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

Insulin has been shown to lower cyclic AMP (cAMP) levels in hormonally sensitive tissue. The mechanism by which this lowering occurs has not yet been fully defined. We studied the effects of insulin on rat adipose tissue cyclic nucleotide phosphodiestrase (PDE) in an incubation system. The adipose tissue used was from both normal animals and animals rendered diabetic by intravenous injections of streptozotocin. Rat epididymal fat pads were incubated in a Krebs-Ringer bicarbonate-4% albumin system with O, 100, 1,000 or 10,000 PU/ml insulin (INS); epinephrine (EPI) or glucagon (GLU) at several different concentrations. After 15 min of incubation, each tissue was homogenized, centrifugated, and the supernatant assayed for cAMP PDE activity using the breakdown of (3-H)cAMP. The data was used to characterize cAMP PDE into apparent high and low K-m PDE components. In the normal animals, INS increased Vmax of the low Km PDE components; 100 pU/ml INS, 30%, 1000 p1/ML INS, 40; and 10,000 pU/ml INS, 20%. In contrast, streptoxotocin diabetes lowered this Vmax by 30%. In the diabetic animals, INS also increased Vmax by 30%. In the diabetic animals, INS also increased Vmax of the low Km PDE component; 100 pU/ml INS, 30%; 1000 pU/ml INS, 50% and 10,000 pU/ml INS, 100%. Epinephrine at 1, 10, and 100 pg/ml stimulated low Km cAMP PDE activity by 67%, 73% and 44% respectively. The stimulatory effect of EPI on both the low and high Km cAMP PDE activity was neutralized by propranolol or adenosine. In comparison to EPI, GLU at very low concentrations, 10-9M, stimulated low Km cAMP PDE. These studies suggest that some of the biologic actions of insulin, an antilipolytic substance, are mediated through activation of low Km PDE. Furthermore, this enzymatic activity is lower in experimental diabetes. The stimulation of low Km PDE by lipolytic hormones may reflect a long-range protective action of these agents.
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PMID:Effect of insulin and lipolytic hormones on cyclic AMP phosphodieterase activity in normal and diabetic rat adipose tissue. 16 58

Concentrations of serum cholesterol, triglyceride, and free glycerol were neasured, and serum lipoprotein electrophoresis was performed in normal dogs and in dogs with hypothyroidism, diabetes mellitus, and acute pancreatitis. Twelve privately owned dogs and 20 Basset Hounds from a research colony served as normal subjects. Privately owned had higher serum lipid concentrations than did research dogs. On electrophorisis of normal dog serum, lipoprotein bands were detected at the beta, pre-beta, alpha-2, and alpha-1 positions. Hypercholesterolemia was associated with increased intensity of the alpha-2-lipoprotein band, and hypertriglyceridemia occurred with increased lipoprotein at the origin, or the beta or pre-beta positions. Hypothyroid dogs had normal lipid values and lipoprotein electrophoretic patterns, hypercholesterolemia with increased intensity of the alpha-2-lipoprotein band, or hypercholesterolemia and hypertiglyceridemia with prominent beta-, pre-beta, and alpha-2-lipoprotein electrophoretic patterns were changed to near-normal values after levothyroxine administration. Diabetic dogs had increased serum cholesterol and triglyceride content and a predominance of lower density lipoproteins, as detected by electrophoresis. Insulin therapy caused the lipid concentrations to decrease and the electrophoretic pattern to revert to near normal. Dogs with acute pancreatitis had moderately increased serum lipid content and electrophoretic patterns characterized by increased intensity of the beta-lipoprotein band and by altered migration of alpha-1-lipoproteins.
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PMID:Lipids and lipoproteins in normal dogs and in dogs with secondary hyperlipoproteinemia. 16 57

