Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm

Matschinsky, Franz M.

doi:10.2337/diabetes.45.2.223

Cited by 308 publications

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“…Moreover, they depend on an increase in the cellular metabolism of glucose. Because the rate of glucose metabolism is thought to be largely determined at the glucokinase step, glucokinase is often viewed as the ''glucose sensor'' for the physiological responses of the ␤-cell to the sugar (7). Consistent with this view, human subjects with inherited mutations of glucokinase (maturity onset diabetes of the young, MODY 2) present a disorder in their capacity to secrete insulin in response to hyperglycemia (8).…”

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confidence: 66%

Modulation of glucose responsiveness of insulinoma β-cells by graded overexpression of glucokinase

Wang

Iynedjian

1997

Proc. Natl. Acad. Sci. U.S.A.

126

142

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Insulinoma ␤-cells capable of overexpressing glucokinase under the control of a doxycycline-dependent transcriptional transactivator were established from parental INS-1 cells. Glucokinase could be maximally induced to a level more than 20 times the basal level after 36 h of culture with doxycycline. Intermediate levels of induction could be achieved by varying doses of, and time of culture with, the inducer. The rate of glycolysis was measured in cells with 3-, 5-, and 8-fold increment in glucokinase activity above the noninduced level. Proportionate increases in glycolytic f lux occurred in cells cultured at low physiological glucose concentration. At high glucose concentration, induction of glucokinase in excess of 2-fold above basal resulted in little additional increase in glycolysis. The consequences of graded increases of glucokinase on two physiological glucose effects were investigated. Increments in glucokinase activity were accompanied by a stepwise shift to the left of the doseresponse curve for the inductive effect of glucose on the L-type pyruvate kinase mRNA. Similarly, the insulin secretory response to glucose was shifted leftward in glucokinase-induced cells. The following conclusions are drawn: (i) glucokinase is the major rate-limiting enzyme for glycolysis in these cells; (ii) downstream metabolic steps become limiting at high extracellular glucose concentration with moderate increases in glucokinase over the wild-type level; (iii) within limits, glucokinase activity is a determining factor for two types of glucose responses of the ␤-cell, the induction of specific gene expression, and insulin release.The endocrine ␤-cell of the pancreas contains glucokinase, a hexokinase isoenzyme with distinctive kinetics, and tissue expression shared by only a few cell types in the body, including mostly the liver besides the endocrine pancreas (1-3). Halfsaturation of glucokinase with glucose occurs at a substrate concentration around 6 mM, close to the concentration of glucose in the extracellular fluids (4). Because glucose transport in the ␤-cell is not rate-limiting (5), the glucose concentration in the intracellular space is close to the extracellular concentration, physiologically around 5 mM. Thus, glucokinase operates in the cell under conditions close to halfsaturation with glucose, allowing changes in the extracellular glucose concentration to be translated into parallel changes in the rate of glucose phosphorylation, the first step of glucose metabolism. In addition, glucose phosphorylation appears to be the major rate-limiting step in the glycolytic pathway in the ␤-cell, because assayable glucokinase activity is the lowest of the activities of all glycolytic enzymes, and glucose utilization displays a glucose concentration dependency similar to that of glucokinase (6). Therefore, glucokinase is considered to be the enzyme that allows glucose to regulate its own rate of metabolism in the ␤-cell.Important physiological effects, including effects on the rate of specific gene transcriptio...

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confidence: 66%

Modulation of glucose responsiveness of insulinoma β-cells by graded overexpression of glucokinase

Wang

Iynedjian

1997

Proc. Natl. Acad. Sci. U.S.A.

126

142

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“…In a beta-cell, glucose is phosphorylated by glucokinase, which determines the rate of glycolysis and the generation of pyruvate (30). In mitochondria, pyruvate enters the TCA cycle, which produces reducing equivalents that activate ATP formation (64).…”

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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“…Altered intracellular Ca 2ϩ homeostasis and perturbed ␤-cell metabolism are hallmarks of diabetes (37,38). In addition, islet transplant failure is associated with hypoxia and related stresses during isolation, culture, and the post-transplantation period (39,40).…”

Section: Discussionmentioning

confidence: 99%

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

Dror¹,

Kalynyak

Bychkivska

et al. 2008

Journal of Biological Chemistry

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Pancreatic ␤-cell death is a critical event in type 1 diabetes, type 2 diabetes, and clinical islet transplantation. We have previously shown that prolonged block of ryanodine receptor (RyR)-gated release from intracellular Ca 2؉ stores activates calpain-10-dependent apoptosis in ␤-cells. In the present study, we further characterized intracellular Ca 2؉ channel expression and function in human islets and the MIN6 ␤-cell line. All three RyR isoforms were identified in human islets and MIN6 cells, and these endoplasmic reticulum channels were observed in close proximity to mitochondria. Blocking RyR channels, but not sarco/endoplasmic reticulum ATPase (SERCA) pumps, reduced the ATP/ADP ratio. Blocking Ca 2؉ flux through RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of hypoxia-inducible factor (HIF-1␤). Moreover, inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1␤ and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1␤, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signaling network in ␤-cells. We demonstrate that this pathway is controlled by Ca 2؉ flux through intracellular channels, likely via changes in mitochondrial metabolism and ATP. These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca 2؉ homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.

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Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm

Cited by 308 publications

References 0 publications

Modulation of glucose responsiveness of insulinoma β-cells by graded overexpression of glucokinase

Modulation of glucose responsiveness of insulinoma β-cells by graded overexpression of glucokinase

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

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

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