A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets

Patel, Roma; Parmar, Nishant; Rathwa, Nirali; Palit, Sayantani Pramanik; Li, Yansui; Garcı́a-Ocaña, Adolfo; Begum, Rasheedunnisa

doi:10.1016/j.bbamcr.2022.119263

Cited by 13 publications

(15 citation statements)

References 48 publications

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“…In a preclinical study of the effects of melatonin alone or combined with the dipeptidyl peptidase IV, sitagliptin, combination therapy induced mouse pancreatic β-cell regeneration under glucotoxic stress, which was replicated in the human islet transplant mouse model. Combination therapy also induced pancreatic β-cell proliferation, reduced fasting blood glucose levels, and enhanced plasma insulin levels and glucose tolerance [ 109 ]. When used alone, melatonin reduced pancreatic β-cell apoptosis [ 109 ].…”

Section: Melatonergic Pathway and T1dmmentioning

confidence: 99%

“…Combination therapy also induced pancreatic β-cell proliferation, reduced fasting blood glucose levels, and enhanced plasma insulin levels and glucose tolerance [ 109 ]. When used alone, melatonin reduced pancreatic β-cell apoptosis [ 109 ]. Melatonin also prevents kidney disorders, bone loss, retinal dysfunction, and cognitive dysfunction evident in streptozotocin-induced T1DM in preclinical models [ 110 ].…”

Section: Melatonergic Pathway and T1dmmentioning

confidence: 99%

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Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Anderson¹

2023

IJMS

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Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic β-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic β-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin’s induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, N-acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic β-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic β-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway—including by bacteriophages—contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as ‘autoimmune’ effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications.

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Section: Melatonergic Pathway and T1dmmentioning

confidence: 99%

Section: Melatonergic Pathway and T1dmmentioning

confidence: 99%

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Anderson¹

2023

IJMS

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“…After 21-days of GC flattening, mice were sacrificed, and the pancreas was harvested. To study b-cell proliferation [Insulin/Ki67], immunofluorescence staining was carried out as previously described (Patel et al, 2022). Briefly, the pancreas was fixed in 4% paraformaldehyde for histological processing and paraffin embedding.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy

et al. 2022

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“…Interestingly, many recent studies have investigated the antioxidant and anti-inflammatory effects of these inhibitors. 6 - 13 …”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, many recent studies have investigated the antioxidant and antiinflammatory effects of these inhibitors. [6][7][8][9][10][11][12][13] Further, many antioxidants, anti-inflammatory, and antiinfective bioactive compounds have been studied to be effective biocontrols against animal and human diseases including zoonotic conditions of intestine. 3,[14][15][16][17][18] Nevertheless, antioxidants are mostly present in fruits and vegetable and possess great potential against oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Investigation of Therapeutic Potentials of Plant-Based Bioactive Compounds as Stimulators of Glucagon like peptide-1 Secretion

et al. 2022

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This study was aimed to investigate the therapeutic potentials of plant-based bioactive compounds; lutein and resveratrol alone and/or in combination with DPP-4 enzyme inhibitor; sitagliptin on the secretion and bioavailability of Glucagon like peptide-1(GLP). For this, experimental rats were divided into seven groups. Group 1 was marked as control, while other six groups received streptozotocin (60 mg/kg I.P.). Later, group 2 was kept disease-control. While group 3 received 10 mg/kg/day sitagliptin (DDP-4i). Group 4 received 40 mg/kg/day lutein (LUT) and group 5 received 30 mg/kg/day resveratrol (RES). While group 6 and 7 were received combination of DPP-4i+LUT and DPP-4i+RES, respectively. Combined administration of DPP-4i+LUT or DPP-4i+RES showed expected therapeutic effects by lowering the fasting blood glucose and maintaining the serum insulin concentrations with improved glucose sensitivity and reduced insulin resistance. Further, co-administration of LUT and RES with DPP-4i revealed beneficial effects on measures of insulin resistance, circulating lipids, glycemic index, oxidative stress, and inflammatory status along with restoration of histological morphology of pancreatic cells and enterocytes that seemed to improve the level of GLP-1. Hence, substantial verdicts of this study showing therapeutic potentials of LUT and RES would surely help to recognize the potential effects in combination with DPP-4i as stimulators of GLP-1 secretion.

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A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets

Cited by 13 publications

References 48 publications

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy

Biochemical Investigation of Therapeutic Potentials of Plant-Based Bioactive Compounds as Stimulators of Glucagon like peptide-1 Secretion

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