Nadolol reduces insulin sensitivity in liver cirrhosis: a randomized double-blind crossover trial.
Liver cirrhosis is frequently complicated by portal hypertension leading to increased mortality from variceal bleeding and hepatic decompensation. Noncardioselective β-blockers not only reduce portal hypertension and prevent variceal bleeding in cirrhosis but also impair glucose tolerance and insulin sensitivity in other settings. This study aimed to determine whether nonselective β-blockade with nadolol impairs glucose metabolism in liver cirrhosis.



A randomized, double-blind, placebo-controlled crossover trial of nadolol in cirrhotic patients examined insulin sensitivity, disposition index, and glucose tolerance. Stable cirrhotic patients of mixed etiology underwent an intravenous glucose tolerance test and hyperinsulinemic-euglycemic clamp for the measurement of insulin secretion and insulin sensitivity (n = 16) and a 75-g oral glucose tolerance test (n = 17). These measurements were conducted twice (after 3 months of treatment with nadolol or placebo and, after a 1-month washout period, after 3 months on the alternative treatment). Total body fat and plasma catecholamines were measured at the end of each 3-month treatment.



Compared with placebo, nadolol treatment reduced insulin sensitivity (79.7 ± 10.1 vs 99.6 ± 10.3 μL/kg fat-free mass·min-1·(mU/L)-1, P = .005). Insulin secretion was unchanged (P = .24), yielding a lower disposition index with nadolol (6083 ± 2007 vs 8692 ± 2036, P = .050). There was no change in total body fat or plasma catecholamines. A 2-hour plasma glucose concentration from the oral glucose tolerance test was higher on nadolol than placebo (10.8 ± 0.9 vs 9.9 ± 0.9 mmol/L, P = .035).



Nadolol significantly worsened insulin sensitivity, glycemia, and disposition index in patients with liver cirrhosis. These findings may have significant clinical implications because cirrhosis is already associated with an increased prevalence of diabetes.
Department of Surgery, University of Auckland, Auckland, New Zealand.
Wai Gin
WG
Lee
Department of Medicine, University of Auckland, Auckland, New Zealand.
Rinki
R
Murphy
Section of Surgery, Department of Medical and Surgical Sciences, University of Otago, Dunedin, New Zealand.
John L
JL
McCall
New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
Edward J
EJ
Gane
Department of Surgery, University of Auckland, Auckland, New Zealand.
Mattias
M
Soop
Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padua, Italy.
Andrea
A
Tura
Department of Surgery, University of Auckland, Auckland, New Zealand.
Lindsay D
LD
Plank
D000319:Adrenergic beta-Antagonists / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced* / Q000473:pathology; D007333:Insulin Resistance; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009248:Nadolol / Q000009:adverse effects*; D011379:Prognosis; D011446:Prospective Studies
D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D009248:Nadolol
beta-blocker; cirrhosis; glucose tolerance; hyperinsulinemic-euglycemic clamp; insulin resistance; intravenous glucose tolerance test