Pancreas Flashcards
What is the exocrine function of the pancreas?
Digestion of food
What types of cells are found in the exocrine pancreas?
Acinar cells
What is secreted by the exocrine pancreas?
Proenzymes:
Trypsinogen Chymotrypsinogen Procarboxypeptidase Proelastase Kaliikreinogen Prophsopholipase
Where do the proenzymes/enzymes secreted by acinar cells go after being secreted?
Carried by ducts to the duodenum where they are activated
What is the endocrine pancreas composed of?
Islets of Langerhans cells
What is secreted by the Islets of Langerhans cells?
Insulin by beta cells
Glucagon by alpha cells
Somatostatin by gamma cells
PP cells secrete pancreatic polypeptide
What do ductal cells release?
Bicarbonate to neutralize digestive enzymes
Before proenzymes can become active, what must they undergo?
Cleavage
What is Diabetes Mellitus?
Group of metabolic disorders sharing the common feature of hyperglycemia
What is hyperglycemia in diabetes Mellitus caused by?
Defects in insulin secretion
Insulin action
What does the chronic hyperglycemia and associated metabolic dysregulation of diabetes Mellitus cause?
Secondary damage in multiple organ systems like the kidneys, eyes, nerves, and blood vessels
What is normal glucose homeostasis?
Glucose production in the liver
Glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle
Actions of insulin and glucagon, on glucose uptake and metabolism
What are fasting plasma glucose levels determined by?
Hepatic glucose output
What occurs following a meal?
Insulin levels rise and glucagon levels fall in response to the large glucose load
Insulin then promotes glucose uptake and utilization in tissues
What is insulin produced by?
Beta cells in pancreatic islets
Where is insulin stored?
Secretory granules
What is the most important stimulus for insulin synthesis and release?
Glucose
How does glucose enter the beta cells?
Via GLUT 2 glucose transporter
How does insulin get glucose to be taken in by the cell?
Insulin binds to insulin receptors on cell surface and causes translocation of GLUT 4 within the cell which allows the uptake of glucose by the cell
What does the translocation of GLUT 4 allow to happen?
Uptake of glucose by the cell
Alterations in glucose, lipid, and protein metabolism
Changes in gene expression and cell growth
Where are GLUT 2 glucose receptors found?
Beta cells
Liver
Where are GLUT 3 glucose receptors found?
All tissues
Major transporter in neurons of CNS
Where are GLUT 4 glucose receptors found?
Skeletal muscle
Fat cells
What do we use to measure glycemic control?
HbA1c test
What is the HbA1C test?
Test that measures a person’s average blood glucose level over the past 2 to 3 months
Test shows the amount of glucose that sticks to the RBCs which is proportional to the amount of glucose in the blood
What does insulin cause to happen in adipose tissue?
Increased Glucose uptake
Increased lipogenesis
Decreased Lipolysis
What does insulin cause to happen in striated muscle cells?
Increased Glucose uptake
Increased GLycogen synthesis
Increased protein synthesis
What does insulin cause to happen in the liver?
Decreased Gluconeogenesis
Increased GLycogen synthesis
Increased lipogenesis
What three main sources is glucose obtained from?
Intestinal absorption of food
Glycogenolysis
Gluconeogenesis
What is insulin’s effects on glucose metabolism?
Inhibition of glycogenolysis and gluconeogenesis
Increased glucose transport into fat and muscle
Increased glycolysis in fat and muscle
Stimulation of glycogen synthesis
What is insulin’s effect on lipid metabolism?
Inhibition of lipolysis in fat
Decreased plasma fatty acid concentrations
Stimulation of fatty acid and triacylglycerol synthesis in fat and liver
What is insulin’s effect on protein metabolism?
Increased transport of some amino acids into muscle, adipose tissue, liver, and other cells
Increased rate of protein synthesis in muscle, adipose tissue, liver, and other tissues
What two factors stimulate insulin release?
Glucose
Vagal Stimulation
What factor amplifies glucose-induced insulin release?
Beta-adrenergic stimulation
What inhibits insulin release?
Alpha-adrenergic effect
What is Type 1 diabetes?
An autoimmune disease characterized by pancreatic beta cell destruction and an absolute deficiency of insulin
What is Type 2 diabetes?
Caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic beta cells
What is type 2 diabetes caused by?
