Relationship between lipoprotein levels and in vivo insulin action in normal young white men

In epidemiologic studies, hyperinsulinemia has been found to be an independent risk factor for coronary heart disease (CHD). However, the mechanisms responsible for its role in atherogenesis remain unclear. We studied the relationship of in vivo insulin action and plasma lipids and lipoproteins in 44 normotriglyceridemic white men (aged 18 to 34 years). The euglycemic, hyperinsulinemic glucose clamp technique was used to quantitate insulin-mediated glucose disposal (M/I value) at a plasma insulin concentration of approximately 100 microU/mL. The M/I value correlated negatively with plasma triglycerides (r = -0.553, P less than .0001), as well as with fasting plasma insulin levels (r = -0.483, P less than .001), independent of age, body mass index, and fasting plasma glucose levels. A negative correlation of the M/I value was also observed with very low density lipoprotein (VLDL)-cholesterol (r = -0.347, P less than .05), VLDL-triglycerides (r = -0.474, P less than 0.005), and total cholesterol/high density lipoprotein (HDL)-cholesterol ratio (r = -0.431, P less than .01). The relationship between the M/I value and the total cholesterol/HDL-cholesterol ratio was independent of VLDL-cholesterol and VLDL-triglycerides, however, not independent of plasma triglycerides. No relationship was observed between insulin-mediated glucose uptake and total cholesterol, low density lipoprotein (LDL)-cholesterol, and HDL-cholesterol values. Individual differences in plasma triglycerides, fasting insulin concentration, and the total cholesterol/HDL-cholesterol ratio accounted for about half the variance observed in the M/I value.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term treatment of hypercholesterolemic non-insulin dependent diabetics (NIDDM) with pravastatin (CS-514)

We examined the long-term effect of pravastatin, a new potent inhibitor of endogenous cholesterol biosynthesis, on glucose and lipid metabolism in hyperlipidemic NIDDM. Ten patients (5 on sulfonylurea, 5 on diet) were studied over 12 months. Five were WHO type IIa and 5 were type IIb. Blood was taken before and then 1, 6 and 12 months after initiating 10 or 20 mg daily of pravastatin. The cholesterol concentration in whole plasma and very low density lipoprotein (VLDL), plasma triglyceride and apolipoprotein (apo) B were all significantly decreased within the first month. These changes lasted for 1 year. High density lipoprotein (HDL)-cholesterol increased in the first month but returned to base line thereafter. Low density lipoprotein (LDL)-cholesterol tended to decrease in the first month, and was suppressed significantly from the 6th month (11%) to the 12th month (16%). The effect of pravastatin on LDL-cholesterol in NIDDM was slower and weaker than that published for non-diabetic hypercholesterolemia. Therefore, the mechanism by which pravastatin suppresses plasma cholesterol levels in these two conditions may differ. After 1 year, no adverse effects were noted on hematopoietic, hepatic or renal function. Blood glucose level, hemoglobin A1c and the insulin response to oral glucose were unchanged. In addition, serum creatine phosphokinase showed no abnormal increase. Careful ophthalmological examinations before and after pravastatin treatment revealed no development of new lenticular opacities. Thus, pravastatin appears to be a safe and effective drug for the long-term treatment of NIDDM with hypercholesterolemia.     

Plasma lipoprotein alterations in squirrel monkeys (Saimiri sciureus) during ethanol administration and abstinence

