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A novel combination of sitagliptin and melatonin ameliorates T2D manifestations: studies on experimental diabetic models

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Abstract

Introduction

Type 2 diabetes (T2D) is an endocrine disorder characterized by hyperglycemia, insulin resistance, dysregulated glucose and lipid metabolism, reduced pancreatic β-cell function and mass, and a reduced incretin effect. Circadian rhythm disruption is associated with increased T2D risk. We have investigated the therapeutic potential of a combination of melatonin (M) and sitagliptin (S), a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the amelioration of T2D manifestations in high-fat diet (HFD) induced T2D mouse model and also on β-cell proliferation under gluco-lipotoxicity stress in vitro.

Methods

For in vivo study, mice were fed with HFD for 25 weeks to induce T2D and were treated with monotherapies and S + M for four weeks. For the in vitro study, primary mouse islets were exposed to normal glucose and high glucose + palmitate to induce gluco-lipotoxic stress.

Results

Our results suggest that monotherapies and S + M improve metabolic parameters and glyco-lipid metabolism in the liver and adipose tissue, respectively, and improve mitochondrial function in the skeletal muscle. Moreover, it increases peripheral insulin sensitivity. Our in vitro and in vivo studies suggest that β-cell mass was preserved in all the drug-treated groups.

Conclusion

The combination treatment is superior to monotherapies in the management of T2D.

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Data availability

All data generated or analyzed during this study are included in this article.

Abbreviations

T2D:

Type 2 diabetes

FBG:

Fasting blood glucose

BW:

Body weight

TC:

Total cholesterol

HDL:

High density lipoprotein

TG:

Triglycerides

LDL:

Low density lipoprotein

BMI:

Body mass index

HFD:

High fat diet

M:

Melatonin

S:

Sitagliptin

References

  1. Reutrakul S, Hood MM, Crowley SJ, Morgan MK, Teodori M, Knutson KL, Van Cauter E (2013) Chronotype is independently associated with glycemic control in type 2 diabetes. Diabetes Care 36(9):2523–2529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Scheer FA, Hilton MF, Mantzoros CS, Shea SA (2009) Adverse metabolic and cardiovascular consequences of circadian misalignment. PNAS 106(11):4453–4458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lin Y, Sun Z (2010) Current views on type 2 diabetes. J Endocrinol 204(1):1

    Article  CAS  PubMed  Google Scholar 

  4. Pan M, Song YL, Xu JM, Gan HZ (2006) Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats. J Pineal Res 41(1):79–84

    Article  CAS  PubMed  Google Scholar 

  5. Peschke E (2008) Melatonin, endocrine pancreas and diabetes. J Pineal Res 44(1):26–40

    CAS  PubMed  Google Scholar 

  6. Stumpf I, Mühlbauer E, Peschke E (2008) Involvement of the cGMP pathway in mediating the insulin-inhibitory effect of melatonin in pancreatic β-cells. J Pineal Res 45(3):318–327

    Article  CAS  PubMed  Google Scholar 

  7. Peschke E, Mühlbauer E (2010) New evidence for a role of melatonin in glucose regulation. Best Pract Res Clin Endocrinol Metab 24(5):829–841

    Article  CAS  PubMed  Google Scholar 

  8. Ríos-Lugo MJ, Cano P, Jiménez-Ortega V et al (2010) Melatonin effect on plasma adiponectin, leptin, insulin, glucose, triglycerides and cholesterol in normal and high fat–fed rats. J Pineal Res 49(4):342–348

    Article  PubMed  Google Scholar 

  9. Nduhirabandi F, Du Toit EF, Blackhurst D, Marais D, Lochner A (2011) Chronic melatonin consumption prevents obesity-related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet-induced obesity. J Pineal Res 50(2):171–182

    CAS  PubMed  Google Scholar 

  10. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51(1):1–6

    Article  CAS  PubMed  Google Scholar 

  11. Korkmaz A, Topal T, Tan DX, Reiter RJ (2009) Role of melatonin in metabolic regulation. Rev Endocr Metab Disord 10(4):261–270

    Article  CAS  PubMed  Google Scholar 

  12. Kanter M, Uysal H, Karaca T, Sagmanligil HO (2006) Depression of glucose levels and partial restoration of pancreatic β-cell damage by melatonin in streptozotocin-induced diabetic rats. Arch Toxicol 80(6):362–369

