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ACVIM Specialty 2023 > Insulinoma and Diabetes Mellitus > Flashcards

Insulinoma and Diabetes Mellitus Flashcards

1
Q

Beta cells make up what percent of the cells in the islets of Langerhans?

A

70%

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2
Q

Are insulinomas malignant or benign? What percent metastasize?

A

Vast majority are carcinomas with rare adenomas reported

Rate of metastasis 50-60%

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3
Q

Where do insulinomas typically metastasize to?

A

Regional LN and liver

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4
Q

How does glucose increase insulin secretion in a normal animal?

A
  • 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
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5
Q

In healthy animals, insulin secretion is completely inhibited when BG is less than what?

A

<80 mg/dl

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6
Q

What counter regulatory hormones are released in response to hypoglycemia?

A

Most important in the short term: glucagon, catecholamines

Also secreted: GH, glucocorticoids

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7
Q

What clinical signs of an insulinoma are secondary to neuroglycopenia?

A

Seizures, weakness, ataxia, mental dullness, visual disturbances

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8
Q

What clinical signs of an insulinoma are secondary to catecholamine release?

A

Tremors, hunger, nervousness

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9
Q

If gradual hypoglycemia develops, clinical signs may be less severe. Why?

A

Gradual decreases are less likely to stimulate catecholamine release

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10
Q

What activities can make the clinical signs of an insulinoma worse?

A

Fasting, exercise, increased sympathetic stimulation

Sometimes feeding, if it does not provide enough glucose to normalize BG but triggers insulin release

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11
Q

How does glucagon increase blood glucose?

A

Stimulates gluconeogenesis and glycogenolysis

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12
Q

What is the mechanism of action of streptozocin?

A

Selectively destroys beta cells in the pancreas or metastasis

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13
Q

Why is streptozocin not currently recommended as a treatment for insulinoma?

A

Nephrotoxic in some dogs, even with iv fluids

Caused DM in a majority of dogs

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14
Q

How does prednisone increase BG?

A
  • Increases gluconeogenesis
  • increases glucose 6-phosphatase activity
  • Decreases glucose uptake into tissues
  • Stimulates glucagon secretion
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15
Q

What dose of prednisone should be started for patients with insulinoma?

A

0.5 mg/kg/day - can increase if needed

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16
Q

What is diazoxide and how does it increase BG for patients with insulinomas?

A

Benzothiadiazine derivative
- inhibits closure of beta cell ATP-dependent K channels to inhibit exocytosis of insulin
- increases gluconeogenesis and glycogenolysis

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17
Q

How does octreatide inhibit insulin secretion?

A

Binds to any of 5 somatostatin receptors present on insulin secreting tumors to decrease insulin release

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18
Q

Why doesn’t octreatide work in some patients with insulinoma?

A

Also suppresses glucagon and GH secretion - if the suppression of these hormones outweighs the suppression of insulin release, hypoglycemia can actually get worse

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19
Q

What factors are associated with greater odds of relapse and decreased survival times in dogs with insulinoma?

A

Stage of disease, post operative hypoglycemia

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20
Q

What are common pancreatic histologic findings in dogs with DM?

A

Reduction in number/size of islets, decreased number of beta cells, beta cell vacuolization and degeneration

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21
Q

What are potential causes of beta cell loss?

A
  • Congenital hypoplasia or aplasia
  • immune mediated destruction
  • loss from pancreatitis
  • exhaustion/glucose toxicity from prolonged insulin resistance
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22
Q

Older, intact female dogs may be diagnosed with DM while in diestrus. Why and what is the treatment?

A

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

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23
Q

Glucose entry into what organs is NOT affected by a lack of insulin?

A

Erythrocytes, kidneys, brain

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24
Q

Describe the changes in protein metabolism with DM

A

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

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25
Q

Describe the changes in lipid metabolism in DM

A
  • 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
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26
Q

How are ketones formed in DM?

