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Biomedical subjects

R S Clements

Publications and source records attributed to R S Clements.

At least 37 records · Page 2Linked to original sources
PubMed1986

The polyol pathway. A historical review.

Polyhydric alcohols (polyols) are widely distributed in nature, and the enzymes of the polyol pathway (aldose reductase and sorbitol dehydrogenase) are present in many mammalian tissues. The function of this pathway remains a mystery. A primary role for the pathway in the pathogenesis of 'sugar cataract' was provided by a number of experimental observations and in the 1960s the 'osmotic hypothesis' was propounded. This hypothesis also had implications for the pathogenesis of diabetic neuropathy. However, in the 1970s doubts were raised about the validity of the hypothesis, culminating in experiments which suggested that abnormalities in myo-inositol metabolism in nerve and lens were more closely related to the glucose-induced functional changes in these tissues than was the polyol pathway. Nevertheless, increased activity of the polyol pathway must still be regarded as an instigator of the biochemical abnormalities that lead to damage of lens and nerve in diabetes mellitus.

Animals↗
PubMed1985

Complications of diabetes. Prevalence, detection, current treatment, and prognosis.

The late complications associated with diabetes mellitus affect the eye (retinopathy and cataract), the kidney (diabetic glomerulosclerosis), the nerves (mononeuropathies, distal symmetric polyneuropathy, and autonomic neuropathy), and the large blood vessels (coronary artery, cerebrovascular, and peripheral vascular disease). With the exception of large blood vessel disease, evidence in animals and humans has suggested that the development of diabetes-associated complications is related to metabolic abnormalities associated with hyperglycemia. Although the exact mechanism by which hyperglycemia causes damage in individual tissues is unknown, a number of potentially pathogenic mechanisms have been proposed. These include increased activity of the polyol pathway, disturbance in the metabolism of myo-inositol and its phospholipid derivatives, abnormal permeability of the small blood vessels, and excessive glycosylation of various proteins. With the introduction of potent aldose reductase inhibitors, the role of increased activity of the polyol pathway (and related abnormalities in myo-inositol metabolism) in the pathogenesis of diabetes-associated complications can be clarified.

Adult↗
PubMed1983

Endogenous prostaglandin synthesis and glucose-induced insulin secretion from the adult rat pancreatic islet.

Although exogenous prostaglandins are recognized modulators of insulin secretion, the relationship between their endogenous synthesis and insulin secretion has not been rigorously studied in isolated adult rat islets. Using 3H-arachidonic acid as a tracer, we evaluated the effect of glucose stimulation upon the incorporation of this fatty acid into islet phospholipids and prostaglandins (separated by extraction and sequential silicic acid, thin-layer and paper chromatography). We observed that 3H-arachidonic acid was incorporated into islet phospholipids and prostaglandins under basal conditions (0.3 mg/ml glucose). Furthermore, exposure of islets to a stimulatory glucose concentration led to significant increases in the recovery of 3H-arachidonic acid-derived radioactivity in islet phosphatidylethanolamine, phosphatidylserine, sphingomyelin, and phosphatidylinositol as well as into all of the measured prostaglandins (A2, B2, D2, E2, and F2 alpha). The most marked increases in recovered radioactivity resulting from a stimulatory glucose concentration were in islet phosphatidylethanolamine and prostaglandin A2 (which we believe to be derived, in large part, from endogenously synthesized prostaglandin E2). These glucose-induced increases in 3H-arachidonic acid-derived radioactivity in both the phospholipid and the prostaglandin fractions were eliminated by the inhibition of phospholipase A2 activity with mepacrine or by the inhibition of cyclooxygenase activity with sodium salicylate. When islets prelabeled with 3H-arachidonic acid were exposed to a high glucose concentration in a perifusion system, there was a brisk extracellular release of radioactivity (presumably representing unidentified prostaglandins) that began within 1 min and that peaked slightly before the peak of the first phase of insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Diabetic neuropathy: peripheral and autonomic syndromes.

Incidence and prevalence of diabetic neuropathy increase with age and increasing duration of diabetes. Evidence supports an ischemic cause for mononeuropathies, but the pathogenesis of polyneuropathy is still uncertain. Mononeuropathies, involving discrete cranial or peripheral nerves, usually resolve spontaneously or respond to therapy. Distal symmetrical polyneuropathy, the most common form of diabetic neuropathy, tends to be progressive and difficult to treat. Autonomic neuropathy occurs as an extension of polyneuropathy in up to 70% of diabetics. Since no organ supplied by the autonomic nervous system is immune.

Cachexia↗
PubMed1982

Diagnostic, pathogenetic, and therapeutic aspects of diabetic neuropathy.

