Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study is to explore whether the renal and cardiovascular response to clonidine in type II diabetic patients is different from that in control subjects, and to clarify the role of central alpha 2-receptor in the regulation of cardiovascular response and sodium handling in type II diabetes mellitus (DM). Thirty-five diabetic inpatients aged 30-71 years (54.1 +/- 9.7) and ten control subjects (N) were enrolled in this study after their fasting plasma glucose had been improved. To evaluate the peripheral sympathetic nerve activity, 24-hour urinary catecholamine was measured, and pulse rate (PR) responses to a 30-second standing test was determined. On another day, blood pressure (BP), PR, plasma norepinephrine (PNE), cyclic AMP (p-cAMP), renin activity (PRA), aldosterone (PAC) and growth hormone (p-GH) were measured at 0, 30, 60, 90, 120, 150, 180 minutes following the oral administration of clonidine (150 micrograms). Type II DM were classified as DM with hyper-response (DM-HR, n = 12) when their PR decreased after clonidine more than that of N, and if not, they were classified as DM with normal response (DM-NR, n = 23). Urinary catecholamine excretions in type II DM were within the normal range. BP, PNE and p-cAMP were markedly decreased with clonidine in similar fashion in DM-NR, DM-HR and N. The percent changes of PNE were correlated positively with the changes of p-cAMP in both N and DM-NR (r = 0.660 and 0.449, respectively), but not in DM-HR. No significant difference in the changes of p-GH (delta p-GH) and integral of GH (the area under the curve) following clonidine administration was observed in the three groups. The decrease in PR was correlated with neither delta p-GH (N: r = 0.082, DM-NR: r = -0.400, DM-HR: r = 0.242) or integral of GH (N: r = 0.191, DM-NR: r = 0.382, DM-HR: r = 0.162). The fractional excretion of sodium (FENa) decreased in N (p < 0.01), increased in DM-NR (p < 0.05) and did not change in DM-HR. The changes of FENa were not correlated with those of PRA and PAC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Altered responses of heart rate, renal sodium handling and plasma growth hormone to clonidine in type II diabetic patients]. 133 89

Slow infusion of neutral insulin causes in patients with insulin dependent and noninsulin dependent diabetes mellitus diverse changes in the levels of cAMP, cGMP and the cAMP/cGMP ratio in leukocytes in spite of one-type changes in the concentration of contrainsular hormones in the venous blood: in patients with noninsulin dependent DM a raised cAMP/cGMP factor was lowered whereas in patients with insulin dependent DM it was increased. The authors put forward for discussion the problem of the postreceptor mechanisms of tissue insulin resistance in noninsulin dependent DM and a possibility of the use of the above indices for differential diagnosis of DM types.
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PMID:[Intracellular metabolism in patients with insulin-dependent and non-insulin-dependent diabetes mellitus]. 185 91

The influence of diabetes mellitus on phosphodiesterase (PDE) activity in human sc adipose tissue was investigated in 8 patients with insulin-dependent (IDDM) and 9 with noninsulin-dependent (NIDDM) diabetes mellitus. The results were compared with data from 10 healthy normal weight subjects. The apparent maximal PDE activity (Vmax) of the low Km form of PDE was 60% lower (P less than 0.01) in untreated IDDM and NIDDM than in the control state. After treatment of IDDM and NIDDM, the Vmax of the low Km PDE was normalized. In untreated IDDM and NIDDM, the Vmax of the low Km PDE was correlated to the cAMP level (r = 0.8). This correlation was not observed after antidiabetic treatment or in the control state. The apparent Vmax values of the high Km form of PDE were similar in the diabetic states and in control subjects. The results suggest that the low Km PDE is inhibited in untreated IDDM and NIDDM. In these conditions, PDE may be one factor responsible for regulation of the cAMP level.
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PMID:Phosphodiesterase activity in human subcutaneous adipose tissue in insulin- and noninsulin-dependent diabetes mellitus. 628 60

This study was undertaken to investigate the effect of experimental type 2 diabetes in the rat on the insulin and glucagon receptors and on the early steps of glucagon action. The binding of insulin and glucagon and the glucagon-stimulated cyclic AMP accumulation in the presence of a phosphodiesterase inhibitor (IBMX, 0.1 mmoles/l) were studied in liver cells isolated from 7-9-month-old rats with chronic type 2 diabetes and from control rats. No significant change was observed in [125I] insulin binding and [125I]glucagon binding of diabetic liver cells as compared to controls. Scatchard analysis of the competition experiments indicated that affinity and number of insulin and glucagon receptors were not significantly changed in the liver cells of diabetic rats. The basal cyclic AMP level was significantly lower in the diabetic hepatocytes (2.3 +/- 0.9 pmoles/10(6) cells) than in the controls (4.0 +/- 0.6 pmoles/10(6) cells). Cyclic AMP response to physiological concentrations of glucagon (0.1-1 nmoles/l) was about 2 times lower in the diabetic hepatocytes than in the controls. Furthermore, the basal liver membrane adenylate cyclase activity and the fluoride-activatable adenylate cyclase activity were about 2 times lower in the diabetics as compared to control rats, while the liver cyclic AMP and cyclic GMP phosphodiesterase activities were unchanged. The ability of glucagon to stimulate liver membrane adenylate cyclase over a 10(-12)-10(-6) M concentration range was decreased in diabetic rats. Taken together, these data are consistent with the thesis that the impairment of the liver cyclic AMP response to glucagon in rats with type 2 diabetes is caused by a decrease in the amount of adenylate cyclase in the liver plasma membranes.
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PMID:Decreased glucagon-stimulated cyclic AMP production by isolated liver cells of rats with type 2 diabetes. 631 52

