Endocrinology
Abstract
Background: Metabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T-allele at rs7903146 in TCF7L2, previously associated with β–cell dysfunction, would be associated with changes in these insulin pulse characteristics. Methods: 29 nondiabetic subjects (age = 46 ± 2, BMI = 28 ± 1 Kg/M2) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T allele. Deconvolution of peripheral C-peptide concentrations allowed the reconstruction of portal insulin secretion over time. This data was used for subsequent analyses. Pulse orderliness was assessed by Approximate Entropy (ApEn) and the dispersion of insulin pulses was measured by a Frequency Dispersion Index (FDI) applied to a Fourier Transform of individual insulin secretion rates. Results: During fasting conditions, the CC genotype group exhibited decreased pulse disorderliness compared to the TT genotype group (1.10 ± 0.03 vs. 1.19 ± 0.04, p = 0.03). FDI decreased in response to hyperglycemia in the CC genotype group, perhaps reflecting less entrainment of insulin secretion during fasting.Conclusion: Diabetes-associated variation in TCF7L2 is associated with decreased orderliness and pulse dispersion unchanged by hyperglycemia. Quantification of ApEn and FDI could represent novel markers of β-cell health.
Authors
Marcello C. Laurenti, Chiara Dalla Man, Ron T. Varghese, James C. Andrews, Robert A. Rizza, Aleksey Matveyenko, Giuseppe De Nicolao, Claudio Cobelli, Adrian Vella
Abstract
Leptin receptor (LepRb)-expressing neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and which produce the food intake-suppressing PPG cleavage product, glucagon-like peptide-1 (GLP1)) represent a subpopulation of mouse LepRbNTS cells. Using Leprcre, Ppgcre, and Ppgflox mouse lines, along with designer receptors exclusively activated by designer drugs (DREADDs), we examined roles for Ppg in GLP1NTS and LepRbNTS cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppgflox early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1NTS cells decreased food intake, LepRbNTS cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppgflox blunted the ability of GLP1NTS neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRbNTS cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1NTS cells, additional pathways engaged by LepRbNTS cells dominate for the suppression of food intake.
Authors
Wenwen Cheng, Ermelinda Ndoka, Chelsea R. Hutch, Karen Roelofs, Andrew Mackinnon, Basma Khoury, Irwin J. Magrisso, Ki-Suk Kim, Christopher J. Rhodes, David P. Olson, Randy J. Seeley, Darleen A. Sandoval, Martin G. Myers Jr.
Abstract
SGLT2 inhibitors are beneficial in halting diabetic kidney disease; complete mechanisms is unknown. The epithelial to mesenchymal transition (EMT) is associated with Sirt3 suppression and aberrant glycolysis. Here, we hypothesized that the SGLT2 inhibitor restores normal kidney histology/function associated with the inhibition of aberrant glycolysis in diabetic kidneys. CD-1 mice with streptozotocin-induced diabetes displayed kidney fibrosis associated with the EMT at 4-months after diabetes induction. Empagliflozin intervention for one month restored all changes; adjustment of blood glucose by insulin did not. Empagliflozin normalized suppressed Sirt3 levels and aberrant glycolysis (characterized by hypoxia-inducible factor-1α accumulation, hexokinase 2 induction and pyruvate kinase isozyme M2 dimer formation) in diabetic kidneys. Empagliflozin also suppressed the accumulation of glycolysis byproducts in diabetic kidneys. Another SGLT2 inhibitor, canagliflozin, demonstrated similar in vivo effects. High-glucose media induced the EMT, which was associated with Sirt3 suppression and aberrant glycolysis induction, in the HK2 proximal tubule cell line; SGLT2 knockdown suppressed the EMT with restoration of all aberrant functions. SGLT2 suppression in tubular cells also inhibited the mesenchymal transition of neighboring endothelial cells. Taken together, SGLT2 inhibitors exhibit renoprotective potential that is partially dependent on the inhibition of glucose reabsorption and subsequent aberrant glycolysis in kidney tubules.
