Page 48 - EASL POSTGRADUATE COURSE
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Abbreviations: OGTT, oral glucose tolerance test; OGIS, oral glucose IS index; ISI, IS index; SiOGTT,
IS index derived from oral glucose tolerance test; HepIR, hepatic insulin resistance index; LIRI, liver
insulin resistance index; HOMA, homeostasis model of assessment; QUICKI, quantitative IS check
index; FIRI, fasting insulin resistance index; IGR, insulin to glucose ratio.
Insulin resistance and liver damage
The notion that IR is closely related with liver fat accumulation is well proven, but there is important
evidence that IR promotes the progression of simple steatosis to NASH and fibrosis. The method used
to measure IS/IR is critical to unveil the association between IR and liver damage.
Several studies employing the glucose clamp technique have shown a close association between NAFLD
and both hepatic and adipose tissue IR, as well as reduced whole-body IS (i.e. peripheral IR). Glucose
disposal, a measure of whole-body IS, was reduced by 45-50% in NAFLD, together with an impaired
ability of insulin to suppress endogenous glucose production, indicative of hepatic IR [6, 7]. Additionally,
subjects with NAFLD exhibited a marked defect in insulin suppression of FFAs, in keeping with IR at
the adipocyte level [6, 7]. Hepatic insulin-resistance correlates well with the intrahepatic triglyceride
content and is a strong predictor of steatosis, independent of BMI and insulin action in liver, skeletal
muscle and adipose tissues [2]. Adipose tissue IR has been repeatedly associated with the degree of liver
fibrosis in NASH [6-8]. Adipose tissue IR and skeletal muscle IR are tightly linked, but the role of the
latter in the onset and progression of liver damage is less clear.
HOMA-IR is calculated as the product of insulin and glucose concentration (fasting plasma insulin
x fasting plasma glucose / 22.5) and is a rather crude index reflecting the final effects of hepatic and
peripheral IR on fasting glucose homeostasis [9]. Since the first demonstration of IR in NAFLD, HOMA-
IR has been used in epidemiological studies to demonstrate the close association between NAFLD and
MetS; patients with NASH generally have more increased HOMA-IR compared to patients with simple
steatosis [10]. However, this index does not provide any clue to the site of IR.
The oral glucose IS (OGIS) index [11] is calculated on the basis of glucose and insulin in the two
hours following glucose ingestion (75 g), which activates the insulin–glucose homeostatic processes,
and this index mostly reflects glucose uptake by muscle tissue (i.e. peripheral IR). For this reason, it
correlates significantly with glucose clearance measured by the clamp technique, and is considered a
more sensitive measure of IS than HOMA-IR. Severe fibrosis has been associated with decreased IS
measured by OGIS in both NAFLD and chronic hepatitis C patients, independently of BMI, sex, age
and MetS, and with the clustering of the clinical and biochemical features of MetS [12, 13].
Many other indices have been developed, including clinical and anthropometric parameters (e.g. age,
gender and BMI), but they are not superior to the above tests and are scarcely used in clinical practice.
Of note, all these surrogate indices of IR have been validated in diabetic and non-diabetic subjects against
the euglycemic hyperinsulinemic clamp, but none of them has been validated in NAFLD patients by
state-of-the art-techniques.
Putative mechanisms for the association between insulin resistance and liver damage
IR plays a central role in intrahepatic lipotoxic injury by allowing an excessive flow of fatty acids from
adipose tissue and also by impairing peripheral glucose disposal. Supply processes include inappropriate
lipolysis by insulin resistant adipocytes and increased carbohydrate precursors for de novo lipogenesis,
secondary to peripheral and hepatic IR. Metabolites of FFAs cause lipotoxic hepatocellular injury
manifested as endoplasmic reticulum stress, inflammation, apoptosis, necrosis, and dysmorphic features
(e.g. ballooning and MDB formation) [14]. Reversal of adipose tissue IR by a glitazone is associated
with an improvement of the necroinflammatory damage in the liver. Furthermore, hyperglycemia and
hyperinsulinemia can cause an up-regulation of the connective tissue growth factor, thus promoting
fibrogenesis [14, 15]. Other key players in the progression to steatohepatitis are the adipokines
(adiponectin, leptin, and resistin) and several cytokines (such as TNF-alpha, IL-6 and IL-1) secreted
48 Postgraduate Course Syllabus • Metabolic Liver Disease
IS index derived from oral glucose tolerance test; HepIR, hepatic insulin resistance index; LIRI, liver
insulin resistance index; HOMA, homeostasis model of assessment; QUICKI, quantitative IS check
index; FIRI, fasting insulin resistance index; IGR, insulin to glucose ratio.
