Comparison of Insulin Secretory Function in Two Mouse Models with Different Susceptibility to β-Cell Failure

Kooptiwut, Suwattanee; Zraika, Sakeneh; Thorburn, Anne W.; Dunlop, Marjorie; Darwiche, Rima; Kay, Thomas W. H.; Proietto, Joseph; Andrikopoulos, Sofianos

doi:10.1210/endo.143.6.8859

Cited by 67 publications

(18 citation statements)

References 49 publications

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“…In the context of diabetes, increased mRNA levels of Hk1 have been reported in Px rats and db/db mouse islets (Jonas et al 1999, Kjorholt et al 2005. In agreement, HK enzymatic activity was upregulated in the islets of ZDF rats (Cockburn et al 1997), DBA/2 mice (Kooptiwut et al 2002) and Psammomys obesus on high energy diet (Nesher et al 1999). Moreover, exposure of rat islets to elevated glucose levels in vitro upregulated the mRNA levels of Hk2 (Ghanaat-Pour et al 2007) (Table 3).…”

Section: (Continued)supporting

confidence: 60%

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Bensellam

Jonas

Laybutt

2018

Journal of Endocrinology

200

171

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Like all the cells of an organism, pancreatic β-cells originate from embryonic stem cells through a complex cellular process termed differentiation. Differentiation involves the coordinated and tightly controlled activation/repression of specific effectors and gene clusters in a time-dependent fashion thereby giving rise to particular morphological and functional cellular features. Interestingly, cellular differentiation is not a unidirectional process. Indeed, growing evidence suggests that under certain conditions, mature β-cells can lose, to various degrees, their differentiated phenotype and cellular identity and regress to a less differentiated or a precursor-like state. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional β-cell mass in diabetes. β-cell dedifferentiation involves: (1) the downregulation of β-cell-enriched genes, including key transcription factors, insulin, glucose metabolism genes, protein processing and secretory pathway genes; (2) the concomitant upregulation of genes suppressed or expressed at very low levels in normal β-cells, the β-cell forbidden genes; and (3) the likely upregulation of progenitor cell genes. These alterations lead to phenotypic reconfiguration of β-cells and ultimately defective insulin secretion. While the major role of glucotoxicity in β-cell dedifferentiation is well established, the precise mechanisms involved are still under investigation. This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress, inflammation and hypoxia. It discusses the role of Foxo1, Myc and inhibitor of differentiation proteins and underscores the emerging role of non-coding RNAs. Finally, it proposes a novel hypothesis of β-cell dedifferentiation as a potential adaptive mechanism to escape cell death under stress conditions.

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Section: (Continued)supporting

confidence: 60%

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Bensellam

Jonas

Laybutt

2018

Journal of Endocrinology

200

171

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“…Consistent with these observations, GK activity and glucose metabolism in ␤ cells are increased in several animal models of type 2 diabetes (19 -23). Furthermore, the susceptibility to high glucose-induced ␤ cell failure in DBA/2 mice is accompanied by enhanced GK activity and increased glucose metabolism in ␤ cells (24). Our results show that enhanced GK activity accelerates glycolysis when the extracellular glucose is increased and that this is accompanied by accumulation of intracellular ROS, oxidative damage to mitochondria and DNA, and apoptotic cell death.…”

mentioning

confidence: 58%

Oxidative Stress Is a Mediator of Glucose Toxicity in Insulin-secreting Pancreatic Islet Cell Lines

