Endocrine Pancreas Physiology Flashcards
Exocrine Pancreas
Acinar cells and duct cells
Involved in GI function
Secretes enzymes into the lumen of the duodenum
Endocrine Pancreas
Organized in islets of langerhans
2-3% of the pancreas
Richly innervated by both vagal parasympathetic system and splanchnic sympathetic fibers
Islets of Langerhans cell types
Alpha (20%)- glucagon
Beta (70%)- insulin
Delta (5%) - somatostatin
F (5%) Pancreatic polypeptide
All hormones are involved in glucose metabolism
Insulin
A polypeptide hormone produced produced by beta cells in response to hyperglycemia
Like other peptide hormones, is synthesized as a larger molecule inside of the golgi apparatus and packages into secretory granules awaiting secretion
Insulin synthesis and secretion
- Messenger RNA on the ribosome of the ER binds aa into a peptide chain called a preprohormone. The chain is directed into the ER lumen by a signal sequence of aa
- Enzymes in the ER chop off the signal sequence, creating an inactive pro hormone
- The pro hormone passes from the ER through the golgi
- Secretory vesicles containing enzymes and pro hormone bud off the golgi. The enzymes chop the prohormon into one or more active peptides plus additional peptide fragments
- The secretory vesicles releases its contents by exocytosis into he extracellular space
- The hormone moves into the circulation for transport to its target
C peptide and active insulin
Insuline chains
A protein consisting of 2 chains (alpha and beta) connected by 2 disulfide bridges
Differences in aa sequences between species are small
- Cattle, sheep, horses, dogs, and whales differ only in positions 8, 9, and 10 of the alpha chain
- Porcine differs from Human by 1 aa
- Bovine from cat by 1 aa
- Porcine and canine are the same
- Human from cat by 4 aa
- Porcine from human by 1 aa
Influences on insulin release
Several nutritional, neural, paracrine, and endocrine variables govern insulin release
-secretagogues for insulin vary by species
- -Glucose in omnivores
- Amino acids in carnivores
- -fatty acids
Factors affecting insulin secretion
Stimulatory:
Nutrients- Glucose, aa, FA, and ketones
Hormones- Growth Hormone, glucagon
Inhibitory:
Hormones- Adrenocorticosteroids, somatostatin, adrenalin, noradrenalin
Insulin secretion
Biphasic secretion kinetics
Acute phase: involves the release of preformed insulin
Chronic phase: involves the synthesis of protein
How is insulin released form B cells
Beta cells have a glucose transporter (GLUT2) in the membrane surface
Allows glucose to diffuse freely into the cell
ECF glucose concentration directly affects glucose concentration inside the beta cell
An increase in blood glucose concentration leads to insulin secretion and synthesis
Increase in Glucose into the cell through GLUT 2 leads to increase in ATP production.
This inhibits K ATPase- causes depolarization.
