Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 3/2010

01-03-2010 | Article

Regulation of oxidative stress by glycaemic control: evidence for an independent inhibitory effect of insulin therapy

Published in: Diabetologia | Issue 3/2010

Login to get access

Abstract

Aims/hypothesis

We examined whether type of diabetes and/or insulin treatment can modulate the impact of sustained hyperglycaemia and glycaemic variability as activators of oxidative stress.

Methods

This was an observational study in 139 patients with diabetes, 48 with type 1, 60 with type 2 treated by oral hypoglycaemic agents (OHAs) alone and 31 with type 2 treated with insulin plus OHAs. In addition, two groups of ten patients with type 2 diabetes were investigated either before and after introducing insulin treatment (add-on insulin group) or before and after add-on OHA therapy to metformin (add-on OHA group). Oxidative stress was estimated from 24 h urinary excretion rates of 8-isoprostaglandin \( {{\text{F}}_{2\alpha }}\left( {8 - {\text{iso}} - {\text{PG}}{{\text{F}}_{2\alpha }}} \right) \). HbA1c was assessed and mean amplitude of glycaemic excursions (MAGE) was estimated by continuous monitoring.

Results

The 24 h excretion rate of \( 8 - {\text{iso}} - {\text{PG}}{{\text{F}}_{2\alpha }} \) (median [range] picomoles per millimole of creatinine) was much higher (p < 0.0001) in type 2 diabetes patients treated with OHAs alone (112 [26–329]) than in the type 1 diabetes group (65 [29–193]) and the type 2 diabetes group treated with insulin (69 [30–198]). It was associated with HbA1c (F = 12.9, p = 0.0008) and MAGE (F = 7.7, p = 0.008) in non-insulin-treated, but not in insulin-treated patients. A significant reduction in 24 h excretion rate of \( 8 - {\text{iso}} - {\text{PG}}{{\text{F}}_{2\alpha }} \) from 126 (47–248) to 62 (35–111] pmol/mmol of creatinine was observed in the add-on insulin group (p = 0.005) but not in the add-on OHA group.

Conclusions/interpretation

In type 1 and type 2 diabetes, insulin exerts an inhibitory effect on oxidative stress, a metabolic disorder that is significantly activated by sustained hyperglycaemia and glucose variability in non-insulin-treated type 2 diabetes.

