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)

Glucokinase (ATP:D-glucose-6-phosphotransferase), expressed exclusively in liver and pancreatic islet beta-cells, catalyzes the first step of glycolysis and acts as glucose sensor and metabolic signal generator in these tissues. The enzyme plays a key role in glucose homeostasis and as such is an excellent candidate for inherited defects predisposing to non-insulin-dependent diabetes mellitus (NIDDM). A compound-imperfect dinucleotide (CA)n repeat element was found approximately 10-kb 3' of the human glucokinase gene on chromosome 7p, which revealed polymorphism with alleles differing in size by 2-15 nucleotides in unrelated individuals. A polymerase chain reaction assay was developed, and genomic DNA from 275 biologically unrelated American black individuals was typed for glucokinase alleles. The differences in allelic frequencies between individuals with NIDDM and nondiabetic individuals were compared. After typing 112 diabetic and 163 nondiabetic subjects, we found five different-sized alleles, with Z defined as the most common allele, Z + 2, Z + 4, Z + 10, and Z - 15. The Z allele was more common in nondiabetic subjects than in diabetic patients (60.4 vs. 49.6%, P = 0.012). The Z + 4 allele was more common in diabetic patients than in nondiabetic subjects (20.1 vs. 12.0%, P = 0.009). After adjusting for age, sex, and body mass index, the Z + 4 allele continued to have a positive association with NIDDM (P = 0.0018), and the Z allele had a negative association with NIDDM (P = 0.0334). The Z + 4 allele, transmitted as an autosomal dominant trait, appeared to be the most significant one at this locus.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Jul
PMID:Glucokinase gene is genetic marker for NIDDM in American blacks. 161 98

ATP-sensitive K+ channels (KATP channels) are known to play a key role in the cellular mechanism of insulin secretion from pancreatic beta cells. In order to examine the possible impairment of KATP channel function in non-insulin-dependent diabetes mellitus (NIDDM), we have studied the properties of the KATP channels in single beta cells of neonatally streptozotocin-induced diabetic rats (NSZ rats) using the patch-clamp technique. The unitary conductance of the channel in diabetic beta-cells was virtually identical to that in control beta cells and there was no difference in the sensitivity to ATP and glibenclamide of KATP channels between the NIDDM and control groups. In response to glucose, the activity of the KATP channels was diminished in a dose-dependent manner in both control and diabetic cells. However, the inhibition of the KATP channels in beta-cells of NSZ rats was significantly less than that in control cells. Even in the presence of 11.1 mM glucose, the openings of a few single KATP channels were consistently observed in cell-attached patch membranes of diabetic, but not control, beta-cells. Thus, it appears that the impaired insulinotropic action of glucose in beta-cells in NSZ rats is associated with a reduced sensitivity of the KATP channel to glucose, but not to ATP, presumably due to a deficiency in glucose metabolism.
Diabetes 1992 Jul
PMID:Impaired glucose sensitivity of ATP-sensitive K+ channels in pancreatic beta-cells in streptozotocin-induced NIDDM rats. 161 1

Antidiabetic sulfonylureas act through receptors coupled to ATP-dependent potassium channels. Using the binding of [3H]glibenclamide, a highly potent sulfonylurea, to rat brain membranes to follow the purification procedure, we extracted from ovine brain, purified, and partially characterized two peptides that are endogenous ligands for the central nervous system sulfonylurea receptors. These peptides, referred to as alpha and beta endosulfine, differ by their isoelectric points, the beta form being more basic. Each form of endosulfine is recognized equally by the sulfonylurea receptors from the central nervous system and from insulin-secreting beta cells. In the same concentration range that is active on the receptors, beta endosulfine releases insulin from a beta-cell line. Endosulfine is a good candidate for being implicated in the physiology of beta cells and their disorders (e.g., type II diabetes) and in certain pathologies related to modifications of ion fluxes.
 ...
PMID:Endosulfine, an endogenous peptidic ligand for the sulfonylurea receptor: purification and partial characterization from ovine brain. 163 Nov 65

