Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver
In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved. (Source: Diabetes)
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Jelenik, T.; Kaul, K.; Sequaris, G.; Flögel, U.; Phielix, E.; Kotzka, J.; Knebel, B.; Fahlbusch, P.; Hörbelt, T.; Lehr, S.; Reinbeck, A. L.; Müller-Wieland, D.; Esposito, I.; Shulman, G. I.; Szendroedi, J.; Roden, M. Tags: Integrated Physiology-Liver Pathophysiology Source Type: research
Glucagon-Like Peptide 1 Receptor Activation Augments Cardiac Output and Improves Cardiac Efficiency in Obese Swine After Myocardial Infarction
This study tested the hypothesis that glucagon-like peptide 1 (GLP-1) therapies improve cardiac contractile function at rest and in response to adrenergic stimulation in obese swine after myocardial infarction. Obese Ossabaw swine were subjected to gradually developing regional coronary occlusion using an ameroid occluder placed around the left anterior descending coronary artery. Animals received subcutaneous injections of saline or liraglutide (0.005–0.015 mg/kg/day) for 30 days after ameroid placement. Cardiac performance was assessed at rest and in response to sympathomimetic challenge (dobutamine 0.3–10 &m...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Sassoon, D. J.; Tune, J. D.; Mather, K. J.; Noblet, J. N.; Eagleson, M. A.; Conteh, A. M.; Sturek, J. T.; Goodwill, A. G. Tags: Obesity-Animal Pathophysiology Source Type: research
In Vivo Enrichment of Diabetogenic T Cells
We describe a method to enrich and harvest autoimmune T cells in vivo by using a biomaterial scaffold loaded with protein antigens. In model antigen systems, we found that antigen-specific T cells become enriched within scaffolds containing their cognate antigens. When scaffolds containing lysates from an insulin-producing β-cell line were implanted subcutaneously in autoimmune diabetes–prone NOD mice, β-cell–reactive T cells homed to these scaffolds and became enriched. These T cells induced diabetes after adoptive transfer, indicating their pathogenicity. Furthermore, T-cell receptor (TCR) sequencin...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Thelin, M. A.; Kissler, S.; Vigneault, F.; Watters, A. L.; White, D.; Koshy, S. T.; Vermillion, S. A.; Mooney, D. J.; Serwold, T.; Ali, O. A. Tags: Immunology Immunology and Transplantation Source Type: research
SOX4 Allows Facultative {beta}-Cell Proliferation Through Repression of Cdkn1a
The high-mobility group box transcription factor SOX4 is the most highly expressed SOX family protein in pancreatic islets, and mutations in Sox4 are associated with an increased risk of developing type 2 diabetes. We used an inducible β-cell knockout mouse model to test the hypothesis that Sox4 is essential for the maintenance of β-cell number during the development of type 2 diabetes. Knockout of Sox4 at 6 weeks of age resulted in time-dependent worsening of glucose tolerance, impairment of insulin secretion, and diabetes by 30 weeks of age. Immunostaining revealed a decrease in β-cell mass in knockout mic...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Xu, E. E.; Sasaki, S.; Speckmann, T.; Nian, C.; Lynn, F. C. Tags: Islet Studies Source Type: research
Neprilysin Is Required for Angiotensin-(1-7)s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2)
In conclusion, in islets, intact angiotensin-(1–7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1–7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1–7) compounds and neprilysin inhibitors as therapies for diabetes. (Source: Diabetes)
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Brar, G. S.; Barrow, B. M.; Watson, M.; Griesbach, R.; Choung, E.; Welch, A.; Ruzsicska, B.; Raleigh, D. P.; Zraika, S. Tags: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism Islet Studies Source Type: research
Temporal Transcriptomic and Proteomic Landscapes of Deteriorating Pancreatic Islets in Type 2 Diabetic Rats
