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Lewellen KA, Maatman TK, House MG, McGreevy K, Cavaghan MK, Dorwart MR, Fogel EL, Haste PM, Montero AM, Roch AM, Zyromski NJ. Total Pancreatectomy With Percutaneous Islet Autotransplant After Remote Islet Processing: A Viable Paradigm? Pancreas 2024; 53:e796-e801. [PMID: 38820448 DOI: 10.1097/mpa.0000000000002376] [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: 06/02/2024]
Abstract
OBJECTIVES Total pancreatectomy with islet autotransplant (TPIAT) is important therapy for select chronic pancreatitis (CP) patients. The specialized technique of islet isolation limits widespread TPIAT use. We hypothesized that remote islet isolation provides satisfactory islet yield and perioperative outcomes. METHODS A retrospective review of TPIAT patients between 2020 and 2022 was conducted. Islet isolation was performed off-site, with percutaneous intraportal islet autotransplant (IAT) completed the morning following pancreatectomy. Demographics and perioperative outcomes were analyzed. RESULTS Fourteen patients underwent TPIAT; median age was 43 (interquartile range, 12.5) years. Operation occurred 7.5 (14.8) years after pancreatitis diagnosis. The most common pancreatitis etiology was genetic (50%). All patients underwent preoperative endoscopic therapy; three underwent prior pancreatectomy. Operative time was 236 (51) minutes; subsequent percutaneous IAT time was 87 (35) minutes. The islet equivalent (IEQ)/kilogram (kg) yield was 3456 (3815) IEQ/kg. Nine patients had positive islet cultures. Two thromboembolic events and one bacteremia occurred. One perihepatic hematoma occurred after percutaneous portal venous access. The median postoperative length of stay was 14.5 days, and five patients (36%) were readmitted within 90 days. All patients were discharged home on insulin. No mortality occurred. CONCLUSIONS Total pancreatectomy with remote islet isolation provides excellent islet yield for autotransplant and satisfactory perioperative outcomes.
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Affiliation(s)
| | | | | | | | | | | | - Evan L Fogel
- Division of Gastroenterology and Hepatology, Department of Medicine
| | - Paul M Haste
- Department of Clinical Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN
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2
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Haddad EN, Lansang MC, Xiao H, Walsh RM, Simon R, Hatipoglu BA, Zhou K. Preoperative and Postoperative Predictors of Insulin Independence From Total Pancreatectomy and Islet Autotransplantation. Endocr Pract 2024; 30:752-757. [PMID: 38871053 DOI: 10.1016/j.eprac.2024.05.013] [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: 03/19/2024] [Revised: 05/20/2024] [Accepted: 05/21/2024] [Indexed: 06/15/2024]
Abstract
OBJECTIVE This study examined the preoperative and postoperative variables associated with 1 year and long-term insulin independence following total pancreatectomy and islet autotransplantation (TPIAT). METHODS 46 TPIAT patients from 2010 to 2022 in a single hospital system were retrospectively analyzed. Pre- and postoperative variables were compared between short-term (1 year) and long-term (last follow-up after year 1) insulin-independent versus -dependent patients. RESULTS Nine (20%) and seven (15%) patients achieved short- and long-term insulin independence, respectively. The patients were followed up for a median of 2.8 years (interquartile range [IQR] 1.0, 4.7). Short-term insulin independence was associated with higher median transplanted islet equivalents (IEQ) per kg (6981 vs 4493, P = .02), lower units of basal insulin on discharge (7 vs 12, P = .009), and lower rates of discharge with an insulin regimen (67% vs 100%, P = .006). Odds of short-term insulin independence increased by 80% for every 1000 increase in IEQ per kg (OR 1.80, CI 1.18-3.12, P = .005) and decreased by 32% for every additional basal unit of insulin on discharge (OR 0.68, CI 0.42-0.91, P = .003) on average. Long-term insulin independence was also associated with transplanted IEQ per kg. No patient on antihyperglycemic medication before surgery achieved insulin independence. CONCLUSION Short- and long-term insulin independence after TPIAT is associated with higher transplanted IEQ per kg and immediate postoperative variables that can be used to inform the discussions clinicians have with their patients regarding glycemic prognosis following TPIAT.
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Affiliation(s)
- Eliot N Haddad
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - M Cecilia Lansang
- Department of Endocrinology and Metabolism, Cleveland Clinic, Cleveland, Ohio
| | - Huijun Xiao
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
| | - R Matthew Walsh
- Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
| | - Robert Simon
- Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
| | - Betul A Hatipoglu
- Center for Diabetes and Metabolic Care, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Keren Zhou
- Department of Endocrinology and Metabolism, Cleveland Clinic, Cleveland, Ohio.
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3
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Yamane K, Anazawa T, Nagai K, Ito T, Hatano E. Current status of total pancreatectomy with islet autotransplantation for chronic and recurrent acute pancreatitis. Ann Gastroenterol Surg 2024; 8:401-412. [PMID: 38707227 PMCID: PMC11066494 DOI: 10.1002/ags3.12767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/17/2023] [Accepted: 12/12/2023] [Indexed: 05/07/2024] Open
Abstract
Total pancreatectomy with islet autotransplantation (TPIAT) is an established and effective treatment modality for patients diagnosed with intractable chronic pancreatitis (CP) and recurrent acute pancreatitis (RAP). TPIAT primarily aims to manage debilitating pain leading to impaired quality of life among patients with CP or RAP, which can be successfully managed with medical, endoscopic, or surgical interventions. TPIAT is significantly successful in relieving pain associated with CP and improving health-related quality of life outcomes. Furthermore, the complete loss of pancreatic endocrine function attributed to total pancreatectomy (TP) can be compensated by autologous islet transplantation (IAT). Patients receiving IAT can achieve insulin independence or can be less dependent on exogenous insulin compared with those receiving TP alone. Historically, TPIAT has been mainly used in the United States, and its outcomes have been improving due to technological advancements. Despite some challenges, TPIAT can be a promising treatment for patients with CP-related intractable pain. Thus far, TPIAT is not commonly performed in Japan. Nevertheless, it may improve health-related quality of life in Japanese patients with CP, similar to Western patients. This review article aimed to provide an overview of the indications, related procedures, and outcomes of TPIAT and to discuss future prospects in Japan.
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Affiliation(s)
- Kei Yamane
- Department of SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
| | - Takayuki Anazawa
- Department of SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
| | - Kazuyuki Nagai
- Department of SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
| | - Takashi Ito
- Department of SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
| | - Etsuro Hatano
- Department of SurgeryGraduate School of Medicine, Kyoto UniversityKyotoJapan
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Hasse JM, Meng S, Silpe S, Naziruddin B. Nutrition challenges following total pancreatectomy with islet autotransplantation. Nutr Clin Pract 2024; 39:86-99. [PMID: 38213274 DOI: 10.1002/ncp.11106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/06/2023] [Accepted: 11/07/2023] [Indexed: 01/13/2024] Open
Abstract
Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical treatment option for patients with chronic pancreatitis who have not responded to other therapies. TP offers pain relief whereas IAT preserves beta cell mass to reduce endocrine insufficiency. During the surgical procedure, the entire pancreas is removed. Islet cells from the pancreas are then isolated, purified, and infused into the liver via the portal vein. Successful TPIAT relieves pain for a majority of patients but is not without obstacles, specifically gastrointestinal, exocrine, and endocrine challenges. The postoperative phase can be complicated by gastrointestinal symptoms causing patients to have difficulty regaining adequate oral intake. Enteral nutrition is frequently provided as a bridge to oral diet. Patients undergoing TPIAT must be monitored for macronutrient and micronutrient deficiencies following the procedure. Exocrine insufficiency must be treated lifelong with pancreatic enzyme replacement therapy. Endocrine function must be monitored and exogenous insulin provided in the postoperative phase; however, a majority of patients undergoing TPIAT require little or no long-term insulin. Although TPIAT can be a successful option for patients with chronic pancreatitis, nutrition-related concerns must be addressed for optimal recovery.
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Affiliation(s)
- Jeanette M Hasse
- Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Shumei Meng
- Division of Endocrinology, Internal Medicine, Baylor University Medical Center, Dallas, Texas, USA
| | - Stephanie Silpe
- Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Bashoo Naziruddin
- Islet Cell Laboratory, Baylor Research Institute, Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
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Bellin MD, Ramanathan K, Chinnakotla S. Total Pancreatectomy with Islet Auto-Transplantation: Surgical Procedure, Outcomes, and Quality of Life. Adv Surg 2023; 57:15-30. [PMID: 37536850 DOI: 10.1016/j.yasu.2023.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
Chronic pancreatitis is a progressive and irreversible process of pancreatic inflammation and fibrosis that can lead to intractable abdominal pain and severely impaired quality of life (QoL). Often patients are refractory to standard medical or endoscopic treatments. Total pancreatectomy (TP) and islet auto-transplantation (TP-IAT) can offer pain relief to patients by removing the entire pancreas and the auto-transplant component ameliorates the resulting diabetes. QoL is significantly improved after TP-IAT when insulin independence is present. Recent data support offering TP-IAT rather than TP alone and treating with exogenous insulin for patients with debilitating chronic pancreatitis.
