Protective effect of melatonin on β-cell damage in streptozotocin-induced diabetes in rats

doi:10.1078/0065-1281-00711

Acta Histochemica

Volume 105, Issue 3, 2003, Pages 261-266

https://doi.org/10.1078/0065-1281-00711 Get rights and content

Summary

The aim of the present study was the evaluation of possible protective effects of melatonin against β-cell damage in streptozotocin-induced diabetes in rats. Malondialdehyde levels and glutathione peroxidase activity were measured in pancreatic homogenates. Pancreatic β-cells were examined by immunohistochemical methods. Streptozotocin was injected intraperitoneally at a single dose of 60 mg/kg for induction of diabetes. Melatonin (200 μg/kg/day, ip) was injected for 3 days prior to administration of streptozotocin; these injections were continued until the end of the study (4 weeks). Streptozotocin induced a significant increase in malondialdehyde levels (p < 0.01) and a significant decrease in glutathione peroxidase activity (p < 0.05) in pancreatic tissue. Degeneration of islet cells and weak immunohistochemical staining of insulin was observed in diabetic rats. Treatment of diabetic rats with melatonin markedly reduced malondialdehyde production (p < 0.05) and increased glutathione peroxidase activity (p < 0.01) without affecting hyperglycemia. Increased staining of insulin and preservation of islet cells were apparent in the melatonin-treated diabetic rats. These data suggest that melatonin treatment has a therapeutic effect in diabetes by reduction of oxidative stress and preservation of pancreatic β-cell integrity.

