Endocrine Pancreas and Diabetes Mellitus Flashcards
Describe briefly the chemical structure of insulin and proinsulin, and how proinsulin converted to native insulin
Insulin characteristics:
• ONLY SOURCE is pancreatic beta-cells
• Composed of a 2 chain protein 6000 MW
o Alpha chain & Beta chain linked by disulfide bridges.
The active form (native insulin) is produced from proinsulin.
• Preproinsulin Proinsulin Insulin + C-Peptide
o First synthesized as preproinsulin in pancreatic B cells
o It is taken to the ER and is cleaved, turning into proinsulin.
o Proinsulin folds into correct conformation and 3 disulfide bonds are formed.
Correct conformation is the ring diagram, with the two ends overlapping (the alpha and beta chains), with disulfide bridges forming between them.
• Highly conserved between species
List which tissues in the body require insulin, and discuss how many tissues make insulin
- Insulin faciliatates glucose uptake by most tissues, except RBCS, most of the brain, intestinal mucosa, lens of eye, kidney tubules
- In the liver it converts glucose to glycogen, and inhibits gluconeogenesis.
- In adipose it converts glucose to TGs (triglycerides)
islets of langerhans in the pancreas (specifically beta cells) are the only tissue in the body to make insulin
List the major actions and sites of action of insulin in regulating carbohydrate, lipid, and protein metabolism
Carbohydrate metabolism:
• Liver
o GLUT 2 DOES NOT need insulin for membrane transport of glucose
o Insulin aids in phosphorylation of glucose
Glycogen storage
o Insulin inhibits gluconeogenesis
o Insulin decreases glycogenolysis
o OVERALL effect is to decrease glucose output by the liver.
• Muscle
o Stimulates glucose transport into cell by aiding GLUT 4
o Aids in glycogen storage
• Adipose
o Insulin stimulates glucose transport into cell by aiding GLUT 4
o Insulin aids in esterification of FFA into triglycerides
o Limited conversion of glucose into stored fat.
Lipid metabolism:
• Adipose
o Promotes FFA storage as Triglycerides by inducing “Lipoprotein Lipase”
o Prevents Lipolysis by inhibiting hormone-sensitive lipase
o Stimulates use of ketacids for energy
Protein metabolism:
• Enhances protein and AA sequestration in target tissues, so is considered “Anabolic Hormone” and promotes growth
• Inhibits proteolysis
List the biological stimuli that control the rate of insulin secretion and the effect of these stimuli
Insulin secretion INCREASED by: Glucose** (this is the major stimulator of insulin secretion) Amino acids FFA Ketoacids
Insulin secretion is DECREASED by: Epinephrine Somatostatin Leptin Fasting, Exercise, Endurance training
List the major actions of glucagon, and where glucagon exerts its actions
Glucagon is produced in pancreas cells, its actions include:
• In the liver
o Increases gluconeogenesis
Increases every rate limiting enzyme
o Increases glycogenolysis
If glycogen is present, it’s mobilized.
o Decreases glyconeogenesis
• Increases protein catabolism
• Increases lipolysis
Mechanisms of Glucagon Effects
• Liver (increases glucose output)
• Muscle (Glucagon increases FFA, indirectly inhibits glucose uptake by muscle and fat)
• Adipose tissue (promotes lipolysis)
Describe the major physiological changes that occur in diabetes mellitus
decreased glucose uptake, increased protein catabolism, increased lipolysis leading to:
weight loss, pu/pd, glucosuria (glycosuria), polyphagia, ketoacidosis (sweet smelling breath); cataracts (dogs)
Discuss whether diabetes in dogs and cats is a disease of young or older animals
older; over 50% cats >10 y/o; dogs 7-9 y/o
Describe why obese animals are often resistant to the action of insulin
perpetually high levels of glucose in the blood, constant pressure on beta cells to produce insulin, destruction of beta cells
Describe the “C” fragment of insulin and its clinical use
seen in endogenous insulin; able to determine bodies ability to produce insulin
List factors (and their effects) that modulate insulin secretion
Carbohydrate metabolism:
• Liver
o GLUT 2 DOES NOT need insulin for membrane transport of glucose
o Insulin aids in phosphorylation of glucose
Glycogen storage
o Insulin inhibits gluconeogenesis
o Insulin decreases glycogenolysis
o OVERALL effect is to decrease glucose output by the liver.
• Muscle
o Stimulates glucose transport into cell by aiding GLUT 4
o Aids in glycogen storage
• Adipose
o Insulin stimulates glucose transport into cell by aiding GLUT 4
o Insulin aids in esterification of FFA into triglycerides
o Limited conversion of glucose into stored fat.
