In this article, some of our findings of epidemiologic and clinical studies on the actual state of insulin resistance in hypertension occurring in Japanese were described. In epidemiologic studies, a high prevalence of concomitant hypertension and impaired glucose tolerance was observed, and a significant positive correlation was found between blood pressure and blood glucose levels, even at a low degree, in two towns, the agricultural districts of Hokkaido. In clinical studies, insulin sensitivity, which was measured as M-values by the euglycemic hyperinsulinemic glucose clamp method, was significantly lower in essential hypertensives than in normotensive subjects. Moreover, this suppression of insulin sensitivity was also observed in young normotensive subjects with an apparent family history of hypertension, preceding the manifestation of hypertension. At the same time, obesity and aging were definitely correlated to the decrease in insulin sensitivity. On the assumed criterion that the normal range of M-values is mean ±1 SD of non-obese, non-diabetic young normotensive subjects, the prevalence of individuals with lowered M-value, which means existence of insulin resistance, was calculated as 45.4% in essential hypertensives and as 16.3% in normotensive subjects in this study. Increases in plasma norepinephrine levels and plasma renin activity, and decreases in urinary excretion of sodium and fractional excretion of sodium were observed during hyperinsulinemia produced by glucose clamp test. These responses to hyperinsulinemia were not different from those in normotensive subjects and, therefore, not specific to essential hypertensives. From these results, it was concluded that insulin resistance definitely exists among Japanese essential hypertensives, and that it plays an important role in the pathophysiology of essential hypertension. (Hypertens Res 1996; 19 Suppl. I:S1-S8)

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Since the original observations by Vague almost 50 years ago, a massive literature has documented the pathological consequences of upper body or visceral obesity. These consequences likely relate to the presence of hyperinsulinemia. More recently, the presence of hyperinsulinemia has also been recognized in nonobese hypertensives as a feature of the insulin resistance syndrome. This paper will provide an historical overview of the two clinical syndromes. (Hypertens Res 1996; 19 Suppl. I: S9-S11)

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To clarify whether significant interrelations between hyperinsulinemia and cardiovascular diseases exist in Japanese, we analyzed serum insulin levels, fasting and after oral glucose load, in relation to blood pressure (BP), serum lipids, and incidence of acute myocardial infarction (MI) and stroke in 584 male employees of a railroad company with borderline to mild hypertension (age: 49±7 years, BP: 139± 13/90±8mmHg, body mass index: BMI 24.0±2.8, mean±SD). Those who were taking antihypertensive drugs and/or hypoglycemic agents were excluded. The subjects were classified into five groups of comparable size according to ∑IRI (area composed by insulin levels at 0, 1, 2 hours post glucose load). Although averaged age, levels of fasting glucose and HbA_1c were not significantly different among quintiles, the hyperinsulinemic groups had higher levels of fasting IRI and ∑ glucose. Multiple regression analysis revealed that ∑IRI was associated positively with BMI, ∑glucose, systolic BP, total cholesterol, and negatively with HDL-cholesterol. During 7-year follow-up 7 cases with MI and 15 cases with stroke were registered. The subjects with MI, but not with stroke were involved in higher deciles of insulin levels. These results indicate that the insulin resistance sendrome exists in Japanese middle-aged men with borderline to mild hypertension. The association with cardiovascular morbid events appeared to be evident in coronary heart disease but not in cerebrovascular disease. (Hypertens Res 1996; 19 Suppl. I:S13-S18)

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This study was designed to investigate the possibility of sex and age differences in the insulin-blood pressure relationship in a general Japanese population with a wide age range. Fasting serum insulin, lipids, plasma glucose, blood pressure and anthropometric measurements were made on 1, 537 men and 843 women aged 16 to 65 years. Of the 2, 380 subjects in the present analysis, 290 (184 men, 106 women) were hypertensive. When divided into four age groups (16 to 17, 21 to 22, 30 to 49 and 50 to 65 years), the male hypertensive subjects were found to have significantly higher fasting insulin levels, triglycerides levels and body mass index and lower glucose/insulin ratios than normotensive male subjects in all age groups. In the women, there was no significant difference in serum insulin levels or glucose insulin ratios between the hypertensive and normotensive groups in any age group. Simple correlation analysis showed that blood pressure was statistically significantly correlated with serum insulin levels and body mass index in the men in all age groups. In women, the correlation between blood pressure and serum insulin was insignificant in the 21- to 22-year-old age group. In men but not women, multivariate analysis showed that blood pressure was significantly and independently correlated with fasting serum insulin levels. The results of this study suggests the existence of sex and age differences in the insulin-blood pressure relationship in a Japanese population. (Hypertens Res 1996; 19 Suppl. I: 519-522)

