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Tompach MC, Gridley CK, Marin M, Murphy PF, Lee J, Clark JM, Timme-Laragy AR. Developmental perfluorooctanesulfonic acid exposure impairs exocrine pancreas function in zebrafish (Danio rerio). Toxicol Sci 2025; 206:46-57. [PMID: 40156144 PMCID: PMC12198669 DOI: 10.1093/toxsci/kfaf041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025] Open
Abstract
Developmental perfluorooctanesulfonic acid (PFOS) exposure in zebrafish reduces digestive gene expression and pancreas length, indicating exocrine insufficiency. This project focuses on the production and function of digestive proteases with PFOS exposure. We test the hypothesis that developmental PFOS exposure impairs exocrine pancreas function in the absence of severe morphological changes. Three larval timepoints were assessed, where the nutrient source varies (yolk feed at 4-d postfertilization [dpf], yolk depleted at 6 dpf, and exogenously fed at 9 dpf) to understand how nutrients were being used throughout exocrine pancreas development. Tg(ptf1a: GFP) zebrafish were exposed to 0 (0.01% DMSO), 1, 2, and 4 μM PFOS from 0 to 4 dpf. At 4 dpf, pancreas length was decreased with 1 μM and yolk sac area was reduced with 2 and 4 μM PFOS. By 6 dpf, pancreata of zebrafish exposed to 1 μM PFOS had recovered, and pancreas size was decreased with 4 μM PFOS. Protease activity was reduced with PFOS exposure, accompanied by decreases in digestive protease gene expression and trypsin protein. At 9 dpf, there was no measurable change in pancreas size or protease activity with 1 and 2 μM PFOS, indicating morphological and functional recovery even though PFOS was detected in the larvae. This study demonstrates that PFOS exposure can affect the function of the exocrine pancreas in the absence of a detectable change in organ size. We also highlight the mishandling of yolk nutrients, leading to undernutrition at later larval stages and show catch-up growth in morphology and function.
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Affiliation(s)
- Madeline C Tompach
- Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, United States
- Biotechnology Training Program, University of Massachusetts Amherst, Amherst, MA 01003, United States
| | - Charlotte K Gridley
- Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, United States
| | - Marjorie Marin
- Biotechnology Training Program, University of Massachusetts Amherst, Amherst, MA 01003, United States
- Department of Environmental Health Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
| | - Patrick F Murphy
- Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, United States
| | - Junghak Lee
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
| | - John M Clark
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
| | - Alicia R Timme-Laragy
- Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, United States
- Department of Environmental Health Sciences, University of Massachusetts Amherst, Amherst, MA 01003, United States
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Deji-Oloruntoba O, Okpete UE, Byeon H. Editorial on amylase and the acini-islet-acinar reflex: A new frontier in metabolic health research. World J Exp Med 2025; 15:101289. [PMID: 40115752 PMCID: PMC11718580 DOI: 10.5493/wjem.v15.i1.101289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/05/2024] [Accepted: 11/20/2024] [Indexed: 12/26/2024] Open
Abstract
This editorial comments on the study by Pierzynowska et al investigating the acini-islet-acinar (AIA) reflex, which integrates the exocrine and endocrine functions of the pancreas. The study investigates whether exogenous amylase introduced to the interstitial fluid surrounding pancreatic islets can inhibit insulin release. Historically, high serum amylase levels were associated with pancreatitis, but recent findings suggest that low amylase levels are more linked to metabolic diseases like diabetes and obesity. In their experiment, six pigs were used to examine the effects of amylase infusion on insulin release during an intravenous glucose tolerance test. The pigs received different treatments (amylase, saline, or bovine serum albumin), and blood samples were taken over two hours to measure insulin and glucose levels. The results showed amylase delayed glucose-stimulated insulin release, whereas bovine serum albumin increased insulin levels supporting the existence of the AIA reflex and suggesting amylase as a key metabolic regulator. Enzyme supplementation, particularly with α-amylases, may offer therapeutic benefits in preventing and managing metabolic disorders, including diabetes and obesity. Further research is warranted to explore the full scope of amylase's role in metabolic health and its therapeutic potential.
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Affiliation(s)
- Opeyemi Deji-Oloruntoba
- Biohealth Convergence Unit, Food and Drug Biotechnology, Inje University, Gimhae 50834, South Korea
| | - Uchenna E Okpete
- Department of Digital Anti-aging Healthcare (BK21), Inje University, Gimhae 50834, South Korea
| | - Haewon Byeon
- Department of Digital Anti-aging Healthcare (BK21), Inje University, Gimhae 50834, South Korea
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Zaworski K, Wychowański P, Szkopek D, Woliński J, Donaldson J, Pierzynowski S, Pierzynowska K. The Regulatory Role of Pancreatic Enzymes in the Maintenance of Small Intestinal Structure and Enterocyte Turnover with Special Reference to Alpha Amylase. Int J Mol Sci 2024; 26:249. [PMID: 39796104 PMCID: PMC11719925 DOI: 10.3390/ijms26010249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/18/2024] [Accepted: 12/28/2024] [Indexed: 01/13/2025] Open
Abstract
The aim of this study was to elucidate the impact of porcine pancreatic enzymes (Creon® pancrelipase) in comparison to microbial-derived alpha amylase (MD amylase) on the small intestine wall structure, mucosal glycogen accumulation, and enterocyte turnover. The impact of enzyme supplementation on the small intestine was explored in 18 pigs with surgically induced exocrine pancreatic insufficiency (EPI). Four healthy pigs served as the control group. EPI led to reduced villus length, crypt depth, and thickness of the mucosa and muscularis layers compared to those of healthy pigs. All these changes appeared to be reversible after enzyme supplementation. Brush border thickness was decreased in EPI and increased with both enzyme preparations, with MD amylase treatment leading to the highest values in the proximal jejunum. No EPI-induced changes were observed in the goblet cell (GC) population, but significant increases in GC number and area were observed following MD amylase treatment. Glycogen accumulation within the duodenal mucosa was significantly increased in EPI pigs. EPI was also shown to significantly increase apoptotic activity and decrease proliferative activity in comparison to healthy animals, while both enzyme preparations resulted in the complete recovery of both proliferative and apoptotic activity in all investigated intestinal segments. Creon® influenced the morphology of the small intestine. However, supplementation of exogenous microbial amylase alone also affected gut morphology in a similar way to that of the complex host pancreatic enzymes offered orally. These data indicate that in addition to their role in digestion of nutrients in EPI, intraluminal pancreatic enzymes, especially amylase, contribute to gut health through maintenance of the intestinal wall architecture and physiological enterocyte turnover.
