Impact on the Oxidative Stress of the Different Analogues of Insulin in People With Type 1 Diabetes. (Ineox Study)

Type 1 Diabetes Mellitus Clinical Trial

— INEOX  

Official title:

Impact on the Oxidative Stress of the Different Analogues of Insulin in People With Type 1 Diabetes. Clinical Trial of Low Level of Intervention. (Ineox Study)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03328845
• Other study ID #: FIM-EOX-2016-01
• Status: Completed
• Phase: Phase 4
• Start date: January 20, 2017
• Est. completion date: November 20, 2021

Study information

• Verified date: November 2021
• Source: Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluates in a group of people with DM 1 the influence in parameters of oxidative stress of the treatments with the different current analogs of insulin

Description:

To evaluate by a randomized study in a group of people with DM 1 the influence in parameters of oxidative stress of the treatments with the different current analogs of

Insulin by analyzing:

1. - The circulating levels of oxidative stress markers: A) Anti oxidation: Total antioxidant capacity (CAT), B) Oxidation: 8-iso-prostaglandin F2 alpha (8-iso-PGF2α), acid reactive substances Thiobarbituric (TBARS) and LDL-oxidized.

2. - The relationship between glycemic control variables (HbA1c and mean glycemia) and variability (Standard deviation (SD), coefficient of variation (CV), and MAGE (mean amplitude of Glycemic excursions) and oxidative stress parameters analyzed.

Goal 2:

Study the activation of cellular pathways associated with processes and oxidation states, by means of a Array of expression of up to 50 genes encoding oxidative stress response genes as CPT1a (Carnitine Palmitoyl Transferase 1a, mitochondrial oxidizing b limiting enzyme), TAS (Fatty acyl synthetase), acetyl-coA carboxylase, Acadm (medium chain acyl dehydrogenase), Acadl (long chain acyl dehydrogenase), Acadvl (long chain acyl coA dehydrogenase), SOD1, Hmox1 and Glutamine-Cysteine ligase (Gclc).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: November 20, 2021
• Est. primary completion date: November 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age between 18 years and 65 years (inclusive).

• DM1 of more than two years of evolution with habitual follow-up in the Diabetes Unit of the University Regional Hospital of Malaga.

• HbA1c = 10%

• Intensive treatment with basal MDI - Bowl for more than 12 months prior to the start of study.

• Gives informed consent.

Exclusion Criteria:

• Chronic kidney disease, liver disease, thyroid dysfunction (except hypothyroidism correctly treated and controlled).

• Pregnancy or pregnancy planning.

• Diabetes mellitus type 2.

• Hyperuricemia (uric acid =7 mg / dl at the time of inclusion or current treatment With allopurinol).

• Absence of collaboration (informed consent).

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes Mellitus

Intervention

Drug:
• Toujeo SoloStar
Basal insulin at 16.00h and optimization of this basal doses with objetives of glycaemia before breakfast betwen 80-130 mg/ dl.
• Tresiba
Basal insulin at 16.00h and optimization of this basal doses with objetives of glycaemia before breakfast betwen 80-130 mg/ dl.
• Humalog Kwikpen
Ultrarrapid insulin that the patient had already and dose adjustement to obtain postprandial glycaemia levels < 150 mg/dl
• NovoRapid
Ultrarrapid insulin that the patient had already and dose adjustement to obtain postprandial glycaemia levels < 150 mg/dl
• Apidra
Ultrarrapid insulin that the patient had already and dose adjustement to obtain postprandial glycaemia levels < 150 mg/dl

Locations

Country	Name	City	State
Spain	Regional University Hospital of Málaga	Málaga

Sponsors (1)

Lead Sponsor	Collaborator
Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud

Country where clinical trial is conducted

Spain, 

References & Publications (71)

Aljada A, Ghanim H, Saadeh R, Dandona P. Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab. 2001 Jan;86(1):450-3. — View Citation