    Article  CAS  PubMed  Google Scholar 

  13. Nishida S, Sato R, Murai I, Nakagawa S (2003) Effect of pinealectomy on plasma levels of insulin and leptin and on hepatic lipids in type 2 diabetic rats. J Pineal Res 35(4):251–256

    Article  CAS  PubMed  Google Scholar 

  14. Nishida S, Segawa T, Murai I, Nakagawa S (2002) Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Δ-5 desaturase activity. J Pineal Res 32(1):26–33

    Article  CAS  PubMed  Google Scholar 

  15. Peschke E, Frese T, Chankiewitz E et al (2006) Diabetic Goto Kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status. J Pineal Res 40(2):135–143

    Article  CAS  PubMed  Google Scholar 

  16. Patel R, Rathwa N, Palit SP, Ramachandran AV, Begum R (2018) Association of melatonin & MTNR1B variants with type 2 diabetes in Gujarat population. Biomed Pharmacother 103:429–434

    Article  CAS  PubMed  Google Scholar 

  17. Prokopenko I, Langenberg C, Florez JC et al (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41(1):77–81

    Article  CAS  PubMed  Google Scholar 

  18. Bouatia-Naji N, Bonnefond A, Cavalcanti-Proença C et al (2009) A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet 41(1):89–94

    Article  CAS  PubMed  Google Scholar 

  19. Sakura H, Hashimoto N, Sasamoto K et al (2016) Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study. BMC Endocr Disord 16(1):1–1

    Article  Google Scholar 

  20. Herman GA, Bergman A, Stevens C et al (2006) Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 91(11):4612–4619

    Article  CAS  PubMed  Google Scholar 

  21. Mu J, Petrov A, Eiermann GJ et al (2009) Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol 623(1–3):148–154

    Article  CAS  PubMed  Google Scholar 

  22. Mu J, Woods J, Zhou YP et al (2007) Sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Diabetes 56(Suppl 1):A550

    Google Scholar 

  23. Dobrian AD, Ma Q, Lindsay JW et al (2011) Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab 300(2):E410-421

    Article  CAS  PubMed  Google Scholar 

  24. Patel R, Parmar N, Rathwa N et al (2022) A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets. BBA Mol Cell Res 1869(8):119263

    CAS  Google Scholar 

  25. Ricordi C, Rastellini C (2000) Methods in pancreatic islet separation. Methods Cell Transplant 2000:433–438

    Google Scholar 

  26. Butterick TA, Stone LH, Duffy C et al (2016) Pioglitazone increases PGC1-α signaling within chronically ischemic myocardium. Basic Res Cardiol 111(3):37

    Article  PubMed  Google Scholar 

  27. Li Z, Graham BH (2012) Measurement of mitochondrial oxygen consumption using a Clark electrode. Mitochondrial Disorders. Humana Press, pp 63–72

    Chapter  Google Scholar 

  28. Stoscheck CM (1990) [6] Quantitation of protein. Meth Enzymol 182:50–68

    Article  CAS  Google Scholar 

  29. Cecon E, Oishi A, Jockers R (2018) Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol 175(16):3263–3280

    Article  CAS  PubMed  Google Scholar 

  30. Oishi A, Cecon E, Jockers R (2018) Melatonin receptor signaling: impact of receptor oligomerization on receptor function. Int Rev Cell Mol Biol 338:59–77

    Article  CAS  PubMed  Google Scholar 

  31. Ha E, Yim SV, Chung JH et al (2006) Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res 41(1):67–72

    Article  CAS  PubMed  Google Scholar 

  32. Poon AM, Choy EH, Pang SF (2001) Modulation of blood glucose by melatonin: a direct action on melatonin receptors in mouse hepatocytes. Neurosignals 10(6):367–379

    Article  CAS  Google Scholar 

  33. Mühlbauer E, Albrecht E, Bazwinsky-Wutschke I, Peschke E (2012) Melatonin influences insulin secretion primarily via MT1 receptors in rat insulinoma cells (INS-1) and mouse pancreatic islets. J Pineal Res 52(4):446–459

    Article  PubMed  Google Scholar 

  34. Zalatan F, Krause JA, Blask DE (2001) Inhibition of isoproterenol-induced lipolysis in rat inguinal adipocytes in vitro by physiological melatonin via a receptor-mediated mechanism. Endocrinology 142(9):3783–3790