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Kanemitsu E, Masui T, Nagai K, Anazawa T, Kasai Y, Yogo A, Ito T, Mori A, Takaori K, Uemoto S, Hatano E. Propensity Score Matching Analysis of the Safety of Completion Total Pancreatectomy for Remnant Pancreatic Tumors Versus that of Initial Total Pancreatectomy for Primary Pancreatic Tumors. Ann Surg Oncol 2023; 30:4392-4406. [PMID: 36933081 DOI: 10.1245/s10434-023-13309-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/15/2023] [Indexed: 03/19/2023]
Abstract
BACKGROUND The safety and feasibility of completion total pancreatectomy (TP) for remnant pancreatic neoplasms remain controversial and are rarely compared with that of initial TP. Thus, we aimed to compare the safety of these two procedures inducing a pancreatic state. METHODS Patients who underwent TP for pancreatic neoplasms between 2006 and 2018 at our institution were included in this study. Tumor pathologies were classified into three subgroups according to survival curves. We used 1:1 propensity score matching (PSM) to analyze age, sex, Charlson Comorbidity Index, and tumor stage. Finally, we analyzed the primary outcome Clavien-Dindo classification (CDC) grade, risks of other safety-related outcomes, and the survival rate of patients with invasive cancer. RESULTS Of 54 patients, 16 underwent completion TP (29.6%) and 38 (70.4%) underwent initial TP. Before PSM analysis, age and Charlson Comorbidity Index were significantly higher, and T category and stage were significantly lower for the completion TP group. Upon PSM analysis, these two groups were equivalent in CDC grade [initial TP vs. completion TP: 71.4% (10/14) vs. 78.6% (11/14); p = 0.678] and other safety-related outcomes. Additionally, while the overall survival and recurrence-free survival of patients with invasive cancer were not significantly different between these two groups, the T category and stage tended to be remarkably severe in the initial TP group. CONCLUSIONS PSM analysis for prognostic factors showed that completion TP and initial TP have similar safety-related outcomes that can be used as a decision-making reference in the surgery of pancreatic tumors.
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Affiliation(s)
- Eisho Kanemitsu
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshihiko Masui
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Kazuyuki Nagai
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takayuki Anazawa
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yosuke Kasai
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akitada Yogo
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tatsuo Ito
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akira Mori
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kyoichi Takaori
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Etsuro Hatano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Kabakchieva P, Assyov Y, Gerasoudis S, Vasilev G, Peshevska-Sekulovska M, Sekulovski M, Lazova S, Miteva DG, Gulinac M, Tomov L, Velikova T. Islet transplantation-immunological challenges and current perspectives. World J Transplant 2023; 13:107-121. [PMID: 37388389 PMCID: PMC10303418 DOI: 10.5500/wjt.v13.i4.107] [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: 03/22/2023] [Revised: 05/16/2023] [Accepted: 06/06/2023] [Indexed: 06/16/2023] Open
Abstract
Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes (T1D) by transplanting pancreatic beta cells. Overall, pancreatic islet transplantation has improved to a great extent, and cellular replacement will likely become the mainstay treatment. We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced. Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h. Approximately 54% of the patients gained insulin independence at the end of the first year, while only 20% remained insulin-free at the end of the second year. Eventually, most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation, which imposed the need to improve immunological factors before transplantation. We also discuss the immunosuppressive regimens, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, pretransplant infusions of donor apoptotic cells, B cell depletion, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc.
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Affiliation(s)
- Plamena Kabakchieva
- Clinic of Internal Diseases, Naval Hospital-Varna, Military Medical Academy, Varna 9010, Bulgaria
| | - Yavor Assyov
- Clinic of Endocrinology, Department of Internal Diseases, University Hospital "Alexandrovska", Medical University-Sofia, Sofia 1434, Bulgaria
| | | | - Georgi Vasilev
- Department of Neurology, Faculty of Medicine, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
| | - Monika Peshevska-Sekulovska
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Anesthesiology and Intensive Care, University hospital Lozenetz, Sofia 1407, Bulgaria
| | - Snezhina Lazova
- Department of Pediatric, University Hospital "N. I. Pirogov", Sofia 1606, Bulgaria
- Department of Healthcare, Faculty of Public Health "Prof. Tsekomir Vodenicharov, MD, DSc", Medical University of Sofia, Sofia 1527, Bulgaria
| | | | - Milena Gulinac
- Department of General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
| | - Latchezar Tomov
- Department of Informatics, New Bulgarian University, Sofia 1618, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Lad SU, Ali KF, Johnston PC, San Martin VT, Bottino R, Lin YK, Walsh RM, Stevens T, Tu C, Hatipoglu B. Follow-Up of Patients After Total Pancreatectomy and Islet Cell Autotransplantation at Off-Site Islet Isolation Facility. J Clin Endocrinol Metab 2023; 108:1425-1431. [PMID: 36510395 PMCID: PMC10413425 DOI: 10.1210/clinem/dgac674] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 12/14/2022]
Abstract
CONTEXT Total pancreatectomy with islet autotransplantation (TPIAT) is a definitive management for intractable pain in patients with chronic pancreatitis (CP). Islet autotransplantation (IAT) allows for the preservation of beta cells to prevent complications of long-term diabetes. OBJECTIVE Our study follows TPIAT recipients for up to 12 years to determine the efficacy of the procedure completed with an off-site islet isolation facility. METHODS Patient demographics, mixed meal tolerance test measures, glycosylated hemoglobin, insulin requirements, and homeostatic model assessment for insulin resistance values were collected prior to surgery and at the most recent follow-up assessment. RESULTS Forty-four patients (median age, 46.0 years; range, 20-78 years) underwent TPIAT for CP. At an overall median follow-up time of 845.5 days (range, 195-4470 days) 8 patients were insulin independent and 36 patients were insulin dependent. At the most recent follow-up time point, islet yield per kilogram was the strongest indicator of insulin independence. Homeostatic model assessment for insulin resistance values were comparable between insulin independent and dependent cohorts. CONCLUSIONS Our long-term follow-up data suggest that IAT can effectively reduce insulin requirements and improve postoperative glycemic control.
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Affiliation(s)
- Saloni U Lad
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA
| | - Khawla F Ali
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Muharraq, Bahrain
| | - Philip C Johnston
- Department of Medicine, Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, Northern Ireland, UK
| | - Vicente T San Martin
- Division of Endocrinology and Diabetes, Macromedica Dominicana, Santo Domingo, Dominican Republic
| | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny Health Network Research Institute, Pittsburgh PA 15222, USA
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA
| | - Yu Kuei Lin
- Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - R Matthew Walsh
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Tyler Stevens
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Chao Tu
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Betul Hatipoglu
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Diabetes & Obesity Center, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
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9
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Effectiveness of Intraoperative Versus Dedicated Islet Cell Laboratory Isolation for Total Pancreatectomy With Islet Autotransplant. Transplant Direct 2022; 8:e1314. [PMID: 35415216 PMCID: PMC8989781 DOI: 10.1097/txd.0000000000001314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 11/25/2022] Open
Abstract
Background. Total pancreatectomy with islet autotransplantation (TPIAT) requires a complex islet isolation process of the explanted pancreas. Islet isolation has historically required a specialized laboratory to perform islet isolation. We report our experience with a novel technique of intraoperative islet isolation that does not require a specialized islet laboratory, thereby making the isolation process simpler, more accessible, and less costly. Methods. We performed a retrospective, comparative effectiveness analysis of 50 adult patients who underwent TPIAT from 2012 to 2020 (TPIAT with remote isolation [n = 20] versus intraoperative isolation of islet cells [n = 30]). The primary outcome was islet equivalents per body weight (IEQ/kg) for patients in each group. Results. Mean IEQ/kg‘s (4294 remote group versus 3015 intraoperative group, P = 0.06) and 1-y postoperative C-peptide levels (1.51 ng/mL remote group versus 0.91 ng/mL intraoperative group, P = 0.10) were not different between groups. Mean 1-y HbA1c levels (7.7% in the remote group versus 7.1% intraoperative group, P = 0.67) and 1-y insulin requirements (P = 0.31) were not statistically different. Lower average cost of hospitalization was seen in the intraoperative group, although this was not statistically significant ($104 398 remote versus $78 986 intraoperative, P = 0.81). Conclusions. Intraoperative islet isolation has similar effectiveness in regard to glycemic outcomes compared with the use of a dedicated islet cell isolation laboratory at a lower cost.
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10
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Swauger SE, Hornung LN, Elder DA, Balamurugan AN, Vitale DS, Lin TK, Nathan JD, Abu-El-Haija M. Predictors of Glycemic Outcomes at 1 Year Following Pediatric Total Pancreatectomy With Islet Autotransplantation. Diabetes Care 2022; 45:295-302. [PMID: 35007330 PMCID: PMC8914422 DOI: 10.2337/dc21-1222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 11/23/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Total pancreatectomy with islet autotransplantation (TPIAT) is indicated to alleviate debilitating pancreas-related pain and mitigate diabetes in patients with acute recurrent and chronic pancreatitis when medical/endoscopic therapies fail. Our aim was to evaluate predictors of insulin requirement at 1 year following TPIAT in a cohort of children. RESEARCH DESIGN AND METHODS This was a review of 43 pediatric patients followed after TPIAT for 1 year or longer. Primary outcome was insulin use at 1 year, categorized as follows: insulin independent, low insulin requirement (<0.5 units/kg/day), or high insulin requirement (≥0.5 units/kg/day). RESULTS At 1 year after TPIAT, 12 of 41 (29%) patients were insulin independent and 21 of 41 (51%) had low and 8 of 41 (20%) had high insulin requirement. Insulin-independent patients were younger than those with low and high insulin requirement (median age 8.2 vs. 14.6 vs. 13.1 years, respectively; P = 0.03). Patients with insulin independence had a higher number of transplanted islet equivalents (IEQ) per kilogram body weight (P = 0.03) and smaller body surface area (P = 0.02), compared with those with insulin dependence. Preoperative exocrine insufficiency was associated with high insulin requirement (P = 0.03). Higher peak C-peptide measured by stimulated mixed-meal tolerance testing (MMTT) at 3 and 6 months post-TPIAT was predictive of lower insulin requirement at 1 year (P = 0.006 and 0.03, respectively). CONCLUSIONS We conclude that insulin independence following pediatric TPIAT is multifactorial and associated with younger age, higher IEQ per kilogram body weight transplanted, and smaller body surface area at time of operation. Higher peak C-peptide measured by MMTT following TPIAT confers a higher likelihood of low insulin requirement.
