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This study reports the result of a 12-month, open-label multicenter study of the efficacy and tolerability of pravastatin in the management of hypercholesterolemia associated with non-insulin-dependent diabetes mellitus. Pravastatin produced a decrease, in 138 diabetic and 51 non-diabetic patients, in total serum cholesterol by 19 and 20%, in low-density lipoprotein (LDL) cholesterol by 25 and 29%, in apolipoprotein B by 15 and 19% and in triglycerides by 8 and 5%, respectively. High-density lipoprotein cholesterol levels were increased by 9% in both groups. All of these changes were significant ( P 1c levels and by the presence of hypertension or gross proteinuria, although a decrease in the two variables were less in those with body mass index ≥26.4 kg/m 2 or in those with age 1c levels in diabetic patients throughout the study. Pravastatin was generally effective in improving the serum lipids of hypercholesterolemic diabetic patients.

Long-term effects of bezafibrate on in vivo production of VLDL-triglyceride were studied in the rat. Bezafibrate given at a daily dose of 30 mg/kg body weight for 14 days produced a decrease not only in triglyceride by 51% but in cholesterol by 28% and phospholipid by 18%. Despite a marked reduction in plasma triglyceride concentrations, there was no significant change in the rate of VLDL-triglyceride secretion from the liver into the circulation between bezafibrate-treated and control animals (1113 +/- 58 and 1234 +/- 63 micrograms/min, respectively). In addition, bezafibrate produced no change in lipid composition in VLDL. These results suggest that bezafibrate enhances triglyceride removal from the circulation, which leads to reduction in plasma triglyceride.

Patients with diabetes mellitus have a higher rate of mortality than the general population. This higher mortality may be attributed mainly to cardiovascular disease. A high prevalence of dyslipidemia in diabetics can be one of the reasons for this. The most commonly recognized lipid abnormality in non-insulin-dependent diabetics (NIDDM) is hypertriglyceridemia, which is known to be an independent risk factor for coronary heart disease in diabetics. Hypertriglyceridemia can be produced by two mechanisms, increased synthesis of very-low-density lipoprotein (VLDL) triglyceride and removal defect of plasma triglyceride. It has been a matter of debate whether insulin always stimulates hepatic VLDL secretion but it is generally accepted that insulin deficiency results in an impairment of plasma triglyceride clearance. Considerable attention has recently been focused on the atherogenecity of postprandial hyperlipidemia, remnant lipoproteins, small, dense LDL, lipoprotein (a) [Lp(a)] and isolated hypo-alphalipoproteinemia in NIDDM subjects. Several reports suggested that these atherogenic lipoprotein abnormalities are present in NIDDMs even if they are apparently normolipidemic. Association of visceral fat obesity, insulin resistance and nephropathy may aggravate the atherogenic lipoprotein profile. Therefore, we propose here that plasma lipid levels of diabetic subjects must be more strictly controlled than for the non-diabetic population in order to avoid an increased risk for coronary heart disease. If they are obese or associated with insulin resistance or nephropathy, these conditions should be carefully controlled.

The diabetogenic action of alloxan is known to be attenuated by several oxygen radical scavengers. The present study was conducted to see if probucol, a drug with strong free radical scavenger action, can reduce pancreatic B-cell damage induced by alloxan in male Wistar rats. After 2 weeks of a 1% probucol diet, 50 mg/kg alloxan was intravenously injected in rats (group PA, n = 34). Urine glucose of most of the injected rats not pretreated with probucol (group A, n = 22) was positive, while more than half of the rats of group PA failed to show urine glucose. The blood glucose level in group PA was significantly lower than that in group A (326 +/- 25 vs. 487 +/- 28 mg/dl, P less than 0.001). Histological examination revealed that most of the pancreatic islets of group A were degranulated, whereas a lot of islets remained unaffected in group PA. Thus, the in vivo diabetogenic action of alloxan was reduced by pretreatment with probucol, although the effect was incomplete. This effect can be explained by probucol's strong free radical scavenger action. Since accumulation of free radicals can be an initial step of B-cell damage in animal models of type 1 (insulin-dependent) diabetes, the drug can be useful for the prevention of type 1 diabetes with its long-term clinical history of safety.

Exogenously induced hyperinsulinemia can increase in vivo triglyceride production in rats receiving dietary fructose, either as monosaccharide or as sucrose, but not in those receiving only glucose. Thus, in the presence of fructose, but not glucose, insulin stimulates triglyceride production. Dietary fructose can also impair the removal of circulating triglyceride. Exogenous insulin overcomes this fructose-associated impairment of triglyceride removal. On the other hand, streptozotocin-diabetic rats showed a suppressed triglyceride secretion rate (TgSR) but their plasma triglyceride level was unchanged. Therefore, insulin deficiency may result in not only decreased production of triglyceride but also impaired triglyceride removal from the circulation. Fructose-fed diabetic rats showed higher plasma triglyceride levels than chow-fed diabetic rats without a concomitant increase in TgSR, suggesting impaired triglyceride removal from the circulation induced by fructose in diabetic rats. Glucose-fed diabetic rats did not differ in TgSR or plasma triglyceride level from chow-fed diabetic rats. These observations indicate that circulating insulin and dietary fructose, but not glucose, have a key role in very-low-density lipoprotein triglyceride turnover in rats.