The time course of lipoprotein changes during ethanol (EtOH) consumption followed by abstinence was examined in 3 groups of male squirrel monkeys: 1) controls fed isocaloric liquid diet; 2) low EtOH monkeys given liquid diet with vodka substituted isocalorically for carbohydrate at 12% of calories; and 3) high EtOH animals fed diet plus vodka at 24% of calories. After 2 weeks, high EtOH monkeys showed significant elevations in total plasma cholesterol which continued to increase at 4 weeks and then declined at 8 weeks. These elevations were the result of increases in both low density (LDL)- and high density lipoprotein (HDL)-cholesterol. Low EtOH monkeys had a modest increase in total cholesterol throughout 8 weeks which was attributed to increments in HDL-cholesterol alone. During abstinence, total, HDL- and LDL-cholesterol concentrations decreased rapidly in the high EtOH group and were similar to control values after 4 days. HDL-cholesterol showed a more gradual decline in animals fed 12% EtOH while LDL-cholesterol remained low and not significantly different from controls. Liver function tests were normal for all animals. Our results indicate that low-dose EtOH favors a coronary protective lipoprotein profile (increases HDL, decreases LDL) in squirrel monkeys while the higher alcohol regimen causes both favorable and unfavorable alterations in plasma lipids which quickly revert to control levels during abstinence.     

Relationship between plasma insulin levels and high density lipoprotein cholesterol levels in healthy men

Summary Insulin and high density lipoproteins are considered to play a role in the development of atherosclerosis. In order to study whether there was a relationship between endogenous plasma insulin response and high density lipoproteins, an acute intravenous glucose tolerance test (0.5 g glucose/kg body weight) was performed in 94 healthy men, aged 20–49 years. Cholesterol and triglyceride levels were measured in very low density lipoproteins, low density lipoproteins and high density lipoproteins isolated from fasting serum by preparative ultracentrifugation. The subjects were divided into quartiles according to their fasting and post-glucose load plasma insulin and high density lipoprotein cholesterol levels. The results obtained in the subjects of the upper quartiles were compared with the results obtained in the subjects of the lower quartiles. The mean glucose disappearance rates were within the normal range and did not differ between the upper and lower quartiles. Subjects with high fasting plasma insulin had lower high density lipoprotein cholesterol levels (1.11±0.34 mmol/l, p=0.01) than men with low fasting plasma insulin (1.40±0.37 mmol/l). Higher mean post-glucose plasma insulin was associated with lower high density lipoprotein cholesterol levels (1.18±0.32 mmol/l, p<0.05) and increased high density lipoprotein triglyceride levels (0.14±0.07 mmol/l, p<0.01) when compared with the men with low post-glucose plasma insulin (1.40±0.36 mmol/l and 0.09±0.03 mmol/l respectively). These observations reflect the close relationship between endogenous insulin and lipoprotein metabolism.     

Effect of different insulin regimens on plasma lipoprotein and apolipoprotein concentrations in patients with non-insulin-dependent diabetes mellitus

The effect of insulin treatment with 2 different insulin regimens on the plasma concentrations of lipoproteins and apolipoproteins A1 and B was studied in 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) and secondary failure to oral hypoglycaemic agents. The investigation was performed as a randomized crossover study with treatment periods of 8 weeks. Insulin was given either as mainly intermediate acting insulin before breakfast and dinner (2-dose insulin) or as regular insulin preprandially with intermediate acting insulin at bedtime (4-dose insulin). A similar improvement in glycaemic control was obtained with both insulin regimens. On treatment with oral agents the patients were found to have higher total plasma triglycerides and lower plasma high density lipoprotein (HDL) cholesterol than a matched non-diabetic control group. Insulin treatment almost completely normalized these lipid disturbances by reducing mean total plasma triglycerides with 36% and increasing plasma HDL cholesterol with 20% on 2-dose and 17% on 4-dose. The triglyceride concentration in the very low density lipoprotein (VLDL) fraction was reduced. Mean plasma low density lipoprotein (LDL)-cholesterol was not affected by any treatment. There was an increase of similar magnitude in both HDL2 and HDL3 concentrations but only the change in the HDL3 subfraction was statistically significant. Mean plasma apolipoprotein A1 concentration increased with 9% (P less than 0.05) while there was no significant change in the plasma apolipoprotein B concentration. The changes in the plasma concentrations of lipoproteins and apolipoproteins A1 and B were almost identical on 2- and 4-dose insulin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of exogenous hyperinsulinaemia on atherogenesis in cholesterol-fed rabbits