Incorporation of alanine-U-14C into glucose and liver glycogen increased linearly over sixty-five hours in culture of human fetal liver explants. This rate of incorporation was stimulated two- to tenfold by incubation with N6,2'O-dibutyryl adenosine 3'-5:cyclic monophosphate (dibutyryl cyclic AMP) (0.1 mM) plus theophylline (0.5 mM) or glucagon (7.5 mug./ml.) plus theophylline. No apparent lag period was detected, and the hormonal effect continued throughout the observation period. Insulin (1 U./ml.) significantly decreased both the basal rate of incorporation and the stimulated rate resulting from dibutyryl cyclic AMP or glucagon incubation. These effects were observed at both high (10mM) and low (2.8 mM) media glucose and from both 2.3 muM and 5 mM alanine-U-14C. Triamcinolone (20 mug./ml.) alone stimulated the rate of alanine-U-14C incorporation into glucose, whereas triamcinolone in the presence of dibutyryl cyclic AMP produced an increase in incorporation greater than the sum of the individual effects. The basal incorporation of alanine-U-14C into glucose by these human fetal liver explants provide a rate of approximately 4 nmoles glucose/gm. min, which is discussed in relation to the physiologic needs of the fetus and newborn.
Diabetes 1975 Jul
PMID:Hormonal regulation of incorporation of alanine-U-14C into glucose in human fetal liver explants. Effect of dibutyryl cyclic AMP, glucagon, insulin, and triamcinolone. 16 72

The presence of insulin receptors in the heart muscle was investigated by measuring the binding of 125I-insulin to specific subcellular fractions of the rat and mouse myocardium. 125I-insulin bound to the plasma membrane fraction with a high degree of specificity and affinity. Insulin analogues competed with 125I-insulin in direct proportion to their biologic potency in vitro. Unlabeled insulin within the range of its concentrations in vivo inhibited 15 to 60 per cent of the 125I-insulin binding. The specific binding sites were finite in number and represented about 90 per cent of the total binding. The insulin-binding capacity of the plasma membrane fraction was twelve- to fifteenfold higher than that of the mitochondrial fraction. As in the liver, the binding was time- and temperature-dependent with a slower but higher binding achieved at a lower temperature. The binding sites appeared to be heterogeneous with respect to affinity. At 5 degrees C., the "higher-affinity" site had a K of about 2 times 10(9) M-1. No more than 10 per cent of the 125I-insulin was degraded by the heart plasma membranes after one hour at 30 degrees C. or twenty-two hours at 5 degrees C. Studies in the obese hyperglycemic (ob/ob) mouse revealed that the insulin binding is impaired in the heart muscle of this animal. Over a wide range of insulin concentrations, the plasma membrane fraction of ob/ob mice bound only 25 to 40 per cent as much insulin as did membranes of the thin littermates, suggesting that, as in the liver, the fat tissue, and the thymic lymphocyte, the number of insulin-binding sites is decreased in the heart of the ob/ob mouse. This defect selectively affected the plasma membrane fraction and could not be explained by differences in membrane purification or insulin-degrading activity. Heart and liver membranes of forty-hour fasted ob/ob mice bound two to three times as much insulin as did membranes of ob/ob mice fed ad libitum. These studies demonstrate and characterize the binding of insulin to heart muscle membranes; they extend to the heart muscle the insulin receptor defect also found in liver membranes and cells, in fat cell membranes, and in thymic lymphocytes of the ob/ob mouse.
Diabetes 1975 Aug
PMID:Insulin receptors in the heart muscle. Demonstration of specific binding sites and impairment of insulin binding in the plasma membrane of the obese hyperglycemic mouse. 16 73

