Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mounting evidence indicates that aldose reductase catalyzed reduction of excess glucose to sorbitol initiates the onset of certain diabetic complications. However, the kidney contains a large amount of aldehyde reductase, another NADPH-dependent reductase. The study was designed to assess the importance of these reductases to sugar alcohol (polyol) production in the kidney. To study the ability to reduce aldoses to polyols, both aldose and aldehyde reductases were purified from rat kidneys. Incubation studies with purified enzymes clearly demonstrated the polyol formation by both enzymes. Galactose feeding induced polyol accumulation in both medulla and cortex of the rat kidney. Al 1576, a potent inhibitor of both enzymes, reduced this polyol accumulation in both cortex and medulla, while the selective inhibitors Ponalrestat or FK 366 resulted in greater inhibition in medulla than cortex. These results suggest that kidney polyols may be generated by both aldose and aldehyde reductases and that aldehyde reductase contributes to polyol production in the kidney cortex, the predominant site of diabetes-linked kidney lesions.
 ...
PMID:Rat kidney aldose reductase and aldehyde reductase and polyol production in rat kidney. 144 70

Aldose reductase is an NADPH-dependent oxidoreductase that catalyzes the reduction of a broad range of aldehydes, including glucose. Since aldose reductase has been strongly implicated in the development of the chronic complications of diabetes mellitus, much effort has been devoted to understanding the structure and mechanism of this enzyme, and many aldose reductase inhibitors have been developed as potential drugs for the treatment of these complications. We describe here the 2.75 A crystal structure of recombinant human aldose reductase (Cys-298 to Ser mutant) complexed with NADPH. This mutant displays unusual kinetic behavior characterized by high Km/high Vmax substrate kinetics and reduced sensitivity to certain aldose reductase inhibitors. The crystal structure revealed that the enzyme is a beta/alpha-barrel with the coenzyme-binding domain located at the carboxyl-terminal end of the parallel strands of the barrel. The enzyme undergoes a large conformational change upon binding NADPH which involves the reorientation of loop 7 to a position which appears to lock the coenzyme into place. NADPH is bound to aldose reductase in an unusual manner, more similar to FAD- rather than NAD(P)-dependent oxidoreductases. No disulfide bridges were observed in the crystal structure.
 ...
PMID:The crystal structure of the aldose reductase.NADPH binary complex. 144 21

The effect of 2 months aminoguanidine treatment on nerve conduction abnormalities was studied in streptozotocin-diabetic rats. Treatment with aminoguanidine from the induction of diabetes mellitus prevented a 22% decrease in sciatic motor nerve conduction velocity (p less than 0.001), and a 10% deficit in sensory saphenous conduction velocity (p less than 0.01). There was a 49% increase in resistance of sciatic nerve to hypoxic conduction failure in vitro. This was not significantly affected by aminoguanidine treatment. Sciatic nerve polyol pathway metabolites, sorbitol and fructose, were elevated 10-fold by diabetes (p less than 0.001). Myo-inositol levels were 18% decreased by diabetes. Aminoguanidine treatment had no significant effect on sorbitol, fructose or myo-inositol levels. Aminoguanidine has been identified as both an inhibitor of the formation of advanced glycation end products, and an aldose reductase inhibitor. The data suggest that beneficial actions on nerve function do not depend on the latter property. They support the notion that advanced glycation end products contribute to the aetiology of early diabetic neuropathy, possibly acting via a vascular mechanism, and that aminoguanidine treatment may have therapeutic applications.
 ...
PMID:Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats. 145 51

Diabetic nephropathy is a serious complication of insulin-dependent diabetes mellitus (IDDM) that affects 30% to 40% of IDDM patients with a predictable time of onset. Epidemiologic data suggest that either a genetic susceptibility, perhaps for hypertension (HTN), or an environmental exposure selects out that subset of IDDM patients and destines them to develop diabetic nephropathy. Hopefully, assessing glomerular hyperfiltration, urinary albumin excretion rate (AER), glycemic control, mean arterial pressure (MAP), and perhaps early morphologic changes will allow early identification of this high-risk group of IDDM patients before overt nephropathy is present. Once nephropathy appears, renal function inexorably declines, although the natural history of this progression may be changing with earlier therapeutic intervention. IDDM patients with nephropathy suffer a high mortality rate compared with IDDM patients without nephropathy or with nondiabetic end-stage renal disease patients. This is primarily due to malignant atherosclerotic disease manifested as coronary, peripheral, and cerebral arterial disease. Therapeutic interventions of demonstrated benefit in slowing the rate of decline of glomerular filtration rate (GFR) include blood pressure control and low-protein diets. Strict blood sugar control or treatment with aldose reductase inhibitors, converting enzyme inhibitors (CEIs), or inhibitors of advanced glycosylation end-product formation are of possible benefit, but are awaiting clinical trial results.
 ...
PMID:Diabetic nephropathy in insulin-dependent patients. 146 80

