The diagnosis and treatment of lipid disorders in NIDDM - abstract

Dyslipidaemia in NIDDM is multifactorial due in part to diabetes mellitus and in part to the effects of aging, inactivity, obesity, late expression of genetic disorders and the use of drugs which may adversely influence lipid levels. The dyslipidaemia of NIDDM is characterized by hypertriglyceridaemia, low HDL-C and small dense LDL particles. Post-prandial lipaemia is also exaggerated in NIDDM due to impaired clearance of atherogenic particles (chylomicron remnants, small VLDL). Hypercholesterolaemia is not a typical feature of NIDDM except when the total cholesterol is increased due to increased VLDL-C. When LDL-C is increased, it is usually not due to NIDDM but to disorders or factors that commonly increase LDL-C in the adult non-diabetic population. Glycosylation of apoproteins and increased susceptibility of lipoproteins to oxidation probably also contribute to the increased risk of macrovascular disease. Treatment involves diet, exercise, weight loss, improved glycaemic control, elimination of secondary causes of dyslipidaemia and, when necessary, pharmocological lipid-lowering drugs. The response to diet may be variable. In some patients, the plasma triglyceride level may paradoxically increase in response to the NCEP diets which contain 55 - 60 per cent of calories from CHO and 45 per cent of calories from fat (saturated and polyunsaturated fat should each represent 10 per cent of calories and mono-unsaturated fat should represent 25 per cent of calories). Gemfibrozil and reductase inhibitors are the only drugs which can be consistently and safely utilized in NIDDM. Bile acid-binding resins may aggravate hypertriglyceridaemia and cause a paradoxical increase in serum total cholesterol level. Niacin is relatively contraindicated in NIDDM because it produces insulin resistance, intensifies hyperglycaemia and increases the requirement for oral sulfonylurea agents and/or insulin. Use of increased doses of an oral sulfonylurea agent may predispose to niacin-induced hepatotoxicity. Whether hyperinsulinaemia and the use of larger doses to control hyperglycaemia contribute to the risk of macrovascular disease is unresolved at this time (AU)

Aetiology, treatment and prevention of diabetic nephropathy: an overview - abstract

In the studies of the aetiology, treatment and prevention of diabetic nephropathy, several end-points can be used, including death due to renal failure, uraemia, azotaemia, proteinuria, microalbuminuria and changes in glomerular and tubular functions. The two parameters commonly used, though not ideal, are glomerular filtration rate and protein excretion. Several factors contribute to the development and progression of diabetic nephropathy. These include hereditary factors, severity of hyperglycaemia, hypertension and hyperlipidaemia. Siblings of probands free of diabetic nephropathy have less evidence of renal disease than do siblings of probands with diabetic nephropathy. Several studies have also shown that individuals with high glycosylated haemoglobin concentrations (poor glycaemic control) are more likely to develop diabetic nephropathy. It is not clear, however, if this is a direct relationship (e.g. via glycosylation) or indirect (e.g. increased flux through the aldose reductase pathway, or alteration in vascular permeability). It is also unclear whether there is a direct relationship between glucose level and the development of diabetic nephropathy. The route of administration of insulin, e.g. into systemic circulation or into the portal system, may be important in the development of diabetic nephropathy. Specific inhibitors in the metabolic pathways (e.g. aldose reductase inhibitors, glycosylation inhibitors) may slow or prevent the development of diabetic nephropathy. Several studies have shown that increase in albumin excretion rate and decrease in glomerular filtration rate precede the development of hypertension and, once present, contribute to the rate of progression of diabetic nephropathy. Some, on the other hand, feel that hypertension reduces protein excretion, and a few studies have shown that it also preserves renal function and/or prevents azotaemia. It is also not clear at what level blood pressure should be treated, as urinary albumin excretion decreases when normotensive individuals are treated with angiotensin-converting enzyme inhibitors. Reduction of protein consumption in humans (to approximately 0.6 gm protein/kg body weight per day) can slow the rate of decline in glomerular filtration. Also influencing the rate of development of hyperlipidaemia, if necessary, with hypolipidaemic drugs is potentially beneficial in hypertensive diabetic patients. In summary, although definite data are lacking, an attempt should be made to optimize glycaemic control and hypertension should be treated early and vigorously. Hyperlipidaemia which persists in the presence of normoglycaemia should be treated with diet and hypolipidaemic drugs (AU)

The catabolism of valine in the malnourished rat: studies in vivo and in vitro with different labelled forms of valine

