scholarly journals Hypoglycemia Induced Mitochondrial Connexin-43 Accumulation Aggravates Diabetic Cardiomyopathy

2021 ◽  
Author(s):  
Xing Wei ◽  
Andrew Chia Hao Chang ◽  
Haishuang Chang ◽  
Shan Xu ◽  
Yilin Xue ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Murine Model ◽  
Connexin 43 ◽  
Calcium Handling ◽  
Glucose Fluctuation ◽  
Increased Risk

Abstract Background: Diabetic cardiomyopathy (DCM) is a complex multifaceted disease responsible for elevated hospitalization and mortality in patients with diabetes mellitus (DM). DCM patients exhibit subclinical diastolic dysfunction, progression towards systolic impairment, and abnormal electrophysiology. Hypoglycemia events that occur spontaneously or due to excess insulin administration threaten the lives of DM patients – with the increased risk of sudden death. However, the molecular underpinnings of hypoglycemia-aggravated DCM remain to be elucidated. Methods and Results: Here we used the established streptozotocin-induced type 1 diabetic cardiomyopathy (T1 DCM) murine model to investigate how hypoglycemia aggravates DCM progression. We showed that chronic hyper- or hypoglycemic challenges dampened cardiac diastolic function in vivo as well as myocardial contractility and calcium handling in isolated cardiomyocytes. Similar contractile defects were recapitulated using neonatal mouse ventricular myocytes (NMVMs) under glucose fluctuation challenges. Using immunoprecipitation mass spectrometry, we identified and validated that hypoglycemia challenge activates the MEK/ERK and PI3K/Akt pathways which results in Cx43 phosphorylation by Src protein in cardiomyocytes. Cx43 dissociation and accumulation at mitochondrial inner membrane was confirmed both in human and murine cardiomyocytes. To determine causality, we overexpressed a mitochondrial targeting Cx43 (mtCx43) using AAV2. At normal blood glucose levels, mtCx43 overexpression recapitulated cardiomyocytes contractile deficiencies, cardiac diastolic dysfunction as well as aberrant electrophysiology both in vitro as well as in vivo. Conclusions: Hypoglycemia challenges results in the accumulation of mtCx43 through the MEK/ERK/Src and PI3K/Akt/Src pathways. We provide evidence that Cx43 mislocalization is present in diabetes mellitus patient hearts, STZ-induced DCM murine model, and glucose fluctuation challenged NMVMs. Mechanistically, we demonstrated that mtCx43 is responsible for inducing aberrant contraction and disrupts electrophysiology in cardiomyocytes and our results support targeting of mtCx43 in treating DCM. Translational perspective: Severe hypoglycemia drives cardiac dysfunction and aggressive ventricular arrhythmias in patients with DCM that leads to sudden cardiac death. Here we demonstrate that Cx43 mislocalization to mitochondria occurs upon hypoglycemic challenge and mtCx43 accumulation is responsible for cardiac diastolic dysfunction, cardiomyocyte contractile dysfunction, and aberrant electrophysiology in vivo. Our findings give support for therapeutic targeting of MEK/ERK/Src and PI3K/Akt/Src pathways to prevent mtCx43-driven DCM.

scholarly journals Sulfated poly-amido-saccharides (sulPASs) are anticoagulants in vitro and in vivo

2021 ◽  
Vol 12 (38) ◽  
pp. 12719-12725
Author(s):  
Maria Varghese ◽  
Rae S. Rokosh ◽  
Carolyn A. Haller ◽  
Stacy L. Chin ◽  
Jiaxuan Chen ◽  
...  
Keyword(s):  
Murine Model ◽  
Protamine Sulfate ◽  
Clotting Time ◽  
Risk Of Bleeding ◽  
Increased Risk

Heparin mimicking sulfated poly-amido-saccharides (sulPASs) are anticoagulants resistant to heparanases and reversed by protamine sulfate. In an in vivo murine model, sulPASs extend clotting time without the increased risk of bleeding.

Platelets, vascular disease, and diabetes mellitus

1994 ◽  
Vol 72 (3) ◽  
pp. 295-303 ◽  
Author(s):  
Peter D. Winocour
Keyword(s):  
Diabetes Mellitus ◽  
Vascular Disease ◽  
Platelet Activity ◽  
Platelet Surface ◽  
Clinical Complications ◽  
Fibrinogen Binding ◽  
Increased Risk ◽  
Adhesive Proteins

