The Transgenerational Transmission of the Paternal Type 2 Diabetes-Induced Subfertility Phenotype

Diabetes is a chronic metabolic disorder characterized by hyperglycemia and associated with many health complications due to the long-term damage and dysfunction of various organs. A consequential complication of diabetes in men is reproductive dysfunction, reduced fertility, and poor reproductive outcomes. However, the molecular mechanisms responsible for diabetic environment-induced sperm damage and overall decreased reproductive outcomes are not fully established. We evaluated the effects of type 2 diabetes exposure on the reproductive system and the reproductive outcomes of males and their male offspring, using a mouse model. We demonstrate that paternal exposure to type 2 diabetes mediates intergenerational and transgenerational effects on the reproductive health of the offspring, especially on sperm quality, and on metabolic characteristics. Given the transgenerational impairment of reproductive and metabolic parameters through two generations, these changes likely take the form of inherited epigenetic marks through the germline. Our results emphasize the importance of improving metabolic health not only in women of reproductive age, but also in potential fathers, in order to reduce the negative impacts of diabetes on subsequent generations.

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Metabolic diseases affect male reproduction and induce signatures in gametes that may compromise the offspring health

Environmental Epigenetics ◽

10.1093/eep/dvaa019 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Sara C Pereira ◽

Luís Crisóstomo ◽

Mário Sousa ◽

Pedro F Oliveira ◽

Marco G Alves

Keyword(s):

Type 2 Diabetes ◽

Metabolic Disorders ◽

Sperm Quality ◽

Epigenetic Inheritance ◽

Male Reproduction ◽

Reproductive Age ◽

Metabolic Abnormalities ◽

Obesity And Diabetes ◽

Harmful Effects

Abstract The most prevalent diseases worldwide are non-communicable such as obesity and type 2 diabetes. Noteworthy, the prevalence of obesity and type 2 diabetes is expected to steadily increase in the next decades, mostly fueled by bad feeding habits, stress, and sedentarism. The reproductive function of individuals is severely affected by abnormal metabolic environments, both at mechanical and biochemical levels. Along with mechanical dysfunctions, and decreased sperm quality (promoted both directly and indirectly by metabolic abnormalities), several studies have already reported the potentially harmful effects of metabolic disorders in the genetic and epigenetic cargo of spermatozoa, and the epigenetic inheritance of molecular signatures induced by metabolic profile (paternal diet, obesity, and diabetes). The inheritance of epigenetic factors towards the development of metabolic abnormalities means that more people in reproductive age can potentially suffer from these disorders and for longer periods. In its turn, these individuals can also transmit this (epi)genetic information to future generations, creating a vicious cycle. In this review, we collect the reported harmful effects related to acquired metabolic disorders and diet in sperm parameters and male reproductive potential. Besides, we will discuss the novel findings regarding paternal epigenetic inheritance, particularly the ones induced by paternal diet rich in fats, obesity, and type 2 diabetes. We analyze the data attained with in vitro and animal models as well as in long-term transgenerational population studies. Although the findings on this topic are very recent, epigenetic inheritance of metabolic disease has a huge societal impact, which may be crucial to tackle the ‘fat epidemic’ efficiently.

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Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

International Journal of Molecular Sciences ◽

10.3390/ijms22020660 ◽

2021 ◽

Vol 22 (2) ◽

pp. 660

Author(s):

María Aguilar-Ballester ◽

Gema Hurtado-Genovés ◽

Alida Taberner-Cortés ◽

Andrea Herrero-Cervera ◽

Sergio Martínez-Hervás ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Molecular Mechanisms ◽

Foam Cell ◽

Leukocyte Adhesion ◽

Experimental Studies ◽

Lipid Lowering ◽

Foam Cell Formation ◽

Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

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Molecular mechanisms and the vital roles of resistin, TLR 4, and NF-κB in treating type 2 diabetic complications

Beni-Suef University Journal of Basic and Applied Sciences ◽

10.1186/s43088-020-00078-4 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Venkataiah Gudise ◽

Bimalendu Chowdhury

Keyword(s):