    Article  CAS  PubMed  Google Scholar 

  35. Lima FB, Machado UF et al (1998) Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats. Am J Physiol Endocrinol Metab 275(6):E934-941

    Article  CAS  Google Scholar 

  36. Nogueira TC, Lellis-Santos C, Jesus DS et al (2011) Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response. Endocrinology 152(4):1253–1263

    Article  CAS  PubMed  Google Scholar 

  37. Sartori C, Dessen P, Mathieu C et al (2009) Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice. Endocrinology 150(12):5311–5317

    Article  CAS  PubMed  Google Scholar 

  38. Shieh JM, Wu HT, Cheng KC, Cheng JT (2009) Melatonin ameliorates high fat diet-induced diabetes and stimulates glycogen synthesis via a PKCζ-Akt-GSK3β pathway in hepatic cells. J Pineal Res 47(4):339–344

    Article  CAS  PubMed  Google Scholar 

  39. Tuomi T, Nagorny CL, Singh P et al (2016) Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metab 23(6):1067–1077

    Article  CAS  PubMed  Google Scholar 

  40. Brydon L, Petit L, Delagrange P, Strosberg AD, Jockers R (2001) Functional expression of MT2 (Mel1b) melatonin receptors in human PAZ6 adipocytes. Endocrinology 142(10):4264–4271

    Article  CAS  PubMed  Google Scholar 

  41. Owino S, Sánchez-Bretaño A, Tchio C et al (2018) Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI 3K activity. J Pineal Res 64(3):e12462

    Article  Google Scholar 

  42. Cipolla-Neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ (2014) Melatonin, energy metabolism, and obesity: a review. J Pineal Res 56(4):371–381

    Article  CAS  PubMed  Google Scholar 

  43. Karamitri A, Jockers R (2019) Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol 15(2):105–125

    Article  CAS  PubMed  Google Scholar 

  44. Karamitri A, Renault N, Clement N, Guillaume JL, Jockers R (2013) Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes. Mol Endocrinol 27(8):1217–1233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Peschke E, Bähr I, Mühlbauer E (2013) Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int J Mol Sci 14(4):6981–7015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kemp DM, Ubeda M, Habener JF (2002) Identification and functional characterization of melatonin Mel 1a receptors in pancreatic β cells: potential role in incretin-mediated cell function by sensitization of cAMP signaling. Mol Cell Endocrinol 191(2):157–166

    Article  CAS  PubMed  Google Scholar 

  47. Cagnacci A, Arangino S, Renzi A et al (2001) Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol 54(3):339–346

    Article  CAS  Google Scholar 

  48. Rubio-Sastre P, Scheer FA, Gómez-Abellán P, Madrid JA, Garaulet M (2014) Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep 37(10):1715–1719

    Article  PubMed  PubMed Central  Google Scholar 

  49. Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N (2011) Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes 4:307

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ramracheya RD, Muller DS, Squires PE et al (2008) Function and expression of melatonin receptors on human pancreatic islets. J Pineal Res 44(3):273–279

    Article  CAS  PubMed  Google Scholar 

  51. Costes S, Boss M, Thomas AP, Matveyenko AV (2015) Activation of melatonin signaling promotes β-cell survival and function. Mol Endocrinol 29(5):682–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. de Oliveira AC, Andreotti S, Sertie RA et al (2018) Combined treatment with melatonin and insulin improves glycemic control, white adipose tissue metabolism and reproductive axis of diabetic male rats. Life Sci 199:158–166

    Article  PubMed  Google Scholar 

  53. Goldsmith F, Keenan MJ, Raggio AM et al (2015) Induction of energy expenditure by sitagliptin is dependent on GLP-1 receptor. PLoS ONE 10(5):e0126177

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sangle GV, Lauffer LM, Grieco A, Trivedi S, Iakoubov R, Brubaker PL (2012) Novel biological action of the dipeptidylpeptidase-IV inhibitor, sitagliptin, as a glucagon-like peptide-1 secretagogue. Endocrinology 153(2):564–573

    Article  CAS  PubMed  Google Scholar 

  55. Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L, Joly E, Prentki M (2004) Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 47(5):806–815

    Article  CAS  PubMed  Google Scholar 

  56. Li L, El-Kholy W, Rhodes CJ, Brubaker PL (2005) Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B. Diabetologia 48(7):1339–1349

