Rac1 and AMPK Account for the Majority of Muscle Glucose Uptake Stimulated by Ex Vivo Contraction but Not In Vivo Exercise
Exercise bypasses insulin resistance to increase glucose uptake in skeletal muscle and therefore represents an important alternative to stimulate glucose uptake in insulin-resistant muscle. Both Rac1 and AMPK have been shown to partly regulate contraction-stimulated muscle glucose uptake, but whether those two signaling pathways jointly account for the entire signal to glucose transport is unknown. We therefore studied the ability of contraction and exercise to stimulate glucose transport in isolated muscles with AMPK loss of function combined with either pharmacological inhibition or genetic deletion of Rac1.
Muscle-speci...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Sylow, L.; Moller, L. L. V.; Kleinert, M.; DHulst, G.; De Groote, E.; Schjerling, P.; Steinberg, G. R.; Jensen, T. E.; Richter, E. A. Tags: Metabolism Source Type: research
Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ER{alpha}/HGF/Met Pathway
We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatocyte growth factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 (Esr1 [encoding ERα]) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of ...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Zhang, Y.-Y.; Li, C.; Yao, G.-F.; Du, L.-J.; Liu, Y.; Zheng, X.-J.; Yan, S.; Sun, J.-Y.; Liu, Y.; Liu, M.-Z.; Zhang, X.; Wei, G.; Tong, W.; Chen, X.; Wu, Y.; Sun, S.; Liu, S.; Ding, Q.; Yu, Y.; Yin, H.; Duan, S.-Z. Tags: Metabolism Source Type: research
Palmitate-Induced Vacuolar-Type H+-ATPase Inhibition Feeds Forward Into Insulin Resistance and Contractile Dysfunction
In conclusion, lipid oversupply increases CD36-mediated lipid uptake that directly impairs v-ATPase function. This feeds forward to enhanced CD36 translocation and further increased lipid uptake. In the case of palmitate, its accelerated uptake ultimately precipitates into cardiac insulin resistance and contractile dysfunction. (Source: Diabetes)
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Liu, Y.; Steinbusch, L. K. M.; Nabben, M.; Kapsokalyvas, D.; van Zandvoort, M.; Schönleitner, P.; Antoons, G.; Simons, P. J.; Coumans, W. A.; Geomini, A.; Chanda, D.; Glatz, J. F. C.; Neumann, D.; Luiken, J. J. F. P. Tags: Metabolism Source Type: research
Endothelial HIF-1{alpha} Enables Hypothalamic Glucose Uptake to Drive POMC Neurons
Glucose is the primary driver of hypothalamic proopiomelanocortin (POMC) neurons. We show that endothelial hypoxia-inducible factor 1α (HIF-1α) controls glucose uptake in the hypothalamus and that it is upregulated in conditions of undernourishment, during which POMC neuronal activity is decreased. Endothelium-specific knockdown of HIF-1α impairs the ability of POMC neurons to adapt to the changing metabolic environment in vivo, resulting in overeating after food deprivation in mice. The impaired functioning of POMC neurons was reversed ex vivo or by parenchymal glucose administration. These observations ...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Varela, L.; Suyama, S.; Huang, Y.; Shanabrough, M.; Tschöp, M. H.; Gao, X.-B.; Giordano, F. J.; Horvath, T. L. Tags: Metabolism Source Type: research
Exercise Increases Human Skeletal Muscle Insulin Sensitivity via Coordinated Increases in Microvascular Perfusion and Molecular Signaling
Insulin resistance is a major health risk, and although exercise clearly improves skeletal muscle insulin sensitivity, the mechanisms are unclear. Here we show that initiation of a euglycemic-hyperinsulinemic clamp 4 h after single-legged exercise in humans increased microvascular perfusion (determined by contrast-enhanced ultrasound) by 65% in the exercised leg and 25% in the rested leg (P < 0.05) and that leg glucose uptake increased 50% more (P < 0.05) in the exercised leg than in the rested leg. Importantly, infusion of the nitric oxide synthase inhibitor l-NG-monomethyl-l-arginine acetate (l-NMMA) into both femo...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Sjoberg, K. A.; Frosig, C.; Kjobsted, R.; Sylow, L.; Kleinert, M.; Betik, A. C.; Shaw, C. S.; Kiens, B.; Wojtaszewski, J. F. P.; Rattigan, S.; Richter, E. A.; McConell, G. K. Tags: Metabolism Source Type: research
GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake or Hypertrophic Growth in Mouse Skeletal Muscle
GLUT4 is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine whether GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [3H]-2-deoxy-d-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes. To assess w...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: McMillin, S. L.; Schmidt, D. L.; Kahn, B. B.; Witczak, C. A. Tags: Metabolism Source Type: research
VEGF-A-Expressing Adipose Tissue Shows Rapid Beiging and Enhanced Survival After Transplantation and Confers IL-4-Independent Metabolic Improvements