Non-insulin-dependent diabetes (NIDDM) was obtained in adult rats following a neonatal streptozotocin injection. Rats with NIDDM exhibited slightly lowered plasma insulin, slightly elevated basal plasma glucose values (less than 200 mg/dl), and low pancreatic insulin stores (50% of the controls). Insulin secretion was studied in this model using the isolated perfused pancreas technique. Insulin response to glucose stimulation over the range 5.5-22 mM was lacking, thus indicating complete loss of B-cell sensitivity to glucose. Even in presence of theophylline, the B-cells remained insensitive to glucose. In contrast, glyceraldehyde elicited an insulin release as important as that obtained in the control pancreata. This could possibly suggest that the B-cell dysfunction in rats with NIDDM involves a block in glucose metabolism in the early steps of glycolysis prior to the triose-phosphate. Mannose stimulated insulin secretion less in the diabetics than in the controls. The insulin secretion obtained in response to isoproterenol indicated that the ability of the adenylcyclase to generate cAMP in the B-cells of the diabetics was not decreased. The insulinotropic actions of acetylcholine and tolbutamide were normal and increased, respectively, as compared with the controls. In the absence of glucose, the B-cells of the diabetics were unexpectedly hypersensitive to arginine and leucine. The alpha-ketoisocaproate effect in the diabetics was not significantly different from that obtained in the controls. The possibility that enhancement of insulin response to leucine in the diabetics might be related to a more active conversion of leucine to ketoisocaproate along the first steps of intraislet leucine metabolism is proposed.
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PMID:Glucose insensitivity and amino-acid hypersensitivity of insulin release in rats with non-insulin-dependent diabetes. A study with the perfused pancreas. 634 Nov 28

Glucose-dependent insulinotropic polypeptide (GIP) plays an important role in the regulation of postprandial insulin secretion and proinsulin gene expression of pancreatic beta-cells. This study demonstrates the molecular cloning of a cDNA for the GIP-receptor from a human insulinoma lambda gt11 cDNA library. The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids which showed high homology (41%) to the human glucagon-like peptide 1 (GLP-1) receptor. Homology to the GIP receptor from rat or hamster was 79% and 81%, respectively. When transfected stably into fibroblast CHL-cells a high affinity receptor was expressed which coupled to the adenylate cyclase with normal basal cAMP and increasing intracellular cAMP levels under stimulation with human GIP-1-42 (EC50 = 1.29 x 10(-13) M). The receptor accepted only human GIP 1-42 (Kd = 1.93 +/- 0.2 x 10(-8) M) and porcine truncated GIP 1-30 (Kd = 1.13 +/- 0.1 x 10(-8) M) as high affinity ligands. At 1 microM, exendin-4 and (9-39)amide weakly reduced GIP-binding (25%) whereas secretin, glucagon, glucagon-like peptide-1, vasoactive intestinal polypeptide, peptide histidine-isoleucine, and pituitary adenylyl cyclase activating peptide were without effect. In transfected CHL cells, GIP-1-42 did not increase intracellular calcium. Northern analysis revealed one transcript of human GIP receptor mRNA with an apparent size of 5.5 kb. The exact understanding of GIP receptor regulation and signal transduction will aid in the understanding of the incretin hormone's failure to exert its biological action at the pancreatic B-cell in type II diabetes mellitus.
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PMID:Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. 758 26