Glycogen accumulates in human fetal liver beginning at the eighth week of gestation. A parallel increase in total glycogen synthase activity is found, although the I-form activity remains low and constant throughout the first two thirds of gestation. Total phosphorylase activity increases slightly during this period, with the proportion in the active form amounting to about one half of the total throughout. After an initial rapid decline, the glycogen concentration in explants of human fetal liver remained constant for twenty to forty hours at about 20 per cent of the in vivo level. Incubation with glucagon, cyclic AMP (adenosine 3',5'-monophosphate) or its dibutyryl derivative markedly reduced tissue glycogen concentrations while insulin brought about a small increase. The effect of maximal doses of dibutyryl cyclic AMP and glucagon were the same, and the combination of agents produced no further effect. The response to dibutyryl cyclic AMP was apparent by one hour and maximal by three to six hours, whereas the response to insulin required about six hours to be detected, and it continued for at least eighteen hours. Insulin antagonized the glycogenolytic effect of low doses of glucagon or theophylline but was without significant effect in the presence of high glucagon concentrations. Glucagon stimulated cyclic AMP output from explants, and this effect was further augmented by theophylline. Insultin had no consistent effect on cyclic AMP output in either the presence or the absence of glucagon or theophylline. Incubation with dibutyryl cyclic AMP resulted in a decrease of glycogen synthase I-form activity, while insulin tended to increase this enzyme activity. In neither circumstance was the proportion of active phosphorylase altered. These results suggest that the regulation of glycogen levels in human fetal liver by cyclic AMP, glucagon, and insulin may entail alterations in the activity of glycogen synthase activity without necessitating alterations in phosphorylase activity. Cyclic AMP or glucagon was capable of depleting tissue glycogen stores in tissue from fetuses of six weeks' gestation. Insulin increased tissue glycogen concentrations in tissue from fetuses of seven or more weeks.
Diabetes 1975 Dec
PMID:Hormonal regulation of glycogen metabolism in human fetal liver. I. Normal development and effects of dibutyryl cyclic AMP, glucagon, and insulin in liver explants. 17 97

In order to study human insulin resistance, we have first characterized the interaction of insulin with specific insulin receptors in cultures of normal human fibroblasts. 125 I-insulin bound rapidly to human fibroblasts in suspension at 15 degrees, achieving steady state between one and three hours. Insulin was not degraded during the binding assays. In competitive binding experiments, 2 ng/ml. (3.3 X 10(-10) M) of unlabeled insulin reduced 125 I-insulin binding by 50 per cent. Insulin analogues competed for binding in proportion to their biologic potencies. A curvilinear Scatchard plot was obtained, suggesting the existence of negatively cooperative site-site interactions among the insulin receptors. This was confirmed directly by studies of the dissociation kinetics. The high affinity, specificity, and negative cooperativity of the fibroblast insulin receptor closely resembles the properties of other human insulin receptors. The cultuted human fibroblast should prove a useful tissue for the study of insulin-resistant states in man.
Diabetes 1976 Apr
PMID:Insulin receptors in cultured human fibroblasts. 17 54

Supplementation of rat lymphocyte cultures with plasma from alloxan-diabetic rats produced a dose-dependent suppression of mitogen-induced blastogenic responses. Viability measurements indicated that this inhibition was not due to a direct cytotoxic effect of alloxan-diabetic plasma on rat mononuclear leukocytes in vitro. This inhibition was not explained by hyperglycemia alone and was observed when blastogenesis was induced in vitro by phytohemagglutinin (PHA), concanavalin A (con A), or allogeneic cells. Peripheral blood lymphocytes from alloxan-diabetic rats appeared to be more sensitive than normal cells to the inhibitory effect of diabetic plasma. Heating at 56 degrees for 60 minutes produced only a partial loss of the inhibition by diabetic plasma. Alloxan-diabetic rat plasma promoted an increased accumulation of adenosine 3',5'-monophosphate (cyclic AMP) in mononuclear leukocytes. Insulin (1 and 100 muU./ml.) in vitro enhanced PHA-induced blastogenesis but failed to reverse the inhibition caused by diabetic plasma. Ultrafiltration through a cellulose dialysis membrane with an exclusion size of 12,000 molecular weight did not remove the inhibitory factor(s). These results indicate that a depressed cellular immune response is produced during an insulin-deficient diabetic state. The suppressed in-vitro blastogenic response of lymphocytes from alloxan-diabetic rats appears to involve some circulating inhibitory factor(s) in diabetic plasma. This inhibition may be explained, in part, by the ability of diabetic plasma to elevate cyclic AMP in mononuclear leukocytes.
Diabetes 1976 Jul
PMID:Inhibition of lymphocyte blastogenesis by factor(s) in alloxan-diabetic rat plasma. 17 6