Arufe MC, Lu M, Lin RY. Differentiation of murine embryonic stem cells to thyrocytes requires insulin and insulin-like growth factor-1. Biochem Biophys Res Commun. 2009 Apr 3;381(2):264-70. doi: 10.1016/j.bbrc.2009.02.035. Epub 2009 Feb 14. — View Citation

Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev. 2009 Jan;89(1):27-71. doi: 10.1152/physrev.00014.2008. Review. — View Citation

Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999 Jan;48(1):1-9. Review. — View Citation

Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991 Apr;40(4):405-12. Review. — View Citation

Berg TJ, Nourooz-Zadeh J, Wolff SP, Tritschler HJ, Bangstad HJ, Hanssen KF. Hydroperoxides in plasma are reduced by intensified insulin treatment. A randomized controlled study of IDDM patients with microalbuminuria. Diabetes Care. 1998 Aug;21(8):1295-300. — View Citation

Bergenstal RM, Bailey TS, Rodbard D, Ziemen M, Guo H, Muehlen-Bartmer I, Ahmann AJ. Comparison of Insulin Glargine 300 Units/mL and 100 Units/mL in Adults With Type 1 Diabetes: Continuous Glucose Monitoring Profiles and Variability Using Morning or Evening Injections. Diabetes Care. 2017 Apr;40(4):554-560. doi: 10.2337/dc16-0684. Epub 2017 Jan 23. — View Citation

Bode BW, Buse JB, Fisher M, Garg SK, Marre M, Merker L, Renard E, Russell-Jones DL, Hansen CT, Rana A, Heller SR; BEGIN® Basal-Bolus Type 1 trial investigators. Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal-bolus treatment with mealtime insulin aspart in Type 1 diabetes (BEGIN(®) Basal-Bolus Type 1): 2-year results of a randomized clinical trial. Diabet Med. 2013 Nov;30(11):1293-7. doi: 10.1111/dme.12243. Epub 2013 Jun 17. — View Citation

Bravi MC, Armiento A, Laurenti O, Cassone-Faldetta M, De Luca O, Moretti A, De Mattia G. Insulin decreases intracellular oxidative stress in patients with type 2 diabetes mellitus. Metabolism. 2006 May;55(5):691-5. — View Citation

Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005 Jun;54(6):1615-25. — View Citation

Ceolotto G, Bevilacqua M, Papparella I, Baritono E, Franco L, Corvaja C, Mazzoni M, Semplicini A, Avogaro A. Insulin generates free radicals by an NAD(P)H, phosphatidylinositol 3'-kinase-dependent mechanism in human skin fibroblasts ex vivo. Diabetes. 2004 May;53(5):1344-51. — View Citation

Ceriello A, Esposito K, Ihnat M, Thorpe J, Giugliano D. Effect of acute hyperglycaemia, long-term glycaemic control and insulin on endothelial dysfunction and inflammation in Type 1 diabetic patients with different characteristics. Diabet Med. 2010 Aug;27(8):911-7. doi: 10.1111/j.1464-5491.2009.02928.x. — View Citation

Ceriello A, Ihnat M. Oxidative stress is, convincingly, the mediator of the dangerous effects of glucose variability. Diabet Med. 2010 Aug;27(8):968. doi: 10.1111/j.1464-5491.2010.02931.x. — View Citation

Ceriello A, Novials A, Ortega E, Canivell S, La Sala L, Pujadas G, Esposito K, Giugliano D, Genovese S. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Diabetes Care. 2013 Aug;36(8):2346-50. doi: 10.2337/dc12-2469. Epub 2013 Apr 5. — View Citation

Ceriello A. Hyperglycaemia and the vessel wall: the pathophysiological aspects on the atherosclerotic burden in patients with diabetes. Eur J Cardiovasc Prev Rehabil. 2010 May;17 Suppl 1:S15-9. doi: 10.1097/01.hjr.0000368193.24732.66. Review. — View Citation

Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med. 2004 Jul-Dec;10(7-12):65-71. Review. — View Citation