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Affiliation(s)
- Kamil Zaworski
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland
| | - Piotr Wychowański
- Anara AB, Alfagelgranden 24, 231 32 Trelleborg, Sweden; (P.W.); (J.D.); (S.P.)
- Division of Oral Surgery and Implantology, Department of Head and Neck and Sensory Organs, Institute of Clinical Dentistry, Gemelli Foundation for the University Policlinic, Catholic University of the “Sacred Heart”, 00168 Rome, Italy
- Department of Oral Surgery, Medical University of Gdańsk, M. Skłodowskiej-Curie 3a, 80-210 Gdańsk, Poland
| | - Dominika Szkopek
- Large Animal Models Laboratory, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland; (D.S.); (J.W.)
| | - Jarosław Woliński
- Large Animal Models Laboratory, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland; (D.S.); (J.W.)
| | - Janine Donaldson
- Anara AB, Alfagelgranden 24, 231 32 Trelleborg, Sweden; (P.W.); (J.D.); (S.P.)
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg 2193, South Africa
| | - Stefan Pierzynowski
- Anara AB, Alfagelgranden 24, 231 32 Trelleborg, Sweden; (P.W.); (J.D.); (S.P.)
- Department of Biology, Lund University, 221 00 Lund, Sweden
- Department of Medical Biology, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland
| | - Kateryna Pierzynowska
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland
- Anara AB, Alfagelgranden 24, 231 32 Trelleborg, Sweden; (P.W.); (J.D.); (S.P.)
- Department of Biology, Lund University, 221 00 Lund, Sweden
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Pierzynowska K, Wychowański P, Zaworski K, Woliński J, Donaldson J, Szkopek D, Roszkowicz-Ostrowska K, Kondej A, Pierzynowski SG. Amylase intrapancreatic infusion delays insulin release during an intravenous glucose tolerance test, proof of acini-islet-acinar interactions. World J Exp Med 2024; 14:92589. [PMID: 39312707 PMCID: PMC11372737 DOI: 10.5493/wjem.v14.i3.92589] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/19/2024] [Accepted: 07/10/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND The possible existence of an acini-islet-acinar (AIA) reflex, involving mutual amylase and insulin interactions, was investigated in the current acute experiment on pigs. AIM To confirm the existence of an AIA reflex and justify the placement of the exocrine and endocrine pancreatic components within the same organ. METHODS The study was performed on six pigs under general anesthesia. An intravenous glucose tolerance test was performed, with a bolus infusion of 50% glucose to the jugular vein, while amylase (5000 U/kg) or vehicle intrapancreatic infusions were administered via the pancreaticoduodenalis cranialis artery during 30 min with a 1 mL/min flow rate. RESULTS The amylase infusion to pancreatic arterial circulation inhibited and delayed the insulin release peak which is usually associated with the highest value of blood glucose and is typically observed at 15 min after glucose infusion, for > 1 h. The intrapancreatic infusion of the vehicle (saline) did not have any effect on the time frame of insulin release. Infusion of 1% bovine serum albumin changed the insulin release curve dramatically and prolonged the high range of insulin secretion, far beyond the glucose peak. CONCLUSION Intrapancreatic arterial infusion of amylase interrupted the integrated glucose-insulin interactions. This confirms an AIA reflex and justifies placement of the exocrine and endocrine pancreatic components within the same organ.
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Affiliation(s)
- Kateryna Pierzynowska
- Department of Biology, Lund University, Lund 22362, Sweden
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna 05110, Poland
- Anara AB, Trelleborg 23132, Sweden
| | - Piotr Wychowański
- Department of Head and Neck and Sensory Organs, Division of Oral Surgery and Implantology, Institute of Clinical Dentistry, Gemelli Foundation for the University Policlinic, Catholic University of the “Sacred Heart”, Rome 00168, Italy
- Department of Oral Surgery, Medical University of Gdańsk, Gdańsk 80211, Poland
| | - Kamil Zaworski
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna 05110, Poland
| | - Jarosław Woliński
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna 05110, Poland
| | - Janine Donaldson
- Anara AB, Trelleborg 23132, Sweden
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand (WITS), Johannesburg 2050, South Africa
| | - Dominika Szkopek
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna 05110, Poland
| | - Katarzyna Roszkowicz-Ostrowska
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna 05110, Poland
| | - Agata Kondej
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna 05110, Poland
| | - Stefan G Pierzynowski
- Department of Biology, Lund University, Lund 22362, Sweden
- Anara AB, Trelleborg 23132, Sweden
- Department of Medical Biology, Institute of Rural Health, Lublin 20090, Poland
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Chui JN, Ziaziaris WA, Nahm CB, Fuchs T, Sahni S, Lim CSH, Gill AJ, Samra JS, Mittal A. Lipase-to-Amylase Ratio for the Prediction of Clinically Relevant Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy. Pancreas 2024; 53:e579-e587. [PMID: 38696382 DOI: 10.1097/mpa.0000000000002345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/04/2024]
Abstract
OBJECTIVE Postoperative pancreatic fistula (POPF) represents a leading cause of morbidity and mortality following major pancreatic resections. This study aimed to evaluate the use of postoperative drain fluid lipase-to-amylase ratio (LAR) for the prediction of clinically relevant fistulae (CR-POPF). METHODS Consecutive patients undergoing pancreaticoduodenectomy between 2017 and 2021 at a tertiary centre were retrospectively reviewed. Univariable and multivariable analyses were performed to identify predictors for CR-POPF (ISGPS grade B/C). Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the performance of LAR and determine optimum prediction thresholds. RESULTS Among 130 patients, 28 (21.5%) developed CR-POPF. Variables positively associated with CR-POPF included soft gland texture, acinar cell density, diagnosis other than PDAC or chronic pancreatitis, resection without neoadjuvant therapy, and postoperative drain fluid lipase, amylase, and LAR (all P <0.05). Multivariable regression analysis identified LAR as an independent predictor of CR-POPF ( P <0.05). ROC curve analysis showed that LAR had moderate ability to predict CR-POPF on POD1 (AUC,0.64; 95%CI,0.54-0.74) and excellent ability on POD3 (AUC,0.85; 95%CI,0.78-0.92) and POD 5 (AUC,0.86; 95%CI,0.79-0.92). Optimum thresholds were consistent over PODs 1 to 5 (ratio>2.6) and associated with 92% sensitivity and 46% to 71% specificity. CONCLUSIONS Postoperative drain fluid LAR represents a reliable predictor for the development of CR-POPF. With early prognostication, the postoperative care of patients at risk of developing high-grade fistulas may be optimized.
