Acipimox in Type 1 Diabetes: fatty acids as a potential, but challenging, therapeutic target
Main Article Content
Abstract
Objective: To examine the effect of acute, isolated non-esterified fatty acid lowering, on insulin action, arterial stiffness and cardiac autonomic function in type I diabetes.
Methods: Randomized, double-blind, crossover trial of acipimox versus placebo in participants with and without type 1 diabetes (n=9 and 8, respectively).
Results: Participants with type 1 diabetes were more insulin resistant than controls and exhibited increased arterial stiffness (pulse wave velocity and augmentation index), autonomic dysregulation (heart rate variability), cardiac diastolic dysfunction (E:A ratio), and increased cardiac contractility (fractional shortening) with preserved cardiac output. Acipimox treatment was confounded by a pronounced early rebound effect. However, independent of acipimox, within-subject higher pretest fatty acid levels corresponded to greater insulin resistance, higher mean tachycardic heart rates at rest, and possibly increased cardiac output.
Conclusions: These findings confirm and expand upon previous observations that individuals with type 1 diabetes are more insulin resistant and exhibit cardiovascular changes consistent with increased sympathetic tone. The correlation of poor peripheral glucose utilization and cardiovascular changes with elevated fatty acid levels suggests that lowering fatty acid levels may improve insulin sensitivity and decrease sympathetic tone. In the future, a more durable or targeted method of fatty acid lowering could represent a novel cardioprotective target of intervention in people with type 1 diabetes.
Article Details
How to Cite
KAPUT, Katie L.; LYON, Ellen; SCHAUER, irene E..
Acipimox in Type 1 Diabetes: fatty acids as a potential, but challenging, therapeutic target.
Medical Research Archives, [S.l.], v. 12, n. 12, jan. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6170>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6170.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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13. Hoeg LD, Sjoberg KA, Jeppesen J, et al. Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. Diabetes. Jan 2011;60(1):64-73. doi:db10-0698 [pii]
10.2337/db10-0698
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10.1210/jc.2010-1174
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18. McLachlan KA, Alford FP. The impact of acute elevation of non-esterified fatty acids on insulin sensitivity and secretion in women with former gestational diabetes. Clin Endocrinol (Oxf). Jan 2005;62(1):79-84.
19. Bajaj M, Suraamornkul S, Kashyap S, Cusi K, Mandarino L, DeFronzo RA. Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes. J Clin Endocrinol Metab. Sep 2004;89(9):4649-55.
20. Cusi K, Kashyap S, Gastaldelli A, Bajaj M, Cersosimo E. Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes. Am J Physiol Endocrinol Metab. Jun 2007;292(6):E1775-81. doi:00624.2006 [pii]
10.1152/ajpendo.00624.2006
21. Hadigan C, Liebau J, Torriani M, Andersen R, Grinspoon S. Improved Triglycerides and Insulin Sensitivity with 3 Months of Acipimox in HIV-infected Patients with Hypertriglyceridemia. J Clin Endocrinol Metab. Aug 29 2006;
22. Lehto HR, Parkka J, Borra R, et al. Effects of acute and one-week fatty acid lowering on cardiac function and insulin sensitivity in relation with myocardial and muscle fat and adiponectin levels. J Clin Endocrinol Metab. Sep 2012;97(9):3277-84. doi:10.1210/jc.2012-1219
23. Phielix E, Jelenik T, Nowotny P, Szendroedi J, Roden M. Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial. Diabetologia. Mar 2014;57(3):572-81. doi:10.1007/s00125-013-3127-2
24. Saloranta C, Taskinen MR, Widen E, Harkonen M, Melander A, Groop L. Metabolic consequences of sustained suppression of free fatty acids by acipimox in patients with NIDDM. Diabetes. Nov 1993;42(11):1559-66.
25. Santomauro AT, Boden G, Silva ME, et al. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes. Sep 1999;48(9):1836-41.
26. Goodpaster BH, Coen PM. Improved mitochondrial function is linked with improved insulin sensitivity through reductions in FFA. Diabetes. Aug 2014;63(8):2611-2. doi:10.2337/db14-0277
27. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Research Support, U.S. Gov't, P.H.S. Am J Physiol. Sep 1979;237(3):E214-23.
28. Papaioannou TG, Stamatelopoulos KS, Gialafos E, et al. Monitoring of arterial stiffness indices by applanation tonometry and pulse wave analysis: reproducibility at low blood pressures. J Clin Monit Comput. Apr 2004;18(2):137-44. doi:10.1023/b:jocm.0000032809.71793.b8
29. Ravikumar R, Deepa R, Shanthirani C, Mohan V. Comparison of carotid intima-media thickness, arterial stiffness, and brachial artery flow mediated dilatation in diabetic and nondiabetic subjects (The Chennai Urban Population Study [CUPS-9]). The American journal of cardiology. Oct 1 2002;90(7):702-7. doi:10.1016/s0002-9149(02)02593-6
30. Nadeau KJ, Regensteiner JG, Bauer TA, et al. Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function. J Clin Endocrinol Metab. Feb 2010;95(2):513-21.