Costacou T, Evans RW, Schafer GL, Orchard TJ. Oxidative stress and response in relation to coronary artery disease in type 1 diabetes. Diabetes Care. 2013 Nov;36(11):3503-9. doi: 10.2337/dc12-2378. Epub 2013 Aug 6. — View Citation

Costacou T, Lopes-Virella MF, Zgibor JC, Virella G, Otvos J, Walsh M, Orchard TJ. Markers of endothelial dysfunction in the prediction of coronary artery disease in type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study. J Diabetes Complications. 2005 Jul-Aug;19(4):183-93. — View Citation

Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001 Jul;86(7):3257-65. — View Citation

Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Effect of hyperglycemia and insulin in acute coronary syndromes. Am J Cardiol. 2007 Jun 4;99(11A):12H-18H. Review. — View Citation

Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Insulin as an anti-inflammatory and antiatherogenic modulator. J Am Coll Cardiol. 2009 Feb 3;53(5 Suppl):S14-20. doi: 10.1016/j.jacc.2008.10.038. Review. — View Citation

Davies MJ, Derezinski T, Pedersen CB, Clauson P. Reduced weight gain with insulin detemir compared to NPH insulin is not explained by a reduction in hypoglycemia. Diabetes Technol Ther. 2008 Aug;10(4):273-7. doi: 10.1089/dia.2008.0282. — View Citation

Delmastro MM, Piganelli JD. Oxidative stress and redox modulation potential in type 1 diabetes. Clin Dev Immunol. 2011;2011:593863. doi: 10.1155/2011/593863. Epub 2011 May 18. — View Citation

Domínguez C, Ruiz E, Gussinye M, Carrascosa A. Oxidative stress at onset and in early stages of type 1 diabetes in children and adolescents. Diabetes Care. 1998 Oct;21(10):1736-42. — View Citation

Fawcett J, Tsui BT, Kruer MC, Duckworth WC. Reduced action of insulin glargine on protein and lipid metabolism: possible relationship to cellular hormone metabolism. Metabolism. 2004 Aug;53(8):1037-44. — View Citation

Francescato MP, Stel G, Geat M, Cauci S. Oxidative stress in patients with type 1 diabetes mellitus: is it affected by a single bout of prolonged exercise? PLoS One. 2014 Jun 6;9(6):e99062. doi: 10.1371/journal.pone.0099062. eCollection 2014. — View Citation

Franklin VL, Khan F, Kennedy G, Belch JJ, Greene SA. Intensive insulin therapy improves endothelial function and microvascular reactivity in young people with type 1 diabetes. Diabetologia. 2008 Feb;51(2):353-60. Epub 2007 Nov 27. — View Citation

García-Escobar E, Rodríguez-Pacheco F, Haro-Mora JJ, Gomez-Zumaquero JM, Rubio-Martín E, Gutierrez-Repiso C, Soriguer F, Rojo-Martínez G. Effect of insulin analogues on 3t3-l1 adipogenesis and lipolysis. Eur J Clin Invest. 2011 Sep;41(9):979-86. doi: 10.1111/j.1365-2362.2011.02492.x. Epub 2011 Mar 2. — View Citation

Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010 Oct 29;107(9):1058-70. doi: 10.1161/CIRCRESAHA.110.223545. Review. — View Citation

Goldman J, White JR Jr. New Insulin Glargine 300 U/mL for the Treatment of Type 1 and Type 2 Diabetes Mellitus. Ann Pharmacother. 2015 Oct;49(10):1153-61. doi: 10.1177/1060028015597915. Epub 2015 Aug 3. Review. — View Citation

Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care. 2000 May;23(5):644-9. — View Citation

Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012 Sep;14(9):859-64. doi: 10.1111/j.1463-1326.2012.01627.x. Epub 2012 Jun 7. — View Citation

