Currently, the most effective strategy for dealing with Alzheimer’s disease (AD) is delaying the onset of dementia. Severe hypoglycemia is strongly associated with dementia; however, the effects of recurrent moderate hypoglycemia (RH) on progression of cognitive deficits in diabetic patients with genetic susceptibility to AD remain unclear. Here, we report that insulin-controlled hyperglycemia only slightly aggravated AD-type pathologies and cognitive impairment; however, RH significantly increased neuronal hyperactivity and accelerated the progression of cognitive deficits in streptozotocin(STZ)-induced diabetic APP/PS1 mice. GLUT3-mediated neuronal glucose uptake was not significantly altered under hyperglycemia, but was markedly reduced by RH, which induced excessive mitochondrial fission in the hippocampus. Overexpression of GLUT3 specifically in DG area of hippocampus enhanced mitochondrial function and improved cognitive deficits induced by RH. Activation of TRPC6 increased GLUT3-mediated glucose uptake in brain and alleviated RH-induced cognitive deficits, and inactivation of Ca2+/AMPK pathway was responsible for TRPC6-induced GLUT3 inhibition. Taken together, RH impairs brain GLUT3-mediated glucose uptake and further provokes neuronal mitochondrial dysfunction by inhibiting TRPC6 expression, which then accelerates the progression of cognitive deficits in diabetic APP/PS1 mice. Avoiding RH is essential for glycemic control in diabetic patients, and TRPC6/GLUT3 represent potent targets for delaying the onset of dementia in diabetic patients.
Chengkang He, Qiang Li, Yuanting Cui, Peng Gao, WenTao Shu, Qing Zhou, Lijuan Wang, Li Li, Zongshi Lu, Yu Zhao, Huan Ma, Xiaowei Chen, Hongbo Jia, Hongting Zheng, Gangyi Yang, Daoyan Liu, Martin Tepel, Zhiming Zhu
Type 1 diabetes is an autoimmune disease characterized by insulin-producing beta-cell destruction. While islet transplantation restores euglycemia and improves patient outcomes, an ideal transplant site remains elusive. Brown adipose tissue (BAT) is a highly vascularized and anti-inflammatory microenvironment. As these tissue features can promote islet graft survival, we hypothesize that islets transplanted into BAT will maintain islet graft and BAT function, while delaying immune-mediated rejection. We performed syngeneic and allogeneic islet transplants into BAT or under the kidney capsule of streptozotocin (STZ)-induced diabetic NOD.Rag and NOD mice to investigate islet graft function, BAT function, metabolism, and immune-mediated rejection. Islet grafts within BAT restored euglycemia similarly to kidney capsule controls. Islets transplanted in BAT maintained expression of islet hormones, transcription factors, and were vascularized. Compared to kidney capsule and euglycemic mock surgery controls, no differences in glucose or insulin tolerance, thermogenic regulation, or energy expenditure were observed with islet grafts in BAT. Immune profiling of BAT revealed enriched anti-inflammatory macrophages and T cells. Compared to kidney capsule, islets transplanted in BAT demonstrated significant delays in autoimmune and allograft rejection, possibly due to increased anti-inflammatory immune populations. Our data support BAT as an alternative islet transplantation site that may improve graft survival.
Jessica D. Kepple, Jessie M. Barra, Martin E. Young, Chad S. Hunter, Hubert M. Tse
While current thinking posits that insulin signaling to GLUT4 exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle causes a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e. 1 h) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulates this phenotype in human and rodent myotubes, 3T3-L1 adipocytes, and mouse muscle. Mechanistically, these effects are due to p300/CBP-mediated regulation of GLUT4 exocytic translocation and occurs downstream of Akt signaling. Taken together, we highlight a fundamental role for acetylation and p300/CBP in the direct regulation of insulin-stimulated glucose transport in skeletal muscle and adipocytes.