Genetic defects of Beta cell function
Genetics defects in insulin action
Exocrine pancreatic defects
Endocrinopathies
Infections
Drugs
Genetics syndromes associated with diabetes
Gestational diabetes Mellitus
What are the short term effects of exercising for non diabetics?
Muscles initially use glucose and later convert muscle glycogen to glucose to provide energy
Glucose CANNOT be transferred out of muscle to prevent hypoglycemia
Exercising muscle takes up glucose from circulation, which requires the availability of insulin
If exercise continues, NE and Epi stimulate lipolysis
What are the long term training effects of non-diabetics?
Development of new muscle capillaries
Increased translocation of insulin-responsive GLUT 4 transporters
What are the effects of exercise on Type 1 diabetics?
Exercise modestly lowered blood glucose concentration and raised blood ketone concentrations in normal and well controlled diabetics
What are the effects of exercise on type 2 diabetics?
Insulin-independent increase in glucose uptake
INcreased skeletal muscle GLUT4 protein expression
Who does type 1 diabetes most commonly develop in?
Children
Where are the major susceptibility genes for type 1 diabetes located?
HLA region
What genes are most commonly carried in patient with type 1 diabetes?
DR4
DQB*0302 and/or DR3
DQB*0201
What is the immunologic response happening in type 1 diabetes?
Relapsing remitting disease course with autoantibodies and T cellular responses to islet autoantigens
- Antigen binds to MHC class II molecules on APCs
- Binding allows antigen to be presented to antigen receptors on autoreactive CD4+ cells which initiate autoimmune injury to the pancreatic beta cells
- Binding of other molecules to T cells are important costimulatory pathways that further increase T cell activation
What is the natural history of type 1 diabetes?
Triggered by one or more environmental agents and usually progresses over many months or years
Most patients during that time are asymptomatic and euglycemic
Large percentage of the functioning beta cells are lost before hyperglycemia appears
What is prerequisite screening done for individuals who are at risk of developing type 1 diabetes?
Measurement of islet autoantibodies
What is the entry criteria for immunological response in type 1 diabetes?
Presence of two or more of the islet autoantibodies
What are the confirmed targets of autoantibodies in type 1 diabetes?
Insulin
Glutamic acid decarboxylase
Insulinomia associated antigens 2
ZnT8 = zinc transporter
When do the genetic markers appear for type 1 diabetes?
Present from birth
When to the immune markers appear for type 1 diabetes?
First appear at the time of the environmental triggering events
When does clinically evident type 1 diabetes occur?
Does NOT occur until there has been a much greater loss of functioning beta cell mass
At what percentage of insulin secretion do we see subclinical beta cell dysfunction?
70-80%
At what percentage of insulin secretion do we see critical beta cell mass and clinical type 1 diabetes Mellitus develops?
< 40%
What is the fundamental problem with autoimmune disease portion of the type 1 diabetes?
Autoreactive T cells
Failure of self tolerance
What is the generation of ketone a normal response to?
Fasting
When does diabetic ketoacidosis occur?
Happens after depletion of liver glycogen stores
How is diabetic ketoacidosis produced?
In glucose poor environment, too much oxaloacetate is diverted away into gluconeogenesis
This prevents acetyl-CoA from entering the Krebs cycle which results in a buildup of acetyl CoA
What are ketone bodies?
Acetate
Acetone
Beta hydroxybuterate
What is type 2 diabetes characterized by?
Hyperglycemia
Insulin resistance
Relative impairment in insulin secretion
What can occur with hyperglycemia?
Impair pancreatic beta cell function and magnify insulin resistance
What is metabolic syndrome?
Co-occurrence of metabolic risk factors for both type 2 diabetes and CVD
What is the first predictor of type 2 diabetes?
Insulin resistance
What causes inadequate insulin secretion?
Insulin secretion by beta cells requires glucose transport into the cell, which is mediated by GLUT-2
Genetic alteration affecting GLUT-2 expression causes impaired insulin secretion
What occurs in impaired insulin processing in type 2 diabetes?
Insulin production in normal subjects involves cleavage of insulin from proinsulin
The processing of proinsulin to insulin in the beta cells is impaired in type 2 diabetes
What is insulin resistance?
Broadly defined as a subnormal biological response to normal insulin
What disorders is insulin resistance a component of?
Target cell resistance Type 2 diabetes Obesity Stress Infection Uremia Acromegaly Glucocorticoid excess Pregnancy
Metabolic syndrome
Hypertension
Hyperlipidemia
Coronary artery disease
What are the major organs associated with insulin resistance?
