Valeria Grancini1, Maddalena Trombetta2, Maria Elena Lunati1, Maria Linda Boselli2, Stefano Gatti3, Maria Francesca Donato4, Eva Palmieri1, Veronica Resi1, Giuseppe Pugliese5, Riccardo C Bonadonna6, Emanuela Orsi7. 1. Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. 2. Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy. 3. General Surgery Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, Milan, Italy. 4. A. Migliavacca Centre for Liver Disease, Division of Gastroenterology and Hepatology, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, Milan, Italy. 5. Department of Clinical and Molecular Medicine, "La Sapienza" University, and Diabetes Unit, Sant'Andrea University Hospital, Rome, Italy. 6. Department of Medicine and Surgery, University of Parma, and Division of Endocrinology and Metabolic Diseases, Azienda Ospedaliera Universitaria, Parma, Italy. 7. Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address: emanuela_orsi@yahoo.it.
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 A1c (HbA1c) 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 HbA1c 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.
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 A1c (HbA1c) 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 HbA1c 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 diabeticpatients (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.
Authors: Francesca D'Addio; Anna Maestroni; Emma Assi; Moufida Ben Nasr; Giovanni Amabile; Vera Usuelli; Cristian Loretelli; Federico Bertuzzi; Barbara Antonioli; Francesco Cardarelli; Basset El Essawy; Anna Solini; Ivan C Gerling; Cristina Bianchi; Gabriella Becchi; Serena Mazzucchelli; Domenico Corradi; Gian Paolo Fadini; Diego Foschi; James F Markmann; Emanuela Orsi; Jan Škrha; Maria Gabriella Camboni; Reza Abdi; A M James Shapiro; Franco Folli; Johnny Ludvigsson; Stefano Del Prato; Gianvincenzo Zuccotti; Paolo Fiorina Journal: Nat Commun Date: 2022-02-03 Impact factor: 17.694