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Articles by M Graham
Total Records ( 3 ) for M Graham
  J Xu , S Stanislaus , N Chinookoswong , Y. Y Lau , T Hager , J Patel , H Ge , J Weiszmann , S. C Lu , M Graham , J Busby , R Hecht , Y. S Li , Y Li , R Lindberg and M. M. Veniant

Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance (ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40–60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues.

  W Gu , K. A Winters , A. S Motani , R Komorowski , Y Zhang , Q Liu , X Wu , I. C Rulifson , G Sivits , M Graham , H Yan , P Wang , S Moore , T Meng , R. A Lindberg and M. M. Veniant

Antagonism of the glucagon receptor (GCGR) is associated with increased circulating levels of glucagon-like peptide-1 (GLP-1). To investigate the contribution of GLP-1 to the antidiabetic actions of GCGR antagonism, we administered an anti-GCGR monoclonal antibody (mAb B) to wild-type mice and GLP-1 receptor knockout (GLP-1R KO) mice. Treatment of wild-type mice with mAb B lowered fasting blood glucose, improved glucose tolerance, and enhanced glucose-stimulated insulin secretion during an intraperitoneal glucose tolerance test (ipGTT). In contrast, treatment of GLP-1R KO mice with mAb B had little efficacy during an ipGTT. Furthermore, pretreatment with the GLP-1R antagonist exendin-(9–39) diminished the antihyperglycemic effects of mAb B in wild-type mice. To determine the mechanism whereby mAb B improves glucose tolerance, we generated a monoclonal antibody that specifically antagonizes the human GLP-1R. Using a human islet transplanted mouse model, we demonstrated that pancreatic islet GLP-1R signaling is required for the full efficacy of the GCGR antagonist. To identify the source of the elevated GLP-1 observed in GCGR mAb-treated mice, we measured active GLP-1 content in pancreas and intestine from db/db mice treated with anti-GCGR mAb for 8 wk. Elevated GLP-1 in GCGR mAb-treated mice was predominantly derived from increased pancreatic GLP-1 synthesis and processing. All together, these data show that pancreatic GLP-1 is a significant contributor to the glucose-lowering effects observed in response to GCGR antagonist treatment.

  K. S Galea , M Van Tongeren , A. J Sleeuwenhoek , D While , M Graham , A Bolton , H Kromhout and J. W. Cherrie

Objectives: Wood dust data held in the Health and Safety Executive (HSE) National Exposure DataBase (NEDB) were reviewed to investigate the long-term changes in inhalation exposure from 1985 to 2005. In addition, follow-up sampling measurements were obtained from selected companies where exposure measurements had been collected prior to 1994, thereby providing a follow-up period of at least 10 years, to determine whether changes in exposure levels had occurred, with key staff being interviewed to identify factors that might be responsible for any changes observed.

Methods: Analysis of the temporal trend in exposure concentrations was performed using Linear Mixed Effect Models on the log-transformed NEDB data set and expressed as the relative annual change in concentration.

Results: For the NEDB wood dust data, an annual decline of geometric mean (GM) exposure of 8.1% per year was found based on 1459 exposure measurements collected between 1985 and 2003. This trend was predominantly observed in data from inspection visits (measurements collected on a mandatory basis by a Specialist HSE Inspector) (n = 1009), while data from representative surveys (measurements collected on a voluntary basis to provide information on current practices and exposures) remained relatively stable. Ten follow-up surveys in individual workplaces in 2004–2005 resulted in 70 new measurements and for each of the companies resurveyed, the GM of the wood dust exposure decreased between sampling surveys.

Conclusion: Analysis of the temporal trend in UK wood dust exposure concentrations revealed declines of 8% per annum. Interviews with key long-serving employees and management suggest that factors such as technological changes in production processes, response to new legislation, and enforcement agency inspections, together with global economic trends, could be linked to the downward trends observed.

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