Central role of the β-cell in driving regression of diabetes after liver transplantation in cirrhotic patients

Valeria Grancini, Maddalena Trombetta, Maria Elena Lunati, Maria Linda Boselli, Stefano Gatti, Maria Francesca Donato, Eva Palmieri, Veronica Resi, Giuseppe Pugliese, Riccardo C. Bonadonna, Emanuela Orsi

Research output: Contribution to journalArticle

Abstract

Background & Aims: Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A 1c (HbA 1c ) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., β-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT. Methods: Eighty cirrhotic patients with non-diabetic FPG and HbA 1c levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of β-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity. Results: At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups. Conclusions: Increased insulin bioavailability driven by improved β-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity. Lay summary: Diabetes occurring in cirrhosis as a direct consequence of loss of liver function should regress after transplantation of a new functioning liver, though the pathophysiological mechanisms are unclear. This is the first study evaluating the contribution of all 3 direct determinants of insulin-dependent glucose regulation using a sophisticated mathematical model. Results show that β-cell function is the key process governing favourable or detrimental changes in glucose regulation in cirrhotic patients undergoing transplantation, pointing to the need to develop therapies to sustain β-cell function in these individuals. Trial registration: ClinicalTrials.gov, NCT02038517.

Original languageEnglish
Pages (from-to)954-962
Number of pages9
JournalJournal of Hepatology
Volume70
Issue number5
DOIs
Publication statusPublished - May 1 2019

Keywords

  • Hepatogenous diabetes
  • Insulin resistance
  • Liver cirrhosis
  • Orthotopic liver transplantation
  • β-cell dysfunction

ASJC Scopus subject areas

  • Hepatology

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