Science, medicine, and the future Non-insulin dependent diabetes mellitus: the gathering storm

O'Rahilly, S

doi:10.1136/bmj.314.7085.955

Cited by 89 publications

(71 citation statements)

References 10 publications

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“…Notably, the fact that only 7% of the studied population showed elevated glucose concentrations, but 34% elevated BMI, indicates that obesity alone does not unavoidably induce insulin resistance. Other factors, such as genetic predisposition for example in addition to obesity will be necessary to develop NIDDM [1,15]. Recently, TNF-a produced by adipocytes of the obese state has been reported to induce insulin resistance of NIDDM by inhibiting the activity of tyrosine kinase of the insulin receptor b-subunit, specifically in muscle and fat tissue [2,3].…”

Section: Discussionmentioning

confidence: 99%

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Association between insulin resistance, body mass and neopterin concentrations

Ledochowski

Murr

Widner

et al. 1999

Clinica Chimica Acta

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Section: Discussionmentioning

confidence: 99%

“…Although genetic factors are highly likely to have a role in this disease, obesity is the most common factor in insulin resistance [1]. The association between obesity and insulin resistance in this disease is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Association between insulin resistance, body mass and neopterin concentrations

Ledochowski

Murr

Widner

et al. 1999

Clinica Chimica Acta

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“…Clinical diabetes may also be improved by increasing insulin sensitivity, improving f3 cell function at a cellular level or moderating insulin need by weight reduction and exercise. 202 The quest for near euglycaemia, although laudable, has the potential for inducing acute, recurrent and even prolonged hypoglycaemia in insulin-dependent diabetics?03 Hypoglycaemia may trigger the release of potent vasoconstrictors such as adrenaline, vasopressin and angiotensin II, alter blood coagulability and viscosity and activate neutrophils with the combined effect of damaging capillary endothelium, inducing capillary closure and exaggerating proliferative retinopathy. Relative 'hypoglycaemia' following acute normalisation of blood glucose levels in ill-controlled diabetics (re-entry phenomenon) may cause sudden intensification of an ischaemic retinopathy and has been attributed in part to increased IGF-l levels.…”

Section: Achieving 'Near' Euglycae Miamentioning

confidence: 99%

Diabetic retinopathy: Some cellular, molecular and therapeutic considerations

Archer

1999

Eye

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“…3 It is estimated that by the year 2020, there will be approximately 250 million people affected by type 2 diabetes mellitus worldwide. 4 It is therefore important to understand the pathogenic mechanisms of insulin resistance in order to identify novel targets for primary and secondary prevention. In this short review, we will focus on some recent advances in our understanding of insulin resistance in man.…”

Section: Introductionmentioning

confidence: 99%

Cellular mechanism of insulin resistance: potential links with inflammation

Perseghin¹,

2003

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Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential ratecontrolling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using 13 C/ 31 P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar 13 C/ 31 P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase Cy and IKK-b, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.

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Science, medicine, and the future Non-insulin dependent diabetes mellitus: the gathering storm

Cited by 89 publications

References 10 publications

Association between insulin resistance, body mass and neopterin concentrations

Association between insulin resistance, body mass and neopterin concentrations

Diabetic retinopathy: Some cellular, molecular and therapeutic considerations

Cellular mechanism of insulin resistance: potential links with inflammation

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