Authors
Jinpeng Li, Haijie Liu, Susumu Takagi, Kyoko Nitta, Munehiro Kitada, Swayam Prakash Srivastava, Yuta Takagaki, Keizo Kanasaki, Daisuke Koya
Abstract
Patients with active acromegaly (ACRO) exhibit low hepatocellular lipids (HCL) despite pronounced insulin resistance (IR). This contrasts the strong association of IR with non-alcoholic fatty liver disease in the general population. Since low HCL in acromegaly might be caused by changes in oxidative substrate metabolism, we investigated mitochondrial activity and plasma metabolomics/lipidomics in active acromegaly. Fifteen ACRO and seventeen healthy controls (CON) matched for age, BMI, gender and body composition underwent 31P/1H-7T-MR-spectroscopy of the liver and skeletal muscle, as well as plasma metabolomic profiling and an oral glucose tolerance test. ACRO showed significant lower HCL but ATP-synthesis rate was significantly increased compared to CON. Furthermore, a decreased ratio of unsaturated to saturated intrahepatocellular fatty acids was found in ACRO. Within assessed plasma lipids, lipidomics, and metabolomics, decreased carnitine species also indicate increased mitochondrial activity. We therefore conclude that excess of growth hormone (GH) in humans counteracts hepatocellular lipid accumulation by increased hepatic ATP-synthesis. This is accompanied by a decreased ratio of unsaturated-to-saturated lipids in hepatocytes and by a metabolomic profile reflecting the increase in mitochondrial activity. Thus, these findings help to better understand GH-regulated antisteatotic pathways and provide a better insight into potential novel therapeutic targets for treating NAFLD.
Authors
Paul Fellinger, Peter Wolf, Lorenz Pfleger, Patrik Krumpolec, Martin Krssak, Kristaps Klavins, Stefan Wolfsberger, Alexander Micko, Patricia Carey, Bettina Gürtl, Greisa Vila, Wolfgang Raber, Clemens Fürnsinn, Thomas Scherer, Siegfried Trattnig, Alexandra Kautzky-Willer, Michael Krebs, Yvonne Winhofer
Abstract
SNAP23 is the ubiquitous SNAP25 isoform that mediates secretion in non-neuronal cells, similar to SNAP25 in neurons. However, some secretory cells like pancreatic islet β cells contain an abundance of both SNAP25 and SNAP23, where SNAP23 is believed to play a redundant role to SNAP25. We show that SNAP23, when depleted in mouse β cells in vivo and human β cells (normal and type 2 diabetes [T2D] patients) in vitro, paradoxically increased biphasic glucose-stimulated insulin secretion corresponding to increased exocytosis of predocked and newcomer insulin granules. Such effects on T2D Goto-Kakizaki rats improved glucose homeostasis that was superior to conventional treatment with sulfonylurea glybenclamide. SNAP23, although fusion competent in slower secretory cells, in the context of β cells acts as a weak partial fusion agonist or inhibitory SNARE. Here, SNAP23 depletion promotes SNAP25 to bind calcium channels more quickly and longer where granule fusion occurs to increase exocytosis efficiency. β Cell SNAP23 antagonism is a strategy to treat diabetes.
Authors
Tao Liang, Tairan Qin, Fei Kang, Youhou Kang, Li Xie, Dan Zhu, Subhankar Dolai, Dafna Greitzer-Antes, Robert K. Baker, Daorong Feng, Eva Tuduri, Claes-Goran Ostenson, Timothy J. Kieffer, Kate Banks, Jeffrey E. Pessin, Herbert Y. Gaisano
Abstract
Successful reproduction is a fundamental physiological process that relies on the integration of sensory cues of attraction with appropriate emotions and behaviors and the reproductive axis. However, the factors responsible for this integration remain largely unexplored. Using functional neuroimaging, hormonal, and psychometric analyses, we demonstrate that the reproductive hormone kisspeptin enhances brain activity in response to olfactory and visual cues of attraction in men. Furthermore, the brain regions enhanced by kisspeptin correspond to areas within the olfactory and limbic systems that govern sexual behavior and perception of beauty as well as overlap with its endogenous expression pattern. Of key functional and behavioral significance, we observed that kisspeptin was most effective in men with lower sexual quality-of-life scores. As such, our results reveal a previously undescribed attraction pathway in humans activated by kisspeptin and identify kisspeptin signaling as a new therapeutic target for related reproductive and psychosexual disorders.
Authors
Lisa Yang, Lysia Demetriou, Matthew B. Wall, Edouard G.A. Mills, David Zargaran, Mark Sykes, Julia K. Prague, Ali Abbara, Bryn M. Owen, Paul A. Bassett, Eugenii A. Rabiner, Alexander N. Comninos, Waljit S. Dhillo
Abstract
Posttransplantation diabetes mellitus (PTDM) is a common and significant complication related to immunosuppressive agents required to prevent organ or cell transplant rejection. To elucidate the effects of 2 commonly used agents, the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SIR), on islet function and test whether these effects could be reversed or prevented, we investigated human islets transplanted into immunodeficient mice treated with TAC or SIR at clinically relevant levels. Both TAC and SIR impaired insulin secretion in fasted and/or stimulated conditions. Treatment with TAC or SIR increased amyloid deposition and islet macrophages, disrupted insulin granule formation, and induced broad transcriptional dysregulation related to peptide processing, ion/calcium flux, and the extracellular matrix; however, it did not affect regulation of β cell mass. Interestingly, these β cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced β cell dysfunction and partially prevented SIR-induced β cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human β cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.
