Clinical trial NCT02038517: Cirrhosis, Effects of TRAnsplantation and Diabetes
Official title: Insulin Secretion and Sensitivity in Subjects With Liver Cirrhosis Undergoing Orthotopic Liver Transplantation (OLT): Pre- and Post-OLT Analysis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Liver Cirrhosis
Keywords: Insulin secretion
Insulin sensitivity
Orthotopic liver transplantation
Type 2 diabetes
Metabolic syndrome
Cardiovascular disease
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sponsor class: OTHER
First posted: 2014-01-16
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Secondary care outpatients clinic

Brief summary: This observational study is aimed at assessing insulin secretion and sensitivity by the use of a mathematical modeling from oral glucose tolerance test in subjects with liver cirrhosis undergoing orthotopic liver transplantation (OLT), before and at various time points after OLT.

Detailed description: Background

Diabetes is frequent in subjects with liver cirrhosis, especially in those with liver disease related to alcohol, hepatitis C, hemochromatosis and NASH, though it goes often unrecognised if screened by measuring fasting glucose. These individuals might suffer from classical type 2 diabetes, in which β-cell dysfunction plays a major role, or from hepatogenous diabetes, in which insulin resistance predominates. Orthotopic liver transplantation (OLT) improves life quality and expectancy of individuals with end-stage liver cirrhosis, thus representing the elective treatment for these patients. OLT has different effects on glucose metabolism. On the one hand, restoration of liver function reduces insulin resistance by improving hepatic insulin clearance, thus favouring regression of hepatogenous diabetes. On the other hand, OLT may worsen insulin secretion and sensitivity, due to immunosuppression and lifestyle modifications, with return to free food intake.

Aims

This observational study is aimed at assessing insulin secretion and sensitivity by the use of a mathematical modeling from oral glucose tolerance test in subjects with liver cirrhosis undergoing orthotopic liver transplantation (OLT), before and at various time points after OLT over a 10-year follow-up and to establish the relation of alterations in insulin secretion and sensitivity and their changes with transplantation with the development or persistence of abnormalities of glucose metabolism after OLT.

Secondary endpoints are to assess in these individuals:

* the relation of alterations in insulin secretion and sensitivity and their changes with transplantation with morbidity and mortality after OLT;
* the relation of alterations in insulin secretion and sensitivity and their changes with transplantation with the development or persistence of the metabolic syndrome and its components (central) obesity , dyslipidemia and hypertension;

Other pre-specified endpoints are to assess in these subjects:

* prevalence and incidence of unknown diabetes mellitus (and IFG/IGT);
* prevalence and incidence of the metabolic syndrome and its components (central) obesity , dyslipidemia and hypertension;
* morbidity and mortality from OLT-related and unrelated causes, including rejection, infection, and cardiovascular disease.

Patients Consecutive patients with normal fasting plasma glucose and HbA1c levels in waiting list for OLT will be recruited from electronic records of the diabetic clinic of the Endocrinology and Diabetes Unit, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy.

Measures

Routine clinical and laboratory data will be recorded at baseline and over the subsequent 10 years to obtain information about:

* cardiovascular risk factors (smoking, physical activity, family history of diabetes, dyslipidemia, hypertension and cardiovascular disease, BMI and waist circumference, total, LDL, HDL and non-HDL cholesterol, triglycerides, arterial blood pressure and HbA1c);
* cardiovascular events (myocardial infarction, stroke, lower limb ulcer/gangrene/amputation and coronary, carotid and lower limb revascularization, endovascular/surgical) and deaths.
* renal function (albumin/creatinine ratio, serum creatinine with estimation of glomerular filtration rate \[eGFR\]);
* current glucose-, lipid- and blood pressure-lowering and anti-platelet or anti-coagulant treatment;
* other illnesses and non-cardiovascular deaths. In addition, glucose, insulin and C-peptide levels from blood sample collected before and 15, 30, 45, 60, 90, 120', 150, and 180 min after a 75 g oral glucose tolerance test (OGTT) will be recorded. This test is routinely performed to all cirrhotic subjects before and at various time points after OLT. The response to OGTT will be evaluated by the use of a mathematical model to derive measures of insulin secretion (Proportional and Derivative Control) and sensitivity (OGIS, Oral Glucose Insulin Sensitivity).

Time schedule

This observational study was submitted for approval to the Ethics Committee of the Organization (Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy) on October 24, 2012. The transferral of patient records (concerning the 2007-2013 visits) from the electronic database of the centre to the study database has been started on June 2013 and will terminate on September 2014.

The enrolled patients will be followed for at least 10 years with (at least) yearly visits and consultation of death records in case of drop-out for unknown reasons.

Eligibility criteria: Inclusion Criteria:

Subjects with end-stage liver cirrhosis in waiting list for orthotopic liver transplantation at the Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy

Exclusion Criteria:

* Known diabetes
* Cystic fibrosis
* Pregnancy

Primary outcomes:
measure: Relationship of insulin secretion and sensitivity with the development of abnormalities of glucose metabolism after OLT
timeFrame: 10 years
Secondary outcomes:
measure: Relationship of insulin secretion and sensitivity with morbidity and mortality after OLT
timeFrame: 10 years
measure: Relationship of insulin secretion and sensitivity with the development of the metabolic syndrome after OLT
timeFrame: 10 years
Other outcomes:
measure: Prevalence and incidence of impaired glucose metabolism (IFG, IGT and diabetes)
timeFrame: 10 years
measure: Prevalence and incidence of the metabolic syndrome and its components (central) obesity , dyslipidemia and hypertension
timeFrame: 10 years
measure: Morbidity and mortality after OLT
timeFrame: 10 years
Locations:
city: Milan
country: Italy
facility: Endocrinology and Diabetes Unit, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico
state: MI
Study officials:
affiliation: Endocrinology and Diabetes Unit, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy
name: Emanuela Orsi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grancini V, Trombetta M, Lunati ME, Boselli ML, Gatti S, Donato MF, Palmieri E, Resi V, Pugliese G, Bonadonna RC, Orsi E. Central role of the beta-cell in driving regression of diabetes after liver transplantation in cirrhotic patients. J Hepatol. 2019 May;70(5):954-962. doi: 10.1016/j.jhep.2019.01.015. Epub 2019 Jan 21.