Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.
OBJECTIVE
Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition.


METHODS
We performed a two-step (1.5 and 6 pmol min(-1) kg(-1)) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects.


RESULTS
In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48+/-12 vs 63+/-13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability.


CONCLUSIONS
Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.
Bugianesi
E
E
Division of Gastro-hepatology, San Giovanni Battista Hospital, University of Turin, Turin, Italy. ebugianesi@yahoo.it
Gastaldelli
A
A
Vanni
E
E
Gambino
R
R
Cassader
M
M
Baldi
S
S
Ponti
V
V
Pagano
G
G
Ferrannini
E
E
Rizzetto
M
M
D020155:3-Hydroxybutyric Acid / Q000097:blood / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D002096:C-Peptide / Q000097:blood; D002153:Calorimetry, Indirect; D004798:Enzymes / Q000097:blood; D005215:Fasting / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000097:blood / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction
D001786:Blood Glucose; D002096:C-Peptide; D004798:Enzymes; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008055:Lipids; D008077:Lipoproteins, LDL; D005947:Glucose; D005990:Glycerol; D020155:3-Hydroxybutyric Acid