Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperglycemia and impaired glucose tolerance are well known phenomena occurring in patients with renal failure. In contrast to true diabetic subjects, an elevated ratio of insulin to glucose during the glucose tolerance test is consistently observed indicating a peripheral insulin insensitivity. Among the possible reasons, a disturbance at the cellular level seems to be most likely. There is some evidence of reduced peripheral glucose utilization on the one hand and increased hepatic glucose output--probably by stimulation of gluconeogenesis--on the other. Agents that have been suggested to be involved in these alterations of carbohydrate metabolism in uremia are hormones, electrolytes, pH, and "toxic" metabolic intermediates or end-products. Of these, an increase in insulin antagonistic hormones; among them growth hormone, catecholamines, and glucagon, seems to be of most significance. Although for the individual hormones no equivocal correlation with glucose intolerance has been proved, the interaction of all of them may result in a preponderance of insulin antagonism thus leading to an apparent insulin resistance.
 ...
PMID:Carbohydrate metabolism in renal failure. 2 64

Chronic renal failure results in a variety of metabolic derangements that perturb glucose homeostasis. These may in part result from the fact that the kidney plays a prominent role in the metabolism of insulin as well as a number of other low-molecular-weight peptide hormones that affect carbohydrate metabolism. Specific abnormalities in glucose utilization that appear to be related to alterations in membrane receptors, resulting in increased glucagon sensitivity and decreased insulin action, are a newly recognized factor in intolerance to oral glucose. Glucose production and utilization are both abnormally increased in patients with chronic uremia, and these disturbances are only partially corrected by hemodialysis treatment. The mechanism(s) contributing to these changes is unclear, but seems to involve a combination of humoral and cellular factors. These include some degree of insulin resistance, probably inadequately modulated proteolytic responses to glucagon and parathyroid hormone, and a basic defect in energy production that alters intracellular concentrations of high-energy phosphate-containing nucleotides. It is unclear whether these changes in carbohydrate tolerance pose an increased risk for the premature development of cardiovascular disease in patients with renal failure, as they appear to do in the nonuremic population. The occasional patient with renal failure may develop clinical hypoglycemia when glucose utilization continues in a setting in which the hepatic capacity to produce glucose is reduced, probably as a consequence of altered substrate delivery and/or inhibition of one or more key gluconeogenic enzymes.
 ...
PMID:Disorders of glucose metabolism in uremia. 11 52

3', 5'-Adenosine monophosphate (cAMP) levels were determined in skeletal and heart muscle tissue of rats in chronic renal failure. Compared to normal animals no alteration in cAMP concentration was observed in heart muscle, whereas the cAMP levels in skeletal muscle were increased by 34%. This cAMP rise may be caused by the elevated plasma catecholamines, glucagon or parathyroid hormone levels in uraemia. The results suggest that the increased cAMP levels in skeletal muscle of rats in chronic renal failure contribute to the raised cAMP levels in the plasma.
 ...
PMID:[Raised cAMP content of striated muscle in experimental chronic renal failure (author's transl)]. 17 Nov 31

Plasma lipids and lipoproteins were studied in a group of chronic uraemia patients some of whom were maintained by regular haemodialysis. Compared with healthy individuals, there was a significant increase in plasma triglycerides and in the prebeta-1- and prebeta-2-lipoprotein plasma concentrations. There was no difference between dialyzed and undialyzed patients. Carbohydrate intake was normal, basal plasma insulin and free fatty acid levels were within the normal range. There was no correlation between plasma triglyceride levels and the degree of hypoalbuminaemia, the latter being marked in 30% of the patient. Basal plasma glucagon levels were very high in nearly all dialyzed patients and post-heparin lipoprotein-lipase activity was very low in dialyzed patients. In our experience, regular haemodialysis for 32 weeks did not improve hypertriglyceridaemia.
 ...
PMID:Lipids and lipoproteins in chronic uraemia. A study of the influence of regular haemodialysis. 17 95