Vitor F. Martins, Samuel A. LaBarge, Alexandra Stanley, Kristoffer Svensson, Chao-Wei Hung, Omer Keinan, Theodore P. Ciaraldi, Dion Banoian, Ji E. Park, Christina Ha, Byron Hetrick, Gretchen A. Meyer, Andrew Philp, Larry L. David, Robert R. Henry, Joseph E. Aslan, Alan R. Saltiel, Carrie E. McCurdy, Simon Schenk
Background IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.Methods We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years).Results There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.Conclusion Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial Registration ClinicalTrials.gov NCT02293837.Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.
Carla J. Greenbaum, Elisavet Serti, Katharina Lambert, Lia J. Weiner, Sai Kanaparthi, Sandra Lord, Stephen E. Gitelman, Darrell M. Wilson, Jason L. Gaglia, Kurt J. Griffin, William E. Russell, Philip Raskin, Antoinette Moran, Steven M. Willi, Eva Tsalikian, Linda A. DiMeglio, Kevan C. Herold, Wayne V. Moore, Robin Goland, Mark Harris, Maria E. Craig, Desmond A. Schatz, David A. Baidal, Henry Rodriguez, Kristina M. Utzschneider, Hendrik J. Nel, Carol L. Soppe, Karen D. Boyle, Karen Cerosaletti, Lynette Keyes-Elstein, S. Alice Long, Ranjeny Thomas, James G. McNamara, Jane H. Buckner, Srinath Sanda, for the ITN058AI EXTEND Study Team
During pregnancy, fetal glucose production is suppressed, with rapid activation immediately postpartum. Fatty acid–binding protein 4 (FABP4) was recently demonstrated as a regulator of hepatic glucose production and systemic metabolism in animal models. Here, we studied the role of FABP4 in regulating neonatal glucose hemostasis. Serum samples were collected from pregnant women with normoglycemia or gestational diabetes at term, from the umbilical circulation, and from the newborns within 6 hours of life. The level of FABP4 was higher in the fetal versus maternal circulation, with a further rise in neonates after birth of approximately 3-fold. Neonatal FABP4 inversely correlated with blood glucose, with an approximately 10-fold increase of FABP4 in hypoglycemic neonates. When studied in mice, blood glucose of 12-hour-old WT, Fabp4–/+, and Fabp4–/– littermate mice was 59 ± 13 mg/dL, 50 ± 11 mg/dL, and 43 ± 11 mg/dL, respectively. Similar to our observations in humans, FABP4 levels in WT mouse neonates were approximately 8-fold higher compared with those in adult mice. RNA sequencing of the neonatal liver suggested altered expression of multiple glucagon-regulated pathways in Fabp4–/– mice. Indeed, Fabp4–/– liver glycogen was inappropriately intact, despite a marked hypoglycemia, with rapid restoration of normoglycemia upon injection of recombinant FABP4. Our data suggest an important biological role for the adipokine FABP4 in the orchestrated regulation of postnatal glucose metabolism.
Idit Ron, Reut Kassif Lerner, Moran Rathaus, Rinat Livne, Sophie Ron, Ehud Barhod, Rina Hemi, Amit Tirosh, Tzipora Strauss, Keren Ofir, Ido Goldstein, Itai M. Pessach, Amir Tirosh
Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid–induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).
Jae-Su Moon, Flavia Franco da Cunha, Jin Young Huh, Alexander Yu Andreyev, Jihyung Lee, Sushil K. Mahata, Felipe C.G. Reis, Chanond A. Nasamran, Yun Sok Lee
Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used to treat diabetes and obesity and reduce rates of major cardiovascular events such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R-expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of the Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood and gut. Glp1r expression in bone marrow cells was very low, and not further reduced in Glp1rTie2-/- mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2-/- mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2-/- mice and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression, triglyceride content and collagen accumulation in high fat high cholesterol (HFHC) diet-fed Glp1rTie2+/+ but not Glp1rTie2-/- mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the anti-atherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the anti-inflammatory actions of semaglutide in the liver.