Hoeldtke RD, Bryner KD, Hoeldtke ME, Christie I, Ganser G, Hobbs G, Riggs J. Sympathetic sudomotor disturbance in early type 1 diabetes mellitus is linked to lipid peroxidation. Metabolism. 2006 Nov;55(11):1524-31. — View Citation

Højlund K, Poulsen M, Staehr P, Brusgaard K, Beck-Nielsen H. Effect of insulin on protein phosphatase 2A expression in muscle in type 2 diabetes. Eur J Clin Invest. 2002 Dec;32(12):918-23. — View Citation

Home PD, Bergenstal RM, Bolli GB, Ziemen M, Rojeski M, Espinasse M, Riddle MC. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4). Diabetes Care. 2015 Dec;38(12):2217-25. doi: 10.2337/dc15-0249. Epub 2015 Jun 17. — View Citation

Homko C, Deluzio A, Jimenez C, Kolaczynski JW, Boden G. Comparison of insulin aspart and lispro: pharmacokinetic and metabolic effects. Diabetes Care. 2003 Jul;26(7):2027-31. — View Citation

Järvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Rontu R, Laine S, Lehtimäki T, Rönnemaa T, Viikari J, Raitakari OT. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation. 2004 Apr 13;109(14):1750-5. Epub 2004 Mar 15. — View Citation

Kalra S, Baruah MP, Niazi AK. Degludec: a novel basal insulin. Recent Pat Endocr Metab Immune Drug Discov. 2012 Jan;6(1):18-23. Review. — View Citation

Korytkowski MT, Salata RJ, Koerbel GL, Selzer F, Karslioglu E, Idriss AM, Lee KK, Moser AJ, Toledo FG. Insulin therapy and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a randomized controlled clinical trial. Diabetes Care. 2009 Apr;32(4):594-6. doi: 10.2337/dc08-1436. — View Citation

Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, Trüb T. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000 Jun;49(6):999-1005. — View Citation

Laaksonen DE, Atalay M, Niskanen L, Uusitupa M, Hänninen O, Sen CK. Increased resting and exercise-induced oxidative stress in young IDDM men. Diabetes Care. 1996 Jun;19(6):569-74. — View Citation

Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000 Dec;49(12):2142-8. — View Citation

Liebl A, Prager R, Binz K, Kaiser M, Bergenstal R, Gallwitz B; PREFER Study Group. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab. 2009 Jan;11(1):45-52. doi: 10.1111/j.1463-1326.2008.00915.x. Epub 2008 Jul 17. — View Citation

Liu HY, Cao SY, Hong T, Han J, Liu Z, Cao W. Insulin is a stronger inducer of insulin resistance than hyperglycemia in mice with type 1 diabetes mellitus (T1DM). J Biol Chem. 2009 Oct 2;284(40):27090-100. doi: 10.1074/jbc.M109.016675. Epub 2009 Aug 4. — View Citation

Mäkimattila S, Virkamäki A, Malmström R, Utriainen T, Yki-Jarvinen H. Insulin resistance in type I diabetes mellitus: a major role for reduced glucose extraction. J Clin Endocrinol Metab. 1996 Feb;81(2):707-12. — View Citation

Mannucci E, Monami M, Marchionni N. Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: a meta-analysis. Diabetes Obes Metab. 2009 Jan;11(1):53-9. doi: 10.1111/j.1463-1326.2008.00934.x. Epub 2008 Jul 29. Review. — View Citation

Marra G, Cotroneo P, Pitocco D, Manto A, Di Leo MA, Ruotolo V, Caputo S, Giardina B, Ghirlanda G, Santini SA. Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type 1 diabetes: a case for gender difference. Diabetes Care. 2002 Feb;25(2):370-5. — View Citation

Matsuhisa M, Koyama M, Cheng X, Sumi M, Riddle MC, Bolli GB, Hirose T; EDITION JP 1 study group. Sustained glycaemic control and less nocturnal hypoglycaemia with insulin glargine 300U/mL compared with glargine 100U/mL in Japanese adults with type 1 diabetes (EDITION JP 1 randomised 12-month trial including 6-month extension). Diabetes Res Clin Pract. 2016 Dec;122:133-140. doi: 10.1016/j.diabres.2016.10.002. Epub 2016 Oct 13. — View Citation