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Affiliation(s)
- Sarah E Swauger
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Lindsey N Hornung
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Deborah A Elder
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Appakalai N Balamurugan
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Department of Surgery, University of Cincinnati College of Medicine Cincinnati, OH
| | - David S Vitale
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.,Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Tom K Lin
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.,Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Jaimie D Nathan
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Department of Surgery, University of Cincinnati College of Medicine Cincinnati, OH
| | - Maisam Abu-El-Haija
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.,Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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11
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McDowell RE, Ali KF, Lad S, San Martin VT, Bottino R, Walsh M, Stevens T, Wilke W, Kirwan JP, Hatipoglu B. Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation. Cell Transplant 2021; 30:9636897211057440. [PMID: 34757864 PMCID: PMC8586172 DOI: 10.1177/09636897211057440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients (n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients (n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients (P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT (P=0.01, R2=0.489 and P=0.03, R2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration (P<0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.
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Affiliation(s)
- Ruth E McDowell
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Biology, Oberlin College, Oberlin, OH, USA
| | - Khawla F Ali
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, USA.,Royal College of Surgeons in Ireland-Medical University of Bahrain, Muharraq, Bahrain
| | - Saloni Lad
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
| | | | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny Health Network Research Institute, Pittsburgh, PA, USA.,Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Matthew Walsh
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Tyler Stevens
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - William Wilke
- Orthopaedic & Rheumatologic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - John P Kirwan
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Betul Hatipoglu
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, USA.,Diabetes & Obesity Center, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
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12
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Eldredge J, Couper MR, Moore DJ, Khurana S, Chen JW, Couper JJ, Drogemuller CJ, Radford T, Kay TW, Loudovaris T, Wilks M, Coates PT, Couper RT. South Australian experience with paediatric total pancreatectomy and islet autotransplantation for PRSS1-associated hereditary pancreatitis. Med J Aust 2021; 215:294-296.e1. [PMID: 34490631 DOI: 10.5694/mja2.51247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 11/17/2022]
Affiliation(s)
| | | | - David J Moore
- Women's and Children's Hospital, Adelaide, SA.,University of Adelaide, Adelaide, SA
| | - Sanjeev Khurana
- Women's and Children's Hospital, Adelaide, SA.,University of Adelaide, Adelaide, SA
| | - John Wc Chen
- Flinders Medical Centre, Adelaide, SA.,Flinders University, Adelaide, SA
| | - Jennifer J Couper
- Women's and Children's Hospital, Adelaide, SA.,University of Adelaide, Adelaide, SA
| | | | | | - Thomas W Kay
- St Vincent's Institute of Medical Research, Melbourne, VIC.,University of Melbourne, Melbourne, VIC
| | - Tom Loudovaris
- St Vincent's Institute of Medical Research, Melbourne, VIC
| | - Michael Wilks
- Women's and Children's Hospital, Adelaide, SA.,Radiology SA, Adelaide, SA
| | - Patrick T Coates
- University of Adelaide, Adelaide, SA.,Royal Adelaide Hospital, Adelaide, SA
| | - Richard Tl Couper
- Women's and Children's Hospital, Adelaide, SA.,University of Adelaide, Adelaide, SA
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13
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Nanno Y, Wastvedt S, Freeman ML, Trikudanathan G, Schwarzenberg SJ, Downs EM, Kirchner VA, Pruett TL, Beilman GJ, Chinnakotla S, Hering BJ, Bellin MD. Metabolic measures before surgery and long-term diabetes outcomes in recipients of total pancreatectomy and islet autotransplantation. Am J Transplant 2021; 21:3411-3420. [PMID: 33754431 PMCID: PMC11246612 DOI: 10.1111/ajt.16573] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/14/2021] [Accepted: 03/13/2021] [Indexed: 01/25/2023]
Abstract
In this single-center, retrospective cohort study, we aimed to elucidate simple metabolic markers or surrogate indices of β-cell function that best predict long-term insulin independence and goal glycemic HbA1c control (HbA1c ≤ 6.5%) after total pancreatectomy with islet autotransplantation (TP-IAT). Patients who underwent TP-IAT (n = 371) were reviewed for metabolic measures before TP-IAT and for insulin independence and glycemic control at 1, 3, and 5 years after TP-IAT. Insulin independence and goal glycemic control were achieved in 33% and 68% at 1 year, respectively. Although the groups who were insulin independent and dependent overlap substantially on baseline measures, an individual who has abnormal glycemia (prediabetes HbA1c or fasting glucose) or estimated IEQs/kg < 2500 has a very high likelihood of remaining insulin dependent after surgery. In multivariate logistic regression modelling, metabolic measures correctly predicted insulin independence in about 70% of patients at 1, 3, and 5 years after TP-IAT. In conclusion, metabolic testing measures before surgery are highly associated with diabetes outcomes after TP-IAT at a population level and correctly predict outcomes in approximately two out of three patients. These findings may aid in prognostic counseling for chronic pancreatitis patients who are likely to eventually need TP-IAT.
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Affiliation(s)
- Yoshihide Nanno
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota
- Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Solvejg Wastvedt
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Martin L. Freeman
- Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Guru Trikudanathan
- Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Sarah J. Schwarzenberg
- Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Elissa M. Downs
- Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Varvara A Kirchner
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Timothy L. Pruett
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Gregory J. Beilman
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Srinath Chinnakotla
- Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota
- Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Bernhard J. Hering
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota
- Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Melena D. Bellin
- Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota
- Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, Minnesota
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14
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Abstract
This review focuses on the human pancreatic islet-including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.
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Affiliation(s)
- John T Walker
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Diane C Saunders
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Marcela Brissova
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alvin C Powers
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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15
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Naples R, Perlmutter BC, Thomas JD, McMichael J, Bottino R, Solomina J, Trucco M, Augustin T, Simon R, Walsh RM. Clinical Significance of Postoperative Antibiotic Treatment for Positive Islet Cultures After Total Pancreatectomy With Islet Autotransplantation. Pancreas 2021; 50:1000-1006. [PMID: 34629454 DOI: 10.1097/mpa.0000000000001874] [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: 12/10/2022]
Abstract
OBJECTIVES Islet cultures are routinely performed in total pancreatectomy with islet autotransplantation (TPIAT), and the need for empiric antibiotic treatment based on culture results is unknown. We evaluated the effect of postoperative antibiotic treatment for positive islet cultures on clinical infection. METHODS Seventy-nine patients undergoing TPIAT were reviewed. Prophylactic perioperative ceftriaxone and metronidazole were administered, and transplanted islet preparations included ciprofloxacin. Postoperative antibiotics were not routinely given for positive cultures unless a clinical infection was suspected. The primary end point was 30-day infectious complications. RESULTS Fifty-one patients (65%) had a positive culture. Overall, 39 patients (87%) had organisms susceptible to our perioperative antibiotic regimen. There was no difference in the infectious complication rate between those with positive compared with negative cultures (16% vs 29%, P = 0.17). Patients with a positive culture had similar 30-day postoperative infectious complication rates whether receiving postoperative antibiotics (n = 7) or not (14% vs 16%, P = 0.91). Only 1 patient had a correlation of clinical and islet cultures. CONCLUSIONS Beyond prophylactic antibiotics, empiric antibiotic treatment for a positive culture is not warranted and provides a rationale for the abandonment of routine cultures in TPIAT.
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Affiliation(s)
- Robert Naples
- From the Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - Breanna C Perlmutter
- From the Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - Jonah D Thomas
- From the Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - John McMichael
- From the Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - Rita Bottino
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA
| | - Julia Solomina
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA
| | - Massimo Trucco
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA
| | - Toms Augustin
- From the Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - Robert Simon
- From the Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
| | - R Matthew Walsh
- From the Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
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16
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Kochar IS, Jain R. Pancreas transplant in type 1 diabetes mellitus: the emerging role of islet cell transplant. Ann Pediatr Endocrinol Metab 2021; 26:86-91. [PMID: 34218630 PMCID: PMC8255858 DOI: 10.6065/apem.2142012.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/12/2021] [Indexed: 11/28/2022] Open
Abstract
Pancreas transplant, both whole pancreas and islet cell, is a known therapeutic option for treatment of type 1 diabetes mellitus. Islet cell transplant began as an experimental therapy but is emerging to be quite beneficial due to less surgical risk and fewer complications. It is also considered a promising option in pediatric patients. In this review the authors discuss the indications, procedure, and benefits of islet cell transplant along with newer strategies for improving outcomes.
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Affiliation(s)
- Inderpal Singh Kochar
- Department of Pediatric and Adolescent Endocrinology, Indraprastha Apollo Hospital, New Delhi, India
| | - Rakhi Jain
- Department of Pediatric and Adolescent Endocrinology, Indraprastha Apollo Hospital, New Delhi, India,Address for correspondence: Rakhi Jain Department of Pediatric and Adolescent Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi 110076, India
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17
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Vasu S, Yang JM, Hodges J, Abu-El-Haija MA, Adams DB, Balamurugan AN, Beilman GJ, Chinnakotla S, Conwell DL, Freeman ML, Gardner TB, Hatipoglu B, Kirchner V, Lara LF, Morgan KA, Nathan JD, Posselt A, Pruett TL, Schwarzenberg SJ, Singh VK, Wijkstrom M, Witkowski P, Naziruddin B, Bellin MD. Circulating miRNA in Patients Undergoing Total Pancreatectomy and Islet Autotransplantation. Cell Transplant 2021; 30:963689721999330. [PMID: 33902338 PMCID: PMC8718159 DOI: 10.1177/0963689721999330] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples (n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p (P = 0.03), hsa-miR-148a-3p (P = 0.04) and hsa-miR-221-3p (P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p (P = 0.04) and hsa-miR-7-5p (P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p (P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p (P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg (r = −0.20, P = 0.02). Also, hsa-miR-200c (r = 0.18, P = 0.03) and hsa-miR-221-3p (r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.
