Diabetes and liver
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Diabetes and Liver
Outline
1. Diabetes and liver -? Vicious cycle
2.Hepatogenous diabetes
3.Elevated transaminases
4.Which agent
1. Diabetes and liver -? Vicious cycle
2.Hepatogenous diabetes
3.Elevated transaminases
4.Which agent
The putative mechanisms underlying the contribution of
NAFLD to the increased risk of developing CVD and T2DM
Anstee, Q. M. et al. (2013) Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis
Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2013.41
Anstee, Q. M. et al. (2013) Progression of NAFLD to diabetes mellitus, cardiovascular disease or
irrhosis Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2013.41
1. Diabetes and liver -? Vicious cycle
2.Hepatogenous diabetes
3.Elevated transaminases
4.Which agent
Hyperinsulinaemia
Down
regulation of
insulin
receptors
• Hepatogenous diabetes differs from type 2 diabetes
in that there is less often a positive family history
and that the cardiovascular and retinopathic risk is
low.
• The prognosis of cirrhotic patients with diabetes is
more likely to be negatively affected by the
underlying hepatic disease and its complications
than by the diabetes.
• Liver transplantation did not correct the diabetes
in one-third of patients with hepatogenous
diabetes undergoing transplantation.
• HbA 1c is an unreliable
- undetected bleeding episodes
- hemolysis due to hypersplenism are
frequent in
• Using a fructosamine test in addition to blood
glucose self-monitoring may provide a more
suitable assessment of metabolic control.
• no dietary restrictions should be prescribed for patients with hepatogenous diabetes.
The survival of patients with liver cirrhosis depends on an adequate calorie intake; a hypocaloric diet even leads to increased mortality.
Patients with liver cirrhosis, may suffer from protein malnutrition, should eat a balanced diet with sufficient calories;
a late snack prevents nocturnal hypoglycemia and improves nutritional status
1. Diabetes and liver -? Vicious cycle
2.Hepatogenous diabetes
3.Elevated transaminases
4.Which agent
1.Are elevations in serum aminotransferase levels
associated with 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitor, or
statin, therapy?. YES
2. Are statin-associated elevations in
aminotransferase levels indicative of liver
damage or dysfunction? NO
3. Should liver enzymes and liver function tests be
monitored in patients receiving long-term statin
therapy? NO
4.Are any of the following conditions a
contraindication for statin therapy?
- Chronic liver disease: No
- Compensated cirrhosis :No
- Decompensated cirrhosis or acute liver failure:Yes
5. Can statins be used in patients with NAFLD or
nonalcoholic steatohepatitis (NASH)? Yes
1. Diabetes and liver -? Vicious cycle
2.Hepatogenous diabetes
3.Elevated transaminases
4.Which agent
• Can metformin and TZDs be used to treat NASH
• Preferred agent for management of diabetes in
NASH and advanced liver disease
NASH Advanced liver disease
Metformin
NASH Advanced liver disease
Metformin
Sulphonyureas
NASH Advanced liver disease
Metformin
Sulphonyureas
TZD
NASH Advanced liver disease
Metformin
Sulphonyureas
TZD
Dpp4 inhibitor
NASH Advanced liver disease
Metformin
Sulphonyureas
TZD
Dpp4 inhibitor
AGI
NASH Advanced liver disease
Metformin
Sulphonyureas
TZD
Dpp4 inhibitor
AGI
Insulin
1. Diabetes and liver -? Vicious cycle
2.Hepatogenous diabetes
3.Elevated transaminases
4.Which agent
Liver biopsy
NAFLD
Pathophysiology of hepatogenous diabetes
MECHANISMS UNDERLYING THE
EFFECTS OF LIVER DISEASES ON
T2DM
• Gut microbiota
• Hepatic inflammation and associated insulin
resistance
• Hepatic fat accumulation
• Reactive oxygen species
• Hepatokines
• HCV infection
• Insulin resistance of the peripheral tissues and the liver caused by liver damage is regarded as the central disturbance of glucose metabolism.
• Reduced insulin extraction by the liver as a result of the functional disturbance or portosystemic shunts results in hyperinsulinemia,
• This hyperinsulinaemia is potentiated by raised levels of contrainsulin hormones (e.g. glucagon, growth hormone, insulin-like growth factor), free fatty acids and cytokines
• The “two-hit” hypothesis proposed by Day and
James in 1998[15] postulates that the steatotic liver
is susceptible to secondary insults including a
vulnerability to reactive oxygen species, gut-derived
endotoxins, and adipocytokines such as tumor
necrosis factor-α (TNF-α) and other cytokines. The
first “hit” is thought to be an accumulation of fatty
acids and triglycerides within the liver, possibly due
to insulin resistance. Chronic stress such as portal
endotoxemia (the second “hit”) leads to
mitochondrial dysfunction and Kupffer cell adaptive
changes[16,17], which in turn result in hepatocyte
survival adaptation[18] and subsequent necrosis
• The excess in free fatty acids found in the insulin-
resistant state is directly toxic to hepatocytes.
mechanisms include
- cell membrane disruption at high concentration,
- mitochondrial dysfunction
- oxidant stress from reactive lipid peroxidation,
peroxisomal beta-oxidation
- increase in proinflammatory cytokines TNF-a
contribute to hepatocellular injury