31. Nadeau KJ, Zeitler PS, Bauer TA, et al. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity. J Clin Endocrinol Metab. Oct 2009;94(10):3687-95.
32. Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes care. Jul 2010;33(7):1578-84. doi:10.2337/dc10-0125
33. Hadigan C, Rabe J, Meininger G, Aliabadi N, Breu J, Grinspoon S. Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution. The American journal of clinical nutrition. Feb 2003;77(2):490-4.
34. van de Weijer T, Phielix E, Bilet L, et al. Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes. Apr 2015;64(4):1193-201. doi:10.2337/db14-0667
35. Diaz Ludovico I, Sarkar S, Elliott E, et al. Fatty acid-mediated signaling as a target for developing type 1 diabetes therapies. Expert Opin Ther Targets. Jul-Dec 2023;27(9):793-806. doi:10.1080/14728222.2023.2259099
36. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. Dec 1996;45(12):1661-9. doi:10.2337/diab.45.12.1661
37. Dhalla AK, Wong MY, Voshol PJ, Belardinelli L, Reaven GM. A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents. Am J Physiol Endocrinol Metab. May 2007;292(5):E1358-63. doi:10.1152/ajpendo.00573.2006
38. Jain S, Barella LF, Wess J, Reitman ML, Jacobson KA. Adenosine A(1) receptor is dispensable for hepatocyte glucose metabolism and insulin sensitivity. Biochem Pharmacol. Oct 2021;192:114739. doi:10.1016/j.bcp.2021.114739
39. Morandi A, Piona C, Bonafini S, et al. Long chain fatty acids metabolism and cardiovascular risk factors in youth with type 1 diabetes. Nutr Metab Cardiovasc Dis. Jan 4 2021;31(1):297-305. doi:10.1016/j.numecd.2020.08.023
40. O'Mahoney LL, Churm R, Stavropoulos-Kalinoglou A, et al. Associations Between Erythrocyte Membrane Fatty Acid Compositions and Biomarkers of Vascular Health in Adults With Type 1 Diabetes With and Without Insulin Resistance: A Cross-Sectional Analysis. Can J Diabetes. Mar 2022;46(2):111-117. doi:10.1016/j.jcjd.2021.06.005
2. Zgibor JC, Piatt GA, Ruppert K, Orchard TJ, Roberts MS. Deficiencies of cardiovascular risk prediction models for type 1 diabetes. Diabetes care. Aug 2006;29(8):1860-5. doi:10.2337/dc06-0290
3. Action to Control Cardiovascular Risk in Diabetes Study G, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. Jun 12 2008;358(24):2545-59. doi:10.1056/NEJMoa0802743
4. Kahler P, Grevstad B, Almdal T, et al. Targeting intensive versus conventional glycaemic control for type 1 diabetes mellitus: a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ Open. Aug 19 2014;4(8):e004806. doi:10.1136/bmjopen-2014-004806
5. Orchard TJ, Olson JC, Erbey JR, et al. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes care. May 2003;26(5):1374-9. doi:10.2337/diacare.26.5.1374
6. Wajchenberg BL, Feitosa AC, Rassi N, Lerario AC, Betti RT. Glycemia and cardiovascular disease in type 1 diabetes mellitus. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Oct 2008;14(7):912-23. doi:10.4158/EP.14.7.912
7. Bonora E, Formentini G, Calcaterra F, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes care. Jul 2002;25(7):1135-41. doi:10.2337/diacare.25.7.1135
8. Bonora E, Kiechl S, Willeit J, et al. Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in caucasian subjects from the general population: the Bruneck study. Diabetes care. Feb 2007;30(2):318-24.
9. Fontbonne A, Charles MA, Thibult N, et al. Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up. Diabetologia. May 1991;34(5):356-61. doi:10.1007/BF00405009
10. Schauer IE, Snell-Bergeon JK, Bergman BC, et al. Insulin resistance, defective insulin-mediated fatty acid suppression, and coronary artery calcification in subjects with and without type 1 diabetes: The CACTI study. Diabetes. Jan 2011;60(1):306-14. doi:10.2337/db10-0328
11. Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. Jul 2001;50(7):1612-7.
12. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. Jan 1999;103(2):253-9. doi:10.1172/JCI5001
13. Hoeg LD, Sjoberg KA, Jeppesen J, et al. Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. Diabetes. Jan 2011;60(1):64-73. doi:db10-0698 [pii]
10.2337/db10-0698
14. Homko CJ, Cheung P, Boden G. Effects of free fatty acids on glucose uptake and utilization in healthy women. Diabetes. Feb 2003;52(2):487-91.
15. Kashyap SR, Ioachimescu AG, Gornik HL, et al. Lipid-induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL. Obesity (Silver Spring). Dec 2009;17(12):2142-8.
16. Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z. Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab. Feb 2011;96(2):438-46. doi:jc.2010-1174 [pii]
10.1210/jc.2010-1174
17. Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. Sep 2009;94(9):3543-9.
18. McLachlan KA, Alford FP. The impact of acute elevation of non-esterified fatty acids on insulin sensitivity and secretion in women with former gestational diabetes. Clin Endocrinol (Oxf). Jan 2005;62(1):79-84.