Since nearly all patients with diabetes mellitus will manifest evidence of dysfunction of their peripheral and autonomic nerves, neuropathy can be considered to be the most common of the so-called "late complications of diabetes." Mononeuropathies are uncommon, but can affect virtually any cranial or nerve and are thought to be due to vascular occlusion. Distal symmetrical polyneuropathy usually begins insidiously with the development of sensory symptoms involving the feet. These symptoms progressively ascend and are accompanied by progressive motor dysfunction as well as cardiac, gastrointestinal, and genitourinary manifestations of autonomic neuropathy. Numerous biochemical abnormalities including impaired neural protein synthesis, abnormal axoplasmic transport, disturbed polyol pathway activity, and abnormal myo-inositol metabolism have been described and have been postulated to underlie the development of diabetic peripheral and autonomic neuropathies. At the present time, the available treatments for diabetic neuropathies are largely palliative and are not curative. In the future, a better understanding of the pathophysiologic basis of diabetic neuropathy will undoubtedly lead to the development of more rational therapeutic approaches.

Aging↗
PubMed1981

Substrate requirements for the phosphoinositide response in rat pancreatic islets.

The relationship between phosphatidylinositol hydrolysis and the first phase of insulin secretion has been investigated by briefly exposing rat pancreatic islets that had been prelabelled with myo-[2-3H]inositol to various agonists and antagonists of insulin secretion. The recovery of lipid-bound radioactivity progressively decreased as the D-glucose concentration of the incubation medium was increased. Those carbohydrates that stimulated insulin secretion evoked a phosphoinositide response, whereas non-stimulatory carbohydrates did not. With the notable exception of amino acids, non-carbohydrate secretagogues were also found to decrease the islet lipid-bound radioactivity. Inhibition of islet glucose metabolism was found to decrease the recovery of lipid-bound radioactivity, largely as a result of impaired de novo phosphoinositide synthesis. The phosphoinositide response to glucose was not affected by inhibition of microtubular function, but was dependent upon the availability of extracellular calcium ions. We conclude that the phosphoinositide response in carbohydrate-stimulated islets is not directly related to the activation of membrane-associated glucose receptors, but may occur as a consequence of the subsequent transmembrane movement of calcium ions. Finally, the observation that stimulatory amino acids did not evoke a phosphoinositide response suggests that, under certain circumstances, this phenomenon can be dissociated from insulin secretion.

Animals↗
PubMed1981

Alterations in fetal lung phosphatidylinositol metabolism associated with maternal glucose intolerance.

Prior to conception, female rabbits were made hyperglycemic by streptozotocin administration. Fetal hyperglycemia and hyperinsulinemia were documented. Although plasma myoinositol concentration were higher in the fetuses of diabetic mothers, the ratio of lung to plasma myoinositol concentrations in 29-day fetal rabbits were lower than control values. CDP-diglyceride:inositol phosphatidyltransferase was reduced by 70% in the diabetic fetuses and their lung tissue phosphatidylinositol content was decreased.

Animals↗
PubMed1980

Myo-inositol content of common foods: development of a high-myo-inositol diet.

Since virtually no information is available concerning the myo-inositol content of dietary constituents, we have measured the amount of this material present in 487 foods by gas-liquid chromatography. We observed that the greatest amounts of myo-inositol were present in fruits, beans, grains, and nuts. Fresh vegetables and fruits were found to contain more myo-inositol than did frozen, canned, or salt-free products. The data provided in this report were used to develop diets that contained varying, but known amounts of myo-inositol. The myo-inositol intake that could be provided by such diets ranged from 225 to 1500 mg/day per 1800 kcal and within this range the agreement between the calculated and measured amounts of this material was excellent (r = 0.98). Since abnormalities in the metabolism of myo-inositol have been speculated to play a role in the pathogenesis of the polyneuropathies associated with diabetes mellitus and chronic renal failure, it is possible that the natural history of these neuropahties can be altered by modifying the amount of dietary myo-inositol that is ingested by patients with these diseases.

Bread↗
PubMed1980

The effect of insulin and of anti-insulin serum on handling of sodium by the isolated, perfused kidney of the streptozotocin-diabetic rat.

We studied the effects of insulin and of anti-insulin serum (AIS) on sodium excretion in isolated diabetic and normal, fed, rat kidneys perfused at a constant pressure of 100 mm Hg with Krebs-Ringer bicarbonate buffer containing 7.5% bovine serum albumin and 5 mM glucose and gassed with 95% O2 and 5% CO2. The addition of insulin produced antinatriuresis in kidneys from diabetic rats but not in those from normal rats. Moreover, before the addition of insulin, the baseline rate of sodium excretion was greater in the diabetic rat kidney than in the normal rat kidney, while no differences in glomerular filtration rate (GFR) were observed. The addition of AIS (enough to bind 1.4 mU of insulin per milliliter of perfusate) produced a brisk natriuresis in kidneys from normal rats, and this natriuresis could be reversed by the addition of saturating amounts of insulin. By contrast, the addition of normal guinea pig serum to the perfusate of normal kidneys or AIS to the perfusate of diabetic kidneys was unassociated with natriuresis. We conclude that (a) insulin promoted antinatriuresis in diabetic but not in normal rat kidneys, (b) AIS promoted natriuresis in normal kidneys, and (c) this natriuresis was a specific effect of AIS and was reversed by the addition of insulin. Our data support the view that insulin-induced antinatriuresis depends on endogenous levels of circulating insulin and on the availability of insulin-binding sites in the kidney.

Animals↗