    Article  CAS  PubMed  Google Scholar 

  57. Villanueva-Penacarrillo ML, Marquez L, Gonzalez N, Diaz-Miguel M, Valverde I (2001) Effect of GLP-1 on lipid metabolism in human adipocytes. Horm Metab Res 33(02):73–77

    Article  CAS  PubMed  Google Scholar 

  58. Vendrell J, El Bekay R, Peral B et al (2011) Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance. Endocrinology 152(11):4072–4079

    Article  CAS  PubMed  Google Scholar 

  59. Polakof S, Miguez JM, Soengas JL (2011) Evidence for a gut-brain axis used by glucagon-like peptide-1 to elicit hyperglycaemia in fish. J Neuroendocrinol 23(6):508–518

    Article  CAS  PubMed  Google Scholar 

  60. Lamont BJ, Drucker DJ (2008) Differential antidiabetic efficacy of incretin agonists versus DPP-4 inhibition in high fat–fed mice. Diabetes 57(1):190–198

    Article  CAS  PubMed  Google Scholar 

  61. Raz I, Chen Y, Wu M et al (2008) Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin 24(2):537–550

    Article  CAS  PubMed  Google Scholar 

  62. Bergenstal RM, Wysham C, MacConell L et al (2010) Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 376(9739):431–439

    Article  PubMed  Google Scholar 

  63. Green BD, Irwin N, Duffy NA, Gault VA, O’harte FP, Flatt PR (2006) Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1. Eur J Pharmacol 547(1–3):192–199

    Article  CAS  PubMed  Google Scholar 

  64. Souza-Mello V, Gregorio BM, Cardoso-de-Lemos FS, de Carvalho L, Aguila MB, Mandarim-de-Lacerda CA (2010) Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. Clin Sci 119(6):239–250

    Article  CAS  Google Scholar 

  65. Yeom JA, Kim ES, Park HS et al (2011) Both sitagliptin analogue & pioglitazone preserve the β-cell proportion in the islets with different mechanism in non-obese and obese diabetic mice. BMB Rep 44(11):713–718

    Article  CAS  PubMed  Google Scholar 

  66. Poucher SM, Cheetham S, Francis J, Zinker B, Kirby M, Vickers SP (2012) Effects of saxagliptin and sitagliptin on glycaemic control and pancreatic β-cell mass in a streptozotocin-induced mouse model of type 2 diabetes. Diabetes Obes Metab 14(10):918–926

    Article  CAS  PubMed  Google Scholar 

  67. Akaslan SB, Degertekin CK, Yilmaz G, Cakir N, Arslan M, Toruner FB (2013) Effects of sitagliptin on nonalcoholic fatty liver disease in diet-induced obese rats. Metab Syndr Relat Disord 11(4):243–250

    Article  CAS  PubMed  Google Scholar 

  68. Reimer RA, Grover GJ, Koetzner L et al (2012) Sitagliptin reduces hyperglycemia and increases satiety hormone secretion more effectively when used with a novel polysaccharide in obese Zucker rats. J Nutr 142(10):1812–1820

    Article  CAS  PubMed  Google Scholar 

  69. Yang J, Ba T, Chen L et al (2016) Effects of metformin and sitagliptin on glycolipid metabolism in type 2 diabetic rats on different diets. Arch Med Sci: AMS 12(2):233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Apaijai N, Pintana H, Chattipakorn SC, Chattipakorn N (2013) Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats. Br J Pharmacol 169(5):1048–1057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Copps KD, White MF (2012) Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55(10):2565–2582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jia G, Aroor AR, Martinez-Lemus LA, Sowers JR (2014) Overnutrition, mTOR signaling, and cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol 307(10):R1198-1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Qiao S, Mao G, Li H et al (2018) DPP-4 inhibitor sitagliptin improves cardiac function and glucose homeostasis and ameliorates β-cell dysfunction together with reducing S6K1 activation and IRS-1 and IRS-2 degradation in obesity female mice. J Diabetes Res. https://doi.org/10.1155/2018/3641516

    Article  PubMed  PubMed Central  Google Scholar 

  74. Shen T, Xu B, Lei T, Chen L, Zhang C, Ni Z (2018) Sitagliptin reduces insulin resistance and improves rat liver steatosis via the SIRT1/AMPKα pathway. Exp Ther Med 16(4):3121–3128

