Insulin sensitivity in familial hypercholesterolemia

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isolation, cloning and characterization of a putative type-1 astrocyte cell line

The high prevalence of cholesterol gallstone disease in hypertriglyceridemic patients may be associated with frequent metabolic defects in cholesterol and bile acid syntheses and in the concomitant formation of bile supersaturated with cholesterol. This study had the two aims: 1) to assess whether the defects as well as the degree of biliary cholesterol supersaturation in patients with hyperlipoproteinemia (HLP) can be estimated by the simultaneous determination of plasma mevalonate (MVL) and 7alpha-hydroxy-4-cholesten-3-one (C4); and 2) to assess the possible application of an estimated cholesterol saturation index ([CSI]E) as a means of evaluating the clinical effects of simvastatin on biliary lipid composition. Biliary cholesterol supersaturation was observed in patients with both IIa and IV HLP types. Consistent with the high activity and steady-state messenger RNA level of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, plasma MVL was significantly higher in 86 patients with HLP (38 type IIa, 44.1 +/- 2.4 nmol/L and 48 type IV, 56.7 +/- 2.3; P < .01) than in 41 normolipidemic subjects (34.2 +/- 1.5), closely correlating with the molar percentage of cholesterol in bile (r = .61, P = .0001; n = 86). On the other hand, consistent with the high activity and messenger RNA level of cholesterol 7alpha-hydroxylase, plasma C4 was significantly higher in patients with HLP (type IIa, 28.8 +/- 2.3 nmol/L and type IV, 38.3 +/- 2.7; P < .01) than in normolipidemic subjects (17.4 +/- 1.5). Plasma C4 was closely correlated with plasma MVL (r = .40, P = .0001; n = 86), but was inversely correlated with the molar percentage of bile acids in bile (r = .49, P = .0001; n = 86). Assuming that cholesterol supersaturation in patients with HLP may be governed by both an enhanced cholesterol secretion (closely reflected by plasma MVL) and a decreased secretion of bile acids (closely reflected by plasma C4), the multivariate linear regression-analyses revealed that an index defined as estimated CSI ([CSI]E) (%) in patients with HLP was given by the following equation using plasma MVL and C4 (nmol/L): [CSI]E = 1[MVL] + 0.7[C4] + 44.4. Biliary cholesterol supersaturation in patients treated with simvastatin improved in a manner parallel to the time course of decreases in plasma MVL and C4. The [CSI]E before and at the end of treatment were correlated with biliary CSI. These results indicate that defects of hepatic cholesterogenesis, and bile acid synthesis, and the degree of biliary cholesterol supersaturation in patients with HLP can be estimated exactly by the simultaneous determination of plasma MVL and C4; furthermore [CSI]E may be adopted for clinical use as a convenient index of biliary CSI.     

The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes

STUDY OBJECTIVES: To determine the efficacy of the lung as an alternative route of delivery for insulin in controlling glucose below diabetic levels (11.2 mmol/L) 2 h after the ingestion of a meal in patients with type 2 diabetes mellitus. DESIGN: Single-blinded, nonrandomized, placebo-controlled pilot study consisting of two visits. SETTING: A primary care facility. PATIENTS: Seven patients with type 2 diabetes mellitus. INTERVENTIONS: On the first study visit, fasting glucose levels were normalized. Then, patients inhaled 1.5 U/kg insulin by aerosol into the lungs 5 min before ingesting a test meal. On the second visit, patients inhaled placebo aerosol 5 min before ingesting the same meal. On both visits, plasma samples were collected and analyzed for glucose levels for 3 h during the postprandial state. MEASUREMENTS AND RESULTS: No one coughed after inhalation of insulin aerosol or demonstrated hypoglycemia. During the postprandial period, glucose levels were significantly lower at 20 min (5.12+/-1.08 mmol/L), 1 h (7.87+/-0.73 mmol/L), 2 h (8.05+/-1.24 mmol/L) and 3 h (7.50+/-1.43 mmol/L) following inhalation of insulin than when the placebo was used. Data for the placebo were 10.36+/-1.23 mmol/L at 20 min, 14.0+/-1.68 mmol/L at 1 h, 16.18+/-1.45 mmol/L at 2 h, and 14.37+/-2.11 mmol/L at 3h (for all comparisons, p < 0.05). On the insulin visit, glucose levels were < 11.2 mmol/L 2 h after the meal in six of seven patients. None attained this level at the placebo visit. In addition, glucose levels were within the normal postprandial range of < 7.84 mmol/L in four of seven patients 2 h after eating on the insulin visit. CONCLUSIONS: These results suggest that, once plasma glucose levels are normalized, postprandial glucose levels can be maintained below diabetic levels by delivering 1.5 U/kg insulin into the lungs 5 min before the ingestion of a meal.     

Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein a

Lipoprotein a [Lp(a)] has emerged as a critical factor in the assessment of cardiovascular risk. In the study reported here, Lp(a) concentrations were monitored in patients taking pravastatin, a new hydrophilic, HMG-CoA reductase inhibitor. A cohort of patients with frozen plasma aliquots at baseline, week 12 of the double-blind therapy, and week 48 of open-label therapy (1 years' treatment) was selected from 306 participants in a phase 2 dose-ranging study of pravastatin. The 125 men and women in the cohort had mean low-density lipoprotein cholesterol (LDL-C) concentrations of at least 150 mg/dL (3.88 mmol/L), and mean plasma triglyceride concentrations less than 250 mg/dL (2.82 mmol/L) during the baseline diet phase. During the double-blind phase, 46 patients received placebo, and 79 received pravastatin 10, 20, or 40 mg daily. Only the 79 pravastatin-treated patients in the cohort continued in the 48-week open-label study of pravastatin. During the double-blind phase, Lp(a) decreased 4.6% in patients taking placebo, and 0.4% in patients taking pravastatin. Net change was not significant. At week 48, in the patients taking pravastatin, Lp(a) had increased 2.4%, a difference that again was not statistically significant. Low-density lipoprotein cholesterol (-33.6%), total cholesterol (-25.6%), triglycerides (-19.9%), high-density lipoprotein cholesterol (HDL-C) (+7.0%), apolipoprotein A-I (+13.3%), and apolipoprotein B (-33.0%) changed significantly (P < .01). Among 19 patients with baseline Lp(a) levels greater than 30 mg/dL, Lp(a) decreased insignificantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Short-term treatment with low-dose pravastatin attenuates oxidative susceptibility of low-density lipoprotein in hypercholesterolemic patients

The effects of treatment with low-dose 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin on the changes of chemical composition and in vitro oxidative susceptibility of low-density lipoprotein (LDL) were studied in 20 type Ila hyperlipidemic patients with a plasma total cholesterol level > 240 mg/dL at the end of a diet control period for 3 months using the American Heart Association recommended step I diet. Treatment with pravastatin in a dose of 5 mg twice daily for 4 weeks resulted in lowering plasma total and LDL cholesterol levels by 17.0% and 22.9%, respectively. There was no further decline in plasma lipid thereafter. Chemical composition analysis showed that LDL particles did not contain significantly less cholesterol and thiobarbituric acid reactive substances (TBARS) until the end of 8 weeks (130.6 +/- 17.8 vs. 106.6 +/- 37.1 mg/mg protein, P < 0.05 and 0.16 +/- 0.06 vs. 0.08 +/- 0.02 nmol/mg protein, P < 0.005, respectively). Vitamin E, phospholipid, and triglyceride contents remained at the same levels throughout the study. In terms of oxidative kinetics, lag time and time to maximal diene concentration were not prolonged during the treatment period for 12 weeks, while total diene concentration and reaction rate were not significantly reduced until 8 weeks of treatment. Plasma enzyme activity of glutathione reductase and peroxidase, as well as the whole blood level of reduced and oxidized glutathione, remained similar during the study. In conclusion, pravastatin, at the low dose of 5 mg twice daily, produced a significant decline in plasma lipid levels to a steady-state range by 4 weeks; however, 8-weeks treatment is necessary to reduce the cholesterol and TBARS content, as well as to attenuate the oxidative susceptibility of LDL. These effects are not related to the antioxidant glutathione.     

Discriminative stimulus effects of S(-)-methcathinone (CAT): a potent stimulant drug of abuse

Elevated circulating plasma nonesterified fatty acids (NEFA) may contribute to the insulin resistance and hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM), and decreasing plasma NEFA could provide a therapeutic benefit. A sustained-release preparation of acipimox, a lipolysis inhibitor, was used in an attempt to decrease circulating plasma NEFA levels long-term, and the effects on glycemic control, insulin resistance, and serum lipids were measured. Sixty NIDDM patients (43 males and 17 females) took part in a randomized controlled trial of acipimox or placebo for 12 weeks. Fasting plasma NEFA levels did not change in acipimox-treated patients (baseline v 12 weeks, 0.84 +/- 0.35 v 0.88 +/- 0.55 mmol x L(-1), mean +/- SD). Fasting blood glucose was unchanged (mean difference v placebo, -0.5 mmol x L(-1); 95% confidence interval [CI], -1.4 to 0.3 mmol x L[-1]), but serum fructosamine decreased (mean difference v placebo, -26 micromol x L(-1); 95% CI, -51 to 0 mmol x L[-1]), as did the standardized hemoglobin A1 ([HbA1] mean difference v placebo, -1.4%; 95% CI, -3.0% to -0.1%). Insulin resistance measured as steady-state plasma glucose during an insulin-dextrose infusion test was unchanged (mean difference v placebo, -1.4 mmol x L(-1); 95% CI, -3.2 to 0.5 mmol x L[-1]). Serum total cholesterol (mean difference v placebo, -0.4 mmol x L(-1); 95% CI, -0.6 to -0.1 mmol x L[-1]), serum apolipoprotein B ([apo B] mean difference v placebo, -0.19 g x L(-1); 95% CI, -0.3 to -0.1 g x L[-1]), and serum triglycerides (mean difference v placebo for pretreatment v posttreatment ratio, 0.59; 95% CI, 0.40 to 0.88) were all lower with acipimox. Serum high-density lipoprotein (HDL) cholesterol (mean difference v placebo, 0.10 mmol x L(-1); 95% CI, -0.05 to 0.3 mmol x L[-1]), serum apo A1 (mean difference v placebo, 0.03 g x L(-1); 95% CI, -0.04 to 0.1 g x L[-1]), and serum lipoprotein(a) ([Lp(a)] acipimox v placebo, 154 (0 to 1,574) v 71 (0 to 1,009), median and range) were unchanged. Despite the lack of change in fasting plasma NEFA levels, acipimox caused a modest beneficial improvement in overall glycemic control and plasma lipids in NIDDM patients and could be a useful agent in the treatment of dyslipidemic NIDDM patients.     