Voltage gated Ca channels open and Ca2+ activates insulin gene expression via CREB. Exocytosis of stored insulin
How does insulin act on target cells
After release, insulin binds to a specific membrane receptor on target tissues known as the insulin receptor or insulin receptor tyrosine kinase
2 insulin binds to receptors and form a dimer that activates cell responses
Most important insulin-sensitive tissues
Liver
Muscle
Fat
Physiological effect of insulin
Lower blood concentration of glucose, fatty acids, and amino acids
Promoting intracellular conversion of these compounds to their storage forms: Glycogen, Triglycerides, Proteins
Insulin Mediated Simulation via GLUT 4
Insulin binds to insulin receptor- dimer is formed
Insulin signal pathways activated: effects of protein metabolism, Effects on growth, Effects on lipid metabolism
Also causes translocation of GLUT4 vesicle to the cell membrane to allow glucose to enter the cell
Non-insulin mediated stimulation of GLUT 4
Exercise-responsive GLUT 4 containing vesicles
Insulin action of fat
Insulin facilitates glucose entry into cells by increasing the number of specific glucose transporters (GLUT 4) in the cell membrane
GLUT 4 is the only insulin sensitive
Insulin action on muscle
Smooth, striated and cardiac muscle
Stimulates glycogen synthesis enzymes
-promoting storage of glucose molecules in the form of glycogen
Promotes the use of glucose as a fuel source
-reduces fatty acid oxidation
-in the absence of insulin muscle rely more on fatty acids as a fuel source
Enhances amino acid uptake which promotes muscle growth
Increase glucose transport Increase glycogen synthesis Decrease glycogenolysis Increase aa uptake Increase protein synthesis Decrease protein degradation
Insulin action on adipose tissue
Increase glucose transport and consequently:
Glycerol formation- combines with fatty acids delivered to adipose tissue to form triglycerides
-fatty acids come from very low density lipoproteins (VLDL) produced in the liver
Glycogen synthesis
Insulin inhibits lipolysis which promotes adipose deposition
Increase glucose transport Increase glycogen synthesis Decrease glycogenolysis Increase lipogenesis Decrease lipolysis
Insulin action on liver
Promotes fatty acid synthesis in hepatocytes
-stimulates incorporation of those fatty acids and triglycerides into lipoprotein-bound vesicles such as VLDL for transport to adipocytes
Increase glycogen synthesis Decrease glycogenolysis Decrease gluconeogenesis Increase lipogenesis Decrease lipolysis Decrease gluconeogenesis
Insulin inactivation
Is metabolized mainly by the liver and kidneys
Specific enzymes reduced the disulfide bonds
Chains are subjected to protease activity
-reduce them to peptides and amino acids
Half life is about 10 minutes
Glucose homeostasis summary
Consumption of carbohydrate, fat, protein
Insulin release
Carbohydrates main source of energy for cells
Excess stored as glycogen fat (in liver, fat, muscles)
Release of glucagon and epinephrin
Hepatic glycogenolysis
Release of cortisones and GH
Gluconeogenesis- production of glucose from glycerol, aa, and lactate
Reduced glucose uptake on cells- fat is used as energy source except in brain
Which hormones counteract the efforts of insulin
Glucagon (acute phase)
Epinephrin/norepinephrin (acute phase)
Cortisol (Chronic Phase)
Growth hormone (Chronic Phase)
Glucagon
Is a polypeptide hormone consisting of 29 amino acids produced in the alpha cells of the pancreatic islets
Close relationship with insulin
Considerable homology between species
Half life of 5 minutes
Glucagon is encoded by the proglucagon gene which is located not only in alpha cells but also other cells of the body
- A large peptide is first produced= proglucagon
- Proglucagon is cleaves in alpha cells to form glucagon
Glucagon synthesis
Mainy stimulated by decreased glucose concentration- hypoglycemia
The secretion is triggered when levels of glucose decline below threshold, which differs between species
Opposed most insulin actions to help maintain blood glucose concentration
-glucagon is one of the counter regulatory hormones
Synthesized in a manner similar to insulin:
Membrane depolarization is independent from K channels
Secretion is promoted via voltage-dependent sodium and calcium channels
