Underexpression of β Cell High
            <i>K</i>
            <sub>m</sub>
            Glucose Transporters in Noninsulin-Dependent Diabetes

Johnson, John H.; Ogawa, Atsushi; Chen, Ling; Orci, Lelio; Newgard, Christopher B.; Alam, Tausif; Unger, Roger H

doi:10.1126/science.2237405

Cited by 189 publications

(99 citation statements)

References 24 publications

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“…Consequently, if glucose uptake into the beta cell is impaired, glucose oxidation will be diminished. In fact, localisation and expression of GLUT2 in beta cells in C57BL/6J mice given an HF diet have previously been shown to be perturbed [21,25]. Indeed, we found a similar dislocation of GLUT2, and this is presumably responsible, to some extent, for the perturbation of glucose oxidation that we and others have observed.…”

Section: Discussionsupporting

confidence: 86%

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

et al. 2006

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Aim/hypothesis Hyperinsulinaemia maintains euglycaemia in insulin-resistant states. The precise cellular mechanisms by which the beta cells adapt are still unresolved. A peripherally derived cue, such as increased circulating fatty acids, may instruct the beta cell to initiate an adaptive programme to maintain glucose homeostasis. When this fails, type 2 diabetes ensues. Because mitochondria play a key role in beta cell pathophysiology, we tested the hypothesis that mitochondrial metabolism is critical for beta cell adaptation to insulin resistance. Methods C57BL/6J mice were given high-fat (HF) diet for 12 weeks. We then analysed islet hormone secretion, metabolism in vivo and in vitro, and beta cell morphology.Results HF diet resulted in insulin resistance and glucose intolerance but not frank diabetes. Basal insulin secretion was elevated in isolated islets from HF mice with almost no additional response provoked by high glucose. In contrast, a strong secretory response was seen when islets from HF mice were stimulated with fuels that require mitochondrial metabolism, such as glutamate, glutamine, alpha-ketoisocaproic acid and succinate. Moreover, while glucose oxidation was impaired in islets from HF mice, oxidation of glutamine and palmitate was enhanced. Ultrastructural analysis of islets in HF mice revealed an accumulation of lipid droplets in beta cells and a twofold increase in mitochondrial area. Conclusions/interpretation We propose that beta cells exposed to increased lipid flux in insulin resistance respond by increasing mitochondrial volume. This expansion is associated with enhanced mitochondrial metabolism as a means of beta cell compensation.

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Section: Discussionsupporting

confidence: 86%

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

et al. 2006

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“…Such glucose dependence is consistent with the fact that high K m GLUT2 is the dominating glucose transporter in rodent β-cells Johnson et al, 1990). It was therefore unexpected that human β-cells preferentially express low K m GLUT1 (De Vos et al, 1995), whose capacity is close to saturation already at threshold concentrations of glucose.…”

Section: Role Of Metabolism For Glucose-induced Insulin Secretionsupporting

confidence: 74%

Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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“…In the Zucker diabetic fatty (ZDF) rat, overabundance of islet lipid is associated with impaired glucose-stimulated insulin secretion and decreased expression of the glucose transporter GLUT2/Slc2a2 (25), as well as enhanced nitric oxide formation (42) and apoptosis (44). Although the mechanisms underlying these changes, collectively termed "lipotoxicity" or "glucolipotoxicity" (36) are not fully elucidated, elevated levels of "lipogenic" transcription factors, such as sterol response element-binding protein-1c (SREBP-1c) (26) and peroxisome proliferator-activated receptor-␥ (PPAR␥) (26,28), may play a role.…”

mentioning

confidence: 99%

Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

Parton¹,

Diraison²,

Neill³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. Impact of PPAR␥ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays. Am J Physiol Endocrinol Metab 287: E390 -E404, 2004. First published May 4, 2004 10.1152/ajpendo.00016.2004.-Peroxisome proliferator-activated receptor-␥ (PPAR␥) serves as a target for the thiazolidinedione class of antidiabetic drugs and is an important regulator of adipose tissue differentiation. By contrast, the principal target genes for PPAR␥ in the pancreatic islet and the impact of their induction on insulin secretion are largely undefined. Here, we show that mRNAs encoding both isoforms of rodent PPAR␥, ␥1 and ␥2, are expressed in primary rat islets and are upregulated by overexpresssion of the lipogenic transcription factor sterol response element-binding protein 1c. Unexpectedly, however, oligonucleotide microarray analysis demonstrates that graded activation of PPAR␥ achieved with 1) the thiazolidinedione GW-347845, 2) transduction with adenoviral PPAR␥1, or 3) a combination of both treatments progressively enhances the expression of genes involved in fatty acid oxidation and transport. Moreover, maximal activation of PPAR␥1 reduces islet triglyceride levels and enhances the oxidation of exogenous palmitate while decreasing glucose oxidation, cellular ATP content, and glucose-, but not depolarization-stimulated, insulin secretion. We conclude that, in the context of the pancreatic islet, the principal response to PPAR␥ expression and activation is the activation of genes involved in the disposal, rather than the synthesis, of fatty acids. Although fatty acid oxidation may have beneficial effects on ␤-cell function in the longer term by countering ␤-cell "lipotoxicity," the acute response to this metabolic shift is a marked inhibition of insulin secretion.␤-cell; insulin; secretion; peroxisome proliferator-activated receptor-␥; sterol regulatory element-binding protein-1c; thiazolidinedione; glucolipotoxicity GROWING EVIDENCE SUGGESTS that ␤-cell secretory failure in some forms of type 2 diabetes is correlated with the accumulation of triglyceride (TG) within the pancreatic islet (28). In the Zucker diabetic fatty (ZDF) rat, overabundance of islet lipid is associated with impaired glucose-stimulated insulin secretion and decreased expression of the glucose transporter GLUT2/Slc2a2 (25), as well as enhanced nitric oxide formation (42) and apoptosis (44). Although the mechanisms underlying these changes, collectively termed "lipotoxicity" or "glucolipotoxicity" (36) are not fully elucidated, elevated levels of "lipogenic" transcription factors, such as sterol response element-binding protein-1c (SREBP-1c) (26) and peroxisome proliferator-activated receptor-␥ (PPAR␥) (26, 28), may play a role.PPAR␥, a member of the nuclear hormone receptor family, is translated from an alternately spliced mRNA in humans and rodents, generating three (␥1, ␥2, and ␥3) or two (␥1 and ␥2) isoforms, respectively, in these species (see Fig. 1A) (16,17,45,48). Whereas PPAR␥1 is present in many m...

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Underexpression of β Cell High K _m Glucose Transporters in Noninsulin-Dependent Diabetes

Cited by 189 publications

References 24 publications

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

Oscillatory control of insulin secretion

Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

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Underexpression of β Cell High K m Glucose Transporters in Noninsulin-Dependent Diabetes

Cited by 189 publications

References 24 publications

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

Oscillatory control of insulin secretion

Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

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Underexpression of β Cell High K _m Glucose Transporters in Noninsulin-Dependent Diabetes