Insulin Resistance, Type 2 Diabetes and chronic Liver Disease. A ...

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Insulin Resistance, Type 2 Diabetes and chronic Liver
Disease. A Deadly Trio
Amedeo Lonardo and Paola Loria
University of Modena and reggio Emilia Department of Internal Medicine, Endocrinology, Geriatrics nuovo ospedale
Sant’Agostino Estense di Baggiovara, Baggiovara, Modena, Italy. Email: a.lonardo@libero.it
Abstract: In this commentary to the paper by Donadon V. et al (Clinical Medicine: Endocrinology and Diabetes. 2009;2:25–33.)
the association and significance of insulin resistance with chronic liver disease are shortly reviewed and the molecular mechanisms
underlying the diabetogenic and oncogenic potentials of advanced liver disease are summarized. Literature studies demonstrate that
hepatocellular carcinoma (HCC) can be part of the natural history of NASH. HCCs in patients with features of metabolic syndrome as
the only risk factor for liver disease have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in
the background liver. Moreover, data indicate that the presence of diabetes carries an approximately three to four-fold increased risk of
HCC and such a risk is strongly increased by concurrent viral infections. Finally, the relationship between insulin resistance, steatosis
and diabetes in NAFLD and HCV infection will be commented, along with the directions for future studies.
Keywords: T2DM, hepatitis, cirrhosis, hepatocellular carcinoma
Clinical Medicine: Endocrinology and Diabetes 2009:2 81–88
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Lonardo and Loria
The Diabetogenic potential
in the risk of HCC among patients with diabetes11
of Advanced Liver Disease
indirectly suggests that metabolic pathways such
Insulin resistance (IR) is a concept popular among
as synthesis of bile acids, sonic Hedgehog, Kras,
diabetologists who, historically, have contributed
and the Rho family, p21 and p27 cyclin-dependent
to its most explicit conceptualization in the last two
kinase inhibitors and fibrogenesis could be addi-
decades.1 During the same time period, however,
tional potential mechanisms involved in hepatocar-
IR has also become of great current interest among
cinogenesis in diabetics.10,11
hepatologists. This is essentially the result of IR
playing a key-role in the pathogenesis of nonalcoholic
nAsH, cryptogenic cirrhosis and Hcc
fatty liver disease (NAFLD)2 and being a cofactor
Nonalcoholic steatohepatitis (NASH) is the most
of progression/impaired response to treatment in
advanced histological form in the NAFLD spec-
chronic hepatitis C.3 Such close links between IR and
trum. The association between NASH-cirrhosis—
two among the most common chronic liver disorders
sometimes indistinguishable from cryptogenic
in western countries are likely to account for why
cirrhosis—and HCC has been consistently confirmed
diabetes almost invariably follows most chronic liver
by several studies summarized in Table 1.12–26 Such an
diseases. Moreover, they explain why cirrhosis, in
association comes as no surprise given that cirrhosis
particular, was depicted to be an overt diabetogenic
of various etiologies is known to be a pre-cancerous
condition a few years before Reaven had conceptual-
condition27 and NASH is indeed strongly associated
ized the importance of IR in human disease.4 Closing
with IR.28 Overall, literature studies summarized in
the circle, we now are aware that increasing stages of
Table 1 demonstrate that HCC can be part of the
hepatic fibrosis are associated with increasing risks of
natural history of NASH.12–26 HCCs in patients with
developing type 2 diabetes via increasing levels of IR.
features of MS as the only risk factor for liver dis-
The paper by Donadon5 is further evidence for this
ease have distinct morphological characteristics and
pathogenic cascade of events.