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Affiliation(s)
| | | | | | | | - Sumit Sahni
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, University of Sydney
| | - Christopher S H Lim
- From the Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital
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Stickel KC, Shah NR, Claeboe ET, Orr KS, Mosley AL, Doud EH, Belecky-Adams TL, Baucum AJ. Mechanisms of spinophilin-dependent pancreas dysregulation in obesity. Am J Physiol Endocrinol Metab 2024; 327:E155-E171. [PMID: 38630048 PMCID: PMC11427100 DOI: 10.1152/ajpendo.00099.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 03/18/2024] [Accepted: 04/04/2024] [Indexed: 05/07/2024]
Abstract
Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino-/-) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. Although spinophilin is enriched in neurons, its roles in nonneuronal tissues, such as β cells of the pancreatic islets, are unclear. We have corroborated and expanded upon previous studies to determine that Spino-/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity. We have identified multiple putative spinophilin-interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that normally act to mediate peptide hormone production, processing, and/or release in Leprdb/db and/or high-fat diet-fed (HFF) models of obesity. In addition, we have found that spinophilin interacts with proteins from similar classes in isolated islets, suggesting a role for spinophilin in the pancreatic islet. Consistent with a pancreatic β cell type-specific role for spinophilin, using our recently described conditional spinophilin knockout mice, we found that loss of spinophilin specifically in pancreatic β cells improved glucose tolerance without impacting body weight in chow-fed mice. Our data further support the role of spinophilin in mediating pathophysiological changes in body weight and whole body metabolism associated with obesity. Our data provide the first evidence that pancreatic spinophilin protein interactions are modulated by obesity and that loss of spinophilin specifically in pancreatic β cells impacts whole body glucose tolerance.NEW & NOTEWORTHY To our knowledge, these data are the first to demonstrate that obesity impacts spinophilin protein interactions in the pancreas and identify spinophilin specifically in pancreatic β cells as a modulator of whole body glucose tolerance.
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Affiliation(s)
- Kaitlyn C Stickel
- Department of Biology, Indiana University-Indianapolis, Indianapolis, Indiana, United States
| | - Nikhil R Shah
- Medical Neurosciences and Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Emily T Claeboe
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Kara S Orr
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Amber L Mosley
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Emma H Doud
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Teri L Belecky-Adams
- Department of Biology, Indiana University-Indianapolis, Indianapolis, Indiana, United States
| | - Anthony J Baucum
- Department of Biology, Indiana University-Indianapolis, Indianapolis, Indiana, United States
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
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Szkopek D, Pierzynowski SG, Pierzynowska K, Zaworski K, Kondej A, Wychowański P, Konieczka P, Seklecka B, Donaldson J, Jank M, Woliński J. A review: Pancreatic enzymes in the treatment of chronic pancreatic insufficiency in companion animals. J Vet Intern Med 2024; 38:2026-2033. [PMID: 38721836 PMCID: PMC11256127 DOI: 10.1111/jvim.17096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 04/18/2024] [Indexed: 07/19/2024] Open
Abstract
The purpose of this review was to analyze the scientific literature on exocrine pancreatic insufficiency (EPI) in dogs and cats and our own research on porcine model to compare animal- and microbial-derived enzymes in the treatment of animals with this disease. Clinical signs of EPI occur when more than 85% of the pancreatic parenchyma is non-functional. EPI can be a consequence of various diseases. The insufficient activity or deficiency of pancreatic enzymes leads to impaired digestion and absorption, and consequently, to malnutrition. The primary treatment for enzyme insufficiency is pancreatic enzyme replacement therapy (PERT). PERT in animals with EPI is a lifetime therapy. Most commercially available products are of animal origin (processed pancreata obtained from a slaughter house) and contain lipases, alpha-amylase, and proteases. Enzymes of microbial and plant origin seem to be a promising alternative to animal-derived enzymes, but to date there are no registered preparations containing all enzymes simultaneously for use in clinical practice to treat EPI. Results from some previous studies have highlighted the "extra-digestive" functions of pancreatic enzymes, as well as the actions of pancreatic-like microbial enzymes. For example, trypsin activates protease-activated receptor and provokes maturation of enterocytes and enterostatin inhibits fat absorption. It has been postulated that intrapancreatic amylase is the main component of the acini-islet-acinar axis-the reflex which down regulates insulin release, while gut and blood amylase exhibit anti-incretin actions "per se." Additionally, high but still physiological blood amylase activity coincide with physiological glucose homeostasis and a lack of obesity.
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Affiliation(s)
- Dominika Szkopek
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and NutritionPolish Academy of Sciences, Instytucka 3JabłonnaPoland
| | - Stefan G. Pierzynowski
- Anara ABTrelleborgSweden
- Department of Medical BiologyWitold Chodźka Institute of Rural MedicineLublinPoland
- Department of BiologyLund UniversityLundSweden
| | - Kateryna Pierzynowska
- Department of BiologyLund UniversityLundSweden
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and NutritionPolish Academy of Sciences, Instytucka 3JabłonnaPoland
| | - Kamil Zaworski
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and NutritionPolish Academy of Sciences, Instytucka 3JabłonnaPoland
| | - Agata Kondej
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and NutritionPolish Academy of Sciences, Instytucka 3JabłonnaPoland
| | - Piotr Wychowański
- Oral Surgery and Implantology Unit, Division of Oral Surgery and Implantology, Department of Head and Neck, Institute of Clinical DentistryFondazione Policlinico Universitario A. Gemelli IRCCS, Universita Cattolica del Sacro CoureRomeItaly
| | - Paweł Konieczka
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and NutritionPolish Academy of Sciences, Instytucka 3JabłonnaPoland
- Department of Poultry Science and ApicultureUniversity of Warmia and Mazury, Oczapowskiego 5OlsztynPoland
| | | | - Janine Donaldson
- School of Physiology, Faculty of Health SciencesUniversity of the WitwatersrandParktown, Johannesburg 2193South Africa
| | - Michał Jank
- Department of Pre‐Clinical Sciences and Infectious Diseases, Faculty of Veterinary Medicine and Animal SciencePoznan University of Life SciencesPoznańPoland
| | - Jarosław Woliński
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and NutritionPolish Academy of Sciences, Instytucka 3JabłonnaPoland
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and NutritionPolish Academy of Sciences, Instytucka 3JabłonnaPoland
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Smandri A, Al-Masawa ME, Hwei NM, Fauzi MB. ECM-derived biomaterials for regulating tissue multicellularity and maturation. iScience 2024; 27:109141. [PMID: 38405613 PMCID: PMC10884934 DOI: 10.1016/j.isci.2024.109141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2024] Open
Abstract
Recent breakthroughs in developing human-relevant organotypic models led to the building of highly resemblant tissue constructs that hold immense potential for transplantation, drug screening, and disease modeling. Despite the progress in fine-tuning stem cell multilineage differentiation in highly controlled spatiotemporal conditions and hosting microenvironments, 3D models still experience naive and incomplete morphogenesis. In particular, existing systems and induction protocols fail to maintain stem cell long-term potency, induce high tissue-level multicellularity, or drive the maturity of stem cell-derived 3D models to levels seen in their in vivo counterparts. In this review, we highlight the use of extracellular matrix (ECM)-derived biomaterials in providing stem cell niche-mimicking microenvironment capable of preserving stem cell long-term potency and inducing spatial and region-specific differentiation. We also examine the maturation of different 3D models, including organoids, encapsulated in ECM biomaterials and provide looking-forward perspectives on employing ECM biomaterials in building more innovative, transplantable, and functional organs.
