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)

The urinary excretion of two low-molecular-weight proteins (beta 2-microglobulin and retinol-binding protein) was measured in 12 insulin-dependent diabetic patients with persistent microalbuminuria and an equal number with normal albumin excretion; reference ranges for the excretion of beta 2-microglobulin (beta 2M) and retinol-binding protein (RBP) were also obtained in 40 non-diabetic subjects. To ensure the stability of beta 2M in urine a urinary pH greater than or equal to 7 was achieved by giving oral sodium bicarbonate. beta 2M and RBP excretion was significantly higher in the diabetics than in the controls (p less than 0.01), but no higher in microalbuminuric than non-albuminuric diabetics. In the diabetics as a group a significant correlation was found between the excretion of beta 2M and RBP (r = 0.53, p less than 0.01), but more patients had an abnormal excretion of beta 2M than RBP (p less than 0.001). No significant correlation was found between the urinary excretion of either low-molecular-weight protein and duration of diabetes, insulin dose, HbA1, urinary glucose excretion or systemic blood pressure. Measured under appropriate alkaline conditions beta 2M appears to be more sensitive than RBP in detecting an abnormality of the renal proximal tubule which may be an early feature of diabetic renal involvement not characterized by microalbuminuria; microalbuminuria may have glomerular and tubular components.
Diabetes Res 1989 Sep
PMID:Low-molecular-weight proteinuria in insulin-dependent diabetes mellitus: a study of the urinary excretion of beta 2-microglobulin and retinol-binding protein in alkalinized patients with and without microalbuminuria. 269 3

Diabetes mellitus is associated with important changes in renal hemodynamics and transport function. Disturbances in solute transport have also been characterized in nonrenal tissues during hyperglycemia and insulinopenia. The purpose of this study was to determine if diabetes is associated with adaptive changes in function of the brush-border membrane of the proximal tubule. We studied Na+ and glucose transport in rat microvillus membrane vesicles isolated from the renal cortex of streptozotocin-induced and BB/W autoimmune diabetic rats. Untreated diabetes was associated with an increase in pH-stimulated total and amiloride-sensitive 22Na+ uptake into vesicles. Insulin treatment returned vesicle 22Na+ uptake to control levels. The increased Na+/H+ exchange was shown to be a result of increased net renal acid production rather than a specific response to insulinopenia because treatment with NaHCO3 also returned 22Na+ uptake to control levels. On the other hand, Na+-glucose cotransport, which was depressed in vesicles from untreated diabetics, returned to control levels with insulin but not NaHCO3 administration. This decreased Na+-glucose cotransport was not secondary to reduction in transport sites in untreated diabetics. These results show that in diabetes mellitus, increased Na+/H+ exchange activity is not the direct result of insulinopenia. However, the diabetic state appears to alter the functioning of the luminal Na+-glucose cotransporter.
 ...
PMID:Sodium-hydrogen exchange and glucose transport in renal microvillus membrane vesicles from rats with diabetes mellitus. 300 62

