Sitagliptin plus pantoprazole can restore but not maintain insulin independence after clinical islet transplantation: results of a pilot study

Senior, Peter; Koh, Angela; Yau, J. M.; Imes, Sharleen; Dinyari, Parastoo; Malcolm, Andrew J.; Light, Peter E.; Shapiro, A. M. James

doi:10.1111/dme.13131

Cited by 13 publications

(11 citation statements)

References 21 publications

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“…However, even many allo transplant recipients were unable to tolerate exenatide owing to nausea, vomiting and weight loss, which made it a particularly impractical therapy early after TPIAT and led us instead to consider DPP‐4 inhibitor therapy in this study. A more recent trial with DPP‐4 inhibitor therapy in allotransplantation at the time of islet graft function (late after transplant) showed only a modest benefit in reduced insulin need, which did not persist when therapy was stopped . In contrast, we observed no apparent benefit from treating TPIAT patients with sitagliptin immediately after transplant.…”

Section: Discussioncontrasting

confidence: 67%

“…Furthermore, GLP‐1 agonists such as exenatide may benefit glycemic control through delayed gastric emptying and suppression of postprandial glucagon, beneficial effects that may not occur with DPP‐4 inhibitor therapy . Other studies have combined sitagliptin therapy with a proton‐pump inhibitor (PPI) to increase gastrin levels, targeting a synergistic effect of GLP‐1 with gastrin for beta cell replication , Although our study protocol did not include a specific PPI, our routine clinical management protocol for TPIAT patients includes PPI therapy immediately after TPIAT and most often continues it for 1 year or more.…”

Section: Discussionmentioning

confidence: 99%

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Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized, Placebo-Controlled Study

Bellin

Beilman

Dunn

et al. 2017

American Journal of Transplantation

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Insulin independence after total pancreatectomy and islet autotransplant (TPIAT) for chronic pancreatitis is limited by a high rate of post-procedure beta cell apoptosis. Endogenous GLP-1 and GIP, which are increased by DPP-4 inhibitor therapy (sitagliptin) may protect against beta cell apoptosis. To determine the effect of sitgalitpin after TPIAT, 83 adult TPIAT recipients were randomized to receive sitagliptin (n=54) or placebo (n=29) for 12 months after TPIAT. At 12 and 18 months after TPIAT, participants were assessed for insulin independence; metabolic testing was performed with mixed meal tolerance testing (MMTT) and frequent sample intravenous glucose tolerance testing (FSIVGTT). Insulin independence did not differ between the sitagliptin and placebo groups at 12 months (42% vs 45%, p=0.82) or 18 months (36% vs 44%, p=0.48). At 12 months, insulin dose was 9.0 (SE 1.7) unit/day and 7.9 (2.2) unit/day in the sitagliptin and placebo groups respectively (p=0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) respectively (p=0.32). HbA1c levels and insulin secretory measures were similar in the two groups, as were adverse events. In conclusion, sitagliptin could be safely administered but did not improve metabolic outcomes after TPIAT.

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Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized, Placebo-Controlled Study

Bellin

Beilman

Dunn

et al. 2017

American Journal of Transplantation

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“…The BETA-2 score, unlike the beta score, does not consider the use of oral hypoglycemic agents or noninsulin antihyperglycemic agents. Although insulin was preferred previously because of adverse effects of antihyperglycemics (side effects, metabolic burnout, potential drug interactions [unpublished observations]), newer therapies (dipeptidyl peptidase 4 inhibitors) are well tolerated (35). The use of antidiabetic drugs may serve to either increase or decrease the BETA-2 score, although it is difficult to predict the magnitude of change.…”

Section: Discussionmentioning

confidence: 99%

Validation of the BETA-2 Score: An Improved Tool to Estimate Beta Cell Function After Clinical Islet Transplantation Using a Single Fasting Blood Sample