Summary To examine the hypothesis that hyperinsulinaemia promotes atherosclerosis, cholesterol-fed rabbits were injected subcutaneously with 6 IU of human insulin (n = 16) or placebo (n = 20) daily for 24 weeks; injection of insulin resulted in hyperinsulinaemia for up to 16 h after injection. Compared to placebo rabbits, insulin-treated rabbits had higher levels of insulin antibodies in plasma, similar levels of intermediate density, low density and high density lipoprotein cholesterol and similar activities of hepatic and lipoprotein lipase in post-heparin plasma, but lower levels of plasma C-peptide, blood glucose, postprandial plasma triglycerides, plasma cholesterol and very low density lipoprotein cholesterol. On univariate analysis, with and without adjustment for differences in plasma cholesterol levels between the two groups, there were no significant differences in extent or severity of atherosclerosis between insulin and placebo rabbits. Furthermore, after combining the results from all the rabbits to examine plasma insulin levels and the other variables mentioned above as predictors of atherosclerosis severity, plasma insulin level was not a predictor, on univariate or multiple linear regression analysis; the first ranked independent predictors were postprandial intermediate density lipoprotein cholesterol in the arch, and postprandial plasma triglyceride in both the thoracic and abdominal aorta. These results suggest that exogenous hyperinsulinaemia does not promote atherogenesis in cholesterol-fed rabbits, but that postprandial levels of intermediate density lipoprotein cholesterol or plasma triglycerides may be involved in atherogenesis. [Diabetologia (1997) 40: 512–520] Received: 10 October 1996 and in revised form: 28 January 1997     

Associations of lecithin: cholesterol acyltransferase (LCAT) mass concentrations with exercise, weight loss, and plasma lipoprotein subfraction concentrations in men

The relationships between plasma lecithin:cholesterol acyltransferase (LCAT) mass concentrations and lipids, apolipoprotein, and lipoprotein subfraction concentrations were studied in men assigned at random to a one-year exercise program (n = 48) and to a sedentary control condition (n = 31). Exercise training did not significantly affect mean concentrations of LCAT-mass. Moreover changes in LCAT within the exercise group were unrelated to distance run and weight loss. The baseline data and the one-year change data showed consistent positive correlations between LCAT concentrations and total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, and apolipoprotein B concentrations, and consistently weak correlations between LCAT concentrations and high density lipoprotein (HDL)-cholesterol, HDL2, and apolipoprotein A-I concentrations. The strong correlation between LCAT and total cholesterol may account for LCAT's relationships with lipoprotein subfractions, apolipoprotein B and other lipoprotein cholesterol concentrations.     

Plasma glucose, insulin and lipid responses to high-carbohydrate low-fat diets in normal humans

Two levels of dietary carbohydrate (40% and 60% of calories) were incorporated into typical U.S. diets and fed for 10 days each to 11 healthy volunteers. Fasting blood samples were drawn on days 8, 9, and 10 of each dietary period and analyzed for glucose, insulin, cholesterol, triglyceride (TG) and high density lipoprotein (HDL)-cholesterol concentrations. In addition, plasma glucose, insulin and TG concentrations were determined before, and for 3 hr after the noon meal on days 8 and 10. No differences were observed in fasting plasma glucose, insulin or cholesterol concentrations. However, fasting plasma TG levels were significantly elevated on the 60% carbohydrate diet, and HDL-cholesterol concentrations were significantly decreased. Furthermore, the plasma insulin and triglyceride responses to the meal tolerance test during the 60% carbohydrate dietary period were significantly elevated. These results indicate that high-carbohydrate diets lead to changes in insulin, TG, and HDL-cholesterol concentrations which have been associated with an increase in incidence of coronary artery disease.     