A

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

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27
Q

How does DM lead to diabetic cataracts in dogs?

A

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

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28
Q

Name 2 intermediate acting insulins

A

Lente, NPH

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29
Q

Name 3 long acting insulins

A

PZI , glargine, detemir

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30
Q

Describe Lente (Vetsulin) insulin in terms of its structure, origin, concentration, and duration

A
  • 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
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31
Q

Describe NPH insulin (Humulin, Novolin) in terms of its structure, origin, concentration, and duration

A
  • Recombinant human insulin
  • 100 U/mL
  • Duration: q4-10 hours, dose q12
  • Starting dose 0.25U/kg
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32
Q

Postprandial hyperglycemia can occur in even well regulated dogs on what insulin?

A

NPH

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33
Q

Describe PZI (Prozinc) insulin in terms of its structure, origin, concentration, and duration

A
  • Recombinant human
  • 40 U/mL
  • Duration: q10-16, dose q12
  • Starting dose 0.25 U/kg
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34
Q

Describe glargine (Lantus) insulin in terms of its structure, origin, concentration, and duration

A
  • Recombinant human origin
  • 100U/mL
  • Duration: q8-16
  • Starting dose 0.25-0.3 U/kg
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35
Q

Describe detemir (Levemir) insulin in terms of its structure, origin, concentration, and duration

A
  • Recominant human origin
  • U 100
  • Duration q8-16
  • Starting dose 0.1 U/kg
36
Q

Describe why glargine is long acting

A

At a pH 4, glargine is completely soluble (in the bottle). After it is injected SC and encounters a neutral pH, it forms microprecipitates that slowly absorb and delay the onset of action

Never dilute glargine or mix with any substance that can alter pH

37
Q

Describe why detemir is long acting

A

Modified to reversibly bind to albumin, slowing absorption

38
Q

What is fructosamine?

A

Glycated proteins produced by irreversible non-enzymatic reactions between glucose and plasma proteins

Determined by the average BG over the prior 2-3 weeks

39
Q

On a blood glucose curve, what is the ideal nadir?

A

90-150

40
Q

What are the clinical signs of diabetic neuropathy in dogs? When is it most commonly recognized?

A

Weakness, muscle atrophy, hyporeflexia, hypotonia

Recognized in dogs that have been diabetic for 5+ years

41
Q

What is the mechanism of diabetic neuropathy in dogs?

A

Distal polyneuropathy - segmental demyelination and axonal degeneration

42
Q

What are the microscopic changes associated with diabetic nephropathy?

A

Membranous glomerulonephropathy
- fusion of the foot processes
- glomerular and tubular basement membrane thickening
- increased mesangial matriz
- glomerular fibrosis or sclerosis

43
Q

What cat breed develops DM at 4 times the rate of other cats?

A

Burmese

44
Q

What is islet amyloid polypeptide and how does it contribute to beta cell failure?

A

Accumulation of misfolded IAPP oligomers with the beta cells and amyloid is the islets leads to beta cell death by triggering apoptosis

45
Q

Chronic hyperglycemia results in increased glucose metabolism through oxidative phosphorylation. What is a side effect of this?

A

Generation of ROS, leading to down regulation of insulin production and upregulation of pro inflammatory pathways

46
Q

Cats with DM and hyperthyroidism may have falsely low what?

A

Fructosamine

47
Q

Tight glycemic control (BG 72-180) lead to remission in what percent of cats at 6 months?

A

84% compared to 35% of cats without tight control

48
Q

What is the definition of diabetic remission?

A

Euglycemia for 2-4 weeks without the need for insulin or hypoglycemic therapy

49
Q

What are factors associated with DM remission in cats?

A

Low carbohydrate diet, long acting insulin, higher age, lower maximum dose of insulin, early institution of tight glycemic control, lower cholesterol

50
Q

Diabetic neuropathy in cats is associated with what clinical signs?

