effects of the calcium channel blocker manidipine on insulin-dependent glucose uptake (insulin sensitivity) and insulin action to renal sodium handling and pressor systems in essential hypertensive (EHT). Seven EHT were hospitalized and a 2-h euglycemic hyperinsulinemic glucose clamp was performed in a fasting condition before and after 2 weeks administration of manidipine (20 mg/day). Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Manidipine administration decreased mean blood pressure and increased M-value significantly in EHT. Before the manidipine treatment, hyperinsulinemia during the clamp induced a decrease of urinary sodium excretion and increases of plasma norepinephrine and plasma renin activity in EHT. After manidipine treatment, however, hyperinsulinemia induced natriuresis and did not augment the pressor systems activity. Thus, the calcium channel blocker improved insulin resistance as assessed by glucose clamp technique in EHT. Suppression of augmented renal sodium reabsorption and pressor system activities of insulin may be connected with the hypotensive mechanisms and the natriuresis caused by calcium channel blockers.

Effects of the angiotensin converting enzyme inhibitor temocapril on insulin sensitivity and its effects on renal sodium handling and the pressor system in essential hypertensive patients

The effects of the angiotensin converting enzyme (ACE) inhibitor temocapril on insulin sensitivity and its effects on renal sodium handling and the pressor system were investigated in essential hypertensive patients (EHT). Seven EHT were hospitalized and underwent a 2-h euglycemic hyperinsulinemic glucose clamp before and after 2 weeks administration of temocapril (4 mg/day). Insulin sensitivity was calculated using the M value from the infusion rate of glucose with hyperinsulinemia using the glucose clamp method. Renal clearances of sodium, lithium, creatinine, and paraaminohippuric acid were used to calculate fractional proximal and distal tubular reabsorption of sodium (FPR(Na), FDR(Na)) and renal plasma flow (RPF) before and during insulin infusion by the glucose clamp method. Temocapril decreased blood pressure and increased M value significantly. Before temocapril treatment, hyperinsulinemia by the glucose clamp induced significant decreases of urinary excretion of sodium (U(Na) V) and fractional excretion of sodium (FENa). After treatment, these decreases were attenuated, and the change of U(Na) V (deltaU(Na) V) with hyperinsulinemia was significantly higher and deltaFENa showed a higher tendency, compared with before the treatment. FPR(Na) showed no change with hyperinsulinemia before treatment, but significantly decreased after treatment. DeltaFPR(Na) was significantly lower after treatment than that before treatment. FDR(Na) showed an increase with hyperinsulinemia, and deltaFDR(Na) was similar between before and after treatment. RPF showed no change with hyperinsulinemia, and no difference was found in deltaRPF between before and after treatment. Plasma norepinephrine level (PNE) and plasma renin activity (PRA) showed increases, whereas plasma aldosterone concentration (PAC) did not change with hyperinsulinemia. There were no significant differences in deltaPNE, deltaPRA, and deltaPAC between before and after treatment. From these results, it is suggested that in EHT 1) temocapril improves insulin resistance, and 2) although temocapril shows no significant influence on the augmentation of pressor systems by hyperinsulinemia, this agent attenuates the sodium-retaining action of hyperinsulinemia, which may be attributable to suppression of insulin-induced sodium reabsorption at the proximal tubules. These effects may lead to additional beneficial effects in the treatment of essential hypertensives with insulin resistance.

The Mechanisms of the Improvement of Insulin Sensitivity by Angiotensin Converting Enzyme Inhibitor

To investigate the role of kinins in augmentation of insulin sensitivity by angiotensin converting enzyme inhibitor (ACEI), the effects of ACEI (delapril) on the insulin resistance in fructose-fed rats (FFR) were evaluated with or without the administration of bradykinin receptor antagonist (Hoe 140). Male Sprague-Dawley rats were fed on fructose rich chow (FFR) or standard chow (control) for 4 weeks and treated with 10 mg/kg/day of delapril with or without Hoe 140 (0.5 mg/kg/day) for an additional 2 weeks. Steady state plasma glucose (SSPG) and steady state plasma insulin (SSPI) were determined while the rats were conscious. Insulin (2.5 mU/kg/min) and glucose (8 mg/kg/min) were simultaneously infused to determine insulin sensitivity in each group. Mean blood pressure (MBP), SSPG and SSPI were significantly higher in FFR than in control, and were significantly lower in the FFR+delapril than in FFR+vehicle. There were no difference in MBP, SSPG and SSPI between FFR+delapril+vehicle and FFR+delapril+Hoe 140. We concluded that the main mechanisms of improving the insulin sensitivity by ACEI may not be the enhancement of kinins but the suppression of angiotensin II in FFR.

Differences in insulin action and secretion, plasma lipids and blood pressure levels between impaired fasting glucose and impaired glucose tolerance in Japanese subjects.

