From receptor to transporter: insulin signalling to glucose transport

Holman, Geoffrey D.; Kasuga, Masato

doi:10.1007/s001250050780

Cited by 204 publications

(167 citation statements)

References 128 publications

(71 reference statements)

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“…SiM is also a good predictor of diabetes, especially in Europids [32]. We subsequently tested fasting and 2-h glucose based on the hypothesis that direct stimulation of the mobilisation of glucose transporter GLUT4 by PI3K [10] could occur independently of metabolic effects initiated via its activation of PKB. …”

Section: Discussionmentioning

confidence: 99%

“…Hence, defective activation of PI3K could also be a novel mechanism of peripheral leptin resistance. Direct interaction between PI3K and membrane vesicles leads to mobilisation of GLUT4 glucose transporters in response to insulin stimulation in adipose, muscle and liver cells [10], so it is possible that defective PI3K activity may also contribute to peripheral insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylinositol 3-kinase p85α regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population

et al. 2006

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Aims/hypothesis Phosphatidylinositol 3-kinase (PI3K) couples the leptin and insulin signalling pathways via the insulin receptor substrates IRS1 and IRS2. Hence, defective activation of PI3K could be a novel mechanism of peripheral leptin or insulin resistance. We investigated associations of tagging single-nucleotide polymorphisms (tSNPs) in the PI3K p85α regulatory subunit gene PIK3R1 with anthropometry, leptin, body fat and insulin sensitivity in a female twin population of European extraction. Materials and methods Eight tSNPs were genotyped in 2,778 women (mean age 47.4±12.5 years) from the St Thomas' UK Adult Twin Registry (Twins UK). Results SNP rs1550805 was associated with serum leptin (p=0.028), BMI (p=0.025), weight (p=0.019), total fat (p=0.004), total fat percentage (p=0.002), waist circumference (p=0.025), central fat (p=0.005) and central fat percentage (p=0.005). SNPs rs7713645 and rs7709243 were associated with BMI (p=0.020 and p=0.029, respectively), rs7709243 with weight, total and central fat (p=0.026, p=0.031 and p=0.023, respectively) and both SNPs with fasting glucose (p=0.003 and p=0.001, respectively) and glucose 2-h post OGTT (p=0.023 and p=0.007, respectively). Subjects with haplotype 222 (frequency 7.2%) showed higher serum leptin concentration (p=0.007) and body fat measures (p≤0.001 for all), and those with haplotype 221 (frequency 38.7%) showed higher fasting and 2-h glucose (p=0.035 and p=0.021, respectively) compared with subjects with the most common haplotype, 111 (frequency 45.5%). Conclusions/interpretation Association of the PIK3R1 SNP rs1550805 with serum leptin and body fat may reflect a diminished ability of PI3K to signal via IRS1 or IRS2 in response to leptin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase p85α regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population

et al. 2006

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“…The signalling pathways through which these distinct mechanisms operate differ [5]. While the insulin pathway involves insulin binding to its receptor inducing tyrosine kinase activity, phosphorylation of insulin receptor substrate proteins with subsequent activation of phosphatidylinositol-3-kinase [6], the contraction pathway, is independent of these steps [7][8][9]. A number of molecules including calcium [5,10], protein kinase C [5], AMP-activated protein kinase (AMPK) [11], bradykinin [12] and NO [13] have been implicated in contractionmediated glucose uptake.…”

Section: Introductionmentioning

confidence: 99%

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

et al. 2005

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Aims/hypothesis: Nitric oxide (NO) has been implicated as an important signalling molecule in the contraction-mediated glucose uptake pathway and may represent a novel strategy for blood glucose control. The current study sought to determine whether acute infusion of the NO donor, sodium nitroprusside (SNP), increases leg glucose uptake at rest in patients with type 2 diabetes. Methods: Fifteen male patients with type 2 diabetes (aged 54±4 years, mean±SD) were entered into a randomised, cross-over design study, examining the effect of a 30-min intra-femoral infusion of SNP on leg glucose uptake. Comparison was made with a 30-min infusion of verapamil, titrated to elicit similar leg blood flow responses to SNP. Leg blood flow was measured by thermodilution in the femoral vein, and leg glucose uptake was calculated as the product of leg blood flow and the femoral arterio-venous (A-V) glucose concentration gradient. Results: The two drugs increased leg blood flow to a similar extent (p= 0.50). Both leg A-V glucose concentration gradient (SNP 0.12±0.05, verapamil −0.06±0.04 mmol/l; mean±SEM, p=0.03) and leg glucose uptake (SNP 0.17±0.09, verapamil −0.09±0.06 mmol/min; p=0.03) were higher with the SNP treatment than with verapamil. These results occurred independently of any significant difference in plasma insulin concentration between drugs (p=0.56). Conclusions/interpretation: Acute infusion of SNP resulted in greater glucose uptake relative to verapamil. NO may therefore be an important mediator of peripheral glucose disposal and a potential therapeutic target in patients with type 2 diabetes.

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“…Insulin stimulates glucose disposal in peripheral tissues by virtue of the expression of the Glut4 isoform [1,2,35]. In the absence of insulin, this transporter is intracellularly sequestered within the elements of the endosomal system, the trans-Golgi network and a specialized storage compartment [3][4][5][6].…”

Section: Resultsmentioning

confidence: 99%

Trafficking of Glut4–Green Fluorescent Protein chimaeras in 3T3-L1 adipocytes suggests distinct internalization mechanisms regulating cell surface Glut4 levels

Campbell

Tavaré

Leader

et al. 1999

Biochemical Journal

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Insulin stimulates glucose transport in adipose and muscle tissue by stimulating the movement (‘translocation’) of an intracellular pool of glucose transporters (the Glut4 isoform) to the plasma membrane. We have engineered a series of chimaeras between Glut4 and green fluorescent protein (GFP) from Aequoria victoria and expressed these proteins in 3T3-L1 adipocytes by microinjection of plasmid cDNA. In the absence of insulin, GFP-Glut4 is localized intracellularly within a perinuclear compartment and multiple intracellular punctate structures. In response to insulin, chimaeric GFP-Glut4 species exhibit a profound redistribution to the cell surface with kinetics comparable with the endogenous protein. The intracellular localization of GFP-Glut4 overlaps partially with compartments labelled with Texas Red transferrin, but is largely distinct from intracellular structures identified using Lysotracker-Red®. K+-depletion resulted in the accumulation of GFP-Glut4 at the cell surface, but to an lesser extent than that observed in response to insulin. In contrast with native Glut4, removal of the insulin stimulus or treatment of insulin-stimulated cells with phosphatidylinositol 3′-kinase inhibitors did not result in re-internalization of the chimaeric GFP-Glut4 from the plasma membrane, suggesting that the recycling properties of this species differ from the native Glut4 molecule. We suggest that the recycling pathway utilized by GFP-Glut4 in the absence of insulin is distinct from that used to internalize GFP-Glut4 from the plasma membrane after withdrawal of the insulin stimulus, which may reflect distinct pathways for internalization of endogenous Glut4 in the presence or absence of insulin.

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From receptor to transporter: insulin signalling to glucose transport

Cited by 204 publications

References 128 publications

Phosphatidylinositol 3-kinase p85α regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population

Phosphatidylinositol 3-kinase p85α regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

Trafficking of Glut4–Green Fluorescent Protein chimaeras in 3T3-L1 adipocytes suggests distinct internalization mechanisms regulating cell surface Glut4 levels

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