Effect of fish oil treatment on plasma lipoproteins in type III hyperlipoproteinaemia

Nine patients with type III hyperlipoproteinaemia and homozygosity for the apolipoprotein E2 isoform were treated with 15 g daily of MaxEPA, a fish oil preparation rich in eicosapentaenoic acid (2.7 g daily) and docosahexaenoic acid (1.8 g daily) for 16 weeks. Plasma lipoprotein and apolipoprotein concentrations were compared with those obtained during treatment with an olive oil preparation. MaxEPA treatment decreased plasma median total cholesterol, triglyceride and apolipoprotein B concentrations by 16, 53 and 19%, respectively. Plasma median very low density lipoprotein (VLDL)-cholesterol, triglyceride and apolipoprotein B concentrations were reduced by 45, 62 and 75% respectively, while the abnormal VLDL-cholesterol/triglyceride ratio remained unchanged. Individual reductions of VLDL concentrations varied considerably, for VLDL-cholesterol between 10 and 75%. In the majority of cases the abnormal late pre beta-bands on agarose electrophoresis, typical for type III hyperlipoproteinaemia normalized to pre beta-mobility on MaxEPA treatment. LDL-cholesterol and apolipoprotein B tended to increase after 8 weeks on MaxEPA but decreased again after 16 weeks. Median plasma high density lipoprotein cholesterol and apolipoprotein A-I did not change during MaxEPA treatment. It is concluded that MaxEPA have decreasing effects on plasma VLDL lipid and apolipoprotein concentrations in apolipoprotein E2 homozygous type III hyperlipoproteinaemia but that this effect is variable and unpredictable.     

Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with metformin

Background: Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin, whereas the combination of metformin with thiazolidinediones is relatively less studied. The aim of the present study was to assess the differential effect on glycaemic metabolism and lipid variables of the combination of metformin plus pioglitazone or metformin plus rosiglitazone in diabetic patients with metabolic syndrome. Methods: All patients began metformin and were randomized to receive pioglitazone or rosiglitazone for 12 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, homeostasis model assessment index, total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, apolipoprotein A‐I, and apolipoprotein B. Results: Significant decreases in glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, and postprandial plasma insulin were seen after 9 and 12 months in both groups. Homeostasis model assessment index improved at 12 months in both groups. Significant total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, apolipoprotein A‐I, and apolipoprotein B improvement was observed in pioglitazone group after 12 months, but not in the rosiglitazone group. These variations were significant between groups. Conclusion: The combination of metformin plus thiazolidinediones was able to improve glycaemic control compared with previous therapy. Pioglitazone was associated with a significant improvement in lipid and lipoprotein variables.     

Reduced plasma high density lipoprotein-cholesterol concentrations need not increase when hyperglycemia is controlled with insulin in noninsulin-dependent diabetes mellitus

The ability of intensive insulin treatment to increase plasma high density lipoprotein (HDL)-cholesterol levels was evaluated in 12 patients with noninsulin-dependent diabetes mellitus. Patients were treated for 6 weeks with one daily morning injection of ultralente insulin, in combination with administration of regular insulin before breakfast, lunch, and dinner. The mean (+/- SEM) fasting plasma glucose concentration fell from 289 +/- 21 to 122 +/- 9 mg/dl (P less than 0.001), and the mean hourly postprandial glucose concentration fell from 313 +/- 24 to 102 +/- 7 mg/dl (P less than 0.001). In addition, insulin treatment was associated with a reduction in both fasting plasma triglyceride (256 +/- 45 to 137 +/- 18 mg/dl; P less than 0.001) and cholesterol (224 +/- 25 to 199 +/- 19 mg/dl; P less than 0.05) concentrations. However, plasma HDL-cholesterol concentrations, which were low to begin with, did not rise in association with excellent glycemic control. These results demonstrate that hyperglycemia and hypertriglyceridemia can be effectively reduced by an aggressive program of insulin treatment in patients with noninsulin-dependent diabetes mellitus, but this intervention need not lead to an improvement in the abnormal HDL-cholesterol metabolism in these patients.     