Maternal country of origin and infant birthplace: implications for birth-weight

Insulin-dependent diabetes mellitus (IDDM) is characterized by altered composition of atherogenic lipoproteins, especially a depletion in choline-containing phospholipids (PL) of apolipoprotein (apo) B lipoproteins (LpB). To determine the effects of continuous intraperitoneal (IP) insulin infusion (CIPII) on this qualitative lipoprotein abnormality, we compared lipoprotein profiles of 14 IDDM patients treated by continuous subcutaneous insulin infusion (CSII) and at 2 and 4 months after treatment with CIPII using an implantable pump. IDDM patients were in fair metabolic control and were compared with 14 healthy control subjects matched for sex, age, body mass index, and plasma lipids. The following parameters were studies: hemoglobin A1c (HbA1c), monthly blood glucose, daily insulin dose (units per kilogram per day), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, apo A-I, and apo B. Choline-containing PL were assessed in plasma and in apo B- and no-apo B-containing lipoprotein particles (LpB and Lp no B). As compared with the control group, plasma PL and LpB-PL were significantly lower in IDDM patients treated by CSII (2.95 +/- 0.26 v 3.30 +/- 0.45 mmol/L,P<.05, and 1.09 +/- 0.45 v 1.68 +/- 0.33 mmol/L,P<.01, respectively). No significant differences were observed for Lp no B lipid determinations between both groups. After initiation of CIPII, IDDM patients did not experience any significant changes in mean values for body mass index, HbA1c, and monthly blood glucose throughout the study. Daily insulin doses were identical to those observed before IP therapy. Lipid parameters remained unchanged in IDDM patients (TC, TG, HDL and LDL cholesterol, apo A-I, and apo B). A moderate but progressive elevation of plasma PL was noted, and after 4 months of CIPII, PL and LpB-PL levels were no longer significantly different between IDDM patients and controls. The increase in plasma and LpB choline-containing PL observed after 2 and 4 months of CIPII is not linked to changes in blood glucose control, body weight or daily insulin requirements. These changes may be related to the route of insulin administration, which may be accompanied by a reduction of lipoprotein lipase (LPL) activity and consequently a reduction of phospholipase activity. These results suggest that IP insulin delivery may be a more physiological route that increases the choline-containing PL content of LpB particles.     

Effect of 14 days'' subcutaneous administration of the human amylin analogue, pramlintide (AC137), on an intravenous insulin challenge and response to a standard liquid meal in patients with IDDM

Individuals with insulin-dependent diabetes mellitus (IDDM or type 1 diabetes) are deficient in both insulin and amylin, peptides secreted by the beta cell. We have investigated the effects of amylin replacement therapy employing the human amylin analogue, pramlintide (25, 28, 29-pro-human amylin, previously referred to as AC137), upon the responses to a standardized insulin infusion (40 mU. kg-1. h-1) for 100 min and a liquid Sustacal meal (360 kcal) in 84 healthy IDDM patients. Following baseline evaluations, patients were randomly assigned to receive subcutaneous injections of placebo, 30, 100 or 300 micrograms pramlintide 30 min before meals for 14 days. There was no meaningful difference between adverse events reported by the 30-micrograms pramlintide and the placebo groups, but ten subjects withdrew due to nausea, eight of these in the 300-micrograms dose group. Peak plasma pramlintide concentrations for the 30-micrograms group were 21 +/- 3 and 29 +/- 5 pmol/l on Days 1 and 14, respectively. These values are similar to postprandial plasma amylin concentrations in normal volunteers. The plasma glucose, free insulin, glucagon, epinephrine and norepinephrine concentrations during the insulin infusion test before and after therapy were identical in each of the group. Prior to pramlintide therapy, Sustacal ingestion produced a 4.0-4.8 mmol/l rise in plasma glucose concentrations in each of the groups. Pramlintide therapy reduced postprandial hyperglycaemia as reflected by the 3-h incremental AUCglucose (AUCglucose above or below fasting glucose concentration) Day 1 vs Day 14: 30 micrograms, 322 +/- 92 vs -38 +/- 161 mmol/l.min, p = 0.010; 100 micrograms, 317 +/- 92 vs -39 +/- 76 mmol/l.min, p = 0.001; and 300 micrograms, 268 +/- 96 vs -245 +/- 189 mmol/l.min, p = 0.077. Thus, pramlintide therapy with these regimens did not appear to impair either in vivo insulin action or the counter-regulatory response to hypoglycaemia but did show a clear effect of blunting postprandial hyperglycaemia following a standardized meal.     