-depolarization increased calcium influx
-glucagon is released by exocytosis
G protein coupled receptors
After secretion, glucagon binds to G protein couples receptors in the target tissues Liver Adipocytes Kidney Heart Brain GI tract
Blood glucose
Insulin decreases blood glucose
Glucagon increases
Glucagon pt 2
Glucagon is not always an opposing hormone to insulin
Protein ingestion stimulates both insulin and glucose release
-specially the aa alanine and arginine
-Important feature in obligate carnivores
-Insulin released in response to increased amino acid levels –> lower glucose concentration
-Glucagon promotes rapid conversion of the amino acids to glucose by stimulating gluconeogenesis
Glucagon action in the liver
Leads to the activation or inactivation of specific liver enzymes
Main effect is centered in the liver and enhances the availability of glucose to other cells of the body
1. decrease glycogen synthesis
–inhibition of glycogen synthase
2. breakdown of liver glycogen-glycogenolysis
–activation of glycogen phosphorylase
3. increase in liver gluconeogenesis
All increase blood glucose
Glucagon action in adipose tissue
Activates hormone sensitive lipase in adipocytes
Promotes breakdown of fat- lipolysis
Increase availability of fatty acids to tissues (energy source)
Also inhibits storage of triacylglycerol in the liver
-help make additional amounts of fatty acids available for other tissues
Activation of hormone sensitive lipases
Epinephrin or glucagon binds to GPCR
HSL activates and leads to glycerol and liver gluconeogenesis
HSL also leads to FA which is a source of energy for tissues in the absence of glucose
Pancreatic somatostatin
Produced by delta cells
-in the same way as other protein hormones
Inhibitory actions
-decreases motility and secretory activity of GI tract
-Inhibits secretion of all endocrine cell types of the islet of langerhans (glucagon is more affected than insulin)
Pancreatic polypeptide
Produced by F or PP cells
-secretion is stimulated by GI hormones, vagal stimulation and protein ingestion
-Inhibition occurs through somatostatin
Effects are directed toward the GI tract
-Decrease gut motility and gastric emptying
-Inhibits secretion of pancreatic enzymes and the contraction of gallbladder
Diabetes Mellitus
Lack or deficiency of insulin
Can be absolute or relative
Absolute= absence of insulin= type 1
Relative= insulin is not working properly= type 2
Causes blood glucose to increase. Glucose uptake from insulin sensitive tissues will be compromised
Insulin directly inhibits glucagon release by binding to what receptor and cell type
Insulin receptor
Alpha cells
Diabetes Mellitus affects glucagon
Insulin deficiency has effects on glucagon production
Insulin directly inhibits glucagon release by binding to the insulin receptor on alpha cells
Glucagon stimulates insulin secretion directly
-by binding to insulins receptor on the beta cell
-also stimulates indirectly though induction hyperglycemia by glycogenolysis and gluconeogenesis
Diabetes Mellitus affects adipose tissue
Insulin deficiency causes lipolysis of storage fat and release FFA
The enzyme hormone sensitive lipase (HSL) is strongly activated
-hydrolysis of stored triglycerides occurs releasing large amounts of FFA and glycerol in the blood. FFA will be used as a source of energy in the absence of glucose
-Excess FFA will be converted into phospholipids and cholesterol
-Triglycerides will be formed at the same time in liver. An increase in blood lipids is expected in any diabetic patient
Insulin inhibits HSL while glucagon activates it
HSL is highly expressed in adipose tissue and steroidogenic tissue
Dibetes Mellitus
Insulin deficiency causes protein depletion and increased plasma amino acids
-catabolism of protein increases and protein synthesis stops
Amino acids in the blood will be used as: a direct energy source in the liver or a substrate for gluconeogenesis
Insuline deficiency (absolute or relative)
Increase in glucagon
Hepatic gluconeogenesis
Hyperglycemia
Compromised glucose transport in the muscle and adipose tissue Protein and fat catabolism AA and glycerol in blood Hepatic gluconeogenesis Hyperglycemia
Insulin deficiency
Glucose does not enter the satiety center: Poliphagia