mainly occur in the absence of significant fibrosis in
the background liver.22,23 Awareness of these specific
The Oncogenic potential of Advanced
features of disease can be exploited to implement
Liver Disease is Influenced by IR
specific strategies aimed at obtaining earlier diagno-
Not only does insulin regulate glucose metabolism,
ses and more effective treatment results.26
but it is also directly and indirectly involved in the
risk of promoting the development of cancer at
Association of Diabetes, steatosis
various extrahepatic organ sites such as colon, pros-
and Hcc
tate, and pancreas.6 There is strong epidemiologic
Population studies from Northern Italy have shown
evidence linking the metabolic syndrome (MS) and
type 2 diabetic patients to have an increased risk
hepatocellular carcinoma (HCC); the molecular mech-
of death from gastrointestinal diseases, particu-
anisms sustaining hepatic carcinogenesis in those
larly from liver cirrhosis after 5 years of follow-
with IR, however, are not completely understood.7
up and a higher risk of mortality from liver cancer
Primary liver cancer might result from activation
after 10 years of follow-up, particularly in obese
of the tumor suppressor PTEN, a phosphoinositide
patients.29 Such findings are strongly supported
phosphatase regulating the PI3K/Akt signaling
by several studies, summarized in Table 2.30–46
pathways and the dysregulated expression and
Data indicate that the presence of diabetes carries
activity of which critically affects hepatic insulin
an approximatively three to four-fold increased
sensitivity, triggers the development of NAFLD and
risk of HCC.32,36,45 Moreover, the metabolic risk of
participates in the molecular pathogenesis of HCC.8,9
diabetes is strongly potentiated by concurrent viral
The Hydroxymethyl-glutaryl-CoA inhibitors statins
infections.31,37,44,45 Given that steatosis is a sensi-
exert pleiotropic actions in liver physiology and
tive barometer of metabolic health, the associa-
particularly on cholesterol-related cell signalling
tion of steatosis with HCC risk is also biologically
pathways.10 On this basis, the recent finding that
plausible35,43 although a study contrasts with such
statin use is associated with a significant reduction
a view.38
82
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Insulin resistance, T2DM and chronic liver disease
Table 1. Evidence for a relationship between nASh, cryptogenic cirrhosis and hCC.
Author, (Ref.)
series
Main finding
Powell EE12
42 nASh patients. Cirrhosis was
The patient with cirrhosis later died
present at initial diagnosis in one
of hCC.
subject.
Cotrim hP13
A patient with nASh-cirrhosis
hCC can be part of the natural history
developed hCC after a 6-yr follow-up.
of nASh.
Shimada14
6 patients with nASh and hCC out of
In patients with nASh-cirrhosis, the
a series of 82 cases with nASh.
development of treatable hCC is
sufficiently common to warrant regular
screening for this grave complication.
Bugianesi15
44/641 cryptogenic cirrhosis-
hypertriglyceridemia, diabetes, and
associated HCCs, were identified. Of
normal aminotransferases are factors
these, 23 were actively followed- up
independently associated with hCC
and compared in a case-control study
arising in cryptogenic cirrhosis,
with viral- and alcohol-associated
suggesting that hCC may represent a late
hCC.
complication of nASh-related cirrhosis.
regimbeau JM16
18/210 hCC patients (8.6%) had no
The prevalence of obesity, diabetes, AST/
identifiable cause for the underlying
ALT ratio  1 , steatosis 20% and wel -
liver disease.
dif erentiated tumors was significantly higher
in patients with cryptogenic liver disease.
hai S17
2/481 (0.4%) patients who
Follow-up and screening for hCC should
underwent liver resection for hCC
be done for patients with hepatic fibrosis
had associated nASh with moderate
caused by nASh.
hepatic fibrosis in one patient and
cirrhosis in the other.
Sanyal AJ18
152 patients with nASh cirrhosis
Compensated nASh cirrhosis is
were compared with 150 matched
associated with a lower mortality rate,
patients with cirrhosis due to hCV.
decompensation rate, development of
hCC; and greater cardiovascular mortality
in patients with nASh.
hashizume h19
nine patients with hCC in nASh.
All patients except one met the criteria for
metabolic syndrome.
Tsutsumi K20
Two cases of patients with hCC that
These cases progressed from nASh and
developed into cryptogenic cirrhosis
fatty liver, respectively, to nASh-related
suggestive of nASh as background
cirrhosis, eventually developing hCC.
liver disease.
Guzman G21
Three out of 50 patients with hCC.
nAFLD may predispose patients to hCC
in the absence of cirrhosis.
Paradis22
hCC patients with features of MS as
hCCs in patients with features of MS as
the only risk factor for liver diseases
the only risk factor for liver disease have
(n = 31) were compared to hCC
distinct morphological characteristics and
patients with overt causes of CLD
mainly occur in the absence of significant
(n = 81) or without causes of CLD
fibrosis in the background liver.
