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)

A new oral agent, 5-[4-[2-(5-ethyl-12-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione, or pioglitazone, has been developed for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). We examined its effectiveness in high-fat-fed rats resistant to insulin. Administration of the agent (10 mg.kg-1 x d-1) for 2 weeks resulted in decreases in hyperlipidemia and hyperinsulinemia, indicating that insulin sensitivity had increased in vivo in high-fat-fed rats. To clarify the mechanism of the drug, we examined insulin binding and kinase activity of insulin receptors from muscles of both untreated and treated high-fat-fed rats. Pioglitazone treatment did not change insulin binding in high-fat-fed rats, but increased insulin-stimulated autophosphorylation of insulin receptors to the level of control animals. Kinase activity toward an exogenous substrate, poly Glu4-Tyr1, in pioglitazone-treated high-fat-fed rats was also increased to the level of control animals. These results suggest that pioglitazone increases insulin sensitivity by activating tyrosine kinase activity of receptors in high-fat-fed rats, and this drug appears to be a useful one with a new mode of action for the treatment of NIDDM with insulin resistance.
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PMID:Effect of pioglitazone on insulin receptors of skeletal muscles from high-fat-fed rats. 834 5

Increased routing of glucose through the hexosamine-biosynthetic pathway has been implicated in the development of glucose-induced insulin resistance of glucose transport in cultured adipocytes. Because both glucosamine and glucose enter this pathway as glucosamine-6-phosphate, we examined the effects of preincubation with glucosamine in isolated rat diaphragms and in fibroblasts overexpressing the human insulin receptor (HIR-cells). In muscles, pre-exposure to glucosamine inhibited subsequent basal and, to a greater extent, insulin-stimulated glucose transport in a time- and dose-dependent manner and abolished the stimulation by insulin of glycogen synthesis. Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment. In HIR-cells, which express GLUT1 and not GLUT4, basal and insulin-stimulated glucose transport were unaffected by glucosamine, but glycogen synthesis was markedly inhibited. Insulin-stimulated activation of protein kinases (MAP and S6) was unaffected, and the fractional velocity and apparent total activity of glycogen synthase was increased in glucosamine-treated HIR-cells. In pulse-labeling studies, addition of glucosamine during the chase prolonged processing of insulin proreceptors to receptors and altered the electrophoretic mobility of proreceptors and processed alpha-subunits, consistent with altered glycosylation. Glucosamine-induced insulin resistance of glucose transport appears to be restricted to GLUT4-expressing cells, i.e., skeletal muscle and adipocytes; it may reflect impaired translocation of GLUT4 to the plasmalemma. The glucosamine-induced imbalance in UDP sugars, i.e., increased UDP-N-acetylhexosamines and decreased UDP-glucose, may alter glycosylation of critical proteins and limit the flux of glucose into glycogen.
Diabetes 1993 Sep
PMID:Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. 834 45

Peptides representing two putative G-protein-binding motifs (GPBP1 and GPBP2) derived from insulin-receptor sequences were tested for their ability to stimulate guanosine 5'-[gamma-thio]-triphosphate (GTP[S]; 'GTP gamma S') binding to a preparation containing the 41 and 67 kDa G-proteins that are associated with the insulin receptor [Jo, Cha, Davis and McDonald (1992) Endocrinology (Baltimore) 131, 2855-2861]. GPBP2 (residues 1135-1156) specifically stimulated GTP[S] binding, whereas GPBP1 (1319-1333) did not. Substitution of Arg-1152 with Gln in GPBP2 corresponding to a mutation site in insulin-resistant patients [Cocozza, Porcellini, Riccardi, Monticelli, Condorelli, Ferrera, Pianese, Miele, Capaldo, Beguinot and Varrone (1992) Diabetes 41, 521-526] attenuated the stimulatory potency of GPBP2. Size-exclusion chromatography and studies with purified 67 kDa G-protein revealed that GPBP2 stimulated GTP[S] binding only to the 67 kDa G-protein. These studies provide evidence for a potential regulatory site for G-protein interaction with the insulin receptor in the tyrosine kinase domain.
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PMID:An insulin receptor peptide (1135-1156) stimulates guanosine 5'-[gamma-thio]triphosphate binding to the 67 kDa G-protein associated with the insulin receptor. 836 71

