Mechanism and clinical implication of insulin resistance syndrome.

The insulin resistance syndrome has been noted as an interesting and important new risk factor for coronary artery disease. The syndrome consists of hypertension, glucose intolerance, and dyslipidemia, all of which are likely to be derived from insulin insensitivity. In subjects with nonobese and nondiabetic essential hypertension, steady-state plasma glucose (SSPG) was higher than in normotensive subjects during an insulin sensitivity test, indicating reduced insulin sensitivity to glucose metabolism in the hypertensive group. SSPG correlated with the percentage decrease of branched chain amino acids, free fatty acids, and serum potassium during the insulin sensitivity test. With a 2-h insulin infusion, serum norepinephrine, epinephrine, plasminogen activator inhibitor 1, and intraplatelet Ca2+ decreased significantly, but 6-keto-prostaglandin (PG) F1 alpha and PGE2 did not change. Insulin resistance decreased by using antihypertensive treatments with bunazosin, cilazapril, amlodipine, and benidipine in hypertensive subjects. Diagnostic criteria for the insulin resistance syndrome, including clinical values for each risk factor, were developed. Lowered insulin sensitivity and hyperinsulinemia were demonstrated in subjects with both vasospastic and coronary artery stenotic angina. The insulin resistance syndrome together with hyperinsulinemia is likely to induce atherosclerotic changes, possibly through reduced rather than excessive action of insulin.

New alpha 2-adrenergic blocker (DG-5128) improves insulin secretion and in vivo glucose disposal in NIDDM patients.

Effects of oral administration of DG-5128, a new oral hypoglycemic agent, on glycemic control after a mixed meal and an in vivo glucose disposal were measured in subjects with nonobese non-insulin-dependent diabetes mellitus (NIDDM). Oral administration of DG-5128 significantly (P less than .05) enhanced insulin secretion both 30 and 60 min after a mixed meal (550 kcal), with a concomitant decrease in postprandial plasma glucose levels at 60 and 120 min. Glucose disposal rate between the 2nd and 4th h of a euglycemic insulin clamp, developed through a constant infusion of insulin (0.77 mU X kg-1 X min-1) together with somatostatin (80 ng X kg-1 X min-1), was 2.5-fold higher in a DG-5128-treated group (P less than .01) than in a control group. However, there was no difference between the two groups in either plasma glucose concentration or plasma insulin concentration at either the 2nd or the 4th h. These results indicate that DG-5128 is effective in controlling plasma glucose levels in subjects with NIDDM by stimulation of both insulin secretion and in vivo glucose disposal.

Risk factor analyses for macrovascular complication in nonobese NIDDM patients. Multiclinical Study for Diabetic Macroangiopathy (MSDM).

To examine the characteristic features of risk factors for macroangiopathy (MA) in nonobese Japanese NIDDM patients, 899 NIDDM patients with and without MA were registered from 40 facilities. Of these, 386 subjects were identified as having any form of MA (total MA); these included 211 with ischemic heart disease (IHD), 163 with cerebrovascular disease (CVD), and 77 with peripheral vascular disease (PVD). Univariate analyses revealed the following common risk factors for total MA, IHD, CVD, and PVD: age, hypertension, systolic blood pressure (sBP) or diastolic blood pressure (dBP), duration of diabetes, diabetic microangiopathy (retinopathy, nephropathy, and neuropathy), low HDL cholesterol level, and higher LDL cholesterol/HDL cholesterol ratio. Additional significant risk factors for specific conditions were also identified, respectively, as male sex for total MA, IHD, and PVD, smoking for IHD and PVD, and high fasting plasma glucose level for total MA and CVD. With stepwise multivariate logistic regression analysis, older age, duration of diabetes, smoking, and low LDL cholesterol/HDL cholesterol ratio were identified as significant and independent risk factors for total MA, IHD, CVD, and PVD. Other risk factors identified were high dBP for IHD, CVD, and PVD, high sBP for total MA, and low BMI for PVD. These results clearly demonstrated that duration of diabetes, smoking, hypertension, and dyslipidemia are major risk factors for MA in NIDDM patients. Since the mean BMI was similar for both groups (approximately 23 kg/m2) and there were no significant differences in immunoreactive insulin levels before and after 75-g oral glucose challenge testing, obesity and hyperinsulinism at the time of the analyses were not considered to play an important role for the pathogenesis of MA in Japanese NIDDM patients. By using the chi 2 test, cutoff points were determined for six of the most commonly measured risk factors. The cutoff point was the level beyond which a significantly higher prevalence of MA occurred. The cutoff points (rounded slightly upward in some cases) for fasting plasma glucose, sBP, dBP, serum total cholesterol level, serum triglyceride level, and BMI were 140 mg/dl, 140 mmHg, 80 mmHg, 180 mg/dl, 120 mg/dl, and 23 kg/m2, respectively. When these cutoff points were used as control criteria, the prevalence of MA was significantly lower in subjects whose risk factor measurements remained under the proposed control criteria for four or more of the six variables. In conclusion, in nonobese NIDDM patients, age, hypertension, and dyslipidemia were found to be risk factors for MA. Duration of diabetes was also demonstrated as an independent risk factor, indicating the close association of deranged glucose metabolism with the pathogenesis of MA in NIDDM patients. It seems to be crucial to control these risk factors for the prevention of MA in NIDDM patients.