Forbes

Oram

Smith

et al. 2016

American Journal of Transplantation

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The beta score, a composite measure of beta cell function after islet transplantation, has limited sensitivity because of its categorical nature and requires a mixed‐meal tolerance test (MMTT). We developed a novel score based on a single fasting blood sample. The BETA‐2 score used stepwise forward linear regression incorporating glucose (in millimoles per liter), C‐peptide (in nanomoles per liter), hemoglobin A1c (as a percentage) and insulin dose (U/kg per day) as continuous variables from the original beta score data set (n = 183 MMTTs). Primary and secondary analyses assessed the score's ability to detect glucose intolerance (90‐min MMTT glucose ≥8 mmol/L) and insulin independence, respectively. A validation cohort of islet transplant recipients (n = 114 MMTTs) examined 12 mo after transplantation was used to compare the score's ability to detect these outcomes. The BETA‐2 score was expressed as follows (range 0–42): normalBETA−20.166667emnormalscore=)(normalfasting0.166667emnormalC−normalpeptide0.166667emfalse(normalnmolfalse/normalLfalse)×(1−normalinsulin0.166667emnormaldose0.166667emfalse[normalunitsfalse/normalkgfalse])normalFasting0.166667emnormalplasma0.166667emnormalglucose0.166667emfalse(normalmmolfalse/normalLfalse)×normalHbA1normalc(%)×1000 A score <20 and ≥15 detected glucose intolerance and insulin independence, respectively, with >82% sensitivity and specificity. The BETA‐2 score demonstrated greater discrimination than the beta score for these outcomes (p < 0.05). Using a fasting blood sample, the BETA‐2 score estimates graft function as a continuous variable and shows greater discrimination of glucose intolerance and insulin independence after transplantation versus the beta score, allowing frequent assessments of graft function. Studies examining its utility to track long‐term graft function are required.

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“…DPP4 inhibitors increase circulating levels of active GLP-1 and have been shown to increase β cell mass in animals. In a clinical pilot study, the DPP4 inhibitor sitagliptin was combined with pantoprazole to successfully restore insulin independence from failing grafts, although insulin independence was lost after treatment was stopped [10]. However, in a randomized, placebo controlled study using sitagliptin in islet autotransplantation after total pancreatectomy, sitagliptin was well tolerated, although there was no metabolic benefit from treatment [11].…”

Section: Introductionmentioning

confidence: 99%

The DPP4 Inhibitor Sitagliptin Increases Active Glp-1 Levels from Human Islets and May Increase Islet Cell Survival Prior to Transplantation

Campbell¹,

Hubert²,

Johnson³

et al. 2019

obm transplant

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Background: One of the goals of clinical islet transplantation is to achieve a single-donor transplant that is dependent on obtaining enough quality  cell mass from one donor pancreas. Human islets are routinely cultured prior to transplantation, and pro-survival factors such as GLP-1 analogues have been reported to maintain  cell mass and survival. Interestingly, human islets may secrete GLP-1 and they also express the enzyme DPP4 that proteolytically cleaves GLP-1 into an inactive form. The aim of this study is to investigate GLP-1 secretion from human islets and to test if the DPP4 inhibitor sitagliptin may increase levels of active GLP-1 to increase islet survival in culture. Methods: Active GLP-1, glucagon, and insulin were measured from non-diabetic and type 2 diabetic islets using a glucose suppression test. Human islet cultures were treated with sitagliptin, and active GLP-1 levels were taken at 48 hours. These levels were then correlated with islet isolation parameters (SI, viability, culture time, cold ischemia time, and DNA was used to measure cell death in human islet cultures treated with sitagliptin. Results: We found that both non-diabetic and type 2 diabetic islets secrete active GLP-1. Active GLP-1 levels from human islet cultures negatively correlated with the stimulation index for insulin and this correlation was maintained when active GLP-1 levels were increased with sitagliptin. No strong correlations were found for other islet or donor parameters. The fold change in active GLP-1 in sitagliptin treated islet cultures was correlated with increased islet survival. Conclusions: Human islets have a local paracrine source of the prosurvival peptide, active GLP-1. Although low levels of active GLP-1 are associated with greater  cell function, these levels may be increased with the DPP4 inhibitor sitagliptin. The increase in active GLP-1 levels may confer protection from islet cell death and pre-treatment of islets with DPP4 inhibitors prior to transplantation has the potential to improve post-transplant islet survival.

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Sitagliptin plus pantoprazole can restore but not maintain insulin independence after clinical islet transplantation: results of a pilot study

Cited by 13 publications

References 21 publications

Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized, Placebo-Controlled Study

Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized, Placebo-Controlled Study

Validation of the BETA-2 Score: An Improved Tool to Estimate Beta Cell Function After Clinical Islet Transplantation Using a Single Fasting Blood Sample

The DPP4 Inhibitor Sitagliptin Increases Active Glp-1 Levels from Human Islets and May Increase Islet Cell Survival Prior to Transplantation

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