Monnier L, Colette C, Mas E, Michel F, Cristol JP, Boegner C, Owens DR. Regulation of oxidative stress by glycaemic control: evidence for an independent inhibitory effect of insulin therapy. Diabetologia. 2010 Mar;53(3):562-71. doi: 10.1007/s00125-009-1574-6. Epub 2009 Nov 5. — View Citation

Monnier L, Hanefeld M, Schnell O, Colette C, Owens D. Insulin and atherosclerosis: how are they related? Diabetes Metab. 2013 Apr;39(2):111-7. doi: 10.1016/j.diabet.2013.02.001. Epub 2013 Mar 15. Review. — View Citation

Muchmore DB, Heinemann L, Tamborlane W, Wu XW, Fleming A. Assessing rates of hypoglycemia as an end point in clinical trials. Diabetes Care. 2015 Oct;38(10):e160-1. doi: 10.2337/dc15-0808. Epub 2015 Aug 17. — View Citation

Muretta JM, Mastick CC. How insulin regulates glucose transport in adipocytes. Vitam Horm. 2009;80:245-86. doi: 10.1016/S0083-6729(08)00610-9. Review. — View Citation

Nandish S, Wyatt J, Bailon O, Smith M, Oliveros R, Chilton R. Implementing cardiovascular risk reduction in patients with cardiovascular disease and diabetes mellitus. Am J Cardiol. 2011 Aug 2;108(3 Suppl):42B-51B. doi: 10.1016/j.amjcard.2011.03.015. Review. — View Citation

ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11. — View Citation

Østerberg O, Erichsen L, Ingwersen SH, Plum A, Poulsen HE, Vicini P. Pharmacokinetic and pharmacodynamic properties of insulin aspart and human insulin. J Pharmacokinet Pharmacodyn. 2003 Jun;30(3):221-35. — View Citation

Razavi Nematollahi L, Kitabchi AE, Stentz FB, Wan JY, Larijani BA, Tehrani MM, Gozashti MH, Omidfar K, Taheri E. Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects. Metabolism. 2009 Apr;58(4):443-8. doi: 10.1016/j.metabol.2008.10.018. Erratum in: Metabolism. 2009 Jul;58(7):1046. Kitabchi, Abbas Eghbal [corrected to Kitabchi, Abbas E]. — View Citation

Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care. 2005 Apr;28(4):950-5. — View Citation

Sanders EJ, Harvey S. Peptide hormones as developmental growth and differentiation factors. Dev Dyn. 2008 Jun;237(6):1537-52. doi: 10.1002/dvdy.21573. Review. — View Citation

Scheen AJ. New therapeutic approaches in type 2 diabetes. Acta Clin Belg. 2008 Nov-Dec;63(6):402-7. Review. — View Citation

Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013 May;36(5):1384-95. doi: 10.2337/dc12-2480. Epub 2013 Apr 15. — View Citation

Singh P, Jain A, Kaur G. Impact of hypoglycemia and diabetes on CNS: correlation of mitochondrial oxidative stress with DNA damage. Mol Cell Biochem. 2004 May;260(1-2):153-9. — View Citation

Somwar R, Sweeney G, Ramlal T, Klip A. Stimulation of glucose and amino acid transport and activation of the insulin signaling pathways by insulin lispro in L6 skeletal muscle cells. Clin Ther. 1998 Jan-Feb;20(1):125-40. — View Citation

Steensgaard DB, Schluckebier G, Strauss HM, Norrman M, Thomsen JK, Friderichsen AV, Havelund S, Jonassen I. Ligand-controlled assembly of hexamers, dihexamers, and linear multihexamer structures by the engineered acylated insulin degludec. Biochemistry. 2013 Jan 15;52(2):295-309. doi: 10.1021/bi3008609. Epub 2013 Jan 3. — View Citation