Plasma lipids in beta-thalassemia minor

Because total cholesterol levels have been found to be lower in patients affected by thalassemia major and intermedia, we examined the plasma lipid pattern of 628 beta-thalassemia trait carriers and 4552 controls in order to evaluate whether the plasma lipid impairment is also present in the heterozygous state. Total cholesterol and low density lipoprotein (LDL)-cholesterol levels were significantly lower in beta-thalassemia trait carriers when compared to controls, whereas plasma triglycerides and high density lipoprotein (HDL)-cholesterol levels did not differ between the two groups. We suggest that accelerated erythropoiesis and increased uptake of LDL by macrophages and histiocytes of the reticuloendothelial system are the main determinants of low plasma cholesterol levels in heterozygous thalassemia.     

Hyperglycemia in normotriglyceridemic, hypercholesterolemic insulin-treated diabetic rabbits does not accelerate atherogenesis

Severely hyperlipidemic alloxan-diabetic cholesterol-fed rabbits were treated with different daily doses of insulin in order to study the effect of insulin on plasma lipids, lipoproteins and postheparin lipoprotein lipase activity. At plasma triglyceride levels of 15,000 mg/dl, untreated diabetic rabbits carried 73% (1950 mg/dl) of plasma total cholesterol in lipoproteins with a diameter larger than 75 nm (Sf greater than 400), 25% in smaller very low density lipoproteins (VLDL) and 1% in both low and high density lipoproteins (LDL, HDL). Insulin treatment greatly reduced plasma total cholesterol and triglyceride concentrations. The decrease of plasma total cholesterol concentration was paralleled by a decrease in the cholesterol of the largest lipoproteins (Sf greater than 400) and an increase in cholesterol of both smaller very low density lipoproteins and low density lipoproteins. At the same time, postheparin plasma lipoprotein lipase activity increased 2-8-fold. When plasma triglyceride levels were normalized by insulin treatment, the lipoprotein cholesterol distribution in diabetic cholesterol-fed rabbits was similar to that of normal cholesterol-fed rabbits. To study development of atherosclerosis, diabetic rabbits were cholesterol-fed and treated with insulin for eight weeks such that the triglyceride levels were normalized, but plasma glucose levels were still greatly elevated. Nondiabetic rabbits were cholesterol-fed simultaneously. Plasma cholesterol and triglyceride levels were similar in the two groups of rabbits, as well as cholesterol in Sf greater than 400 or smaller VLDL and cholesterol in HDL. However, LDL-cholesterol concentration in the insulin-treated diabetic rabbits was 1.5-2 times that in the nondiabetic rabbits. The two groups of rabbits developed similar degrees of atherosclerosis, as judged by aortic cholesterol content. Apparently, partially controlled diabetes in cholesterol-fed rabbits does not accelerate atherogenesis beyond that observed in nondiabetic cholesterol-fed rabbits.     

The effect of fluvastatin on plasma adiponectin levels in dyslipidaemia

OBJECTIVE: There is controversy about the effects of statins on insulin resistance and plasma adiponectin. The aim of this study was to investigate the effects of fluvastatin treatment on these parameters in a group of dyslipidaemic patients who had no confounding factors for insulin resistance or alterations in plasma adiponectin. DESIGN AND PATIENTS: Forty-nine patients [27 males, 22 females; mean age 47.2 +/- 10.3 years; body mass index (BMI) 29.64 +/- 3.2 kg/m2] with dyslipidaemia and 20 controls (six males, 14 females; mean age 45.3 +/- 9.31 years; BMI 30.07 +/- 4.04 kg/m2) were enrolled. All patients were treated initially with therapeutic lifestyle changes (TLC) for 6 weeks. Six out of 49 subjects were excluded from the study. Then, 24 out of 43 patients with high blood cholesterol despite TLC were allocated to fluvastatin 80 mg daily plus TLC, and the remaining 19 patients with normal cholesterol were subjected to TLC alone for additional 12 weeks. MEASUREMENTS: Plasma adiponectin, immunoreactive insulin levels, BMI, waist circumference, blood pressure, lipids, and glucose were determined. The insulin sensitivity index was quantified using the homeostasis model assessment (HOMA). RESULTS: TLC caused significant improvement in plasma insulin (P = 0.02) and elevation in plasma adiponectin (P = 0.02). Fluvastatin treatment decreased total cholesterol and low density lipoprotein (LDL)-cholesterol significantly (P = 0.01 and P = 0.02, respectively). No significant effect of fluvastatin was observed on plasma insulin or adiponectin or on the HOMA index. CONCLUSIONS: Fluvastatin does not improve plasma adiponectin levels and insulin sensitivity, despite its beneficial effects on lipid levels. Our data, however, were limited by the fact that a more accurate method of assessing insulin sensitivity, the euglycaemic-hyperinsulinaemic glucose clamp technique, was not used.     