To investigate the role of glucagon and insulin receptor binding in the glucagon hypersensitivity and insulin resistance which characterize the glucose intolerance of uremia, liver plasma membranes were prepared from control rats (blood urea nitrogen [BUN] 15+/-1 mg/100 ml, creatinine 0.7+/-0.2 mg/100 ml), and from 70% nephrectomized rats (BUN 30+/-2 mg/100 ml, creatinine 2.2+/-0.2 mg/100 ml), and from 90% nephrectomized rats (BUN 46+/-3 mg/100 ml, creatinine 4.20+/-0.7 mg/100 ml), 4 wk after surgery. As compared to controls, the 90% nephrectomized rats had significantly higher levels of plasma glucose (95+/-4 vs. 125+/-11 mg/100 ml), plasma insulin (28+/-9 vs. 52+/-11 muU/ml), and plasma glucagon (28+/-5 vs. 215+/-18 pg/ml). Similar, but less marked, elevations were observed in the 70% nephrectomized animals. In liver plasma membranes from nephrectomized rats, specific binding of (125)I-glucagon was increased by 80-120%. Furthermore, glucagon (2 muM)-stimulated adenylate cyclase activity in nephrectomized rats was twofold higher than in controls. In contrast, fluoridestimulated adenylate cyclase activity was similar in both groups of rats. In marked contrast to glucagon binding, specific binding of (125)I-insulin to liver membranes from nephrectomized rats was reduced by 40-50% as compared to controls. Data analysis suggested that the changes in both glucagon and insulin binding are a consequence of alterations in binding capacity rather than changes in affinity. Liver plasma membranes from nephrectomized rats degraded (125)I-glucagon and (125)I-insulin to the same extent as control rats. THESE RESULTS DEMONSTRATE THAT: (a) the 70 and 90% nephrectomized rats simulate the hyperglycemia, hyperinsulinemia, and hyperglucagonemia observed in clinical uremia; (b) in these animals specific binding of glucagon to liver membranes is increased and is accompanied by higher glucagon-stimulated adenylate cyclase activity; and (c) specific binding of insulin is markedly decreased. These findings thus provide evidence of oppositely directed, simultaneous changes in glucagon and insulin receptor binding in partially nephrectomized rats. Such changes may account for the hypersensitivity to glucagon and may contribute to resistance to insulin observed in the glucose intolerance of uremia.
 ...
PMID:Glucagon and insulin binding to liver membranes in a partially nephrectomized uremic rat model. 700 82

Glucose tolerance and insulin and glucagon secretion were investigated in two groups of uremic patients, respectively on conservative and hemodialytic treatment. For this purpose, a glucose infusion was performed in the fasting state. Glucose intolerance was observed in uremic patients; hemodialysis improved, but did not normalize the glucose disposal. In uremic patients both on conservative and dialytic treatment plasma insulin and glucagon levels were higher than in the control group; the pattern of glucagon suppression was well maintained. The data obtained suggest that glucose intolerance in uremia is related mainly to peripheral insulin resistance and is not due to hyperglucagonemia.
 ...
PMID:Glucose intolerance in uremia (A- and B-cell function during conservative and dialytic management. 61 88

Lipid metabolism was studied in experimental uremia. Uremic (U) rats were compared with sham-operated, pair-fed (PF) controls and with ad-lib-fed (AL) controls. In U animals, fasting glucose concentrations were normal, immunoreactive serum insulin (IRI) levels were decreased, and immunoreactive glucagon levels were increased. A significant increase in the serum concentration of all lipid classes was observed: triglycerides were elevated 10-fold above the values in PF and AL controls; phospholipids, twofold; total cholesterol, threefold; and free cholesterol, sixfold. Cholesterol concentration was increased in beta- and pre-beta-lipoproteins and even more so in alpha- and pre-alpha-lipoproteins. There was an increase in the ratio of free cholesterol/total cholesterol. The fatty acid composition of serum lipoproteins was unchanged. Concomitantly, in liver tissue, there was no change in lipid content (triglyceride, cholesterol) and fatty acid composition. These findings argue against glucose- or insulin-mediated changes in hepatic de novo fatty acid synthesis, chain elongation, or poly-desaturation. In U animals, the HMG-CoA-reductase activity of liver microsomes was slightly, but not significantly, reduced as was tritiated water incorporation into cholesterol in isolated perfused liver preparations. In adipose tissue, there was a decrease in triglyceride content. The results provide evidence against insulin-mediated hepatic overproduction as a major cause of hyperlipoproteinemia in this model of experimental renal insufficiency and point to peripheral under-utilization of lipoproteins.
 ...
PMID:Hyperlipoproteinemia in experimental chronic renal insufficiency in the rat. 69 73