Nicholson

Knobel

et al. 2004

Journal of Biological Chemistry

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Pancreatic ␤ cells secrete insulin in response to changes in the extracellular glucose. However, prolonged exposure to elevated glucose exerts toxic effects on ␤ cells and results in ␤ cell dysfunction and ultimately ␤ cell death (glucose toxicity). To investigate the mechanism of how increased extracellular glucose is toxic to ␤ cells, we used two model systems where glucose metabolism was increased in ␤ cell lines by enhancing glucokinase (GK) activity and exposing cells to physiologically relevant increases in extracellular glucose (3.3-20 mM). Exposure of cells with enhanced GK activity to 20 mM glucose accelerated glycolysis, but reduced cellular NAD(P)H and ATP, caused accumulation of intracellular reactive oxygen species (ROS) and oxidative damage to mitochondria and DNA, and promoted apoptotic cell death. These changes required both enhanced GK activity and exposure to elevated extracellular glucose. A ROS scavenger partially prevented the toxic effects of increased glucose metabolism. These results indicate that increased glucose metabolism in ␤ cells generates oxidative stress and impairs cell function and survival; this may be a mechanism of glucose toxicity in ␤ cells. The level of ␤ cell GK may also be critical in this process.Pancreatic ␤ cells play a crucial role in maintaining glucose homeostasis through secretion of insulin in response to changes in the extracellular glucose. Glucose-stimulated insulin secretion (GSIS) 1 is regulated by the rate of glucose metabolism within ␤ cells (1, 2), and a key event in this process is the phosphorylation of glucose by glucokinase (GK). GK, also referred to as hexokinase IV, is a member of the mammalian hexokinase (HK) family that catalyzes the initial step in glucose metabolism by most metabolic pathways (e.g. glycolysis, pentose phosphate cycle and glycogen synthesis) (3). In pancreatic ␤ cells, GK assumes the rate-limiting role for glucose metabolism (4). GK has a K m for glucose of ϳ5 mM, a value that is within the physiological range of blood glucose levels and almost two orders of magnitude higher than any other HK (3-5). Furthermore, the activity of GK is insensitive to feedback inhibition by physiological concentrations of its product, glucose 6-phosphate (Glc-6-P) (3). These characteristics of GK enable ␤ cells to increase glucose metabolism in proportion to elevations in extracellular glucose. Subsequent to glucose phosphorylation, glucose metabolism involves both cytosolic and mitochondrial processes and generates signals leading to insulin secretion (2).In contrast to the ability of glucose to acutely stimulate insulin secretion, chronic exposure of ␤ cells to increased glucose concentrations results in ␤ cell dysfunction and ultimately ␤ cell death, a phenomenon termed ␤ cell glucose toxicity (glucotoxicity) (6 -8). During the progression of type 2 diabetes, glucose toxicity is likely an important factor that contributes to progressive ␤ cell failure and development of overt diabetes. The molecular mechanisms of how chronic exposure to elevated...

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“…These strains are hyperinsulinaemic and have increased islet hexokinase activity compared with lean Wistar rats [16] and ZDF lean controls [17]. Similar observations were made in DBA/2 mice [18]. In these rodent models, hyperglycaemia was one of the plausible factors responsible for changes in β-cell gene expression [14].…”

Section: Hexokinase Isoforms and The Triggering Setpoint Of The Glucomentioning

confidence: 70%

Why expression of some genes is disallowed in β-cells

Quintens

Hendrickx

Lemaire

et al. 2008

Biochemical Society Transactions

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A differentiated beta-cell results not only from cell-specific gene expression, but also from cell-selective repression of certain housekeeping genes. Indeed, to prevent insulin toxicity, beta-cells should handle insulin stores carefully, preventing exocytosis under conditions when circulating insulin is unwanted. Some ubiquitously expressed proteins would significantly jeopardize this safeguard, when allowed to function in beta-cells. This is illustrated by two studied examples. First, low-K(m) hexokinases are disallowed as their high affinity for glucose would, when expressed, significantly lower the threshold for glucose-induced beta-cell function and cause hypoglycaemia, as happens in patients with beta-cell tumours. Thus the beta-cell phenotype means not only expression of glucokinase but also absence of low-K(m) hexokinases. Secondly, the absence of MCTs (monocarboxylic acid transporters) in beta-cells explains the pyruvate paradox (pyruvate being an excellent substrate for mitochondrial ATP production, yet not stimulating insulin release when added to beta-cells). The relevance of this disallowance is underlined in patients with exercise-induced inappropriate insulin release: these have gain-of-function MCT1 promoter mutations and loss of the pyruvate paradox. By genome-wide ex vivo mRNA expression studies using mouse islets and an extensive panel of other tissues, we have started to identify in a systematic manner other specifically disallowed genes. For each of those, the future challenge is to explore the physiological/pathological relevance and study conditions under which the phenotypically disallowed state in the beta-cell is breached.

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Comparison of Insulin Secretory Function in Two Mouse Models with Different Susceptibility to β-Cell Failure

Cited by 67 publications

References 49 publications

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Oxidative Stress Is a Mediator of Glucose Toxicity in Insulin-secreting Pancreatic Islet Cell Lines

Why expression of some genes is disallowed in β-cells

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