scholarly journals Depleting Hypothalamic Somatostatinergic Neurons Recapitulates Diabetic Phenotypes in Brain, Bone Marrow, Adipose, and Retina

2021 ◽  
Author(s):  
Chao Huang ◽  
Robert Follett Rosencrans ◽  
Raluca Bugescu ◽  
Cristiano P Vieira ◽  
Ping Hu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Leptin Receptor ◽  
Brain Inflammation ◽  
Optokinetic Response ◽  
Adeno Associated Virus ◽  
Peripheral Tissues ◽  
Periventricular Nucleus ◽  
Hypothalamic Inflammation

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunologic pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. The present data show that leptin receptor deficient (db/db) mice exhibit reduced hypothalamic somatostatinergic cells, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus (AAV) delivery of diphtheria toxin (DTA) driven by an SST-cre system to deplete these cells in SSTcre/gfp mice (SST-DTA). SST-DTA mice exhibit enhanced hypothalamic c-fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed hematopoiesis, generating excess granulocyte-monocyte precursors and increased pro-inflammatory (CCR2hi) monocytes. Visceral mesenteric adipose tissue from DTA-treated animals was resistant to catecholamine induced lipolysis. Finally, SST-DTA mice exhibited a diabetic retinopathy like phenotype: reduced visual function by optokinetic response and electroretinogram, as well as increased percentages of retinal monocytes. Importantly, hyperglycemia was not observed in SST-DTA mice. Thus, the isolated reduction in hypothalamic somatostatinergic neurons was able to recapitulate several hallmark features of type 2 diabetes in disease relevant tissues.

scholarly journals Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 268
Author(s):  
Jonathan Ribot ◽  
Cyprien Denoeud ◽  
Guilhem Frescaline ◽  
Rebecca Landon ◽  
Hervé Petite ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Therapeutic Modality ◽  
Multipotent Stromal Cells ◽  
Cell Therapies

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

CD4+ T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes

Bone ◽  
2021 ◽  
pp. 116292
Author(s):  
S.E. Cifuentes-Mendiola ◽  
D.L. Solis-Suarez ◽  
A. Martínez-Dávalos ◽  
M. Godínez-Victoria ◽  
A.L. García-Hernández
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Bone Marrow ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Fragility ◽  
Cd4 T Cell

scholarly journals PHYSIOLOGICAL ROLES AND ASSOCIATED DISORDERS OF ADIPONECTIN

2016 ◽  
Vol 10 (1) ◽  
pp. 32
Author(s):  
Preeti Sharma ◽  
Shailaza Shrestha ◽  
Pradeep Kumar ◽  
Saxena Sp ◽  
Rachna Sharma
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Adipose Tissue ◽  
Human Plasma ◽  
Mode Of Action ◽  
Skeletal Muscles ◽  
High Concentration ◽  
Peripheral Tissues ◽  
Cardioprotective Effects

ABSTRACTAmong the adipokines, adiponectin is the first one to be described just over a decade ago. It is produced exclusively by adipose tissue and circulatesin high concentration in human plasma accounting for 0.01% of proteins in plasma, almost thousand times higher than that of leptin. The normalcirculating level of adiponectin ranges from 2 to 30 µg/ml. It is now observed that besides adipose tissue, adiponectin can also be produced byseveral other tissues such as hepatocytes, cardiomyocytes, and placenta. Adiponectin executes its action via autocrine as well as and paracrine effects.Researchers working in this area have revealed that adiponectin has insulin-sensitizing, anti-inflammatory and cardioprotective effects. Our reviewfocuses on adiponectin, its mode of action on different peripheral tissues such as skeletal muscles, heart, liver, brain and its the correlative accountin various diseases.Keywords: Adiponectin, Obesity, Type 2 diabetes, Inflammation, Malignancies, Cardiovascular disease.