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.     

Metabolic abnormalities following heart transplantation in patients with idiopathic cardiomyopathy

The purpose of this study was to evaluate the risk factors for coronary artery disease associated with initiation of immunosuppressive therapy in patients with a pre-heart transplant diagnosis of idiopathic cardiomyopathy. This study was performed in 15 consecutive patients, mean +/- SEM age of 39 +/- 2 years, with a pre-operative diagnosis of idiopathic cardiomyopathy, who underwent cardiac transplantation at the Tri-Services General Hospital, Taipei, Taiwan, from July 1992 to June 1993. All patients were treated with cyclosporine, azathioprine and prednisolone, and the following measurements were performed prior to hospital discharge (mean +/- SEM) 36 +/- 3 days after successful transplantation: 1) fasting plasma lipid and lipoprotein concentrations; 2) plasma glucose and insulin concentrations in response to a 75 g oral glucose challenge; and 3) steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations in response to a continuous infusion of somatostatin, insulin, and glucose. Since the SSPI concentrations are similar in all individuals, the SSPG concentrations provide an estimate of the ability of insulin to stimulate glucose disposal. Only six of the patients had a normal oral glucose tolerance test and the following diagnoses were found in the remaining nine patients: not diagnised (n = 3), impaired glucose tolerance (n = 4), and non-insulin-dependent diabetes (n = 2). Plasma lipid and lipoprotein concentrations were also frequently abnormal in the heart transplant patients; eight of the 15 patients had a plasma cholesterol > 5 mmol/l, nine had a high density lipoprotein (HDL)-cholesterol concentration < 1 mmol/l, and nine had a ratio of total to HDL-cholesterol > 5.0. Finally, the SSPG concentration was greater than 11.0 mmol/l in eight of the 15 patients, a value rarely exceeded in healthy volunteers. In conclusion, significant metabolic abnormalities were present at discharge in patients who had undergone successful cardiac transplantation for idiopathic cardiomyopathy. These metabolic abnormalities were probably caused by the use of immunosuppressive drugs. Given the magnitude of these changes, it would seem prudent to initiate therapeutic programs in patients with cardiac transplants that are not simply aimed at preventing rejection, but also address the metabolic abnormalities associated with the immunosuppressive agents used to prolong allograft survival.     

Modification of postprandial hyperglycemia with insulin lispro improves glucose control in patients with type 2 diabetes

OBJECTIVE: Insulin lispro is a rapid-acting analog of human insulin that can be used to target the postprandial rise in plasma glucose. We designed an open-label randomized crossover study of type 2 diabetic patients with secondary failure of sulfonylurea therapy to determine whether improvement of postprandial hyperglycemia would affect total daily glucose control. RESEARCH DESIGN AND METHODS: Twenty-five type 2 diabetic patients who were poorly controlled on a maximum dose of sulfonylureas were studied in a university hospital clinical research center. In one arm of the study, patients continued therapy with maximum-dose sulfonylureas. In the other arm, patients used a combination therapy with insulin lispro before meals and sulfonylureas. After 4 months, patients were crossed over to the opposite arm. Fasting plasma glucose (FPG) and 1- and 2-h postprandial glucose (after a standardized meal), HbA1c, total, HDL, and LDL cholesterol, and triglyceride levels were measured at the end of each arm of the study. RESULTS: Insulin lispro in combination with sulfonylurea therapy significantly reduced 2-h postprandial glucose concentrations compared with sulfonylureas alone, from 18.6 to 14.2 mmol/l (P < 0.0001), and incremental postprandial glucose area from 617.8 to 472.9 mmol.min.1-1 (P < 0.0007). FPG levels were decreased from 10.9 to 8.5 mmol/l (P < 0.0001), and HbA1c values were reduced form 9.0 to 7.1% (P < 0.0001). Total cholesterol was significantly decreased in the lispro arm from 5.44 to 5.10 mmol/l (P < 0.02). HDL cholesterol concentrations were increased in the lispro arm from 0.88 to 0.96 mmol/l (P < 0.01). The patients weighed significantly more after lispro therapy than after sulfonylureas alone, but the difference was small in absolute terms (sulfonylurea therapy alone, 90.6 kg; lispro therapy, 93.8 kg; P < 0.0001). Two episodes of hypoglycemia (glucose concentrations, < 2.8 mmol/l) were reported by the patients while using lispro. CONCLUSIONS: Previously, it has not been possible to address the effect of treatment of postprandial hyperglycemia specifically. We have now shown that the treatment of postprandial hyperglycemia with insulin lispro markedly improves overall glucose control and some lipid parameters in patients with type 2 diabetes.     