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Diabetes mellitus (DM) and diabetes-related complications are amongst the leading causes of mortality worldwide. The international diabetes federation (IDF) has estimated 592 million people to suffer from DM by 2035. Hence, finding a novel biomolecule that can effectively aid diabetes management is vital, as other existing drugs have numerous side effects.
Melatonin, a pineal hormone having antioxidative and anti-inflammatory properties, has been implicated in circadian dysrhythmia-linked DM. Reduced levels of melatonin and a functional link between melatonin and insulin are implicated in the pathogenesis of type 2 diabetes (T2D). Additionally, genomic studies revealed that rare variants in melatonin receptor 1b (MTNR1B) are also associated with impaired glucose tolerance and increased risk of T2D. Moreover, exogenous melatonin treatment in cell lines, rodent models, and diabetic patients has shown a potent effect in alleviating diabetes and other related complications. This highlights the role of melatonin in glucose homeostasis. However, there are also contradictory reports on the effects of melatonin supplementation. Thus, it is essential to explore if melatonin can be taken from bench to bedside for diabetes management.
This review summarizes the therapeutic potential of melatonin in various diabetic models and whether it can be considered a safe drug for managing diabetic complications and diabetic manifestations like oxidative stress, inflammation, ER stress, mitochondrial dysfunction, metabolic dysregulation, etc.
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Citation Excerpt :
Administration of melatonin in vitro protects β-cells from glucotoxicity, increases its survival, and reduces oxidative stress in both human islets from T2D patients and rodent INS-1832/13 β-cells [27,28]. Further, melatonin administration restored β-cell mass (proliferation and neogenesis), improved glucose tolerance, and reduced blood glucose levels in various T1D rodent models [14,29–32]. Further, in human pancreatic islets, melatonin treatment increases insulin secretion and promotes β-cell survival via decreased c-JUN N-terminal kinase (JNK) activation [33].
Autoimmune-led challenge resulting in β-cell loss is responsible for the development of type 1 diabetes (T1D). Melatonin, a pineal hormone or sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has increased β-cell mass in various diabetic models and has immunoregulatory property. Both β-cell regenerative capacity and melatonin secretion decrease with ageing. Thus, we aimed to investigate the therapeutic potential of melatonin combined with sitagliptin on β-cell regeneration under glucotoxic stress, in the streptozotocin-induced young and old diabetic mouse models, and euglycemic humanized islet transplant mouse model. Our results suggest that combination therapy of sitagliptin and melatonin show an additive effect in inducing mouse β-cell regeneration under glucotoxic stress, and in the human islet transplant mouse model. Further, in the young diabetic mouse model, the monotherapies induce β-cell transdifferentiation and reduce β-cell apoptosis whereas, in the old diabetic mouse model, melatonin and sitagliptin induce β-cell proliferation and β-cell transdifferentiation, and it also reduces β-cell apoptosis. Further, in both the models, combination therapy reduces fasting blood glucose levels, increases plasma insulin levels and glucose tolerance and promotes β-cell proliferation, β-cell transdifferentiation, and reduces β-cell apoptosis. It can be concluded that combination therapy is superior to monotherapies in ameliorating diabetic manifestations, and it can be used as a future therapy for β-cell regeneration in diabetes patients.
Melatonin relieves diabetic complications and regenerates pancreatic beta cells by the reduction in NF-kB expression in streptozotocin induced diabetic rats
2022, Saudi Journal of Biological Sciences
Melatonin, a pleiotropic hormone, has many regulatory effects on the circadian and seasonal rhythms, sleep and body immune system. It is used in the treatment of blind circadian rhythm sleep disorders, delayed sleep phase and insomnia. It is a potent antioxidant, anti-inflammatory, free radical scavenger, helpful in fighting infectious disease and cancer treatment. Decreased level of circulating melatonin was associated with an increased blood glucose level, losing the anti-oxidant protection and anti-inflammatory responses. We aimed to evaluate the effect of melatonin administration, in streptozotocin (STZ) induced diabetic rats, on blood glucose level and pancreatic beta (β) cells. Diabetes mellitus was induced in Sprague dawley male rats by the intravenous (i.v) injection of 65 mg/kg of STZ. Diabetic rats received melatonin at a dose of 10 mg/kg daily for 8 weeks by oral routes. The results showed, after 8 weeks of melatonin administration, a reduction in: 1- fasting blood glucose (FBG) and fructosamine (FTA) levels, 2- kidney and liver function parameters, 3- levels of serum triglycerides, cholesterol and LDL-C, 4- malondialdehyde (MDA), 5- NF-κB expression in treated group, 6- pro-inflammatory cytokines (IL-1β and IL-12) and immunoglobulins (IgA, IgE and IgG). Furthermore, an elevation in insulin secretion was noticed in melatonin treated group that indicated β cells regeneration. Therefore, melatonin administration, in STZ induced diabetic rats; reduced hyperglycemia, hyperlipidemia and oxidative stress. Melatonin acted as an anti-inflammatory agent that reduced pro-inflammatory cytokines (IL-1β and IL-12) and oxidative stress biomarkers (MDA). Melatonin succeeded in protecting β cells under severe inflammatory situations, which was apparent by the regeneration of islets of Langerhans in treated diabetic rats. Moreover, these results can open a gate for diabetes management and treatment.
Mesenchymal stem cells versus curcumin in enhancing the alterations in the cerebellar cortex of streptozocin-induced diabetic albino rats. The role of GFAP, PLC and α-synuclein
2020, Journal of Chemical Neuroanatomy
Diabetes mellitus is the disease, termed either by insulin paucity or resistance and hyperglycemia. The selection of the cerebellum was built on its specific functions. The aim of this study was to investigate a comparison between the possible therapeutic effects of MSCs and curcumin against fluctuations in the cerebellar cortex of STZ-induced diabetic albino rats.