1. The catabolism of valine was estimated in vivo by measurement of the production of labelled CO2 for 2 h after the oral administration of either [U-14C] valine. It was also estimated in vitro in homogenates of liver and muscle incubated with labelled valine. Experiments were performed in rats given diets providing either 215 g (HP) or 25 g (LP) protein per kg diet. 2. The proportion of [U-14C] valine excreted as 14 CO2 was not reduced in rats given the LP diet for 16 d but the excretion of 14 CO 2 from [1-14C] valine was reduced by 40 percent in these animals. When rats were transferred from the HP diet to the LP diet there was a reduction in the excretion of 14CO2 from [1-14C] valine; when the diet was changed from LP to HP output of 14CO2 increased to control values. 3. Homogenates of muscle and liver catabolized valine to CO2. Both liver and muscle from rats fed on the LP diet catabolized less [1-14C] valine than tissues from control animals. 4. Valine aminotransferase activity was higher in muscle than in liver, and did not change in tissues from rats fed on the LP diet. In these animals 2-ketoisovaleric acid dehydrogenase activity was reduced in both liver and muscle. 5. The production of 14CO2 was lower with [U-14C] valine as the substrate than with [1-14C]-valine and there was no difference between tissues from rats fed on the HP and LP diets. 6. The results with [1-14C] valine suggest that both liver and muscle from protein-depleted rats catabolize valine at a reduced rate. The reason for the discrepancy between these results and those with [U-14C] valine is not clear. It is concluded that the results with [U-14C] valine in vitro are affected by dilution of the label before the formation of 14CO2, but that this does not hold in vivo (AU)

Rhein, a selective inhibitor of the DPNH-flavin step in mitochondrial electron transport

Previous findings in the literature that rhein inhibits DPNH-linked mitochondrial oxidations by acting in the DPNH dehydrogenase region of the respiratory chain have been confirmed and extended. In the micromolar range rhein inhibits DPNH oxidase and DPNH-ferricyanide activities and the energy-linked reduction of DPNH by succinate in membrane preparations from heart, as wellas the DPNH dehydrogenase and transhydrogenase activities of the soluble, purified enzyme. The inhibition of the activities of the soluble enzyme are purely competitive with respect to substrate. These facts localize the primary inhibition site of rhein between substrate and FMN. In heart ETP a second noncompetitive inhibition is also present but is detectable only at very low (<10æM) rhein concentrations. Rhein also inhibits DPNH dehydrogenase in Candida utilis mitochondria and the purified enzyme from liver. On conversion of the heart enzyme to the low molecule weight DPNH-cytochrome reductase the typical effect of rhein disappears and is replaced by a slight stimulation or inhibition, depending on the electron acceptor used, showing that the substrate binding site is modified in this form of the enzyme. In beef liver mitochondria DPNH oxidation may appear insensitive to rhein, probably because of the strong binding of rhein to other proteins. To a lesser extent unspecific binding of rhein and resultant interference with the inhibition of DPNH dehydrogenase is also shown by BSA and by proteins in heart ETP. Rhein also inhibits transhydrogenations in mitochondria and at higher concentrations lactate and malate dehydrogenases but has no effect on sccinate, alcohol (liver nad yeast), and glucose-6-p dehydrogenases or on Neuospora DPN-ase, glucose-6-phosphatase, and amine oxidase. (SUMMARY)

A histochemical investigation of the concept of placental insufficiency

Using histochemical methods, the distribution and quantities of 10 enzymes were studied in 91 placentae representing normal and various types of abnormal pregnancies. It was concluded that the increasing concentration of alkaline phosphatase and glucose-6-phosphatase, and the decreasing concentration of acid phosphatase in the trophoblast are probably features of placental aging, and may also be associated with placental insufficiency (Summary)

Observations on enzymes in the human liver: general considerations and preliminary results

It has long been supposed that malnutrition predisposes the liver to injury. An attempt has been made to characterize this vulnerable state in biochemical terms. A diet deficient in protein causes the liver cell to lose a large proportion of its cytoplasmic protein and ribonucleic acid. It is suggested that this might lead to a disturbance in the amount or pattern of enzymes, which could have serious metabolic consequences. To test this hypothesis, measurements were first made of a number of single-enzyme systems, e.g. dehydrogenases transaminase choline esterase, cytochrome oxidase, cytochromec reductase. Only choline esterase was reduced in activity in the malnourished liver; the other enzymes were well preserved. Preliminary evidence suggests that more complex systems,involving a chain of enzymes, may be more easily damaged. (AU)