We have recently reported increased cholesterol concentrations in high-density and very-low-density lipoproteins (HDL and VLDL) in sucrose-fed rats with exogenous hyperinsulinemia. In order to see if exogenous hyperinsulinemia has any effect on the alterations in plasma lipoproteins induced by cholesterol feeding, we fed a cholesterol-rich diet supplemented with lard, cholic acid and propylthiouracil to hyperinsulinemic, sucrose-supplemented rats and examined plasma lipoprotein profiles. Three control groups were investigated: one receiving chow only, the other receiving a cholesterol-rich diet, the third receiving exogenous insulin, sucrose, and no cholesterol-rich diet but chow. Hyperinsulinemia was induced by a constant s.c. infusion of porcine insulin (6 U/day) from an osmotic minipump. Insulin infusion plus sucrose produced an increase in HDL cholesterol concentrations similar to that seen in the previously reported injection model in the face of no change in total and low-density lipoprotein (LDL) cholesterol. Rats receiving a cholesterol-rich diet but no insulin developed marked hypercholesterolemia characterized by an elevation of cholesterol not only in LDL but also in intermediate-density lipoprotein (IDL) and VLDL. Infusing insulin into cholesterol-fed rats produced a further increase in IDL and VLDL cholesterol but was not accompanied by any further increase in LDL cholesterol. HDL cholesterol was decreased below normal. The present studies have revealed that dietary cholesterol increases cholesterol concentrations not only in LDL but in triglyceride-rich lipoproteins, the latter being further increased by exogenous hyperinsulinemia. They also demonstrate that a combination of hyperinsulinemia, sucrose and cholesterol feeding is a useful tool in producing cholesterol-rich VLDL and IDL in rat plasma.

The effects of sucrose feeding on in vivo kinetics of triglyceride metabolism were compared in rats aged 2 and 12 months. Sucrose was supplied as a 10% solution in their drinking water for 2 weeks. Although plasma triglyceride concentrations doubled with age, total triglyceride secretion rates for the whole rat (mg/min/rat) increased by 40%, suggesting a decrease in the efficiency of triglyceride removal from plasma with aging. The rate of triglyceride secretion per unit body mass (mg/min/kg body weight), however, decreased by 40% as the rats grew to 12 months of age. These age-related differences were statistically significant only in rats receiving supplementary sucrose. Feeding sucrose to rats of both ages doubled the secretion rates of triglyceride not only for the whole rat but also per unit body mass. However, it tripled triglyceride concentrations, implying that the sugar decreases the removal efficiency of plasma triglyceride equally in rats at either age. Fasting hypertriglyceridemia induced by sucrose supplement was much greater in old rats than in young rats (162 +/- 30 vs. 80 +/- 8 mg/dl). The present studies demonstrate that dietary sucrose enhances age-related changes in triglyceride kinetics in the rat.

We report here a new formula for estimating apolipoprotein (apo) B concentration in the low-density lipoprotein (LDL) fraction from measurements of plasma triglyceride and apoB. ApoB in plasma and in the triglyceride-rich lipoprotein fraction (VLDL, d less than 1.019) and plasma triglyceride were measured in 112 subjects, including 56 diabetics. There was a significant correlation between VLDL-apoB and plasma triglyceride (Y = 0.07X + 1, r = 0.73, P less than 0.001). We calculated LDL-apoB according to this formula: LDL-apoB = total apoB - (0.07 x total triglyceride + 1). We found an excellent relationship between LDL-apoB (total apoB - VLDL-apoB) and calculated LDL-apoB (Y = 1.0X + 1, r = 0.96, P less than 0.001). This new formula will enable us to estimate the apoB concentration in the LDL fraction without ultracentrifugation.

CS-514, one of the derivatives of ML-236B which is an inhibitor of endogenous cholesterol synthesis, has been previously shown to effectively reduce low density lipoprotein (LDL) cholesterol in dogs, rabbits and humans. We determined the effect of CS-514 on glucose, lipid, lipoprotein and apolipoprotein (apo) levels in plasma of 8 hypercholesterolemic diabetics (2 males). Total and LDL cholesterol and apo B levels were significantly decreased (P less than 0.005) 3 months after CS-514 treatment. High density lipoprotein (HDL) cholesterol was increased (P less than 0.05). Fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) did not change throughout the observation period. No clinically serious adverse effects were experienced by the patients. We conclude that CS-514 can be a useful drug in the treatment of hypercholesterolemic diabetics and is remarkably free of any evidence of toxicity or unwanted side effects even in diabetics.