Abstract

Primary objective of this pilot study was to collect data for hypothesis generation regarding the impact of short-acting insulin analogs (insulin aspart/IA and insulin glulisine/IG in comparison to regular human insulin/RHI) on biomarkers of inflammation and oxidative stress in patients with type 2 diabetes. Twelve patients on basal insulin and oral drug treatment (11 male, age: 64 ± 9 yrs., HbA1c: 7.1 ± 0.6%, BMI: 31.5 ± 4.9 kg/m2) were randomized to intensive insulin therapy with insulin glargine and either IA, IG, or RHI. An OGGT was performed at baseline and after six months with assessment of nitrotyrosine, hsCRP, microcirculation (laser doppler) and mRNA macrophage activation markers (IL6, TNFalpha, eNOS, MAPK) after 0/1/2h. Reduction of HbA1c to near normal levels, and similar glucose excursions and microcirculation results were seen in all three groups. At endpoint, reductions in nitrotyrosine were observed with both analogs (-33 %) but not with RHI (+31 %, p < 0.05 vs. the combined analogs. IL-6 expression decreased with IG (-5 %) but increased with IA (+142%) and RHI (+64 %). TNFalpha expression decreased in all three groups (IG: -35%, IA: -71%, RHI: -30%). Vasoprotective eNOS expression increased with IG (+25 %) and decreased with IA (-28 %; RHI: +1 %). MAPK1- expression was reduced in all three groups (-16%, -23%, -33%). hsCRP was reduced by -78 % with IG only (IA: -2%, RHI: - 11%, p < 0.05 vs. IG in both groups). In this pilot study, improvement of the inflammatory vascular situation could be observed consistently with IG, partly with IA and barely with RHI.

Keywords: Insulin Analogs; Biomarkers; Oxidative Stress; Chronic Systemic Inflammation; Type 2 Diabetes

References

1. American Diabetes Association. “6. Glycemic Targets: Standards of Medical Care in Diabetes-2020”. Diabetes Care1 (2020): S66-S76.
2. Buse JB., et al. “2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)”. Diabetologia 63 (2020): 221-228.
3. Heinemann L., et al. “Pharmacokinetics and pharmacodynamics of subcutaneously administered U40 and U100 formulations of regular human insulin”. Diabetes and Metabolism 18 (1992): 21-24.
4. Torlone E., et al. “Pharmacokinetics, pharmacodynamics and glucose counter regulation following subcutaneous injection of the monomeric insulin analogue [Lys(B28), Pro(B29)] in IDDM”. Diabetologia7 (1994): 713-720.
5. Heinemann L., et al. “Comparison of the time-action profiles of U40- and U100-regular human insulin and the rapid-acting insulin analogue B28 Asp”. Experimental and Clinical Endocrinology and Diabetes 3 (1997): 140-144.
6. Becker RH and Frick AD. “Clinical pharmacokinetics and pharmacodynamics of insulin glulisine”. Clinical Pharmacokinetics 1 (2008): 7-20.
7. Home PD. “The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences”. Diabetes, Obesity and Metabolism 9 (2012): 780-788.
8. Becker RH., et al. “Insulin glulisine, a new rapid-acting insulin analogue, displays a rapid time-action profile in obese non-diabetic subjects”. Experimental and Clinical Endocrinology and Diabetes 113 (2005): 435-443.
9. Mudaliar SR., et al. “Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects”. Diabetes Care 22 (1999): 1501-1506.
10. Plank J., et al. “A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes”. Diabetes Care 25 (2002): 2053-2057.
11. Becker RH. “Insulin glulisine complementing basal insulins: a review ofstructure and activity”. Diabetes Technology and Therapeutics 9 (2007): 109-121.
12. Heise T., et al. “Insulin glulisine: a faster onset of action compared with insulin lispro”. Diabetes, Obesity and Metabolism 9 (2007): 746-753.
13. Bolli GB., et al. “Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with type 2 diabetes”. Diabetes, Obesity and Metabolism 13 (2011): 251-257.
14. Arnolds S., et al. “Insulin glulisine has a faster onset of action compared with insulin aspart in healthy volunteers”. Experimental and Clinical Endocrinology and Diabetes 118 (2010): 662-664.
15. Forst T., et al. “Cardiovascular effects of disturbed insulin metabolism in metabolic syndrome and type 2 diabetes patients”. Hormone and Metabolic Research 41 (2009): 123-131.
16. Tokarz VL., et al. “The cell biology of systemic insulin function”. Journal of Cell Biology 217 (2018): 2273-2289.
17. Pfützner A., et al. “Postprandial Vascular Effects of Viaject™ compared with Insulin Lispro and Regular Human Insulin in Patients with Type 2 Diabetes Mellitus”. Diabetes Care 33 (2010): 116-120.
18. Antoniades C., et al. “Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines”. The American Journal of Clinical Nutrition 84 (2006): 781.
19. Oner-Iyidogan Y., et al. “Dimethylarginines and inflammation markers in patients with chronic kidney disease undergoing dialysis”. Clinical and Experimental Medicine 9 (2009): 235-241.
20. Hellmann B. “Pulsatility of insulin release - a clinically important phenomenon”. Upsala Journal of Medical Sciences 114 (2009): 193-205.
21. Pfützner A., et al. “Downregulation of the Proinflammatory State of Circulating Mononuclear Cells by Short-Term Treatment with Pioglitazone in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease”. PPAR Research (2011): 647017.
22. Forst T., et al. “Impact of insulin on microvascular blood flow and endothelial cell function in thepostprandial state in patients with Type 1 diabetes”. Journal of Diabetic Complications 19 (2005): 128-132.
23. Hohberg C., et al. “Effect of Insulin Glulisine on Microvascular Blood Flow and Endothelial Function in the Postprandial State”. Diabetes Care 31 (2008): 1021-1025.
24. Westerbacka J., et al. “Glargine and regular human insulin similarly acutely enhance endothelium-dependent vasodilatation in normal subjects”. Arteriosclerosis, Thrombosis, and Vascular Biology 24 (2004): 320-324.
25. Ghanim H., et al. “Circulating mononuclear cells in the obese are in a proinflammatory state”. Circulation 110 (2004): 1564-1571.
26. Dandona P., et al. “Anti-inflammatory effects of insulin”. Current Opinion in Clinical Nutrition and Metabolic Care 10 (2007): 511-517.
27. Dandona P., et al. “Proinflammatory effects of glucose and antiinflammatory effect of insulin: relevance to cardiovascular disease”. The American Journal of Cardiology 99 (2007): 15B-26B.