Physiologic hyperinsulinemia enhances counterregulatory hormone responses to hypoglycemia in IDDM

We evaluated the effect of physiologic hyperinsulinemia (plasma insulin 329 +/- 62 vs 687 +/- 62 pmol/L) on counterregulatory hormone responses in 8 IDDM subjects studied during a 2-hour hypoglycemic clamp study with an equivalent degree of hypoglycemia (plasma glucose 3.1 +/- 0.1 and 3.0 +/- 0.1 mmol/L, respectively). Plasma epinephrine levels were increased by 71% during the last 60 minutes of hypoglycemia in the high insulin study (840 +/- 180 vs 1440 +/- 310 pmol/L, respectively p = 0.006). In addition, plasma cortisol and norepinephrine were also increased in the high insulin study (by 19% and 24% respectively, p < 0.01, for both). Plasma growth hormone and glucagon concentrations were not altered by high dose insulin infusion. In spite of increased epinephrine secretion, the glucose infusion rate required to maintain glucose was 2-fold greater in the high insulin study, and there was greater suppression of lipolysis in that group. We conclude that hyperinsulinemia may enhance counterregulatory hormone secretion in IDDM.     

Effects of sire, dam traits, calf traits, and environment on dystocia and subsequent reproduction of two-year-old heifers

This study examined the hypocholesterolemic effect and hormonal changes resulting from 30 d of supplementation with Vicia faba L. (field bean) flour of diets of young men (aged 18-21 y; n = 40) with borderline-high or high serum cholesterol values. All subjects (groups A-D) consumed the same basic diet. Additionally, volunteers in the control group (A) consumed 90 g control flour/d whereas those in the three bean groups received either 90 g cooked field bean flour (groups B and C) or 90 g raw field bean flour (group D) daily. Groups A and B included volunteers with borderline-high cholesterol values [5.2-6.2 mmol total cholesterol/L and 3.4-4.1 mmol low-density-lipoprotein (LDL) cholesterol/L]. Subjects in groups C and D had high serum cholesterol concentrations (total cholesterol > 6.2 mmol/L and LDL cholesterol > 4.1 mmol/L). After 30 d, serum glucose, insulin, triacylglycerol, total, LDL-cholesterol, and very-low-density-lipoprotein (VLDL)-cholesterol values were significantly lower than initial values in all subjects who consumed diets containing field bean flour (P < or = 0.0001, except for LDL-cholesterol concentrations in group C, for which P < or = 0.0007). Legume intake also resulted in a significant increase (P < or = 0.0001) in glucagon and high-density-lipoprotein cholesterol. Neither cortisol nor thyroid hormone values changed significantly. The results suggest that the hypocholesterolemic effect of field bean intake depends at least partly on a concomitant increase in glucagon and decrease in insulin values. The more marked reduction in triacylglycerol and VLDL-cholesterol concentrations in subjects who consumed raw field beans indicates a coparticipation of their thermolabile components.     

Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia

Low-density lipoprotein (LDL) apheresis is a potent treatment for patients with coronary heart disease and severe hereditary forms of LDL hypercholesterolemia not adequately responsive to drug treatment. Until now, the beneficial effect of aggressive reduction of LDL cholesterol by LDL apheresis on the course of coronary heart disease has been demonstrated in one 3-year study and several studies lasting 2 years. We now report on the clinical course, lipoprotein concentrations, coronary angiograms, and side effects in patients undergoing LDL apheresis for as long as 8.6 years. Thirty-four patients (21 men and 13 women) with coronary heart disease and heterozygous familial hypercholesterolemia (FH) not adequately responsive to lipid-lowering drugs received weekly (four patients biweekly) LDL apheresis for 4.6 +/- 2.6 years under diet and lipid-lowering drug therapy; after 0.5 to 3 years, simvastatin in the maximal tolerable dose was added. The baseline LDL cholesterol concentration was 6.9 +/- 1.6 mmol/L. Combined treatment in the steady state yielded a pretreatment and posttreatment LDL cholesterol concentration of 4.8 +/- 0.9 and 1.8 +/- 0.4 mmol/L, respectively. The calculated interval mean LDL cholesterol was 3.3 +/- 0.6 mmol/L. Evaluation of the coronary angiographies revealed a definite regression of coronary lesions in four patients (11.8%); in 19 patients, there was a cessation of progression. Two patients developed atheromatous lesions in bypass grafts (L.H., 60% stenosis; S.M., occlusion). Of 23 patients eligible for the scoring of anginal symptoms, five (21.7%) reported a reduction of the frequency and severity of angina pectoris. The mean coronary symptom score in 23 patients changed from 1.65 +/- 0.83 at baseline to 1.39 +/- 0.66 at the end of the study. During the whole observation period, we observed three sudden deaths, one nonfatal myocardial infarction, and five patients requiring hospital admission because of unstable angina pectoris, one of which was followed by a transluminal coronary angioplasty. Aggressive reduction of LDL cholesterol with combined LDL apheresis and drugs induced regression of coronary lesions in four of 34 patients and prevented progression in 29 patients for as long as 8.6 years. The effect on LDL and high-density lipoprotein (HDL) cholesterol and lipoprotein(a) [Lp(a)] was comparable with all three apheresis techniques. Therefore, no obvious difference between the three techniques was found regarding changes in coronary lesions.     

Alterations in glucose metabolism in patients with Alzheimer's disease

OBJECTIVE: To determine the alterations in glucose metabolism that occur in patients with Alzheimer's Disease (AD). DESIGN: Cross-sectional comparison of AD and healthy controls. SETTING: A University teaching hospital. PATIENTS: Healthy controls (n = 14, BMI: 24.9 +/- 0.5 kg/M2, age 73 +/- 1 years) and patients with AD (n = 12, BMI: 23.9 +/- 1.0 kg/M2, age 72 +/- 1 years). All controls and patients with AD had a normal history and physical examination, a negative family history of diabetes, and took no medications. MEASUREMENTS: All patients and controls underwent an assessment of their dietary intake and physical activity, a 3-hour oral glucose tolerance test (OGTT), and a 2-hour hyperglycemic glucose clamp study. RESULTS: Total caloric intake (AD: 27.1 +/- 1.3 kcal/kg/day; Control: 23.6 +/- 1.6 kcal/kg/day; P = ns) and intake of complex carbohydrates (AD: 5.9 +/- 0.4 kcal/kg/day; Control: 6.5 +/- 0.3 kcal/kg/day; P = ns) were not different between groups. Leisure time physical activity was greater in controls (AD: 2970 +/- 411 kcal/week; Control: 5229 +/- 864 kcal/week; P < 0.05). Patients with AD had higher fasting glucose (AD: 5.9 +/- 0.2 mmol/L; Control: 5.1 +/- 0.1 mmol/L; P < 0.01) and insulin (AD: 144 +/- 20 pmol/L; Control: 100 +/- 6 pmol/L; P < 0.05) values. In response to the OGTT, the area under the curve for glucose and insulin was similar in both groups. During the hyperglycemic clamp, steady-state glucose values were higher in the Alzheimer's patients (AD: 11.5 +/- 0.2 mmol/L; Control: 10.9 +/- 0.1 mmol/L, P < 0.01). First- and second-phase insulin responses were similar in each group. The insulin sensitivity index (units: mL/kg.min per pmol/L x 100), a measure of tissue sensitivity to insulin, was reduced in the patients with AD (AD: 0.59 +/- 0.06; Control: 0.79 +/- 0.07; P < 0.05). CONCLUSIONS: We conclude that early AD is characterized by alterations in peripheral glucose metabolism, which may relate, in part, to alterations in physical activity.     

Prolactin and beta-endorphin responses to hypoglycemia are reduced in well-controlled insulin-dependent diabetes mellitus