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To elucidate the effect of aging and blood pressure on glucose tolerance, we examined the subjects who received 75g OGTT annually for 10 years. They were classified into 2 groups by blood pressure, and into 4 groups by age. The study group consisted of 34 cases (mean 62 years old), including 11 hypertensive (HT) and 23 normotensive (NT) control. All cases had thier body weight fluctuate in less than 4kgs. After blood pressure was measured, blood was drawn for determination of plasma glucose and insulin concentrations in each subject before 75g OGTT and 30, 60, 90, 120 minutes afterward. ∑BS and ∑IRI were defined as the sum of 5 points in BS and IRI, respectively. Insulinogenic index (I.I) was defined as ΔIRI/ΔBS in 30min. ∑IRI/∑BS and I.I of each year were calculated serially. They were compared between HT and NT group, and among 4 groups of age; 40s, 50s, 60s and 70s. ∑IRI/∑BS was significantly decreased in both HT and NT groups (0.52±0.05 (mean±SE) to 0.29±0.04; p<0.0001 vs. 0.42± 0.05 to 0.23±0.02; p< 0.0001, respectively). But significant difference between the 2 groups was not observed. No significant difference of ∑IRI/∑BS among 4 groups of age was found. There were significant differences between I.I of the first year and that of several years, but they did not correlate linearly. These data indicate that the effect of age on the diminution of ∑IRI/∑BS was significant for 10 years follow-up of the same subjects in both HT and NT groups. But there were no significant differences in classified groups by blood pressure and age. (Hypertens Res 1996; 19 Suppl. I: S23-S26)

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Although insulin resistance has been involved in the pathogenesis of essential hypertension in non-diabetic patients, few studies were performed regarding to the association between insulin resistance, hypertension and nephropathy in diabetes mellitus. We observed the changes of blood pressure and proteinuria for 7 years in normotensive 28 patients with non-insulin-dependent diabetes mellitus (NIDDM), following measurement of insulin sensitivity. Patients were over 40 years old and not obese, and fasting plasma glucose levels were less than 140mg/dl. Insulin sensitivity was determined using glucose-clamp method or glucose, insulin, and somatostatin infusion method. In 28 subjects, 12 subjects developed hypertension and 16 subjects were remained normotensive. Insulin induced glucose clearance was significantly decreased in subjects developed hypertension (30±12ml/kg/10min) than in subjects remained normotensive (50±19ml/kg/10min). Furthermore, we found significantly higher incidence of proteinuria in patients developed hypertensive (7 out of 12 patient) than in patients remained normotensive (one out of 16 patients; p<0.05). These results suggest that insulin resistance is involved in the etiology of hypertension in NIDDM patients, and that this derangement has an important role for the progression of diabetic nephropathy. (Hypertens Res 1996; 19 Suppl. I: S27-S29)

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To clarify the genetic basis of insulin resistance in hypertension, case-control association studies were performed to examine candidate genes for insulin resistance in hypertension. Since the main site of insulin resistance in hypertension is glycogen synthesis in skeletal muscle, genes that encode molecules involved in this pathway, i.e. insulin receptor (INSR), insulin-responsive glucose transporter (GLUT4) and glycogen synthase (GSY), were studied. In addition, since recent studies suggest the contribution of β₃ adrenergic receptor to the insulin resistance syndrome, the gene encoding β₃ adrenergic receptor (ADRB3) was also studied. Frequency of homozygotes for common C allele of a microsatellite polymorphism in the INSR gene was higher in the hyperinsulinemia group, but not in the normoinsulinemia group of hypertensive patients than in normotensive control subjects. Insulin sensitivity, however, was not significantly different between hypertensive patients with C/C genotype and those without this genotype. No significant differences were observed in the distribution of alleles or genotypes of the GLUT4, GSY and ADRB3 genes between hyperinsulinemia and normoinsulinemia groups of hypertensive patients or between these groups and the control group. These data suggest that the INSR polymorphism is associated with hyperinsulinemia, but not with insulin resistance, in hypertension. (Hypertens Res 1996; 19 Suppl. I: S31-S34)