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Affiliation(s)
- Srividya Vasu
- Islet Cell Laboratory, Baylor University Medical Center, Dallas TX, USA
| | - Jiemin M Yang
- School of Public Health (Biostatistics), University of Minnesota, Minneapolis, MN, USA
| | - James Hodges
- School of Public Health (Biostatistics), University of Minnesota, Minneapolis, MN, USA
| | | | - David B Adams
- Medical University of South Carolina, Charleston, SC, USA
| | - Appakalai N Balamurugan
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,University of Louisville, Louisville, KY, USA
| | - Greg J Beilman
- University of Minnesota Medical School, Minneapolis, MN, USA
| | | | - Darwin L Conwell
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | | | | | | | - Luis F Lara
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | - Jaimie D Nathan
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Andrew Posselt
- University of California San Francisco, San Francisco, CA, USA
| | | | | | | | | | | | - Bashoo Naziruddin
- Islet Cell Laboratory, Baylor University Medical Center, Dallas TX, USA
| | - Melena D Bellin
- University of Minnesota Medical School, Minneapolis, MN, USA
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18
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Continuous Glucose Monitoring in the Intensive Care Unit Following Total Pancreatectomy with Islet Autotransplantation in Children: Establishing Accuracy of the Dexcom G6 Model. J Clin Med 2021; 10:jcm10091893. [PMID: 33925523 PMCID: PMC8123839 DOI: 10.3390/jcm10091893] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/21/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
Hyperglycemia is detrimental to postoperative islet cell survival in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT). This makes continuous glucose monitoring (CGM) a useful management tool. We evaluated the accuracy of the Dexcom G6 CGM in pediatric intensive care unit patients following TPIAT. Twenty-five patients who underwent TPIAT had Dexcom G6 glucose values compared to paired serum glucose values. All paired glucose samples were obtained within 5 minutes of each other during the first seven days post TPIAT. Data were evaluated using mean absolute difference (MAD), mean absolute relative difference (MARD), %20/20, %15/15 accuracy, and Clarke Error Grid analysis. Exclusions included analysis during the CGM "warm-up" period and hydroxyurea administration (known drug interference). A total of 183 time-matched samples were reviewed during postoperative days 2-7. MAD was 14.7 mg/dL and MARD was 13.4%, with values of 15.2%, 14.0%, 12.1%, 11.4%, 13.2% and 14.1% at days 2, 3, 4, 5, 6 and 7, respectively. Dexcom G6 had a %20/20 accuracy of 78%, and a %15/15 accuracy of 64%. Clarke Error Grid analysis showed that 77% of time-matched values were clinically accurate, and 100% were clinically acceptable. The Dexcom G6 CGM may be an accurate tool producing clinically acceptable values to make reliable clinical decisions in the immediate post-TPIAT period.
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19
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Swentek L, Chung D, Ichii H. Antioxidant Therapy in Pancreatitis. Antioxidants (Basel) 2021; 10:657. [PMID: 33922756 PMCID: PMC8144986 DOI: 10.3390/antiox10050657] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatitis is pathologic inflammation of the pancreas characterized by acinar cell destruction and oxidative stress. Repeated pancreatic insults can result in the development of chronic pancreatitis, characterized by irreversible fibrosis of the pancreas and many secondary sequelae, ultimately leading to the loss of this important organ. We review acute pancreatitis, chronic pancreatitis, and pancreatitis-related complications. We take a close look at the pathophysiology with a focus on oxidative stress and how it contributes to the complications of the disease. We also take a deep dive into the evolution and current status of advanced therapies for management including dietary modification, antioxidant supplementation, and nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1(Nrf2-keap1) pathway activation. In addition, we discuss the surgeries aimed at managing pain and preventing further endocrine dysfunction, such as total pancreatectomy with islet auto-transplantation.
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Affiliation(s)
| | | | - Hirohito Ichii
- Department of Surgery, University of California, Irvine, CA 92868, USA; (L.S.); (D.C.)
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20
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Maatman TK, Zyromski NJ. In Brief. Curr Probl Surg 2021. [PMID: 32297552 DOI: 10.1016/j.cpsurg.2020.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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21
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Factors Associated With Morbidity Following Total Pancreatectomy and Islet Autotransplantation: A NSQIP Analysis. Transplant Proc 2021; 53:705-711. [PMID: 33563474 DOI: 10.1016/j.transproceed.2020.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/28/2020] [Accepted: 11/23/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND Total pancreatectomy with islet autotransplantation is a therapeutic surgical option for patients with chronic pancreatitis leading to significant reduction in pain, improvement in quality of life, and potential for preservation of partial to full endocrine function. Data on the factors associated with short-term morbidities are limited. METHODS We queried the American College of Surgeons National Surgery Quality Improvement Project for patients undergoing total pancreatectomy with islet autotransplantation from 2005 to 2015. We determined 30-day morbidity and mortality and performed univariate and multivariate analysis to determine the preoperative and intraoperative factors associated with development of postoperative infectious complications. RESULTS The rate of 30-day postoperative morbidity in 384 patients undergoing total pancreatectomy with islet autotransplantation was 36% with an overall mortality of 1%. Postoperative infectious complications developed in 29% of patients and were associated with increased operative time (P = .016),and higher postoperative wound class (P = .045). After risk adjustment, only increased operative time was independently associated with increased rates of infectious complications (OR=1.1, 95% CI = 1.01-1.13, P = .02). CONCLUSIONS Total operative time is independently associated with increased postoperative infectious complications in total pancreatectomy with islet autotransplantation. Future interventions aimed at optimizing islet isolation, surgical approach, and refinement of patient selection criteria present opportunities for reducing operative time and potentially reducing the morbidity of this surgical procedure.
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22
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Imaging prediction of islet yield and post-operative insulin requirement in children undergoing total pancreatectomy with islet autotransplantation. Pancreatology 2021; 21:269-274. [PMID: 33339723 DOI: 10.1016/j.pan.2020.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/10/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Predicting post-operative glycemic control in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) remains difficult. The purpose of our study was to explore preoperative imaging as a marker for islet yield and insulin need in pediatric patients undergoing TPIAT. METHODS This was a retrospective study of children (≤18 years) who had undergone TPIAT between April 2015 and December 2018 and had 6 or more months of post-TPIAT follow-up. Patient specific factors (height, weight, body mass index [BMI], body surface area [BSA]) and pancreas volume segmented from the most recent pre-operative cross-sectional imaging were explored as predictors of islet yield (total islet counts [TIC], total islet equivalents [TIE], islet equivalents per kilogram body weight [IEQ/kg]) and glycemic control (total daily dose of insulin per kilogram body weight [TDD/kg], insulin independence) using Pearson correlation and univariate and multiple regression. RESULTS Thirty-three patients, median age 13 years (IQR: 10-15 years), 64% female (21/33) met inclusion criteria. Nine patients (27%) achieved insulin independence at six months. Median TIE isolated was 310,000 (IQR: 200,000-460,000). Segmented pancreas volume was moderately associated with TIE (coefficient estimate = 0.34, p = 0.034). On multiple regression analysis, there was no significant predictor of insulin independence but number of attacks of pancreatitis (estimate = 0.024; p = 0.018) and segmented pancreas volume by body weight (estimate = -0.71; p < 0.001) were significant predictors of insulin TDD/kg. CONCLUSION Pancreas volume segmented from pre-TPIAT imaging has predictive performance for post-TPIAT insulin need in children.
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23
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Short- and long-term surgical outcomes of total pancreatectomy with islet autotransplantation: A comparative analysis of surgical technique and intraoperative heparin dosing to optimize outcomes. Pancreatology 2021; 21:291-298. [PMID: 33268025 DOI: 10.1016/j.pan.2020.11.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/16/2020] [Accepted: 11/21/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Total pancreatectomy with islet autotransplantation (TP-IAT) is an uncommon surgical procedure with unique perioperative management. We evaluated the short- and long-term morbidity and mortality of TP-IAT to optimize surgical technique and heparin dosing during islet autotransplantation. METHODS Eighty patients with chronic pancreatitis undergoing TP-IAT were reviewed. Primary outcome was to evaluate morbidity and mortality based on operative technique: classic (resection of antrum) vs pylorus-preserving. Secondary outcome was to evaluate the effect of heparin dosing (<60 vs ≥ 60 units/kg) during islet autotransplantation on postoperative hemorrhage and portal vein thrombosis (PVT) rates. RESULTS There was no 90-day mortality, and median length of stay was 9 days. All patients underwent an open operation with 53 (66%) pylorus-preserving resections. The 30-day morbidity rate was 39%, with no difference between operative technique (p = 0.82). The median dose was different for each heparin group (<60: 52 units/kg vs ≥ 60: 66 units/kg, p < 0.0001). No difference was observed in postoperative hemorrhage rates between heparin groups (<60: 9% vs ≥ 60: 9%, p = 0.97), with no known incidence of PVT. Median follow-up was 36 months (IQR, 14-71). Morbidity >30 days after TP-IAT was 43% with a higher rate in the pylorus-preserving group (55% vs 15%, p < 0.0001), mainly attributed to marginal ulcer formation (15% vs 0%, p = 0.03). CONCLUSIONS A classic TP-IAT technique should be universally adopted to achieve optimal outcomes, particularly to prevent the formation of marginal ulcers. When considering PVT versus postoperative hemorrhage risk, a lower heparin dose nearing 50 units/kg is optimal. These findings highlight potential areas for future improvement.