We examined insulin action/secretion and cardiovascular disease risk factors in Japanese subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who were not taking any medications known to affect glucose tolerance, blood pressure (BP) or plasma lipids (PLs). A total of 1,399 subjects received measurements of anthropometry, BP, PLs, and plasma glucose/insulin concentrations during 75 g-oral glucose tolerance test (OGTT). According to 2003 American Diabetes Association criteria, subjects were classified as having normal fasting glucose (NFG)/normal glucose tolerance (NGT) (n=1,173), IFG (n=128), IGT (n=55), and IFG/IGT (n=43). Insulin action was calculated using the HOMA-R (index of hepatic insulin resistance) and Matsuda index (reflects whole body insulin sensitivity). The ratio of the incremental area under the curve of insulin to that of glucose during OGTT (ΔAUCPI/ΔAUCPG) was used as an index of β-cell function. HOMA-R was higher in IFG (2.3±0.1) and IFG/IGT (2.5±0.2) than in NFG/NGT (1.8±0.03). The Matsuda index was lower in IFG (6.5±0.3), IGT (5.4±0.4) and IFG/IGT (5.1±0.5) than in NFG/NGT (9.6±0.2). ΔAUCPI/ΔAUCPG was lower in IGT (0.6±0.05) and IFG/IGT (0.5±0.05) than in IFG (1.4±0.12) or NFG/NGT (1.2±0.03). Mean BP was higher in IGT (100±1.7 mmHg) than in NFG/NGT (91±0.3) or IFG (95±1.1). The plasma triglyceride level was higher in IGT (155±14 mg/dL) and IGT/IFG (173±12) than in IFG (132±7) or NFG/NGT (122±2). In conclusion, 1) whole body insulin sensitivity is decreased in IFG and IGT, with a greater reduction in IGT, 2) hepatic insulin resistance and preserved β-cell function are characteristics of IFG, and 3) higher BP and triglyceride levels are observed in IGT. IGT is more closely associated with risk factors for cardiovascular disease than is IFG.

Angiotensin II inhibits glucose uptake of skeletal muscle via the adenosine monophosphate-activated protein kinase pathway

Adenosine monophosphate-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between the renin-angiotensin system and AMPK. To determine this correlation, we performed studies with glucose clamp in vivo, and glucose uptake by skeletal muscle ex vivo using 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Six-week-old male Sprague-Dawley rats were fed standard chow (standard-diet rats; SD) or fructose-rich chow (fructose-fed rats; FFR) for 6 weeks. At the age of 12 weeks, SD and FFR were treated by oral gavage, either with angiotensin II (Ang II) receptor blockade (ARB; valsartan 30 mg/kg) or vehicle. Thirty minutes after the treatment, we performed glucose clamp studies to measure glucose infusion rates during infusion of insulin (GIR(I)) and of AICAR (GIR(A)), which stimulates AMPK, and studied the effect of ARB on either GIR(I) or GIR(A). In an ex vivo study, we used bilateral fresh soleus muscles from 3-week-old male Sprague-Dawley rats to examine the glucose uptake (measured by (3)H-2-deoxyglucose uptake) of one side of soleus muscle incubated with AICAR with or without Ang II, or with tumor necrosis factor-alpha, in comparison with that of the other (untreated control) side of the muscle. Blood pressure of FFR was significantly higher than that of SD rats. GIR(I) was significantly lower in FFR than in SD, and treatment with ARB did not change GIR(I). GIR(A) of FFR was significantly lower than that of SD, but GIR(A) of FFR treated with ARB was significantly increased compared with that of FFR treated with vehicle. In the ex vivo study, incubation with AICAR significantly increased glucose uptake of soleus muscles, Ang II significantly decreased AICAR-activated glucose uptake in a dose-dependent manner, and ARB canceled the effect of Ang II. The results suggest that acute inhibition of the angiotensin 1 receptor improves glucose metabolism via not insulin but AMPK pathway through the angiotensin 1 receptor in FFR.

Effects of angiotensin II receptor blockade on glucose metabolism via AMP-activated protein kinase in insulin-resistant hypertensive rats

AMP-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system (RAS) might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between RAS and AMPK. To determine the correlations between insulin resistance, the RAS, and AMPK, we performed glucose clamp studies using both insulin and 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) to investigate the effects of various hypotonics on insulin and AMPK sensitivities. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (SD) and those fed a fructose-rich chow (fructose-fed rats [FFRs]) for 6 weeks. FFRs were treated either with a vehicle or with valsartan or hydralazine for the last 2 weeks. We also performed Western blotting for AMPK, phospho-AMPK, and stimulating glucose transporter (GLUT)-4 proteins in each group. The glucose infusion rate for insulin (GIR(I)) was significantly lower in FFRs (10.5 +/- 1.8 mg/kg/min) than in SD (15.5 +/- 0.4 mg/kg/min), and GIR(I) was improved by valsartan (13.0 +/- 1.0 mg/kg/min) but not by hydralazine (8.3 +/- 1.6 mg/kg/min). The glucose infusion rate for AICAR (GIR(A)) in FFRs (11.1 +/- 2.2 mg/kg/min) was significantly lower than that in SD (15.5 +/- 2.8 mg/kg/min), and GIR(A) was improved by valsartan (17.5 +/- 3.1 mg/kg/min) but not by hydralazine in FFRs (11.8 +/- 1.5 mg/kg/min). Serum triglyceride level was significantly higher in FFRs; however, no difference was observed in serum triglyceride level after AICAR infusion among the groups. The amounts of AMPKalpha protein and the amounts of phospho-AMPK protein in the soleus muscle in basal conditions were not different among SD, FFRs, and FFRs treated with valsartan. There was no difference in the levels of phosphorylation of AMPK in the soleus muscle by AICAR among these three groups. No difference was observed in acetyl-CoA carboxylase (ACC) protein or phospho-ACC in both the basal condition and after AICAR infusion between SD and FFRs. Treatment with valsartan significantly increased GLUT-4 content of the soleus muscle compared with that in FFRs. These results suggest that the RAS has a significant role in the AMPK system and that impairment of response to AICAR in FFRs could be downstream of AMPK or ACC phosphorylation.