To determine whether the tendency for NIDDM to run in families could relate to genetically determined defects in insulin stimulation of glycogen synthesis, skin fibroblasts from subjects with a strong family history of NIDDM were studied. Fibroblasts from nondiabetic subjects without any family history of NIDDM were studied as control subjects. The cells were studied after 7-16 passages in culture. Rates of glycogen synthesis were lower in fibroblasts from NIDDM subjects both basally and with maximal insulin stimulation (0.77 +/- 0.11 vs. 0.46 +/- 0.04 pmol.well-1 x h-1 [P < 0.02] and 1.49 +/- 0.26 vs. 0.69 +/- 0.05 pmol.well-1 x h-1 +adP < 0.01]). Rates of glycogen synthesis were stimulated 1.9 +/- 0.2-fold above basal in the control cells and 1.5 +/- 0.1-fold above basal in the NIDDM cells (P < 0.02). Rates of [3H]thymidine uptake were similar in control and NIDDM fibroblasts (basal, 28.3 +/- 2.8 vs. 39.2 +/- 8.0; maximum, 50.9 +/- 7.2 vs. 69.3 +/- 16.9 dpm x 10(-3), respectively). Rates of uptake increased similarly in control and NIDDM cells by 1.8 +/- 0.1- and 1.7 +/- 0.1-fold above basal. Maximum specific fibroblast insulin binding was similar for control and NIDDM subjects (194.0 +/- 29.2 vs. 176.1 +/- 24.9 fmol 125I-labeled insulin bound/mg protein respectively). The tyrosine kinase activity of insulin receptors isolated from the control and NIDDM fibroblasts was similar (basal, 135 +/- 30 vs. 149 +/- 33; submaximal, 153 +/- 28 vs. 155 +/- 30; and maximal insulin, 191 +/- 45 vs. 213 +/- 48 dpm.mg protein-1 x min-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Apr
PMID:Abnormal activation of glycogen synthesis in fibroblasts from NIDDM subjects. Evidence for an abnormality specific to glucose metabolism. 838 33

We evaluated a 35-year-old diabetic male patient with type A insulin resistance, showing acanthosis nigricans. Insulin binding to the patient's Epstein-Barr-virus transformed lymphocytes was mildly reduced. The maximal insulin-stimulated autophosphorylation of the insulin receptor from the patient's transformed lymphocytes was decreased to 45% of that from the control subjects. On examination, the biological activities of insulin and insulin-like growth factor I in the patient's cultured fibroblasts, insulin sensitivity of amino isobutyric acid uptake and thymidine incorporation was decreased, but insulin-like growth factor I action was normal. The sequence analysis of amplified genomic DNA revealed that the patient was heterozygous for a mutation substituting Leu for Trp at codon 1193 in exon 20 of the insulin receptor gene. The patient's mother and sister were also heterozygous for a mutation in the insulin receptor gene that substituted Leu for Trp1193 in the beta subunit of the receptor. Therefore, the mutation causes insulin resistance in a dominant fashion. They were less hyperglycaemic and more hyperinsulinaemic than the proband after glucose loading. The mother had diabetes mellitus but did not show acanthosis nigricans, while the sister did not have diabetes and showed acanthosis nigricans. These results suggest that this mutation causes defective tyrosine kinase activity of the insulin receptor, which results in insulin resistance. Insulin action and phenotypic appearance may be mediated by different factors.
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PMID:A mutation (Trp1193-->Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance. 839 Sep 49

Reduced insulin receptor tyrosine kinase activity and internalization have been reported in non-insulin-dependent diabetes mellitus (NIDDM) patients. To clarify whether in NIDDM the defective internalization is caused by the defective kinase activity, we studied receptor tyrosine kinase activity and internalization in monocytes from eight lean control and six obese subjects and 10 obese NIDDM patients. Receptor internalization was also stimulated by an anti-insulin receptor antibody (MA-10) that is unable to stimulate receptor kinase activity. Basal exogenous tyrosine kinase activity was not different in monocytes from the three groups of subjects. As compared with control subjects (2,690 +/- 637 fmol 32P incorporated), insulin (100 nmol/L)-stimulated tyrosine kinase activity was lower in NIDDM patients (1,262 +/- 318, P < .05), but not in obese subjects (2,640 +/- 731). Basal receptor autophosphorylation did not differ between the three groups, whereas insulin-stimulated autophosphorylation in comparison to that in control subjects was reduced in NIDDM patients (P < .05), but not in obese subjects. In NIDDM patients, receptor internalization induced by both insulin and MA-10, was lower (P < .05) than that in control and obese subjects. No correlation was found between receptor internalization and exogenous tyrosine kinase activity (r = .30, NS) or autophosphorylation (r = .08, NS).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship between insulin receptor tyrosine kinase activity and internalization in monocytes of non-insulin-dependent diabetes mellitus patients. 839 56

Recently, we demonstrated insulin resistance due to reduced glucose storage in young relatives of Type 2 diabetic patients. To investigate whether this was associated with a defective insulin receptor kinase, we studied ten of these young (27 +/- 1 years old) non-obese glucose tolerant first degree relatives of patients with Type 2 diabetes and eight matched control subjects with no family history of diabetes. Insulin sensitivity was assessed by a hyperinsulinaemic, euglycaemic clamp. Insulin receptors were partially purified from muscle biopsies obtained in the basal and the insulin-stimulated state during the clamp. Insulin binding capacity was decreased by 28% in the relatives (p < 0.05) in the basal biopsy. Tyrosine kinase activity in the receptor preparation was decreased by 50% in both basal and insulin-stimulated biopsies from the relatives. After stimulation with insulin "in vitro", kinase activity was reduced in the relatives in basal (p < 0.005) and insulin-stimulated (p < 0.01) biopsies and also when expressed per insulin binding capacity (p approximately 0.05). Insulin stimulation of non-oxidative glucose metabolism correlated with "in vitro" insulin-stimulated tyrosine kinase activity (r = 0.61, p < 0.01) and also when expressed per binding capacity (r = 0.53, p < 0.025). We suggest that the marked defect in tyrosine kinase activity in partially purified insulin receptors from skeletal muscle is an early event in the development of insulin resistance and contributes to the pathophysiology of Type 2 diabetes.
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PMID:Decreased tyrosine kinase activity in partially purified insulin receptors from muscle of young, non-obese first degree relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus. 839 36