Diabetic nephropathy leading to kidney failure is a major complication of type I (insulin-dependent) diabetes mellitus and is associated with progressive proteinuria. In the present 6-month study, effects of two structurally dissimilar aldose reductase inhibitors (sorbinil and ponalrestat or Statil) were examined on prevention of proteinuria in insulin-dependent spontaneously diabetic BB rats and compared with age-matched BB resistant controls. Prior to aldose reductase inhibitor treatment, all diabetic BB rats exhibited hyperglycemia (> 300 mg/dl), glycosuria (> 2,000 mg/dl) and 24-hour urinary protein excretion ranging from 5.01 to 11.23 mg/day. After daily administration of ponalrestat (20 mg/kg) for 3 months, 24-hour urinary protein excretion was 11.53 +/- 1.76 mg/day in ponalrestat-treated rats, despite persistence of hyperglycemia (444 +/- 31 mg/dl) and glycosuria (> 2,000 mg/dl); by contrast, urinary protein excretion was 17.76 +/- 2.59 mg/day in the control group of untreated BB diabetic rats. Ponalrestat initially protected against excretion of an array of urinary proteins having molecular weights between 30,000 and 100,000 daltons. These effects sustained throughout the 4th month of treatment, tended to change toward valves in control rats by the 5th month. At the end of 6 months, ponalrestat-treated diabetic rats excreted 18.73 +/- 3.20 mg/day of protein, similar to valves in untreated BB diabetic rats; both demonstrated a 4-fold increase in urinary protein excretion when compared to age-matched BB resistant controls. Proteinuria was attributed to an increase in albumin and an array of proteins having molecular weights between 30,000 and 100,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Comparison of sorbinil and ponalrestat (Statil) diminution of proteinuria in the BB rat. 146 75

1. The aim of the study was to examine the effects in rats of two different doses of the aldose reductase inhibitor, ponalrestat, on functional measures of nerve conduction and sciatic nerve biochemistry. 2. After 1 month, streptozotocin-induced diabetes produced 22%, 23% and 15% deficits in conduction velocity of sciatic nerves supplying gastrocnemius and tibialis anterior muscles and saphenous sensory nerve respectively compared to controls. These deficits were maintained over 2 months diabetes. 3. Slower-conducting motor fibres supplying the interosseus muscles of the foot did not show a diabetic deficit compared to onset controls, however, there was a 13% reduction in conduction velocity after 2 months diabetes relative to age-matched controls, indicating a maturation deficit. 4. Resistance to hypoxic conduction failure was investigated for sciatic nerve trunks in vitro. There was an increase in the duration of hypoxia necessary for an 80% reduction in compound action potential amplitude with diabetes. This was progressive; after 1 month, hypoxia time was increased by 22% and after 2 months by 57%. 5. The effect of 1-month treatment with the aldose reductase inhibitor, ponalrestat, on the abnormalities caused by an initial month of untreated diabetes was examined. Two doses of ponalrestat were employed, 8 mg kg-1 day-1 (which is equivalent to, or greater than, the blockade employed in clinical trials), and 100 mg kg-1 day-1. 6. Sciatic nerve sorbitol content was increased 7 fold by diabetes. Both doses were effective in reducing this; 70% for 8 mg kg-1 day-1, and to within the control range for 100 mg kg-1 day-1.
 ...
PMID:Dissociation between biochemical and functional effects of the aldose reductase inhibitor, ponalrestat, on peripheral nerve in diabetic rats. 146 42

The metabolic effects of 52 weeks treatment with the aldose reductase inhibitor ponalrestat were examined in 32 diabetic patients (16 insulin treated) in a randomized, double-blind, placebo-controlled clinical trial. Twelve hour metabolic profiles were performed on two separate occasions in each patient (a) during a single-blind placebo run-in period and (b) after 52 weeks treatment with either ponalrestat 600 mg/day or matching placebo. No effects attributable to ponalrestat were evident in glucose, pyruvate, or alanine metabolism. A significant overall treatment effect was observed for lactate concentration (ponalrestat vs. placebo 12 h least square mean at 52 weeks: 1.35 vs. 1.65 mmol/l, p = 0.024). For glycerol (p = 0.018), non-esterified fatty acids (p = 0.003) and total ketone bodies (p = 0.045) there was evidence for a variation of treatment with time between the insulin treated and non-insulin treated patients, although no statistically significant overall treatment effects were observed for any metabolite. Fasting total ketone body concentration at 52 weeks was significantly elevated in the insulin-treated patients receiving ponalrestat (antilog LS mean: 0.12 vs. 0.01 mmol/l, p = 0.01). In conclusion, ponalrestat has no effect on glucose metabolism in diabetic patients. A potentially beneficial effect on lactate metabolism was accompanied by a minor ketogenic effect in insulin-treated patients.
Diabetes Res 1992 Jan
PMID:Metabolic effects of aldose reductase inhibition in diabetic man. 146 86