Catabolic state: weight loss
Increase in blood glucose levels: hyperglycemia
Exceed renal tubular threshold: glycosuria
Osmotic diuresis: Polyuria
Compensatory: Polydipsia
Type I diabetes
Characterized by permanent hypoinsulinemia
Absolute deficiency
-no increase in endogenous insulin after stimulation; absolute necessity for exogenous insulin to maintain control of glycemic, avoid ketoacidosis and survive
Common in dogs (95% of cases)
Cataracts in dogs
The most common long term complication
Related with altered osmotic relationships in the lens induced by accumulation of sorbitol and galactitol
Sugar alcohols produced following reduction of glucose and galactose by the enzyme Aldose reductase in the lens
Potent hydrophilic agents causing influx of water
-swelling and rupture of the lens fibers
Type II diabetes mellitus
Characterized by the resistance to the metabolic effects of insulin
Relative deficiency: it is a combination of impaired insulin action in liver, muscle and adipose tissue (insulin resistance) and beta cell failure
Common in cats (80% if cases)
Type II diabetes in cats
For diabetes to develop, there must be a beta cell dysfunction
-healthy beta cells can adapt to obesity and insulin resistance by increasing insulin secretion
Amylin (or islet amyloid polypeptid IAPP)
- it is a polypeptide produced and secreted by beta cells together with insulin secretion
- increases satiety, decreases gastric empty and reduced glucagon production
Only humans, cats, and non human primates have an amyloidogenic aa structure with the potential to form amyloid depositions within the islets
Islets of Langerhans amyloidosis
When allying aggregates it forms the amyloid
The amyloid deposition within the pancreatic islets is called amyloidosis
The deposition is toxic to beta cells and leads to beta cell dysfunction
Common causes of insulin resistance in cats
OBESITY cushing infection pancreatitis Hyperthyroidism renal failure
Obese cat insulin resistance
Hormone action is compromised
Pancreas will compensate producing more insulin
OVER TIME
Initiates the lost of capacity to compensate (B cell)
Glucose levels cannot be maintained in the normal range
Glucose intolerance
When the levels of insulin start to decrease
Sever hyperglycemia and diabetes mellitus
Type 2 diabetes in cats
Clinical remission can occur Clinical signs disappear, blood glucose concentration normalizes and insulin treatment or other anti diabetic drug can be discontinued Depends on beta cell dysfunction Irreversible damage: amyloidosis Reversible damage: glucotoxicity
Diabetic neuropathy
One of the most common chronic complications Hyperglycemia leads to nerve injury -in shawn cells and axons of myelinated fibers -microvascular abnormalities Pathogenesis is not completely understood Clinical signs range from mild to severe -limb weakness -difficulty jumpin -base-narrow gait -ataxia -muscle atrophy in pelvic limbs -plantigrade posture -postural reaction deficits -decreased tendon reflexes -irritability when feet are touched
What diagnostic methods could we use to detect ketoacidosis in dogs
Measuring Beta-hydroxybutyrate in the serum of dogs
Using a urine dipstick to measure acetoacetic acid and acetone
Diabetic ketoacidosis
Sever complication of diabetes mellitus
Results in unrestrained ketone body formation in the liver, metabolic acidosis, severe dehydration, shock, and possibly death
Before the availability of insulin DKA was fatal
Keton bodies
Derived from oxidation of free fatty acids by the liver
Used as an energy source by many tissues during periods of glucose deficiency
-oxidation of FFAs leads to the production of acetoacetate
-in the presence of NADH, acetoacetate is reduced to B-hydroxybutyrate
-acetone is formed by the spontaneous decarboxylation of acetoacetate
Excessive production results in ketosis and ketoacidosis
Insulin deficiency increases FFAs release from adipocytes, thus increasing the availability of FFAs to the liver and in turn promoting ketogenesis. Also reduced the peripheral utilization of glucose and ketones
Keton bodies synthesis
For the synthesis of ketone bodies to be enhances, there must be two major alterations in intermediary metabolism
- increased mobilization of FFAs from triglycerides stored in adipose tissue
