Management of

Diabetes in liver
diseases
Liver in Glucose Homeostasis
 Liver in Glucose
Insulin Glucogon
• Promotes • Promotes
glycogenesis glycogenolysis
glycolysis gluconeogenesis
• Inhibits ketogenesis.
glycogenolysis
gluconeogenesis
ketogenesis.
Net : dec Bld Sugar Net : Inc Bld Sugar
 Hepatic complications of
diabetes mellitus
• Glycogen deposition
• Steatosis and nonalcoholic
steatohepatitis (NASH)
• Fibrosis and cirrhosis
• Biliary disease, cholelithiasis,
cholecystitis
• Complications of  therapy
Role of adipokines
Liver disease altering Glucose
homeostasis

• Hepatitis
Viral – B,C
Alcoholic
• Cirrhosis/PHtn
• Hepatocellular carcinoma
• Fulminant hepatic failure
• Post orthotopic liver
transplantation
Liver disease coincidental

• Hemochromatosis
• Glycogen storage
diseases
• Autoimmune biliary
disease
Alcoholic liver disease
Hyper Glycemia
• Reduced binding of insulin to the hepatic
receptors.
• Decreased glycogenesis / Increased
glycogenolysis .
• Reduced glucose uptake by the liver cells
• Non-suppression of hepatic glucose
output.
• Enhance insulin-induced phosphorylation
of IR and IRS-1 and IRS-2.
• Triggers insulin resistance.
• Local chronic inflammatory reaction with
oxidative stress.
 Viral Hepatitis
HBV

Hyper Glycemia
• Direct pancreatic islet injury .
• HBV DNA and HBsAg have been
identified both in pancreatic acini
and islets.
• Reduced peripheral insulin
sensitivity.
• Down-regulation of IR and tyrosine
kinase due to the direct injury on
Beta cells.
 Viral Hepatitis
HCV
Hyper Glycemia
• Peripheral Insulin resistance
• Pro-inflammatory cytokine profile.
• Insulin clearance and hepatic insulin
extraction preserved.
• But a compensatory hyper-secretory
response to glucose stimulation and
markedly reduced insulin sensitivity.
 Viral Hepatitis
Interferon therapy
Hyper Glycemia
• Type 1 diabetes
insulin autoantibodies -
increased insulin requirements
• Worsens type 2 diabetes and
Severe Triglyceridemia.
 Fulminant Hepatic
Failure
Hypoglycemia
• Destruction of hepatocytes
• Hyperinsulinism
• Inadequate storage of glucose in
extrahepatic organs.

Portend a poor prognosis and

increased mortality.
Close observation reqd and most
require glucose supplementation.
Chronic liver disease

• Altered glucose tolerance

• Acquired growth hormone (GH)
resistance low
concentrations IGF-1 and a normal or
elevated GH levels.
• TNF alpha blunts the hepatic response
to GH.
• Pro-inflammatory cytokines directly
modulate the signal cascade that
follows insulin binding to its receptor.
 Cirrhosis
Hepatogenous Diabetes