Endothelin, a vasoconstrictor peptide secreted from endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with accelerated atherosclerosis and microvascular damage. Although the basis for the vessel insult is multifactorial, hyperinsulinemia is thought to contribute by an unknown mechanism. In this study, we sought to determine whether insulin stimulates the production and secretion of ET-1 as a possible basis for the association of hyperinsulinemia and vascular disease. We demonstrated that insulin significantly stimulates the gene expression and secretion of ET-1 from cultured BAEC, and that insulin increases ET-1 mRNA expressed in BBCEC. Insulin caused a maximal twofold inducement above control ET-1 mRNA expression in a dose-related fashion in BAEC. The increased mRNA resulted from increased transcription, as determined by nuclear run-off studies. Increased ET-1 mRNA was seen after 4 h of incubation with insulin: the peak occurred at 6-8 h and persisted for 24 h. Insulin caused as much as a fourfold stimulation of ET-1 secretion from BAEC in a dose-related fashion, including a twofold increase at a physiological concentration (10(-9) M): The increase began at 1 h of incubation and continued for the entire 24-h incubation period. The insulin-induced increases in both ET-1 mRNA and ET-1 protein secretion were significantly attenuated by genistein, a tyrosine kinase inhibitor. This stimulation probably occurred through the insulin receptor, because IGF-1 had no effect on ET-1 gene expression or secretion from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Feb
PMID:Insulin stimulates production and secretion of endothelin from bovine endothelial cells. 842 73

INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM. We previously have screened members of 18 familial NIDDM pedigrees for mutations in exons encoding the tyrosine kinase domain of the INSR gene (exons 13-21) by SSCP. That analysis initially detected only patterns consistent with silent polymorphisms, but on direct sequence analysis of exon 17 we detected a Met-for-Val substitution at position 985 in 1/18 pedigrees. We confirmed the substitution by sequence analysis of subcloned, PCR-amplified DNA from two pedigree members and by hybridization to labeled primers for the normal and mutant sequences. We did not find the mutation in any other individuals. Pedigree members were typed for presence or absence of the Met985 substitution by hybridization of PCR-amplified exon 17 DNA to allele-specific oligonucleotide probes, and typing was confirmed by segregation of INSR haplotypes and by SSCP analysis. The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was present in only 50% of NIDDM siblings in generation 2, however. To determine the clinical effect of the Met985 substitution, we compared the 5 nondiabetic pedigree members who carried the mutation with the 9 nondiabetic pedigree members without the mutation and with 266 members of other pedigrees. Fasting and 1-h postglucose insulin levels were not different between carriers and noncarriers (fasting, 71.4 pM vs. 74.5 pM; 1-h, 381 pM vs. 354 pM), even after correction for age, sex, and BMI.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Mar
PMID:Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM. 843 14

This study evaluated the insulin and insulin-like growth factor-1 (IGF-1) receptor function among patients with type II diabetes who did or did not respond to 1 month of treatment with the oral sulfonylurea agent glyburide. Patients with type II diabetes were initially placed on dietary treatment alone. Patients whose fasting plasma glucose level exceeded 9 mmol/L were enrolled in a prospective 1-month trial of oral glyburide. Clinical, laboratory, and receptor characteristics were assessed before and after glyburide therapy and were compared between the responders and non-responders as well as with matched nondiabetic control subjects. Of the 34 patients who participated in the study, 17 (50%) responded (fasting plasma glucose decreased to 7.8 mmol/L or by 30% from basal level) to the drug. There were no clinical parameters that could distinguish between patients responding and not responding to glyburide. Iodine 125-labeled insulin binding to intact erythrocytes tended to be higher among responders both before and after glyburide. However, the studies of specific insulin binding and insulin receptor tyrosine kinase activities of purified erythrocyte receptors could not distinguish between the two groups of patients with diabetes either before or after glyburide treatment. Compared with weight-matched nondiabetic controls, the erythrocyte insulin receptor tyrosine kinase activity in the patients with diabetes was significantly (by about 45%) decreased. Studies of the IGF-1 receptor likewise did not reveal differences between the two diabetic groups. In conclusion, one half of ambulatory patients with type II diabetes showed a satisfactory hypoglycemic response to a short-term glyburide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin and IGF1 receptor function among type II diabetic responders and nonresponders to glyburide. 845 33


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