Glucose-sensing mechanisms in pancreatic β-cells

MacDonald, Patrick E.; Joseph, Jamie W.; Rorsman, Patrik

doi:10.1098/rstb.2005.1762

Cited by 297 publications

(278 citation statements)

References 223 publications

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“…However, insulin secretion at 16.7 mmol/l glucose, despite a blunted ATP production suggests alternative pathways of exocytotic triggering in male and female LP islets. The classical ATP elevation-induced insulin closure of K ϩ channels may not be the only player for triggering insulin secretion (14,29). Evidence that ROS might contribute to glucose-stimulated insulin secretion is emerging (25,42).…”

Section: Discussionmentioning

confidence: 99%

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Theys

Bouckenooghe

Ahn

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Theys N, Bouckenooghe T, Ahn M-T, Remacle C, Reusens B. Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat. Am J Physiol Regul Integr Comp Physiol 297: R1516 -R1525, 2009. First published September 16, 2009; doi:10.1152/ajpregu.00280.2009.-Mitochondrial dysfunction may be a long-term consequence of a poor nutritional environment during early life. Our aim was to investigate whether a maternal low-protein (LP) diet may program mitochondrial dysfunction in islets of adult progeny before glucose intolerance ensues. To address this, pregnant Wistar rats were fed isocaloric diets containing either 20% protein (control) or 8% protein (LP diet) throughout gestation. From birth, offspring received the control diet. The mitochondrial function was analyzed in islets of 3-mo-old offspring. Related to their basal insulin release, cultured islets from both male and female LP offspring presented a lower response to glucose challenge and a blunted ATP production compared with control offspring. The expression of malate dehydrogenase as well as the subunit 6 of the ATP synthase encoded by mitochondrial genome (mtDNA) was lower in these islets, reducing the capacity of ATP production through the Krebs cycle and oxidative phosphorylation. However, mtDNA content was unchanged in LP islets compared with control. Several consequences of protein restriction during fetal life were more marked in male offspring. Only LP males showed an increased reactive oxygen species production associated with a higher expression of mitochondrial subunits of the electron transport chain NADH-ubiquinone oxireductase subunit 4L, an overexpression of peroxisome proliferator-activated receptor-␥ and uncoupling protein-2, and a strongly reduced beta-cell mass. In conclusion, mitochondrial function is clearly altered in islets from LP adult offspring in a sex-specific manner. That may provide a cellular explanation for the earlier development of glucose intolerance in male than in female offspring of dams fed an LP diet. developmental programming; malnutrition; metabolic syndrome; insulin secretion EPIDEMIOLOGICAL AND EXPERIMENTAL evidence shows a convincing relationship between a poor intrauterine nutritional environment and the subsequent development of metabolic disorders like insulin resistance, obesity, and cardiovascular disease in adulthood (11,12). The original concept of fetal programming of Type 2 diabetes mellitus (T2DM) was proposed by Hales et al. (12) who found in a cohort of adult men who had been smaller at birth that they were six times more prone to develop T2DM compared with individuals heavier at birth. These first epidemiological clues of programming have been largely replicated in many studies throughout the world (17, 27, 61). Currently, this concept is widely accepted, but the mechanistic basis is unclear.Recently, attention has focused on the involvement of mitochondria as putative targets linking physiological and molecular consequences of environmental disorders du...

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Section: Discussionmentioning

confidence: 99%

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Theys

Bouckenooghe

Ahn

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…ATP-sensitive potassium channels (K ATP channels) on the plasma membrane sense the increase in ATP and consequently close [1][2][3][4], triggering membrane depolarisation and opening of voltage-sensitive L-type Ca 2+ channels [4,5]. The secretory response is biphasic; within minutes a readily releasable pool (RRP) of granules docked at the plasma membrane is released [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

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Aims/hypothesis Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. Methods To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. Results Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1 −/− beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. Conclusions/interpretation Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.

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“…The mitochondrial electron transport chain pumps protons across the mitochondrial inner membrane, restoring a high protonmotive force and ATP production, until ATP rises and oxidative phosphorylation, glycolysis and glucose utilization are once more shut down. In this way, a muscle cell maintains stable NADH/NAD and ATP/ADP ratios over a wide range of energy demands, regardless of the amount or nature of its fuel supply [1].Pancreatic β-cells [2], and a few other glucose-sensing cell types, such as some hypothalamic glucose-sensing neurons [3], run their bioenergetics quite differently. Instead of regulating glucose metabolism to maintain their ATP/ADP ratio, they respond to glucose by altering their ATP/ADP ratios.…”

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confidence: 99%

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

Brand

Parker

Affourtit

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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Glucose-sensing mechanisms in pancreatic β-cells

Cited by 297 publications

References 223 publications

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

LKB1 couples glucose metabolism to insulin secretion in mice

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

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