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The eggshell is the major source of Ca required during growth of chick embryos. Therefore, chick embryos placed ex ovo for long-term (SL) are rendered severe systemic calcium deficiency. We report here that SL chick embryos express Ca-deficiency related atherogenic disorders, and that in vitro Ca- deficiency induces dedifferentiation, i.e. loss of cell-type specific features and accelerated proliferative activities, in the various types of cultured cells. Systemic blood pressure is significantly higher and an accelerated weight gain of the heart is noted in SL compared to normal embryos (NL) at the incubation Day-14. Plasma cholesterol was lower, while triglyceride and glucose were higher in SL. Varying Ca in the culture medium (FCa, 1.8mM; HCa, 2.8mM; Ca/2, 0.9mM) clearly affected the phenotype of the cultured cardiomyocytes and vascular cells isolated from the chick embryos. The cell number and total DNA were significantly larger and the level of LDH and proliferating cell nuclear antigen (PCNA) was elevated in Cal/2 compared to FCa. On the contrary, the level of CPK and contractile proteins were lowered in Ca/2. Thus, it is indicated that Ca-deficiency induces atherogenic disorders in vivo, and accelerates cell proliferation and decelerates sarcomeric protein expression in vitro. Taken together, it is suggested that the atherogenic, developmental disorders in SL may be the integrated result of the phenotype alteration in the various cell types directly induced by Ca-deficiency. (Hypertens Res 1996; 19 Suppl. I: S35-S40)

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The direct effect of insulin on NaCl transport in proximal tubules and thick ascending limbs of Henle's loop were examined. First, the effects of insulin on intracellular pH (pHi) in the in vitro microperfused rabbit S2 proximal straight tubules (PST) were examined using a fluorescent technique. Addition of insulin to the bath increased pHi in a dose-dependent manner at concentrations ranging from 10^-11 to 10^-6mol/l, and its ED₅₀ was 10^-9mol/l. The insulin-induced pHi increase was almost completely inhibited by 10^-3mol/l amiloride in the lumen, indicating that insulin activates luminal Na/H exchange in PST. Next, the effect of insulin on the transepithelial voltage (Vt) and lumen-to-bath Cl flux (J_cl) were examined in the in vitro microperfused rabbit medullary thick ascending limbs of Henle's loop (MTAL). Insulin in the bath increased Vt in a dose-dependent manner, and its ED₅₀ was 5×10^-9mol/l. Insulin significantly increased J_ci. The insulin-mediated increase in Vt was abolished by ouabain and furosemide. Dibutyryl-cAMP (dbcAMP) increased Vt and J_cl. H-8 abolished the effect of dbcAMP, while it did not inhibit the actions of insulin. Removal of extracellular Ca did not affect the effects of insulin on Vt and J_cl. Chelation of intracellular Ca with BAPTA/AM inhibited the actions of insulin without affecting basal values. Calmodulin (CaM) inhibitors, trifluoperazine and W-7, inhibited the actions of insulin more than 90%. These results indicate that insulin directly increases NaCl reabsorption in the MTAL, which requires the activation of Ca-CaM system, independent of the adenylate cyclase-cAMP- PKA system. In conclusion, insulin directly stimulates NaCl reabsorption in the in vitro microperfused rabbit PST and MTAL. (Hypertens Res 1996; 19 Suppl. I: S41-S45)

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In this article, I will review the recent progress in the relationship between hyperinsulinemia and control of vascular resistance. I particularly focus on effects of intra-arterial infusion of insulin on control of resting forearm vascular resistance and on vascular reactivity to vasoconstrictor agents in normotensive and hypertensive subjects. In conclusion, the physiological levels of local hyperinsulinemia may decrease resting forearm vascualr resistance in some normotensive subjects but not in all. Insulin-induced vasodilation may be due to the production of prostacyclin but not due to nitric oxide. Hyperinsulinemia attenuates vasoconstriction induced by phenylephrine and angiotensin II in normotensive subjects. Although acute intra-venous infusion of insulin activates the sympathetic nerve system, it may not elevate blood pressure in normotensive subjects possibly due to above mentioned anti- vasoconstrictor effects of insulin. In contrast, insulin-induced anti-vasoconstrictor mechanisms may be lost in hypertensive subjects, which may result in hypertension. (Hypertens Res 1996; 19 Suppl. I: S47-S50)

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Obesity is one component of a risk factor constellation that consists of insulin resistance (and/or hyperinsulinemia), hypertension, and a dyslipidemia characterized by a low HDL cholesterol level and high triglyceride levels. This risk factor constellation, which conveys enhanced risk for cardiovascular disease, is sometimes referred to as the "insulin resistance syndrome", "syndrome x", or the "metabolic" syndrome. Although the hyperinsulinemia and insulin resistance associated with the syndrome appear to play a central role, the relationship between insulin and the other manifestations of the syndrome have remained obscure. (Hypertens Res 1996; 19 Suppl. I: S51-S55)

