Predictors of Glycemic Outcomes at 1 Year Following Pediatric Total Pancreatectomy With Islet Autotransplantation

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 one year following TPIAT in a cohort of children. <p>Research Design and Methods: This was a review of 43 pediatric patients followed after TPIAT for one year or longer. Primary outcome was insulin use at one year, categorized as: insulin independent, low (< 0.5 u/kg/day) or high insulin (≥ 0.5 u/kg/day) requirement. </p> <p>Results: At one year after TPIAT, 12/41 (29%) patients were insulin independent, 21/41 (51%) had low and 8/41 (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 higher transplanted IEQ/kg (p=0.03) and lower body surface area (p=0.02), compared to 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 one year (p=0.006 and 0.03, respectively). </p> <p>Conclusions: We conclude that insulin independence following pediatric TPIAT is multifactorial and associated with younger age, higher IEQ/kg transplanted and lower body surface area at time of operation. Higher peak C-peptide measured by MMTT following TPIAT confers a higher likelihood of low insulin requirement. </p>

Predictors of Glycemic Outcomes at 1 Year Following Pediatric Total Pancreatectomy With Islet Autotransplantation

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 one year following TPIAT in a cohort of children. <p>Research Design and Methods: This was a review of 43 pediatric patients followed after TPIAT for one year or longer. Primary outcome was insulin use at one year, categorized as: insulin independent, low (< 0.5 u/kg/day) or high insulin (≥ 0.5 u/kg/day) requirement. </p> <p>Results: At one year after TPIAT, 12/41 (29%) patients were insulin independent, 21/41 (51%) had low and 8/41 (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 higher transplanted IEQ/kg (p=0.03) and lower body surface area (p=0.02), compared to 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 one year (p=0.006 and 0.03, respectively). </p> <p>Conclusions: We conclude that insulin independence following pediatric TPIAT is multifactorial and associated with younger age, higher IEQ/kg transplanted and lower body surface area at time of operation. Higher peak C-peptide measured by MMTT following TPIAT confers a higher likelihood of low insulin requirement. </p>

Predictors of Glycemic Outcomes at 1 Year Following Pediatric Total Pancreatectomy With Islet Autotransplantation

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 (&lt;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.

What Is New with Total Pancreatectomy and Autologous Islet Cell Transplantation? Review of Current Progress in the Field

Patients with chronic pancreatitis have benefited from total pancreatectomy and autologous islet cell transplantation (TPAIT) since the 1970s. Over the past few decades, improvements have been made in surgical technique and perioperative management that have led to improved success of islet cell function, insulin independence and patient survival. This article focuses on recent updates and advances for the TPAIT procedure that continue to expand and innovate the impact on patients with debilitating disease.

The promise of stem cell-derived islet replacement therapy

Present-day treatments for people that are insulin dependent require multiple insulin injections, sometimes with an insulin pump, coupled with regular blood glucose monitoring. The availability of modified insulins, each with peaks of activity at varying times, has improved diabetes management. On the other hand, there have been impressive results leading to insulin independence by transplantation of cadaveric islets coupled with immune suppression. This review focuses on the possibility of treating diabetes with cellular transplants, specifically with the use of pluripotent stem cells, to produce a virtually unlimited and uniform supply of human islet-like clusters by directed differentiation. Prospects for improving the in vitro differentiation of human endocrine cells for the study of endocrine function and their possible clinical uses are also discussed. Graphical abstract

Cardioprotective Function of Green Rooibos (Aspalathus linearis) Extract Supplementation in Ex Vivo Ischemic Prediabetic Rat Hearts

Diabetic patients develop ischemic heart disease and strokes more readily. Following an ischemic event, restoration of blood flow increases oxidative stress resulting in myocardial damage, termed ischemia/reperfusion injury. Aspalathus linearis (rooibos), rich in the antioxidant phenolic compound aspalathin, has been implicated as cardioprotective against ischemia/reperfusion injury with undefined mechanism in control rats. Primarily, the therapeutic potential of Afriplex green rooibos extract to prevent ischemia/reperfusion injury in cardiovascular disease-compromised rats was investigated. Additionally, Afriplex Green rooibos extractʼs cardioprotective signaling on metabolic markers and stress markers was determined using western blotting. Three hundred male Wistar rats received either 16-wk standard diet or high-caloric diet. During the final 6 wk, half received 60 mg/kg/day Afriplex green rooibos extract, containing 12.48% aspalathin. High-caloric diet increased body weight, body fat, fasting serum triglycerides, and homeostatic model assessment of insulin resistance – indicative of prediabetes. High-caloric diet rats had increased heart mass, infarct size, and decreased heart function. Afriplex green rooibos extract treatment for 6 wk lowered pre-ischemic heart rate, reduced infarct size, and improved heart function pre- and post-ischemia, without significantly affecting biometric parameters. Stabilized high-caloric diet hearts had decreased insulin independence via adenosine monophosphate activated kinase and increased inflammation (p38 mitogen-activated protein kinase), whereas Afriplex green rooibos extract treatment decreased insulin dependence (protein kinase B) and conferred anti-inflammatory effect. After 20 min ischemia, high-caloric diet hearts had upregulated ataxia–telangiectasia mutated kinase decreased insulin independence, and downregulated insulin dependence and glycogen synthase kinase 3 β inhibition. In contrast, Afriplex green rooibos extract supplementation downregulated insulin independence and inhibited extracellular signal-regulated kinase 1 and 2. During reperfusion, all protective signaling was decreased in high-caloric diet, while Afriplex green rooibos extract supplementation reduced oxidative stress (c-Jun N-terminal kinases 1 and 2) and inflammation. Taken together, Afriplex green rooibos extract supplementation for 6 wk preconditioned cardiovascular disease-compromised rat hearts against ischemia/reperfusion injury by lowering inflammation, oxidative stress, and heart rate.

