Insulin resistance – its causes and therapy possibilities

Česká verzia

Authors: Terezie Pelikánová
Authors place of work: Centrum diabetologie IKEM Praha, přednostka prof. MUDr. Terezie Pelikánová, DrSc.
Published in the journal: Vnitř Lék 2014; 60(9): 746-755
Category:

Summary

Insulin resistance (IR) is defined as a condition where normal plasma free insuconcentrations induce a reduced response of the body. In the narrower sense we understand IR as the impairment of insulin action in the target structure which may arise at any level of the insulin signalling cascade. In the clinical conditions we usually define it as the impairment of insulin action in glucose metabolism, although it is true that the impairment may concern different effects of insulin and different cell structures. The characteristic feature of IR linked to the metabolic syndrome or Type 2 diabetes is defective signalling which affects PI3-kinase branch of insulin signalling cascade. Other insulin actions depending on the signalling through the Ras complex and MAP-kinase, may not be affected. Due to compensatory hyperinsulinemia they may be even increased. The article summarizes some recent findings regarding the structure and regulation of insulin signalling cascade and analyses selected primary and secondary causes of IR which include genetic and epigenetic factors, the microRNA regulation role, metabolic, humoral and immunological factors. The detailed knowledge of the causes of IR opens possibilities of its rational treatment. This is currently based on the treatment of curable causes of IR, i.e. consistent compensation of diabetes, weight reduction, regimen arrangements (diet, physical activity), re-assessment of the need to use corticosteroids in therapy, treatment of coexisting conditions and possibly administration of metformin or pioglitazone.

Key words:
cytokines – insulin resistance – insulin signalling cascade

Zdroje

1. Kurland IJ, Accili D, Burant C et al. Application of combined omics platforms to accelerate biomedical discovery in diabesity. Ann NY Acad Sci 2013; 1287: 1–16.

2. Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol 2014; 220(2): T1-T23.

3. Saltiel AR. Putting the brakes on insulin signaling. N Engl J Med 2003; 349(26): 2560–2562.

4. Grarup N, Sandholt CH, Hansen T et al. Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia 20147; 57: 1528–1541.

5. Ahlqvist E, Ahluwalia TS, Groop L. Genetics of type 2 diabetes. Clin Chem 2011; 57(2): 241–254.

6. Sookoian S, Pirola CJ. Epigenetics of insulin resistance: an emerging field in translational medicine. Curr Diab Rep 2013; 13(2): 229–237.

7. Raitoharju E, Seppala I, Oksala N et al. Blood microRNA profile associates with the levels of serum lipids and metabolites associated with glucose metabolism and insulin resistance and pinpoints pathways underlying metabolic syndrome: the cardiovascular risk in Young Finns Study. Mol Cell Endocrinol 2014; 391(1–2): 41–49.

8. Chen H, Lan HY, Roukos DH et al. Application of microRNAs in diabetes mellitus. J Endocrinol 2014; 222(1): R1-R10.

9. Mohamed JS, Hajira A, Pardo PS et al.MicroRNA-149 inhibits PARP-2 and promotes mitochondrial biogenesis via SIRT-1/PGC-1alpha network in skeletal muscle. Diabetes 2014; 63(5): 1546–1559.

10. Svensson K, Handschin C. MicroRNAs emerge as modulators of NAD+-dependent energy metabolism in skeletal muscle. Diabetes 2014; 63(5): 1451–1453.

11. Škrha J. Biochemické důsledky dlouhodobé hyperglykémie. In: Škrha J (ed). Diabetologie. Galén: Praha 2009: 66–75. ISBN 978–80–7262–607–6.

12. Evans JL, Goldfine ID, Maddux BA et al. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003; 52(1): 1–8.

13. Randle PJ, Garland PB, Hales CN et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 1(7285): 785–789.

14. Unger RH, Clark GO, Scherer PE et al. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010; 1801(3): 209–214.

15. Krusinova E, Pelikanova T. Fatty acid binding proteins in adipose tissue: a promising link between metabolic syndrome and atherosclerosis? Diabetes Res Clin Pract 2008; 82(Suppl 2): S127-S134.