In previous studies in the Sprague-Dawley rat, Williams and coworkers reported the phenomenon of selective urinary excretion of glucosylated albumin (editing, i.e., the percent glucosylation of urinary albumin is more than that of plasma albumin) by the mammalian kidney. Ghiggeri and coworkers subsequently found that the extent of editing is reduced in human diabetics. Moreover, the reduction in editing in diabetes correlates inversely with levels of microalbuminuria. We also find reduction in the extent of editing in diabetic humans. We find a striking inverse correlation not only with the magnitude of microalbuminuria but also with the extent of plasma albumin glucosylation. In contrast, we found little correlation between the reduction in editing and the duration of diabetes in human subjects. Stz induced diabetes in the Sprague-Dawley rat is associated with a striking and rapid reduction in editing which develops virtually with the same kinetics exhibited by the appearance of hyperglycemia. This loss of editing is rapidly reversed by daily administration of insulin but not by aldose reductase inhibitors. Mannitol infusion in anesthetized Wistar rats resulted in an increase in urine volume, GFR, and microalbuminuria, and was also accompanied by a marked reduction in editing. This reduction was rapidly reversed by a cessation of mannitol infusion. We propose here that glucosylated albumin (in contrast to unmodified albumin) is not reabsorbed by the proximal tubule, and thus, is preferentially excreted in the urine. We postulate that the increase in GFR which emerges as a consequence of increased plasma osmolality in diabetes mellitus delivers more albumin to the proximal tubule than can be reabsorbed. This results in a dilution of excreted glucosylated albumin molecules by excreted unmodified albumin, which appears as the early microscopic albuminuria of diabetes. Paradoxically, the fall in apparent editing is accompanied by an absolute increase in the total quantity of glucosylated albumin excreted. In contrast, we found that editing of glucosylated albumin by the normal kidney is found to gradually decline as a function of age without the appearance of microalbuminuria. This suggests that a different mechanism operates to produce the loss of editing seen with aging in man, and as clearly (but in a shorter absolute time intervals) in the Fischer-344 rat.
 ...
PMID:Suggested mechanism for the selective excretion of glucosylated albumin. The effects of diabetes mellitus and aging on this process and the origins of diabetic microalbuminuria. 311 57

The substrate specificities of calcium/phospholipid-dependent kinase-C (PKC) were examined in rat kidney cortex, and localization of the protein was studied after the induction of diabetes. The cytosolic kinase was eluted from an anion exchange resin using a linear gradient of 0-0.15 M NaCl. A sharp peak of activity was demonstrated at approximately 80 mM using histone as a substrate. The kinase demonstrated a broad pH optimum of 6.5-8.0. ATP was the preferred phosphorus donor. The Ka for ATP averaged 2.6 +/- 0.1 microM (n = 4) and was not different in diabetic animals. Lysine-rich histones, but not arginine-rich or mixed histones, were the most suitable phosphorus acceptors. Phosphatidylserine stimulated kinase activity with Ka of 4.5 +/- 0.7 microM in the presence of 20 microM diolein (n = 3). Twenty micromolar diolein in the presence of 25 microM phosphatidylserine lowered the apparent Ka for calcium from 17.2 +/- 1.4 to 3.3 +/- 1.5 microM (n = 3; P less than 0.01). Similar data were evident in diabetic animals. Diabetic renal growth was induced by the injection of streptozotocin (35 mg/kg, iv). At the end of 4 weeks, blood glucose averaged 119.6 +/- 7.4 mg/dl in vehicle-injected controls and 548.7 +/- 21.6 mg/dl in diabetic animals (n = 5; P less than 0.001). Despite reduced weight gains in diabetic animals, renal protein content was increased in this group compared to the control value. Neither cytosolic nor proximal tubule basolateral membrane PKC activity changed after the induction of diabetes; however, luminal brush border PKC activity increased from 83.8 +/- 4.6 pmol/mg.min in control animals to 107.3 +/- 55 pmol/mg.min in diabetic animals (n = 5; P less than 0.02). The increased activity in the brush border membrane may have important consequences for the growth response of the kidney in diabetes.
 ...
PMID:Characterization and localization of calcium/phospholipid-dependent protein kinase-C during diabetic renal growth. 340 97

We examined the hypothesis that the reduced accumulation of aminoglycoside in renal cortex of rats with streptozotocin-induced diabetes mellitus (DM) is secondary to lower rates of tubular transport of drug compared with non-DM rats. Using whole kidney clearance techniques we found that the fractional excretion of [3H]netilmicin in DM rats rose from an initial value of 92.4 +/- 1.3% to 101 +/- 4.5% (N = 10) after eight 20-min periods. These values were not significantly different from those of non-DM rats (96.4 +/- 1.8 and 106.7 +/- 1.4%, respectively, N = 7). The plasma concentration of drug was similar in the two groups whereas inulin clearance and the filtered load of drug were higher in DM rats. In both groups microinjection experiments revealed the presence of an absorptive flux of [3H]netilmicin along the proximal tubule and loop of Henle, but no absorptive flux was detected along the distal nephron. In free-flow micropuncture experiments in DM rats a net secretory flux of netilmicin was detected in the early proximal tubule and a net absorptive flux was detected along the loop of Henle, presumably the pars recta. No net flux occurred along the distal tubule. These findings are similar to those previously reported by us for non-DM rats. At the end of the clearance experiments the concentration of netilmicin in renal cortex of DM rats (56 +/- 5 micrograms/g wet wt.) was significantly less (P less than .01) than that in the renal cortex of non-DM rats (122 +/- 6 micrograms/g wet wt).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Renal handling of netilmicin in the rat with streptozotocin-induced diabetes mellitus. 357 81