Authors
Chunhua Dai, John T. Walker, Alena Shostak, Ana Padgett, Erick Spears, Scott Wisniewski, Greg Poffenberger, Radhika Aramandla, E. Danielle Dean, Nripesh Prasad, Shawn E. Levy, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Alvin C. Powers
Abstract
Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective and frataxin-inducing effects of glucagon-like-peptide 1 (GLP-1) analogs in in vivo and in vitro models and in Friedreich ataxia patients. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β-cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in β-cells and brain, and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress and improved mitochondrial function in Friedreich ataxia patients’ induced pluripotent stem cell-derived β-cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia.
Authors
Mariana Igoillo-Esteve, Ana F. Oliveira, Cristina Cosentino, Federica Fantuzzi, Céline Demarez, Sanna Toivonen, Amélie Hu, Satyan Chintawar, Miguel Lopes, Nathalie Pachera, Ying Cai, Baroj Abdulkarim, Myriam Rai, Lorella Marselli, Piero Marchetti, Mohammad Tariq, Jean-Christophe Jonas, Marina Boscolo, Massimo Pandolfo, Décio L. Eizirik, Miriam Cnop
Abstract
Background: Inflammation is implicated in many aging-related disorders. In animal models, menopause leads to increased gut permeability and inflammation. Our primary objective was to determine if gut permeability increases during the menopause transition (MT) in women. Our exploratory objectives were to examine whether greater gut permeability is associated with more inflammation and lower bone mineral density (BMD).Methods: We included 65 women from the Study of Women’s Health Across the Nation. Key measures were markers of gut permeability (gut barrier dysfunction [fatty acid binding protein 2 [FABP2]) and immune activation secondary to gut microbial translocation (lipopolysaccharide binding protein [LBP], soluble CD14 [sCD14]); inflammation (high-sensitivity CRP); and lumbar spine (LS) or total hip (TH) BMD. Results: In our primary analysis, FABP2, LBP, and sCD14 increased by 22.8% (P = 0.001), 3.7% (P = 0.05), and 8.9% (P = 0.0002), respectively from pre- to postmenopause. In exploratory, repeated measures, mixed-effects linear regression (adjusted for age at the premenopausal visit, body mass index, race/ethnicity, and study site), greater gut permeability was associated with greater inflammation, and lower LS and TH BMD. Conclusions: Gut permeability increases during the MT. Greater gut permeability is associated with more inflammation and lower BMD. Future studies should examine the longitudinal associations of gut permeability, inflammation, and BMD.Funding: NIH, Department of Health and Human Services, through the National Institute on Aging, National Institute of Nursing Research, and NIH Office of Research on Women’s Health (U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495).
Authors
Albert Shieh, Marta Epeldegui, Arun S Karlamangla, Gail A. Greendale
Abstract
Small molecule inhibitors of Dual Specificity, Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A), including harmine and others, are able to drive human beta cell regeneration. While DYRK1A is certainly a target of this class, whether it is the only, or the most important target, is uncertain. Here, we employ a combined pharmacologic and genetic approach to refine the potential mitogenic targets of the DYRK1A inhibitor family in human islets. A combination of human beta cell RNAseq, DYRK1A inhibitor kinome screens, pharmacologic inhibitors, and targeted silencing of candidate genes confirms that DYRK1A is a central target. Surprisingly, however, DYRK1B also proves to be an important target: silencing DYRK1A results in an increase in DYRK1B; simultaneous silencing of both DYRK1A and DYRK1B yields greater beta cell proliferation than silencing either individually. Importantly, other potential kinases, such as the CLK and the GSK3 families, are excluded as important harmine targets. Finally, we describe adenoviruses that are able to silence up to seven targets simultaneously. Collectively, we report that inhibition of both DYRK1A and DYRK1B is required for induction of maximal rates of human beta cell proliferation, and provide clarity for future efforts at structure-based drug design for human beta cell regenerative drugs.
Authors
Courtney Ackeifi, Ethan Swartz, Kunal Kumar, Hongtao Liu, Suebsuwong Chalada, Esra Karakose, Donald K. Scott, Adolfo Garcia-Ocaña, Roberto Sanchez, Robert J. DeVita, Andrew F. Stewart, Peng Wang
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