(n = 16).
hashimoto E23
34 nASh patients with hCC were
Older age and advanced fibrosis were
compared with 348 nASh without
important risk factors for hCC. hCC was
hCC.
the major cause of mortality in nASh
patients with advanced fibrosis. Regular
screening for hCC is warranted for nASh
patients with advanced fibrosis
Malik24
17/98 patients (17%) with nASh
Patients with nASh cirrhosis, especially
cirrhosis were diagnosed with hCC.
men older than 50 years, should undergo
surveillance imaging.
(Continued)
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Lonardo and Loria
Table 1. (Continued)
Author, (Ref.)
series
Main finding
Kawada n25
Eight (1%) hCC patients were
hCC might arise frequently from
diagnosed with nASh. Six (75%)
non-cirrhotic nASh.
of them showed non-cirrhosis in
non-cancerous areas.
Giannini EG26
45 consecutive CC patients with hCC
hCC patients with CC had similar
were compared with 426 consecutive
impairments in liver function as
patients with hCC and only hCV
patients with hCV infection. however,
infection.
the hCC patients with CC had lower
aminotransferase levels and higher
platelet counts. HCC was significantly less
likely to be diagnosed during surveillance
and thus to be more advanced and less
amenable to treatment compared with
hCV patients.
Abbreviations: CC, cryptogenic cirrhosis; hCC, hepatocellular carcinoma; MS, metabolic syndrome; nAFLD, nonalcoholic fatty liver disease; nASh,
nonalcoholic steatohepatitis.
The Relationship Between Insulin
Collectively, these animal and human studies have
Resistance, steatosis and Diabetes
relevant clinical implications. On the HCV side,
in nAFLD and HcV Infection
eradication of viral infection with combined IFN+
Early stages of both NAFLD and HCV infection
Ribavirin regimens, which is associated with pre-
share steatosis as a common histologic feature and IR
vention of fibrosis, has resulted in the prevention of
is a physiopathologic feature of both liver diseases.
the development of diabetes51 although this finding
Such findings have generated interest in the possi-
has not been invariably confirmed.52 On the NAFLD
bility of transferring knowledge from one disease to
side, these patients are often glucose-intolerant or
the other.47 In the transgenic mouse model express-
diabetics either at the first diagnosis or during fol-
ing HCV core protein, IR anticipates the develop-
low-up.53–56 Furthermore, in a study conducted in
ment of steatosis. Overt diabetes only occurs once
patients with type 2 diabetes, a weight loss of only
these animals gain weight as a result of a high-fat
approximately 8 kg resulted in improved basal and
diet. A high level of tumor necrosis factor-alpha,
insulin-stimulated hepatic glucose metabolism asso-
which acts by disturbing tyrosine phosphorylation
ciated with an 80% reduction in intrahepatic lipid
of insulin receptor substrate-1 and is a common find-
content.57
ing also in human chronic hepatitis C, is considered
to be one of the bases of IR in the transgenic mice.48
conclusions and Research Agenda
Studies conducted by short-term high fat feeding
In conclusion, data reviewed here strongly support
rats support the hypothesis that hepatic steatosis
that advanced hepatic fibrosis is associated with
leads to hepatic insulin resistance by stimulating
diabetes and that diabetes increses the risk of devel-
gluconeogenesis and activating PKC-epsilon and
oping HCC. Such a view is also confirmed in the
JNK1, which may interfere with tyrosine phosphor-
study by Donadon.5 Asssociation, however, does
ylation of IRS-1 and IRS-2 and impair the ability of
not prove causality. The paper by Donadon, owing
insulin to activate glycogen synthase.49 Our group
to its cross-sectional design does not show which,
recently compared the predictors of IR in HCV and
between IR and HCC, comes first.5 Prospective
NAFLD. Data show IR to be independently assso-
studies are, therefore, needed to address the issue
ciated with BMI and triglyceridemia in NAFLD;
whether those chronic liver disease patients who
male gender and fibrosis in chronic HCV infection.50
are more insulin-resistant are at an increased risk
84
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Insulin resistance, T2DM and chronic liver disease
Table 2. Evidence for an association between diabetes (or steatosis) and hCC.
Author, (Ref.)
series
Main finding
Braga C30
320 hCC patients and 1408 controls.
In the development of hCC, the
attributable risk for diabetes was 8%
compared with 40% for low vegetable
and fruit consumption, 31% for low
education, 18% for liver cirrhosis, 16%
for hepatitis, and 7% for heavy alcohol
consumption.
El-Serag hB31
823 patients with PLC and 3459 controls.