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24
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Narayanan S, Bhutiani N, Adamson DT, Jones CM. Pancreatectomy, Islet Cell Transplantation, and Nutrition Considerations. Nutr Clin Pract 2020; 36:385-397. [PMID: 33002260 DOI: 10.1002/ncp.10578] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pancreatic islet transplantation is a reliable approach for treating insulin-deficient diabetes. This established β-cell replacement approach has shown considerable improvements in the last 2 decades. It has helped achieve metabolic homeostasis and safe outcomes for a subset of patients with type 1 diabetes and severe pancreatitis. Nutrition support, until recently, was considered as a secondary factor, merely identified as a means of providing all the necessary nutrients for such patients. However, new literature suggests that several factors, such as the route, timing, quantity, and composition of all the nutrients administered, have key disease-altering properties and are vital during the perioperative management of such patients. This review will highlight the benefits of performing the clinical islet transplantation on a subgroup of patients with type 1 diabetes and pancreatitis and summarize new data that identify the pivotal role of nutrition support as a critical intervention in their management.
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Affiliation(s)
- Siddharth Narayanan
- Division of Transplantation, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, Kentucky, USA
| | - Neal Bhutiani
- Division of Transplantation, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, Kentucky, USA
| | - Dylan T Adamson
- Division of Transplantation, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, Kentucky, USA
| | - Christopher M Jones
- Division of Transplantation, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, Kentucky, USA
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25
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Ali KF, Hatipoglu B. Pancreatic Islet Cell Transplantation: Graft Stability and Metabolic Outcomes. OBM TRANSPLANTATION 2020; 4:1-9. [PMID: 32775966 PMCID: PMC7409867 DOI: 10.21926/obm.transplant.2003115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Pancreatic islet transplantation is a rapidly evolving field. It has been increasingly regarded as a promising approach for the correction of dysglycemia associated with type 1 diabetes mellitus (allogenic islet transplantation), or the prevention of surgical diabetes in chronic pancreatitis subjects undergoing total pancreatectomy (autologous islet transplantation). In this review, we discuss the latest literature pertaining to metabolic outcomes of autologous and allogenic islet transplantation, shedding close light on our own latest experience in the autologous islet transplantation setting.
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Affiliation(s)
- Khawla F Ali
- Department of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Bahrain
| | - Betul Hatipoglu
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, USA
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Pottakkat B. Islet cell dysfunction in patients with chronic pancreatitis. World J Diabetes 2020; 11:280-292. [PMID: 32843931 PMCID: PMC7415230 DOI: 10.4239/wjd.v11.i7.280] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/02/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency. Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption. Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP. Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP. However, the emerging evidence is varied probably because of dependence on the study procedure, the study population as well as on the stage of the disease. The mechanism behind islet cell dysfunction in CP is multifactorial. The intra-islet alpha and beta cell regulation of each other is often lost. Moreover, secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated. This significantly contributes to islet cell disturbances. Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP. In addition, the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function. Hence, different factors such as chronic inflammation, dysregulated incretin axis, surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP. Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Maatman TK, Zyromski NJ. Chronic Pancreatitis. Curr Probl Surg 2020; 58:100858. [PMID: 33663691 DOI: 10.1016/j.cpsurg.2020.100858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Thomas K Maatman
- Resident in General Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nicholas J Zyromski
- Professor of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA..
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Nanno Y, Wilhelm JJ, Heller D, Schat R, Freeman ML, Trikudanathan G, Kirchner VA, Pruett TL, Beilman GJ, Hering BJ, Bellin MD. Combination of pancreas volume and HbA1c level predicts islet yield in patients undergoing total pancreatectomy and islet autotransplantation. Clin Transplant 2020; 34:e14008. [DOI: 10.1111/ctr.14008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 05/11/2020] [Accepted: 06/04/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Yoshihide Nanno
- Schulze Diabetes Institute University of Minnesota School of Medicine Minneapolis MN USA
- Department of Surgery University of Minnesota School of Medicine Minneapolis MN USA
| | - Joshua J. Wilhelm
- Schulze Diabetes Institute University of Minnesota School of Medicine Minneapolis MN USA
- Department of Surgery University of Minnesota School of Medicine Minneapolis MN USA
| | - David Heller
- Schulze Diabetes Institute University of Minnesota School of Medicine Minneapolis MN USA
- Department of Surgery University of Minnesota School of Medicine Minneapolis MN USA
| | - Robben Schat
- Department of Radiology University of Minnesota School of Medicine Minneapolis MN USA
| | - Martin L. Freeman
- Department of Medicine University of Minnesota School of Medicine Minneapolis MN USA
| | - Guru Trikudanathan
- Department of Medicine University of Minnesota School of Medicine Minneapolis MN USA
| | - Varvara A. Kirchner
- Department of Surgery University of Minnesota School of Medicine Minneapolis MN USA
| | - Timothy L. Pruett
- Department of Surgery University of Minnesota School of Medicine Minneapolis MN USA
| | - Gregory J. Beilman
- Department of Surgery University of Minnesota School of Medicine Minneapolis MN USA
| | - Bernhard J. Hering
- Schulze Diabetes Institute University of Minnesota School of Medicine Minneapolis MN USA
- Department of Surgery University of Minnesota School of Medicine Minneapolis MN USA
| | - Melena D. Bellin
- Schulze Diabetes Institute University of Minnesota School of Medicine Minneapolis MN USA
- Department of Pediatrics University of Minnesota School of Medicine Minneapolis MN USA
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Abu-El-Haija M, Anazawa T, Beilman GJ, Besselink MG, Del Chiaro M, Demir IE, Dennison AR, Dudeja V, Freeman ML, Friess H, Hackert T, Kleeff J, Laukkarinen J, Levy MF, Nathan JD, Werner J, Windsor JA, Neoptolemos JP, Sheel ARG, Shimosegawa T, Whitcomb DC, Bellin MD. The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis. Pancreatology 2020; 20:762-771. [PMID: 32327370 DOI: 10.1016/j.pan.2020.04.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 03/18/2020] [Accepted: 04/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Advances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT. METHODS Expert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review. RESULTS Consensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery. CONCLUSIONS Agreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.
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Affiliation(s)
- Maisam Abu-El-Haija
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Takayuki Anazawa
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Japan
| | - Gregory J Beilman
- Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Marc G Besselink
- Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Marco Del Chiaro
- Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, CO, USA
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Ashley R Dennison
- Department of Hepatobiliary and Pancreatic Surgery, University of Leicester, UK
| | - Vikas Dudeja
- Department of Surgery, University of Miami, Miami, FL, USA
| | - Martin L Freeman
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Helmut Friess
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Thilo Hackert
- Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Germany
| | - Jorg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Johanna Laukkarinen
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Faculty of Medicine and Health Technology, Tampere University, Finland
| | - Marlon F Levy
- Division of Transplant Surgery, Department of Surgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Jaimie D Nathan
- Division of Pediatric General and Thoracic Surgery Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, University of Munich, LMU, Germany
| | - John A Windsor
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - John P Neoptolemos
- Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Andrea R G Sheel
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - David C Whitcomb
- Department of Medicine, Cell Biology & Physiology, and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Melena D Bellin
- Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.
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30
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Liu Q, Simioni A, Del Angel Diaz L, Quintini C. Pancreas perfusion preservation: State of the art with future directions. Artif Organs 2020; 44:445-448. [DOI: 10.1111/aor.13644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Qiang Liu
- Transplantation Center Department of Surgery Digestive Disease and Surgery Institute Cleveland Clinic Cleveland OH USA
| | - Andrea Simioni
- Transplantation Center Department of Surgery Digestive Disease and Surgery Institute Cleveland Clinic Cleveland OH USA
| | - Laurent Del Angel Diaz
- Transplantation Center Department of Surgery Digestive Disease and Surgery Institute Cleveland Clinic Cleveland OH USA
| | - Cristiano Quintini
- Transplantation Center Department of Surgery Digestive Disease and Surgery Institute Cleveland Clinic Cleveland OH USA
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Verma N, Rajab A, Buss J, Lara L, Porter K, Hart P, Conwell D, Washburn WK, Black S, Kuntz K, Meng S. Immediate Postoperative Insulin Requirements May Predict Metabolic Outcome after Total Pancreatectomy and Islet Autotransplantation. J Diabetes Res 2020; 2020:9282310. [PMID: 33426086 PMCID: PMC7772034 DOI: 10.1155/2020/9282310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/10/2020] [Indexed: 11/17/2022] Open
Abstract
Chronic pancreatitis (CP) is a progressive disease that leads to eventual loss of endocrine and exocrine function. Total pancreatectomy and islet autotransplantation (TPIAT) is a treatment option for patients with CP; however, predicting postoperative metabolic outcomes remains elusive. In this single-center retrospective study, we report pre-TPIAT characteristics, beta cell function indices, islet yield, and post-TPIAT glucose management data to further understand their relationship. Islet yield, glucose level, and insulin requirement for 72 hours postoperatively were collected for a total of 13 TPIAT recipients between 9-2013 and 9-2018. In addition, their glucose control and basal insulin requirements at 3, 6, and 12 months post-TPIAT were analyzed. All 13 subjects had normal baseline fasting glucose levels. Median islet yield was 4882 IEq/kg (interquartile range 3412 to 8987). Median postoperative total insulin requirement on day 3 was 0.43 units/kg. Pre-TPIAT baseline glucose, insulin, or c-peptide level did not have a significant correlation with the islet yield. Similarly, there was no correlation between islet yield and insulin requirement at 72-hour postoperatively. However, there was an inverse correlation between the absolute islet yield (IEq) and insulin requirement at 6 months and 12 months following post-TPIAT. Further analysis of the relationship between 72-hour post-op insulin requirement and insulin requirement at discharge, 3, 6, and 12 months showed a positive correlation. Despite the finding of inverse correlation of islet yield with long-term basal insulin requirement, this study was not able to detect a correlation between the preoperative parameters to postoperative short-term or long-term outcome as noted in other studies. The 72-hour postoperative insulin requirement is a helpful postoperative predictor of patients needing long-term insulin management following TPIAT. This observation may identify a high-risk group of patients in need of more intensive diabetes education and insulin treatment prior to hospital discharge.