The effect of molybdate, tungstate, molybdate plus H2O2 or tungstate plus H2O2 on 3-O-methylglucose (3-O-MG) uptake was studied in isolated rat adipocytes to investigate whether these agents possess an insulin-like action. High concentrations (10-30 mM) of molybdate or tungstate significantly stimulated the uptake of 3-O-MG while 1 mM of the metaloxides did not. The combination of 1 mM molybdate and 1 mM H2O2, or 1 mM tungstate and 1 mM H2O2 induced striking stimulation of the uptake of 3-O-MG in a synergistic manner, whereas 1 mM H2O2 alone showed only a small effect. The effect of metaloxides plus H2O2 (1 mM) and the effect of insulin (20 nM) were not additive, and both effects were ATP or energy dependent based on experiments using KCN. These results indicate that a weak insulin-like effect of molybdate or tungstate is potentiated synergistically with H2O2, presumably by producing peroxocompounds. Based on the present findings, these new agents may be useful for investigating the mechanism of insulin action and may indicate a new class of drugs for diabetes mellitus.
 ...
PMID:Synergism in insulin-like effects of molybdate plus H2O2 or tungstate plus H2O2 on glucose transport by isolated rat adipocytes. 163 32

1. The effects of diabetes of 6 months' duration on autonomic function of the vas deferens were examined in spontaneously diabetic BB rats and diabetes-resistant BB rats. 2. Diabetes caused significant decreases in rat and testes weights, but had no effects on the weights of vasa deferentia compared to diabetes-resistant controls. 3. The contractile responses of vasa deferentia to nerve stimulation and to carbachol were increased compared to controls. However, the contractile responses of vasa deferentia from diabetic BB rats to ATP, phenylephrine, and 120 mM KCl were unaltered. 4. The increased responses to carbachol were associated with increases in the muscarinic receptor density, but no changes were detected in the number of dihydropyridine binding sites. 5. The data indicate that, in contrast to vasa deferentia from streptozotocin-diabetic rats which exhibit decreases in responsiveness to nerve stimulation and a non-specific supersensitivity to contractile agents, vasa deferentia from diabetic BB rats have no changes in sensitivity, and increased contractile responses to only nerve stimulation and carbachol. These differences in urogenital sensitivity to diabetes may be related to the insulin treatment which diabetic BB rats require to keep them alive.
 ...
PMID:In vitro contractile responses of vasa deferentia from spontaneously diabetic BB rats. 164 3

We studied both autophosphorylation and phosphotransferase activity of insulin receptors from abdominal skeletal muscles of nonobese subjects with non-insulin-dependent diabetes mellitus (NIDDM). Partially purified insulin receptors were labeled on their alpha-subunit with 125I-labeled insulin by chemical cross-linking and on their beta-subunit by autophosphorylation with 1000 microM ATP. Thereafter, phosphorylated insulin receptors were separated from total receptors with the anti-phosphotyrosine antibody. Thus, the percentage of phosphorylated receptors in total receptors revealed the autophosphorylation activity. Using this method, we studied the function of insulin receptors from muscle obtained by biopsy during surgery in 10 nonobese NIDDM and 8' control subjects. In diabetic subjects, insulin binding capacity from abdominal skeletal muscles was 69.4% of the control subjects. Furthermore, the percentage of phosphorylated insulin receptors stimulated by 8.3 nM insulin was significantly lower than the control subjects (mean +/- SD, 29.0 +/- 12.0 vs. 56.0 +/- 7.4%, P less than 0.01), and there was a significant inverse correlation between fasting plasma glucose levels and the percentage of phosphorylated receptors among diabetic subjects (r = 0.73, P less than 0.025). Moreover, the insulin-stimulated kinase activity toward a synthetic peptide (Glu80Tyr20) was also impaired in diabetic subjects (28.5% of control). In summary, this is the first demonstration that the autophosphorylation step of insulin receptors from abdominal skeletal muscles is impaired in nonobese NIDDM subjects.
Diabetes 1991 Jul
PMID:Impaired autophosphorylation of insulin receptors from abdominal skeletal muscles in nonobese subjects with NIDDM. 164 93

The responsiveness to nerve stimulation in the prostatic end of the rat vas deferens and the influence thereupon of streptozotocin-induced diabetes were examined. The rat vas deferens showed a biphasic contractile response to field stimulation: a rapid twitch contraction followed by a slower tonic contraction. Diabetic rats, at 8 and 12 weeks after induction of diabetes, showed a significant increase in the tonic response when compared with age-matched control rats. The twitch response was slightly increased in 12 week diabetic rats at low frequencies of stimulation. Treatment with insulin reversed the augmented response to nerve stimulation found in diabetic rats. The tonic phase in control rats was inhibited by prazosin (73.5%), and by alpha,beta-methylene ATP (34.6%). In diabetic rats at 12 weeks, about 30% of the tonic response was inhibited by prazosin; in the presence of prazosin, the response was still significantly augmented in comparison with that in control rats. In contrast, the tonic response in the presence of alpha,beta-methylene ATP was the same in diabetic and control rats. These results indicate that diabetes induces an increase in the purinergic component of the response to sympathetic nerve stimulation of the rat vas deferens.
 ...
PMID:Augmented responsiveness to sympathetic nerve stimulation of isolated vas deferens of diabetic rats. 165 61