Forty rats were divided into five groups: control, sham control, streptozotocin-induced diabetes, diabetes and MSCs administered and diabetes and curcumin administered. Light microscopic (H&E), immune-histochemical; Glial fibrillary acidic protein (GFAP), real-time PCR; phospholipase-C (PLC) and α-synuclein, histomorphometric analysis, oxidative / anti-oxidatants; malondialdehyde (MDA)/ superoxide dismutase (SOD) glutathione (GSH) and were made.
The histopathological examination of the STZ-induced diabetic rats revealed alterations in the molecular, purkinje and granular layers. Abnormal organizations, vacuolation, patchy loss of purkinje cells were detected. Some purkinje cells migrated into the granular layer.Hemorrhage in pia mater outspreading to cerebellar layers is discerned. Purkinje cells showed karyorrhexis. The mean value of area percentage for GFAP immune- reactivity revealed 360 % significant increase compared to that of the control group. Also, MDA level was significantly increased while the SOD and GSH levels were significantly lower when compared to the control group. Meanwhile, mean values of PLC demonstrated significant decrease, while α-synuclein levels displayed a significant increment in the diabetic group. Administration of curcumin and MSCs extremely ameliorated the previous alterations.
the deleterious alterations on the cerebellar cortex induced by diabetes were obviously improved when treated with either MSCs or curcumin.
Melatonin regulates the expression of inflammatory cytokines, VEGF and apoptosis in diabetic retinopathy in rats
2020, Chemico-Biological Interactions
The present study analyzed whether melatonin could mediate the expression of VEGF, IL-6 and TNF-α, as well as the apoptotic index in rats with diabetic retinopathy. Fifty Wistar albino rats were divided into the following groups: GC: rats without induction of diabetes by streptozotocin; GD: rats induced to diabetes by streptozotocin and treated with placebo; GDM: rats induced to diabetes by streptozotocin and after confirmation treated with melatonin at a dose of 10 mg/kg for 20 days; GDMS: rats induced to diabetes by streptozotocin and treated simultaneously with melatonin at a dosage of 10 mg/kg for 20 days; GDI: rats induced to diabetes by streptozotocin and after confirmation treated with insulin for 20 days. Diabetes was induced by intraperitoneal injections of streptozotocin (60 mg/kg), and insulin (5 U/day) was administered subcutaneously. For apoptosis TUNEL was used, while for the analysis of VEGF, IL-6 and TNF-α. The results showed that the groups that were treated with melatonin decreased the expression of cytokines and VEGF, in addition to apoptosis. Thus, it is concluded that melatonin can regulate the expression of these factors by improving the condition of the retina in diabetic retinopathy.
Potential therapeutic role of melatonin on STZ-induced diabetic central neuropathy: A biochemical, histopathological, immunohistochemical and ultrastructural study
2018, Acta Histochemica
Citation Excerpt :
Mel is also a potent endogenous antioxidant (Karaaslan and Suzen, 2015; Reiter et al., 2016) and inhibits oxidative stress by activating the master endogenous Nrf2 antioxidant defense pathway (Yu et al., 2017), as well as other antioxidant enzymes (Reiter et al., 2000). In addition, it enhances insulin growth factor production and tyrosine phosphorylation of insulin receptor (Sharma et al., 2015), activates muscular glucose uptake (Ha et al., 2006), elevates hepatocyte glucose release (Poon et al., 2001), downregulates insulin-dependent glucose transport in the adipocytes (Brydon et al., 2001), lowers adrenal cortisol secretion (Weitzman et al., 1971), and protects pancreatic β-cells against apoptosis and stimulates their neogenesis (Costes et al., 2015; Simsek et al., 2012; Yavuz et al., 2003). These physiological functions of Mel are mediated via the activation of its two receptors–MT1 and MT2 (Dubocovich and Markowska, 2005).
The aim of the present study was to assess the therapeutic potential of melatonin (Mel) in diabetic central neuropathy in a rat model of streptozotocin (STZ)-induced diabetes. The rats were injected with 60 mg/kg STZ and diabetes was confirmed by blood glucose levels (BGL) ≥ 250 mg/dL. Mel treatment (50 mg/kg) was started 72 h before the STZ injection and continued for 45 days. In addition, normal control, vehicle (5% ethanol) control, and Mel-treated non-diabetic control were also included. STZ induced a diabetic phenotype with persistent hyperglycemia and elevated oxidative stress in the brain, liver, and kidneys compared to the control groups. In addition, the diabetic rats showed severe β-cell necrosis with reduced insulin levels, cerebral neuronopathy, myelinopathy, axonopathy, microglial and astroglial activation, and vascular damage. While Mel treatment did not prevent the development of STZ-induced diabetes mellitus and had no significant effect on the BGLs of the diabetic rats, it significantly ameliorated the diabetes-induced oxidative stress and neurodegeneration. Taken together, Mel showed potent therapeutic effects against the neurological complications of hyperglycemia and therefore can be used to treat diabetic neuropathy.

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Protective effect of melatonin on β-cell damage in streptozotocin-induced diabetes in rats

Summary

Pharmacol Res

Biochem Biophys Res Commun

Free Radic Biol Med

Neurochem Int

Metabolism

Free Radic Biol Med

Pharmacol Res

Acta Histochem

J Biol Chem

Free Radic Biol Med

Biochem Med

Life Sci

Acta Histochem

J Diabetes Complications

Free Radic Biol Med

Life Sci

Environmental factors in the ethiology of type 1diabetes

Am J Med Genet

Melatonin protects against streptozotocin, but not interleukin-1beta-induced damage of rodent pancreatic beta cells

J Pineal Res

Comparative analysis of the protective effects of melatonin and vitamin E on streptozotocin-induced diabetes mellitus

J Pineal Res

A textbook of histology

Consequences of the diabetic status on the oxidant/antioxidant balance

Diabetes Metab

Influence of melatonin on free radicalinduced changes in rat pancreatic beta-cells in vitro

J Pineal Res