[11C]5-hydroxy-tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes
[11C]5-hydroxy-tryptophan ([11C]5-HTP) positron emission tomography of the pancreas has been shown to be a surrogate imaging biomarker of pancreatic islet mass. The change in islet mass in different stages of type 2 diabetes (T2D) as measured by noninvasive imaging is currently unknown. Here, we describe a cross-sectional study where subjects at different stages of T2D development with expected stratification of pancreatic islet mass were examined in relation to individuals without diabetes. The primary outcome was the [11C]5-HTP uptake and retention in pancreas, as a surrogate marker for the endogenous islet mass. We foun...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Carlbom, L.; Espes, D.; Lubberink, M.; Martinell, M.; Johansson, L.; Ahlström, H.; Carlsson, P.-O.; Korsgren, O.; Eriksson, O. Tags: Islet Studies Source Type: research
Glucagon-Like Peptide 1 Protects Pancreatic {beta}-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function
In this study, we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5 mmol/L palmitate and 25 mmol/L glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilization and release of cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Cotreatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunc...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Zummo, F. P.; Cullen, K. S.; Honkanen-Scott, M.; Shaw, J. A. M.; Lovat, P. E.; Arden, C. Tags: Islet Studies Source Type: research
Identification and Functional Implications of Sodium/Myo-Inositol Cotransporter 1 in Pancreatic {beta}-Cells and Type 2 Diabetes
Myo-inositol (MI), the precursor of the second messenger phosphoinositide (PI), mediates multiple cellular events. Rat islets exhibit active transport of MI, although the mechanism involved remains elusive. Here, we report, for the first time, the expression of sodium/myo-inositol cotransporter 1 (SMIT1) in rat islets and, specifically, β-cells. Genetic or pharmacological inhibition of SMIT1 impaired glucose-stimulated insulin secretion by INS-1E cells, probably via downregulation of PI signaling. In addition, SMIT1 expression in INS-1E cells and isolated islets was augmented by acute high-glucose exposure and reduced...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Li, S. Y. T.; Cheng, S. T. W.; Zhang, D.; Leung, P. S. Tags: Islet Studies Source Type: research
Direct Substrate Delivery Into Mitochondrial Fission-Deficient Pancreatic Islets Rescues Insulin Secretion
In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control ...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Kabra, U. D.; Pfuhlmann, K.; Migliorini, A.; Keipert, S.; Lamp, D.; Korsgren, O.; Gegg, M.; Woods, S. C.; Pfluger, P. T.; Lickert, H.; Affourtit, C.; Tschöp, M. H.; Jastroch, M. Tags: Islet Studies Source Type: research
Mast Cells Promote Seasonal White Adipose Beiging in Humans
Human subcutaneous (SC) white adipose tissue (WAT) increases the expression of beige adipocyte genes in the winter. Studies in rodents suggest that a number of immune mediators are important in the beiging response. We studied the seasonal beiging response in SC WAT from lean humans. We measured the gene expression of various immune cell markers and performed multivariate analysis of the gene expression data to identify genes that predict UCP1. Interleukin (IL)-4 and, unexpectedly, the mast cell marker CPA3 predicted UCP1 gene expression. Therefore, we investigated the effects of mast cells on UCP1 induction by adipocytes....
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Finlin, B. S.; Zhu, B.; Confides, A. L.; Westgate, P. M.; Harfmann, B. D.; Dupont-Versteegden, E. E.; Kern, P. A. Tags: Obesity Studies Source Type: research
Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice
Low-grade sustained inflammation links obesity to insulin resistance and nonalcoholic fatty liver disease (NAFLD). However, therapeutic approaches to improve systemic energy balance and chronic inflammation in obesity are limited. Pharmacological activation of nuclear factor (erythroid-derived 2)–like 2 (Nrf2) alleviates obesity and insulin resistance in mice; however, Nrf2 inducers are not clinically available owing to safety concerns. Thus, we examined whether dietary glucoraphanin, a stable precursor of the Nrf2 inducer sulforaphane, ameliorates systemic energy balance, chronic inflammation, insulin resistance, an...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Nagata, N.; Xu, L.; Kohno, S.; Ushida, Y.; Aoki, Y.; Umeda, R.; Fuke, N.; Zhuge, F.; Ni, Y.; Nagashimada, M.; Takahashi, C.; Suganuma, H.; Kaneko, S.; Ota, T. Tags: Obesity Studies Source Type: research
Vascular Effects of Obestatin in Lean and Obese Subjects
Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)–mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)–dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1–dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating ...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Schinzari, F.; Veneziani, A.; Mores, N.; Barini, A.; Di Daniele, N.; Cardillo, C.; Tesauro, M. Tags: Obesity Studies Source Type: research
Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway
Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice from high-fat diet–induced obesity and insulin resistance. On the one hand, Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beiging and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and uncoupling...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Meng, W.; Liang, X.; Chen, H.; Luo, H.; Bai, J.; Li, G.; Zhang, Q.; Xiao, T.; He, S.; Zhang, Y.; Xu, Z.; Xiao, B.; Liu, M.; Hu, F.; Liu, F. Tags: Obesity Studies Source Type: research
Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice
In conclusion, the FAM3C-HSF1-CaM-Akt pathway plays important roles in regulating glucose and lipid metabolism in hepatocytes independent of insulin and calcium. Restoring hepatic FAM3C expression is beneficial for the management of type 2 diabetes and fatty liver. (Source: Diabetes)
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Chen, Z.; Ding, L.; Yang, W.; Wang, J.; Chen, L.; Chang, Y.; Geng, B.; Cui, Q.; Guan, Y.; Yang, J. Tags: Metabolism Source Type: research
Correcting Postprandial Hyperglycemia in Zucker Diabetic Fatty Rats With an SGLT2 Inhibitor Restores Glucose Effectiveness in the Liver and Reduces Insulin Resistance in Skeletal Muscle
In conclusion, SGLT2-I treatment improves impaired glucose effectiveness in the liver and insulin sensitivity in muscle by eliminating glucotoxicity, which reinstates metabolic flexibility with restored preprandial lipid oxidation and postprandial glucose flux in ZDF rats. (Source: Diabetes)
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: OBrien, T. P.; Jenkins, E. C.; Estes, S. K.; Castaneda, A. V.; Ueta, K.; Farmer, T. D.; Puglisi, A. E.; Swift, L. L.; Printz, R. L.; Shiota, M. Tags: Metabolism Source Type: research
Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet-Induced Obesity and Insulin Resistance by Inhibiting Lipolysis
In this study, we showed that fat-specific Sirt6 knockout (FKO) sensitized mice to high-fat diet–induced obesity, which was attributed to adipocyte hypertrophy rather than adipocyte hyperplasia. The adipocyte hypertrophy in FKO mice likely resulted from compromised lipolytic activity as an outcome of decreased expression of adipose triglyceride lipase (ATGL), a key lipolytic enzyme. The suppression of ATGL in FKO mice was accounted for by the increased phosphorylation and acetylation of FoxO1, which compromises the transcriptional activity of this positive regulator of ATGL. Fat-specific Sirt6 KO also increased infla...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Kuang, J.; Zhang, Y.; Liu, Q.; Shen, J.; Pu, S.; Cheng, S.; Chen, L.; Li, H.; Wu, T.; Li, R.; Li, Y.; Zou, M.; Zhang, Z.; Jiang, W.; Xu, G.; Qu, A.; Xie, W.; He, J. Tags: Metabolism Source Type: research
ATF4/ATG5 Signaling in Hypothalamic Proopiomelanocortin Neurons Regulates Fat Mass via Affecting Energy Expenditure
In this study, we showed that hypothalamic proopiomelanocortin (POMC) neuron–specific ATF4 knockout (PAKO) mice are lean and have higher energy expenditure. Furthermore, PAKO mice were resistant to high-fat diet–induced obesity, glucose intolerance, and leptin resistance. Moreover, the expression of autophagy protein 5 (ATG5) was increased or decreased by ATF4 knockdown or overexpression, respectively, and ATF4 inhibited the transcription of ATG5 by binding to the basic zipper-containing protein sites on its promoter. Importantly, mice with double knockout of ATF4 and ATG5 in POMC neurons gained more fat mass a...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Xiao, Y.; Deng, Y.; Yuan, F.; Xia, T.; Liu, H.; Li, Z.; Liu, Z.; Ying, H.; Liu, Y.; Zhai, Q.; Chen, S.; Guo, F. Tags: Metabolism Source Type: research
Priming Effect of a Morning Meal on Hepatic Glucose Disposition Later in the Day
We used hepatic balance and tracer ([3H]glucose) techniques to examine the impact of "breakfast" on hepatic glucose metabolism later in the same day. From 0–240 min, 2 groups of conscious dogs (n = 9 dogs/group) received a duodenal infusion of glucose (GLC) or saline (SAL), then were fasted from 240–360 min. Three dogs from each group were euthanized and tissue collected at 360 min. From 360–600 min, the remaining dogs underwent a hyperinsulinemic (4x basal) hyperglycemic clamp (arterial blood glucose 146 ± 2 mg/dL) with portal GLC infusion. The total GLC infusion rate was 14% greater in dogs infus...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Moore, M. C.; Smith, M. S.; Farmer, B.; Kraft, G.; Shiota, M.; Williams, P. E.; Cherrington, A. D. Tags: Metabolism Source Type: research
Adiponectin Deficiency Impairs Maternal Metabolic Adaptation to Pregnancy in Mice
Hypoadiponectinemia has been widely observed in patients with gestational diabetes mellitus (GDM). To investigate the causal role of hypoadiponectinemia in GDM, adiponectin gene knockout (Adipoq–/–) and wild-type (WT) mice were crossed to produce pregnant mouse models with or without adiponectin deficiency. Adenoviral vector–mediated in vivo transduction was used to reconstitute adiponectin during late pregnancy. Results showed that Adipoq–/– dams developed glucose intolerance and hyperlipidemia in late pregnancy. Increased fetal body weight was detected in Adipoq–/– dams. Adiponec...
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Qiao, L.; Wattez, J.-S.; Lee, S.; Nguyen, A.; Schaack, J.; Hay, W. W.; Shao, J. Tags: Metabolism Source Type: research
Postprandial Suppression of Glucagon Secretion: A Puzzlement
(Source: Diabetes)
Source: Diabetes - April 20, 2017 Category: Endocrinology Authors: Geary, N. Tags: Commentaries Source Type: research