Effect of Nicardipine Treatment on Carbohydrate and Lipoprotein Metabolism in Patients with Hypertension

This study evaluated the effect of nicardipine, calcium channel blocker, monotherapy on blood pressure and metabolic changes. Various aspect of carbohydrate and lipoprotein metabolism were studied before and after 12 weeks of nicardipine treatment in 23 patients with mild to moderate essential hypertension. Nicardipine was well tolerated and induced a significant decrease (p<0.001) in both systolic and diastolic blood pressure without any changes in heart rate. Plasma levels of fasting glucose, insulin, C-peptide and hemoglobin A 1 c, hepatic extraction of insulin were similar following nicardipine treatment. Plasma glucose and insulin responses to an oral glucose challenge did not change in association with nicardipine therapy. Although high density lipoprotein (HDL) cholesterol concentration increased slightly, it did not reach statistical significance. Total cholesterol and low density lipoprotein (LDL) cholesterol levels also increased insignificantly. LDL triglyceride and very low density lipoprotein (VLDL) triglyceride concentrations were higher marginally, which resulted in slightly but insignificantly increase in total triglyceride concentration in association with nicardipine monotherapy for 12 weeks. In conclusion, treatment of patients with mild to moderate hypertension with nicardipine led to lower blood pressure effectively while had no significant influence on carbohydrate and lipoprotein metabolism.     

Effect of high-carbohydrate-low-fat diets on plasma glucose,insulin and lipid responses in hypertriglyceridemic humans

Two levels of dietary carbohydrate (40% and 60% of calories) were incorporated into typical US diets and fed for 15 days each to eight patients with endogenous hypertriglyceridemia. Fasting blood samples were drawn on days 13, 14, and 15 of each dietary period, and analyzed for glucose, insulin, cholesterol, and triglyceride concentrations, as well as for triglyceride and cholesterol content of the various lipoprotein classes. In addition, these same measurements were made before and for three hours after the noon meal on days 14 and 15. Fasting plasma triglyceride (TG) and very-low-density lipoprotein (VLDL)-TG concentrations were significantly increased (P < 0.005) on the low-fat-high-carbohydrate diet. In addition, integrated postprandial insulin, TG, and VLDL-TG responses to the noon meal were significantly (P < 0.01?0.001) elevated on the low-fat-high-carbohydrate diet. No dietary-induced changes were noted in either the fasting or postprandial values of glucose cholesterol, chylomicron-TG, low-density lipoprotein-cholesterol, high-density lipoprotein (HDL)-cholesterol, HDL₂-cholesterol, or HDL₃-cholesterol. These results indicate that low-fat-high-carbohydrate diets accentuate the metabolic risk factors for coronary artery disease that are already present in patients with endogenous hypertriglyceridemia.     

