Volume 28, Issue 3 (September 2024)                   Physiol Pharmacol 2024, 28(3): 304-313 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Bagali S, Kanthe P, Reddy R C, Shaikh G B, Patil S, Das K. Hypoxia-Induced Impairment of Glucose Homeostasis: Sympathovagal Imbalance and the Potential Therapeutic Role of L/N type Calcium Channel Blocker Cilnidipine. Physiol Pharmacol 2024; 28 (3) : 7
URL: http://ppj.phypha.ir/article-1-2122-en.html
Hypoxia-Induced Impairment of Glucose Homeostasis: Sympathovagal Imbalance and the Potential Therapeutic Role of L/N type Calcium Channel Blocker Cilnidipine
Shrilaxmi Bagali , Pallavi Kanthe , R Chandramouli Reddy , Gouher Banu Shaikh , Sumangala Patil , Kusal Das
Abstract:   (1145 Views)

Introduction: Frequent occurrence of diabetes mellitus type 2 (T2DM) in patients with respiratory disease suggests a role of underlying chronic hypoxia (CH) in its pathogenesis. The present study aimed to delineate the link between CH, sympathovagal balance, and glucose homeostasis (GH) as well as to explore the role of L/N type calcium channel blocker, cilnidipine in alleviating CH-induced pathophysiology in experimental animals.
Methods: Wister rats were divided into four groups: group I: control, (normoxia, 21%O2); group II: chronic hypoxia (CH) (10%O2, 90%N2); group III: normoxia+cilnidipine (cil, 2mg/kg/day); group IV: CH+Cil (10%O2, 90%N2 + cil, 2mg/kg/day). Sympathovagal balance was assessed by heart rate variability (HRV) analysis. Glucose homeostasis was evaluated by fasting plasma glucose (FPG), fasting plasma insulin, oral glucose tolerance test (OGTT), HOMA-IR, and HOMA-β. The fasting lipid profile was also assessed.  
Results: CH increased LF (nu), LF/HF, and decreased HF (nu). Additionally, CH increased FPG and HOMA-IR which were positively correlated with LF/HF and induced an atherogenic lipid profile. OGTT revealed normal 2h post-challenge glucose levels. In the cilnidipine-treated CH exposed group, LF (nu), HF (nu), and LF/HF were lower compared CH and glucose homeostasis parameters were comparable to control. 
Conclusion: CH, by enhancing sympathetic activity, disturbs glucose homeostasis, leading to isolated impaired fasting glycemia (i-IFG), a prediabetic state. Cilnidipine improved glucose homeostasis in CH-exposed experimental animals by ameliorating sympathetic hyperactivity with complementary effects on lipid profile, suggesting its utility as an adjunctive therapy against CH-induced T2DM.

Article number: 7
Keywords: Cilnidipine, HOMA IR, Hypoxia, Glucose Tolerance Test, Prediabetes
Full-Text [PDF 834 kb]   (106 Downloads)    
Type of Manuscript: Experimental research article | Subject: Respiratory Physiology/Pharmacology
References
1. Abu Eid S, Hackl M T, Kaplanian M, Winter M P, Kaltenecker D, Moriggl R, et al. Life under hypoxia lowers blood glucose independently of effects on appetite and body weight in mice. Front Endocrinol (Lausanne) 2018; 9: 490. [DOI:10.3389/fendo.2018.00490]
2. Bagali S, Nerune S M, Reddy R C, Yendigeri S M, Patil B S, Naikwadi A A, et al. Low oxygen microenvironment and cardiovascular remodeling: Role of dual L/N type Ca2+ channel blocker. Indian J Pharmacol 2020; 52(5): 383-391. [DOI:10.4103/ijp.IJP_136_20]
3. Bowe J E, Franklin Z J, Hauge-Evans A C, King A J, Persaud S J, Jones P M. Metabolic phenotyping guidelines: assessing glucose homeostasis in rodent models. J Endocrinol 2014; 222(3): G13-25. [DOI:10.1530/JOE-14-0182]
