Investigating Predictive Factors of Diabetes Occurence After Duodenalpancreatectomy

Regeneration of mature cells that produce functional insulin represents a major focus of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes. The capacity to adapt in response to diverse physiological conditions during life and the consequent ability to cope for increased metabolic demands is a distinctive feature of the endocrine pancreas in the regulation of glucose homeostasis. Both beta and alpha cells are dynamically regulated to continually maintain a balance between proliferation, neogenesis, and apoptosis. In this proposal, the investigators will focus on exploring key mechanism(s) that potentially regulate islet cell plasticity in altered glucose metabolic states.

Investigators will explore in a unique cohort of individuals who undergo duodenal pancretectomy. Prior to their surgery will be performed in vivo studies (Hyperglycemic clamp, Euglycemic Hyperinsulinemic clamp and Mixed Meal Tests) to accurately assess glucose homeostasis parameters to classify each individual into metabolic phenotypes. Then exploit the opportunity to collect pancreas samples from these patients who will be evaluated again after surgery, the investigators will determine the ability of the remnant pancreas to compensate for the acute reduction in islet mass and perform correlations between ex vivo and in vivo parameters.

Specifically, the patients will be subjected to incretin secretion (mixed meal), metabolic status (OGTT), insulin secretion characteristics (first and second phase responses), β-cell insulin content evaluation (arginine bolus). Subsequently, pancreas samples will be evaluated for morphometry, and proteomics and gene expression analyses of islet cell samples obtain by laser capture will allow a detailed investigation of mechanisms that contribute to islet plasticity. The overall goal of this project is to investigate key mechanisms driving the ability of islet mass to adapt to diverse metabolic states. We aim to explore modifications in gene expression and proteomics and correlate them with specific metabolic phenotypes, in order to determine key regulators of islet morphology.

Study Overview

• Status: Recruiting
• Conditions: Exocrine Pancreatic Insufficiency; DIABETES; Endocrine Pancreas Disorder; GLUCOSE METABOLISM; PANCREATIC ISLETS; Exocrine Pancreatic Dysfunction; Exocrine Pancreas Conditions

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: TERESA MEZZA, MD, PHD; Phone Number: 6664 +39063015; Email: TERESA.MEZZA@UNICATT.IT

Study Locations

• Italy
  • RM
    • Rome, RM, Italy, 00168
      • Recruiting
      • Endocrinology - Catholic University
      • Principal Investigator: ANDREA GIACCARI, MD, PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients scheduled for elective pancreaticoduodenectomy for periampullary neoplasms will be enrolled in the study. Indications for surgery will be periampullary neoplasms, i.e.

tumors of the Vater's ampulla, distal CBD and periampullary duodenum. Patients with pancreatic cancer will be excluded from the study. The metabolic features of all patients will be assessed before and after surgery. The patients will visit the Division of Endocrinology for studies at least 1 week before surgery. Only patients with normal cardiopulmonary and kidney functions, as determined by medical history, physical examination, screening blood tests, electrocardiogram and urinalysis, and not on any antidiabetic medications will be enrolled for metabolic assessments before and after surgery. Each subject will undergo, on separate days, a hyperinsulinemic euglycemic clamp, a hyperglycemic clamp and a mixed meal test one week before and after a variable period of recovery from the surgical procedure.

Description

Inclusion Criteria:

• SCHEDULED FOR PANCREATECTOMY
• NO DIABETIC and DIABETIC

Exclusion Criteria:

• CHRONIC DESEASES
• STEROID THERAPY

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in metabolic status (normal glucose tolerance, impaired glucose tolerance, diabetes)	Metabolic status will be determined with oral glucose tolerance test and patients will be classified according their metabolic status (after 1 month and 1 year after surgery).	baseline, 1 month after surgery and 1year after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in incretin levels from baseline	Incretin levels (GLP1 and GIP) will be measured during mixed meal test.	baseline, 1 months after surgery and 1 year after surgery
Change in insulin secretion from baseline	Insulin secretion will be measured by Hyperglicemic clamp.	baseline, 1 month after surgery and 1 year after surgery
islet cell areas (beta, Alpha and delta cell positive area)	Pancreas section will be immunostained for insulin, glucagon and somatostatin and Each section will be analyzed separately by measuring total insulin, glucagon or somatostatin positive areas, as well as the total pancreas section area, using Image Pro Plus software version 4. 5.1 . The β, α or δ cell areas will be expressed as percentage of total pancreas section area.	baseline
changes in beta cell function in the context of disease of exocrine pancreas	Insulin secretion will be measured by Hyperglicemic clamp and ogtt.	baseline
changes in intraislet ncRNA in different metabolic status	ncRNA sequenting in plasma and pancreas samples	baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in gene expression analysis among different groups of baseline metabolic status	Extract of islet cells will be dissected from pancreatic sections by laser capture microdissection and then extracted RNA will be analyzed by real time PCR analysis.	baseline

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Collaborators: University of Pisa; University of Copenhagen; Joslin Diabetes Center; University of Siena; Istituto di Neuroscienze Consiglio Nazionale delle Ricerche

Publications and helpful links

General Publications

• Mezza T, Ferraro PM, Di Giuseppe G, Moffa S, Cefalo CM, Cinti F, Impronta F, Capece U, Quero G, Pontecorvi A, Mari A, Alfieri S, Giaccari A. Pancreaticoduodenectomy model demonstrates a fundamental role of dysfunctional beta cells in predicting diabetes. J Clin Invest. 2021 Jun 15;131(12):e146788. doi: 10.1172/JCI146788.
• Mezza T, Ferraro PM, Sun VA, Moffa S, Cefalo CMA, Quero G, Cinti F, Sorice GP, Pontecorvi A, Folli F, Mari A, Alfieri S, Giaccari A. Increased beta-Cell Workload Modulates Proinsulin-to-Insulin Ratio in Humans. Diabetes. 2018 Nov;67(11):2389-2396. doi: 10.2337/db18-0279. Epub 2018 Aug 21.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: June 25, 2014
• First Posted (Estimated): June 26, 2014

Study Record Updates

• Last Update Posted (Actual): May 23, 2024
• Last Update Submitted That Met QC Criteria: May 22, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Biomarkers; Beta cell function; MiRNA; Islet cell crosstalk; Incretin intraislet System; ncRNA; Pancreatic exocrine endocrine crosstalk; Diabetes of exocrine pancreas
• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Exocrine Pancreatic Insufficiency
• Other Study ID Numbers: 14081985