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Affiliation(s)
- Ali Smandri
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Maimonah Eissa Al-Masawa
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Ng Min Hwei
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Mh Busra Fauzi
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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Pierzynowska K, Wychowański P, Zaworski K, Woliński J, Donaldson J, Pierzynowski S. Anti-Incretin Gut Features Induced by Feed Supplementation with Alpha-Amylase: Studies on EPI Pigs. Int J Mol Sci 2023; 24:16177. [PMID: 38003366 PMCID: PMC10671445 DOI: 10.3390/ijms242216177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/08/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
The acini-islet-acinar (AIA) axis concept justifies the anatomical placement of the Langerhans islets within the exocrine pancreatic parenchyma and explains the existence of the pancreas as a single organ. Amylase has been suggested to play a key role as an anti-incretin factor. Oral glucose tolerance tests (OGTT) were performed on 18 piglets in both a healthy (prior to pancreatic duct ligation (PDL) surgery, study Day 10) and an exocrine pancreatic insufficient (EPI) state (30 days after PDL, study Day 48)). Amylase (4000 units/feeding) or Creon® (100,000 units/feeding) was administered to pigs with the morning and evening meals, according to study design randomization, for 37 days following the first OGTT. Blood glucose levels, as well as plasma levels of insulin, GLP-1, and GIP, were measured, and the HOMA-IR index was calculated. EPI status did not affect the area under the curve (AUC) of insulin release, fasting insulin levels, or the HOMA-IR index, while amylase supplementation led to a significant (p < 0.05) decrease in the above-mentioned parameters. At the same time, EPI led to a significant (p < 0.05) increase in GLP-1 levels, and neither amylase nor Creon® supplementation had any effects on this EPI-related increase. Fasting plasma levels of GIP were not affected by EPI; however, the GIP response in EPI and Amylase-treated EPI animals was significantly lower (p < 0.05) when compared to that of the intact, healthy pigs. Orally administered amylase induces gut anti-incretin action, normalizing glucose homeostasis and reducing HOMA-IR as a long-term outcome, thus lowering the risk of diabetes type II development. Amylase has long-lasting anti-incretin effects, and one could consider the existence of a long-lasting gut memory for amylase, which decreases hyperinsulinemia and hyperglycemia for up to 16 h after the last exposure of the gut to amylase.
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Affiliation(s)
- Kateryna Pierzynowska
- Department of Biology, Lund University, 223 62 Lund, Sweden;
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jabłonna, Poland; (K.Z.); (J.W.)
- Anara AB, 231 32 Trelleborg, Sweden; (P.W.); (J.D.)
| | - Piotr Wychowański
- Anara AB, 231 32 Trelleborg, Sweden; (P.W.); (J.D.)
- Department of Head and Neck and Sensory Organs, Division of Oral Surgery and Implantology, Institute of Clinical Dentistry, Gemelli Foundation for the University Policlinic, Catholic University of the “Sacred Heart”, 00168 Rome, Italy
- Department of Oral Surgery, Medical University of Gdańsk, 80-211 Gdańsk, Poland
- Specialized Private Implantology Clinic Wychowanski Stomatologia, 02-517 Warsaw, Poland
| | - Kamil Zaworski
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jabłonna, Poland; (K.Z.); (J.W.)
| | - Jarosław Woliński
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jabłonna, Poland; (K.Z.); (J.W.)
- Large Animal Models Laboratory, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jabłonna, Poland
| | - Janine Donaldson
- Anara AB, 231 32 Trelleborg, Sweden; (P.W.); (J.D.)
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand (WITS), Johannesburg 2050, South Africa
| | - Stefan Pierzynowski
- Department of Biology, Lund University, 223 62 Lund, Sweden;
- Anara AB, 231 32 Trelleborg, Sweden; (P.W.); (J.D.)
- Department of Medical Biology, Institute of Rural Health, 20-090 Lublin, Poland
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10
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Pierzynowski SG, Stier C, Pierzynowska K. Hypothesis that alpha-amylase evokes regulatory mechanisms originating in the pancreas, gut and circulation, which govern glucose/insulin homeostasis. World J Diabetes 2023; 14:1341-1348. [PMID: 37771332 PMCID: PMC10523231 DOI: 10.4239/wjd.v14.i9.1341] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/28/2023] [Accepted: 08/02/2023] [Indexed: 09/13/2023] Open
Abstract
The anti-incretin theory involving the abolishment of diabetes type (DT) II by some of methods used in bariatric surgery, first appeared during the early years of the XXI century and considers the existence of anti-incretin substances. However, to date no exogenous or endogenous anti-incretins have been found. Our concept of the acini-islet-acinar axis assumes that insulin intra-pancreatically stimulates alpha-amylase synthesis ("halo phenomenon") and in turn, alpha-amylase reciprocally inhibits insulin production, thus making alpha-amylase a candidate for being an anti-incretin. Additionally, gut as well as plasma alpha-amylase, of pancreatic and other origins, inhibits the appearance of dietary glucose in the blood, lowering the glucose peak after iv or oral glucose loading. This effect of alpha-amylase can be interpreted as an insulin down regulatory mechanism, possibly limiting the depletion of pancreatic beta cells and preventing their failure. Clinical observations agree with the above statements, where patients with high blood alpha-amylase concentrations are seldom obese and seldom develop DT2. Obese-DT2, as well as DT1 patients, usually develop exo-crine pancreatic insufficiency (EPI) and vice versa. Ultimately, DT2 patients develop DT1, when the pancreatic beta cells are exhausted and insulin production ceases. Studies on biliopancreatic diversion (BPD) and on BPD with duodenal switch, a type of bariatric surgery, as well as studies on EPI pigs, allow us to observe and investigate the above-mentioned phenomena of intra-pancreatic interactions.
