taurochenodeoxycholic-acid and Diabetes-Mellitus--Type-1

The effect of selenium on diabetes is significant. As pharmaceutical chaperones, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA) can effectively improve the oxidative stress of the endoplasmic reticulum. This study established a mice model with type 1 diabetes (T1D) to evaluate the effects of pharmaceutical chaperones on selenium distribution. Streptozotocin was used to induce Friend virus B-type mice to establish a T1D mice model. Mice were administered with TUDCA or 4-PBA. Selenium levels in different tissues were measured by inductively coupled plasma-mass spectroscopy (ICP-MS). After treatment with TUDCA and 4-PBA, related laboratory findings such as glucose and glycated serum protein were significantly reduced and were closer to normal levels. At 2 weeks, 4-PBA normalized selenium levels in the heart, and 4-PBA and TUDCA maintained the selenium in the liver, kidney, and muscle at normal. At 2 months, 4-PBA and TUDCA maintained the selenium in the heart, liver, and kidney at normal levels. The serum selenium had a positive correlation with zinc and copper in the diabetes group and the control group, while the serum selenium had no significant association with magnesium and calcium at 2 weeks and 2 months. TUDCA and 4-PBA have crucial effects on selenium distribution in diabetic mice, and further research is needed to research their internal mechanisms.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Endoplasmic Reticulum Stress; Mice; Pharmaceutical Preparations; Selenium; Taurochenodeoxycholic Acid

Persistent hyperglycemia in type 1 diabetes triggers numerous signaling pathways, which may prove deleterious to the endothelium. As hyperglycemia damages the endothelial layer via multiple signaling pathways, including enhanced oxidative stress, downregulation of angiotensin-converting enzyme 2 signaling, and exacerbation of endoplasmic reticulum (ER) stress, it becomes difficult to prevent injury using monotherapy. Thus, the present study was conceived to evaluate the combined effect of ER stress inhibition along with angiotensin-converting enzyme 2 activation, two major contributors to hyperglycemia-induced endothelial dysfunction, in preventing endothelial dysfunction associated with type 1 diabetes. Streptozotocin-induced diabetic animals were treated with either diminazene aceturate (5 mg·kg

Topics: Angiotensin-Converting Enzyme 2; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diminazene; Drug Therapy, Combination; Endoplasmic Reticulum Stress; Endothelium, Vascular; Male; Oxidative Stress; Rats, Wistar; Streptozocin; Taurochenodeoxycholic Acid

Topics: Animals; Cell Line; Cell Survival; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; Insulin-Secreting Cells; Mice; Mice, Knockout; S100 Calcium Binding Protein G; Taurochenodeoxycholic Acid; Thapsigargin

Recent evidence has identified a role of micronutrients, such as magnesium (Mg

Topics: Animals; Calcium; Diabetes Mellitus, Type 1; Heart; Kidney; Liver; Magnesium; Male; Mice; Myocardium; Phenylbutyrates; Spleen; Streptozocin; Taurochenodeoxycholic Acid

Despite substantial advances in the research exploring the pathogenesis of Type 1 Diabetes (T1D), the pathophysiological mechanisms involved remain unknown. We hypothesized in this study that interferon alpha (IFNα) participates in the early stages of T1D development by triggering endoplasmic reticulum (ER) stress. To verify our hypothesis, human islets and human EndoC-βH1 cells were exposed to IFNα and tested for ER stress markers, glucose stimulated insulin secretion (GSIS) and insulin content. IFNα treatment induced upregulation of ER stress markers including Binding immunoglobulin Protein, phospho-eukaryotic translation initiation factor 2α, spliced- X-box binding protein-1, C/EBP homologous protein and activating transcription factor 4. Intriguingly, IFNα treatment did not impair GSIS but significantly decreased insulin production in both human islets and EndoC-βH1 cells. Furthermore, IFNα decreased the expression of both proinsulin convertase 1 and proinsulin convertase 2, suggesting an altered functional state of the beta cells characterized by a slower proinsulin-insulin conversion. Pretreatment of both human islets and EndoC-βH1 cells with chemical chaperones 4-phenylbutyric acid and tauroursodeoxycholic acid completely prevented IFNα effects, indicating an ER stress-mediated impairment of insulin production. We demonstrated for the first time that IFNα elicits ER stress in human beta cells providing a novel mechanistic role for this virus-induced cytokine in the development of T1D. Compounds targeting molecular processes altered in ER-stressed beta cells could represent a potential therapeutic strategy to prevent IFNα-induced beta cell dysfunction in the early onset of T1D.

