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)

The discovery of glycogenin as a self-glucosylating protein that primes glycogen synthesis has significantly increased our understanding of the structure and metabolism of this storage polysaccharide. The amount of glycogenin will influence how much glycogen the cell can store. Therefore, the production of active glycogenin primer in the cell has the potential to be the overall rate-limiting process in glycogen formation, capable of overriding the better understood hormonally controlled mechanisms of protein phosphorylation/dephosphorylation that regulate the activities of glycogen synthase and phosphorylase. There are indications that a similar covalent modification control is also being exerted on glycogenin. Glycogenin has the ability to glucosylate molecules other than itself and to hydrolyze UDPglucose. These are independent of self-glucosylation, so that glycogenin, even when it has completed its priming role and become part of the glycogen molecule, retains its catalytic potential. Another new component of glycogen metabolism has been discovered that may have even greater influence on total glycogen stores than does glycogenin. This is proglycogen, a low molecular mass (approximately 400 kDa) form of glycogen that serves as a stable intermediate on the pathways to and from depot glycogen (macroglycogen, mass 10(7) Da, in muscle). It is suggested that glycogen oscillates, according to glucose supply and energy demand, between the macroglycogen and proglycogen, but not usually the glycogenin, forms. The proportion of proglycogen to macroglycogen varies widely between liver, skeletal muscle, and heart, from 3 to 15% to 50% by weight, respectively. On a molar basis, proglycogen is greatly in excess over macroglycogen in muscle and heart, meaning that if the proglycogen in these tissues could be converted into macroglycogen, they could store much more total glycogen. Discovering the factors that regulate the balance between glycogenin, proglycogen, and macroglycogen may have important implications for the understanding and management of noninsulin-dependent diabetes and for exercise physiology.
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PMID:A new look at the biogenesis of glycogen. 767 5

Glycogen synthesis is impaired in first degree relatives of subjects with non-insulin-dependent diabetes mellitus and genes relevant to this metabolic pathway are considered reasonable candidates in the pathogenesis of the disease. In skeletal muscle the de novo synthesis of glycogen in primed by an enzyme named glycogenin. We have cloned the glycogenin cDNA from human skeletal muscle mRNA: human glucogenin is a 333 amino acid protein exhibiting 93% identity with rabbit glycogenin. A single transcript of about 2.4 kb, prominent in skeletal muscle, was detected by Northern blot analysis. In situ hybridization unequivocally located the human glycogenin gene to chromosome 3q25.1. Furthermore, we mapped two intronless glycogenin-related sequences to human chromosomes 12 and 13.
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PMID:The human skeletal muscle glycogenin gene: cDNA, tissue expression and chromosomal localization. 860 61

The finding of a reduced insulin-stimulated glucose uptake and glycogen synthesis in the skeletal muscle of glucose-tolerant first-degree relatives of patients with NIDDM, as well as in cultured fibroblasts and skeletal muscle cells isolated from NIDDM patients, has been interpreted as evidence for a genetic involvement in the disease. The mode of inheritance of the common forms of NIDDM is as yet unclear, but the prevailing hypothesis supports a polygenic model. In the present study, we tested the hypothesis that the putative inheritable defects of insulin-stimulated muscle glycogen synthesis might be caused by genetic variability in the genes encoding proteins shown by biochemical evidence to be involved in insulin-stimulated glycogen synthesis in skeletal muscle. In 70 insulin-resistant Danish NIDDM patients, mutational analysis by reverse transcription-polymerase chain reaction-single strand conformation polymorphism-heteroduplex analysis was performed on genomic DNA or skeletal muscle-derived cDNAs encoding glycogenin, protein phosphatase inhibitor-1, phophatase targeting to glycogen, protein kinase B-alpha and -beta, and the phosphoinositide-dependent protein kinase-1. Although a number of silent variants were identified in some of the examined genes, we found no evidence for the hypothesis that the defective insulin-stimulated glycogen synthesis in skeletal muscle in NIDDM is caused by structural changes in the genes encoding the known components of the insulin-sensitive glycogen synthesis pathway of skeletal muscle.
Diabetes 1999 Feb
PMID:Mutational analysis of the coding regions of the genes encoding protein kinase B-alpha and -beta, phosphoinositide-dependent protein kinase-1, phosphatase targeting to glycogen, protein phosphatase inhibitor-1, and glycogenin: lessons from a search for genetic variability of the insulin-stimulated glycogen synthesis pathway of skeletal muscle in NIDDM patients. 1033 21

Under various pathophysiological muscle-wasting conditions, such as diabetes and starvation, a family of ubiquitin ligases, including muscle-specific RING-finger protein 1 (MuRF1), are induced to target muscle proteins for degradation via ubiquitination. We have generated transgenic mouse lines over-expressing MuRF1 in a skeletal muscle-specific fashion (MuRF1-TG mice) in an attempt to identify the in vivo targets of MuRF1. MuRF1-TG lines were viable, had normal fertility and normal muscle weights at eight weeks of age. Comparison of quadriceps from MuRF1-TG and wild type mice did not reveal elevated multi-ubiquitination of myosin as observed in human patients with muscle wasting. Instead, MuRF1-TG mice expressed lower levels of pyruvate dehydrogenase (PDH), a mitochondrial key enzyme in charge of glycolysis, and of its regulator PDK2. Furthermore, yeast two-hybrid interaction studies demonstrated the interaction of MuRF1 with PDH, PDK2, PDK4, PKM2 (all participating in glycolysis) and with phosphorylase beta (PYGM) and glycogenin (both regulating glycogen metabolism). Consistent with the idea that MuRF1 may regulate carbohydrate metabolism, MuRF1-TG mice had twofold elevated insulin blood levels and lower hepatic glycogen contents. To further examine MuRF1's role for systemic carbohydrate regulation, we performed glucose tolerance tests (GTT) in wild type and MuRF1-TG mice. During GTT, MuRF1-TG mice developed striking hyperinsulinaemia and hepatic glycogen stores, that were depleted at basal levels, became rapidly replenished. Taken together, our data demonstrate that MuRF1 expression in skeletal muscle re-directs glycogen synthesis to the liver and stimulates pancreatic insulin secretion, thereby providing a regulatory feedback loop that connects skeletal muscle metabolism with the liver and the pancreas during metabolic stress.
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PMID:MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies. 1846 20