    PubMed  PubMed Central  Google Scholar 

  75. Prakash S, Rai U, Kosuru R, Tiwari V, Singh S (2020) Amelioration of diet-induced metabolic syndrome and fatty liver with Sitagliptin via regulation of adipose tissue inflammation and hepatic Adiponectin/AMPK levels in mice. Biochimie 168:198–209

    Article  CAS  PubMed  Google Scholar 

  76. Liu Y, Xu F, Jiang P (2020) Effect of sitagliptin on expression of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1 α and irisin in a rat model of type 2 diabetes mellitus. J Int Med Res 48(5):0300060519885569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Xu E, Charbonneau A, Rolland Y et al (2012) Hepatocyte-specific Ptpn6 deletion protects from obesity-linked hepatic insulin resistance. Diabetes 61(8):1949–1958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. van der Heijden RA, Sheedfar F, Morrison MC, Hommelberg PP, Kor D et al (2015) High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice. Aging (Albany NY) 7(4):256

    Article  PubMed  Google Scholar 

  79. Oliveira MC, Menezes-Garcia Z, Henriques MCC, Soriani FM, Pinho V et al (2013) Acute and sustained inflammation and metabolic dysfunction induced by high refined carbohydrate containing diet in mice. Obesity (Silver Spring) 21:E396-406

    Article  CAS  PubMed  Google Scholar 

  80. Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M et al (2003) Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 289:1799–1804

    Article  CAS  PubMed  Google Scholar 

  81. Atkinson BJ, Griesel BA, King CD, Josey MA, Olson AL (2013) Moderate GLUT4 overexpression improves insulin sensitivity and fasting triglyceridemia in high-fat diet–fed transgenic mice. Diabetes 62(7):2249–2258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kim J, Jeong JI, Kim KM, Choi I, Pratley RE, Lee YH (2014) Improved glucose tolerance with restored expression of glucose transporter 4 in C57BL/6 mice after a long period of high-fat diet feeding. Anim Cells Syst 18(3):197–203

    Article  Google Scholar 

  83. Patel R, Palit SP, Rathwa N, Ramachandran AV, Begum R (2019) Genetic variants of tumor necrosis factor-α and its levels: A correlation with dyslipidemia and type 2 diabetes susceptibility. Clin Nutr 38(3):1414–1422

    Article  CAS  PubMed  Google Scholar 

  84. Patel R, Parmar N, Palit SP, Rathwa N, Ramachandran AV, Begum R (2022) Diabetes mellitus and melatonin: Where are we? Biochimie 202:2–14

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Prof. A.V. Ramachandran (Navrachana University, Vadodara, India) for his kind help throughout this study. We thank Prof. Adolfo Garcia Ocana, Diabetes, Obesity & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, for helping with the in vitro studies. We thank Dr. Deepak Sharma, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre (BARC), Mumbai, India, for providing the confocal facilities. We thank Dr. Dhruv Gohel, Department of Biochemistry, MSU Baroda, India, for helping us in sample preparation for western blot analysis and ddPCR study. RP thanks Council for Scientific and Industrial Research, New Delhi, India, for awarding SRF. NR thanks University Grants Commission-National Fellowship for higher education for ST students, New Delhi, India, for awarding SRF.

Funding

This work was supported by the Department of Biotechnology, New Delhi, India (BT/PR12584/MED/31/289/2014) to Rasheedunnisa Begum.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India

    R. Patel, N. Parmar, S. P. Palit, N. Rathwa & R. Begum

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  1. R. Patel
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  2. N. Parmar
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  3. S. P. Palit
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  4. N. Rathwa
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  5. R. Begum
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Contributions

RB and RP conceived the idea and designed the experiments. RP performed the experiments, data acquisition, and data analysis, and wrote the manuscript; NP, SP, and NR helped in data acquisition and data analysis. RB contributed to the critical revision of the manuscript.

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Correspondence to R. Begum.

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The animal study was approved by the Institutional Animal Ethical Committee (IAEC) (MSU/BC/13/2017) in accordance with the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines.

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Patel, R., Parmar, N., Palit, S.P. et al. A novel combination of sitagliptin and melatonin ameliorates T2D manifestations: studies on experimental diabetic models. J Endocrinol Invest 46, 1597–1612 (2023). https://doi.org/10.1007/s40618-023-02014-6

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