Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

Recurrent exposure to hypoglycemia can impair the normal counterregulatory hormonal responses that guard against hypoglycemia, leading to hypoglycemia unawareness. This pathological condition known as hypoglycemia-associated autonomic failure (HAAF) is the main adverse consequence that prevents individuals with type 1 diabetes mellitus from attaining the long-term health benefits of tight glycemic control. The underlying molecular mechanisms responsible for the progressive loss of the epinephrine response to subsequent bouts of hypoglycemia, a hallmark sign of HAAF, are largely unknown. Normally, hypoglycemia triggers both the release and biosynthesis of epinephrine through activation of nicotinic acetylcholine receptors (nAChR) on the adrenal glands. We hypothesize that excessive cholinergic stimulation may contribute to impaired counterregulation. Here, we tested whether administration of the nAChR partial agonist cytisine to reduce postganglionic synaptic activity can preserve the counterregulatory hormone responses in an animal model of HAAF. Compared with nicotine, cytisine has limited efficacy to activate nAChRs and stimulate epinephrine release and synthesis. We evaluated adrenal catecholamine production and secretion in nondiabetic rats subjected to two daily episodes of hypoglycemia for 3 days, followed by a hyperinsulinemic hypoglycemic clamp on day 4. Recurrent hypoglycemia decreased epinephrine responses, and this was associated with suppressed TH mRNA induction (a measure of adrenal catecholamine synthetic capacity). Treatment with cytisine improved glucagon responses as well as epinephrine release and production in recurrently hypoglycemic animals. These data suggest that pharmacological manipulation of ganglionic nAChRs may be promising as a translational adjunctive therapy to avoid HAAF in type 1 diabetes mellitus.

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Immunomodulatory Effect of Vitamin D and Its Potential Role in the Prevention and Treatment of Type 1 Diabetes Mellitus—A Narrative Review

Molecules ◽

10.3390/molecules24010053 ◽

2018 ◽

Vol 24 (1) ◽

pp. 53 ◽

Cited By ~ 14

Author(s):

Karolina Rak ◽

Monika Bronkowska

Keyword(s):

Diabetes Mellitus ◽

Vitamin D ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Molecular Mechanisms ◽

Immunological Tolerance ◽

Narrative Review ◽

Immunomodulatory Effect ◽

Transcription Control

Type 1 diabetes mellitus is a chronic autoimmune disease associated with degeneration of pancreatic β-cells that results in an inability to produce insulin and the need for exogenous insulin administration. It is a significant global health problem as the incidence of this disorder is increasing worldwide. The causes are still poorly understood, although it certainly has genetic and environmental origins. Vitamin D formed profusely in the skin upon exposure to sunlight, as well as from dietary sources, exhibits an immunomodulatory effect based on gene transcription control. Indeed, vitamin D can downregulate mechanisms connected with adaptive immunity, induce immunological tolerance and decrease auto-aggression-related inflammation. These properties provide the basis for a preventive and therapeutic role of vitamin D. As many studies have demonstrated, appropriate supplementation with vitamin D reduces the risk of autoimmune diseases, including type 1 diabetes mellitus, and alleviates disease symptoms in patients. The aim of this narrative review is to present the molecular mechanisms for the vitamin D immunomodulatory effect as well as review human clinical studies on the use of vitamin D as adjuvant therapy in type 1 diabetes mellitus.

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Association of the polymorphous marker G6230A of the CTLA4 gene with type 1 diabetes mellitus in the patients of Russian descent

Problems of Endocrinology ◽

10.14341/probl201258414-17 ◽

2012 ◽

Vol 58 (4) ◽

pp. 14-17

Author(s):

O I Kopylova ◽

T L Kuraeva ◽

E Iu Lavrikova ◽

E V Titovich ◽

A G Nikitin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Healthy Subjects ◽