Urinary N-acetyl-beta-D-glucosaminidase (NAG), a lysosomal hydrolase located the proximal tubule of the kidney, has been used as a marker for subtle renal injury. In humans and other animals with diabetes mellitus, urinary NAG activity has been shown to increase within 12 hours of the onset of hyperglycemia and glycosuria. Whether the rise in urinary NAG activity is in response to the hyperglycemia or to the osmotic diuresis associated with glycosuria is not known, nor has the time course of the rise in enzyme activity been determined. A study was designed using four groups of dogs to examine these possibilities: group 1 (n = 5), control dogs; group 2 (n = 5), mannitol-infused dogs; group 3 (n = 5), low-glucose dogs; and group 4 (n = 5), high-glucose dogs. In groups 2 and 4, mannitol and glucose, respectively, were infused at a rate to double urine flow from the left ureter without altering the contralateral urine volume. In group 3, sufficient glucose was infused to elevate left renal vein glucose level without producing glycosuria. In the control dogs infused with normal saline solution at a constant rate throughout the control and study periods, no differences were found in urinary NAG excretion when data from individual clearance periods were compared for the right and left kidneys. In the low-glucose dogs, urinary NAG/creatinine ratios were significantly increased (P less than 0.01) when the left and right kidneys were compared for the duration of the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Differential response of urinary N-acetyl-beta-D-glucosaminidase to two osmotic diuretics in the dog. 392 47

Urinary N-acetyl-beta-D-glucosaminidase (NAG), a proximal tubule lysosomal enzyme, has been used as an indicator of subtle renal injury. Since it has been positively and significantly correlated with hemoglobin A1c and microalbuminuria, it has been suggested that this enzyme may also reflect metabolic control. Albumin excretion is exacerbated in adult diabetic individuals during exercise; such exercise-induced albuminuria may be a forerunner of diabetic nephropathy. Metabolic control, degree of exertion, and duration of diabetes have been suggested to influence this increase in albuminuria during exercise. Studies of children are few and have produced inconsistent results. Thus we studied 28 insulin-dependent diabetic children ranging in age from 5 yr to 16 yr and 27 age-matched controls using treadmill exercise; two exercise periods consisting of (1) graded increases in speed and grade at 3-min intervals until exhaustion and (2) a constant speed and grade necessary to produce 2/3-3/4 maximal heart rate for 30 min were performed. Capillary blood glucose, urinary NAG/creatinine (cr) ratios (UNAG/Ucr) and urinary albumin/creatinine ratio (Ualb/Ucr) were measured before and after each exercise period; hemoglobin A1c was also measured. The latter averaged 11.8 +/- 0.6% (mean +/- SEM); contrary to previous studies, this was not correlated with pre- or postexercise UNAG/Ucr. During both exercise periods, blood glucose dropped 271 +/- 19 mg/dl to 213 +/- 21 mg/dl (period 1) and 230 +/- 22 mg/dl to 157 +/- 21 mg/dl (period 2).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Care
PMID:Effect of exercise on urinary N-acetyl-beta-D-glucosaminidase activity and albumin excretion in children with type I diabetes mellitus. 405 33

