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The statins correct plasma lipid levels optimally, yet the real magnitude of their benefits is marginal and certainly not better than attained with agents that do not affect plasma lipid levels. It is suggested that some of our recommendations and actions relating to plasma cholesterol levels and to atherosclerosis are based on concepts that are fundamentally flawed and need to be revised.

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Little is known about the absorption or metabolism of oxysterols. Toward better appreciating the metabolic consequences of oxidizing cholesterol, we compared labeled cholesterol with the labeled oxysterols 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, and 7-ketocholesterol prepared from [4-14C]cholesterol, [26,26,26,27,27,27-2H6]cholesterol, and [23,24,25,26,27-13C5] cholesterol. Gastrointestinal absorption of oxysterols in rats was 91.5 +/- 0.3% compared with 75 +/- 1.1% for cholesterol, determined by fecal collection (P < .001). When injected intravenously and followed by gas chromatography/mass spectrometry, 7 alpha-hydroxycholesterol was cleared at 23 times the rate of cholesterol. After 5 minutes, only 1.2 +/- 0.2% of 7 alpha-hydroxycholesterol remained in the plasma, whereas 28.0 +/- 1.7% of cholesterol and 40.0 +/- 2.5% of a triglyceride emulsion injected simultaneously were still present. [14C]7 alpha-Hydroxycholesterol injected intravenously was also rapidly cleared from plasma, was widely distributed in tissues and organs, and showed evidence of extensive metabolism at 5 minutes. The fractional rate of uptake of radiolabeled oxysterols by cultured endothelial cells was 15.7 times that of cholesterol (P < .001), and the fractional rate of efflux was 3.4 times that of cholesterol (P < .001). Oxysterols passed through endothelial cells grown on transwell membranes at a rate 4.3 times that of cholesterol (P < .001). Fractional oxysterol transport across the endothelial cell monolayer was increased 62 +/- 17% when HDL was added to the medium in the lower chamber (P = .003). Oxysterols were extensively metabolized to even more polar metabolites during endothelial cell transit. These properties of oxysterols potentially provide a mechanism for enhancing transport of cholesterol through tissues and preventing accumulation of cholesterol in those cells that can oxidize it.

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The preparation of cholesterol and radiocholesterol oxidation products on a microscale is difficult. Cholesterol generally resists oxidation unless it is well dispersed under controlled conditions. A method was developed to reliably produce 7 alpha- and 7 beta-hydroxycholesterol and 7-ketocholesterol. Small changes in pH, metal ions present, or in the colloidal dispersion, resulted in production of completely different oxysterols. Attempts to oxidize aged radiocholesterol were not successful even after purification by several thin-layer chromatographic steps, and this appeared to be due to a time-related change in the radioactive material. Fresh radiocholesterol oxidized readily.

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Sixty people with hyperglycaemia were admitted to Baragwanath Hospital as emergency patients during an 8-week study period in 1981, and one-quarter of them died in hospital. Many of these hyperglycaemic emergencies could have been prevented; 88% of the patients were known diabetics, one-third of whom required only oral hypoglycaemic agents for diabetic control. Sixty-one per cent of the patients had concomitant diseases, primarily infections. Earlier treatment might well have prevented deterioration of diabetic control, yet only 6% of the patients had attended the health services in the previous week in spite of recognizing that they were becoming progressively more ill. These patients were at high risk of subsequent admission, one-third of those discharged being readmitted within 3 months. Attendance compliance during a 3-month follow-up period was poor, and the discharged patients lacked the skills and knowledge necessary to maintain adequate diabetic control. One-quarter of those on insulin could not measure their dose correctly, most could not adequately test their urine and did not know what action to take if they had worsening symptoms of hyperglycaemia or developed intercurrent illness. Hyperglycaemic emergency admissions could be reduced by improving ambulatory diabetic services, thus saving costs of hospital care. Recommendations for improving the hospital service include maintaining a register of patients who have had hyperglycaemic emergencies and special care to ensure that they acquire the necessary knowledge and skills. Other methods of improving compliance regarding attendance and medication should be applied. These recommendations need to be implemented and their efficacy evaluated.