Molecular Mechanisms ◽

Control Group ◽

Diabetic Patients ◽

Potential Candidate ◽

Ctla4 Gene

The risk of devolvement of type 1 diabetes mellitus (DM1) remains a challenging problem because neither etiology of the disease nor its prognosis and genetic predisposition to this condition are clearly understood. The development of any autoimmune process starts from the disturbance of subtle molecular mechanisms involved in the regulation of the immune system. Therefore, the genes controlling the function of its major components are at the same time the potential candidate genes encoding for the predisposition to DM1. Their association with the disease was studied by means of comparative analysis of the frequency distribution of alleles and genotypes of the polymorphous rs3087243 (G6230A) marker of the CTLA4 gene encoding for antigen-4 of cytotoxic T-lymphocytes. The present study included 257 patients presenting with type 1 diabetes mellitus and 526 healthy subjects. Genotypes were identified by the "real time" amplification technique. The AA genotype was found to occur less frequently in the diabetic patients than in the control group (11.3% and 22.1% respectively). In contrast, the frequency of the GG genotype was higher in the patients with DM1 than in the healthy subjects (44.7% and 37.5% respectively). It is concluded that the polymorphous rs3087243 marker of the CTLA4 gene is significantly associated with the predisposition to the development of type 1 diabetes mellitus in the patients of Russian descent.

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Metabolic and Metabolomic Insights Regarding the Omega-3 PUFAs Intake in Type 1 Diabetes Mellitus

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.783065 ◽

2021 ◽

Vol 8 ◽

Author(s):

Carmen Purdel ◽

Anca Ungurianu ◽

Denisa Margina

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Molecular Mechanisms ◽

Potential Role ◽

Dietary Factors ◽

Omega 3 ◽

Beneficial Effects

Type 1 diabetes mellitus (T1DM) is currently considered an autoimmune disease characterized by the destruction of pancreatic β-cells, insulin deficiency, and dysglycemia. Dietary factors, including omega-3 polyunsaturated fatty acids (ω-3 PUFAs), were reported to influence T1DM. Therefore, a better understanding of the potential role of ω-3 PUFAs in the development and progression of T1DM will help to improve the clinical management of the disease. In this review, we explored the current understanding of molecular mechanisms and signaling pathways induced by ω-3 PUFAs and the beneficial effects of ω-3 PUFAs intake in the prevention and treatment of T1DM, as well as the underlying possible metabolomic (lipidomics) changes.

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Carbon Monoxide in Pancreatic Islet Transplantation: A New Therapeutic Alternative to Patients With Severe Type 1 Diabetes Mellitus

Frontiers in Pharmacology ◽

10.3389/fphar.2021.750816 ◽

2021 ◽

Vol 12 ◽

Author(s):

George J. Dugbartey

Keyword(s):

Diabetes Mellitus ◽

Carbon Monoxide ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Islet Transplantation ◽

Pancreatic Islet ◽

Molecular Mechanisms ◽

Pancreatic Islet Transplantation

Pancreatic islet transplantation is a minimally invasive procedure to replace β-cells in a subset of patients with autoimmune type 1 diabetic mellitus, who are extremely sensitive to insulin and lack counter-regulatory measures, and thereby increasing their risk of neuroglycopenia and hypoglycemia unawareness. Thus, pancreatic islet transplantation restores normoglycemia and insulin independence, and prevents long-term surgical complications associated with whole-organ pancreas transplantation. Nonetheless, relative inefficiency of islet isolation and storage process as well as progressive loss of islet function after transplantation due to unvoidable islet inflammation and apoptosis, hinder a successful islet transplantation. Carbon monoxide (CO), a gas which was once feared for its toxicity and death at high concentrations, has recently emerged as a medical gas that seems to overcome the challenges in islet transplantation. This minireview discusses recent findings about CO in preclinical pancreatic islet transplantation and the underlying molecular mechanisms that ensure islet protection during isolation, islet culture, transplantation and post-transplant periods in type 1 diabetic transplant recipients. In addition, the review also discusses clinical translation of these promising experimental findings that serve to lay the foundation for CO in islet transplantation to replace the role of insulin therapy, and thus acting as a cure for type 1 diabetes mellitus and preventing long-term diabetic complications.

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