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R L Engerman

Publications and source records attributed to R L Engerman.

At least 37 records · Page 2Linked to original sources
PubMed1994

Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia.

Similar vascular pathological conditions are observed in diabetic animals and those with diet-induced hypergalactosemia. Both diabetes and hypergalactosemia are believed to cause vascular dysfunction via a common biochemical mechanism. In this study, we have found that both diabetes and hypergalactosemia in the short term (2-4 months) can increase total diacylglycerol (DAG) levels by 52 +/- 9 and 74 +/- 13% in the retina and aorta, respectively, of diabetic dogs, and by 94 +/- 9 and 78 +/- 11% in the retina and aorta, respectively, in dogs with hypergalactosemia as compared with normal control animals (P < 0.01). The elevation of DAG levels was maintained for 5 years in the aortas of diabetic and hypergalactosemic dogs. To characterize the mechanism of the DAG increases, we have determined that total DAG levels were significantly increased in cultured macro- and microvascular cells exposed to elevated glucose (22 mM) and galactose (16.5 mM) levels. These increased levels were not prevented by sorbinil, an aldose reductase inhibitor. One of the sources of the increased DAG levels was probably derived from de novo synthesis from both hexoses as determined by radiolabeling studies. Intracellularly, the DAG elevation activated protein kinase C (PKC) activity with increases of 58 +/- 12% (P < 0.05) and 66 +/- 8% (P < 0.01) in the membrane fraction of cultured aortic smooth muscle cells exposed to elevated glucose and galactose levels, respectively. These findings have clearly demonstrated a possible common biochemical mechanism by which hyperglycemia and hypergalactosemia can chronically activate the DAG-PKC pathway in the vasculature and could be a possible explanation for the development of diabetic vascular complications.

Animals↗
PubMed1994

Comparison of retinal lesions in alloxan-diabetic rats and galactose-fed rats.

Galactose-fed rats develop a retinal microvascular disease, but retinopathy has not been found to develop reproducibly in diabetic rats. We sought to determine which retinal lesions can be reproducibly produced by long-term diabetes in rats, the extent to which the capillary lesions in diabetic rats and galactosemic rats are similar, and whether the retinopathy induced by 50% galactose can be reproduced satisfactorily by a lower concentration of galactose. Alloxan-diabetic rats and rats fed either a 50% galactose diet or a 30% galactose diet were killed after comparable durations of study (18 to 22 months). Rats fed 50% galactose showed greater than normal frequency of retinal pericyte ghosts and acellular capillaries, and thickening of capillary basement membranes by 18 months of galactosemia. Rats eating 30% galactose developed similar retinal lesions, and tended to be healthier than rats fed 50% galactose. Diabetes of 1 1/4 years or more likewise resulted in retinal pericyte ghosts, acellular capillaries and thickened capillary basement membrane. IRMAs and other vascular abnormalities were not reproducibly demonstrated at this duration of study, and saccular microaneurysms were not seen in any groups. In a number of diabetic rats, the severity of diabetes diminished spontaneously (after 1 to 1 1/2 years of insulin deficiency), thus making it essential that glycemia be systematically monitored. Both diabetic rats and experimentally galactosemic rats develop microvascular lesions that are consistent with at least the early stages of diabetic retinopathy, and these models should be useful to screen potential therapies for their ability to inhibit the development of retinopathy.

Alloxan↗
PubMed1994

Abnormalities of retinal metabolism in diabetes or galactosemia. II. Comparison of gamma-glutamyl transpeptidase in retina and cerebral cortex, and effects of antioxidant therapy.

Levels of the intracellular antioxidant, glutathione, become subnormal in retina in diabetes or experimental galactosemia. In order to investigate the cause and significance of this abnormality, activity of gamma-glutamyl transpeptidase (an enzyme important in the synthesis and degradation of glutathione) and levels of reduced glutathione have been measured in retinas of diabetic rats and dogs and of experimentally galactosemic rats and dogs. Retinal gamma-glutamyl transpeptidase activity and glutathione level were significantly less than normal after 2 months of diabetes or galactosemia. In contrast, cerebral cortex from the same diabetic rats and galactosemic rats showed no significant reduction in either gamma-glutamyl transpeptidase activity or glutathione level. These different responses of the two tissues to hyperglycemia might help account for the difference in microvascular disease in these two tissues in diabetes. Consumption of the antioxidants, ascorbic acid (1.0%) plus alpha-tocopherol (0.1%), by diabetic rats and galactosemic rats inhibited the decrease of gamma-glutamyl transpeptidase activity and glutathione levels in retina, suggesting that defects in glutathione regulation in the retina are secondary to hyperglycemia-induced 'oxidative stress'.

