THE ROLE OF INSULIN IN DIABETIC PATIENT WITH CHRONIC

LIVER DISEASE

Andreas Fernandez
OUTLINE

INTRODUCTION
BLOOD GLUCOSE
REGULATION
TYPE OF LIVER DISEASE IN
TYPE 2 DIABETES
MANAGEMENT OF DIABETES
IN PATIENTS WITH LIVER
DISEASE
SUMMARY

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INTRODUCTION
 Liver disease is an important cause of death in type 2
diabetes
 Verona Diabetes Study : cirrhosis was the fourth
leading cause of death and accounted for 4.4% of
diabetes related deaths.
 patients with diabetes have a high prevalence of liver
disease
 management of diabetes in patients with liver disease
is complicated,
 alterations in drug metabolism
 potential interactions between the drugs
 drug induce hepatotoxic

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BLOOD GLUCOSE REGULATION

 High blood glucose ( after meal) →

insulin ↑→glycogen ( store in the liver)
 Low blood glucose ( fasting) → glucagon
↑→glycogenolisis → glucose
 Severe hypoglycemi: hypothalamus
→sympathetic nervous system →
adrenal (epinephrine) → liver → glucose

IDF DIABETES ATLAS - 8TH EDITION 20XX 4

PROSPECTIVE STUDIES EVALUATING THE IMPACT OF DIABETES
MELLITUS ON SURVIVAL OF PATIENTS WITH LIVER CIRRHOSIS

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TYPE OF LIVER DISEASE IN TYPE 2 DIABETES
INTERACTION BETWEEN DM AND NON ALCOHOLIC FATTY
LIVER DISEASE

fibrotic or
cirrhotic

 McPherson et al : DM + NAFLD → severe fibrotic

 retrospective study in the United States : fatty liver
+ DM → 3 x developed cirrhosis or hepatic
DM + hepatic
death
NAFLD
malignant malignant tumors
tumors

 meta-analysis :NAFLD increased the risk of DM

 NAFLD attenuates insulin signaling → insulin
resistance and abnormal hepatic metabolism
hospitalization

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HEPATITIS C IN DIABETES

 Prevalence of hepatitis C virus (HCV)

is higher in patients with diabetes than
in the general population.
 HCV → DM , core protein of HCV
impairs insulin receptor substrate
signaling → metabolic effects of insulin
 HCV genotype 3 have high in fatty liver
disease
 HCV treatment, α interferon associate
with diabetes

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INTERACTION BETWEEN DM AND HEPATITIS C VIRUS
INFECTION
 HCV infection :
 DM accelerates the progression of liver
cirrhosis
 attenuates antiviral effect
 HCV infection + DM, metabolic syndrome,
and NAFLD→ fibrosis cirrhosis, and HCC
 retrospective study in the USA :
compensatory cirrhosis and diabetes → high
risk to HE and acute renal failure, variceal
hemorrhage, acute kidney failure, SBP and
liver cancer
DOI.ORG/10.1155/2019/6430486
 Effect HCV infection to DM
 endocrine dyscrasia → DM
 HCV cirrhotic high risk to Type 2 DM
 direct-acting antiviral (DAA) treatment improves
FBG and glycated hemoglobin (HbA1C) in
diabetic CHC patients and declines the rate of
T2DM
 A prospective case-control study : HCV-genotype
1 treated with DAAs (direct-acting antiviral) →
improve insulin resistance
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INTERACTION BETWEEN DM AND HBV INFECTION
 prospective study in China
 DM and hyperglycemia were connected
with elevated risks of liver cancer
 cohort study in Taiwan
 chronic HBV with poor glicemic state
DM HBV hepatic ( HbA1 c >7.0%) → has prognosticated
injury
the occurrence of cancerous or cirrhotic
• cirrhosis
• liver tumor complications
 Hsiang et al :
 Pts DM risk of of liver cancer was
increased

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EFFECT OF HBV-RELATED DISEASES ON DM

 case-cohort study of HBV in Greek subjects

 correlation between diabetes and fibrotic
degree
 Shen et al in in CHB patients

HBV cirrhosis T2DM  positive relationship between cirrhosis and

diabetes risk
 DM with high BMI, low FGF-21,high
AFABP, HOMA-IR levels showed correlation
with fibrosis/cirrhosis during antiviral
therapy in people infected with CHB

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CIRRHOSIS IN DIABETES

 Cirrhosis associated with insulin

resistance.
 DM (Insulin resistance) stimulate
inflamation and fibrosis through an
increase in mitochondrial oxidative
stress by the action of leptin,
adiponectin, interleukin-6 and TNF-α
 TGF β1 and leptin activate stellate
cells, inducing them to produce
collagen leading to fibrosis

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HEPATOCELLULAR CARCINOMA IN DIABETES

 Prevalence of hepatocellular
carcinoma increase 4 fold
 The pathogenic sequence
hepatocellular to carcinoma : insulin
resistance → ↑lipolysis →lipid
accumulation in the
hepatocytes→oxidative stress, and
cell damage → fibrosis and cell
proliferation → procarcinogenic