Brent McLean, Chi Kin Wong, Kiran Deep Kaur, Randy J. Seeley, Daniel J. Drucker
Hypothesis Obesity is one of the main drivers of type 2 diabetes (T2D), but not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown features of body fat distribution which could additionally contribute to the disease. Methods We used machine learning with dense convolutional neural networks (DCNN) to detect diabetes related variables from 2,371 T1-weighted whole-body magnetic resonance imaging (MRI) datasets. MRI was performed in participants undergoing metabolic screening with oral glucose tolerance tests. Models were trained for sex, age, BMI, insulin sensitivity, HbA1c and prediabetes or incident diabetes. The results were compared to conventional models. Results The Area Under the Receiver Operator Characteristic curve was 87% for the T2D discrimination and 68% for prediabetes, both superior to conventional models. Mean absolute regression errors were comparable to conventional models. Heatmaps showed that lower visceral abdominal regions were critical in diabetes classification. Subphenotyping revealed a group with high future diabetes and microalbuminuria risk. Interpretation Our results show that diabetes is detectable from whole-body MRI without additional data. Our technique of heatmap visualization unravels plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in diabetes pathogenesis.
Benedikt Dietz, Jürgen Machann, Vaibhav Agrawal, Martin Heni, Patrick Schwab, Julia Dienes, Steffen Reichert, Andreas L. Birkenfeld, Hans-Ulrich Häring, Fritz Schick, Norbert Stefan, Andreas Fritsche, Hubert Preissl, Bernhard Schölkopf, Stefan Bauer, Robert Wagner
ER stress and activation of the unfolded protein response in the periphery as well as the central nervous system have been linked to various metabolic abnormalities. Chemically lowering protein kinase R–like ER kinase (PERK) activity within the hypothalamus leads to decreased food intake and body weight. However, the cell populations required in this response remain undefined. In the current study, we investigated the effects of proopiomelanocortin-specific (POMC-specific) PERK deficiency on energy balance and glucose metabolism. Male mice deficient for PERK in POMC neurons exhibited improvements in energy balance on a high-fat diet, showing decreased food intake and body weight, independent of changes in glucose and insulin tolerances. The plant-based inhibitor of PERK, celastrol, increases leptin sensitivity, resulting in decreased food intake and body weight in a murine model of diet-induced obesity (DIO). Our data extend these observations by demonstrating that celastrol-induced improvements in leptin sensitivity and energy balance were attenuated in mice with PERK deficiency in POMC neurons. Altogether, these data suggest that POMC-specific PERK deficiency in male mice confers protection against DIO, possibly providing a new therapeutic target for the treatment of diabetes and metabolic syndrome.
Zhenyan He, Linh Lieu, Yanbin Dong, Sadia Afrin, Dominic Chau, Anita Kabahizi, Briana Wallace, Jianhong Cao, Eun-Sang Hwang, Ting Yao, Yiru Huang, Jennifer Okolo, Bo Cheng, Yong Gao, Ling Hu, Kevin W. Williams
BACKGROUND. Genetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate, androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor (ER)-positive breast cancer. METHODS. A prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer. RESULTS. Prospective and validation studies had 157 and 538 subjects, respectively, for the primary analysis of genotype frequency by estrogen receptor status in White female breast cancer patients postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (p = 0.108) and 9.6% (429/4451) in the general population (p = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and TCGA datasets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (p = 0.007) and the general population (p = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (p = 0.03). CONCLUSION. Adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer. FUNDING. NCI
Megan L. Kruse, Mona Patel, Jeffrey McManus, Yoon-Mi Chung, Xiuxiu Li, Wei Wei, Peter S. Bazeley, Fumihiko Nakamura, Aimalie Hardaway, Erinn Downs, Sarat Chandarlapaty, Mathew Thomas, Halle C.F. Moore, George T. Budd, W.H. Wilson Tang, Stanley L. Hazen, Aaron Bernstein, Serena Nik-Zainal, Jame Abraham, Nima Sharifi
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