Animals↗
PubMed1994

Abnormalities of retinal metabolism in diabetes or galactosemia: ATPases and glutathione.

PURPOSE: Experimental galactosemia and diabetes are known to result in diabetic-like retinopathy in animals, but the mechanism by which the retinopathy develops remains unclear. Defects of retinal metabolism that are common to galactosemia and diabetes are closely associated with the development of retinopathy and might play a role in the pathogenesis of the retinal disease. METHODS: Effects of experimental galactosemia on retinal calcium-activated ATPase [(Ca,Mg)-ATPase], sodium-potassium ATPase [(Na,K)-ATPase], glutathione, ATP, and pertinent ions have been compared with the effects of experimental diabetes in rat and dog models of diabetic retinopathy. RESULTS: Activities of (Ca,Mg)-ATPase and (Na,K)-ATPase were decreased as a result of either experimental galactosemia or diabetes in both the dog and the rat, and the decreases were accompanied by a diminution of reduced glutathione (GSH) in the retina. Ouabain-insensitive ATPase activity in the retina was not significantly reduced by diabetes or galactosemia, suggesting that the observed defects in (Ca,Mg)-ATPase and (Na,K)-ATPase activities were specific. The decrease of retinal GSH levels was associated with an elevated concentration of oxidized glutathione in diabetes but not in galactosemia. Retinal ATP and ion concentrations remained unaffected by experimental galactosemia or diabetes. CONCLUSIONS: Comparison of two etiologically dissimilar models of diabetic retinopathy (diabetes and galactosemia) has revealed abnormalities of retinal metabolism that are shared by the two models. Further comparisons of retinal metabolism between these two models should reveal additional sequelae of hyperglycemia that are associated with, and that might play a role in, the development of diabetic retinopathy.

Adenosine Triphosphate↗
PubMed1993

Aldose reductase inhibition fails to prevent retinopathy in diabetic and galactosemic dogs.

To investigate a possible role of excessive polyol production in the pathogenesis of diabetic retinopathy, 16 ALX-induced diabetic dogs and 20 experimentally galactosemic dogs were randomly assigned to 5 yr of treatment with either sorbinil, an aldose reductase inhibitor, or a placebo. The severity of hyperglycemia in sorbinil-treated and placebo groups was monitored throughout the 5-yr study by assay of glycosuria and nonenzymatically glycated plasma protein and HbA1 needed in an effort to avoid confounding possible group differences in hyperglycemia severity with possible drug effects. Inhibition of polyol production by sorbinil was monitored in erythrocytes throughout the study and also in retina and other tissue obtained at autopsy. Trypsin digests of retinal vessels were compared after 60 mo of diabetes and after 42 and 60 mo of galactosemia. In diabetic dogs, development of retinopathy was not significantly influenced by a sorbinil dose (20 mg.kg-1 x day-1) sufficient to prevent elevation of sorbitol levels in retina and other tissue. Likewise, in dogs made experimentally galactosemic for 42-60 mo, administration of sorbinil (60-80 mg.kg-1 x day-1) had no significant effect on the development of retinopathy notwithstanding prevention of 93-96% of the polyol elevation in retina and other tissue. Retinal capillary basement membrane was significantly thicker than normal in diabetic and in galactosemic dogs and was not significantly influenced by administration of sorbinil in either dog model. Thus, no evidence was found that the development of retinopathy is critically dependent on excessive polyol production or accumulation.

Aldehyde Reductase↗
PubMed1991

Renal hemodynamics in experimentally galactosemic dogs and diabetic dogs.