Progressive reduction in β-cell mass and function comprise the core of the pathogenesis mechanism of type 2 diabetes. The process of deteriorating pancreatic islets, in which a complex network of molecular events is involved, is not yet fully characterized. We used RNA sequencing and tandem mass tag–based quantitative proteomics technology to measure the temporal mRNA and protein expression changes of pancreatic islets in Goto-Kakizaki (GK) rats from 4 to 24 weeks of age. Our omics data set outlines the dynamics of the molecular network during the deterioration of GK islets as two stages: The early stage (4&ndas...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Hou, J.; Li, Z.; Zhong, W.; Hao, Q.; Lei, L.; Wang, L.; Zhao, D.; Xu, P.; Zhou, Y.; Wang, Y.; Xu, T. Tags: Genetics-Type 2 Diabetes Islet Studies Source Type: research
Chronic {beta}-Cell Depolarization Impairs {beta}-Cell Identity by Disrupting a Network of Ca2+-Regulated Genes
We used mice lacking Abcc8, a key component of the β-cell KATP-channel, to analyze the effects of a sustained elevation in the intracellular Ca2+ concentration ([Ca2+]i) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking Abcc8 into pancreatic polypeptide cells but not to α- or -cells. RNA-sequencing analysis of FACS-purified Abcc8–/– β-cells confirmed an increase in Ppy gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca2+ signaling, the maintenance of β-cell identity, a...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Stancill, J. S.; Cartailler, J.-P.; Clayton, H. W.; OConnor, J. T.; Dickerson, M. T.; Dadi, P. K.; Osipovich, A. B.; Jacobson, D. A.; Magnuson, M. A. Tags: Islet Biology-Signal Transduction Islet Studies Source Type: research
Radiomanganese PET Detects Changes in Functional {beta}-Cell Mass in Mouse Models of Diabetes
The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes as well as the viability of transplanted insulin-producing cells. Although previous work using MRI has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)–mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of the Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Hernandez, R.; Graves, S. A.; Gregg, T.; VanDeusen, H. R.; Fenske, R. J.; Wienkes, H. N.; England, C. G.; Valdovinos, H. F.; Jeffery, J. J.; Barnhart, T. E.; Severin, G. W.; Nickles, R. J.; Kimple, M. E.; Merrins, M. J.; Cai, W. Tags: Islet Studies Source Type: research
Overexpression of Kinase-Dead mTOR Impairs Glucose Homeostasis by Regulating Insulin Secretion and Not {beta}-Cell Mass
We examined glucose homeostasis and β-cell function of these mice fed a control chow or high-fat diet. Mice with two copies of the transgene [RIPCre;KD-mTOR (Homozygous)] develop glucose intolerance due to a defect in β-cell function without alterations in β-cell mass with control chow. Islets from RIPCre;KD-mTOR (Homozygous) mice showed reduced mTORC1 and mTORC2 signaling along with transcripts and protein levels of Pdx-1. Islets with reduced mTORC2 signaling in their β-cells (RIPCre;Rictorfl/fl) also showed reduced Pdx-1. When challenged with a high-fat diet, mice carrying one copy of KD-mTOR mutant t...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Alejandro, E. U.; Bozadjieva, N.; Blandino-Rosano, M.; Wasan, M. A.; Elghazi, L.; Vadrevu, S.; Satin, L.; Bernal-Mizrachi, E. Tags: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism Islet Studies Source Type: research
Mechanisms Controlling Glucose-Induced GLP-1 Secretion in Human Small Intestine
In this study, we showed that a 30-min intraduodenal glucose infusion activated half of all duodenal L cells in humans. This infusion was sufficient to increase plasma GLP-1 levels. With an ex vivo model using human gut tissue specimens, we showed a dose-responsive GLP-1 secretion in the ileum at ≥200 mmol/L glucose. In ex vivo tissue from the duodenum and ileum, but not the colon, 300 mmol/L glucose potently stimulated GLP-1 release. In the ileum, this response was independent of osmotic influences and required delivery of glucose via GLUT2 and mitochondrial metabolism. The requirement of voltage-gated Na+ and Ca2+ cha...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Sun, E. W.; de Fontgalland, D.; Rabbitt, P.; Hollington, P.; Sposato, L.; Due, S. L.; Wattchow, D. A.; Rayner, C. K.; Deane, A. M.; Young, R. L.; Keating, D. J. Tags: Integrated Physiology-Other Hormones Signal Transduction Source Type: research
