the pancreas Flashcards
2 main functions of the pancreas
- exocrine
- endocrine
exocrine pancreas
- CCK is released from duodenum and stimulates acinar cells
- acinar cells secrete proenzymes for digestion
- after secretion carried to duodenum to be activated
- neutralizes acids
endocrine pancreas
- islet of langerhans
- secrete insulin, glucagon, somatostatin, pancreatic polypeptide
what cells secrete insulin
beta cells
what cells secrete glucagon
alpha cells
what cells secrete somatostatin
gamma cells
causes of hyperglycemia in diabetes
- defects in insulin secretion
- defects insulin action
- usually both
normal glucose homeostasis
- glucose produced in liver
- glucose uptake and utilized mainly in skel muscle
- insulin and glucagon regulate glucose
what determines fasting plasma glucose levels
hepatic glucose output
GLUT2
- located on beta cells and liver
- allows for glucose to be taken into beta cells -> insulin released
GLUT4
- located on skel muscle and fat cells
- found in cytoplasm
- cascade of events causes translocation to p membrane
- uptake of glucose
where are GLUT3 receptors found
- all tissues
- CNS
how do you measure glycemic control
- HbA1c
- is the average glucose over last 2-3 months
- shows amount of glucose that sticks to RBC which is proportional to amount of glucose in blood
metabolic action of insulin on adipose tissue
- increased glucose uptake
- increased lipogenesis
- decreased lipolysis
- decreased FFA
- stim FA and TG synthesis in fat and liver
metabolic action of insulin on liver
- decreased gluconeogenesis
- increased glycogen
- increased lipogenesis
metabolic action of insulin skeletal muscle
- increased glucose uptake
- increased glycogen synthesis
- increased protein synthesis
where is glucose obtained from
- intestinal absorption of food
- glycogenolysis
- gluconeogenesis
metabolic action of insulin on protein metabolism
- increased transport of AA into muscle, adipose, liver
- increased rate of protein synthesis in muscle, adipose, liver
factors that stimulate insulin release
- glucose
- vagal stimulation
factors that amplify glucose-induced insulin release
beta-adrenergic stimulation
factors that inhibit insulin release
alpha-adrenergic effect
type 1 diabetes
- autoimmune
- destruction of beta cells
- absolute deficiency in insulin
- can also be idiopathic
type 2 diabetes
- combo of peripheral resistance to insulin and inadequate secretory response
- relative insulin deficiency
initial response to exercise in nondiabetics
- use glucose in muscle
- convert glycogen to glucose
- glucose cant be transferred out of muscle to prevent hypoglycemia
- takes up glucose from blood
- E and NE released, cause lipolysis
long term response to exercise in nondiabetics
- dev of new capillaries in muscles
- increased translocation of GLUT4 receptors
- causes increased insulin sensitivity
exercise in type 1 diabetes
- exs modestly lowered blood glucose concentrations and raise blood ketone concentrations in well controlled pts
- in poorly controlled pts have less of a fall of glucose and increased ketogenesis
exercise in type 2 diabetes
- acute exercise- increase in glucose uptake
- exs training causes increased GLUT4 protein expression
immunologic response in type 1 DM
- autoantibodies
- T cell response to islet cells
- antigen binds to MHC class II molecules on APCs
- binding allows antigen to be presented to autoreactive CD4
imbalances in type 1 diabetes
- t reg cells have impaired function -> failing to suppress autoreactive t cells
- t cells resistant to immune regulation
diabetic ketoacidosis
- ketone dev is normal after depletion of liver glycogen
- in glucose poor environment too much oxaloacetete diverted away from gluconeogensis
- prevents ACoA to enter krebs -> ketogenesis
effect of hyperglycemia in type 2 DM
- impair pancreatic beta cell function
- magnify insulin resistance
- worsens metabolic state
metabolic syndrome
- co-occurance of metabolic risk factors for type 2 diabetes and CVD
metabolic defects in type 2 DM
- insulin resistance
- inadequate insulin secretion by beta cells mediated by GLUT2
- genetic alterations in GLUT2 expression