To examine the association between renal hemodynamic abnormalities and the development of diabetic kidney disease, glomerular filtration rate (GFR) and renal plasma flow (RPF) have been determined in dogs with alloxan-induced diabetes or experimental galactosemia of 1 to 5 years duration. GFR and RPF were significantly greater than normal in insulin-deficient diabetic dogs. GFR was also significantly greater than normal in the galactosemic animals, and RPF tended to be elevated even though GFR and RPF were measured at time of day when plasma galactose is no longer elevated. GFR and effective RPF (eRPF) were found to increase in normal animals upon acute elevation of blood galactose or glucose concentration. Thus, GFR is supranormal in experimental galactosemia, as well as in diabetes, although galactosemia has been shown not to cause nephromegaly, mesangial expansion, or glomerular obliteration, which are typical of diabetes. Administration of an aldose reductase inhibitor (Sorbinil) at dosages sufficient to significantly reduce erythrocyte polyol concentration did not significantly influence GFR or RPF in diabetic or galactosemic dogs.

Aldehyde Reductase↗
PubMed1991

Retinal polyol and myo-inositol in galactosemic dogs given an aldose-reductase inhibitor.

Galactitol and myo-inositol concentrations were measured in retinas, erythrocytes, and skeletal muscle of experimentally galactosemic dogs receiving a placebo or the aldose reductase inhibitor, sorbinil, for 5 yr. The concentration of galactitol was increased more than 30-fold in the retina and other tissues by galactosemia, and the increase was inhibited 90-96% in all tissues by sorbinil. The concentration of free myo-inositol was greater than normal in retinas of galactosemic dogs, and its concentration was not altered by the aldose-reductase inhibitor. The myo-inositol concentration likewise was greater than normal in the retinas of dogs that were diabetic for 2-4 months. The marked inhibition of polyol production and accumulation in the retina of sorbinil-treated galactosemic dogs was not associated with a comparable inhibition of retinopathy.

Aldehyde Reductase↗
PubMed1990

Arrest of glomerulopathy in diabetic dogs by improved glycaemic control.

In order to assess the extent to which the progression of diabetic glomerulopathy can be arrested or reversed by improved glycaemic control, glomerular structure has been assessed in dogs randomly divided between a non-diabetic group and three alloxan diabetic groups: dogs assigned to poor glycaemic control for five years (PC), dogs assigned to good glycaemic control for five years (GC), and dogs assigned to poor glycaemic control for 2.5 years followed by good glycaemic control for 2.5 years (P----GC). Glomerular volume, the fractional volume of mesangium as estimated by light microscopy and thickness of glomerular basement membrane as estimated by electron microscopy were significantly greater than normal at 2.5 years of poor glycaemic control, and were even greater at five years. Kidney weight and the frequency of glomerular obliteration were significantly greater than normal at five years of poor control. The development of these renal abnormalities was significantly inhibited if good glycaemic control was begun within the first weeks of diabetes. Good control following 2.5 years of poor control (group P----GC) arrested the progression of the renal abnormalities, but no reversal of the lesions toward normal was apparent.

Animals↗
PubMed1990

Nerve conduction velocity in dogs is reduced by diabetes and not by galactosemia.

To evaluate the role of hyperglycemia and excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes, motor nerve conduction velocity (MNCV) was measured in dogs alloxan diabetic or experimentally galactosemic for 5 years. Diabetic dogs in poor glycemic control showed a progressive decline of MNCV from baseline values. Diabetic dogs that had been randomly assigned to good glycemic control retained normal MNCV. Nondiabetic dogs made galactosemic by a 30% galactose diet developed erythrocyte polyol concentrations many-fold greater than in diabetic animals, but the MNCV remained unchanged and comparable to that of normal dogs. Nerve polyol levels, when compared in short-term diabetic dogs or dogs galactose-fed 2 to 4 months, were elevated at least as much by the galactose-rich diet as by diabetes. Thus, in dogs, excessive tissue polyol accumulation is associated with subnormal MNCV in diabetes, but not in experimental galactosemia.

Animals↗
PubMed1989

Hyperglycemia and development of glomerular pathology: diabetes compared with galactosemia.