1. The effect of streptozotocin (STZ)-induced diabetes on cholinergic motor transmission in the rat urinary bladder was investigated by recording contractile activity of detrusor strips in vitro. 2. The Ca(2+)-channel antagonist, nifedipine, was found to be more effective in blocking the noncholinergic motor transmission than P2-purinoceptor desensitization by alpha,beta-methylene ATP. 3. The neurogenic contractile responses to electrical field stimulation in the presence of nifedipine (cholinergic) were larger in the diabetic detrusor than in the non-diabetic controls. The potentiation of the cholinergic transmission was more evident at higher frequencies. 4. Concentration-response curves for acetylcholine were identical in detrusors from diabetic and non-diabetic animals, thus excluding a postsynaptic supersensitivity to acetylcholine being responsible for the potentiation of cholinergic motor transmission. 5. It is concluded that the potentiation of cholinergic motor transmission is due to enhanced release of acetylcholine in diabetic detrusor. Possible reasons for this enhancement are discussed in relation to diabetes.
 ...
PMID:The effect of streptozotocin-induced diabetes on cholinergic motor transmission in the rat urinary bladder. 165 63

5-Amino-4-imidazolecarboxamide (AICA) riboside, the nucleoside corresponding to AICA ribotide (AICAR or ZMP), an intermediate of the de novo pathway of purine biosynthesis, was found to exert a dose-dependent inhibition on gluconeogenesis in isolated rat hepatocytes. Production of glucose from lactate-pyruvate mixtures was half-maximally inhibited by approximately 100 microM and completely suppressed by 500 microM AICA riboside. AICA riboside also inhibited the production of glucose from all other gluconeogenic precursors investigated, i.e., fructose, dihydroxyacetone, and L-proline. Measurements of intermediates of the glycolytic-gluconeogenic pathway showed that AICA riboside provoked elevations of triose phosphates and fructose-1,6-bisphosphate and decreases in fructose-6-phosphate and glucose-6-phosphate. The effects of AICA riboside persisted when the cells were washed 10 min after its addition but were suppressed by 5-iodotubercidin, an inhibitor of adenosine kinase. AICA riboside provoked a dose-dependent buildup of normally undetectable Z nucleotides. After 20 min of incubation with 500 microM AICA riboside, ZMP, ZTP, and ZDP reached 3, 0.3, and 0.1 mumol/g cells, respectively. Concentrations of ATP were not significantly modified by addition of up to 500 microM AICA riboside when the cells were incubated with lactate-pyruvate but decreased with fructose or dihydroxyacetone. The activity of rat liver fructose-1,6-bisphosphatase was inhibited by ZMP with an apparent Ki of 370 microM. It is concluded that AICA riboside exerts a suppressive effect on gluconeogenesis because it provokes an accumulation of ZMP, which inhibits fructose-1,6-bisphosphatase.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Oct
PMID:Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. 165 65

Hyperglycemia causes insulin-receptor kinase (IRK) resistance in fat cells. We characterized the mechanism of IRK inhibition and studied whether it is the consequence of a glucose-induced stimulation of protein kinase C (PKC). Fat cells were incubated for 1 or 12 h in culture medium containing either a low-(5-mM) or high- (25-mM) glucose concentration. IRK was isolated, insulin binding was determined, and autophosphorylation was studied in vitro with [gamma-32P]ATP or was determined by Western blotting with anti-phosphotyrosine antibodies. Substrate phosphorylation was investigated with the artificial substrate poly(Glu80-Tyr20). Partially purified insulin receptor from rat fat cells, which were cultured under high-glucose conditions for 1 or 12 h, showed no alteration of insulin binding but a reduced insulin effect on autophosphorylation (30 +/- 7% of control) and poly(Glu80-Tyr20) phosphorylation (55.5 +/- 9% of control). Lineweaver-Burk plots of the enzyme kinetics revealed, beside a reduced Vmax, and increased KM (from 30 microM to 80 microM) for ATP of IRK from high-glucose-treated cells. Because a similar inhibition pattern was earlier found for IRK from fat cells after acute phorbol ester stimulation, we investigated whether activation of PKC might be the cause of the reduced IRK activity. We isolated PKC from the cytosol and the membrane fraction of high- and low-glucose fat cells and determined the diacylglycerol- and phospholipid-stimulated PKC activity toward the substrate histone. There was no significant change of cytosolic PKC; however, membrane-associated PKC activity was increased in high-glucose-treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Nov
PMID:Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells. 165 68


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