Insulin resistance and liver damage
The notion that IR is closely related with liver fat accumulation is well proven, but there is important
evidence that IR promotes the progression of simple steatosis to NASH and fibrosis. The method used
to measure IS/IR is critical to unveil the association between IR and liver damage.
Several studies employing the glucose clamp technique have shown a close association between NAFLD
and both hepatic and adipose tissue IR, as well as reduced whole-body IS (i.e. peripheral IR). Glucose
disposal, a measure of whole-body IS, was reduced by 45-50% in NAFLD, together with an impaired
ability of insulin to suppress endogenous glucose production, indicative of hepatic IR [6, 7]. Additionally,
subjects with NAFLD exhibited a marked defect in insulin suppression of FFAs, in keeping with IR at
the adipocyte level [6, 7]. Hepatic insulin-resistance correlates well with the intrahepatic triglyceride
content and is a strong predictor of steatosis, independent of BMI and insulin action in liver, skeletal
muscle and adipose tissues [2]. Adipose tissue IR has been repeatedly associated with the degree of liver
fibrosis in NASH [6-8]. Adipose tissue IR and skeletal muscle IR are tightly linked, but the role of the
latter in the onset and progression of liver damage is less clear.
HOMA-IR is calculated as the product of insulin and glucose concentration (fasting plasma insulin
x fasting plasma glucose / 22.5) and is a rather crude index reflecting the final effects of hepatic and
peripheral IR on fasting glucose homeostasis [9]. Since the first demonstration of IR in NAFLD, HOMA-
IR has been used in epidemiological studies to demonstrate the close association between NAFLD and
MetS; patients with NASH generally have more increased HOMA-IR compared to patients with simple
steatosis [10]. However, this index does not provide any clue to the site of IR.
The oral glucose IS (OGIS) index [11] is calculated on the basis of glucose and insulin in the two
hours following glucose ingestion (75 g), which activates the insulin–glucose homeostatic processes,
and this index mostly reflects glucose uptake by muscle tissue (i.e. peripheral IR). For this reason, it
correlates significantly with glucose clearance measured by the clamp technique, and is considered a
more sensitive measure of IS than HOMA-IR. Severe fibrosis has been associated with decreased IS
measured by OGIS in both NAFLD and chronic hepatitis C patients, independently of BMI, sex, age
and MetS, and with the clustering of the clinical and biochemical features of MetS [12, 13].
Many other indices have been developed, including clinical and anthropometric parameters (e.g. age,
gender and BMI), but they are not superior to the above tests and are scarcely used in clinical practice.
Of note, all these surrogate indices of IR have been validated in diabetic and non-diabetic subjects against
the euglycemic hyperinsulinemic clamp, but none of them has been validated in NAFLD patients by
state-of-the art-techniques.
Putative mechanisms for the association between insulin resistance and liver damage
IR plays a central role in intrahepatic lipotoxic injury by allowing an excessive flow of fatty acids from
adipose tissue and also by impairing peripheral glucose disposal. Supply processes include inappropriate
lipolysis by insulin resistant adipocytes and increased carbohydrate precursors for de novo lipogenesis,
secondary to peripheral and hepatic IR. Metabolites of FFAs cause lipotoxic hepatocellular injury
manifested as endoplasmic reticulum stress, inflammation, apoptosis, necrosis, and dysmorphic features
(e.g. ballooning and MDB formation) [14]. Reversal of adipose tissue IR by a glitazone is associated
with an improvement of the necroinflammatory damage in the liver. Furthermore, hyperglycemia and
hyperinsulinemia can cause an up-regulation of the connective tissue growth factor, thus promoting
fibrogenesis [14, 15]. Other key players in the progression to steatohepatitis are the adipokines
(adiponectin, leptin, and resistin) and several cytokines (such as TNF-alpha, IL-6 and IL-1) secreted
48 Postgraduate Course Syllabus • Metabolic Liver Disease