Quantitative and qualitative derangement of apolipoprotein B-containing lipoproteins as a risk factor for diabetic macroangiopathy in nonobese NIDDM subjects.

Cholesterol, triglyceride (TG), and apolipoprotein (apo) B were determined in plasma and in lipoprotein subfractions (VLDL, intermediate-density lipoproteins [IDL], LDL, and HDL) in nonobese NIDDM subjects, who were classified into well-controlled, fairly controlled, or poorly controlled states with or without macrovascular complications (macroangiopathy [MA]). The same analyses were also performed on subjects who had coronary artery disease (CAD) with stable angina pectoris (SA) or unstable angina pectoris (UA) and acute myocardial infarction, cerebrovascular disease (CVD) with atherothrombotic or lacunar infarction, and arteriosclerosis obliterans (ASO). In nonobese NIDDM subjects, the number of apoB-containing lipoproteins (VLDL, IDL, and LDL) increased. This alteration was more prominent in subjects with poorly or fairly controlled disease as well as in subjects with MA, but not in those with well-controlled NIDDM. Cholesterol/apoB in LDL decreased in subjects with poorly or fairly controlled diabetes or with MA and was correlated with low HDL cholesterol. The disorder is characterized by hyperbetalipoproteinemia with elevated LDL cholesterol and small dense LDL. In obese NIDDM subjects, the similar disorder was more pronounced. Glycemic control had less effect and hyperinsulinemia, if present, aggravated the lipid disorder. In those with CAD, the number of IDLs increased and the LDL fraction had the properties of small dense LDL. HDL cholesterol decreased. In those with UA, the LDL number increased without elevation of LDL cholesterol, indicating typical hyperbetalipoproteinemia. The subjects with atherothrombotic brain infarction, an increased number of small-sized LDLs was noted. In those with ASO, the number of VLDL and IDL increased with small LDL. HDL cholesterol decreased in those with CAD, cerebrovascular disease, and ASO. Since similar quantitative and qualitative alterations of apoB-containing lipoprotein have been observed in NIDDM patients as well as in those with macrovascular diseases, diabetic patients are thought to be more susceptible to the initiation and progression of atheromatous lesions in coronary, brain, and peripheral arteries.

Development of early lesions of microangiopathy in chronically diabetic monkeys.