Lipid metabolism:
• Adipose
o Promotes FFA storage as Triglycerides by inducing “Lipoprotein Lipase”
o Prevents Lipolysis by inhibiting hormone-sensitive lipase
o Stimulates use of ketacids for energy
Protein metabolism:
• Enhances protein and AA sequestration in target tissues, so is considered “Anabolic Hormone” and promotes growth
• Inhibits proteolysis
Compare the mechanisms and sites of action of glucagon and epinephrine in elevating blood glucose
(insulin and hypoglycemic objectives- note Somogyi rebound)
hyperglycemic; epinephrine inhibits insulin secretion
Describe the role of somatostatin in regulating pancreatic function
IGF-1/produce hyperglycemic state
Distinguish between IDDM and NIDDM
IDDM- Insulin dependent DM: destruction or loss of function of beta cells
NIDDM- non-insulin dependent DM (1/3 cat cases): decreased number or responsiveness of insulin receptors; can be insulin tolerance secondary to obesity or other factors
Describe the major symptoms of diabetes mellitus
PU/PD, glycosuria, weight loss, ketoacidosis, cataracts (dogs) hyperphagia
Describe the major cause of PU/PD in diabetic animals
glucose in kidneys, molecule takes a lot of water with it
Describe the source of glycosuria seen in more severe cases of diabetes
leak out into urine, kidney threshold, differs dog/cat
cat threshold: 240-300 mg/dL
dog threshold: 180-220
Discuss what causes diabetes mellitus
obesity, genetics, insulin resistance, death of beta cells; pancreatitis
Define: Islets of Langerhans
pancreas, contain beta cells which produce insulin, alpha cells produce glucagon, delta cells produce somatostatin; endocrine gland function
Define: Insulin
hypoglycemic hormone (only one) produced in beta cells in the islets of langerhans in the pancreas, promotes storage of insulin
Define: Polyuria
excessive urination
Define: Polydipsia
excessive thirst
Define: Hyperphagia
ravenous appetite; excessive eating often without weight gain or continued weight loss
Define: Glucose
sugar; insulin increases mobilization of glucose to glycogen and storage in the tissues; glucagon increases breakdown of glycogen and increases blood glucose
Define: Anabolism
build up
Define: Catabolism
break down
Give the differences between insulin and glucagon on their impact on: Glycogen synthesis Gluconeogenesis Glyconeogenesis Glycogenolysis
Insulin-
Glycogen synthesis: increased in liver and muscle cells
Gluconeogenesis: decreased in liver
Glyconeogenesis: does not act on
Glycogenolysis: (insulin deprivation- increased in liver)
Glucagon- Glycogen synthesis: does not act on Gluconeogenesis: increases Glyconeogenesis: decreases Glycogenolysis: increases
Define: Glycosuria
(glucosuria) glucose present in the urine; hallmark indicator of diabetes mellitus
Define: Ketone bodies
are created when the body begins to mobilize fat due to insulin deficiency
Define: Ketoaciduria
ketone bodies present in urine, present in more advanced cases of diabetes mellitus
Define: Ketoacidosis
build-up of ketones in blood, often detectable on breath; neurologic changes; severe diabetes
Define: Somatostatin
GH; regulatory hormone that inhibits endocrine pancreas function
Define: Glucagon
has the opposite of insulin action, promotes break down of glycogen to glucose to increase blood glucose
Define: Pancreatic polypeptide
regulatory protein that inhibits exocrine pancreas
Insulin-Dependent Diabetes Mellitus (abbrev.)
IDDM
Non-Insulin Dependent Diabetes Mellitus (abbrev.)
NIDDM; usually secondary to diabetes or other factors, can progress to IDDM
Define: Cataracts
clouding of lenses, common in dogs with diabetes mellitus
Define: Plantigrade posture
down on hindlimbs, can be characteristic of diabetes mellitus in cats
List predisposing factors for Diabetes mellitus.
obesity, amyloidosis (cats), pancreatitis, immune-mediated destruction (dogs)
Define: Urinalysis
analysis of urine to look for abnormalities; evaluate values such as pH, glucose, ketones, bilirubin, specific gravity, blood present, etc
Describe how diabetes in the cat differs from that in the dog.
Dogs- IDDM is much more common; Disease of older dogs (7-9 years); Essentially all diabetic dogs require insulin therapy; Dogs can show transient diabetes during pregnancy or progesterone treatment.
Cat- NIDDM + IDDM; 1/3 of cats are NIDDM; Treatment: insulin and/or oral hypoglycemic agents (these are not used in dogs); >50% are over 10 y/o; Obesity increases risk 3 fold, neutering 2 fold, 1.5 fold increase in male cats; 20% of cats will stop being diabetic
Describe why diabetic animals are hyperphagic, but weight loss is a common symptom of diabetes.
Despite the fact animals have an increased appetite for food, insufficient insulin (or insulin resistance) prevents the body from getting glucose from the blood into the body’s cells to use as energy. When this occurs, the body burns fat and muscle for energy instead, which causes weight loss, but still causes an increase in hunger.
Describe drug treatments for diabetes, and explain why they are typically not used in the dog.
Oral hypoglycemic agents
• Increases insulin receptors
• Stimulates insulin production by the functional b-cells left in pancreas
• Almost always used in CATS not dogs (why????)
Insulin
• Used in all dogs, most cats
• Insulin sources
o Animal insulin from bovine/porcine or porcine sources
o Human recombinant insulin
