Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone (GH) deficiency in adults is characterized by central obesity, dyslipidemia, coagulopathy and glucose intolerance, all features of the "metabolic syndrome", explaining the increased cardiovascular morbidity and mortality associated with GH deficiency in adults. Employing the 2-step euglycemic-hyperinsulinemic clamp, we have demonstrated severe insulin resistance in GH-deficient adults, with a reduction in insulin-mediated glucose utilization of -50%. Basal glucose turnover and partitioning of whole body glucose utilization into glycolytic flux (GF) and glycogen synthesis/glucose storage (GS) pathways are normal, but insulin activation of these 2 pathways is reduced, predominantly in the GS pathway. Activation of muscle glycogen synthase by insulin is markedly decreased, as is glycogen content of muscle. Insulin-induced muscle hexokinase activity appears also to be attenuated in GH-deficient adults with raised intramuscular cellular glucose and normal-reduced concentrations of glucose-6-phosphate. Beta-cell function is not excessive in GH-deficient adults and is inappropriately low for the insulin resistance. Following treatment of GH-deficient adults with recombinant GH (rhGH), the insulin resistance is either unchanged or more pronounced by 3, 6 or 24 months of treatment, despite the significant reduction in general and central obesity. The GF and GS pathways and muscle glycogen synthase and hexokinase activities remain severely impaired. Abnormalities in free fatty acid (FFA) metabolism are present in rhGH-treated GH-deficient adults and correlate significantly with the degree of insulin resistance as do the concentrations of rhGH-induced insulin-like growth factor (IGF)-I, the post-basal insulinemia and the duration of the GHD, but is independent of obesity. In conclusion, long-term rhGH treatment in GH-deficient adults results in persistent insulin resistance and abnormalities in the GF and GS pathways due to reduced glycogen synthase and hexokinase activities, in the presence of an ongoing reduction of central obesity. We postulate that the insulin resistance is due to chronic rhGH-induced alterations in FFA metabolism, non-physiological levels of IGF-I and chronic basal hyperinsulinemia.
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PMID:Insulin sensitivity in growth hormone (GH)-deficient adults and effect of GH replacement therapy. 1044 67

Patients with congenital disorder of glycosylation (CDG), type Ib (MPI-CDG or CDG-Ib) have mutations in phosphomannose isomerase (MPI) that impair glycosylation and lead to stunted growth, liver dysfunction, coagulopathy, hypoglycemia, and intestinal abnormalities. Mannose supplements correct hypoglycosylation and most symptoms by providing mannose-6-P (Man-6-P) via hexokinase. We generated viable Mpi hypomorphic mice with residual enzymatic activity comparable to that of patients, but surprisingly, these mice appeared completely normal except for modest (~15%) embryonic lethality. To overcome this lethality, pregnant dams were provided 1-2% mannose in their drinking water. However, mannose further reduced litter size and survival to weaning by 40 and 66%, respectively. Moreover, ~50% of survivors developed eye defects beginning around midgestation. Mannose started at birth also led to eye defects but had no effect when started after eye development was complete. Man-6-P and related metabolites accumulated in the affected adult eye and in developing embryos and placentas. Our results demonstrate that disturbing mannose metabolic flux in mice, especially during embryonic development, induces a highly specific, unanticipated pathological state. It is unknown whether mannose is harmful to human fetuses during gestation; however, mothers who are at risk for having MPI-CDG children and who consume mannose during pregnancy hoping to benefit an affected fetus in utero should be cautious.
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PMID:Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice. 2442 98