Effect of colesevelam hydrochloride on glycemia and insulin sensitivity in men with the metabolic syndrome

Colesevelam hydrochloride (colesevelam) lowers low-density lipoprotein (LDL) cholesterol and glycated hemoglobin in patients with type 2 diabetes mellitus. The present study examined the effects of colesevelam treatment in nondiabetic men with metabolic syndrome. Twenty men completed the study, which consisted of two 8-week phases of treatment with colesevelam (3.75 g/day) or placebo and a 6-week washout between study phases. Of the 20 men, 17 took statins throughout. The fasting plasma LDL cholesterol, triglyceride, glucose, and glycated hemoglobin levels were measured in the last 2 weeks of each study phase. Nonesterified fatty acids and 3-hydroxybutyrate, insulin, and glucose were measured hourly for 5 hours during fasting and during an extended glucose tolerance test. The colesevelam treatment reduced LDL cholesterol from 96 ± 28 mg/dl to 78 ± 32 mg/dl (p <0.006) and non-high-density lipoprotein cholesterol by 8.2% (p = 0.07). Triglycerides increased by 17% (p <0.02). The fasting plasma glucose was reduced by 5 mg/dl (p <0.03), and glycated hemoglobin remained unchanged by colesevelam. No significant treatment changes were noted for the 2-hour glucose test or insulin sensitivity. The fasting nonesterified fatty acid level was significantly reduced with treatment but the 3-hydroxybutyrate level was unchanged. Insulin-mediated suppression of nonesterified fatty acids during extended glucose tolerance test was significantly less effective during treatment than during placebo. In conclusion, colesevelam significantly reduced the LDL cholesterol levels, even though the baseline LDL cholesterol level was low owing to statin treatment. The fasting and postprandial blood glucose level but not the glycated hemoglobin level was lowered by colesevelam therapy. The effect on fasting glucose was unrelated to the changes in insulin resistance or fatty acid oxidation. Finally, an increase in triglycerides with colesevelam therapy might have been related to a lesser suppression of nonesterified fatty acids levels in the postprandial state.     

Beyond fasting plasma glucose: The association between coronary heart disease risk and postprandial glucose,postprandial insulin and insulin resistance in healthy,nondiabetic adults

Objective

Prediabetes is defined by elevations of plasma glucose concentration, and is aimed at identifying individuals at increased risk of type 2 diabetes and coronary heart disease (CHD). However, since these individuals are also insulin resistant and hyperinsulinemic, we evaluated the association between several facets of carbohydrate metabolism and CHD risk profile in apparently healthy, nondiabetic individuals.

Methods

Plasma glucose and insulin concentrations were measured before and at hourly intervals for eight hours after two test meals in 281 nondiabetic individuals. Insulin action was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. CHD risk was assessed by measurements of blood pressure and fasting lipoprotein profile.

Results

For purposes of analysis, the population was divided into tertiles, and the results demonstrated that the greater the 1) fasting plasma glucose (FPG) concentration, 2) incremental plasma insulin response to meals, and 3) SSPG concentration, the more adverse the CHD risk profile (p < 0.05). In contrast, the CHD risk profile did not significantly worsen with increases in the incremental plasma glucose response to meals.

Conclusions

In nondiabetic individuals, higher FPG concentrations, accentuated daylong incremental insulin responses to meals, and greater degrees of insulin resistance are each associated with worse CHD risk profile (higher blood pressures, higher triglycerides, and lower high density lipoprotein cholesterol concentrations). Interventional efforts aimed at decreasing CHD in such individuals should take these abnormalities into consideration.     

Low dose continuously infused growth hormone results in increased lipoprotein(a) and decreased low density lipoprotein cholesterol concentrations in middle-aged men