The pathogenesis of glucose intolerance in uremia was examined with the glucose clamp technique. Hyperglycemic clamp (n = 8): The plasma glucose concentration is acutely raised and maintained at 125 mg/dl above basal levels. Under these steady state conditions the glucose infusion rate, M, equals the amount of glucose metabolized: Predialysis M averaged 4.23 +/- 0.36 mg/kg/min and increased to 7.71 +/- 0.43 postdialysis (p less than 0.001). The plasma insulin response predialysis was 90 +/- 20 microU/ml and decreased to 80 +/- 23 microU/ml following dialysis. Consequently the M/l ratio, a measure of tissue sensitivity to insulin, increased by 80% +/- 25% (p less than 0.001) but still remained less than controls (p less than 0.01). Euglycemic insulin clamp (n = 10): The plasma insulin concentration is acutely raised by 100 microU/ml and the plasma glucose concentration is held constant at the basal level. Predialysis both M (3.37 +/- 0.36 mg/kg/min) and M/l (3.56 +/- 0.33 mg/kg/min per microU/ml X 100) were significantly less than controls (p less than 0.01). Postdialysis both M and M/l increased significantly (p less than 0.01) to a mean that was not significantly different from controls. Basal hepatic glucose production (n = 6), 2.15 +/- 0.09 mg/kg/min, was similar to controls and fell (87% +/- 4%) normally during the insulin clamp. In five uremic subjects in wom insulin binding to monocytes was measured, there was no correlation with tissue sensitivity to insulin (M/l). Significant abnormalities in both growth hormone and glucagon physiology were present in uremic individuals, but no correlation with either the presence or degree of glucose intolerance was demonstrable. In conclusion, glucose intolerance is universally present in uremic subjects and results primarily from peripheral tissue insensitivity to insulin. Insulin secretion is usually enhanced in an attempt to compensate for this insulin resistance but in occasional subjects uremia also inhibits beta cell sensitivity to glucose. Hepatic glucose production is unaffected by uremia. The lack of correlation between insulin binding and tissue sensitivity to insulin suggests that the cellular mechanism accounting for the insulin resistance is probably the result of a defect in intracellular metabolism or in the glucose transport system.
 ...
PMID:Pathogenesis of glucose intolerance in uremia. 72 38

Fasting levels of 5 gut hormones were studied in 30 patients with advanced uraemia (CRF), 40 undergoing regular dialysis (RD) and 555 renal transplant patients (RT). Mean values of gastrin and total glucagon were markedly elevated in CRF and RD patients compared with 20 normal subjects; there were lesser elevations in pancreatic glucagon, insulin and vasoactive intestinal peptide (VIP). Secretin levels were unchanged. In RT patients, fasting levels of VIP and pancreatic glucagon had returned to normal, while levels of gastrin, total glucagon and insulin remained slightly elevated compared with controls. Food stimulated hormone levels were measured in 18 RD patients and compared with 18 controls. After eating, RD patients failed to show the late increase in total glucagon, or the suppression of VIP and secretin seen in normal subjects; the pattern of gastrin and insulin response was similar to controls, but after the initial increase plasma levels in RD patients tended to show a slower decline. Thus involvement of the gastrointestinal tract in uraemia is associated with functional disturbance of the endocrine system of the gut.
 ...
PMID:Elevations of gastrointestinal hormones in chronic renal failure. 74 Jun 78

The salient information regarding the effects of uremia and dialysis on each of the metabolic fuels and hormones presented in the preceding sections is summarized in three tables. Tables 1 and 2 provide data on plasma levels, metabolism, dialysance, and literature references for each substance. Table 3 organizes the data according to the general mechanisms by which uremia and chronic dialysis may affect biological substances. Together these tables provide a reasonably complete summary of the information presently available. The pathophysiology of the uremic syndrome is still incompletely understood. The numerous metabolic and endocrine alterations associated with uremia and chronic dialytic therapy underscore the complexity of the problem and identify several specific areas for future research. One which deserves emphasis is the poolic and endocrine abnormalities found in uremia. A recent review by Chantler and Holliday (63) stressed in the importance of protein-calorie deficiency in the pathogensis of growth retardation and disturbed hormonal metabolism in children with chronic renal failure. The importance of this factor in adult patients with chronic uremia has been less well appreciated. However, striking similarities exist between the metabolic and endocrine abnormalities found in protein-calorie malnutrition and those found in uremia. These include, for example, altered albumin and amino acid metabolism, decreased levels of serum transferrin, peripheral insulin resistance and carbohydrate intolerance, elevated levels of glucagon, cortisol and growth hormone, and possibly diminished secretion of thyrotropin and thyroxine. Although not absolutely identical, the similarities between these two clinical syndromes suggest intriguing possible approaches to a better understanding of the pathophysiology of the uremic syndrome and its treatment.
 ...
PMID:Endocrinology and metabolism in uremia and dialysis: a clinical review. 80 79


1 2 3 4 5 6 Next >>