Liver
Skeletal muscle
Adipose tissue
What are the consequences of insulin resistance?
Failure to inhibit gluconeogenesis in the liver = high fasting blood glucose levels
Failure of glucose uptake and glycogen synthesis to occur in skeletal muscle following a meal = high post-prandial blood glucose level
Failure to inhibit lipoprotein lipase in adipose tissue = excess circulating free fatty acids which amplifies the state of insulin resistance
What are the four things associated with obesity and insulin resistance?
Central obesity
Inflammation
Free fatty acids
Adipokines
What is the effect of free fatty acids in association with obesity and insulin resistance?
Excess free fatty acids compromise beta cell function and decrease insulin release by:
Saturating the oxidative and storage capabilities of hepatocytes and myocytes
Formation of fatty acid intermediates which impair insulin signaling
Induce expression of many inflammatory genes which suppress insulin signaling
What are adipokines?
Variety of proteins secreted into the systemic circulation by adipose tissue
What is the link between inflammation and insulin resistance?
Obesity associated chronic low grade inflammation
What is the state of low grade inflammation in insulin sensitivity caused by?
Obesity = chronic nutrient imbalance activating cellular stress signaling pathways which inhibits insulin signaling and promoting inflammation
Chronic inflammation and insulin resistance
What are the clinical presentations of childhood type 1 diabetes?
New onset of Polydipsia, Polyuria, Weight loss with hyperglycemia and ketonemia
Diabetic ketoacidosis
Silent (asymptomatic) incidental discovery
What are the clinical presentations of type 2 diabetes?
majority of patients are asymptomatic and hyperglycemic
Polyuria
Polydipsia
Nocturia
Blurred vision
The morbidity associated with both types of diabetes is due to damage induced by what?
Large and medium sized muscular arteries = diabetic macrovascular disease
Small vessels = diabetic microvascular disease
What does macrovascular disease cause in diabetics?
Accelerated atherosclerosis
Increased risk of MI
Stroke
Lower extremity ischemia
Where are the effects of microvascular disease most seen in diabetics?
retina = diabetic retinoapathy
Kidneys = diabetic nephropathy
Peripheral nerves = diabetic neuropathy
What do chronic complications of diabetes depend on?
Duration and degree of hypglycemia
What is the pathogenesis of long-term complications of diabetes?
Inflammation
What are two major complications that pathophysiologically effect yoru body as a result of hyperglycemia?
Production of AGE
Reduction of glutathione system
How is Advanced Glycosylation End Products (AGE) formed?
Reversible reaction leads to the formation of an aldimine (Schiff base)
Aldimine is then followed by an Amadori rearrangement to form a ketoamine which is an intermediate in formation of AGEs
What is the significance of AGEs in diabetes?
They form irreversible cross-links with macromolecules like collagen, that contributes to vascular stiffening and myocardial dysfunction
What is acute pancreatitis?
an inflammatory condition of the pancreas characterized clinically by abdominal pain and elevated levels of pancreatic enzymes in the blood
What is the cause of acute pancreatitis?
Gallstones
Alcohol abuse
What is the mechanism of gallstone pancreatitis?
Reflux of bile into the pancreatic duct due to transient obstruction of the ampulla during passage of gallstones OR obstruction at the ampulla secondary to stone(s) of edema caused by the passage of a stone
What are the mechanisms of alcohol-induced pancreatitis?
- Sensitization of acinar cells to cholecystokinin (CCK) induced premature activation of zymogens
- Generation of toxic metabolites such as acetaldehyde and fatty acid ethyl esters
- Activation of pancreatic stellate cells by acetaldehyde and oxidative stress causing increased production of collagen and other matrix proteins
What is the pathogenesis of acute pancreatitis?
- Intraacinar activation of proteolytic enzymes
- Microcirculatory injury
- Leukocyte chemoattraction, release of cytokines, and oxidative stress
What occurs in intraacinar activation of proteolytic enzymes?
Blockade of secretion of pancreatic enzymes while synthesis continues
This causes pancreatic autodigestion which sets up a vicious cycle of active enzymes damaging cells, which then release more active enzymes
What occurs in microcirculatory injury?
Vasoconstriction
Capillary Stasis
Decreased oxygen saturation
Progressive ischemia
Causing…
Increased vascular permeability and swelling of the pancreas
What occurs in leukocyte chemoattraction, release of cytokines, and oxidative stress?