OBJECTIVE Animal studies have shown that slight increases in basal GH concentrations may result in changes in lipoprotein metabolism. Such changes in GH secretion have been observed in physiological and pathophysiological states such as fasting, uncontrolled diabetes and during oestrogen treatment. The aim of this study was to investigate the possible effects of increases in basal plasma GH concentrations on lipoprotein concentrations. DESIGNS Recombinant human growth hormone (rhGH) was given as a continuous subcutaneous infusion in a low dose (0.02 U/kg/day) in an open study. PATIENTS Eight middle-aged (42–59 years) overweight (body mass index: 26.1–33.8 kg/m²) but otherwise healthy men were studied over a period of 14 days. MEASUREMENTS Blood samples were obtained after an over-night fast before and after 2, 7 and 14 days of treatment. Plasma and serum were separated and used for subsequent measurements of hormone and lipoprotein concentrations. On days 0, 7 and 14 of treatment, post-heparin plasma was also obtained for determinations of plasma lipoprotein lipase and hepatic lipase activities. In addition, a hyperinsuiinaemic euglycaemic glucose clamp was performed on days 0 and 13 of the study. Fat biopsies from abdominal and gluteal fat depots were obtained for measurement of lipoprotein lipase activities on days 0 and 14 of the study. RESULTS Serum GH concentrations increased to a steady level of 2–4mU/l during treatment. Serum insulin-like growth factor-l (IGF-I) concentrations increased throughout the treatment period to twice the pretreatment levels. Plasma insulin and blood glucose concentrations increased on day 2 of treatment. After 7 and 14 days of treatment blood glucose concentrations were not different from pretreatment levels, but plasma insulin concentrations were still elevated. Serum cholesterol and low density lipoprotein (LDL) cholesterol concentrations had decreased after 7 and 14 days of treatment. High density lipoprotein (HDL) cholesterol concentrations were not affected, but very low density lipoprotein (VLDL) cholesterol and triglyceride concentrations increased transiently at day 2 of treatment. Serum apolipoprotein (apo) A-l, apoB and apoE concentrations were not significantly affected. Serum lipoprotein(a) concentrations had increased by days 7 and 14 to 147 and 142% of pretreatment concentrations, respectively. Lipoprotein lipase and hepatic lipase activities in post-heparin plasma, as well as abdominal and gluteal adipose tissue lipoprotein lipase activities, were not affected. There was no significant change in glucose disposal rate estimated from the glucose clamp studies. CONCLUSIONS A low dose infusion of GH results in marked changes in lipoprotein concentrations with a transient increase in VLDL cholesterol and thereafter in a decrease in LDL cholesterol. In addition, this low dose of GH resulted in marked increases in lipoprotein(a) concentrations. The observed effects of GH may partly involve changes in IGF-I and insulin secretion.     

Hyperlipemia and arteriosclerotic cardiovascular disease in the Polynesian population of Rarotonga

Total cholesterol, total triglyceride and high density lipoprotein (HDL) cholesterol and their relation to arteriosclerotic cardiovascular disease (ASCVD) were investigated in a population of Polynesian Maoris in Rarotonga who are becoming increasingly westernized. 8.5% of the population had plasma triglyceride elevations (triglyceride greater than or equal to 200 mg/dl), and the occurrence of hypertriglyceridemia was significantly higher in males than females. 5.8% of the population had elevations of total cholesterol (cholesterol greater than or equal to 250 mg/dl), and the proportion with elevation of total cholesterol was similar for males and females. 3.2% of the population had elevations of both triglyceride and cholesterol. HDL cholesterol concentrations were relatively low, and no sex differences were observed at any age. Analysis of lipoprotein cholesterol and triglyceride in a subset of those who had hyperlipemia indicated that the elevations of total cholesterol and triglyceride were mainly due to elevations of low density lipoprotein (LDL) cholesterol and very low density lipoprotein (VLDL) triglyceride, respectively; furthermore, elevations of VLDL triglyceride and LDL cholesterol were significantly correlated with increase in VLDL apolipoprotein B (apo B) and LDL apo B, respectively. Although an appreciable prevalence of diabetes was observed in this population (male: 6.7%, female: 8.4%), the diabetes could not account for the hyperlipemia. Among 693 subjects between the ages of 30 and 59 years, approx. 3% of males and 1% of females had Q-wave changes, and 16% of females and 4% of males had ST-T changes. Among males with Q-wave abnormalities, hyperlipemia was more frequent. There was also increased frequency of hypertension in those with elevated lipids. The data indicate the occurrence of some hyperlipemia in this population which could be of the familial-combined type; the elevated plasma lipids may contribute to the increased frequency of coronary heart disease.