The islet research of our laboratory has four interdependent objectives: 1) To continue exploring the glucokinase-glucose-sensor concept. This includes the study of kinetic and structural features of recombinant human wildtype glucokinase (GK) isoforms and selected mutants of MODY patients and further explorations of the physiological regulation of B-cell glucokinase activity emphasizing acute activation and slow induction by fuels and the role of feed back regulation by the GK regulator protein. 2) To continue exploring metabolic coupling in A- and B-cells. The roles of ATP, free ADP, of the ATP/ADP-free ratio and of the creatine kinase/P- creatine system will be investigated including the use of transgenic mice over-expressing creatine kinase in A- and B-cells. Transgenic mice expressing PEPCK in B-cells will be employed to explore the role of glycolytic intermediates in metabolic coupling with hexoses and pyruvate as stimuli. 3) To continue exploring the biochemical basis of B-cell adaptation in an organ culture system during chronic overload with various fuels including glucose, physiological mixtures of natural amino acids, fatty acids, ketone bodies and model fuels. A variety of techniques will be applied including the study of oxygen consumption, fuel metabolism, ion fluxes and the use of high resolution 2-D PAGE to identify and characterize fuel response proteins. 4) To begin addressing the issue of cellular heterogeneity of islet tissue with a state of the art computerized microscopic image analysis system allowing the investigation of fuel metabolism, Ca2+ levels and cAMP levels in identified and subtyped A- and B-cells during adaptation to fuels. Previous work from our laboratory has helped to set the stage for the present plans and we have the manpower, skills, collaborative backing and facilities to address these fundamentally important issue of islet research.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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Laughlin, Maren R
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University of Pennsylvania
Schools of Medicine
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Zelent, Bogumil; Raimondo, Anne; Barrett, Amy et al. (2014) Analysis of the co-operative interaction between the allosterically regulated proteins GK and GKRP using tryptophan fluorescence. Biochem J 459:551-64
Li, Changhong; Liu, Chengyang; Nissim, Itzhak et al. (2013) Regulation of glucagon secretion in normal and diabetic human islets by ?-hydroxybutyrate and glycine. J Biol Chem 288:3938-51
Zhang, Tingting; Li, Changhong (2013) Mechanisms of amino acid-stimulated insulin secretion in congenital hyperinsulinism. Acta Biochim Biophys Sin (Shanghai) 45:36-43
Prentki, Marc; Matschinsky, Franz M; Madiraju, S R Murthy (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab 18:162-85
Doliba, Nicolai M; Qin, Wei; Najafi, Habiba et al. (2012) Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics. Am J Physiol Endocrinol Metab 302:E87-E102
Zelent, B; Buettger, C; Grimsby, J et al. (2012) Thermal stability of glucokinase (GK) as influenced by the substrate glucose, an allosteric glucokinase activator drug (GKA) and the osmolytes glycerol and urea. Biochim Biophys Acta 1824:769-84
Nissim, Itzhak; Horyn, Oksana; Nissim, Ilana et al. (2012) Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics. Biochem J 444:537-51
Doliba, Nicolai M; Fenner, Deborah; Zelent, Bogumil et al. (2012) Repair of diverse diabetic defects of ?-cells in man and mouse by pharmacological glucokinase activation. Diabetes Obes Metab 14 Suppl 3:109-19
Fenner, Deborah; Odili, Stella; Hong, Hee-Kyung et al. (2011) Generation of N-ethyl-N-nitrosourea (ENU) diabetes models in mice demonstrates genotype-specific action of glucokinase activators. J Biol Chem 286:39560-72
Matschinsky, Franz M; Zelent, Bogumil; Doliba, Nicolai et al. (2011) Glucokinase activators for diabetes therapy: May 2010 status report. Diabetes Care 34 Suppl 2:S236-43

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