Dogs were randomly assigned to experimental galactosemia or diabetes, or to a normal untreated group, and diabetic animals were then randomly assigned to either poor or good glycemic control. At five years duration, kidneys from the animals were compared by quantitative stereology. Glomerulopathy appeared in the poor control diabetes group, and the thickness of glomerular capillary basement membrane, the glomerular tuft volume, and the fraction of glomerulus occupied by mesangium were each significantly greater than normal. The capillary filtering surface area per glomerulus was supranormal also, but nonetheless was subnormal relative to glomerular volume. The development of glomerulopathy was significantly inhibited in dogs assigned to good glycemic control. In galactosemic animals, the basement membrane thickness was greater than normal, but the glomerular volume, fractional and absolute volumes of mesangium, and capillary filtering surface area remained normal. The polyol concentration in renal cortex seemed elevated by galactosemia no less than by diabetes, and was highest in galactosemia. The galactosemic animals are known to have developed a retinopathy morphologically comparable to that of diabetic patients and diabetic dogs. Thus, sequelae of hyperglycemia sufficient to produce glomerular basement membrane thickening and retinopathy proved not necessarily sufficient to produce the mesangial expansion and glomerular hypertrophy typical of diabetes.

Animals↗
PubMed1989

Pathogenesis of diabetic retinopathy.

Diabetic retinopathy involves anatomic changes in retinal vessels and neuroglia. The pathogenetic mechanism responsible for retinopathy is imperfectly understood, but much of the mechanism is apparently reproduced by experimental diabetes in animals and by chronic elevation of blood galactose in nondiabetic animals. The evidence that retinopathy is a consequence of excessive blood sugars and their sequelae is consistent with a demonstrated inhibition of retinopathy by strict glycemic control in diabetic dogs. However, retinopathy in the dog model has shown a tendency to resist intervention by strict control. Biochemical and pathophysiological sequelae of hyperglycemia possibly critical to the development of retinopathy in humans and animal models are being studied in many laboratories. Retinopathy occurs in experimental galactosemia in the absence of the renal hypertrophy, mesangial expansion, and glomerular obliteration typical of diabetes in humans and dogs, implying that retinopathy and nephropathy differ appreciably in pathogenesis.

Animals↗
PubMed1989

Comparison of DNA breaks in diabetic dogs and galactosemic dogs developing retinopathy.

DNA strand breaks have been evaluated in alloxan-diabetic dogs and experimentally galactosemic dogs, both animal models known to develop a retinopathy similar to that in diabetic patients. Lymphocytes were used as the source of DNA, and the presence of strand breaks was detected by monitoring the rate of alkali-induced DNA unwinding. The rate of DNA unwinding from dogs diabetic or galactosemic for up to 4 years was not significantly different from normal. These findings lend no support to previous reports that DNA strand breaks increase in diabetes or hyperglycemia. Retinopathy apparently can develop in the absence of DNA strand breaks, at least as estimated from lymphocytes.

Animals↗
PubMed1989

Inability to detect parasympathetic autonomic neuropathy in experimental canine diabetes mellitus in an electrocardiographic study.

Resting electrocardiography was used to evaluate parasympathetic control of the heart rate and heart rate variability in 25 adult alloxan-diabetic dogs and 34 nondiabetic controls. The duration of diabetes (mean +/- SEM) was 3.0 +/- 0.3 yr. Such long-term diabetes had no apparent effect on resting heart rate, maximum R to R interval variation, or percentage of subjects exhibiting respiratory sinus arrhythmia. In addition, despite significant differences in glycemic control between experimental groups, no differences in the above electrocardiographic parameters were demonstrated. Electrocardiographic indices of autonomic function were not significantly correlated with glycosylated hemoglobin concentration, age, or duration of diabetes. Up to 40% of diabetic humans develop autonomic neuropathy (diabetic autonomic neuropathy), with virtually all studies showing higher heart rates and greater heart rate variability in diabetics as compared to nondiabetic controls. The absence of electrocardiographic indicators of autonomic neuropathy in this study suggests that the dog is less susceptible to the development of diabetic autonomic neuropathy than is the diabetic human and therefore may be a poor model for many studies.

Animals↗
PubMed1988

Urinary protein excretion rates in experimentally diabetic dogs and experimentally galactosaemic dogs.

The relationship between urinary protein excretion and control of diabetes was evaluated in alloxan-diabetic dogs prospectively assigned to poor, moderate, or good glycaemic control. Protein excretion rate increased with the duration of insulin deficiency, and was significantly greater than normal in the poor control group by the fourth year of diabetes. Appreciable differences in the severity of the proteinuria were observed among animals of the poor and moderate glycaemic control groups; some of the animals excreted in excess of 500 mg protein/24 h while others excreted no more than normal throughout the 5 years of study. Differences in glycaemic control among these insulin-deficient animals seem not sufficient to account for the observed differences in protein excretion. Immunoassay for albumin indicated that the defect resulting in supranormal protein excretion was at least partly glomerular in origin. Good glycaemic control prevented the protein loss from exceeding normal. A potential role of hyperglycaemia in the development of proteinuria was examined in nondiabetic dogs made experimentally hyperglycaemic with galactose. Consumption of a 30% galactose diet for up to 5 years duration had little influence on protein excretion.