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Affiliation(s)
- Stefan G Pierzynowski
- Department of Medical Biology, Institute of Rural Health, Lublin 20090, Poland
- Department of Biology, Lund University, Lund 22362, Sweden
- Anara AB, Trelleborg 23132, Sweden
| | - Christine Stier
- Department of General, Visceral, Transplant, Vascular, and Pediatric Surgery and Division of Endocrinology, University Hospital Würzburg, Würzburg 97080, Germany
- Department of Surgical Endoscopy, Sana Hospital, Huerth 50354, Germany
| | - Kateryna Pierzynowska
- Department of Biology, Lund University, Lund 22362, Sweden
- Anara AB, Trelleborg 23132, Sweden
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Jablonna 05110, Poland
- Anagram Therapeutics, Inc, Framingham, MA 01701, United States
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11
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Gosline SJC, Veličković M, Pino JC, Day LZ, Attah IK, Swensen AC, Danna V, Posso C, Rodland KD, Chen J, Matthews CE, Campbell-Thompson M, Laskin J, Burnum-Johnson K, Zhu Y, Piehowski PD. Proteome Mapping of the Human Pancreatic Islet Microenvironment Reveals Endocrine-Exocrine Signaling Sphere of Influence. Mol Cell Proteomics 2023; 22:100592. [PMID: 37328065 PMCID: PMC10460696 DOI: 10.1016/j.mcpro.2023.100592] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 04/24/2023] [Accepted: 06/05/2023] [Indexed: 06/18/2023] Open
Abstract
The need for a clinically accessible method with the ability to match protein activity within heterogeneous tissues is currently unmet by existing technologies. Our proteomics sample preparation platform, named microPOTS (Microdroplet Processing in One pot for Trace Samples), can be used to measure relative protein abundance in micron-scale samples alongside the spatial location of each measurement, thereby tying biologically interesting proteins and pathways to distinct regions. However, given the smaller pixel/voxel number and amount of tissue measured, standard mass spectrometric analysis pipelines have proven inadequate. Here we describe how existing computational approaches can be adapted to focus on the specific biological questions asked in spatial proteomics experiments. We apply this approach to present an unbiased characterization of the human islet microenvironment comprising the entire complex array of cell types involved while maintaining spatial information and the degree of the islet's sphere of influence. We identify specific functional activity unique to the pancreatic islet cells and demonstrate how far their signature can be detected in the adjacent tissue. Our results show that we can distinguish pancreatic islet cells from the neighboring exocrine tissue environment, recapitulate known biological functions of islet cells, and identify a spatial gradient in the expression of RNA processing proteins within the islet microenvironment.
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Affiliation(s)
- Sara J C Gosline
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | | | - James C Pino
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Le Z Day
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Isaac K Attah
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Adam C Swensen
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Vincent Danna
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Camilo Posso
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Karin D Rodland
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Jing Chen
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
| | - Clayton E Matthews
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
| | - Martha Campbell-Thompson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
| | - Julia Laskin
- Department of Chemistry, Purdue University, West Lafayette, Indiana, USA
| | | | - Ying Zhu
- Pacific Northwest National Laboratories, Richland, Washington, USA
| | - Paul D Piehowski
- Pacific Northwest National Laboratories, Richland, Washington, USA.
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12
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Shestakova MV, Maev IV, Ametov AS, Antsiferov MB, Bordin DS, Galstyan GR, Dzgoeva FK, Kucheryavyy YA, Mkrtumyan AM, Nikonova TV, Pashkova EY. Pancreatic exocrine insufficiency in diabetes mellitus. DIABETES MELLITUS 2023; 26. [DOI: 10.14341/dm13027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/20/2023]
Abstract
Diabetes is disease of both the endo- and exocrine parts of the pancreas. Pancreatic exocrine insufficiency (PEI) can occur in every 2–3 patients with diabetes and affect not only the quality, but also life expectancy. At the same time, the diagnosis and treatment of PEI is not getting enough attention. The endocrinologist, as the main specialist leading patients with diabetes, can diagnose and treat patients with pancreatic exocrine insufficiency and diabetes using adequate doses of pancreatic enzyme replacement therapy (PERT).
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Affiliation(s)
| | - I. V. Maev
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry
| | - A. S. Ametov
- Russian Medical Academy of Continuous Professional Education
| | - M. B. Antsiferov
- Endocrinological Dispensary of the Moscow City Health Department
| | - D. S. Bordin
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry; A.S. Loginov Moscow Clinical Scientific Centre; Tver State Medical University
| | | | | | | | - A. M. Mkrtumyan
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry; A.S. Loginov Moscow Clinical Scientific Centre
| | | | - E. Y. Pashkova
- Russian Medical Academy of Continuous Professional Education; Botkin Hospital
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13
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Shestakova MV, Maev IV, Ametov AS, Antsiferov MB, Bordin DS, Galstyan GR, Dzgoeva FK, Kucheryavyy YA, Mkrtumyan AM, Nikonova TV, Pashkova EY. Pancreatic exocrine insufficiency in diabetes mellitus. DIABETES MELLITUS 2023; 26. [DOI: https:/doi.org/10.14341/dm13027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Diabetes is disease of both the endo- and exocrine parts of the pancreas. Pancreatic exocrine insufficiency (PEI) can occur in every 2–3 patients with diabetes and affect not only the quality, but also life expectancy. At the same time, the diagnosis and treatment of PEI is not getting enough attention. The endocrinologist, as the main specialist leading patients with diabetes, can diagnose and treat patients with pancreatic exocrine insufficiency and diabetes using adequate doses of pancreatic enzyme replacement therapy (PERT).