A chronic diabetic state was produced in Macaca fuscatus , and these diabetic monkeys were kept without insulin treatment for up to 25 mo. The metabolic derangements were characterized by hyperglycemia, insulinopenia, hyperglucagonemia, ketonemia, and hyperlipidemia. Significant thickening of the capillary basement membrane of the gastrocnemius muscle was observed in the chronically diabetic monkeys, and became obvious in the course of diabetic state; 732 +/- 35 A in controls, 750 +/- 58 A in diabetic monkeys with duration of 4 mo, and 1165 +/- 112 A in those with duration of more than 11 mo. In addition to duration of the diabetic state, severity of hyperglycemia is also thought to play an important role in the capillary basement membrane thickening judging from the fact that diabetic monkeys with constant hyperglycemia showed a greater membrane thickening. Ultrastructural alterations, such as significant thickening of glomerular basement membrane and increase of mesangial matrix, were observed in kidney as well. These results indicate that diabetic microangiopathy has been produced by metabolic derangements characterized by chronic hyperglycemia, insulinopenia, and hyperlipidemia.

Demonstration of insulin resistance in coronary artery disease documented with angiography.

OBJECTIVE: To evaluate the relation between insulin resistance and coronary atherosclerosis, insulin sensitivity in lean nondiabetic, normotensive subjects with and without obstructive coronary artery disease (CAD). The correlation between insulin resistance and degree of coronary stenosis was also investigated. RESEARCH DESIGN AND METHODS: Four groups were studied: 1) nine subjects with normal glucose tolerance (NGT) without CAD, 2) 10 subjects with NGT with CAD, 3) nine subjects with impaired glucose tolerance (IGT) without CAD, and 4) 10 subjects with IGT with CAD. Insulin sensitivity was determined by the steady-state plasma glucose (SSPG) method using Sandostatin. Coronary angiography was performed in all study subjects, and the severity of coronary artery atherosclerosis was quantified in a modified Gensini score. RESULTS: The SSPG (millimoles per liter) levels were significantly higher in the patients with CAD compared with control subjects (control vs. patient group: 4.8 +/- 0.5 vs. 7.9 +/- 0.9 with NGT, P < 0.05; 5.6 +/- 0.5 vs. 11.1 +/- 0.8 with IGT, P < 0.001), indicating the presence of insulin resistance in patients with CAD. The coronary atherosclerosis score (CAS) was significantly and positively correlated with SSPG (r = 0.74, P < 0.05) and 2-h insulin area (r = 0.78, P < 0.01) in NGT subjects with CAD. On the other hand, the percentage fall of plasma free fatty acid (0-30 min) during an insulin sensitivity test was significantly decreased in the subjects with CAD and was inversely correlated with the CAS (r = -0.43, P < 0.05), especially in NGT subjects with CAD. CONCLUSIONS: These data suggest that in patients with CAD, insulin-mediated glucose metabolism is significantly impaired, and a significant correlation was noted between insulin resistance and severity of CAD. Therefore, the hyperinsulinemia often observed in patients with CAD is attributable to the compensatory mechanism of the beta-cell to the inadequate action of insulin for glucose metabolism. Hyperinsulinemia in the presence of insulin resistance aggravates dyslipidemia and may stimulate the atheromatous process by an as-yet-unknown mechanism.

Development of paper-strip test for 3-hydroxybutyrate and its clinical application.

A rapid paper-strip test for the semiquantitating 3-hydroxybutyrate (3-OHBA) has been developed. The color develops within 5 min after applying the serum to the paper strip, and the purple color was read either visually or by reflectance meter. This can detect 3-OHBA levels as low as 0.1 mmol/L up to 2.0 mmol/L. The more concentrated sample can be measured on serial dilution. Clinical usefulness has been tested in a summer camp for insulin-dependent diabetic children as well as in a routine diabetes clinic. Serum 3-OHBA levels ranged from greater than 100 mumol/L to 4 mmol/L in all the subjects before breakfast in a summer camp. In four subjects, 3-OHBA was elevated to the level of 2-4 mmol/L, and only one of these four subjects exhibited ketonuria by nitroprusside test. In a diabetes clinic, a new paper-strip test for 3-OHBA has revealed ketonemia in 34 (74%) of 46 diabetic subjects, while nitro-prusside test revealed ketonemia in only 4 (13%). The present paper-strip test for 3-OHBA is sensitive enough to detect levels as low as 0.1 mmol/L and is clinically useful for rapid detection of ketosis proneness as well as for monitoring of diabetes control.

Development of stable film test for rapid estimation of blood or plasma 3-hydroxybutyrate.