Varvarovská J, Racek J, Stetina R, Sýkora J, Pomahacová R, Rusavý Z, Lacigová S, Trefil L, Siala K, Stozický F. Aspects of oxidative stress in children with type 1 diabetes mellitus. Biomed Pharmacother. 2004 Dec;58(10):539-45. — View Citation

Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1 and type 2 diabetes mellitus: a meta-analysis of endpoints in phase 3a trials. Diabetes Ther. 2014 Dec;5(2):435-46. doi: 10.1007/s13300-014-0076-9. Epub 2014 Aug 1. — View Citation

Wang J, Alexanian A, Ying R, Kizhakekuttu TJ, Dharmashankar K, Vasquez-Vivar J, Gutterman DD, Widlansky ME. Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase. Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):712-20. doi: 10.1161/ATVBAHA.111.227389. Epub 2011 Dec 29. — View Citation

Weight gain associated with intensive therapy in the diabetes control and complications trial. The DCCT Research Group. Diabetes Care. 1988 Jul-Aug;11(7):567-73. — View Citation

Wolff SP, Dean RT. Glucose autoxidation and protein modification. The potential role of 'autoxidative glycosylation' in diabetes. Biochem J. 1987 Jul 1;245(1):243-50. — View Citation

Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev. 2008 Jul-Aug;24(5):353-63. doi: 10.1002/dmrr.865. Review. — View Citation

Zib I, Raskin P. Novel insulin analogues and its mitogenic potential. Diabetes Obes Metab. 2006 Nov;8(6):611-20. Review. — View Citation

Ziegler D, Buchholz S, Sohr C, Nourooz-Zadeh J, Roden M. Oxidative stress predicts progression of peripheral and cardiac autonomic nerve dysfunction over 6 years in diabetic patients. Acta Diabetol. 2015 Feb;52(1):65-72. doi: 10.1007/s00592-014-0601-3. Epub 2014 Jun 5. — View Citation

* Note: There are 71 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Oxidative stress markers with the new slow insulin analogues	To evaluate the impact on the circulating levels of oxidative stress markers of the different treatments using the new slow insulin analogues. 1a) Anti oxidation: Total antioxidant capacity (CAT), and 1b) Oxidation: 8-iso-prostaglandin F2 alpha (8-iso-PGF2a), thiobarbituric acid reactive substances (TBARS) and LDL-oxidized	6 month
Secondary	HbA1c	Glycemic control: glycosylated hemoglobin	6 month
Secondary	Mean blood glucose	Glycemic control: mean blood glucose (mg/dl)	6 month
Secondary	Standard deviation	Glycemic variability :standard deviation [SD]	6 month
Secondary	Number of mild hypoglycemia	Number of mild hypoglycaemia in two weeks	6 month
Secondary	Number of severe hypoglycemia	Number of severe hypoglycemia in the last 6 months	6 month
Secondary	Number of hyperglycemia	Number of hyperglycemia> 250 mg / dl in two weeks	6 month
Secondary	Episodes of ketosis	Episodes of ketosis in the last 6 months	6 month
Secondary	Number os hospital admissions	Number of hospital admissions for acute diabetes decompensation in the last 6 months.	6 month
Secondary	Quality of life questionnaire in diabetes (DQOL)	34 items on the quality of life of people with type 1 diabetes	6 month
Secondary	Scale of adherence to treatment in patients with diabetes type 1 (DM1)	15 items related to adherence to patient treatment	6 month
Secondary	Diabetes distress scale. DDS	17 items on the problems and stress that people with type 1 diabetes suffer (Polonski y col, 2005)	6 month
Secondary	Fear of hypoglycemia: Questionnaire FH-15	15 items related to the fear of hypoglycemia in patients with type 1 diabetes	6 month
Secondary	Diabetes treatment satisfaction questionnaire (DTSQ).	8 items concerning the satisfaction of the treatment	6 month