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We investigated the correlations between the reduction in body weight (BW) induced by calorie restriction and reductions in blood pressure (BP) and improvement in metabolic disorders in overweight women with essential hypertension. After eating a standard diet (diet-I) for 2 weeks, women in the calorie-restricted group (n=25) received a low calorie diet for 2 weeks, and then standard diet-II for 1 week. Women in the calorie-nonrestricted group (n=13) ate standard diet-I for 5 weeks. The calorie-restricted group exhibited a significant reduction in BP in association with loss of BW; their levels of low-density lipoprotein cholesterol, and triglycerides levels, and their fasting levels of glucose and insulin were also reduced compared with the calorie-nonrestricted group. However, there were no significant differences in the level of high-density lipoprotein cholesterol, the areas under the 2-h glucose and insulin curves (AUC_glu and AUC_ins), or the ratio of AUC_glu to AUC_ins between groups. The change in BW was significantly correlated with a reduction in BP (r=0.62, p<0.01), but not with an improvement in metabolic disorders. Findings suggest that the degree of BW loss, induced by short-term, severe calorie restriction is associated with BP reduction, but not with improvements in glucose and lipid metabolism in overweight hypertensive women. (Hypertens Res 1996; 19 Suppl. I: S57-S60)

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The characteristics of NIDDM seen in Japanese is coexistence of diminished insulin secretion and the impaired sensitivity to insulin in the target tissues. Thus, insulin resistance does not mean hyperinsulinemia. To investigate the organ-specific insulin action on glucose homeostasis, we developed an innovative non-invasive method, using an euglycemic hyperinsulinemic clamp combined with oral glucose load. With this procedure, we could reveal muscle glucose uptake and hepatic glucose uptake following oral glucose load, quantitatively, separately and simultaneously. The effect of strict glycemic control in non- obese NIDDM who were secondary failure to sulfonylurea with 3 times prandial regular insulin injections, on glucose disposals are investigated. Glucose disposal by peripheral tissues was not altered (clamped blood glucose and insulin concentration are, 90mg/dl and 200μU/ml, respectively). The ratio of splanchnic glucose disposal to the amount of ingested glucose, on the other hand, significantly increased to 33.1% from 14.5%. Therefore, short-term strict glycemic control appears to improve glucose handling by splanchnic tissues without affecting insulin sensitivity of peripheral tissues in NIDDM. This method would be feasible to investigate whether insulin resistance seen in hypertensive patients, is located only in peripheral tissues or is also in the liver. To find patients with asymptomatic atherosclerosis, we routinely apply a noninvasive maneuver using high resolution B-mode imaging of the carotidartery, to determine atherosclerosis quantitatively. Impaired glucose tolerance (IGT) male subjects showed significantly greater thickness of the intimal plus medial complex (IMT) than age-matched healthy males and showed no significant differences compared to age-matched NIDDM patients. Among IGT, those with exaggerated insulin secretion (average serum insulin concentration was 100μU/ml at 1 and 2h after), in other words, insulin resistant, showed thicker IMT. The characteristics of IGT groups with high insulin level were, BMI more than 25, diastolic blood pressure more than 83mmHg, serum triglyceride more than 215mg/dl. Thus, among mildly obese, mild hypertensive, mild glucose intolerant, slightly hypertriglyceridemic Japanese male subjects, there exist advanced atherosclerotic subjects. (Hypertens Res 1996; 19 Suppl. I: S61-S64)

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Interrelations between hypertension (HT), ischemic heart disease (IHD) and diabetes mellitus (DM) were investigated in the diabetic subjects without IHD (DM group) or with IHD (DM+IHD group) and subjects with IHD (IHD group) which were not complicated with DM. 1. The incidence of hypertension of DM group, DM+IHD group and IHD group is 40, 54, 38% respectively. 2. The incidence of hyperlipidemia of DM group, DM+IHD group and IHD group is 55, 71, 56% respectively. 3. Serum Mg levels of DM (1.9±0.37mg/dl), DM+IHD (1.8±0.23) and IHD (1.9±0.33) were significantly lower than that of normal control (2.3±0.32). 4. Serum Mg level of poorly controlled diabetic patients is lower than that of well controlled diabetic patients. These results suggested that Magnesium deficient state is one of the cause of insulin resistancy. (Hypertens Res 1996; 19 Suppl. I: S65-S68)

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To investigate the metabolic and atherogenic effect of intra-abdominal fat accumulation, we examined correlation between variables of lipid and glucose and the fat distribution of abdominen by using computed tomography. Subjects were 292 of male and 161 of female who underwent coronary angiography. Intra-abdominal fat area was correlated with insulin concentration at 120min in oral glucose tolerance tests and triglyceride level in male, on the other hand, in female were HDL-cholesterol level, apolipoprotein B, glucose area under curve and insulin concentration at 60 and 120min. In an aspect of atherogenic effect of Intra-abdominal fat, it was not atherogenic in isolated state in male, but atherogenic in diabetic female. Intra-abdominal fat was accompanied with hypertension and mid-band, which appeared between alpha and beta band in polyacrylamide diskgel electrophoresis. Cluster of Intra-abdominal fat accumulation, hypertension and mid-band was atherogenic in male, in which insulin resistance play an important role in the coronary artery disease. On the contrary, Intra-abdominal fat accumulation accompanied with exacerbation of glucose tolerance, hypertensive and high level of apolipoprotein B in female. We concluded that visceral fat accumulation was a generator of metabolic syndrome X in male and was a progression factor for diabetes, hypertensive and high apolipoprotein B level in female. (Hypertens Res 1996; 19 Suppl. I: S69-S74)

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Epidemiological evidence suggests that treatment with β-blockers and diuretics increase the risk to develop diabetes. Prospective, randomized studies of antihypertensive drugs have demonstrated differences between different classes of drugs regarding effects on insulin sensitivity. Thus treatment with β-blockers or diuretics is associated with impairment in insulin sensitivity, whereas most modern calcium-channel blockers and angiotensin converting enzyme inhibitors are neutral. However, captopril treatment seems to be different and result in improvement of insulin sensitivity. The most pronounced improvements have been obtained with α₁-blockers. In populations at high risk for diabetes, it may be justified to select drugs that improve insulin sensitivity when treating hypertension in insulin resistant individuals. (Hypertens Res 1996; 19 Suppl. I: S75-S79)

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In subjects with coronary artery diseases (obstructive and vasospastic angina pectoris (AP)) who have no diabetes, hypertension, obesity and physical inactivity, insulin sensitivity was significantly reduced with compensated hyperinsulinemia on OGTT. Insulin resistance significantly correlated with coronary atherosclerosis score. In vasospastic AP (VAP), those who fulfilled more than 3 risk factors out of 5 (hyperinsulinemia, obesity, glucose intolerance, hypertension, dyslipidemia) consist of 70 and 40% for smokers and nonsmokers respectively. Insulin resistance syndrome who fulfilled all the criteria was 9-10% for VAP. In atherothrombotic brain infarction (ATTI) with the same exclusion criteria, the similar insulin resistance and hyperinsulinemia have been observed, but not in embolic (cardiac origin) or lacunar infarction. In ATTI, high TG and apo B with low HDL-chol were noted in blood. In essential hypertension without diabetes and obesity, hyperinsulinemia was noted in 25-35% and insulin resistance in 56-88%. Reduction of blood pressure with alpha blocker (bunazosin), ACE inhibitor (cilazapril), long- acting Ca⁺⁺ blocker (amlodipine) significantly improved lowered insulin sensitivity. Insulin resistance rather than hyperinsulinemia is more closely associated with blood pressure. Cardiovascular diseases (vasospastic and obstructive AP, brain cortical artery diseases) are prone to develop diabetes because of insulin resistance and also promote the generation of cumulative risk factors resulting in a vicious cycle. Efforts to alleviate insulin resistance is crucial for the primary and secondary prevention of cardiovascular diseases. (Hypertens Res 1996; 19 Suppl. I: S81-S85)

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Both cross-sectional and longitudinal epidemiological studies have shown that sedentary life style elevates blood pressure. Antihypertensive effectiveness of physical exercise has been also proven for the past ten years. We have carried out nine, (mostly controlled comparative) studies in the past over ten years. The mean changes of blood pressure by mild (approximately 50% maximum oxygen uptake) intensity cycle ergometer (60min ×3 times a week ×10 week) in the controlled studies was -11/-6mmHg. We found two mechanisms involved, a) sympathicolytic action and b) plasma depletion. Exercise not only lower blood pressure, but it is also known to improve lipid and glucose metabolism, and hence insulin sensitivity as has been applied for the therapy of diabetes mellitus. Exercise, therefore, should theoretically prevent cardiovascular diseases, and in fact, a prospective large scale epidemiological study has suggested that exercise will prevent cardiovascular death. (Hypertens Res 1996;19 Suppl. I: S87-S91)

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