scholarly journals Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept

2021 ◽  
Vol 12 ◽  
Author(s):  
Marianna Santopaolo ◽  
Niall Sullivan ◽  
Anita Coral Thomas ◽  
Valeria Vincenza Alvino ◽  
Lindsay B. Nicholson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
T Cells ◽  
Insulin Sensitivity ◽  
Adaptive Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
Low Grade ◽  
Cardiac Damage

Background: Chronic low-grade inflammation and alterations in innate and adaptive immunity were reported in Type 2 diabetes (T2D). Here, we investigated the abundance and activation of T cells in the bone marrow (BM) of patients with T2D. We then verified the human data in a murine model and tested if the activation of T cells can be rescued by treating mice with abatacept, an immunomodulatory drug employed for the treatment of rheumatoid arthritis. Clinical evidence indicated abatacept can slow the decline in beta-cell function.Methods: A cohort of 24 patients (12 with T2D) undergoing hip replacement surgery was enrolled in the study. Flow cytometry and cytokine analyses were performed on BM leftovers from surgery. We next compared the immune profile of db/db and control wt/db mice. In an additional study, db/db mice were randomized to receive abatacept or vehicle for 4 weeks, with endpoints being immune cell profile, indices of insulin sensitivity, and heart performance.Results: Patients with T2D showed increased frequencies of BM CD4+ (2.8-fold, p = 0.001) and CD8+ T cells (1.8-fold, p = 0.01), with the upregulation of the activation marker CD69 and the homing receptor CCR7 in CD4+ (1.64-fold, p = 0.003 and 2.27-fold, p = 0.01, respectively) and CD8+ fractions (1.79-fold, p = 0.05 and 1.69-fold, p = 0.02, respectively). These differences were confirmed in a multivariable regression model. CCL19 (CCR7 receptor ligand) and CXCL10/11 (CXCR3 receptor ligands), implicated in T-cell migration and activation, were the most differentially modulated chemokines. Studies in mice confirmed the activation of adaptive immunity in T2D. Abatacept reduced the activation of T cells and the levels of proinflammatory cytokines and improved cardiac function but not insulin sensitivity.Conclusions: Results provide proof-of-concept evidence for the activation of BM adaptive immunity in T2D. In mice, treatment with abatacept dampens the activation of adaptive immunity and protects from cardiac damage.

scholarly journals Association of insulin resistance and leptin receptor gene polymorphism in type 2 diabetes mellitus

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Usha Adiga ◽  
Nandit Banawalikar ◽  
Sriprajna Mayur ◽  
Radhika Bansal ◽  
Nafeesath Ameera ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Gene Polymorphism ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Receptor Gene Polymorphism

scholarly journals Branched-Chain Amino Acid Metabolism is Regulated by ERRα and is Further Impaired by Glucose Loading in Type 2 Diabetes

2020 ◽  
Author(s):  
Rasmus J.O. Sjögren ◽  
David Rizo-Roca ◽  
Alexander V. Chibalin ◽  
Elin Chorell ◽  
Regula Furrer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Metabolites ◽  
Peripheral Tissues ◽  
Branched Chain Amino Acid ◽  
Glucose Challenge ◽  
Metabolic Inflexibility ◽  
Branched Chain ◽  
Estrogen Related Receptor ◽  
Dependent Mechanism

SUMMARYIncreased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes (T2D) pathogenesis. However, most metabolomic studies in T2D are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a glucose challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism in T2D is partially unknown. Using metabolomic and gene expression approaches, we found that impairments in BCAA catabolism in T2D patients under fasting conditions are exacerbated after a glucose load, concomitant with downregulated expression of BCAA-related genes in skeletal muscle. We identified a key regulatory role for Estrogen-Related Receptor α (ERRα) in PGC-1α-mediated upregulation of BCAA genes and leucine oxidation. Thus, metabolic inflexibility in T2D impacts BCAA homeostasis and the transcriptional regulation of BCAA genes via a PGC-1α/ERRα-dependent mechanism.

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