4. Cavaillès A, Brinchault-Rabin G, Dixmier A, Goupil F, Gut-Gobert C, Marchand-Adam S, et al. Comorbidities of COPD. Eur Respir Rev 2013; 22(130): 454-745. [DOI:10.1183/09059180.00008612]
5. Cazzola M, Bettoncelli G, Sessa E, Cricelli C, Biscione G. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration 2010; 80(2): 112-119. [DOI:10.1159/000281880]
6. Das K K, Jargar J G, Saha S, Yendigeri S M, Singh S B. α-tocopherol supplementation prevents lead acetate and hypoxia-induced hepatic dysfunction. Indian J Pharmacol 2015; 47(3): 285-291. [DOI:10.4103/0253-7613.157126]
7. Das K K, Nemagouda S R, Patil S G, Saha S. Possible hypoxia signaling induced alteration of glucose homeostasis in rats exposed to chronic intermittent hypoxia - role of antioxidant (vitamin C) and Ca2+ channel blocker (cilnidipine). Current Signal Transduction Therapy 2016; 11(1): 49-55. [DOI:10.2174/1574362411666160517131248]
8. Faerch K, Borch-Johnsen K, Holst J J, Vaag A. Pathophysiology and aetiology of impaired fasting glycaemia and impaired glucose tolerance: does it matter for prevention and treatment of type 2 diabetes? Diabetologia 2009; 52(9): 1714-1723. [DOI:10.1007/s00125-009-1443-3]
9. Fenik V B, Singletary T, Branconi J L, Davies R O, Kubin L. Glucoregulatory consequences and cardiorespiratory parameters in rats exposed to chronic-intermittent hypoxia: effects of the duration of exposure and losartan. Front Neurol 2012; 3: 51. [DOI:10.3389/fneur.2012.00051]
10. Friedewald W T, Levy R I, Fredrickson D S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18(6): 499-502. [DOI:10.1093/clinchem/18.6.499]
11. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe K B, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci 2020; 21(17): 6275. [DOI:10.3390/ijms21176275]
12. Gläser S, Krüger S, Merkel M, Bramlage P, Herth F J. Chronic obstructive pulmonary disease and diabetes mellitus: a systematic review of the literature. Respiration 2015; 89(3): 253-264. [DOI:10.1159/000369863]
13. Gutch M, Kumar S, Razi S M, Gupta K K, Gupta A. Assessment of insulin sensitivity/resistance. Indian J Endocrinol Metab 2015; 19(1): 160-164. [DOI:10.4103/2230-8210.146874]
14. Hainsworth R, Drinkhill M J, Rivera-Chira M. The autonomic nervous system at high altitude. Clin Auton Res 2007; 17(1): 131-139. [DOI:10.1007/s10286-006-0395-7]
15. Herman J P, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol 2016; 6(2): 603-621. [DOI:10.1002/cphy.c150015]
16. Hinds J A, Sanchez E R. The Role of the hypothalamus-pituitary-adrenal (HPA) axis in test-induced anxiety: assessments, physiological responses, and molecular details. Stresses 2022; 2(1): 146-155. [DOI:10.3390/stresses2010011]
17. Khalili D, Khayamzadeh M, Kohansal K, Ahanchi N S, Hasheminia M, Hadaegh F, et al. Are HOMA-IR and HOMA-B good predictors for diabetes and pre-diabetes subtypes? BMC Endocr Disord 2023; 23(1): 39. [DOI:10.1186/s12902-023-01291-9]
18. Lee C T, Mao I C, Lin C H, Lin S H, Hsieh M C. Chronic obstructive pulmonary disease: a risk factor for type 2 diabetes: a nationwide population-based study. Eur J Clin Invest 2013; 43(11): 1113-1119. [DOI:10.1111/eci.12147]
19. Lewis P, Sheehan D, Soares R, Varela Coelho A, O’Halloran K D. Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle. Front Physiol 2015; 6: 122. [DOI:10.3389/fphys.2015.00122]
20. Mahishale V, Mahishale A, Patil B, Sindhuri A, Eti A. Screening for diabetes mellitus in patients with chronic obstructive pulmonary disease in tertiary care hospital in India. Niger Med J 2015; 56(2): 122-125. [DOI:10.4103/0300-1652.150699]