The effects of 3 months streptozotocin-induced diabetes mellitus on contraction and relaxation of aorta were examined in vitro. A further diabetic group was treated with a novel sulphonylnitromethane-based aldose reductase inhibitor for 3 months following diabetes induction. Diabetes resulted in reduced maximal tension production, particularly for responses to phenylephrine (p < 0.001) and serotonin (p < 0.001). However, with aldose reductase inhibitor treatment, responses were in the non-diabetic range. The ratio of maximum contractions to noradrenaline and phenylephrine were 28% elevated by diabetes (p < 0.01), which may suggest increased alpha 2-adrenoreceptor-mediated responses. Endothelium-independent relaxation to glyceryl trinitrate was unaffected by diabetes or treatment. By contrast, there were 38% deficits in endothelium-dependent relaxation to acetylcholine (p < 0.001) and Ca2+ ionophore A23187 (p < 0.001) with diabetes which were prevented by aldose reductase inhibitor treatment (p < 0.001). A 121% shift in the concentration giving a 50% maximum effect for acetylcholine towards lower sensitivity with diabetes (p < 0.001) was also largely corrected by treatment (p < 0.001). A non-diabetic group treated with aldose reductase inhibitor showed a 30% decrease in the 50% effective concentration for acetylcholine (p < 0.05). A 15% deficit in maximum relaxation to the ATP-sensitive K+ channel opener cromakalim for the diabetic group (p < 0.001) was prevented by aldose reductase inhibitor treatment (p < 0.01). We conclude that there are polyol pathway related abnormalities for contraction, some aspects of endothelium-independent relaxation, but particularly for endothelium-dependent relaxation in aorta from chronic streptozotocin-diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: role of polyol pathway. 147 11

Thickening of capillary basement membrane has been demonstrated in diabetic subjects, and it is considered to be the characteristic pathological lesion of diabetic microvascular disease. There are studies reporting the effects of inhibitors of aldose reductase, the first enzyme of the polyol pathway, on the thickening of the capillary basement membrane. These observations indicate a significant role of the polyol pathway in the development of microvascular disease. However, it is unknown whether or not there is any correlation between the thickness of the capillary basement membrane and the activity of aldose reductase in diabetic patients. To clarify this issue, we measured the width of skeletal-muscle basement membrane and erythrocyte aldose reductase activity in 27 insulin-dependent diabetic and 8 nondiabetic individuals. The results showed that both the aldose reductase activity and the width of capillary basement membrane were increased in diabetic patients as compared to nondiabetic individuals (6.89 +/- 0.38 versus 5.15 +/- 0.60 mL/mU erythrocytes, p < 0.05 and 2257 +/- 166 versus 1136 +/- 69 A, p < 0.0001, respectively) (mean +/- SE), but marked variability was observed in both the enzyme activity and the basement membrane thickness among the diabetic patients. There was a significant correlation between the capillary basement membrane thickness and the activity of erythrocyte aldose reductase (r = 0.51, p < 0.01) in diabetic patients. Our data suggest that the polyol pathway plays an important role in thickening of capillary basement membrane in diabetic individuals, and the variability in aldose reductase activity seen among diabetic patients may result in the varying susceptibility to the development of diabetic microvascular disease.
J Diabetes Complications
PMID:Correlation between erythrocyte aldose reductase activity and the width of skeletal-muscle capillary basement membrane in insulin-dependent diabetes mellitus. 148 82

Although the enhanced activity of the polyol pathway has been detected in diabetic glomeruli, the intraglomerular localization of this pathway has not yet been well defined. In this study, we attempted to identify aldose reductase, a key enzyme of the polyol pathway, in cultured rat mesangial cells and to characterize the properties of this enzyme using enzymological and immunological methods. When the aldose reductase (DL-glyceraldehyde-reducing) activity was analyzed in mesangial cell extract, the Lineweaver-Burk plot showed concave downward curvature, and the Michaelis constant was 0.83 mM DL-glyceraldehyde, and this activity was noncompetitively inhibited by an aldose reductase inhibitor, ICI-128,436. The enzyme activity was enhanced by the addition of sulfate ion and partially suppressed by barbital. The enzyme cross-reacted with the antisera against rat lens and testis aldose reductases on Ouchterlony plate, and migrated to the region of molecular weight of about 36,500 Da on Western blotting. The presence of aldose reductase mRNA was also confirmed by Northern analysis using cDNA for rat aldose reductase, 10Q. From these results, it was concluded that the aldose reductase may exist in rat glomerular mesangial cells and may play a role in the development of diabetic glomerulopathy, though the coexistence of aldehyde reductase(s) may not be fully ruled out.
Diabetes 1992 Sep
PMID:Identification and characterization of aldose reductase in cultured rat mesangial cells. 149 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>