The effects of acutely administered streptozotocin in the male guinea pig were studied for a period of 18 days following treatment. A single intracardiac injection of streptozotocin (150 mg/kg) was administered on Day 0. On Day 2, plasma glucose concentrations were not significantly different from control levels. On Day 7 and 18, an oral glucose tolerance test was performed with streptozotocin-treated animals receiving an acute injection of either insulin (18 U/kg, i.m.) or saline 90 minutes prior to glucose loading. On Day 7, streptozotocin-treated animals receiving saline had significantly elevated plasma and urine glucose concentrations at 3 hours after glucose loading when compared to controls. Streptozotocin-treated animals receiving insulin however, had significantly lower plasma glucose concentrations at 3 hours while urinary glucose was equal to control values. The second glucose tolerance test performed on Day 18 yielded similar results. Necropsies were performed on animals that died after Day 6. Lesions found in the streptozotocin-treated animals included: small and irregular pancreatic islets, pyknotic nuclei and degranulation of beta cells, renal proximal tubule swelling and vacuolization, adrenal cortical hyperplasia, hepatocyte vacuolization, and visceral fat atrophy. Animals surviving until Day 18 were sacrificed and found to have significantly elevated kidney and adrenal weights compared to controls. These changes illustrate the effectiveness of streptozotocin in the acute chemical induction of diabetes in an animal model (guinea pig) which, like humans, requires a dietary source of ascorbic acid.
 ...
PMID:Effects of streptozotocin in the male guinea pig: a potential animal model for studying diabetes. 623 25

Beta-2 microglobulin (beta 2 M) is a low molecular weight protein filtered by the renal glomerulus, then reabsorbed and metabolized at the proximal tubule. Its blood concentration is a good renal index, as it is independent from muscle mass and diet contrary to creatinine. We assayed serum beta 2 M in 190 cases of diabetes mellitus divided into 71 non-insulin-dependent and 119 insulin-dependent forms. We found no significant difference between both groups. Serum beta 2 M was not correlated with Hb A 1 C. Conversely, a highly significant positive correlation between beta 2 M and serum creatinine and a negative correlation between beta 2 M and creatinine clearance were demonstrated. Furthermore, patients with borderline serum creatinine and those with normal renal function show very significant differences in mean serum beta 2 M concentrations, thus making combined assay of both parameters advisable. On the other hand, we were unable to evaluate modifications in beta 2 M according to other complications of diabetes mellitus as vascular and neurologic involvement are very often associated with renal dysfunction.
 ...
PMID:[Beta 2 microglobulin in diabetic patients. Apropos of 190 subjects]. 632 52

Filtered proteins including insulin are absorbed in the proximal tubule by means of pinocytosis. The first step in this process is binding of the protein to brush border membrane. As it is not known whether absorption exhibits specificity, we set out to determine whether specific binding sites for insulin are present in brush border membranes. Rabbit-isolated brush border membranes were incubated with 125I-insulin and varying concentrations of cold insulin or other peptide hormones. Binding and degradation of 125I-insulin occurred in a time- and temperature-dependent manner. Native insulin competitively inhibited 125I-insulin binding, but calcitonin, arginine vasopressin, glucagon, and growth hormone (10(-6) M) were relatively ineffective. Nonspecific binding averaged one-third of the total radioactivity bound. Scatchard analysis of binding data revealed two classes of insulin receptors: high affinity, low capacity receptors and low affinity, high capacity receptors. Gel filtration analysis of 125I-insulin exposed to brush border membrane revealed the formation of low-molecular-weight products similar to that produced by intact kidneys. The degrading process exhibited some specificity, for cold insulin (10(-6) M) was more effective than calcitonin, vasopressin, glucagon, or growth hormone in inhibiting degradation (32% versus less than 13% inhibition; P less than 0.01). Whether this reflects inhibition of insulin specific binding before exposure to degradation or inhibition of specific enzymes is unclear. In summary, it appears that renal brush border membranes have a major insulin-specific receptor component that could potentially mediate tubular insulin absorption. In addition, there is a smaller nonspecific component that may also have the potential to mediate insulin absorption. Finally, it appears that brush border membranes have the ability to degrade insulin to low-molecular-weight products by a process that exhibits some specificity for insulin.
Diabetes 1982 Jul
PMID:Binding and degradation of insulin by isolated renal brush border membranes. 676 Dec


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