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ACUTE LIVER FAILURE

incidence of acute liver

failure increase in patients
diabetes.
unclear
medication or others

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MANAGEMENT OF DIABETES IN PATIENTS WITH
LIVER DISEASE
MANAGEMENT OF DIABETES IN PATIENTS WITH LIVER DISEASE
 Lifestyle modification
 Low-glycemic, low-calorie diets
with a weight loss of 1–2 kg/week
 Mediterranean diet (i.e., high
complex carbohydrates, high
monounsaturated fats, moderate
amounts of wine, and low amounts
of red meat)
 Exercise

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PHARMACOLOGIC THERAPY

 liver failure : ascites, coagulopathy, or

encephalopathy have altered drug
metabolism
 no evidence that patients with liver
disease are predisposed to
hepatotoxicity
 Metformin is not recommended in pts
with advanced liver disease
 Pioglitazone and rosiglitazone
improve ALT and liver histology

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SULFONYLUREAS

 stimulate insulin secretion

 high risk of severe hypoglycemia in pts with advanced age,
chronic liver or kidney disease
 Glibenclamide (glyburide) and gliclazide are metabolized
in the liver and eliminated in bile and kidney
 Glibenclamide and gliclazide had been reported to
hepatotoxic
 chlorpropamide → hepatitis and jaundice
 Clinical trials
 meglitinides in liver disease : nateglinide in patients with
cirrhosis is not significantly different than in control subjects

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METFORMIN

 increase insulin sensitivity,

beneficial effects on lipid
metabolism
 relatively contraindicated in
patients with advanced liver
disease or in binge drinkers
 benefit in patients with NAFLD

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Α-GLUCOSIDASE INHIBITORS

 Inhibit α-glucosidases →degradate

disaccharides in the intestine → reduction
in the absorption of carbohydrates and in
the risk of postprandial hyperglycemia.
 Low liver toxicity
 safety in patients DM and CLD,alcoholic
cirrhosis and mild hepatic
encephalopathy
 reduce blood ammonia levels

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THIAZOLIDINEDIONES

 improve insulin sensitivity in target organs.

the peroxisome proliferator-activated
gamma receptor (PPARy) has selective
agonist effects
 potential hepatotoxic (trolitazone,
withdrawn from US market)
 The risk of acute liver failure with
rosiglitazone and pioglitazone < troglitazone
 Treatment of choice for NASH

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 Incretin-based therapies

• Inhibitors of DPP-4 and GLP-1

receptor agonists are metabolized in
the liver and excreted unchanged by
the kidney
• Liver disease and DM may be
benefited with incretin-based
therapies due to their low liver
toxicity and wide tolerance
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• Liraglutide in CLD : no increase liver enzyms, reduced
inflammation, liver fibrosis
• Linagliptin in severe hepatic impairement : no increase of
drug exposure after administration of multiple doses of
linagliptin
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INCRETIN-BASED THERAPIES

 Inhibitors of DPP-4 and GLP-1 receptor agonists

are metabolized in the liver and excreted
unchanged by the kidney
 Liver disease and DM may be benefited with
incretin-based therapies due to their low liver
toxicity and wide tolerance
 Liraglutide in CLD : no increase liver enzyms,
reduced inflammation, liver fibrosis
 Linagliptin in severe hepatic impairement : no
increase of drug exposure after administration of
multiple doses of linagliptin

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SGLT2 inhibitors
• inhibition of glucose reuptake in
• patients with moderate and severe • well tolerated, hepatotoxicity
the kidney
hepatic impairment had higher is low in patients with mild
• inducing glucosuria and osmotic
systemic exposure to the drug than and moderate liver function
diuresis
healthy subjects impairment
• caution to patients with risks of
• canagliflozin and empagliflozin • no experience in chronic
hypovolemia (older age,
showed an increased drug systemic administration with severely
cardiovascular diseases,
exposure in patients with impaired impaired liver function
treatment with diuretics, liver
liver function (Child C group)→ not
cirrhosis with circulatory
recommended
dysfunction).

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INSULIN

 diabetic patients with liver cirrhosis require insulin

administration
 Insulin requirements high in compensated cirrhosis and
low in decompensated (reduction in hepatic clearance
and gluconeogenesis)
 pharmacokinetic of short-acting insulin analogues is not
significantly altered as a result of hepatic dysfunction
 Insulin degludec has an ultra-long lasting effect and a
stable pharmacokinetic profile
 No serious adverse effects, such as hypoglycemia, have
been observed when using this kind of insulin in patients
with cirrhosis

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STUDIES EVALUATING THE IMPACT OF ANTI DIABETIC THERAPY ON
OUTCOMES OF PATIENTS WITH DIABETES MELLITUS AND LIVER CIRRHOSIS

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SUMMARY

 Type 2 diabetes is associated with elevated liver

enzymes, fatty liver disease, cirrhosis,
hepatocellular carcinoma, and acute liver failure
 decompensated liver disease susceptible to
hypoglycemia and require careful monitoring
 diabetic patients with liver cirrhosis require insulin
administration
 pharmacokinetic of short-acting insulin analogues
is not significantly altered as a result of hepatic
dysfunction

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THANK YOU

Andreas Fernandez
balenagi@gmail.com

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