1. Epinephrine-induced increase in rat liver cyclic AMP in vivo was potentiated when the circulating insulin was suppressed by injection of anti-insulin serum or by induction of diabetes. Consequently, phosphorylase was activated, glycogen synthetase was inactivated and glycogen accumulation induced by glucose load was prevented by epinephrine in the insulin-deficient rats to a much larger extent than in normal rats. 2. Insulin lack was effective in potentiating epinephrine-induced increase in liver and muscule cyclic AMP even after the treatment of rats with theophylline; the potentiation could not be solely accounted for by the inhibition of cyclic AMP phosphodiesterase. Thus, it is likely that insulin lack enhaces epinephrine activation of adenylate cyclase. 3. Unlike epinephrine, glucagon increased liver cyclic AMP to essentially the same extent whether the rat was treated with anti-insulin serum or not. 4. Based on the difference in dose-response curves between normal and insulin-deficient rats, a possibility is discussed that there are two adenylate cylase in the liver with higher and lower affinities for epinephrine and that circulating insulin blocks the high affinity enzyme selectively.
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PMID:Attenuation of epinephrine-induced increase in liver cyclic AMP by endogeneous insulin in vivo. 18 27

The frequency of latent disorders of glucose regulation during pheochromocytoma, is evaluated at 75% of cases. Detailed analysis of 83 cases with a diabetic state, gave the following results: insulin dependent diabetes, 37 cases. Non-insulin dependent, 14 cases. Latent diabetes, 32 cases. The characteristics of the insulin-dependent diabetes were not always suggestive. Insulin dependency was, however, unusual above a certain age. We noted loss of weight in spite of good control of the diabetes, the absence of acidosis and ketosis contrasting with rapid loss of weight. In fact, it is above all the hypertension which should lead to diagnosis. Surgical operation, cures or improves considerably the diabetic state, thus proving the symptomatic nature of this diabetes.
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PMID:[Diabetes mellitus in pheochromocytoma]. 18 6

The activity of two triglyceride lipases was determined by an immunochemical method in the postheparin plasma of 60 diabetic patients and of 47 age- and sex-matched nondiabetic control subjects. The results were related to the type of diabetes, to plasma triglyceride and insulin concentrations, to removal of exogenous fat from the blood, and to turnover of VLDL-triglycerides . The mean postheparin plasma lipoprotein lipase (LPL) activity was decreased by 44 per cent (p less than 0.001) in patients with untreated ketotic diabetes and by 20 per cent (p less than 0.01) in patients with untreated mild to moderate nonketotic early-onset diabetes. Insulin treatment of ketotic diabetes resulted in a rapid increase in the activity of LPL and decrease in serum triglycerdie level, whereas sulfonylurea treatment of non-insulin-requiring diabetics did not significantly influence the enzyme activity. In insulin-treated chronic diabetics the average postheparin plasma LPL activity was not different from that of nondiabetic controls, but some of these patients had high LPL values. In normolipidemic maturity-onset-type diabetics the LPL activity was within normal range, but in those having hypertriglyceridemia the average LPL value was decreased by an average of 26 per cent (p less than 0.01). The LPL activity showed a significant negative correlation with the logarithm of serum triglyceride concentration (r = -0.62) and a positive correlation with fractional removal of Intralipid (r = +0.64) and fractional turnover of V triglyceride (r = +0.40). The activity of LPL was correlated to basal plasma insulin concen tration in the insulin-deficient diabetes r = +0.34) but not in patients with maturity-onset-type diabetes. The hepatic lipase (HL) activity of postheparin plasma was similar in diabetes and controls, with the exception of hypertriglyceridemic maturity-onset diabetics, who had higher mean HL activity than the corresponding control group (p greater than 0.01). The activity of HL was not related to triglyceride removal but showed a significant correlation to VLDL-triglyceride production rate. On the basis of these results it seems that a deficiency of LPL accounts for a great deal of the elevation of serum triglyceride in insulin-deficient human diabetes but has a smaller role in the pathogenesis of the hypertriglyceridemia that is associated with maturity-onset diabetes. The latter abnormality is caused mainly by an increased secretion of triglycerides into the blood even though a decreased LPL may contribute to development of hyperlipemia in cases with gross elevation of serum triglycerides.
Diabetes 1977 Jan
PMID:Postheparin plasma lipoprotein lipase and hepatic lipase in diabetes mellitus. Relationship to plasma triglyceride metabolism. 18 16


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