Diabetes is associated with increased risk for atherosclerosis and its thromboembolic complications. Theories about mechanisms of atherosclerosis in diabetes are similar to those in the nondiabetic population. Platelets contribute to atherosclerosis through effects on vessels by materials released from the platelets, which interact with injured or altered vessels. In diabetes, platelets could contribute to enhanced atherosclerosis through hypersensitivity to agonists at sites of vessel injury and increased release of materials from adherent platelets. Diabetic platelets are hypersensitive to agonists in vitro, and alterations in a number of mechanisms involved in platelet activation occur in these platelets, which could contribute to the hypersensitivity. These alterations include increased presence of glycoprotein receptors for agonists and adhesive proteins on the platelet surface, increased fibrinogen binding, decreased membrane fluidity, enhanced arachidonate pathway activation with increased thromboxane A2 formation, and increased phosphoinositide turnover leading to increased inositol trisphosphate production, Ca2+ mobilization, and protein phosphorylation. There is some evidence for increased platelet activity in vivo in diabetes, but it is unclear whether this reflects platelet hypersensitivity or increased platelet turnover on already diseased vessels. Studies in diabetic animals indicate greater interaction of platelets with injured vessels and incorporation into experimentally induced thrombi, but it is unclear if this reflects changes in platelets or other factors. These changes could be contributing to the enhanced atherosclerosis and its clinical complications in diabetic patients.Key words: platelets, vascular disease, diabetes mellitus.

scholarly journals Dipeptidyl Peptidase 4: A New Link between Diabetes Mellitus and Atherosclerosis?

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Wellington Santana da Silva Júnior ◽  
Amélio Fernando de Godoy-Matos ◽  
Luiz Guilherme Kraemer-Aguiar
Keyword(s):  
Diabetes Mellitus ◽  
Vascular Function ◽  
Dipeptidyl Peptidase ◽  
Noncommunicable Diseases ◽  
Atherosclerotic Cardiovascular Disease ◽  
Dipeptidyl Peptidase 4 ◽  
Increased Risk ◽  
Increase Insulin Secretion

Type 2 diabetes mellitus (T2DM) has become one of the most prevalent noncommunicable diseases in the past years. It is undoubtedly associated with atherosclerosis and increased risk for cardiovascular diseases. Incretins, which are intestinal peptides secreted during digestion, are able to increase insulin secretion and its impaired function and/or secretion is involved in the pathophysiology of T2DM. Dipeptidyl peptidase 4 (DPP4) is an ubiquitous enzyme that regulates incretins and consequently is related to the pathophysiology of T2DM. DPP4 is mainly secreted by endothelial cells and acts as a regulatory protease for cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. In T2DM, the activity of DPP4 seems to be increased and there are a growing number ofin vitroandin vivostudies suggesting that this enzyme could be a new link between T2DM and atherosclerosis. Gliptins are a new class of pharmaceutical agents that acts by inhibiting DPP4. Thus, it is expected that gliptin represents a new pharmacological approach not only for reducing glycemic levels in T2DM, but also for the prevention and treatment of atherosclerotic cardiovascular disease in diabetic subjects. We aimed to review the evidences that reinforce the associations between DPP4, atherosclerosis, and T2DM.

scholarly journals Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues

2005 ◽  
Vol 289 (5) ◽  
pp. E735-E745 ◽  
Author(s):  
Kathryn M. Thrailkill ◽  
Charles K. Lumpkin ◽  
R. Clay Bunn ◽  
Stephen F. Kemp ◽  
John L. Fowlkes
Keyword(s):  
Diabetes Mellitus ◽  
Bone Formation ◽  
Mineral Density ◽  
Anabolic Agent ◽  
Endogenous Insulin ◽  
Animal Data ◽  
Increased Risk ◽  
Diabetic Osteoporosis

Diabetic osteoporosis is increasingly recognized as a significant comorbidity of type 1 diabetes mellitus. In contrast, type 2 diabetes mellitus is more commonly associated with modest increases in bone mineral density for age. Despite this dichotomy, clinical, in vivo, and in vitro data uniformly support the concept that new bone formation as well as bone microarchitectural integrity are altered in the diabetic state, leading to an increased risk for fragility fracture and inadequate bone regeneration following injury. In this review, we examine the contribution that insulin, as a potential anabolic agent in bone, may make to the pathophysiology of diabetic bone disease. Specifically, we have assimilated human and animal data examining the effects of endogenous insulin production, exogenous insulin administration, insulin sensitivity, and insulin signaling on bone. In so doing, we present evidence that insulin, acting as an anabolic agent in bone, can preserve and increase bone density and bone strength, presumably through direct and/or indirect effects on bone formation.

scholarly journals Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katti R. Crakes ◽  
Jully Pires ◽  
Nina Quach ◽  
Riley E. Ellis-Reis ◽  
Rachel Greathouse ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Barrier Function ◽  
Plasma Lipid ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Histopathological Analysis ◽  
Microbial Composition ◽  
Increased Risk