21. Messina G, De Luca V, Viggiano A, Ascione A, Iannaccone T, Chieffi S, et al. Autonomic nervous system in the control of energy balance and body weight: personal contributions. Neurol Res Int 2013; 2013: 639280. [DOI:10.1155/2013/639280]
22. Nair A B, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016; 7(2): 27-31. [DOI:10.4103/0976-0105.177703]
23. Nonogaki K. New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 2000; 43(5): 533-549. [DOI:10.1007/s001250051341]
24. Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga F A. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol 2018; 17(1): 122. [DOI:10.1186/s12933-018-0762-4]
25. Parhofer K G. Interaction between glucose and lipid metabolism: More than diabetic dyslipidemia. Diabetes Metab J 2015; 39(5): 353-362. [DOI:10.4093/dmj.2015.39.5.353]
26. Polak J, Shimoda L A, Drager L F, Undem C, McHugh H, Polotsky V Y, et al. Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure. Sleep 2013; 36(10): 1483-1490. [DOI:10.5665/sleep.3040]
27. Ramirez T A, Jourdan-Le Saux C, Joy A, Zhang J, Dai Q, et al. Chronic and intermittent hypoxia differentially regulate left ventricular inflammatory and extracellular matrix responses. Hypertens Res 2012; 35(8): 811-818. [DOI:10.1038/hr.2012.32]
28. Reddy R C, Devaranavadagi B, Yendigeri S M, Bagali S, Kulkarni R V, Das K K. Effect of L-ascorbic acid on nickel-induced alteration of cardiovascular pathophysiology in wistar rats. Biol Trace Elem Res 2020; 195(1): 178-186. [DOI:10.1007/s12011-019-01829-w]
29. Rogliani P, Calzetta L, Segreti A, Barrile A, Cazzola M. Diabetes mellitus among outpatients with COPD attending a university hospital. Acta Diabetologica 2014; 51(6), 933-940. [DOI:10.1007/s00592-014-0584-0]
30. Rogliani P, Lucà G, Lauro D. Chronic obstructive pulmonary disease and diabetes. COPD Res Pract 2015; 1, 3. [DOI:10.1186/s40749-015-0005-y]
31. Safari S, Amini M, Aminorroaya A, Feizi A. Patterns of changes in serum lipid profiles in prediabetic subjects: results from a 16-year prospective cohort study among first-degree relatives of type 2 diabetic patients. Lipids Health Dis 2020; 19(1): 193. [DOI:10.1186/s12944-020-01371-y]
32. Shaffer F, Ginsberg J P. An overview of heart rate variability metrics and norms. Front Public Health 2017; 5: 258. [DOI:10.3389/fpubh.2017.00258]
33. Takahara A, Koganei H, Takeda T, Iwata S. Antisympathetic and hemodynamic property of a dual L/N-type Ca (2+) channel blocker cilnidipine in rats. Eur J Pharmacol 2002; 434 (1-2): 43-47. [DOI:10.1016/S0014-2999(01)01521-7]
34. Takahara A. Cilnidipine: a new generation Ca channel blocker with inhibitory action on sympathetic neurotransmitter release. Cardiovasc Ther 2009; 27(2): 124-139. [DOI:10.1111/j.1755-5922.2009.00079.x]
35. Thorp A A, Schlaich M P. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res 2015; 2015: 341583. [DOI:10.1155/2015/341583]
36. Xie A, Skatrud J B, Puleo D S, Morgan B J. Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol (1985) 2001; 91(4): 1555-1562. [DOI:10.1152/jappl.2001.91.4.1555]
37. Yang H. Sympathovagal imbalance in type 2 diabetes-Role of brainstem thyrotropin releasing hormone. Type 2013; 2: 115-141. [DOI:10.5772/56541]
38. Yoon H, Jeon D J, Park C E, You H S, Moon A E. Relationship between homeostasis model assessment of insulin resistance and beta cell function and serum 25-hydroxyvitamin D in non-diabetic Korean adults. J Clin Biochem Nutr 2016; 59(2): 139-144. [DOI:10.3164/jcbn.15-143]
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.