19. Bajaj M, Suraamornkul S, Kashyap S, Cusi K, Mandarino L, DeFronzo RA. Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes. J Clin Endocrinol Metab. Sep 2004;89(9):4649-55.
20. Cusi K, Kashyap S, Gastaldelli A, Bajaj M, Cersosimo E. Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes. Am J Physiol Endocrinol Metab. Jun 2007;292(6):E1775-81. doi:00624.2006 [pii]
10.1152/ajpendo.00624.2006
21. Hadigan C, Liebau J, Torriani M, Andersen R, Grinspoon S. Improved Triglycerides and Insulin Sensitivity with 3 Months of Acipimox in HIV-infected Patients with Hypertriglyceridemia. J Clin Endocrinol Metab. Aug 29 2006;
22. Lehto HR, Parkka J, Borra R, et al. Effects of acute and one-week fatty acid lowering on cardiac function and insulin sensitivity in relation with myocardial and muscle fat and adiponectin levels. J Clin Endocrinol Metab. Sep 2012;97(9):3277-84. doi:10.1210/jc.2012-1219
23. Phielix E, Jelenik T, Nowotny P, Szendroedi J, Roden M. Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial. Diabetologia. Mar 2014;57(3):572-81. doi:10.1007/s00125-013-3127-2
24. Saloranta C, Taskinen MR, Widen E, Harkonen M, Melander A, Groop L. Metabolic consequences of sustained suppression of free fatty acids by acipimox in patients with NIDDM. Diabetes. Nov 1993;42(11):1559-66.
25. Santomauro AT, Boden G, Silva ME, et al. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes. Sep 1999;48(9):1836-41.
26. Goodpaster BH, Coen PM. Improved mitochondrial function is linked with improved insulin sensitivity through reductions in FFA. Diabetes. Aug 2014;63(8):2611-2. doi:10.2337/db14-0277
27. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Research Support, U.S. Gov't, P.H.S. Am J Physiol. Sep 1979;237(3):E214-23.
28. Papaioannou TG, Stamatelopoulos KS, Gialafos E, et al. Monitoring of arterial stiffness indices by applanation tonometry and pulse wave analysis: reproducibility at low blood pressures. J Clin Monit Comput. Apr 2004;18(2):137-44. doi:10.1023/b:jocm.0000032809.71793.b8
29. Ravikumar R, Deepa R, Shanthirani C, Mohan V. Comparison of carotid intima-media thickness, arterial stiffness, and brachial artery flow mediated dilatation in diabetic and nondiabetic subjects (The Chennai Urban Population Study [CUPS-9]). The American journal of cardiology. Oct 1 2002;90(7):702-7. doi:10.1016/s0002-9149(02)02593-6
30. Nadeau KJ, Regensteiner JG, Bauer TA, et al. Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function. J Clin Endocrinol Metab. Feb 2010;95(2):513-21.
31. Nadeau KJ, Zeitler PS, Bauer TA, et al. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity. J Clin Endocrinol Metab. Oct 2009;94(10):3687-95.
32. Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes care. Jul 2010;33(7):1578-84. doi:10.2337/dc10-0125
33. Hadigan C, Rabe J, Meininger G, Aliabadi N, Breu J, Grinspoon S. Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution. The American journal of clinical nutrition. Feb 2003;77(2):490-4.
34. van de Weijer T, Phielix E, Bilet L, et al. Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes. Apr 2015;64(4):1193-201. doi:10.2337/db14-0667
35. Diaz Ludovico I, Sarkar S, Elliott E, et al. Fatty acid-mediated signaling as a target for developing type 1 diabetes therapies. Expert Opin Ther Targets. Jul-Dec 2023;27(9):793-806. doi:10.1080/14728222.2023.2259099
36. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. Dec 1996;45(12):1661-9. doi:10.2337/diab.45.12.1661
37. Dhalla AK, Wong MY, Voshol PJ, Belardinelli L, Reaven GM. A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents. Am J Physiol Endocrinol Metab. May 2007;292(5):E1358-63. doi:10.1152/ajpendo.00573.2006
38. Jain S, Barella LF, Wess J, Reitman ML, Jacobson KA. Adenosine A(1) receptor is dispensable for hepatocyte glucose metabolism and insulin sensitivity. Biochem Pharmacol. Oct 2021;192:114739. doi:10.1016/j.bcp.2021.114739
39. Morandi A, Piona C, Bonafini S, et al. Long chain fatty acids metabolism and cardiovascular risk factors in youth with type 1 diabetes. Nutr Metab Cardiovasc Dis. Jan 4 2021;31(1):297-305. doi:10.1016/j.numecd.2020.08.023
40. O'Mahoney LL, Churm R, Stavropoulos-Kalinoglou A, et al. Associations Between Erythrocyte Membrane Fatty Acid Compositions and Biomarkers of Vascular Health in Adults With Type 1 Diabetes With and Without Insulin Resistance: A Cross-Sectional Analysis. Can J Diabetes. Mar 2022;46(2):111-117. doi:10.1016/j.jcjd.2021.06.005