Chemical pancreatectomy treats chronic pancreatitis while preserving endocrine function in preclinical models
Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes
Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes
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Research Article Endocrinology Gastroenterology

Chemical pancreatectomy treats chronic pancreatitis while preserving endocrine function in preclinical models

Abstract

Chronic pancreatitis affects over 250,000 people in the US and millions worldwide. It is associated with chronic debilitating pain, pancreatic exocrine failure, and high risk of pancreatic cancer and usually progresses to diabetes. Treatment options are limited and ineffective. We developed a new potential therapy, wherein a pancreatic ductal infusion of 1%–2% acetic acid in mice and nonhuman primates resulted in a nonregenerative, near-complete ablation of the exocrine pancreas, with complete preservation of the islets. Pancreatic ductal infusion of acetic acid in a mouse model of chronic pancreatitis led to resolution of chronic inflammation and pancreatitis-associated pain. Furthermore, acetic acid–treated animals showed improved glucose tolerance and insulin secretion. The loss of exocrine tissue in this procedure would not typically require further management in patients with chronic pancreatitis because they usually have pancreatic exocrine failure requiring dietary enzyme supplements. Thus, this procedure, which should be readily translatable to humans through an endoscopic retrograde cholangiopancreatography (ERCP), may offer a potential innovative nonsurgical therapy for chronic pancreatitis that relieves pain and prevents the progression of pancreatic diabetes.

Authors

Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes

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Figure 10

Chemical pancreatectomy improves glucose tolerance and insulin secretion.

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Chemical pancreatectomy improves glucose tolerance and insulin secretion...
(A and B) i.p. GTT 8 weeks after surgery (A) comparing AcA group (n = 6) and controls (n = 5/group). Two-way repeated-measures ANOVA, F10,65=7.231; P < 0.0001. For A, *P = 0.035; **P = 0.0026; ***P = 0.0001; ****P < 0.0001; ###P = 0.0006; †††P = 0.0004. AUC (B), 1-way ANOVA, F2,13=9.234; P = 0.0032. (C and D) ITT at 8 weeks (C). (D) Percentage change in glucose levels compared with fasting glucose. n = 4 naive; 5 saline, and 5 AcA. Two-way repeated-measures ANOVA, F8,44=1.130; P = 0.3626. (E and F) i.v. GTT (E) n = 5 per group. Two-way repeated-measures ANOVA, F8,48=3.241; P = 0.005. For E, *P = 0.0367; **P = 0.0082; #P = 0.0108; ##P = 0.0023; †P = 0.0112; ††P = 0.0021; ‡‡P = 0.0035. AUC (F), 1-way ANOVA, F2,12=5.167; P = 0.0241. (G and H) In vivo GSIS (G). n = 5/group. Two-way repeated-measures ANOVA, F8,48=5.267; P < 0.0001. For G, **P = 0.0024; ****P < 0.0001; ##P = 0.0034. AUC (H), 1-way ANOVA F2,12=5.92; P = 0.0163. (I) Eight weeks after surgery, β cell mass quantification. n = 4 AcA, 3 naive, and 3 saline. One-way ANOVA, F2,7=0.8376; P = 0.4719. (J) In vitro GSIS. n = 5 naive, 4 saline, and 5 AcA. Two-way repeated-measures ANOVA, F2,11=0.5903; P = 0.5708. (K–N) i.p. GTT comparing the cerulein+AcA group (n = 6) and cerulein+saline group (n = 5) (K). Two-way repeated-measures ANOVA, F5,45=4.141; P = 0.0035. For K, *P = 0.0150; ***P = 0.0006. AUC (L), unpaired t test, t9=2.394; P = 0.0403. i.p. GTT comparing vehicle+AcA and vehicle+saline groups. n = 7/group (M). Two-way repeated-measures ANOVA, F5,60=5.1; P = 0.0006. For M, **P = 0.0016; ****P < 0.0001; ##P = 0.0068. AUC (N), unpaired t test, t12 =3.475; P = 0.0046. (O and P) i.v. GTT 8 weeks after surgery in NHPs. n = 3/group. Two-way repeated-measures ANOVA, F7,28 =5; P = 0.0008. For O, *P = 0.0152; **P = 0.0026; ##P = 0.0024; ††P = 0.0025, ****P < 0.0001). AUC (P), unpaired t test, t4 =3.472; P = 0.0255. Data are presented as mean ± SD. Holm-Šidák test was used for multiple comparisons.