In the multivariable logistic regression,
diabetes was associated with a
significant increase in the adjusted OR
of PLC (or 1.57) in the presence of
hCV, hBV, or alcoholic cirrhosis.
hassan MM32
115 hCC patients and 230 non-liver
Multivariate ors were 15.3, 12.6, 4.5,
cancer controls.
and 4.3 for anti-hCV, hBsAg, heavy
alcohol consumption, and diabetes
mellitus, respectively.
Tazawa J33
279 patients were followed-up for
With multivariate analysis, only diabetes
65.9 +/- 29.4 months until the occurrence
mellitus and age were associated with
of hCC.
the occurrence of hCC.
huo TI34
245 hCC patients with well-preserved liver
Multivariate Cox regression model
functions undergoing resection.
analysis confirmed that DM and
tumor size 3 cm were independent
prognostic predictors associated
with the occurrence of hepatic
decompensation.
ohata K35
161 patients with chronic hCV infection
Multivariate analysis identified hepatic
followed for up to 15 years.
steatosis, together with aging, cirrhosis,
and no IFn treatment, as independent
and significant risk factors for HCC.
yuan JM36
295 hCC cases and 435 age-, gender-,
Subjects with a history of diabetes had
and race-matched control subjects among
an or of 2.7 for hCC compared with
hispanic and non-hispanic whites and
nondiabetic subjects. A synergistic
blacks.
interaction on hCC risk was observed
between heavy alcohol consumption
and diabetes, or between diabetes and
viral hepatitis.
Davila JA37
2061 hCC patients and 6183 non-cancer
In adjusted multiple logistic regression
controls.
analyses diabetes was associated with
a threefold increase in the risk of hCC.
A significant positive interaction between
hCV and diabetes was detected.
Kumar D38
The histological severity of steatosis
This is the only negative study reporting
was compared in the index liver biopsies
that hepatic steatosis does not augment
of 25 patients with chronic hepatitis C
the risk of hepatocarcinogenesis in
who subsequently developed hCC with
patients with chronic hCV infection.
matched controls.
Lai MS39
out of a prospective cohort of 54,979
After controlling for confounders,
subjects 5,732 individuals with T2D and
the association between type 2
138 confirmed HCC cases were identified.
diabetes and incidence of hCC was
only statistically significant for those
being hCV negative and those having
hypercholesterolemia.
(Continued)
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Lonardo and Loria
Table 2. (Continued)
Author, (Ref.)
series
Main finding
n’Kontchou G40
771 patients with well-compensated
In multivariate analysis, factors
alcohol-or hCV-related cirrhosis
predictive for hCC were BMI, diabetes,
prospectively screened for hCC.
age, sex, hCV, and mixed etiology.
yu L41
158 black compared to 701 white hCC
higher rates of hBV, hCV, concurrent
patients.
hBV and hCV, and viral hepatitis
associated with diabetes might explain
the greater burden of hCC in black
Americans.
Komura T42
90 patients who had undergone curative
Diabetes was a factor independently
resection for hCC.
associated with hCC recurrence after
treatment.
Pekow Jr43
32 patients with hCV-cirrhosis and hCC
Age, AFP and steatosis were
compared to 62 who had hCV-cirrhosis
independent predictors of hCC.
and no hCC.
Chen CL44
23,820 residents in Taiwan followed-up for
Diabetes was associated with hCC in all
14 years.
patients. The highest risk was seen in
those with hCV infection (rr 3.52) and
lowest in hBV carriers (rr(a) 2.27).
hBV or hCV carriers with both obesity
and diabetes had more than 100-fold
increased risk, indicating synergistic
effects of metabolic factors and
hepatitis.
Veldt BJ45
541 hCV patients of whom 85 (16%) had
In patients with chronic hepatitis C and
diabetes mellitus.
advanced cirrhosis, diabetes mellitus
increases the risk of developing hCC
(hazard ratio, 3.28).
Polesel J46
185 hCCs and 404 controls.
After allowance for known risk factors,
BMI  /= 30 and DM (or = 3.7)
were associated to hCC risk. These
associations persisted among subjects
without hBV and/or hCV infection.
Abbreviations: BMI, body mass index (Kg/m2); DM, diabetes mellitus; hCC, hepatocellular carcinoma; or, odds ratio; rr, relative risk; PLC, primary
liver cancer; T2D, type 2 diabetes.
of developing HCC or if it is the presence of HCC
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