Alteration in bovine growth hormone histidine 22 results in transgenic mice with an enhance diabetogenic profile
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Transgenic mice which overexpress growth hormone (GH) may be used a model system to examine growth, kidney pathology, as well as the medical condition known as acromegaly (hyper-growth hormone secretion). GH is a pleiotropic 22 kDa polypeptide hormone which elicits body growth in jeuvenille animals and also mediates protein, carbohydrate, and lipid metabolism. The structure / function relationships of selected residues of bovine (b) GH a-helix I were approached using site-directed mutagenesis in concert with the production of bGH analog transgenic mice. Phenyalanine (Phe, F) 11 and histidine (His, H) 22 in the amino-terminus of bGH were the targeted amino acids. bGH and the bGH analog transgenic mice all exhibited the enhanced growth phenotype similar to bGH transgenic mice and had elevated IGF-1 serum concentrations. However, bGH-H22R mice demonstrated levels of blood urea nitrogen (BUN) and serum creatinine (SCR) several fold higher than the other transgenic mice. Elevated BUN and SCR are an indication of renal insufficiency in this mouse line. Glucose tolerance testing in the bGH-H22R mice revealed that they possessed a lower tolerance for glucose, or an enhancement of the diabetogenic properties of the hormone as compared to wild-type and other GH analog transgenic mice: In addition to the glomerulosclerosis found in bGH mice, histological examination of the mature bGH-H22R mice demonstrated severe glomerulosclerosis, as well as cystic kidney lesions.
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J.J. Kopchick, Ph.D., Edison Biotechnology Institute, Konneker Research Laboratories, Ohio University, The Ridges, Athens, OH 45701-2979 PH: 614-593-4534 FAX: 614-593-4795.