Type 2 Diabetes ◽

Effective Treatment ◽

Diabetic Complications ◽

Molecular Mechanisms ◽

Cellular Proliferation ◽

Vascular Complications ◽

Diabetic Patients ◽

Rapid Progression ◽

Main Body

Abstract Background Type 2 diabetes in obese (≥ 25 and ≥ 30 kg/m2) patients is the foremost cause of cardiovascular complications like stroke, osteoarthritis, cancers (endometrial, breast, ovarian, liver, kidney, colon, and prostate), and vascular complications like diabetic neuropathy, diabetic and retinopathy, and diabetic nephropathy. It is recognized as a global burden disorder with high prevalence in middle-income nations which might lead to a double burden on health care professionals. Hence, this review emphasizes on understanding the complexity and vital signaling tracts involved in diabetic complications for effective treatment. Main body Type 2 diabetes in overweight patients induces the creation of specific ROS that further leads to changes in cellular proliferation, hypothalamus, and fringe. The resistin, TLR4, and NF-κB signalings are mainly involved in the progression of central and fringe changes such as insulin resistance and inflammation in diabetic patients. The overexpression of these signals might lead to the rapid progression of diabetic vascular complications induced by the release of proinflammatory cytokines, chemokines, interleukins, and cyclooxygenase-mediated chemicals. Until now, there has been no curative treatment for diabetes. Therefore, to effectively treat complications of type 2 diabetes, the researchers need to concentrate on the molecular mechanisms and important signaling tracts involved. Conclusion In this review, we suggested the molecular mechanism of STZ-HFD induced type 2 diabetes and the vital roles of resistin, TLR4, and NF-κB signalings in central, fringe changes, and development diabetic complications for its effective treatment. Graphical abstract

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Development and validation of a tool for predicting type 2 diabetes in Mexican women of reproductive age

Endocrinología Diabetes y Nutrición (English ed ) ◽

10.1016/j.endien.2020.11.001 ◽

2020 ◽

Vol 67 (9) ◽

pp. 578-585

Author(s):

Fabiola Mabel Del Razo-Olvera ◽

Enrique Reyes-Muñoz ◽

Rosalba Rojas-Martínez ◽

Fernando Guerrero-Romero ◽

Roopa Mehta ◽

...

Keyword(s):

Type 2 Diabetes ◽

Reproductive Age ◽

Mexican Women ◽

Women Of Reproductive Age ◽

Development And Validation

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Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽

10.3390/cells10051236 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1236

Author(s):

Jesús Burillo ◽

Patricia Marqués ◽

Beatriz Jiménez ◽

Carlos González-Blanco ◽

Manuel Benito ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Type 2 Diabetes Mellitus ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

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High Energy Intake Induced Overexpression of Transcription Factors and Its Regulatory Genes Involved in Acceleration of Hepatic Lipogenesis: A Rat Model for Type 2 Diabetes

Biomedicines ◽

10.3390/biomedicines7040076 ◽

2019 ◽

Vol 7 (4) ◽

pp. 76 ◽

Cited By ~ 3

Author(s):

Suresh P. Khadke ◽

Aniket A. Kuvalekar ◽

Abhay M. Harsulkar ◽

Nitin Mantri

Keyword(s):

Type 2 Diabetes ◽

Transcription Factors ◽

Glucose Tolerance ◽

Molecular Mechanisms ◽

Target Genes ◽

High Energy ◽

Tolerance Test ◽

Diabetic Control ◽

Ppar Γ

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by impaired insulin action and its secretion. The objectives of the present study were to establish an economical and efficient animal model, mimicking pathophysiology of human T2DM to understand probable molecular mechanisms in context with lipid metabolism. In the present study, male Wistar rats were randomly divided into three groups. Animals were fed with high fat diet (HFD) except healthy control (HC) for 12 weeks. After eight weeks, intra peritoneal glucose tolerance test was performed. After confirmation of glucose intolerance, diabetic control (DC) group was injected with streptozotocin (STZ) (35 mg/kg b.w., i.p.). HFD fed rats showed increase (p ≤ 0.001) in glucose tolerance and HOMA-IR as compared to HC. Diabetes rats showed abnormal (p ≤ 0.001) lipid profile as compared to HC. The hepatocyte expression of transcription factors SREBP-1c and NFκβ, and their target genes were found to be upregulated, while PPAR-γ, CPT1A and FABP expressions were downregulated as compared to the HC. A number of animal models have been raised for studying T2DM, but the study has been restricted to only the biochemical level. The model is validated at biochemical, molecular and histopathological levels, which can be used for screening new therapeutics for the effective management of T2DM.

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Development of a Nongenetic Mouse Model of Type 2 Diabetes

Experimental Diabetes Research ◽

10.1155/2011/416254 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 64

Author(s):

Elizabeth R. Gilbert ◽

Zhuo Fu ◽

Dongmin Liu

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mouse Model ◽

Serum Insulin ◽

Cell Mass ◽

Low Fat ◽

Β Cell ◽

Islet Mass ◽

Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

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