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Affiliation(s)
| | - I. V. Maev
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry
| | - A. S. Ametov
- Russian Medical Academy of Continuous Professional Education
| | - M. B. Antsiferov
- Endocrinological Dispensary of the Moscow City Health Department
| | - D. S. Bordin
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry; A.S. Loginov Moscow Clinical Scientific Centre; Tver State Medical University
| | | | | | | | - A. M. Mkrtumyan
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry; A.S. Loginov Moscow Clinical Scientific Centre
| | | | - E. Y. Pashkova
- Russian Medical Academy of Continuous Professional Education; Botkin Hospital
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14
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Zheng Y, Mostamand S. Nutrition in children with exocrine pancreatic insufficiency. Front Pediatr 2023; 11:943649. [PMID: 37215591 PMCID: PMC10196508 DOI: 10.3389/fped.2023.943649] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 04/18/2023] [Indexed: 05/24/2023] Open
Abstract
Exocrine pancreatic insufficiency (EPI) is a condition defined as pancreatic loss of exocrine function, including decreased digestive enzymes and bicarbonate secretion, which leads to maldigestion and malabsorption of nutrients. It is a common complication in many pancreatic disorders. If left undiagnosed, EPI can cause poor digestion of food, chronic diarrhea, severe malnutrition and related complications. Nutritional status and fat-soluble vitamins should be carefully assessed and monitored in patients with EPI. Early diagnosis of EPI is clinically important for appropriate nutritional support and initiating pancreatic enzyme replacement therapy (PERT) which could significantly improve patient outcomes. The evaluation of nutritional status and related unique management in children with EPI will be discussed in this review.
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Affiliation(s)
- Yuhua Zheng
- Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Shikib Mostamand
- Gastroenterology, Hepatology, and Nutrition, Stanford Children’s Health & Stanford University School of Medicine, Palo Alto, CA, United States
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15
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Yong HJ, Toledo MP, Nowakowski RS, Wang YJ. Sex Differences in the Molecular Programs of Pancreatic Cells Contribute to the Differential Risks of Type 2 Diabetes. Endocrinology 2022; 163:bqac156. [PMID: 36130190 PMCID: PMC10409906 DOI: 10.1210/endocr/bqac156] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Indexed: 11/19/2022]
Abstract
Epidemiology studies demonstrate that women are at a significantly lower risk of developing type 2 diabetes (T2D) compared to men. However, the molecular basis of this risk difference is not well understood. In this study, we examined the sex differences in the genetic programs of pancreatic endocrine cells. We combined pancreas perifusion data and single-cell genomic data from our laboratory and from publicly available data sets to investigate multiple axes of the sex differences in the human pancreas at the single-cell type and single-cell level. We systematically compared female and male islet secretion function, gene expression program, and regulatory principles of pancreatic endocrine cells. The perifusion data indicate that female endocrine cells have a higher secretion capacity than male endocrine cells. Single-cell RNA-sequencing analysis suggests that endocrine cells in male controls have molecular signatures that resemble T2D. In addition, we identified genomic elements associated with genome-wide association study T2D loci to have differential accessibility between female and male delta cells. These genomic elements may play a sex-specific causal role in the pathogenesis of T2D. We provide molecular mechanisms that explain the differential risk of T2D between women and men. Knowledge gained from our study will accelerate the development of diagnostics and therapeutics in sex-aware precision medicine for diabetes.
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Affiliation(s)
- Hyo Jeong Yong
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA
| | - Maria Pilar Toledo
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA
| | - Richard S Nowakowski
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA
| | - Yue J Wang
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA
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16
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Alpha-Amylase Inhibits Cell Proliferation and Glucose Uptake in Human Neuroblastoma Cell Lines. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4271358. [PMID: 35924266 PMCID: PMC9343180 DOI: 10.1155/2022/4271358] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 06/17/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022]
Abstract
The present article describes a study of the effects of alpha-amylase (α-amylase) on the human neuroblastoma (NB) cell lines SH-SY5Y, IMR-32, and LA-N-1. NB is the most common malignancy diagnosed in infants younger than 12 months. Some clinical observations revealed an inverse association between the risk of NB development and breastfeeding. α-Amylase which is present in breast milk was shown to have anticancer properties already in the beginning of the 20th century. Data presented here show that pancreatic α-amylase inhibits cell proliferation and has a direct impact on glucose uptake in the human NB cell lines. Our results point out the importance of further research which could elucidate the α-amylase mode of action and justify the presence of this enzyme in breast milk as a possible inhibitor of NB development. α-Amylase can be thus recognized as a potential safe and natural mild/host anticancer agent minimizing chemotherapy-related toxicity in the treatment of NB.
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17
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Chen X, Zhang Q, Yang Q, Huang Z, Liao G, Wang Z. The Effect and Mechanism of Duodenal-Jejunal Bypass to Treat Type 2 Diabetes Mellitus in a Rat Model. Obes Facts 2022; 15:344-356. [PMID: 35299171 PMCID: PMC9209996 DOI: 10.1159/000519417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 08/30/2021] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVES Bariatric surgery can treat obesity and T2DM, but the specific mechanism is unknown. This study investigated the effect and possible mechanism of duodenal-jejunal bypass (DJB) to treat T2DM. METHODS A T2DM rat model was established using a high-fat, high-sugar diet and a low dose of streptozotocin. DJB surgery and a sham operation (SO) were performed to analyze the effects on glucose homeostasis, lipid metabolism, and inflammation changes. Furthermore, the glucagon-like peptide-1 (GLP-1) in the ileum and the markers of endoplasmic reticulum stress (ERS) in the pancreas were examined after the surgery. The insulinoma cells (INS-1) were divided into three groups; group A was cultured with a normal sugar content (11.1 mmol/L), group B was cultured with fluctuating high glucose (11.1 mmol/L alternating with 33.3 mmol/L), and group C was cultured with fluctuating high glucose and exendin-4 (100 nmol/L). The cells were continuously cultured for 7 days in complete culture medium. The viability of the INS-1 cells was then investigated using the MTT method, apoptosis was detected by flow cytometry, and the ERS markers were detected by Western blot. RESULTS The blood glucose, lipids, insulin, and TNF-α were significantly elevated in the T2DM model. A gradual recovery was observed in the DJB group. GLP-1 expression in the distal ileum of the DJB group was significantly higher than that in the T2DM control group (DM) and the SO group (p < 0.05), and the markers of ERS expression in the pancreases of the DJB group decreased significantly more than those of groups DM and SO (p < 0.05). Compared with group A, the cell viability in group B was decreased, and the ERS and apoptosis were increased (p < 0.05). However, compared with group B, the cell viability in group C was improved, and the ERS and apoptosis declined (p < 0.05). CONCLUSIONS DJB can be used to treat T2DM in T2DM rats. The mechanism may be that the DJB stimulates the increased expression of GLP-1 on the far side of the ileum, and then, GLP-1 inhibits ERS in the pancreas, reducing the apoptosis of β cells to create a treatment effect in the T2DM rats.