Several pituitary hormones, including corticotropin (ACTH), growth hormone (GH), prolactin, and beta-endorphin (but not thyrotropin, follicle-stimulating hormone, or luteinizing hormone), are released in response to hypoglycemia in normal subjects. In patients with insulin-dependent diabetes mellitus (IDDM), the degree of glycemic control is known to alter ACTH and GH responses to hypoglycemia. The current study was performed to examine the effect of glycemic control on prolactin and beta-endorphin responses to hypoglycemia in subjects with IDDM. We performed 3-hour stopped hypoglycemic-hyperinsulinemic clamp studies (12 pmol/kg/min) during which plasma glucose was decreased from 5.0 mmol/L to 2.2 mmol/L in steps of 0.6 mmol/L every 30 minutes in 20 subjects with uncomplicated IDDM (12 males and eight females; age, 26 +/- 2 years; IDDM duration, 10 +/- 1 years; body mass index, 23.6 +/- 0.6 kg/m2) and 10 healthy subjects (five males and five females aged 30 +/- 1 years). The 10 diabetic subjects in good glycemic control (mean hemoglobin A1 [HbA1], 7.5% +/- 0.3%; normal range, 5.4% to 7.4%) were compared with the 10 poorly controlled patients (mean HbA1, 12.6% +/- 0.5%; P < .001 v well-controlled diabetic group). During hypoglycemia, prolactin levels in the well-controlled diabetic group did not change (7 +/- 1 microgram/L at plasma glucose 5.0 mmol/L to 9 +/- 2 micrograms/L at plasma glucose 2.2 mmol/L), whereas prolactin levels increased markedly in the poorly controlled diabetic group (7 +/- 2 micrograms/L to 44 +/- 17 micrograms/L) and healthy volunteers (12 +/- 2 micrograms/L to 60 +/- 19 micrograms/L, P < .05 between IDDM groups). The plasma glucose threshold required for stimulation of prolactin secretion was 2.2 +/- 0.1 mmol/L in well-controlled IDDM, 3.0 +/- 0.4 mmol/L in poorly controlled IDDM, and 2.4 +/- 0.1 mmol/L in healthy subjects (P < .05 between IDDM groups). Responses in males and females were similar. The increase in beta-endorphin levels was also attenuated in well-controlled IDDM patients (4 +/- 1 pmol/L at plasma glucose 5.0 mmol/L to 11 +/- 4 pmol/L at plasma glucose 2.2 mmol/L) versus poorly controlled IDDM patients (5 +/- 1 pmol/L to 26 +/- 7 pmol/L) and healthy subjects (8 +/- 1 pmol/L to 56 +/- 13 pmol/L). The plasma glucose threshold required for stimulation of beta-endorphin release was again lower in well-controlled IDDM versus poorly controlled IDDM patients (2.2 +/- 0.1 v 3.0 +/- 0.3 mmol/L) and healthy subjects (2.5 +/- 0.4 mmol/L, P < .05 between IDDM groups). In conclusion, prolactin and beta-endorphin responses to a standardized hypoglycemic stimulus (plasma glucose, 2.2 mmol/L) are reduced and plasma glucose levels required to stimulate release of prolactin and beta-endorphin are lower in well-controlled IDDM compared with poorly controlled IDDM and healthy subjects. Thus, stress hormones not previously considered to have a primary role in plasma glucose recovery from hypoglycemia are affected by glycemic control, suggesting a more generalized alteration of hypothalamic-pituitary responses to hypoglycemia in IDDM patients with strict glycemic control.     

The role of reproductive factors and use of oral contraceptives in the aetiology of breast cancer in women aged 50 to 74 years

BACKGROUND: We examined the cholesterol-lowering effects of a proprietary Chinese red-yeast-rice supplement in an American population consuming a diet similar to the American Heart Association Step I diet using a double-blind, placebo-controlled, prospectively randomized 12-wk controlled trial at a university research center. OBJECTIVE: We evaluated the lipid-lowering effects of this red-yeast-rice dietary supplement in US adults separate from effects of diet alone. DESIGN: Eighty-three healthy subjects (46 men and 37 women aged 34-78 y) with hyperlipidemia [total cholesterol, 5.28-8.74 mmol/L (204-338 mg/dL); LDL cholesterol, 3.31-7.16 mmol/L (128-277 mg/dL); triacylglycerol, 0.62-2.78 mmol/L (55-246 mg/dL); and HDL cholesterol 0.78-2.46 mmol/L (30-95 mg/dL)] who were not being treated with lipid-lowering drugs participated. Subjects were treated with red yeast rice (2.4 g/d) or placebo and instructed to consume a diet providing 30% of energy from fat, <10% from saturated fat, and <300 mg cholesterol daily. Main outcome measures were total cholesterol, total triacylglycerol, and HDL and LDL cholesterol measured at weeks 8, 9, 11, and 12. RESULTS: Total cholesterol concentrations decreased significantly between baseline and 8 wk in the red-yeast-rice-treated group compared with the placebo-treated group [(x+/-SD) 6.57+/-0.93 mmol/L (254+/-36 mg/dL) to 5.38+/-0.80 mmol/L (208+/-31 mg/dL); P < 0.001]. LDL cholesterol and total triacylglycerol were also reduced with the supplement. HDL cholesterol did not change significantly. CONCLUSIONS: Red yeast rice significantly reduces total cholesterol, LDL cholesterol, and total triacylglycerol concentrations compared with placebo and provides a new, novel, food-based approach to lowering cholesterol in the general population.     