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Affiliation(s)
- Neha Verma
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
- Essen Medical Associates, Bronx, New York, NY, USA 10452
| | - Amer Rajab
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
| | - Jill Buss
- The Ohio State University, Columbus, OH, USA 43210
| | - Luis Lara
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
| | - Kyle Porter
- The Ohio State University, Columbus, OH, USA 43210
| | - Philip Hart
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
| | - Darwin Conwell
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
| | | | - Sylvester Black
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
| | - Kristin Kuntz
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
| | - Shumei Meng
- The Ohio State University Wexner Medical Center, Columbus, OH, USA 43210
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32
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Johnston PC, Thompson J, Mckee A, Hamill C, Wallace I. Diabetes and Chronic Pancreatitis: Considerations in the Holistic Management of an Often Neglected Disease. J Diabetes Res 2019; 2019:2487804. [PMID: 31687406 PMCID: PMC6800932 DOI: 10.1155/2019/2487804] [Citation(s) in RCA: 7] [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: 04/30/2019] [Revised: 08/13/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetes secondary to chronic pancreatitis (CP) or type 3cDM refers to a brittle form of diabetes and is often characterised by hypoglycaemic episodes, erratic glycaemic control, and impaired quality of life. It differs from other forms of diabetes and is typically characterised by concurrent pancreatic endocrine and exocrine insufficiency which can present as malabsorption and nutritional deficiencies. In this review, we discuss the pathogenesis, epidemiology, and the practicalities of diagnosis, screening, and management of this condition.
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Affiliation(s)
| | - Judith Thompson
- Dietetics Department, 51 Lisburn Road, BT9 7AB Belfast City Hospital, UK
| | - Allison Mckee
- Dietetics Department, 51 Lisburn Road, BT9 7AB Belfast City Hospital, UK
| | - Connor Hamill
- Diabetes Department, 51 Lisburn Road, BT9 7AB Belfast City Hospital, UK
| | - Ian Wallace
- Diabetes Department, 51 Lisburn Road, BT9 7AB Belfast City Hospital, UK
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Abstract
OBJECTIVES Autologous islet transplantation (AIT) is performed to preserve insulin secretory function in chronic pancreatitis patients undergoing total pancreatectomy (TP). No data exist on the effect of time lapse on beta cell function post TP-AIT. We aimed to investigate the factor of time lapse on beta cell function following TP-AIT. METHODS Retrospectively, we identified 31 adult patients with chronic pancreatitis who underwent TP-AIT between 2008 and 2016. Changes in beta cell function were assessed using (1) BETA-2 scores and (2) analysis of posttransplant mixed-meal tolerance testing. RESULTS Significant decrease in functional beta cell capacity expressed by BETA-2 scores was seen in the first 2 years following TP-AIT, with an annual decrease of 6.3 points in median BETA-2 score (interquartile range, 4.6-11.6; P = 0.002). In the mixed-meal tolerance testing analysis, nonsignificant trends toward higher glucose, lower insulin, and lower C-peptide were seen with time lapse. Additionally, higher hemoglobin A1c values (P = 0.033) and higher insulin requirements (P = 0.04) were seen with longer follow-up after AIT. CONCLUSIONS A steady drop in functional beta cell capacity was observed in the 2 years following TP and AIT. To our knowledge, to date this is the first report of the BETA-2 score applicability in the AIT setting.
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Rickels MR, Robertson RP. Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions. Endocr Rev 2019; 40:631-668. [PMID: 30541144 PMCID: PMC6424003 DOI: 10.1210/er.2018-00154] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/26/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.
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Affiliation(s)
- Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - R Paul Robertson
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
- Pacific Northwest Diabetes Research Institute, Seattle, Washington
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Abstract
The selection of optimum surgical procedure from the range of reported operations for chronic pancreatitis (CP) can be difficult. The aim of this study is to explore geographical variation in reporting of elective surgery for CP. A systematic search of the literature was performed using the Scopus database for reports of five selected procedures for CP: duodenum-preserving pancreatic head resection, total pancreatectomy with islet autotransplantation (TPIAT), Frey pancreaticojejunostomy, thoracoscopic splanchnotomy and the Izbicki V-shaped resection. The keyword and MESH heading 'chronic pancreatitis' was used. Overall, 144 papers met inclusion criteria and were utilized for data extraction. There were 33 reports of duodenum-preserving pancreatic head resection. Twenty-one (64%) were from Germany. There were 60 reports of TPIAT, 53 (88%) from the USA. There are only two reports of TPIAT from outwith the USA and UK. The 34 reports of the Frey pancreaticojejunostomy originate from 12 countries. There were 20 reports of thoracoscopic splanchnotomy originating from nine countries. All three reports of the Izbicki 'V' procedure are from Germany. There is geographical variation in reporting of surgery for CP. There is a need for greater standardization in the selection and reporting of surgery for patients with painful CP.
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The Impact of Endoscopic Retrograde Cholangiopancreatography on Islet Cell Yield During Total Pancreatectomy With Islet Autotransplantation. Pancreas 2019; 48:77-79. [PMID: 30451790 DOI: 10.1097/mpa.0000000000001188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Many patients with recurrent acute and chronic pancreatitis who are candidates for total pancreatectomy and islet cell autotransplantation (TPIAT) undergo endoscopic retrograde cholangiopancreatography (ERCP). However, little is known on the impact of ERCP on TPIAT outcomes. We aimed to explore the effect of antecedent ERCP on islet yield and postoperative insulin requirement after TPIAT. METHODS Through a prospectively maintained database, we identified patients who underwent TPIAT at our institution between 2009 and 2016. After adjusting for confounders, islet cell yield and postoperative insulin requirement were compared between subjects who did and did not undergo ERCP within 2 years prior to TPIAT. RESULTS Data were available on 167 TPIAT patients during the study period; 105 (62.9%) had undergone ERCP within 2 years prior. Prior ERCP was not associated with a reduction in islet equivalents per patient kilogram (odds ratio, 1.37; 95% confidence interval, 0.75-2.5; P = 0.31). Antecedent ERCP was not associated with increased postoperative insulin requirement among patients with no diabetes undergoing TPIAT (odds ratio, 0.85; 95% confidence interval, 0.39-1.83; P = 0.67). CONCLUSIONS Antecedent ERCP does not appear to have a deleterious impact on islet cell yield during TPIAT. Additional multicenter data are needed to more clearly determine the impact of ERCP in this context.
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Abstract
PURPOSE OF REVIEW While there has been a growing utilization of total pancreatectomy with islet autotransplantation (TPIAT) for patients with medically refractory chronic pancreatitis over the past few decades, there remains a lack of consensus clinical guidelines to inform the counseling and management of patients undergoing TPIAT. In this article, we review the current clinical practice and published experience of several TPIAT centers, outline key aspects in managing patients undergoing TPIAT, and discuss the glycemic outcomes of this procedure. RECENT FINDINGS Aiming for lower inpatient glucose targets immediately after surgery (usually 100-120 mg/dl), maintaining all patients on subcutaneous insulin for at least 3 months to "rest" islets before an attempt is made to wean insulin, and close outpatient endocrinology follow-up after TPIAT particularly in the first year is common and related to better outcomes. Although TPIAT procedures and glycemic outcomes may differ across surgical centers, overall, approximately one third of patients are insulin independent at 1 year after TPIAT. Higher islet yield and lower preoperative glucose levels are among the strongest predictors of short-term post-operative insulin independence. Beyond 1 year post-operatively, the clinical management and long-term glycemic outcomes of patients after TPIAT are more variable. A multidisciplinary approach is essential in optimizing the preoperative, inpatient, and post-operative management and counseling of patients about the expected glycemic outcomes after surgery. Consensus guidelines for the clinical management of diabetes after TPIAT and harmonization of data collection protocols among TPIAT centers are needed to address the current knowledge gaps in clinical care and research and to optimize glycemic outcomes after TPIAT.
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Affiliation(s)
- Mohammed E Al-Sofiani
- Division of Endocrinology, Diabetes & Metabolism, The Johns Hopkins University, 1830 East Monument Street, Suite 333, Baltimore, MD, 21287, USA
- Endocrinology Division, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Michael Quartuccio
- Division of Endocrinology, Diabetes & Metabolism, The Johns Hopkins University, 1830 East Monument Street, Suite 333, Baltimore, MD, 21287, USA
| | - Erica Hall
- Division of Endocrinology, Diabetes & Metabolism, The Johns Hopkins University, 1830 East Monument Street, Suite 333, Baltimore, MD, 21287, USA
| | - Rita Rastogi Kalyani
- Division of Endocrinology, Diabetes & Metabolism, The Johns Hopkins University, 1830 East Monument Street, Suite 333, Baltimore, MD, 21287, USA.
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Bottino R, Knoll MF, Knoll CA, Bertera S, Trucco MM. The Future of Islet Transplantation Is Now. Front Med (Lausanne) 2018; 5:202. [PMID: 30057900 PMCID: PMC6053495 DOI: 10.3389/fmed.2018.00202] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 06/25/2018] [Indexed: 12/15/2022] Open
Abstract
Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative. The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States. Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US. Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients. The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation. While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring. Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research.