Topics: Apoptosis; Cells, Cultured; Cytokines; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; Humans; Insulin; Insulin-Secreting Cells; Interferon-alpha; Phenylbutyrates; Proprotein Convertase 1; Proprotein Convertase 2; Taurochenodeoxycholic Acid; Transcription Factor CHOP; X-Box Binding Protein 1

Alternations of copper (Cu) and zinc (Zn) status in diabetes have received a great attention. Tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (PBA) could alleviate the increased endoplasmic reticulum (ER) stress and prevent insulin resistance. This study aimed to investigate the effect of TUDCA and PBA on metabolism of Cu and Zn in diabetic mice model. Diabetes was induced by streptozotocin in FVB mice treated with and without TUDCA and PBA. Determination of Cu and Zn in tissues and serum by acid digestion was followed by ICP-MS. The renal and serum Cu levels were significantly higher, while the hepatic Cu and Zn levels were significantly decreased in the diabetic mice at 2 weeks and 2 months after diabetes onset. The increase of cardiac Cu together with the decrease of muscular Zn was found in the diabetic mice only at 2 months. Cu levels were positively correlated with Zn in the heart, liver, kidney, muscle, spleen, and serum of diabetic and control mice at both 2 weeks and 2 months. Both PBA and TUDCA reduced serum Zn, and PBA reduced hepatic Cu to normal levels in the diabetic mice at two time points, while PBA normalized serum Cu in the diabetic mice only at 2 months. PBA increased hepatic Zn to normal levels in the diabetic mice at 2 weeks, while it partially increased hepatic Zn in the same group at 2 months. Therefore, maintaining homeostasis of Cu and Zn by TUDCA and PBA in diabetes needs to be received with special attention.

Topics: Animals; Copper; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Liver; Mice; Phenylbutyrates; Taurochenodeoxycholic Acid; Zinc

Epidermal growth factor receptor tyrosine kinase (EGFRtk) and endoplasmic reticulum (ER) stress are important factors in cardiovascular complications. Understanding whether enhanced EGFRtk activity and ER stress induction are involved in cardiac damage, and microvascular dysfunction in type 1 diabetes mellitus is an important question that has remained unanswered. Cardiac fibrosis and microvascular function were determined in C57BL/6J mice injected with streptozotocin only or in combination with EGFRtk inhibitor (AG1478), ER stress inhibitor (Tudca), or insulin for 2 weeks. In diabetic mice, we observed an increase in EGFRtk phosphorylation and ER stress marker expression (CHOP, ATF4, ATF6, and phosphorylated-eIF2α) in heart and mesenteric resistance arteries, which were reduced with AG1478, Tudca, and insulin. Cardiac fibrosis, enhanced collagen type I, and plasminogen activator inhibitor 1 were decreased with AG1478, Tudca, and insulin treatments. The impaired endothelium-dependent relaxation and -independent relaxation responses were also restored after treatments. The inhibition of NO synthesis reduced endothelium-dependent relaxation in control and treated streptozotocin mice, whereas the inhibition of NADPH oxidase improved endothelium-dependent relaxation only in streptozotocin mice. Moreover, in mesenteric resistance arteries, the mRNA levels of Nox2 and Nox4 and the NADPH oxidase activity were augmented in streptozotocin mice and reduced with treatments. This study unveiled novel roles for enhanced EGFRtk phosphorylation and its downstream ER stress in cardiac fibrosis and microvascular endothelial dysfunction in type 1 diabetes mellitus.

Topics: Animals; Blotting, Western; Cholagogues and Choleretics; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; ErbB Receptors; Fibrosis; Gene Expression; Heart; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Myocardium; Phosphorylation; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; Streptozocin; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Tyrphostins; Vasodilation