16. Ruderman NB, Carling D, Prentki M et al. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 2013; 123(7): 2764–2772.

17. Larsen PJ, Tennagels N. On ceramides, other sphingolipids and impaired glucose homeostasis. Mol Metab 2014; 3(3): 252–260.

18. Masi LN, Rodrigues AC, Curi R. Fatty acids regulation of inflammatory and metabolic genes. Curr Opin Clin Nutr Metab Care 2013; 16(4): 418–424.

19. Pelikanova T, Kohout M, Valek J et al. Insulin secretion and insulin action related to the serum phospholipid fatty acid pattern in healthy men. Metabolism 1989; 38(2): 188–192.

20. Pelikanova T, Kohout M, Hilgertova J et al. Erythrocyte insulin receptor characteristics and erythrocyte membrane lipid composition in healthy men. Physiol Bohemoslov 1989; 38(5): 419–425.

21. Storlien LH, Jenkins AB, Chisholm DJ et al. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991; 40(2): 280–289.

22. Borkman M, Storlien LH, Pan DA et al. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med 1993; 328(4): 238–244.

23. Pelikanova T, Kazdova L, Chvojkova S et al. Serum phospholipid fatty acid composition and insulin action in type 2 diabetic patients. Metabolism 2001; 50(12): 1472–1478.

24. Suchankova G, Vlasakova Z, Zicha J et al. Effect of acute hyperglycemia on erythrocyte membrane ion transport in offspring of hypertensive parents. J Hypertens 2003; 21(7): 1325–1330.

25. Kahleova H, Matoulek M, Bratova M et al. Vegetarian diet-induced increase in linoleic acid in serum phospholipids is associated with improved insulin sensitivity in subjects with type 2 diabetes. Nutr Diabetes 2007; 3: e75. Dostupné w DOI: <http://doi: 10.1038/nutd.2013.12>.

26. Kahleova H, Belinova L, Malinska H et al. Eating two larger meals a day (breakfast and lunch) is more effective than six smaller meals in a reduced-energy regimen for patients with type 2 diabetes: a randomised crossover study. Diabetologia 2014; 57(8): 1552–1560.

27. Bluher M. Adipokines – removing road blocks to obesity and diabetes therapy. Mol Metab 2014; 3(3): 230–240.

28. Eckardt K, Gorgens SW, Raschke S et al. Myokines in insulin resistance and type 2 diabetes. Diabetologia 2014; 57 (6): 1087–1099.

29. Chatzigeorgiou A, Karalis KP, Bornstein SR et al. Lymphocytes in obesity-related adipose tissue inflammation. Diabetologia 2012; 55(10): 2583–2592.

30. Hocking S, Samocha-Bonet D, Milner KL et al. Adiposity and insulin resistance in humans: the role of the different tissue and cellular lipid depots. Endocr Rev 2013; 34(4): 463–500.

31. Duarte AI, Candeias E, Correia SC et al. Crosstalk between diabetes and brain: glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration. Biochim Biophys Acta 2013; 1832(4): 527–541.

32. Cani PD, Everard A, Duparc T. Gut microbiota, enteroendocrine functions and metabolism. Curr Opin Pharmacol 2013; 13(6): 935–940.

33. Hong SH, Ahmadian M, Yu RT et al. Nuclear receptors and metabolism: from feast to famine. Diabetologia 2014; 57(5): 860–867.

34. Bass J. Circadian topology of metabolism. Nature 2012; 491 (7424): 348–356.

35. Novák J, Bienertová-Vašků J, Slabý O. MikroRNA a diabetes mellitus. In: Kvapil M (ed). Diabetologie 2014. Triton: Praha 2014: 225–233. ISBN 978–80–7387–755–2.

36. Ridker PM, Howard CP, Walter V et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012; 126(23): 2739–2748.