A film test for the rapid detection of plasma/serum 3-hydroxybutyrate (3-OHB) has been developed. The film contains NAD, nitro blue tetrazolium, 3-OHB dehydrogenase, and diaphorase, and the surface is coated with modified biomembrane and can detect 50-1500 microM 3-OHB within 2-3 min. One drop or 50 microliters of plasma/serum or blood is applied to the film, and the violet color is read via reflectance meter after 2 min. Plasma/serum samples greater than 1500 microM 3-OHB can be measured by dilution with saline. In blood with 40% hematocrit, the color developed is 50% less than with plasma/serum, and this was adjusted in the reflectance meter. A good correlation (r = 0.99) was observed between results with automated and film methods and between visual methods and reflectance meter. In insulin-dependent diabetes mellitus, all 3 subjects with positive ketonuria (+ +), 8 of 12 subjects with mild ketonuria (+), and 7 of 25 subjects without ketonuria exhibited elevation of 3-OHB in blood greater than 200 microM. The results indicate that 3-OHB film is valuable not only in the emergency room for the differential diagnosis between ketoacidotic and nonketotic hypersomolar coma but also as a marker for insulin dependency, energy dependency on fatty acid compared with glucose, and metabolic control of diabetes.

Association of insulin resistance with salt sensitivity and nocturnal fall of blood pressure.

Insulin resistance was demonstrated in hypertensive patients and in salt-sensitive subjects. It was recently reported that the salt-sensitive state was related to a reduced fall in blood pressure during the night in essential hypertension. In the present study, the relationship among insulin sensitivity, blood pressure response to salt intake, and nocturnal fall in blood pressure was examined in 20 subjects with nondiabetic and nonobese essential hypertension during a low-salt and a high-salt diet. The subjects were maintained on a low-salt diet (50 mmol/d) and a high-salt diet (255 mmol/d) for 1 week each, in random order. On the sixth day of each diet, blood pressure was measured every hour for 24 hours with an automatic device. Insulin sensitivity was measured according to the steady-state plasma glucose (SSPG) method on the seventh day of each diet. Salt-induced increase in blood pressure, which we defined as the change in 24-hour mean arterial pressure between the low and the high dietary salt intakes, was significantly correlated with SSPG (r=0.60, P<0.01) during the high-salt period. There was a significant negative correlation (r=-0.61, P<0.01) between SSPG and a nocturnal fall in mean arterial pressure during the high-salt period. Salt-induced increase in blood pressure was inversely correlated with a nocturnal fall in mean arterial pressure (r=-0.52, P<0.02) with the high-salt diet. These results suggest that insulin resistance, salt sensitivity, and failed nocturnal fall in blood pressure are associated with each other in subjects with essential hypertension.

Insulin resistance as an independent risk factor for carotid wall thickening.

It has been reported that insulin resistance is associated with essential hypertension and that an aggregation of risk factors-hypertension, dyslipidemia, and glucose intolerance-together with insulin resistance leads to the more frequent appearance of coronary artery disease. We examined the relation between early asymptomatic atherosclerosis and these risk factors in 72 nondiabetic subjects with essential hypertension (41 men, 31 women) aged 50 to 59 years. Intima-media thickness and plaque formation of the carotid artery were assessed by B-mode ultrasonography, and insulin sensitivity was measured by the steady-state plasma glucose method. Lipoprotein profile was analyzed by ultracentrifugation. The intima-media thickness of the common carotid artery significantly correlated with systolic pressure; mean blood pressure; steady-state plasma glucose, indicating insulin resistance; fasting insulin; area under the curve of plasma insulin and glucose; body mass index; apolipoprotein B; apolipoprotein B in low-density lipoprotein; lower ratio of cholesterol to apolipoprotein B of low-density lipoprotein; and decreased high-density lipoprotein cholesterol. By multiple regression analysis, steady-state plasma glucose was the strongest risk, followed by lower high-density lipoprotein and systolic pressure. These three factors accounted for 54.9% of all the risk for increased intima-media thickness of the common carotid artery. In conclusion, insulin resistance was the strongest risk factor for carotid intima-media thickness, followed by lower high-density lipoprotein cholesterol and hypertension. An effort to maintain normal insulin sensitivity is essential for the prevention of early atheromatous lesions in essential hypertension.