Literature
  1. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820View ArticlePubMed
  2. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625View ArticlePubMed
  3. Gorus F, Mathieu C, Gerlo E (2006) How should HbA1c measurements be reported? Diabetologia 49:7–10View ArticlePubMed
  4. Sacks DB, Bruns DE, Goldstein DE, Mac Laren NK, McDonald JM, Parrott M (2002) Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus (Position statement). Diabetes Care 25:750–786View Article
  5. Monnier L, Lapinski H, Colette C (2003) Contributions of fasting and postprandial plasma increments to overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care 26:881–885View ArticlePubMed
  6. Hirsch IB, Brownlee M (2005) Should minimal blood glucose variability become the gold standard of glycemic control? J Diabetes Complications 19:178–181View ArticlePubMed
  7. Monnier L, Colette C (2008) Glycemic variability. Should we and can we prevent it? Diabetes Care 31(Suppl 2):S150–S154View ArticlePubMed
  8. Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P (2000) Glucose challenge stimulates reactive oxygen species (ROS) generation by leukocytes. J Clin Endocrinol Metab 85:2970–2973View ArticlePubMed
  9. Monnier L, Mas E, Ginet C et al (2006) Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 295:1681–1687View ArticlePubMed
  10. Ceriello A, Esposito K, Piconi L et al (2008) Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 57:1349–1354View ArticlePubMed
  11. Kilpatrick ES, Rigby AS, Atkin SL (2006) The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care 29:1486–1490View ArticlePubMed
  12. Wentholt IME, Kulik W, Michels RPJ, Hoekstra JBL, de Vries JH (2008) Glucose fluctuations and activation of oxidative stress in patients with type 1 diabetes. Diabetologia 51:183–190View ArticlePubMed
  13. Lachin JM, Genuth S, Nathan DM, Zinman B, Rutledge BN for the DCCT/EDIC Research Group (2008) Effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Complications Trial-Revisited. Diabetes 57:995–1001View ArticlePubMed
  14. Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ (1990) A series of prostaglandin F2-like compounds are produced in vivo in humans by non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A 87:9383–9387View ArticlePubMed
  15. Roberts LJ, Morrow JD (2000) Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med 28:505–513View ArticlePubMed
  16. Dandona P, Aljada A, Mohanty P et al (2001) Insulin inhibits intracellular NFkB and stimulates IkB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86:3257–3265View ArticlePubMed
  17. Cockcroft DW, Gault HM (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41View ArticlePubMed
  18. Code de la Santé Publique (2009) Partie legislative. Première partie. Livre premier. Titre II, Chapitre 1, Article L-1121-1. 18 Avril 2006 (version consolidée du 29 Août 2009). Available from www.​legifrance.​com, accessed 31 August 2009
  19. Buckingham B, Block J, Wilson DM (2005) Continuous glucose monitoring. Curr Opin Endocrinol Diabetes 12:273–279
  20. Monnier L, Colette C, Boegner C, Pham TC, Lapinski H, Boniface H (2007) Continuous glucose monitoring in patients with type 2 diabetes: why? When? Whom? Diabetes Metab 33:247–252View ArticlePubMed
  21. Friedewald WT, Levy RI, Frederickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifugation. Clin Chem 18:499–502PubMed
  22. Patrono C, Falco A, Davi G (2005) Isoprostane formation and inhibition in atherothrombosis. Curr Opin Pharmacol 5:198–203View ArticlePubMed
  23. Vesby J, Basu S, Mohsen R, Berne C, Vesby B (2002) Oxidative stress and antioxidant status in type 1 diabetes mellitus. J Intern Med 251:69–76View Article
  24. Morales CR, Terry ES, Zackert WE, Montine TJ, Morrow JD (2001) Improved assay for the quantification of the major urinary metabolite of the isoprostane 15-F2t-isoprostanes (8-iso-PGF2α) by a stable isotope dilution mass spectrometric assay. Clin Chim Acta 314:93–99View ArticlePubMed
  25. Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF (1970) Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes 19:644–655PubMed
  26. Service FJ, O’Brien PC, Rizza RA (1987) Measurements of glucose control. Diabetes Care 10:225–237PubMed
  27. Derr R, Garrett E, Stacy GA, Saudek CD (2003) Is HbA1c affected by glycemic instability? Diabetes Care 26:2728–2733View ArticlePubMed
  28. UK Prospective Diabetes Study Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853View Article
  29. Basu S (1998) Metabolism of 8-iso-prostaglandin F2α. FEBS Lett 428:32–36View ArticlePubMed
  30. Ceriello A, Quagliaro L, Catone B et al (2002) Role of hyperglycemia in nitrotyrosine postprandial generation. Diabetes Care 25:1439–1443View ArticlePubMed
  31. Dandona P, Mohanty P, Ghanim H et al (2001) The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxydation, and protein carbonylation. J Clin Endocrinol Metab 86:355–362View ArticlePubMed
  32. Davi G, Guagnano MT, Ciabattoni G et al (2003) Platelet activation in obese women: role of inflammation and oxidant stress. JAMA 289:1781–1782View Article
  33. Dandona P, Aljada A, Mohanty P (2002) The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 45:924–930View ArticlePubMed
  34. Dandona P, Chaudhuri A, Ghanin H, Mohanty P (2009) Insulin as an anti-inflammatory and antiatherogenic modulator. J Am Coll Cardiol 53:S14–S20View ArticlePubMed
  35. De Oliveira Silva C, Delbosc S, Araïs C, Monnier L, Cristol J-P, Herbute N (2008) Modulation of CD36 protein expression by AGEs and insulin in aortic VSMCs from diabetic and non-diabetic rats. Nutr Metab Cardiovasc Dis 18:23–30View ArticlePubMed
  36. Du X, Stocklauser-Farber K, Rosen P (1999) Generation of reactive oxygen intermediates, activation of NF-kappaB and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radic Biol Med 27:752–763View ArticlePubMed
  37. Aljada A, Saadeh R, Assian E, Ghanim H, Dandona P (2000) Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide. J Clin Endocrinol Metab 85:2572–2575View ArticlePubMed
  38. Horvath EM, Benko R, Gero D, Kiss L, Szabo C (2008) Treatment with insulin inhibits poly (ADP-ribose) polymerase activation in a rat model of endotoxemia. Life Sci 82:205–209View ArticlePubMed
  39. Wong VW, McLean M, Boyages SC, Cheung NW (2004) C-reactive protein levels following acute myocardial infarction: effect of insulin infusion and tight glycemic control. Diabetes Care 27:2971–2973View ArticlePubMed
  40. Visser L, Zuurbier CJ, Hoek FJ et al (2005) Glucose, insulin and potassium applied as perioperative hyperinsulinaemic, normoglycaemic clamp: effects on inflammatory response during coronary artery surgery. Br J Anaesth 95:448–457View ArticlePubMed
  41. Rome S, Clemente K, Rabasa-Lhoret R et al (2003) Microarray profiling of human skeletal muscle reveals that insulin regulates 800 genes during a hyperinsulinemic clamp. J Biol Chem 278:18063–18068View ArticlePubMed
  42. Kuboki K, Jiang ZY, Takahar N et al (2000) Regulation of endothelial constitutive nitric synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 101:676–681PubMed
  43. Raz I, Wilson PWF, Strojek K et al (2009) Effects of prandial vs fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D Trial. Diabetes Care 32:381–386View ArticlePubMed
  44. Nathan DM, Buse JB, Davidson MB et al (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association. Diabetes Care 32:193–203View ArticlePubMed
  45. Standl E, Schnell O (2008) Insulin as a first-line therapy in type 2 diabetes. Should the use of sulfonylureas be halted? Diabetes Care 31(Suppl 2):S136–S139View ArticlePubMed
Metadata
Title
Regulation of oxidative stress by glycaemic control: evidence for an independent inhibitory effect of insulin therapy
Publication date
01-03-2010
Published in
Diabetologia / Issue 3/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1574-6

Other articles of this Issue 3/2010

Diabetologia 3/2010 Go to the issue

Article

Case fatality rates after first acute coronary syndrome in persons treated for type 2 diabetes show an improving trend

Article

Prediction of postpartum diabetes in women with gestational diabetes mellitus

Article

Long-term lifestyle intervention lowers the incidence of stroke in Japanese patients with type 2 diabetes: a nationwide multicentre randomised controlled trial (the Japan Diabetes Complications Study)

Commentary

Oxidative stress and glucose metabolism—is there a need to revisit effects of insulin treatment?

Article

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Article

Human IL6 enhances leptin action in mice

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits