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)

Glucose and gluconeogenic substrates promote the activation of hepatic glycogen synthase in vivo and in vitro; activation occurs as inactive glycogen synthase D is dephosphorylated to active glycogen synthase I by glycogen synthase phosphatase. Impairments of glycogen accumulation and glycogen synthase activation in diabetes have been attributed to decreased glycogen synthase phosphatase activity. To determine the role of glycogen synthase phosphatases associated with cytosol and smooth endoplasmic reticulum in the impairment of glycogen synthase activation, livers of normal and streptozotocin-diabetic fed rats were sampled by freeze-clamping before and after perfusion with a mixture of 25 mM glucose, 10 mM glutamine, 4 mM lactate, and 1 mM pyruvate. Perfusion induced activation of glycogen synthase in normal rats, but activation was reduced in the diabetic rats in proportion to the severity of insulin deficiency (r = 0.72, P less than 0.0001). There was also a close correlation between insulin levels and glycogen synthase phosphatase activities of both cytosol (r = 0.76, P less than 0.0001) and SER (r = 0.71, P less than 0.0001) fractions. In contrast, glycogen phosphorylase phosphatase activity and inactivation of glycogen phosphorylase during perfusion were normal in the diabetic livers. This is the first demonstration that glycogen synthase phosphatase activities in both soluble and SER fractions of liver cells are closely related to circulating insulin levels, and that the impairment of glycogen synthesis in diabetes may result from deficient glycogen synthase phosphatase activity in both cell compartments.
Diabetes 1983 Dec
PMID:Impaired glycogenic substrate activation of glycogen synthase is associated with depressed synthase phosphatase activity in diabetic rat liver. 631 99

Protein phosphatase activities have recently been classified into two major groups of enzymes termed type 1 and type 2. In the present study, this classification scheme has been used to explore the types of protein phosphatase activities found in rat heart, liver, and skeletal muscle, and to determine the type of protein phosphatase activity affected by diabetes. Protein phosphatase activities have been measured under conditions designed to minimize the influence of effectors of these enzymes, and a thermostable protein phosphatase inhibitor, termed inhibitor-2, has been used as a probe to specifically inhibit type 1 protein phosphatase. The specific activity of protein phosphatase-1 in extracts of heart, liver, and skeletal muscle from control rats ranged between 0.34 and 0.44 U/mg protein. The specific activity of a type 2 enzyme, termed protein phosphatase-2A, was approximately the same as protein phosphatase-1 in the case of skeletal muscle extracts, but was about 50% higher than type 1 in extracts from liver and heart. The only significant effect of diabetes was on hepatic protein phosphatase-1 in which a 50% decrease in specific activity was noted. Therefore, the effect of diabetes appeared to be confined to protein phosphatase-1 and this effect was only seen in liver.
Diabetes 1984 Jun
PMID:Protein phosphatase-1 and -2A activities in heart, liver, and skeletal muscle extracts from control and diabetic rats. 632 37

Levels of the mRNA encoding the catalytic subunit of protein phosphatase type-1 (PP-1cat) were reduced in skeletal muscle but not liver in response to short-term (2h) chow refeeding after prolonged (40h) starvation in the rat. This reduction did not appear to be mediated by insulin per se since streptozotocin-induced diabetes was associated with a reduction in PP-1cat levels in skeletal muscle. It is suggested that glucose levels may be one factor that modulates skeletal muscle PP-1cat mRNA levels. Despite the changes in PP-1cat mRNA levels in skeletal muscle, total protein phosphatase-1 catalytic activity was not altered by either chow refeeding or streptozotocin-diabetes. By contrast, although total hepatic PP-1cat mRNA levels were not altered in response to chow refeeding, there was a marked reduction in glycogen phosphorylase phosphatase activity in the cytosol but not in the glycogen/microsomal fraction.
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PMID:Protein phosphatase type-1 mRNA levels in response to starvation-refeeding and streptozotocin-diabetes. 754 40

The rate-limiting enzyme in insulin-mediated nonoxidative glucose disposal, glycogen synthase, has reduced activity in insulin-resistant subjects at risk for developing non-insulin-dependent diabetes mellitus (NIDDM). The synthase-activating enzyme, type 1 protein phosphatase (PP1), also has an abnormally low level of activity. Inhibitor 2 (I-2) reversibly inhibits and facilitates the proper conformation of free catalytic subunits of PP1. This study investigates whether genetic alteration(s) in the I-2 coding locus (PPP1R2) could contribute to insulin resistance in Pima Indians. We determined that the authentic PPP1R2 gene is located on chromosome 3q29 and consists of six exons. The previously reported homologue of PPP1R2 on chromosome 5 is identified as an intronless pseudogene. Comparative sequencing of PPP1R2 exons and splice junctions revealed no mutations in insulin-resistant Pima Indians. The information on the genomic structure of PPP1R2 is important for exploring this gene as a potential candidate contributing to insulin resistance and NIDDM in other populations.
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PMID:Genetic analysis of human type 1 protein phosphatase inhibitor 2 in insulin-resistant Pima Indians. 912 90

Selected candidate genes have been analyzed in the Pima Indians of Arizona based on evidence that insulin resistance and type 2 diabetes have significant genetic determinants. An amino acid substitution at codon 905 of the glycogen-targeting subunit of type 1 protein phosphatase that regulates skeletal muscle glycogenesis was recently reported to be associated with changes in insulin action in Danish subjects. In addition to the variant at 905, we report here a novel substitution at codon 883 and common variant of an "ATTTA" element in the 3'-untranslated region (UTR) of the corresponding gene (PPP1R3). The 3'-UTR variant resembled the mRNA-destabilizing AT(AU)-rich elements (AREs) and resulted in a 10-fold difference in reporter mRNA half-life, was correlated with PPP1R3 transcript and protein concentrations in vivo, and was associated with insulin resistance and type 2 diabetes in the Pimas. The variant is more common in Pimas (0.56) than in Caucasians (0.40). Because of its apparent effect on expression of PPP1R3, it may, in part, contribute to the higher prevalence of type 2 diabetes in this Native American population.
Diabetes 1998 Sep
PMID:A common variant in PPP1R3 associated with insulin resistance and type 2 diabetes. 972 44

A polymorphism (PP1ARE) in the 3'-untranslated region of the gene encoding the glycogen-associated regulatory subunit of type 1 protein phosphatase PPP1R3 is associated with insulin resistance in Pima Indians. The aim of this study was to investigate whether two common variants in the PPP1R3 gene, Asp905Tyr and PP1ARE, are associated with reduced insulin sensitivity or can predict the development of impaired glucose tolerance (IGT) or type 2 diabetes during a 20-year follow-up period in 696 50-year-old Caucasian men. The allelic frequency of Tyr905 was 0.11 (95% CI 0.09-0.13) and of PP1ARE 0.34 (0.31-0.37) and the two polymorphisms were in linkage disequilibrium (chi2 = 46, P < 0.0001, Fisher's exact test). None of the polymorphisms was associated with the development of IGT or type 2 diabetes, but the PP1ARE polymorphism was weakly correlated to whole-body insulin sensitivity (r = -0.08, P = 0.04). In conclusion, we found no evidence in Swedish men that the PP1ARE or the Asp905Tyr variants over a 20-year period predict the development of IGT or type 2 diabetes, but the PP1ARE polymorphism could have a higher penetrance in other populations.
Diabetes 2000 Feb
PMID:Polymorphism in the glycogen-associated regulatory subunit of type 1 protein phosphatase (PPP1R3) gene and insulin sensitivity. 1086 47