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Affiliation(s)
- Rita Bottino
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
- College of Medicine, Drexel University, Philadelphia, PA, United States
| | - Michael F. Knoll
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Carmela A. Knoll
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Suzanne Bertera
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Massimo M. Trucco
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
- College of Medicine, Drexel University, Philadelphia, PA, United States
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Ali KF, San Martin VT, Stevens T, Walsh RM, Bottino R, Trucco M, Hatipoglu B. Autoimmunity in Autologous Islet Transplantation. ACTA ACUST UNITED AC 2018; 2. [PMID: 32095782 PMCID: PMC7039533 DOI: 10.21926/obm.transplant.1803014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Total pancreatectomy (TP) is increasingly being utilized for definitive treatment in patients with debilitating chronic pancreatitis (CP). In an effort to prevent surgical diabetes, the procedure can be performed in conjunction with transplantation of islets of Langerhans recovered from the patients’ own resected pancreas (autologous islet transplantation, AIT). Given that patients undergoing TP and AIT are traditionally assumed not to be at risk for the development of beta-cell autoimmunity, it is possible that the presence of autoimmune islet graft failure has been overlooked and underreported in this patient population. Herein, we describe two cases who underwent TP and AIT and later developed new-onset beta-cell autoimmunity (as evidenced by de novo glutamic acid decarboxylase antibody positivity), accompanied by complete insulin-dependent states. These cases emphasize the need for considering a possible autoimmune phenomenon in the workup of TP and AIT patients who manifest with unexpected and rapid deterioration in their glycemic control.
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Affiliation(s)
- Khawla F Ali
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, USA
| | | | - Tyler Stevens
- Digestive Disease Institute, Cleveland Clinic, Cleveland, USA
| | - R Matthew Walsh
- Digestive Disease Institute, Cleveland Clinic, Cleveland, USA
| | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
| | - Massimo Trucco
- Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
| | - Betul Hatipoglu
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, USA
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40
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Mauvais-Jarvis F, Le May C, Tiano JP, Liu S, Kilic-Berkmen G, Kim JH. The Role of Estrogens in Pancreatic Islet Physiopathology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1043:385-399. [PMID: 29224104 DOI: 10.1007/978-3-319-70178-3_18] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In rodent models of insulin-deficient diabetes, 17β-estradiol (E2) protects pancreatic insulin-producing β-cells against oxidative stress, amyloid polypeptide toxicity, gluco-lipotoxicity, and apoptosis. Three estrogen receptors (ERs)-ERα, ERβ, and the G protein-coupled ER (GPER)-have been identified in rodent and human β-cells. This chapter describes recent advances in our understanding of the role of ERs in islet β-cell function, nutrient homeostasis, survival from pro-apoptotic stimuli, and proliferation. We discuss why and how ERs represent potential therapeutic targets for the maintenance of functional β-cell mass.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA.
| | - Cedric Le May
- L'institut du Thorax, INSERM-CNRS, University of Nantes, Nantes, France
| | - Joseph P Tiano
- Diabetes, Endocrinology, and Obesity Branch, NIDDK, Bethesda, MD, USA
| | - Suhuan Liu
- Xiamen Diabetes Institute, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Gamze Kilic-Berkmen
- Department of Pediatric, Emory University School of Medicine, Atlanta, GA, USA
| | - Jun Ho Kim
- Department of Food and Biotechnology, Korea University, Sejong, South Korea
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41
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Benomar K, Chetboun M, Espiard S, Jannin A, Le Mapihan K, Gmyr V, Caiazzo R, Torres F, Raverdy V, Bonner C, D'Herbomez M, Pigny P, Noel C, Kerr-Conte J, Pattou F, Vantyghem MC. Purity of islet preparations and 5-year metabolic outcome of allogenic islet transplantation. Am J Transplant 2018; 18:945-951. [PMID: 28941330 DOI: 10.1111/ajt.14514] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 08/23/2017] [Accepted: 09/04/2017] [Indexed: 01/25/2023]
Abstract
In allogenic islet transplantation (IT), high purity of islet preparations and low contamination by nonislet cells are generally favored. The aim of the present study was to analyze the relation between the purity of transplanted preparations and graft function during 5 years post-IT. Twenty-four patients with type 1 diabetes, followed for 5 years after IT, were enrolled. Metabolic parameters and daily insulin requirements were compared between patients who received islet preparations with a mean purity <50% (LOW purity) or ≥50% (HIGH purity). We also analyzed blood levels of carbohydrate antigen 19-9 (CA 19-9)-a biomarker of pancreatic ductal cells-and glucagon, before and after IT. At 5 years, mean hemoglobin A1c (HbA1c levels) (P = .01) and daily insulin requirements (P = .03) were lower in the LOW purity group. Insulin independence was more frequent in the LOW purity group (P < .05). CA19-9 and glucagon levels increased post-IT (P < .0001) and were inversely correlated with the degree of purity. Overall, our results suggest that nonislet cells have a beneficial effect on long-term islet graft function, possibly through ductal-to-endocrine cell differentiation. ClinicalTrial.gov NCT00446264 and NCT01123187.
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Affiliation(s)
- K Benomar
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France.,UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - M Chetboun
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - S Espiard
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France
| | - A Jannin
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France
| | - K Le Mapihan
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France
| | - V Gmyr
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - R Caiazzo
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - F Torres
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - V Raverdy
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - C Bonner
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - M D'Herbomez
- Department of Biology, CHRU Lille, Lille, France
| | - P Pigny
- Department of Biology, CHRU Lille, Lille, France
| | - C Noel
- Department of Nephrology and Transplantation, CHRU Lille, Lille, France
| | - J Kerr-Conte
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - F Pattou
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - M C Vantyghem
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France.,UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
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Wang H, Strange C, Nietert PJ, Wang J, Turnbull TL, Cloud C, Owczarski S, Shuford B, Duke T, Gilkeson G, Luttrell L, Hermayer K, Fernandes J, Adams DB, Morgan KA. Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy. Stem Cells Transl Med 2018; 7:11-19. [PMID: 29159905 PMCID: PMC5746145 DOI: 10.1002/sctm.17-0139] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 09/28/2017] [Indexed: 01/01/2023] Open
Abstract
Islet engraftment after transplantation is impaired by high rates of islet/β cell death caused by cellular stressors and poor graft vascularization. We studied whether cotransplantation of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (MSCs) with islets is safe and beneficial in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation. MSCs were harvested from the bone marrow of three islet autotransplantation patients and expanded at our current Good Manufacturing Practices (cGMP) facility. On the day of islet transplantation, an average dose of 20.0 ± 2.6 ×106 MSCs was infused with islets via the portal vein. Adverse events and glycemic control at baseline, 6, and 12 months after transplantation were compared with data from 101 historical control patients. No adverse events directly related to the MSC infusions were observed. MSC patients required lower amounts of insulin during the peritransplantation period (p = .02 vs. controls) and had lower 12-month fasting blood glucose levels (p = .02 vs. controls), smaller C-peptide declines over 6 months (p = .01 vs. controls), and better quality of life compared with controls. In conclusion, our pilot study demonstrates that autologous MSC and islet cotransplantation may be a safe and potential strategy to improve islet engraftment after transplantation. (Clinicaltrials.gov registration number: NCT02384018). Stem Cells Translational Medicine 2018;7:11-19.
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Affiliation(s)
- Hongjun Wang
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Charlie Strange
- Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Paul J. Nietert
- Department of Public Health SciencesMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Jingjing Wang
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Taylor L. Turnbull
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Colleen Cloud
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Stefanie Owczarski
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Betsy Shuford
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Tara Duke
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Gary Gilkeson
- Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Louis Luttrell
- Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Kathie Hermayer
- Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Jyotika Fernandes
- Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - David B. Adams
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Katherine A. Morgan
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
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Tillou JD, Tatum JA, Jolissaint JS, Strand DS, Wang AY, Zaydfudim V, Adams RB, Brayman KL. Operative management of chronic pancreatitis: A review. Am J Surg 2017; 214:347-357. [PMID: 28325588 DOI: 10.1016/j.amjsurg.2017.03.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/26/2016] [Accepted: 03/08/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Pain secondary to chronic pancreatitis is a difficult clinical problem to manage. Many patients are treated medically or undergo endoscopic therapy and surgical intervention is often reserved for those who have failed to gain adequate pain relief from a more conservative approach. RESULTS There have been a number of advances in the operative management of chronic pancreatitis over the last few decades and current therapies include drainage procedures (pancreaticojejunostomy, etc.), resection (pancreticoduodenectomy, etc.) and combined drainage/resection procedures (Frey procedure, etc.). Additionally, many centers currently perform total pancreatectomy with islet autotransplantation, in addition to minimally invasive options that are intended to tailor therapy to individual patients. DISCUSSION Operative management of chronic pancreatitis often improves quality of life, and is associated with low rates of morbidity and mortality. The decision as to which procedure is optimal for each patient should be based on a combination of pathologic changes, prior interventions, and individual surgeon and center experience.
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Affiliation(s)
- John D Tillou
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Jacob A Tatum
- Department of Surgery, The University of Virginia Health System, Charlottesville, VA, USA
| | - Joshua S Jolissaint
- Department of Surgery, The University of Virginia Health System, Charlottesville, VA, USA
| | - Daniel S Strand
- Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA, USA
| | - Andrew Y Wang
- Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA, USA
| | - Victor Zaydfudim
- Department of Surgery, The University of Virginia Health System, Charlottesville, VA, USA
| | - Reid B Adams
- Department of Surgery, The University of Virginia Health System, Charlottesville, VA, USA
| | - Kenneth L Brayman
- Department of Surgery, The University of Virginia Health System, Charlottesville, VA, USA.