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Affiliation(s)
- Xuan Chen
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qiang Zhang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - QingQiang Yang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- *QingQiang Yang,
| | - Zhen Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Gang Liao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - ZiWei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- **Ziwei Wang,
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18
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Hostelley TL, Nesmith JE, Larkin E, Jones A, Boyes D, Leitch CC, Fontaine M, Zaghloul NA. Exocrine pancreas proteases regulate β-cell proliferation in zebrafish ciliopathy models and in murine systems. Biol Open 2021; 10:269024. [PMID: 34125181 PMCID: PMC8249909 DOI: 10.1242/bio.046839] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/04/2019] [Indexed: 12/27/2022] Open
Abstract
Pancreatic β-cells are a critical cell type in the pathology of diabetes. Models of genetic syndromes featuring diabetes can provide novel mechanistic insights into regulation of β-cells in the context of disease. We previously examined β-cell mass in models of two ciliopathies, Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS), which are similar in the presence of metabolic phenotypes, including obesity, but exhibit strikingly different rates of diabetes. Zebrafish models of these disorders show deficient β-cells with diabetes in AS models and an increased β-cells absent diabetes in BBS models, indicating β-cell generation or maintenance that correlates with disease prevalence. Using transcriptome analyses, differential expression of several exocrine pancreas proteases with directionality that was consistent with β-cell numbers were identified. Based on these lines of evidence, we hypothesized that pancreatic proteases directly impact β-cells. In the present study, we examined this possibility and found that pancreatic protease genes contribute to proper maintenance of normal β-cell numbers, proliferation in larval zebrafish, and regulation of AS and BBS β-cell phenotypes. Our data suggest that these proteins can be taken up directly by cultured β-cells and ex vivo murine islets, inducing proliferation in both. Endogenous uptake of pancreatic proteases by β-cells was confirmed in vivo using transgenic zebrafish and in intact murine pancreata. Taken together, these findings support a novel proliferative signaling role for exocrine pancreas proteases through interaction with endocrine β-cells. Summary: In this paper, we examine the role of exocrine pancreas protease genes in β-cell number using zebrafish and murine models, and identify a novel relationship between the two.
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Affiliation(s)
- Timothy L Hostelley
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Jessica E Nesmith
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Emily Larkin
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Amanda Jones
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Daniel Boyes
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Carmen C Leitch
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Magali Fontaine
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Norann A Zaghloul
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
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19
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Dybala MP, Kuznetsov A, Motobu M, Hendren-Santiago BK, Philipson LH, Chervonsky AV, Hara M. Integrated Pancreatic Blood Flow: Bidirectional Microcirculation Between Endocrine and Exocrine Pancreas. Diabetes 2020; 69:1439-1450. [PMID: 32198213 PMCID: PMC7306124 DOI: 10.2337/db19-1034] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/09/2020] [Indexed: 02/06/2023]
Abstract
The pancreatic islet is a highly vascularized endocrine micro-organ. The unique architecture of rodent islets, a so-called core-mantle arrangement seen in two-dimensional images, led researchers to seek functional implications for islet hormone secretion. Three models of islet blood flow were previously proposed, all based on the assumption that islet microcirculation occurs in an enclosed structure. Recent electrophysiological and molecular biological studies using isolated islets also presumed unidirectional flow. Using intravital analysis of the islet microcirculation in mice, we found that islet capillaries were continuously integrated to those in the exocrine pancreas, which made the islet circulation rather open, not self-contained. Similarly in human islets, the capillary structure was integrated with pancreatic microvasculature in its entirety. Thus, islet microcirculation has no relation to islet cytoarchitecture, which explains its well-known variability throughout species. Furthermore, tracking fluorescent-labeled red blood cells at the endocrine-exocrine interface revealed bidirectional blood flow, with similar variability in blood flow speed in both the intra- and extra-islet vasculature. To date, the endocrine and exocrine pancreas have been studied separately by different fields of investigators. We propose that the open circulation model physically links both endocrine and exocrine parts of the pancreas as a single organ through the integrated vascular network.
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Affiliation(s)
| | | | - Maki Motobu
- Department of Pathology, The University of Chicago, Chicago, IL
| | | | - Louis H Philipson
- Department of Medicine, The University of Chicago, Chicago, IL
- Department of Pediatrics, The University of Chicago, Chicago, IL
| | | | - Manami Hara
- Department of Medicine, The University of Chicago, Chicago, IL
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20
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Nakajima K, Higuchi R, Iwane T, Iida A. The association of low serum salivary and pancreatic amylases with the increased use of lipids as an energy source in non-obese healthy women. BMC Res Notes 2020; 13:237. [PMID: 32375859 PMCID: PMC7201991 DOI: 10.1186/s13104-020-05078-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 04/23/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE It is unknown whether low serum levels of salivary and pancreatic amylases are associated with the high combustion of carbohydrates or lipids for energy. Elevated blood ketones and a low respiratory quotient (RQ) can reflect the preferential combustion of lipids relative to carbohydrates. Therefore, using the data from our previous study, we investigated if low levels of serum amylases were associated with a high serum ketone level and low RQ in 60 healthy non-obese young women aged 20-39 years old. RESULTS Serum ketones [3-hydroxybutyric acid (3-HBA) and acetoacetic acid (AA)] were inversely correlated with RQs, but not body mass index (BMI) or glycated haemoglobin (HbA1c) levels. Logistic regression analysis showed that high levels of serum ketones (3-HBA ≥ 24 μmol/L and AA ≥ 17 μmol/L) and a low RQ (< 0.766) were significantly associated with low serum salivary (< 60 U/L) and pancreatic (< 29 U/L) amylase levels, respectively. These associations were not altered by further adjustments for age, BMI, HbA1c, and estimated glomerular filtration rate. These results confirm the high combustion of lipids for energy in individuals with low serum amylase levels, suggesting a close relationship between circulating amylases and internal energy production.