Glucose, insulin and somatostatin infusion for the determination of insulin sensitivity.

Glucose, insulin and somatostatin infusion over 2 hours effectively suppressed endogenous secretion of insulin, glucagon and growth hormones. Steady state plasma glucose level (SSPG) which should be inversely proportional to insulin sensitivity was obtained. In 6 adult-onset non-obese untreated diabetics, mean value of insulin sensitivity indices was significantly reduced compared with normal. In 5 insulin-treated diabetics and in 5 subjects with borderline glucose tolerance including 2 obese subjects, insulin sensitivity for glucose utilization was also significantly diminished.

Clinical significance of altered insulin sensitivity in diabetes mellitus assessed by glucose, insulin, and somatostatin infusion.

Insulin sensitivity has been determined in primary nonobese diabetics and subjects with borderline glucose intolerance by a newly devised technique using glucose, insulin, and somatostatin infusion. Insulin sensitivity for glucose utilization was decreased in both adult- and juvenile-onset diabetics. Eight out of 88 diabetics had normal insulin sensitivty and were free from microvascular complications. In lean subjects with borderline glucose intolerance, insulin sensitivity was decreased, although an overlap with normal was noted. All obese subjects with borderline glucose intolerance had reduced insulin sensitivity. An inverse relationship was observed between insulin sensitivity and fasting plasma glucose (FPG), and a significant correlation was observed between FPG and steady state plasma glucose levels (SSPG; r = 0.57; P less than 0.001). Improvement of diabetic control in eight diabetics with sulfonylureas decreased SSPG in all (P less than 0.05), although normalization of SSPG was observed in only one. These results indicate that decreased sensitivity of insulin for peripheral glucose utilization may play an important role in the pathogenesis of diabetes. Elevated FPG levels reflect the presence of decreased insulin sensitivity in diabetes mellitus. Although decreased sensitivity is difficult to normalize, it can be enhanced by improving the diabetic control. An effort to maintain or enhance tissue insulin sensitivity in diabetes mellitus may be more important than attempts to stimulate the deteriorating pancreatic beta-cells to secrete more insulin.

A suppressive role of c-kinase for the stimulation of hepatic ketogenesis by glucagon and epinephrine.

The regulatory mechanism of hepatic palmitate oxidation into ketone bodies by c-kinase has been studied in isolated hepatocytes. Glucagon and epinephrine stimulated [U-14C]palmitate oxidation to ketone bodies by 60 and 25% as early as at 1 h. The stimulatory effects were almost totally prevented by the simultaneous presence of vasopressin, phorbol 12-tetradecanoate 13-acetate (TPA), or diacylglycerol (1-oleoyl-2-acetylglycerol). When hepatocytes were treated with glucagon or epinephrine, carnitine palmitoyltransferase (CPT), a key regulatory enzyme of palmitate oxidation, was activated. This hormone-induced activation of CPT was not observed in the presence of TPA. These observations suggest that c-kinase inhibits glucagon- or epinephrine-stimulated palmitate oxidation to ketone bodies, and that this inhibition may be mediated through a covalent modification of CPT.

Phosphorylation of carnitine palmitoyltransferase and activation by glucagon in isolated rat hepatocytes.

Effects of glucagon and forskolin on the phosphorylation and changes of activity of carnitine palmitoyltransferase (CPT) have been studied in isolated rat hepatocytes using anti-CPT immunoglobulin. When the activity was determined in lysed hepatocytes after glucagon or forskolin treatment, it was found to be stimulated 30-80% mainly through increased affinity for palmitoyl-CoA. By SDS electrophoresis of the immunoprecipitates, CPT subunit (Mr 69000) was noted to be phosphorylated 4-5-fold with glucagon (1.2 X 10(-7) M) and forskolin (0.1 mM) over control. These results indicate that hepatic ketogenesis is regulated with glucagon by phosphorylation of CPT through cAMP-dependent protein kinase.