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Cholesterol in crystalline form cannot be readily cleared from tissue and in this form it is sclerogenic. Phospholipids can solubilise cholesterol, promote its clearance and reduce the sclerosis. The phospholipids accompanying cholesterol deposited in atherogenesis are not adequate to solubilise all the cholesterol. It has been found that some oxidation products of cholesterol act synergistically with phosphatidylcholine to enhance the solubility of cholesterol in vitro. The effect of these oxysterols on solubilisation and clearance of cholesterol in vivo was examined in rats by implanting subcutaneously tablets made of cholesterol, cholesterol plus oxysterols and both with phosphatidylcholine. Tablets containing oxysterols went into solution rapidly, were cleared completely and allowed regression of the initial fibrosis promoted by the sterol without needing exogenous phospholipid. Solubilisation and clearance seem to have been affected by endogenous phospholipid, possibly high density lipoproteins, and by macrophages. Tablets without oxysterols showed no clearance at all but were cleared in part when phosphatidylcholine was added. Oxidation products of cholesterol form readily in foods of animal origin when suitably exposed to light and air. It is suggested that technology designed to prevent spoilage of foods has inadvertently resulted in the elimination from the Western diet of compounds which prevent the accumulation of cholesterol in the arterial wall.

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Compounds promoting the solubility of cholesterol could have a role in preventing its crystallisation and accumulation in tissue and in body fluids. A small quantity of phosphatidylcholine added to a supersaturated solution of cholesterol in a triglyceride oil has limited capacity to maintain solubility of cholesterol. Small quantities of oxidation products of cholesterol (oxysterols) have no material effect on the solubility of cholesterol in this system. However, the combination of phosphatidylcholine and oxysterols effectively maintains cholesterol in stable solution. In aqueous medium, the capacity of phosphatidylcholine to solubilise a molar excess of cholesterol is greatly increased by oxysterols. Oxidation products of cholesterol and phosphatidylcholine acting synergistically enhance enormously the solubility of cholesterol both in supersaturated solution in a triglyceride oil and in aqueous medium.

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Cholesterol, triglyceride and phospholipid levels were measured in the serum of fasting adult diabetics who regularly attended Baragwanath Hospital, Johannesburg. A total of 149 subjects were studied (69 males and 80 females). Correlation coefficients were determined between the lipid levels and between additional variables of age, obesity and duration of diabetes. Significant correlations were found between cholesterol and phospholipid levels in males and females and between cholesterol and triglyceride levels in males only. Of interest is the lack of correlation between the degree of obesity and any lipid level. A notable finding was that the cholesterol concentration was bimodally distributed in the males and possibly in the females. About half the subjects had high serum lipid levels, apparently for the duration of their diabetes. In addition, this population showed a large number of other factors associated with a significant risk of developing coronary heart disease (CHD); yet, this disease was exceedingly rare in the population. It is suggested that there is some undefined factor(s) which is powerfully protective against CHD in Blacks.

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Urine of 198 diabetics and 147 non-diabetics was examined for bacteriuria by means of the Uricult dip slide method. Prevalence of bacteriuria in diabetics (18,7%) was significantly higher than in the control group (7,6%). This increased prevalence in diabetics was due primarily to an exceedingly high prevalence in diabetic women (27%). There was no relation between bacteriuria and age, duration of diabetes, treatment for diabetes, quality of control of diabetes, symptoms of urinary tract infection or hypertension.

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In a double-blind, randomized study which lasted 48 weeks the effects of clofibrate and halofenate were compared in maturity-onset diabetics with hyperlipidaemia. With the use of both clofibrate and halofenate serum cholesterol values were lowered only slightly. Both agents significantly reduced triglyceride values, but the decreases were modest and transient. Both drugs significantly lowered serum urate values, although the effect of halofenate was distinctly greater. Halofenate, but not clofibrate, had a considerable hypoglycaemic effect on the patients, most of whom were also receiving oral antidiabetic medicines. The drugs produced a number of clinical and biochemical adverse reactions, and in about 20% of all patients the trial had to be discontinued prematurely. The management of hyperlipidaemia in maturity-onset diabetics is briefly discussed, and it is concluded that neither clofibrate nor halofenate is to be recommended.

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Two concepts are advanced to explain some fo the puzzling biochemical features found in nonketotic hyperosmolar diabetic coma. It is firstly suggested that an insulinised liver (reflecting residual beta-cell secretory activity) coexists with a diabetic periphery, thereby inactivating intrahepatic oxidation of incoming free fatty acids, which are directed largly along nonketogenic metabolic pathways such as triglyceride synthesis. This could account for the lack of hyperketonaemia. Secondly, it is hypothesised that within the liver enhanced neoglucogenesis occurs, due to the prevailing portal-vein into ratio of glucagon to insulin, and is mainly responsible for the development of massive hyperglycaemia.

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