Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes

Context: Islet transplantation has been shown to improve glucose counterregulation and hypoglycemia symptom recognition in patients with type 1 diabetes (T1D) complicated by severe hypoglycemia episodes and symptom unawareness, but long-term data are lacking. Objective: To assess the long-term durability of glucose counterregulation and hypoglycemia symptom responses 18 months after intrahepatic islet transplantation and associated measures of glycemic control during a 24-month follow-up period. Design, Setting, and Participants: Ten patients with T1D disease duration of approximately 27 years were studied longitudinally before and 6 and 18 months after transplant in the Clinical & Translational Research Center of the University of Pennsylvania and were compared to 10 nondiabetic control subjects. Intervention: All 10 patients underwent intrahepatic islet transplantation according to the CIT07 protocol at the Hospital of the University of Pennsylvania. Main Outcome Measures: Counterregulatory hormone, endogenous glucose production, and autonomic symptom responses derived from stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose. Results: Near-normal glycemia (HbA1c ≤ 6.5%; time 70–180 mg/dL ≥ 95%) was maintained for 24 months in all patients, with one returning to low-dose insulin therapy. In response to insulin-induced hypoglycemia, glucagon secretion was incompletely restored at 6 and 18 months, epinephrine was improved at 6 months and normalized at 18 months, and endogenous glucose production and symptoms, absent before, were normalized at 6 and 18 months after transplant. Conclusions: In patients with T1D experiencing problematic hypoglycemia, intrahepatic islet transplantation can lead to long-term improvement of glucose counterregulation and hypoglycemia symptom recognition, physiological effects that likely contribute to glycemic stability after transplant.

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Islet Transplantation in Type 1 Diabetes: Ongoing Challenges, Refined Procedures, and Long-Term Outcome

The Review of Diabetic Studies ◽

10.1900/rds.2012.9.385 ◽

2012 ◽

Vol 9 (4) ◽

pp. 385-406 ◽

Cited By ~ 61

Author(s):

A.M. James Shapiro

Keyword(s):

Type 1 Diabetes ◽

Islet Transplantation ◽

Term Outcome ◽

Long Term Outcome

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Single-Donor Islet Transplantation and Long-term Insulin Independence in Select Patients With Type 1 Diabetes Mellitus

Transplantation Journal ◽

10.1097/tp.0000000000000217 ◽

2014 ◽

Vol 98 (9) ◽

pp. 1007-1012 ◽

Cited By ~ 41

Author(s):

David P. Al-Adra ◽

Richdeep S. Gill ◽

Sharleen Imes ◽

Doug O’Gorman ◽

Tatsuya Kin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Islet Transplantation ◽

Insulin Independence ◽

Single Donor

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Long-Term Insulin-Independence After Allogeneic Islet Transplantation for Type 1 Diabetes: Over the 10-Year Mark

American Journal of Transplantation ◽

10.1111/j.1600-6143.2008.02481.x ◽

2009 ◽

Vol 9 (2) ◽

pp. 419-423 ◽

Cited By ~ 57

Author(s):

T. Berney ◽

S. Ferrari-Lacraz ◽

L. Bühler ◽

J. Oberholzer ◽

N. Marangon ◽

...

Keyword(s):

Type 1 Diabetes ◽

Islet Transplantation ◽

Insulin Independence

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Subcutaneous transplantation of embryonic pancreas for correction of type 1 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90544.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. E323-E332 ◽

Cited By ~ 9

Author(s):

Subhadra C. Gunawardana ◽

Richard K. P. Benninger ◽

David W. Piston

Keyword(s):

Type 1 Diabetes ◽

Islet Transplantation ◽

Invasive Surgery ◽

Imaging Techniques ◽

Pancreatic Tissue ◽

Endocrine Differentiation ◽

Promising Therapeutic Approach ◽

Subcutaneous Space

Islet transplantation is a promising therapeutic approach for type 1 diabetes. However, current success rates are low due to progressive graft failure in the long term and inability to monitor graft development in vivo. Other limitations include the necessity of initial invasive surgery and continued immunosuppressive therapy. We report an alternative transplantation strategy with the potential to overcome these problems. This technique involves transplantation of embryonic pancreatic tissue into recipients’ subcutaneous space, eliminating the need for invasive surgery and associated risks. Current results in mouse models of type 1 diabetes show that embryonic pancreatic transplants in the subcutaneous space can normalize blood glucose homeostasis and achieve extensive endocrine differentiation and vascularization. Furthermore, modern imaging techniques such as two-photon excitation microscopy (TPEM) can be employed to monitor transplants through the intact skin in a completely noninvasive manner. Thus, this strategy is a convenient alternative to islet transplantation in diabetic mice and has the potential to be translated to human clinical applications with appropriate modifications.

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Carbon Monoxide in Pancreatic Islet Transplantation: A New Therapeutic Alternative to Patients With Severe Type 1 Diabetes Mellitus

Frontiers in Pharmacology ◽

10.3389/fphar.2021.750816 ◽

2021 ◽

Vol 12 ◽

Author(s):

George J. Dugbartey

Keyword(s):

Diabetes Mellitus ◽

Carbon Monoxide ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Islet Transplantation ◽

Pancreatic Islet ◽

Molecular Mechanisms ◽

Pancreatic Islet Transplantation

Pancreatic islet transplantation is a minimally invasive procedure to replace β-cells in a subset of patients with autoimmune type 1 diabetic mellitus, who are extremely sensitive to insulin and lack counter-regulatory measures, and thereby increasing their risk of neuroglycopenia and hypoglycemia unawareness. Thus, pancreatic islet transplantation restores normoglycemia and insulin independence, and prevents long-term surgical complications associated with whole-organ pancreas transplantation. Nonetheless, relative inefficiency of islet isolation and storage process as well as progressive loss of islet function after transplantation due to unvoidable islet inflammation and apoptosis, hinder a successful islet transplantation. Carbon monoxide (CO), a gas which was once feared for its toxicity and death at high concentrations, has recently emerged as a medical gas that seems to overcome the challenges in islet transplantation. This minireview discusses recent findings about CO in preclinical pancreatic islet transplantation and the underlying molecular mechanisms that ensure islet protection during isolation, islet culture, transplantation and post-transplant periods in type 1 diabetic transplant recipients. In addition, the review also discusses clinical translation of these promising experimental findings that serve to lay the foundation for CO in islet transplantation to replace the role of insulin therapy, and thus acting as a cure for type 1 diabetes mellitus and preventing long-term diabetic complications.

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Type 1 diabetes: treat the symptoms or cure the disease?

The Biochemist ◽

10.1042/bio03804005 ◽

2016 ◽

Vol 38 (4) ◽

pp. 5-9

Author(s):

Aileen King ◽

Zheng-Liang Zhi ◽

Shanta Persaud ◽

Peter Jones

Keyword(s):

Type 1 Diabetes ◽

Graft Survival ◽

Islet Transplantation ◽

Experimental Treatment ◽

Great Promise ◽

Clinical Protocols ◽

Host Environment

Islet transplantation has shown great promise as an experimental treatment for Type 1 diabetes, but current clinical protocols have problems with long-term graft survival when islets are transplanted into an inflammatory, immunogenic host environment. Encapsulation strategies designed to present a biocompatible barrier between graft and host may offer solutions to these problems.

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