A pragmatic test of a simple calorimetric method for determining the fragility of some amorphous pharmaceutical materials

This study was performed in 36 healthy volunteers to define the relationship between plasma concentrations of partially oxidized low density lipoprotein (poxLDL), plasma glucose and insulin responses to oral glucose, and steady-state plasma glucose (SSPG) concentrations after a 180-minute infusion of somatostatin, insulin, and glucose. The concentration of poxLDL was estimated by determining the amount of conjugated dienes formed during in vitro LDL oxidation in the presence or absence of alanine. Under these conditions, the greater the in vitro antioxidant effect of alanine, the lower the amount of poxLDL that was present in plasma. The results demonstrated that plasma poxLDL concentration was significantly correlated with plasma glucose (r=.53, P<.001) and insulin (r=.43, P<.01) responses, SSPG concentrations (r=.53, P<.001), and plasma triglyceride (r=.42, P<.01) and HDL cholesterol (r=-.50, P<.002) concentrations. Furthermore, these relationships persisted when the data were corrected for differences in age, sex, body mass index, and the ratio of waist to hip girth. Of note, there was no correlation between poxLDL and LDL cholesterol concentration. When SSPG was entered along with age, sex, body mass index, and waist-to-hip ratio in a multiple regression model, SSPG alone was a significant prediction of poxLDL (r-=.37, P<.02). The addition of plasma glucose and insulin responses and triglyceride and HDL cholesterol concentrations increased the r2 to only .47. These results show that the amount of poxLDL in plasma is significantly correlated with insulin resistance (ie, SSPG) and its metabolic consequences.     

Improvement of lipid profile in type 2 (non-insulin-dependent) diabetes mellitus by insulin-like growth factor I

Type 2 (non-insulin-dependent) diabetes mellitus is associated with increased glucose, insulin, total and VLDL-triglyceride, and often total and LDL-cholesterol levels which promote vascular disease. Recombinant human insulin-like growth factor-I which mimics many effects of insulin, decreased insulin, total and VLDL-triglyceride, and total and LDL-cholesterol levels in healthy man as well as glucose and insulin levels in Type 2 diabetic patients. We, therefore, investigated total and fractionated triglyceride and cholesterol levels, lipoprotein(a), non-esterified fatty acid, and apolipoprotein levels in eight Type 2 diabetic patients during five control, five treatment, and three wash-out days. They received a constant diet throughout and daily 2 x 120 micrograms insulin-like growth factor-I/kg s.c. during the treatment period. Fasting total and VLDL-triglyceride, total and LDL-cholesterol control levels were (mean +/- SD) 3.1 +/- 2.6, 1.3 +/- 1.0, 6.3 +/- 1.3, and 4.5 +/- 1.1 mmol/l and decreased to 1.6 +/- 0.8, 0.6 +/- 0.4, 5.0 +/- 1.0, and 3.5 +/- 1.1 mmol/l, respectively, on the last treatment day (p < 0.01). During therapy, fasting lipoprotein(a) levels and the postprandial area under the triglyceride curve decreased by 48 +/- 22 and 32 +/- 18% of control (p < 0.01), respectively. In conclusion, insulin-like growth factor-I lowered lipid levels in Type 2 diabetic patients directly or indirectly or both because of decreased glucose and insulin levels. Long-term trials would be of interest with respect to the cardiovascular risk in Type 2 diabetes and patients with hyperlipidaemia.     

The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity

OBJECTIVE: To investigate the metabolic effects of losartan (Cozaar) in patients with essential hypertension. METHODS: Twenty patients with mild hypertension (office blood pressure > 140/95 mmHg and home diastolic blood pressure > 90 mmHg) were examined in a double-blind, placebo-controlled cross-over study of 4 weeks of treatment with 50-100 mg losartan. The effects on glucose metabolism were assessed by euglycaemic glucose clamp examinations [glucose disposal rate (GDR, mg/kg per min)] and oral glucose-tolerance tests (OGTT). RESULTS: Supine blood pressure was reduced from 146 +/- 3/90 +/- 3 mmHg on placebo to 134 +/- 4/83 +/- 3 mmHg on losartan and the difference was maintained during 120 min of insulin infusion and glucose clamping. GDR was 6.2 +/- 0.5 mg/kg per min on placebo and 6.4 +/- 0.5 mg/kg per min on losartan. The glucose and insulin responses (the area under the curve) during OGTT were similar with placebo and losartan (0.86 +/- 0.3 versus 0.88 +/- 0.4 and 341 +/- 60 versus 356 +/- 60, respectively; arbitary units). Serum cholesterol was 5.3 +/- 0.2 mmol/l on placebo and 5.1 +/- 0.2 mmol/l losartan treatment. High-density lipoprotein cholesterol and triglycerides were, respectively, 1.1 +/- 0.1 and 1.5 +/- 0.2 mmol/l with placebo, and 1.1 +/- 0.1 and 1.4 +/- 0.1 mmol/l with losartan treatment. CONCLUSION: In mildly hypertensive patients, selective angiotensin II receptor antagonism with losartan for 4 weeks lowers blood pressure at rest and during 120 min of glucose clamping, and has neutral effects on insulin sensitivity, glucose metabolism and serum lipids.