Cationic Polystyrene Resolves Nonalcoholic Steatohepatitis, Obesity, and Metabolic Disorders by Promoting Eubiosis of Gut Microbiota and Decreasing Endotoxemia
In this report, we demonstrate that metabolic disorders in mice generated by feeding with a high-fat diet without dietary vitamin D can be prevented by oral administration of polycationic amine resin. Oral administration of cholestyramine, but not the control uncharged polystyrene, was able to sequester negatively charged bacterial endotoxin in the gut, leading to 1) reduced plasma endotoxin levels, 2) resolved systemic inflammation and hepatic steatohepatitis, and 3) improved insulin sensitivity. Gut dysbiosis, characterized as an increase of the phylum Firmicutes and a decrease of Bacteroidetes and Akkermansia muciniphil...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Zhu, A.; Chen, J.; Wu, P.; Luo, M.; Zeng, Y.; Liu, Y.; Zheng, H.; Zhang, L.; Chen, Z.; Sun, Q.; Li, W.; Duan, Y.; Su, D.; Xiao, Z.; Duan, Z.; Zheng, S.; Bai, L.; Zhang, X.; Ju, Z.; Li, Y.; Hu, R.; Pandol, S. J.; Han, Y.-P. Tags: Metabolism Source Type: research
Maternal Exercise Improves Glucose Tolerance in Female Offspring
In conclusion, maternal exercise negates the detrimental effects of a maternal high-fat diet on glucose tolerance and hepatocyte glucose metabolism in female offspring. The ability of maternal exercise to improve the metabolic health of female offspring is important, as this intervention could combat the transmission of obesity and diabetes to subsequent generations. (Source: Diabetes)
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Stanford, K. I.; Takahashi, H.; So, K.; Alves-Wagner, A. B.; Prince, N. B.; Lehnig, A. C.; Getchell, K. M.; Lee, M.-Y.; Hirshman, M. F.; Goodyear, L. J. Tags: Obesity-Animal Metabolism Source Type: research
Acyl-CoA Thioesterase 1 (ACOT1) Regulates PPAR{alpha} to Couple Fatty Acid Flux With Oxidative Capacity During Fasting
Hepatic acyl-CoA thioesterase 1 (ACOT1) catalyzes the conversion of acyl-CoAs to fatty acids (FAs) and CoA. We sought to determine the role of ACOT1 in hepatic lipid metabolism in C57Bl/6J male mice 1 week after adenovirus-mediated Acot1 knockdown. Acot1 knockdown reduced liver triglyceride (TG) as a result of enhanced TG hydrolysis and subsequent FA oxidation. In vitro experiments demonstrated that Acot1 knockdown led to greater TG turnover and FA oxidation, suggesting that ACOT1 is important for controlling the rate of FA oxidation. Despite increased FA oxidation, Acot1 knockdown reduced the expression of peroxisome prol...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Franklin, M. P.; Sathyanarayan, A.; Mashek, D. G. Tags: Metabolism Source Type: research
Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity
The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKIVMH) or downregulate (Lin28aKDVMH) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not ...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Kim, J. D.; Toda, C.; Ramirez, C. M.; Fernandez-Hernando, C.; Diano, S. Tags: Integrated Physiology-Central Nervous System Regulation of Metabolism Source Type: research
Pair Feeding, but Not Insulin, Phloridzin, or Rosiglitazone Treatment, Curtails Markers of {beta}-Cell Dedifferentiation in db/db Mice
In this study, we asked whether β-cell dedifferentiation can be prevented with diet or pharmacological treatment of diabetes. db/db mice, a widely used model of insulin-resistant diabetes and obesity, were either pair fed or treated with the Sglt inhibitor phloridzin, the insulin-sensitizer rosiglitazone, or insulin. All treatments were equally efficacious in reducing plasma glucose levels. Pair feeding and phloridzin also resulted in significant weight loss. However, pair feeding among the four treatments resulted in a reduction of β-cell dedifferentiation, as assessed by Foxo1 and Aldh1a3 immunohistochemistry. ...
Source: Diabetes - July 21, 2017 Category: Endocrinology Authors: Ishida, E.; Kim-Muller, J. Y.; Accili, D. Tags: Metabolism Source Type: research