AbstractDiabetes mellitus (DM) is associated with a dysfunctional intestinal barrier and an increased risk for systemic infection and inflammation in people, though the pathogenic mechanisms leading to this are poorly understood. Using a canine model of DM, we showed that the peroxisomal proliferator-activated receptor-α agonist fenofibrate modulates plasma lipid profiles and markers of intestinal barrier function. A 3-week course of fenofibrate reduced fasting interstitial glucose and inflammatory cytokine IL-8 and TNF-α concentrations, which correlated with reduced triglyceride levels. The lipidomic profile exhibited significantly lower levels of triacylglycerols, phosphatidylethanolamines, diacylglycerols, and ceramides following fenofibrate administration. On histopathological analysis, we observed an aberrant amount of intraepithelial CD3+ T lymphocytes (IEL) in the small intestine of dogs with spontaneous and induced-DM. Fenofibrate reduced IEL density in the duodenum of dogs with DM and enhanced markers of intestinal barrier function in vivo and in vitro. There were minimal changes in the intestinal microbial composition following fenofibrate administration, suggesting that repair of intestinal barriers can be achieved independently of the resident microbiota. Our findings indicate that lipid metabolism is critical to functionality of the intestinal epithelium, which can be rescued by PPARα activation in dogs with DM.

Ciamexon in low-dose streptozotocin induced diabetes mellitus. In vivo and in vitro studies

1986 ◽  
Vol 113 (1_Suppl) ◽  
pp. S120-S121
Author(s):  
TH. LINN ◽  
H. GERMANN ◽  
B. HERING ◽  
R. BRETZEL ◽  
K. FEDERLIN
Keyword(s):  
Diabetes Mellitus ◽  
Low Dose ◽  
In Vitro Studies ◽  
Streptozotocin Induced Diabetes

scholarly journals Uremic Toxins and Their Relation with Oxidative Stress Induced in Patients with CKD

2021 ◽  
Vol 22 (12) ◽  
pp. 6196
Author(s):  
Anna Pieniazek ◽  
Joanna Bernasinska-Slomczewska ◽  
Lukasz Gwozdzinski
Keyword(s):  
Oxidative Stress ◽  
Uremic Toxins ◽  
Water Medium ◽  
Induce Insulin Resistance ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Stage Renal Disease ◽  
End Stage

The presence of toxins is believed to be a major factor in the development of uremia in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Uremic toxins have been divided into 3 groups: small substances dissolved in water, medium molecules: peptides and low molecular weight proteins, and protein-bound toxins. One of the earliest known toxins is urea, the concentration of which was considered negligible in CKD patients. However, subsequent studies have shown that it can lead to increased production of reactive oxygen species (ROS), and induce insulin resistance in vitro and in vivo, as well as cause carbamylation of proteins, peptides, and amino acids. Other uremic toxins and their participation in the damage caused by oxidative stress to biological material are also presented. Macromolecules and molecules modified as a result of carbamylation, oxidative stress, and their adducts with uremic toxins, may lead to cardiovascular diseases, and increased risk of mortality in patients with CKD.

scholarly journals C-Peptide as a Therapy for Type 1 Diabetes Mellitus

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 270
Author(s):  
Rachel L. Washburn ◽  
Karl Mueller ◽  
Gurvinder Kaur ◽  
Tanir Moreno ◽  
Naima Moustaid-Moussa ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Vascular Complications ◽  
The United States ◽  
Genetically Engineered ◽  
Therapeutic Effects ◽  
Pancreatic Islet Transplantation ◽  
C Peptide ◽  
Increased Risk

Diabetes mellitus (DM) is a complex metabolic disease affecting one-third of the United States population. It is characterized by hyperglycemia, where the hormone insulin is either not produced sufficiently or where there is a resistance to insulin. Patients with Type 1 DM (T1DM), in which the insulin-producing beta cells are destroyed by autoimmune mechanisms, have a significantly increased risk of developing life-threatening cardiovascular complications, even when exogenous insulin is administered. In fact, due to various factors such as limited blood glucose measurements and timing of insulin administration, only 37% of T1DM adults achieve normoglycemia. Furthermore, T1DM patients do not produce C-peptide, a cleavage product from insulin processing. C-peptide has potential therapeutic effects in vitro and in vivo on many complications of T1DM, such as peripheral neuropathy, atherosclerosis, and inflammation. Thus, delivery of C-peptide in conjunction with insulin through a pump, pancreatic islet transplantation, or genetically engineered Sertoli cells (an immune privileged cell type) may ameliorate many of the cardiovascular and vascular complications afflicting T1DM patients.

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