Current Assessment of Clinical Pancreatic Islet Allotransplantation

Clinical islet allotransplantation represents a minimally invasive, efficacious alternative to pancreas transplantation for restoring glycemic control and insulin independence in select patients with type 1 diabetes that is complicated by intractable impaired hypoglycemia awareness and/or severe hypoglycemic events refractory to stabilization by other means. Over the last decade, islet transplantation outcomes have steadily improved in part due to refinements in the selection of optimal donors, islet isolation techniques, safer engraftment methods, and effective immunomodulatory and anti-inflammatory therapies. Insulin independence rates at five years post-transplantation at select centers have reached parity with pancreas alone transplantation, and marked progress has been achieved in islet transplantation outcomes using single-donor pancreas. However, widespread application of the procedure is still hindered due to a limited supply of donor pancreases, inadequate engraftment, and the harmful side effects of chronic immunosuppression. Strategies to address some of these challenges involve the use of alternative sources of beta cells or islets, extrahepatic sites of implantation, encapsulation of islets and novel therapies to induce tolerance. While several countries have now transitioned islet transplantation from experimental status to a funded clinical cure for patients with brittle type 1 diabetes that cannot be stabilized by more conventional means, in the US it still awaits regulatory approval and a financial mechanism for sustainable reimbursement. This review details the history and the current status of clinical islet allotransplantation while summarizing improvements that have been made in techniques involving isolation, purification, culture and assessment of human islets as well as the islet transplantation process itself. Furthermore, it discusses the limitations encountered that prevent its widespread application, strategies that address those limitations, and last but not least, clinical trials being conducted that will help position islet transplantation as a mainstay treatment for the cure of type 1 diabetes.

Body Composition is Associated With Islet Function After Pancreatectomy and Islet Autotransplantation for Pancreatitis

Context Body composition in total pancreatectomy with islet autotransplantation (TPIAT) has never been studied. Objective Determine whether presurgical body composition is associated with islet function and insulin sensitivity after TPIAT. Methods In 88 adults undergoing TPIAT (median age 41.0 years, IQR 32.8-48.0), beta-cell function and insulin sensitivity were assessed using mixed meal tolerance test and frequent sample intravenous glucose tolerance test before surgery and 12 and 18 months afterward. Body composition was measured by dual x-ray absorptiometry. Analyses used linear and logistic regression. Results Before surgery, 8 individuals (9.1%) were underweight, 40 (45.5%) normal weight, 20 (22.7%) overweight, and 20 (22.7%) obese. Overweight/obese patients had higher area under the curve C-peptide and lower insulin sensitivity index. Baseline body weight was positively associated with first-phase insulin secretion (AIRg) at 12 months (average 38.5 [SE 17.1] mU/L/min higher per extra kg; P = 0.03) and 18 months (38.3 [18.5]; P = 0.04), while baseline lean mass was inversely associated with AIRg at 12 months (−0.05 [0.02] per extra kg; P = 0.01) and 18 months (−0.05 [0.02]; P = 0.03). Percent gynoid fat was inversely associated with disposition index at 18 months (−206.0 [97.2] per extra percent; P = 0.04). Percent body fat and percent gynoid fat were associated with glucose effectiveness index at 18 months (1.9 × 10-3 [0.9 × 10-3] per extra percent; P = 0.04 and −1.96 × 10-3 [0.8 × 10-3]; P = 0.02, respectively). Insulin independence was not significantly associated with body weight or composition. Conclusions Half of these chronic pancreatitis patients were overweight/obese; underweight was uncommon. Preoperative body weight and composition were associated with islet function but not insulin independence after TPIAT.

Islet Transplantation in Type 1 Diabetes Mellitus With Hypoglycaemic Unawareness

The primary indications for ICT in T1DM are glycaemic lability and hypoglycaemia unawareness. ICT is an effective, minimally invasive treatment for stabilising glycaemic control, correcting hypoglycaemia unawareness and improving quality of life even when exogenous insulin-independence is not fully achieved. However, the majority of patients require two islet transplants. The need for lifelong immunosuppression, in combination with the limited availability of donor pancreases, currently limits the wider application of ICT, particularly in the treatment of children newly diagnosed with T1DM. New technologies, including macro- and micro-encapsulation, xenotransplantation and stem cell-derived b cells offer hope for the future of b cell replacement. Yet, until then, a continued focus on optimising donor pancreases, improving the islet isolation procedure, use of novel immunosuppression, and understanding the mechanisms behind graft loss is required.