Development of approximate formula for LDL-chol, LDL-apo B and LDL-chol/LDL-apo B as indices of hyperapobetalipoproteinemia and small dense LDL.

Estimation of LDL-chol and LDL-apo B is useful for the diagnosis of hyperapobetalipoproteinemia (normal LDL-chol with increased LDL-apo B), which is one of the most commonly occurring lipoprotein disorders associated with atherosclerotic cardiovascular diseases. The LDL-chol/LDL-apo B ratio reflects the level of small dense LDL, which is an important risk factor for IHD, CVD and ASO. In order to estimate LDL-apo B and LDL-chol/LDL-apo B ratio from blood chol, TG, HDL-chol and apo B values, we developed a formula for LDL-chol ¿0.94Chol- 0.94HDL-chol - 0.19TG¿, LDL-apo B ¿apo B - 0.09Chol + 0.09HDL-chol-0.08TG¿, and LDL-chol/LDL-apo B [¿0.94Chol-0.94HDL-chol - 0.19TG¿/¿apo B - 0.09Chol + 0.09HDL-chol-0.08TG¿] using ultracentrifugal data from 2179 subjects. These were calculated by the least squares method on the assumption that a certain compositional relationship exists between Chol, TG and apo B in VLDL, IDL and LDL. Friedewald's formula for LDL-chol (Chol - HDL-chol - 0.2TG) includes IDL-chol, but the present new formula theoretically excludes IDL-chol. It suggests a better estimation for the correct LDL-chol. Estimated LDL-apo B is useful for the diagnosis of hyperapobetalipoproteinemia and detection of small dense LDL. Without performing ultracentrifuge, additional information is obtained for the quantitative and qualitative alteration of LDL, such as small dense LDL. The above formulae and a new classification of lipoproteinemia including apo B were applied to the analyses of lipoprotein profiles of subjects with cardiovascular diseases, which were compared with those in the general population. Hyperapobetalipoproteinemia with high TG was observed 2-3 times more frequently in subjects with CAD, MI and ASO than in the Suita population. Lower ratios of LDL-chol/LDL-apo B, reflecting preponderance of small dense LDL, were observed in the above three groups. Type IIb and combined low HDL-chol were also frequent phenotypes in CAD, A-Th and ASO. The present formulae are useful for the detailed analyses of lipoprotein disorders in both qualitative as well as quantitative aspects.

Hyperapobetalipoproteinemia with compositional abnormality of LDL and IDL, a characteristic lipoprotein alteration in essential hypertension.

The number and composition of apoprotein B (apoB)-containing lipoproteins that are very low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) have been analyzed in subjects with essential hypertension who have no obesity and glucose intolerance. Twenty-three essential hypertensive subjects without diabetes mellitus and obesity were recruited. VLDL, IDL, LDL, and high-density lipoprotein (HDL) were separated by ultracentrifugation in the 23 hypertensive and 17 healthy subjects (control group). ApoB was determined by highly sensitive latex agglutination method in each lipoprotein fraction. There were no significant differences in age and body mass index between the hypertension and control groups. In hypertension, cholesterol levels significantly increased in plasma (13%, P < .05) and in LDL (20%, P < .05), but decreased in HDL (-14%, P < .05). Triglyceride significantly increased in plasma (66%, P < .05) and in VLDL (105%, P < .05). ApoB also significantly increased in plasma and all lipoprotein fractions except HDL. (plasma, 35%; VLDL, 94%; IDL, 82%; LDL, 42%; P < .05). With respect to lipoprotein composition, the ratio of cholesterol to apoB significantly decreased in IDL (P < .05) and LDL (P < .05). In essential hypertension, the number of apoB-containing lipoproteins (VLDL, IDL, LDL) all increased. A low ratio of cholesterol to apoB without changes in the ratio of triglyceride to apoB was noted in IDL and LDL, indicating the presence of small dense lipoprotein particles. Characteristic disorders of pure essential hypertension are characterized by hyperapobetalipoproteinemia and small dense LDL.

Noninvasive quantitative evaluation of early atherosclerosis and the effect of monatepil, a new antihypertensive agent. An interim report.