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Bondoc AJ, Abu-El-Haija M, Nathan JD. Pediatric pancreas transplantation, including total pancreatectomy with islet autotransplantation. Semin Pediatr Surg 2017; 26:250-256. [PMID: 28964481 DOI: 10.1053/j.sempedsurg.2017.07.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Unlike other solid-organ transplants, whole pancreas transplantation in children is relatively rare, and it occurs more frequently in the context of multivisceral or composite organ transplantation. Because children only infrequently suffer severe sequelae of type 1 diabetes mellitus, pancreas transplantation is rarely indicated in the pediatric population. More commonly, pediatric pancreas transplant occurs in the setting of incapacitating acute recurrent or chronic pancreatitis, specifically islet autotransplantation after total pancreatectomy. In this clinical scenario, total pancreatectomy removes the nidus of chronic pain and debilitation, while autologous islet transplantation aims to preserve endocrine function. The published experiences with pediatric total pancreatectomy with islet autotransplantation (TPIAT) in children has demonstrated excellent outcomes including liberation from chronic opioid use, as well as improved mental and physical quality of life with good glycemic control. Given the complexity of the operation, risk of postoperative complication, and long-term physiologic changes, appropriate patient selection and comprehensive multidisciplinary care teams are critical to ensuring optimal outcomes.
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Affiliation(s)
- Alexander J Bondoc
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Mail Location 2023, Cincinnati, Ohio 45229.
| | - Maisam Abu-El-Haija
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jaimie D Nathan
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Mail Location 2023, Cincinnati, Ohio 45229
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Kesseli SJ, Wagar M, Jung MK, Smith KD, Lin YK, Walsh RM, Hatipoglu B, Freeman ML, Pruett TL, Beilman GJ, Sutherland DER, Dunn TB, Axelrod DA, Chaidarun SS, Stevens TK, Bellin M, Gardner TB. Long-Term Glycemic Control in Adult Patients Undergoing Remote vs. Local Total Pancreatectomy With Islet Autotransplantation. Am J Gastroenterol 2017; 112:643-649. [PMID: 28169284 DOI: 10.1038/ajg.2017.14] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/04/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Total pancreatectomy with islet autotransplantation (TPIAT) is increasingly performed with remote islet cell processing and preparation, i.e., with islet cell isolation performed remotely from the primary surgical site at an appropriately equipped islet isolation facility. We aimed to determine whether TPIAT using remote islet isolation results in comparable long-term glycemic outcomes compared with TPIAT performed with standard local isolation. METHODS We performed a retrospective cohort study of adult patients who underwent TPIAT at three tertiary care centers from 2010 to 2013. Two centers performed remote isolation and one performed local isolation. Explanted pancreata in the remote cohort were transported ∼130 miles to and from islet isolation facilities. The primary outcome was insulin independence 1 year following transplant. RESULTS Baseline characteristics were similar between groups except the remote cohort had higher preoperative hemoglobin A1c (HbA1c; 5.43 vs. 5.25, P=0.02) and there were more females in the local cohort (58% vs. 76%, P=0.049). At 1 year, 27% of remote and 32% of local patients were insulin independent (P=0.48). Remote patients experienced a greater drop in fasting c-peptide (-1.66 vs. -0.64, P=0.006) and a greater rise in HbA1c (1.65 vs. 0.99, P=0.014) at 1-year follow-up. A preoperative c-peptide >2.7 (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.6-14.3) and >3,000 islet equivalents/kg (OR 11.0, 95% CI 3.2-37.3) were associated with one-year insulin independence in the local group. CONCLUSIONS At 1 year after TPIAT, patients undergoing remote surgery have equivalent rates of long-term insulin independence compared with patients undergoing TPIAT locally, but metabolic control is superior with local isolation.
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Affiliation(s)
- Samuel J Kesseli
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Matthew Wagar
- Section of Endocrinology, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - Min K Jung
- Section of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Kerrington D Smith
- Section of General Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Yu Kuei Lin
- Department of Endocrinology, Endocrinology and Metabolism Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - R Matthew Walsh
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Betul Hatipoglu
- Section of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Martin L Freeman
- Section of Gastroenterology, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - Timothy L Pruett
- Deparment of Surgery, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - Gregory J Beilman
- Deparment of Surgery, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - David E R Sutherland
- Deparment of Surgery, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - Ty B Dunn
- Deparment of Surgery, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - David A Axelrod
- Section of Transplant Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Sushela S Chaidarun
- Section of Endocrinology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Tyler K Stevens
- Section of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Melena Bellin
- Section of Endocrinology, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - Timothy B Gardner
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
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Quartuccio M, Hall E, Singh V, Makary MA, Hirose K, Desai N, Walsh C, Warren D, Sun Z, Stein E, Kalyani RR. Glycemic Predictors of Insulin Independence After Total Pancreatectomy With Islet Autotransplantation. J Clin Endocrinol Metab 2017; 102:801-809. [PMID: 27870552 PMCID: PMC5460683 DOI: 10.1210/jc.2016-2952] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/15/2016] [Indexed: 12/17/2022]
Abstract
CONTEXT Total pancreatectomy with islet auto transplantation (TPIAT) is a treatment for medically refractory chronic pancreatitis that can prevent postsurgical diabetes in some patients. Predictors of insulin independence are needed for appropriate patient selection and counseling. OBJECTIVE To explore glycemic predictors of insulin independence after TPIAT. DESIGN A prospective cohort of patients. METHODS We investigated 34 patients undergoing TPIAT from 2011-2016 at Johns Hopkins Hospital, all had a 75-g oral glucose tolerance test (OGTT) administered prior to their TPIAT. The primary outcome was insulin independence 1 year after TPIAT. RESULTS Ten of 34 (29%) patients were insulin independent 1 year after TPIAT. All patients with impaired fasting glucose and/or impaired glucose tolerance preoperatively were insulin dependent at 1 year. In age-adjusted regression analyses, fasting glucose ≤ 90 mg/dL [odds ratio (OR) = 6.56; 1.11 to 38.91; P = 0.04], 1-hour OGTT glucose ≤ 143 mg/dL (OR = 6.65; 1.11 to 39.91; P = 0.04), and 2-hour OGTT glucose ≤ 106 mg/dL (OR = 11.74; 1.46 to 94.14; P = 0.02) were significant predictors of insulin independence. In receiver operating characteristic analyses, homeostatic model assessment of β-cell function (HOMA-β) was the most robust predictor of insulin independence [area under the curve (AUC) = 0.88; 0.73 to 1.00]. CONCLUSIONS Normal preoperative glucose status and lower fasting and postchallenge OGTT glucose values are significant predictors of insulin independence after TPIAT. Higher islet function (HOMA-β) was the strongest predictor. OGTT testing may be a useful tool to aid in patient counseling prior to TPIAT and should be further investigated.
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Affiliation(s)
| | - Erica Hall
- Division of Endocrinology, Diabetes and Metabolism
| | | | - Martin A. Makary
- Division of Surgical Oncology, and
- Division of Transplant Surgery, Johns Hopkins University, Baltimore, Maryland 21287
| | - Kenzo Hirose
- Division of Surgical Oncology, and
- Division of Transplant Surgery, Johns Hopkins University, Baltimore, Maryland 21287
| | - Niraj Desai
- Division of Transplant Surgery, Johns Hopkins University, Baltimore, Maryland 21287
| | | | - Daniel Warren
- Division of Transplant Surgery, Johns Hopkins University, Baltimore, Maryland 21287
| | - Zhaoli Sun
- Division of Transplant Surgery, Johns Hopkins University, Baltimore, Maryland 21287
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Islet Cell Yield Following Remote Total Pancreatectomy With Islet Autotransplant is Independent of Cold Ischemia Time. Pancreas 2017; 46:380-384. [PMID: 28129232 PMCID: PMC5308539 DOI: 10.1097/mpa.0000000000000792] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Total pancreatectomy with islet autotransplantation is increasingly being performed remotely, that is, removing the pancreas in 1 location, isolating the islet cells in another location, then returning the islets to the original location for reimplantation into the patient. We determined the influence of extended cold ischemia time on key clinical outcomes in remote islet autotransplantation. METHODS We evaluated patients who underwent remote islet autotransplantation at 2 centers from 2011 to 2014. Patients were divided into 2 groups: those with and those without a decrease in C-peptide greater than 50% from baseline. The primary clinical outcome was the quantity of isolated islet equivalents per kilogram body weight (IEQs/kg). RESULTS Twenty-five patients met inclusion criteria; 15 had a decrease in C-peptide greater than 50% from baseline and had lower corresponding IEQs/kg compared with those without a decrease greater than 50% (4045 vs 6654 IEQs/kg, P = 0.01). There was no difference in cold ischemia time between the 2 groups (664 vs 600 minutes, P = 0.25). Daily insulin use at 1 year nearly met statistical significance (25.3 vs 8 U, P = 0.06), as did glycated hemoglobin (8.07 vs 6.69 mmol/L, P = 0.06). CONCLUSIONS Cold ischemia time does not influence islet yield in patients undergoing pancreatectomy with remote isolation.
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Mauvais-Jarvis F. Role of Sex Steroids in β Cell Function, Growth, and Survival. Trends Endocrinol Metab 2016; 27:844-855. [PMID: 27640750 PMCID: PMC5116277 DOI: 10.1016/j.tem.2016.08.008] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 08/27/2016] [Accepted: 08/29/2016] [Indexed: 01/08/2023]
Abstract
The gonads have long been considered endocrine glands, producing sex steroids such as estrogens, androgens, and progesterone (P4) for the sole purpose of sexual differentiation, puberty, and reproduction. Reproduction and energy metabolism are tightly linked, however, and gonadal steroids play an important role in sex-specific aspects of energy metabolism in various physiological conditions. In that respect, gonadal steroids also influence the secretion of insulin in a sex-specific manner. This review presents a perspective on the physiological roles of estrogens, androgens, and P4 via their receptors in pancreatic β cells in the gender-specific tuning of insulin secretion. I also discuss potential gender-specific therapeutic avenues that this knowledge may open in the future.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Diabetes Discovery and Gender Medicine Laboratory, Section of Endocrinology and Metabolism, Department of Medicine, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA.
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