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Liver in Glucose Homeostasis
Liver in Glucose
• Promotes glycogenesis glycolysis • Inhibits glycogenolysis gluconeogenesis ketogenesis. Net : dec Bld Sugar Net : Inc Bld Sugar
• Promotes glycogenolysis gluconeogenesis ketogenesis.
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.
• • 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.
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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.
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.
• 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
• 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.
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.
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.
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• 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.
• 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.
• • 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.
• 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.
• With impaired hepatic function – Compensated state - increased need for insulin due to insulin resistance
• With Decompen sation requireme nt decreases due to reduced capacity
• Thus, careful glucose monitoring and frequent dose adjustments of insulin may be necessary. • Hepatic encephalopathy requires highcarbohydrate diets – causing postprandial hyperglycemia, rapid-acting insulin (lispro, aspart, or glulisine) are particularly useful.
LIVER BETTER or GET BETTER LIVER”