In two studies on the same group of patients we evaluated noninvasive methods of assessing atherosclerosis and determined the effect of the new calcium channel-blocking agent monatepil on the progression of early atherosclerosis in humans. Computed tomography (CT) of the lower abdominal aorta and ultrasonography of the carotid arteries were used as noninvasive methods to determine the extent of atherosclerosis. To evaluate the CT images, we developed a new medical image analysis program. This enabled aortic calcification volume (ACV) to be quantified using plain CT images, and aortic wall volume (AWV) and aortic wall and calcification volume (AWCV) to be quantified from contrast CT images. Interobserver coefficients of variation of ACV, AWV, and AWCV (n = 8) were 4.7, 2.4, and 5.0%, respectively. In the monatepil study, the effect of the drug on serum lipid profiles was evaluated. Preliminary results show that shortly after monatepil administration, total serum cholesterol levels decreased significantly from 253.8 +/- 35.6 to 244.8 +/- 38.6 mg/dL (P < .009) and triglyceride levels tended to decrease. A positive correlation between the change in total cholesterol and changes in mean platelet volume was found (P = .028). Fasting immunoreactive insulin levels decreased in the four patients in which they were determined. Although this is a preliminary study, results indicate that CT of the lower abdominal aorta in combination with our new analysis program may be a precise, reproducible means of assessing early atherosclerosis. We have also shown that monatepil significantly decreases total cholesterol levels. However, the long-term effects of monatepil on the progression of atherosclerosis remain to be determined.

Insulin insensitivity in nonobese, nondiabetic essential hypertension and its improvement by an alpha 1-blocker (bunazosin).

To investigate insulin insensitivity and its reversibility, we performed an insulin sensitivity test using the steady state plasma glucose (SSPG) method in 10 lean hypertensive subjects with normal glucose tolerance before and after treatment with alpha 1-blocker bunazosin, and 14 age body mass index-adjusted healthy control subjects. Steady state plasma glucose was significantly higher in the hypertensive subjects compared with the control group (182 +/- 10 mg/dL v 104 +/- 7, P < .01, mean +/- standard error of the mean (SEM). Steady state plasma glucose significantly decreased to 136 +/- 12 mg/dL (P < .01) after the treatment with alpha 1-blocker bunazosin, with a decrease of blood pressure. Hypertensive subjects had shown an increased area under the curve of glucose and insulin during the oral glucose tolerance test compared with normal controls. The glucose area decreased significantly, but the insulin area did not change after the treatment. There was no difference in plasma epinephrine, norepinephrine, and fractional excretion of Na between normal and hypertensive subjects both before and after treatment with bunazosin at basal and during insulin sensitivity tests (2 h). Serum total cholesterol level decreased and HDL cholesterol increased significantly after treatment with bunazosin. A significant correlation was observed between SSPG and blood pressure, but not between insulin level and blood pressure. The results indicate that insulin sensitivity is better related than hyperinsulinemia to hypertension and that this insensitivity is partially reversible by alpha 1-blocker, bunazosin.

Reciprocal changes of insulin and glucagon receptors in primary cultured hepatocytes.

The specific [125I]insulin binding to primary cultured hepatocytes was significantly greater than that to freshly isolated hepatocytes. Low affinity insulin binding sites in cultured cells were 6-fold greater in number than those of freshly isolated cells without a significant change in high affinity sites. However, both sensitivity (insulin concentration for half maximum stimulation) and responsiveness (% of increase above the basal level) to insulin for the stimulation of ODC activity were similar for isolated and cultured cells indicating an important role of high affinity sites in the insulin action. On the other hand, the specific [125I]glucagon binding to cultured cells was significantly decreased. Low affinity glucagon binding sites in cultured cells decreased by about 50% in cultured cells without a significant change in high affinity sites. Both sensitivity and responsiveness to glucagon for the stimulation of ketogenesis from palmitate also decreased as compared with those of isolated cells, indicating an important role of low affinity sites in the glucagon action. These results indicate that insulin and glucagon receptors were reciprocally changed in cultured cells, as compared with isolated cells.