Adipocyte-derived vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and contributes to adipocyte function and systemic metabolism, such as insulin resistance, chronic inflammation, and beiging of subcutaneous adipose tissue. Using a doxycycline-inducible adipocyte-specific VEGF-A–overexpressing mouse model, we investigated the dynamics of local VEGF-A effects on tissue beiging of adipose tissue transplants. VEGF-A overexpression in adipocytes triggers angiogenesis. We also observed a rapid appearance of beige fat cells in subcutaneous white adipose tissue as early as 2 days postinduct...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Park, J.; Kim, M.; Sun, K.; An, Y. A.; Gu, X.; Scherer, P. E. Tags: Metabolism Source Type: research
Functional Human Beige Adipocytes From Induced Pluripotent Stem Cells
We report a straightforward and efficient protocol to generate functional human beige adipocytes from human induced pluripotent stem cells (hiPSCs). Without overexpression of exogenous adipogenic genes, our method recapitulates an adipogenic developmental pathway through successive mesodermal and adipogenic progenitor stages. hiPSC-derived adipocytes are insulin sensitive and display beige-specific markers and functional properties, including upregulation of thermogenic genes, increased mitochondrial content, and increased oxygen consumption upon activation with cAMP analogs. Engraftment of hiPSC-derived adipocytes in mice...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Guenantin, A.-C.; Briand, N.; Capel, E.; Dumont, F.; Morichon, R.; Provost, C.; Stillitano, F.; Jeziorowska, D.; Siffroi, J.-P.; Hajjar, R. J.; Feve, B.; Hulot, J.-S.; Collas, P.; Capeau, J.; Vigouroux, C. Tags: Technological Advances Source Type: research
Checks and Balances--The Limits of {beta}-Cell Endurance to ER Stress
(Source: Diabetes)
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Eizirik, D. L.; Coomans de Brachene, A. Tags: Commentaries Source Type: research
The COX-2/PGE2/EP3/Gi/o/cAMP/GSIS Pathway in the Islet: The Beat Goes On
(Source: Diabetes)
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Robertson, R. P. Tags: Commentaries Source Type: research
Diabetes: Leveraging the Tipping Point of the Diabetes Pandemic
(Source: Diabetes)
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Weng, J.-P.; Hu, G. Tags: Commentaries Source Type: research
GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe?
Glucagon-like peptide 1 receptor (GLP-1R) agonists are increasingly being used as treatment for type 2 diabetes. Since the U.S. Food and Drug Administration published recommendations about the cardiovascular safety of new antidiabetes therapies for treating type 2 diabetes in 2008, the results of two outstanding clinical trials using GLP-1R agonists addressing this issue (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation [LEADER] and Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6]) ...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Simo, R.; Hernandez, C. Tags: Perspectives in Diabetes Source Type: research
Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?
Despite decades of research in humans and mouse models of disease, substantial gaps remain in our understanding of pathogenic mechanisms underlying the development of type 1 diabetes. Furthermore, translation of therapies from preclinical efforts capable of delaying or halting β-cell destruction has been limited. Hence, a pressing need exists to identify alternative animal models that reflect human disease. Canine insulin deficiency diabetes is, in some cases, considered to follow autoimmune pathogenesis, similar to NOD mice and humans, characterized by hyperglycemia requiring lifelong exogenous insulin therapy. Also ...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: OKell, A. L.; Wasserfall, C.; Catchpole, B.; Davison, L. J.; Hess, R. S.; Kushner, J. A.; Atkinson, M. A. Tags: Perspectives in Diabetes Source Type: research
Type 2 Diabetes: Demystifying the Global Epidemic
Type 2 diabetes (T2D) has attained the status of a global pandemic, spreading from affluent industrialized nations to the emerging economies of Asia, Latin America, and Africa. There is significant global variation in susceptibility to T2D, with Pacific Islanders, Asian Indians, and Native Americans being considerably more prone to develop the disorder. Although genetic factors may play a part, the rapidity with which diabetes prevalence has risen among these populations reflects the far-ranging and rapid socioeconomic changes to which they have been exposed over the past few decades. Traditionally, obesity and its correla...
Source: Diabetes - May 22, 2017 Category: Endocrinology Authors: Unnikrishnan, R.; Pradeepa, R.; Joshi, S. R.; Mohan, V. Tags: Perspectives in Diabetes Source Type: research
A Special Thanks to the Reviewers of Diabetes
(Source: Diabetes)
Source: Diabetes - May 22, 2017 Category: Endocrinology Tags: Editor ' s Note Source Type: research