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Affiliation(s)
- Kei Nakajima
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, 1-10-1 Heisei-cho, Yokosuka, Kanagawa, 238-8522, Japan.
- Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan.
- Graduate School of Health Innovation, Kanagawa University of Human Services, Research Gate Building Tonomachi 2-A, 3-25-10 Tonomachi, Kawasaki, Kanagawa, 210-0821, Japan.
| | - Ryoko Higuchi
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, 1-10-1 Heisei-cho, Yokosuka, Kanagawa, 238-8522, Japan
| | - Taizo Iwane
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, 1-10-1 Heisei-cho, Yokosuka, Kanagawa, 238-8522, Japan
| | - Ayaka Iida
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, 1-10-1 Heisei-cho, Yokosuka, Kanagawa, 238-8522, Japan
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21
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Chang GR, Hou PH, Chen WK, Lin CT, Tsai HP, Mao FC. Exercise Affects Blood Glucose Levels and Tissue Chromium Distribution in High-Fat Diet-Fed C57BL6 Mice. Molecules 2020; 25:molecules25071658. [PMID: 32260278 PMCID: PMC7180458 DOI: 10.3390/molecules25071658] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 12/30/2022] Open
Abstract
Obesity is commonly associated with hyperglycemia and type 2 diabetes and negatively affects chromium accumulation in tissues. Exercise prevents and controls obesity and type 2 diabetes. However, little information is available regarding chromium changes for regulating glucose homeostasis in high-fat diet (HFD)-fed animals/humans who exercise. Therefore, this study explored the effects of exercise and whether it alters chromium distribution in obese mice. Male C57BL6/J mice aged 4 weeks were randomly divided into two groups and fed either an HFD or standard diet (SD). Each group was subgrouped into two additional groups in which one subgroup was exposed to treadmill exercise for 12 weeks and the other comprised control mice. HFD-fed mice that exercised exhibited significant lower body weight gain, food/energy intake, daily food efficiency, and serum leptin and insulin levels than did HFD-fed control mice. Moreover, exercise reduced fasting glucose and enhanced insulin sensitivity and pancreatic β-cell function, as determined by homeostasis model assessment (HOMA)-insulin resistance and HOMA-β indices, respectively. Exercise also resulted in markedly higher chromium levels within the muscle, liver, fat tissues, and kidney but lower chromium levels in the bone and bloodstream in obese mice than in control mice. However, these changes were not noteworthy in SD-fed mice that exercised. Thus, exercise prevents and controls HFD-induced obesity and may modulate chromium distribution in insulin target tissues.
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Affiliation(s)
- Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-T.L.)
- Veterinary Teaching Hospital, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan;
| | - Po-Hsun Hou
- Department of Psychiatry, Taichung Veterans General Hospital, 4 Section, 1650 Taiwan Boulevard, Taichung 40705, Taiwan;
- Faculty of Medicine, National Yang-Ming University, 2 Section, 155 Linong Street, Beitou District, Taipei 11221, Taiwan
| | - Wen-Kai Chen
- Department of Veterinary Medicine, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan;
| | - Chien-Teng Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-T.L.)
| | - Hsiao-Pei Tsai
- Veterinary Teaching Hospital, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan;
| | - Frank Chiahung Mao
- Department of Veterinary Medicine, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan;
- Correspondence: ; Tel.: +886-4-22840368 (ext. 25)
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Pierzynowska K, Oredsson S, Pierzynowski S. Amylase-Dependent Regulation of Glucose Metabolism and Insulin/Glucagon Secretion in the Streptozotocin-Induced Diabetic Pig Model and in a Rat Pancreatic Beta-Cell Line, BRIN-BD11. J Diabetes Res 2020; 2020:2148740. [PMID: 33294459 PMCID: PMC7688362 DOI: 10.1155/2020/2148740] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 10/01/2020] [Accepted: 10/28/2020] [Indexed: 01/21/2023] Open
Abstract
The current study was aimed at highlighting the role of blood pancreatic amylase in the regulation of glucose homeostasis and insulin secretion in a porcine model of streptozotocin- (STZ-) induced diabetes and in a rat pancreatic beta-cell line, BRIN-BD11. Blood glucose, plasma insulin, and glucagon levels were measured following a duodenal glucose tolerance test (IDGTT), in four pigs with STZ-induced type 2 diabetes (T2D pigs) and in four pigs with STZ-induced type 1 diabetes (T1D pigs). Four intact pigs were used as the control group. The effect of amylase supplementation on both acute and chronic insulin secretion was determined in a BRIN-BD11 cell line. The amylase infusion had no effect on the glucose utilization curve or glucagon levels in the healthy pigs. However, a significant lowering of insulin release was observed in healthy pigs treated with amylase. In the T2D pigs, the glucose utilization curve was significantly lowered in the presence of amylase, while the insulin response curve remained unchanged. Amylase also significantly increased glucagon release during the IDGTT in the T2D and T1D pigs, by between 2- and 4-fold. Amylase did not affect the glucose utilization curve in the T1D pigs. Amylase supplementation significantly decreased both acute and chronic insulin secretion in the BRIN-BD11 cells. These data confirm our previous observations and demonstrate the participation of pancreatic amylase in glucose absorption/utilization. Moreover, the present study clearly highlights the direct impact of pancreatic blood amylase on insulin secretion from pancreatic beta-cells and its interactions with insulin and glucagon secretion in a porcine model.
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Affiliation(s)
- Kateryna Pierzynowska
- Department of Animal Physiology, The Kielanowski Institute of Animal Nutrition and Physiology Polish Academy of Sciences, Instytucka 3, 05110 Jabłonna, Poland
- Department of Biology, Lund University, Sölvegatan 35, 22362 Lund, Sweden
- SGPlus-Group, Alfågelgränden 24, 23132 Trelleborg, Sweden
| | - Stina Oredsson
- Department of Biology, Lund University, Sölvegatan 35, 22362 Lund, Sweden
| | - Stefan Pierzynowski
- Department of Biology, Lund University, Sölvegatan 35, 22362 Lund, Sweden
- SGPlus-Group, Alfågelgränden 24, 23132 Trelleborg, Sweden
- Department of Biology, Institute Rural Medicine, Jaczewskiego 2, 20950 Lublin, Poland
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