Atrivated pancreatic enzymes
Microcirculatory impairment
Release of inflammatory mediators
Causing…
Rapid worsening of pancreatic damage and necrosis
What are the two diagnostic tests for acute pancreatitis?
Increased amylase and lipase in blood
What does the systemic inflammatory response syndrome that occurs in acute pancreatitis consist of?
ARDS Myocardial depression and shock Acute renal failure Metabolic complications Bacterial translocation
What is the systemic inflammatory response syndrome in acute pancreatitis mediated by?
Activated pancreatic enzymes
Cytokines released into the circulation from the inflamed pancreas
What is ARDS?
Secondary to microvascular thrombosis and may be induced by lecithinase
What is Myocardial depression and shock in association with SIRS?
Secondary to vasoactive peptides an da myocardial depressant factor
What is acute renal failure in SIRS due to?
Hypovolemia
Hypotension
What are the metabolic complications included in SIRS?
Hypocalcemia Hyperlipidemia Hyperglycemia Hypoglycemia Diabetic ketoacidosis
What is the bacterial translocation that occurs in SIRS?
Gut barrier is comprised causing translocation of common bacteria found there to go to blood which in turn causes local and systemic infection
What is chronic pancreatitis?
A progressive fibroinflammatory process of the pancreas that results in irreversible destruction of exocrine parenchyma, fibrosis, and the destruction of endocrine parenchyma
What is the most common cause of chronic pancreatitis?
Long-term alcohol abuse
What are other common causes of chronic pancreatitis?
Cigarette smoking Hereditary pancreatitis Ductal obstruction Systemic disease Idiopathic pancreatitis
What is the pathogenesis of Chronic pancreatitis?
Hypersecretion of digestive enzymes which is NOT compensated for by an increase in ductal bicarbonate secretion
Inflammatory changes
Collagen secretion
Pancreatic fibrosis and acinar cell loss
What are the two primary clinical features of chronic pancreatitis?
Abdominal pain that is epigastric and radiated to the back
Pancreatic insufficiency = protein and fat deficiencies which occur after 90% of pancreatic function is lost
What two clinical features occur with pancreatic insufficiency in chronic pancreatitis?
Fat Malabsorption
Pancreatic Diabetes
What occurs in fat malabsorption in chronic pancreatitis?
Steatorrhea usually occurs prior to protein deficiencies since lipolytic activity decreases faster than proteolysis
What occurs with pancreatic diabetes in chronic pancreatitis?
Hyperglycemia and overt diabetes mellitus usually occurs late in course of disease
Pancreatic alpha cells are also affected and increase the risk of hypoglycemia
What is the pathogenesis of pain in pancreatitis?
Nerve growth factor (NGF) are produced in chronic pancreatitis and mast cells can sensitize the nociceptor neuron by upregulating molecules such as substance P
Inflammatory milieu produces cytokines and inflammatory mediators that act on the neurons and sensitize and/or activate them
What is the difference between acute vs. chronic pancreatitis?
Chronic = asymptomatic, fibrotic mass, normal amylase and lipase
Acute = symptomatic, non-progressive, reversible, amylase and lipase are high
What is the most common type of pancreatic cancer?
Infiltrating ductal adenocarcinoma
Where do invasive pancreatic cancers arise from?
Well-defined noninvasive precursor lesions in pancreatic intraepithelial neoplasia (PanIN)
What is the cancer progression of the pancreas?
Nonneoplastic epithelium –>
PanIN –>
Invasive carcinoma
What mutations can cause pancreatic adenocarcinomas?
Mutational activation of oncogenes = KRAS
Inactivation of tumor suppresor genes = TP53, p16/CDKN2A, and SMAD4
Inactivation of genome maintenance genes
What is the strongest environmental factor that causes pancreatic cancer?
Cigarette Smoking
What causes adipose tissue inflammation?
interaction between pancreatic cancer and adipose tissue
What does the adipose tissue inflammation occuring in pancreatic cancer cause?
Systemic cytokine response
Abnormal adipokine secretion
Lipolysis
Causing…
peripheral insulin resistance and Beta cell dysfunction
What are the most common presenting symptoms in patients with exocrine pancreatic cancer?
Pain
Jaundice
Weight Loss
What is associated most with carcinoma of the HEAD of the pancreas?
Obstructive jaundice
What are advanced symptoms of pancreatic cancer?
Weight loss
Anorexia
Generalized malaise
Weakness
