Insulinoma and Diabetes Mellitus Flashcards
Beta cells make up what percent of the cells in the islets of Langerhans?
70%
Are insulinomas malignant or benign? What percent metastasize?
Vast majority are carcinomas with rare adenomas reported
Rate of metastasis 50-60%
Where do insulinomas typically metastasize to?
Regional LN and liver
How does glucose increase insulin secretion in a normal animal?
- Glucose enters beta cells and is metabolized to ATP
- ATP closed ATP-dependent K channels
- Decreased K efflux decreased the depolarization of the beta cells, reduced opening of Ca channels, and insulin exocytosis
In healthy animals, insulin secretion is completely inhibited when BG is less than what?
<80 mg/dl
What counter regulatory hormones are released in response to hypoglycemia?
Most important in the short term: glucagon, catecholamines
Also secreted: GH, glucocorticoids
What clinical signs of an insulinoma are secondary to neuroglycopenia?
Seizures, weakness, ataxia, mental dullness, visual disturbances
What clinical signs of an insulinoma are secondary to catecholamine release?
Tremors, hunger, nervousness
If gradual hypoglycemia develops, clinical signs may be less severe. Why?
Gradual decreases are less likely to stimulate catecholamine release
What activities can make the clinical signs of an insulinoma worse?
Fasting, exercise, increased sympathetic stimulation
Sometimes feeding, if it does not provide enough glucose to normalize BG but triggers insulin release
How does glucagon increase blood glucose?
Stimulates gluconeogenesis and glycogenolysis
What is the mechanism of action of streptozocin?
Selectively destroys beta cells in the pancreas or metastasis
Why is streptozocin not currently recommended as a treatment for insulinoma?
Nephrotoxic in some dogs, even with iv fluids
Caused DM in a majority of dogs
How does prednisone increase BG?
- Increases gluconeogenesis
- increases glucose 6-phosphatase activity
- Decreases glucose uptake into tissues
- Stimulates glucagon secretion
What dose of prednisone should be started for patients with insulinoma?
0.5 mg/kg/day - can increase if needed
What is diazoxide and how does it increase BG for patients with insulinomas?
Benzothiadiazine derivative
- inhibits closure of beta cell ATP-dependent K channels to inhibit exocytosis of insulin
- increases gluconeogenesis and glycogenolysis
How does octreatide inhibit insulin secretion?
Binds to any of 5 somatostatin receptors present on insulin secreting tumors to decrease insulin release
Why doesn’t octreatide work in some patients with insulinoma?
Also suppresses glucagon and GH secretion - if the suppression of these hormones outweighs the suppression of insulin release, hypoglycemia can actually get worse
What factors are associated with greater odds of relapse and decreased survival times in dogs with insulinoma?
Stage of disease, post operative hypoglycemia
What are common pancreatic histologic findings in dogs with DM?
Reduction in number/size of islets, decreased number of beta cells, beta cell vacuolization and degeneration
What are potential causes of beta cell loss?
- Congenital hypoplasia or aplasia
- immune mediated destruction
- loss from pancreatitis
- exhaustion/glucose toxicity from prolonged insulin resistance
Older, intact female dogs may be diagnosed with DM while in diestrus. Why and what is the treatment?
Progesterone stimulates release of GH from the mammary gland. Both hormones antagonize the effects of insulin and lead to insulin resistance. Spaying may resolve it if it is caught early, before beta cell damage occurs
Glucose entry into what organs is NOT affected by a lack of insulin?
Erythrocytes, kidneys, brain
Describe the changes in protein metabolism with DM
Shifts towards a decrease in synthesis and increase in proteolysis. The available amino acids increase hepatic gluconeogenesis, which contributes to hyperglycemia. Leads to loss of muscle mass and cachexia as well
Describe the changes in lipid metabolism in DM
- Lack of intracellular glucose leads to lipid catabolism and mobilization of FFA
- FFA undergo beta oxidation in the liver to acetyl CoA, which is used in the Krebs cycle for ATP generation
- Increased FFA also leads to increased hepatic production of triglycerides and VLDLs => hyperlipidemia and hepatic lipidosis
How are ketones formed in DM?
If the amount of acetyl CoA produced by FFA beta oxidation exceeds the limit of what can be used in the Kreb cycle, the acetyl CoA is metabolized into ketones
How does DM lead to diabetic cataracts in dogs?
Excessive glucose in the lens is metabolized by aldose reductase into sorbitol. Sorbitol accumulates in the lens and osmotically draws in water, damaging the lens fibers and causing cataracts
Name 2 intermediate acting insulins
Lente, NPH
Name 3 long acting insulins
PZI , glargine, detemir
Describe Lente (Vetsulin) insulin in terms of its structure, origin, concentration, and duration
- Porcine origin
- 30% short acting, amorphous insulin and 70% long acting, microcrystalline insulin
- 40 U/mL
- Duration: 8-14 hours, dose q12
- Starting dose 0.25U/kg
Describe NPH insulin (Humulin, Novolin) in terms of its structure, origin, concentration, and duration
- Recombinant human insulin
- 100 U/mL
- Duration: q4-10 hours, dose q12
- Starting dose 0.25U/kg
Postprandial hyperglycemia can occur in even well regulated dogs on what insulin?
NPH
Describe PZI (Prozinc) insulin in terms of its structure, origin, concentration, and duration
- Recombinant human
- 40 U/mL
- Duration: q10-16, dose q12
- Starting dose 0.25 U/kg
Describe glargine (Lantus) insulin in terms of its structure, origin, concentration, and duration
- Recombinant human origin
- 100U/mL
- Duration: q8-16
- Starting dose 0.25-0.3 U/kg