- processing of proinsulin to insulin is impaired
disorders affected by insulin resistance
- type 2 DM
- obesity
- stress
- infection
- pregnancy
- glucocorticoid excess
- metabolic syndrome
- HTN
- hyperlipidemia
- CAD
consequences of insulin resistance
- failure to inhibit gluconeogenesis
- high fasting blood glucose
- failure of glucose uptake and glycogen synthesis -> high postprandial blood glucose
- failure to inhibit lipoprotein lipase -> excess FFA
what 3 things is obesity associated with
- increased inflammation
- increased FFA
- deficiency in adipokines
how does increased FFA affect insulin resistance
- excess FFA saturate oxidative and storage capabilities of hepatocytes
- FFA intermediates accumulate and impair insulin signaling
- induce expression of inflammatory genes
symptoms of type 1 DM
- polydipsia
- polyuria
- weight loss with hyperglycemia and ketonemia
symptoms of type 2 DM
- mostly asymptomatic and hyperglycemic
- polyuria
- polydipsia
- nocturia
- blurred vision
diabetic macrovascular disease
- stroke
- MI
- lower extremity ischemia
diabetic microvascular disease
- retinopathy
- nephropathy
- neuropathy
advanced glycosylation end products (AGEs)
- form due to chronic hyperglycemia
- glucose form irreversible crosslinks with macromolecules like collagen
- results in vascular stiffening and myocardial dysfunction
acute pancreatitis
- due to gallstones or alcohol abuse
- abdominal pain
- elevated pancreatic enzymes
mechanism of gallstone pancreatitis
- reflux of bile into pancreatic duct
- obstruction of ampulla during gallstone passage
- obstruction of ampulla secondary to stone or edma
alcohol induced pancreatitis
- sensitization of acinar cells to CCK -> premature activation of zymogens
- generate toxic metabolites
- activate stellate cells by acetaldehyde and ROS -> fibrosis
pathogenesis of acute pancreatitis
- intraacinar activation of proteolytic enzymes
- microcirculatory injury
- leukocyte chemoattraction, release of cytokines, oxidative stress
why is intraacinar activation of proteolytic enzymes problematic
- blockade of secretion of pancreatic enzymes
- synthesis continues
- causes autodigestion
- cycle of active enzymes damaging cells while they release more enzymes
systemic inflammatory response syndrome (SIRS)
- happens due to severe acute pancreatitis
- activated by pancreatic enzymes
- cytokines released into circulation from inflamed pancreas
clinical response to SIRS
- ARDS
- myocardial depression and shock
- acute renal failure
- metabolic complications
- bacterial translocation
chronic pancreatitis
- progressive fibroinflammatory process
- irreversible destruction
causes of chronic pancreatitis
- mainly long term alcohol abuse
- cigarette smoking
- hereditary
- ductal obstruction
- systemic disease
- idiopathic
chronic pancreatitis pathogenesis
- hypersecretion of digestive enzymes not compensated by increase in ductal bicarb
- inflammation
- collagen secretion
- fibrosis
- loss of acinar cells
primary clinical features of chronic pancreatitis
- abdominal pain that radiates to back
- pancreatic insufficiency
pancreatic insufficiency
- when 90% of pancreatic fn is lost
- fat malabsorption -> steatorrhea
- pancreatic diabetes due to hyperglycemia
- alpha cells can be affected -> hypoglycemia
pain in pancreatitis
- nerve GF (NGF) produced in chronic pancreatitis
- mast cells sensitize nociceptor neuron by up regulating substance P
- cytokines and inflammatory mediators
what is the most common type of pancreatic cancer?
- pancreatic intrapeithelial neoplasias (PanIN) in small ducts
pathogenesis of pancreatic cancer
- multifactorial
- combo of genetic mutations
- strongest environmental factor is cigarette smoking
interactions of pancreatic cancer and adipose tissue
- causes adipose tissue inflammation
- systemic cytokine response
- abnormal adipokine secretin
- lipolysis
- peripheral insulin resistance and beta cell dysfunction
most common sx of pancreatic cancer
- usually silent until invade into adjacent structures
- pain- usually first sx
- jaundice
- weight loss
- head of pancreas causes obstructive jaundice