Animals↗
PubMed1987

Kidney morphology in experimental hyperglycemia.

To evaluate the role of hyperglycemia in the pathogenesis of diabetic nephropathy, the kidneys from dogs experimentally galactosemic for 5 yr have been compared with the kidneys from age-matched normal dogs and dogs with alloxan-induced diabetes for 5 yr. The width of glomerular capillary basement membrane and the quantity of plasma protein immunohistochemically demonstrable in the basement membrane were supranormal in the galactosemics, as they were in the diabetics. In contrast, kidney weight, mesangial volume, and the prevalence of obliterated glomeruli, glomerular exudates, and mesangial nodules in the galactosemic animals were comparable to those of normal animals and clearly were less than observed in the insulin-deficient diabetic animals. These galactosemic dogs are known to have developed a retinopathy morphologically indistinguishable from that of diabetic patients and dogs. Thus, galactosemia sufficient to produce diabetic-like lesions in the glomerular basement membrane and retina was found to be nevertheless insufficient to elicit several renal abnormalities that are typical of diabetes. The polyol concentration in erythrocytes was greater than normal in the galactosemics and the diabetics and was greatest in the galactosemics. The absence of mesangial expansion, glomerular obliteration, and nephromegaly in galactose-fed dogs raises the possibility that these abnormalities in diabetes are not a result of excessive polyol pathway activity.

Animals↗
PubMed1987

Progression of incipient diabetic retinopathy during good glycemic control.

To assess the extent to which the progression of diabetic retinopathy can be arrested by improved glycemic control, 35 normal dogs were randomly divided into a nondiabetic and three alloxan-induced diabetic groups prospectively identified according to glycemic control: poor control for 5 yr (PC), good control for 5 yr (GC), and poor control for 2.5 yr followed by good control for 2.5 yr (PGC). To achieve good control, insulin was given twice daily together with a measured diet so that hyperglycemia and glucosuria were mild and infrequent, and HbA1 was comparable to normal. Retinal capillary aneurysms and other lesions developed during 60 mo of poor control (group PC) and were inhibited if good control was begun promptly within 2 mo (group GC). In group PGC, retinopathy was absent or equivocal at 2.5 yr of poor control and, surprisingly, was found to develop subsequently despite good glycemic control. Retinopathy in group PGC was greater at autopsy than at 2.5 yr and was greater than in group GC. The results indicate that retinopathy may be preventable but tends to resist arrest even in its incipient stages, before more than the first few aneurysms have appeared.

Aneurysm↗
PubMed1986

Hyperglycemia as a cause of diabetic retinopathy.

Diabetes mellitus is marked by hyperglycemia and a variety of other metabolic disorders. The significance of hyperglycemia in the pathogenesis of diabetic retinopathy has proven difficult to evaluate in patients. Diabetic dogs are known to develop retinal lesions morphologically identical to those typical of diabetes in man, provided hyperglycemia in the animal is allowed to persist at least for many months and usually for 3 to 5 years. The development of retinopathy in this animal model can be inhibited by careful improvement of diabetic (glycemic) control. Comparable retinopathy has recently been found to develop in nondiabetic dogs as a result of experimental galactosemia of several years' duration. Included in this retinopathy and in the retinopathy of diabetic patients and dogs as well are saccular capillary aneurysms, hemorrhages, nonperfused or acellular vessels, varicose vessels, and loss of capillary pericytes. Retinal capillary basement membrane has been measured (to date) in two dogs that had been galactosemic for 5 years, and it was found to be significantly thicker than in normal dogs (P less than 0.01). Many metabolic abnormalities typical of diabetes are absent from galactosemic dogs. Unlike diabetic dogs, the blood levels of glucose, nonesterified fatty acids, branched-chain amino acids, and fibrinogen are not elevated in the galactosemic dogs, and their serum insulin concentration seems normal. Excessive blood hexose itself appears to be an important determinant of retinopathy. One possible mechanism by which excessive blood hexose might produce retinopathy involves the polyol pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