Insulin treatment of platelets is associated with increased prostaglandin E1-stimulated adenylyl cyclase activity and decreased platelet aggregation. Because non-insulin dependent (Type II) diabetes mellitus is associated with hyperinsulinemia, we sought to determine the effect of insulin treatment in vivo and in vitro upon stimulation of platelet adenylyl cyclase by prostaglandin E1. Incubation of platelet-rich plasma obtained from normal subjects with 2 microM prostaglandin E1 resulted in a 16-fold increase in cAMP accumulation. Pre-incubation of platelet-rich plasma with 0.7 nM insulin resulted in a 62% increase in prostaglandin E1 (2 microM)-stimulated cAMP accumulation (p < 0.005). Pretreatment of platelets with cholera toxin prior to incubation with insulin had no effect on subsequent prostaglandin E1-stimulated cAMP accumulation. By contrast, pretreatment of platelets with pertussis toxin prior to incubation with insulin resulted in a nearly 2-fold increase in prostaglandin E1-stimulated cAMP accumulation (p < 0.005). To determine whether platelets exposed in vivo to elevated concentrations of insulin would show similar responses, we isolated platelet-rich plasma from subjects before and after a 120 minute euglycemic clamp study in which insulin was infused (40 mU m-2min-1) intravenously. Patients who underwent the euglycemic clamp study achieved steady state serum levels on insulin of 0.70 +/- 0.19 pmol/ml. Platelets obtained after insulin infusion had a 65% increase in prostaglandin E1-stimulated cAMP. Our results indicate that serum levels of insulin that are common in patients with type II diabetes mellitus can increase the sensitivity of platelet adenylyl cyclase to stimulation by prostaglandin E1.
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PMID:The effects of in vitro and in vivo exposure to insulin upon prostaglandin E1 stimulation of platelet adenylate cyclase activity in healthy subjects. 764 95

Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon, which is processed alternatively by tissue-specific proteolysis to produce glucagon in the pancreatic alpha cells and a GLP-1 in the intestines. GLP-1 hormone is released into the circulation from intestinal L cells in response to meals and is the most potent incretin hormone known; GLP-1 and GIP appear to account for most, if not all, of the intestinal incretin effect in the augmentation of glucose-stimulated insulin secretion. Analyses of the mechanisms of action of GLP-1 and of glucose on isolated cultured rat beta cells using patch-clamp techniques to record ion channel activities has led to the glucose competence concept in which the combined glucose-signaling and GLP-1/cAMP-signaling pathways are required to affect depolarization of beta cells and to thereby stimulate insulin secretion. It is hypothesized that, among other possible target channels, the K-ATP channel is key first event in GLP-1/glucose-mediated activation of the beta cell secretory response. It is proposed that at least one factor contributing to the pathogenesis of NIDDM is a desensitization of the GLP-1 receptor on beta cells induced by the hypersecretion of GLP-1. Because of the discoveries that GLP-1 stimulates both secretion and production of insulin, and that the actions of GLP-1 are entirely glucose-dependent, GLP-1 may provide unique advantages over the sulfonylurea drugs in the treatment of NIDDM.
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PMID:The incretin notion and its relevance to diabetes. 812 72

Potentiation of glucose-induced insulin secretion by intestinal factors has been described for many years. Today, two major peptides with potent insulinotropic action have been recognized: gastric inhibitory peptide and truncated forms of glucagon-like peptide I, GLP-I(7-37) or the related GLP-I(7-36)amide. These hormones have specific beta-cell receptors that are coupled to production of cAMP and activation of cAMP-dependent protein kinase. Elevation in intracellular cAMP levels is required to mediate the glucoincretin effect of these hormones: the potentiation of insulin secretion in the presence of stimulatory concentrations of glucose. In addition, circulating glucoincretins maintain basal levels of cAMP, which are necessary to keep beta-cells in a glucose-competent state. Interactions between glucoincretin signaling and glucose-induced insulin secretion may result from the phosphorylation of key elements of the glucose signaling pathway by cAMP-dependent protein kinase. These include the ATP-dependent K+ channel, the Ca++ channel, or elements of the secretory machinery itself. In NIDDM, the glucoincretin effect is reduced. However, basal or stimulated gastric inhibitory peptide and glucagon-like peptide I levels are normal or even elevated, suggesting that signals induced by these hormones on the beta-cells are probably altered. At pharmacological doses, infusion of glucagon-like peptide I but not gastric inhibitory peptide, can ameliorate postprandial insulin secretory response in NIDDM patients. Agonists of the glucagon-like peptide I receptor have been proposed as new therapeutic agents in NIDDM.
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PMID:Glucagon-like peptide-I and the control of insulin secretion in the normal state and in NIDDM. 834 31

A complementary DNA for a glucagon-like peptide-1 receptor was isolated from a human pancreatic islet cDNA library. The isolated clone encoded a protein with 90% identity to the rat receptor. In stably transfected fibroblasts, the receptor bound [125I]GLP-1 with high affinity (Kd = 0.5 nM) and was coupled to adenylate cyclase as detected by a GLP-1-dependent increase in cAMP production (EC50 = 93 pM). Two peptides from the venom of the lizard Heloderma suspectum, exendin-4 and exendin-(9-39), displayed similar ligand binding affinities to the human GLP-1 receptor. Whereas exendin-4 acted as an agonist of the receptor, inducing cAMP formation, exendin-(9-39) was an antagonist of the receptor, inhibiting GLP-1-induced cAMP production. Because GLP-1 has been proposed as a potential agent for treatment of NIDDM, our present data will contribute to the characterization of the receptor binding site and the development of new agonists of this receptor.
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PMID:Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. 840 12


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