- A shift in hepatic metabolism from fat synthesis to fat oxidation and ketogenesis
Counterregulatory hormones
The body increases production in response to a wide variety of diseases and stress situations- this response is usually beneficial
Circulating levels are typically markedly elevated in DKA
-insulin resistance
-stimulation of lypolisis and the generation of FFAs
-Shift the hepatic metabolism to fat oxidation and ketogenesis
Diabetic ketoacidosis and counter regulatory hormones
Glucagon is considered the most influential ketogenic hormone
-epinephrin also stimulates through stimulation of lypolysis
Both glucagon and epinephrin contribute to insulin resistance
-by inhibiting insulin-mediated glucose uptake in muscle
-by simulating hepatic glucose production through glycogenolysis and gluconeogenesis
Cortison and GH
-enhance lipolysis in the presence of insulin deficienct
-block insulin action in peripheral tissues
-potentiate the stimulating effect of glucagon and epinephrin on hepatic glucose output
The combination of insulin deficiency and excess in counter regulatory hormones also leads to protein catabolism
-impairs insulin action in muscle
-provide substrate to drive gluconeogensis
Chronic insulin deficiency
Increase glucose and ketone bodies
Osmotic diuresis: glycosuria, ketonuria
Loss of water, K, Na, and PO4
Dehydration
Increase glucose and ketone bodies
Decrease in pH: metabolic acidosis- increase anion gap
Hyperventilation, nausea vomiting OR increase K loss
Dehydration
Worsening hyperglycemia and ketonemia
Leads to acidosis, fluid depletion, and hypotension
Influence the progression of DKA in a self-perpetuating spiral of metabolic decompensation
Coexisting disorders increase the secretion of counter regulatory hormones
-pancreatitis
-infection
-CKD
-hormonal disorders
Diabetic ketoacidosis acid base status
Acidosis results form excess accumulation of kenos in the blood
-overwhem the bodys buffering system
Increase in H concentration
Failure of kidney to compensate in DKA is partly a result of the physiochemical properties of B hydrocybutyrate and acetoacetate
- renal threshold is low- the amount exceed the kidney capacity: potentiates loss of water and electrolytes
- They are relatively strong acids and are excreted mostly as sodium and potassium salts- concomitant loss of bicarb
Diabetic ketoacidosis: Sodium
Deficit in total body sodium
Excessive urinary loss caused by osmotic diuresis
Insulin enhances renal sodium reabsorption in the distal portion of the nephron
-insulin deficiency increases sodium wasting
glucagon, vomiting, and diarrhea also contribute
Diabetic ketoacidosis: potassium
Deficit in total body potassium
Increase in plasma and ECF tonicity in DKA leads to shift of water out of the cells and shift of K out of cells
K shift is enhanced by the presence of acidosis and the breakdown of intracellular protein secondary to insulin deficiency
Entry of K into cells is also impaired in the presence of insulinopenia
Osmotic diuresis causes marked urinary losses of K
Secondary hyperalsodteroneism augment the K deficit
Diabetic ketoacidosis: phosphate
Deficit in total body phosphate
Phosphate along with K, shift from the intracellular to extracellular compartment in response to hyperglycemia and hyperosmolality
Osmotic diuresis also leads to enhanced urinary phosphate loss
Hypervolemia and Hemoconcentration
Metabolic stress: increase glucagon, cortisol, GH. Increase gluconeogeneis, proteolysis and insulin resistance
Prerenal azotemia: increase H and K concentrations
Hyperviscosity: trombosis, CNS, renal vein
Shock: acute tubular necrosis, lactic acidosis
Increase Aldosterone: K loss
Increase catecholamines: Increase lipolysis, ketogenesis, glucose production, leucocytosis, insulin resistance
Insulinoma
Malignant functional pancreatic tumors of the pancreatic B cells: occurs primarily in dogs, ferrets, and rare in cats
Neoplastic B cells synthesize and secrete insulin independent of the normal suppressive effect of hypoglycemia
-results in potentially life-threatening periods of hypoglycemia
-remember the brains only energy source is glucose
Glucagonoma
Neoplasm of alpha cells
Insulin resistance- diabetes mellitus
Sever weight loss
Superficial necrolytic dermatitis
