TY - JOUR
T1 - Central role of the β-cell in driving regression of diabetes after liver transplantation in cirrhotic patients
AU - Grancini, Valeria
AU - Trombetta, Maddalena
AU - Lunati, Maria Elena
AU - Boselli, Maria Linda
AU - Gatti, Stefano
AU - Donato, Maria Francesca
AU - Palmieri, Eva
AU - Resi, Veronica
AU - Pugliese, Giuseppe
AU - Bonadonna, Riccardo C.
AU - Orsi, Emanuela
PY - 2019/5/1
Y1 - 2019/5/1
N2 -
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.
AB -
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.
KW - Hepatogenous diabetes
KW - Insulin resistance
KW - Liver cirrhosis
KW - Orthotopic liver transplantation
KW - β-cell dysfunction
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U2 - 10.1016/j.jhep.2019.01.015
DO - 10.1016/j.jhep.2019.01.015
M3 - Article
AN - SCOPUS:85061635191
VL - 70
SP - 954
EP - 962
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 5
ER -