• Have elevated insulin levels

– reduced degradation.
• Impaired insulin secretion .
• Insulin resistance - A
receptor or postreceptor
abnormality.
• Potassium depletion,
excess glucagon, growth
hormone, cortisol (counter
reg Hs) and increased fatty
acid levels in blood, and
 Cirrhosis
• Fasting hypoglycemia
“Insulin Autoimmune Syndrome”
- high levels of insulin
autoantibodies.
• Significant hypoglycemia
prevented by decreased
utilization of glucose and an
increased utilization of
nonglucose fuels such as fat.
 Portal hypertension
Initial Hypo f/b Hyper
• Lesser Insulin reqd- clearance
reduced, because of decreased
hepatic first-pass and spontaneous
porto-systemic shunting.
• Systemic hyperinsulinaemia leads
to insulin resistance, through
receptor down-regulation.
• The splanchnic output of glucagon
is increased.
Blood glucose control deteriorates
following TIPS.
 Hepatocellular
Carcinoma
Hypoglycemia.
• Production of insulin-like growth
factor-II (IGF-II) by HCC cells.
• IGF-II is functions as a partial
insulin agonist.
• Increased glucose utilization by
insulin-sensitive tissue.
Require progressively less
insulin.
 Liver Transplantation
and Diabetes
• 4–20% incidence of
posttransplant diabetes.
• Immunosuppressive agents -
tacrolimus- greater
predisposition to diabetes.
• Liver transplantation may be
performed in patients with type
1 diabetes without any increased
risk for graft or patient survival
regardless of the underlying
Autoimmune Biliary
Disease
• Autoimmune
polyglandular
syndrome : Type 1
diabetes + PBC
• PSC may progress to
cirrhosis, can also
involve the pancreatic
duct and result in
 Lifestyle modification :
• Compromised by poor nutritional status and general health.
• Low-glycemic, low-calorie diets with a weight loss of 1–2 kg/week.
• Mediterranean diet (i.e., high complex carbohydrates, high
monounsaturated fats and low amounts of red meat) – in patients
with type 2 diabetes and NAFLD.
• Exercise improves peripheral insulin sensitivity
• Weight loss decreases hepatic steatosis
• Alcohol should be avoided because of its toxic effects on the liver,
high caloric content and potential interaction with sulfonylureas.
 Insulin secretagogues.
• Hepatic disease is very rare with tolbutamide
and tolazamide.
• Repaglinide and nateglinide have
not been associated with
sev.hepatotoxicity.
• Patients with decompensated
cirrhosis have reduced ability to
counteract hypoglycemia and thus,
the response to therapy should be
monitored closely.
• Drugs with short half-life such as
 Complications of
Sulfonylureas
• Sulfonylureas can cause chronic hepatitis with
necroinflammatory changes and granulomatous
changes.
• Chlorpropamide - most hepatotoxic - cholestatic
hepatitis.
• Acetohexamide and glyburide can cause acute
hepatocellular necrosis, and fatalities.
• Glipizide is metabolized mainly by the liver - hepatic
disease may result in increased blood levels.
 Biguanides
• Metformin - useful in obese in
whom it causes mild weight loss.
• Metformin has not been reported
to cause hepatotoxicity and has
shown some benefit in patients
with NAFLD.
 Complications of
BiGuanides
"Chronic liver disease“
predisposes patients taking
metformin to developing lactic
acidosis.
Due to a reduced ability of the
liver to clear lactate- therefore a
contraindication.
Glucosidase inhibitors

• Safe and effective with hepatic

encephalopathy and type 2 diabetes.
• Act directly on the gastrointestinal tract t
decrease carbohydrate digestion +
glucose absorption, decreasing
postprandial hyperglycemia.
• An increase in bowel movement
frequency- favors proliferation of
saccharolyticbacteria reducing
proteolytic bacteria,reducing intestinal
ammonia.
• Miglitol has not been associated with
hepatotoxicity.
 TZDs
• Especially useful in NAFLD
because they enhance insulin
sensitivity – the underlying
defect.
• The risk of acute liver failure
with rosiglitazone and
pioglitazone is much less than
that with troglitazone
• TZDs are emerging as the
 Complications of TZD
• Severe idiosyncratic hepatocellular
injury, during the early months of
therapy.
• Serum transaminases should be
checked at the start of therapy,
monthly x 6 months, every 2 months x
next 6m, and periodically thereafter.
• If ALT >3 x ULN, therapy should not be
started or should be discontinued.
• ALT >1.5 x ULN, test earlier.
• Any symptoms suggesting hepatic
dysfunction necessitate tests
performed immediately.
 Insulin

• With impaired
hepatic function
• With
– Compensated Decompen
state - increased
need for insulin
sation
due to insulin requireme
resistance
nt
decreases
due to
reduced
capacity
 INSULIN
• Thus, careful glucose monitoring and
frequent dose adjustments of insulin may
be necessary.
• Hepatic encephalopathy requires high-
carbohydrate diets – causing postprandial
hyperglycemia, rapid-acting insulin (lispro,
aspart, or glulisine) are particularly useful.
“GETLIVER BETTER or
GET BETTER LIVER”