Amino acid metabolism, insulin secretion and diabetes

Newsholme, Philip; Bender, Katrin; Kiely, Aoife; Brennan, Lorraine

doi:10.1042/bst0351180

Cited by 194 publications

(162 citation statements)

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“…An upstream open reading frame suppresses translation of Ucp2 mRNA [41]. Glutamine, which has been implicated in the insulin secretion pathway [42], overcomes this suppression [43]. Removal of glutamine from INS-1E cell cultures rapidly halves both cellular and mitochondrial UCP2 protein content without affecting the Ucp2 mRNA level ( figure 3) [12].…”

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confidence: 99%

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

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et al. 2010

Diabetes Obesity Metabolism

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Pancreatic β-cells have remarkable bioenergetics in which increased glucose supply upregulates the cytosolic ATP/ADP ratio and increases insulin secretion. This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2 −/− mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells. Keywords: glucose-stimulated insulin secretion, INS-1E cells, mitochondria, proteasome, protein degradation, turnover, UCP2, UCP3 Date submitted 25 March 2010; date of final acceptance 24 April 2010 IntroductionThe energy metabolism of pancreatic β-cells is extraordinary. Nearly all other mammalian cells rigorously regulate their bioenergetics using internal cues, and only take up fuels when they need them for oxidation and energy release or for storage. Pancreatic β-cells work the other way round, and use fuel supply to regulate their ATP production and cytosolic ATP/ADP ratio.A skeletal muscle cell, for example, will take up glucose from the bloodstream through a plasma membrane glucose transporter, glucose transporter type 4 (GLUT4), when insulin is high and glucose is abundant, otherwise it will use fatty acids as fuel [1]. It will store glucose as glycogen when insulin and ATP are high and calcium (the trigger for muscle contraction and energy demand) is low. Even after glucose enters the cytoplasm, a muscle cell will allow it to enter glycolysis only when that cell requires energy. Glucose 6-phosphate is a non-competitive inhibitor of muscle hexokinase, so when ATP is sufficiently high, glycolysis stalls, glucose 6-phosphate builds up, hexokinase activity is inhibited and glucose metabolism slows. When more ATP is needed because of internal ATP demand, phosphofructokinase and pyruvate kinase are activated, glucose 6-phosphate levels fall and hexokinase channels glucose into glycolysis and to the mitochondria. The mitochondrial electron transport chain pumps protons across the mitochondrial inner membrane, restoring a high protonmotive force and ATP production, until ATP rises and oxidativ...

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confidence: 99%

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

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Parker

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et al. 2010

Diabetes Obesity Metabolism

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“…The presence of glutamate concentration proved the consumption of glutamine in BRIN-BD11 cells in T-flask and MC cultures. Newsholme et al (2007) reported in their study that although glutamine was rapidly taken up and metabolized by the cells, it alone did not stimulate insulin secretion or enhanced glucose-induced insulin secretion. This observation is supported by the study done by Zahid et al (2008) and Newsholme et al (2007) that combination of D-glucose and L-glutamine promote good cell growth and insulin secretion of BRIN-BD11 cells as a step towards mass propagation of insulin production.…”

Section: Discussionmentioning

confidence: 96%

“…In addition, faster cell growth rate observed in HIIMCs is attributed to its surface charge that supports easy attachment of cells and easy detachment with trypsin (Varani et al 1998). Newsholme et al (2007) reported that the major physiological regulator in insulin production is glucose. Based on the results in Fig.…”

Section: Discussionmentioning

confidence: 99%

Comparing BRIN-BD11 culture producing insulin using different type of microcarriers

et al. 2010

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This research was conducted to examine the growth profile, growth kinetics, and insulinsecretory responsiveness of BRIN-BD11 cells grown in optimized medium on different types of microcarriers (MCs). Comparisons were made on modified polystyrene (Hillex Ò II) and crosslinked polystyrene Plastic Plus (PP) from Solohill Engineering. The cell line producing insulin was cultured in a 25 cm 2 T-flask as control while MCs based culture was implemented in a stirred tank bioreactor with 1 L working volume. For each culture type, the viable cell number, glucose, lactate, glutamate, and insulin concentrations were measured and compared. Maximum viable cell number was obtained at 1.47 9 10 5 cell/mL for PP microcarrier (PPMCs) culture, 1.35 9 10 5 cell/mL Hillex Ò II (HIIMCs) culture and 0.95 9 10 5 cell/mL for T-flask culture, respectively. The highest insulin concentration has been produced in PPMCs culture (5.31 mg/L) compared to HIIMCs culture (2.01 mg/L) and T-flask culture (1.99 mg/L). Therefore overall observation suggested that PPMCs was likely preferred to be used for BRIN-BD11 cell culture as compared with Hillex Ò II MCs.

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“…Some reports suggest that high levels of amino acids can have both positive (Tremblay and Marette, 2001;Nobukuni et al, 2005) and negative (Armstrong et al, 2001;Bogan et al, 2001) effects on glucose metabolism and insulin action in peripheral tissues. Amino acid levels can also affect insulin secretion in pancreatic islet β-cells (Newsholme et al, 2007). Therefore, it is possible that S-nitrosation interferes with amino acid metabolic processes and thus contributes to diabetes.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis of S-nitrosated proteins in diabetic mouse liver with ICAT switch method

et al. 2010

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In this study we developed a quantitative proteomic method named ICAT switch by introducing isotope-coded affinity tag (ICAT) reagents into the biotin-switch method, and used it to investigate S-nitrosation in the liver of normal control C57BL/6J mice and type 2 diabetic KK-Ay mice. We got fifty-eight S-nitrosated peptides with quantitative information in our research, among which thirty-seven had changed S-nitrosation levels in diabetic mouse liver. The S-nitrosated peptides belonged to fortyeight proteins (twenty-eight were new S-nitrosated proteins), some of which were new targets of S-nitrosation and known to be related with diabetes. S-nitrosation patterns were different between diabetic and normal mice. Gene ontology enrichment results suggested that S-nitrosated proteins are more abundant in amino acid metabolic processes. The network constructed for Snitrosated proteins by text-mining technology provided clues about the relationship between S-nitrosation and type 2 diabetes. Our work provides a new approach for quantifying S-nitrosated proteins and suggests that the integrative functions of S-nitrosation may take part in pathophysiological processes of type 2 diabetes.

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Amino acid metabolism, insulin secretion and diabetes

Cited by 194 publications

References 54 publications

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

Comparing BRIN-BD11 culture producing insulin using different type of microcarriers

Quantitative proteomic analysis of S-nitrosated proteins in diabetic mouse liver with ICAT switch method

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