A

Ataxia, weakness, plantigrade stance, posterior paresis

51
Q

What percent of cats in DM remission relapse? What is their chance of going into remission again?

A

25-30% relapse, of those less than 25% achieve remission again

52
Q

How long is the duration of action of lente insulin in cats?

A

Only 8-10 hours, often resulting in periods of hyperglycemia and poor control

53
Q

Name 4 characteristics of glucose metabolism in cats, which contribute to relative glucose intolerance compared to dogs

A
  1. Reduced or absent hepatic glucokinase activity
  2. Reduced and delayed insulin secretion
  3. Reduced small intestinal disaccharide activity
  4. Reduced downregulation of gluconeogenic pathways
54
Q

Overweight cats have ____ times the risk of DM as cats in ideal BCS

A

4.6

55
Q

What should the percent carbohydrates be in a diet fed to cats with DM?

A

<13%

56
Q

When is it appropriate to use oral hypoglycemic drugs?

A

In cats with subclinical or pre-DM, combined with insulin in some cats. NOT appropriate as a sole therapy in a newly diagnosed diabetic, unless owners would otherwise euthanize

57
Q

What is the mechanism of action of sulfonylureas and meglitinides?

A

Bind beta cell ATP-ases => closure of K and opening of Ca channels => influx of intracellular Ca => release of stored insulin

58
Q

Name a sulfonylurea drug

A

Glipizide

59
Q

What cats are more likely to respond to Glipizide? What percent respond?

A

Non-ketotic, mild signs of DM, ideal BCS, good health otherwise. 30% respond with 15% achieving near-normal BG

60
Q

What is the mechanism of action of biguanides?

A

Increase hepatic and peripheral tissue response to insulin, thereby decreasing glucose production and increasing glucose uptake. Require functioning beta cells to produce insulin though - may be worth measuring insulin concentrations prior to treatment

61
Q

Name a biguanide drug

A

Metformin

62
Q

What is the mechanism of action of alpha-glucosidase inhibitors, such as acarbose?

A

Inhibit the action of membrane bound brush border disaccharidases in the SI - delay breakdown of complex carbs and slow intestinal glucose absorption to reduce post-prandial BG peaks

63
Q

Does acarbose have a benefit over low carbohydrate meals?

A

Not in one study - cats fed a high carb meal with acarbose and cats fed a low carb meal had similar post-prandial BGs. No additive effect to giving acarbose WITH low carb meals. Might be useful in CKD patients that cannot be fed low carb, high protein food

64
Q

What are incretins?

A

GI hormones rapidly released in response to a meal that stimulate synthesis and release of insulin while suppressing glucagon - GLP-1 is an example

65
Q

What is exenatide?

A

Injectable GLP-1 agonist

66
Q

Are pen injectors accurate for the delivery of insulin?

A

All injections delivered less insulin that intended in one study (variation <8%). Precision increased with increasing doses of insulin

67
Q

What is responsible for the long half life of ultra long acting insulin (q 1 week administration)?

A

Insulin is fused with a feline immunoglobulin fragment crystallizable (Fc) region. Binds to the neonatal Fc receptor, which leads to recycling of the insulin fusion molecule intracellularly - extends the half life

68
Q

What factors were associated with an increased risk of diabetes in cats?

A

Indoor confinement, overweight, eating dry food

69
Q

What is the effect of exenatide on diabetic cats?

A

Reduced glycemic variability in newly diagnosed diabetics treated with glargine and diet - cats with reduced GV were more likely to achieve remission

70
Q

What percent of cats receiving high dose prednisolone will develop diabetes? When?

A

~10% within the first 3 months of steroid therapy

71
Q

What is lispro?

A

Genetically engineered human analogue insulin

72
Q

In dogs with DKA, what is the effect of a lispro insulin CRI vs a regular insulin CRI?

A

Lispro more rapidly resolves hyperglycemia, ketosis, and acidosis at similar dosages to regular insulin (26 hours vs 61 hours)

73
Q

In cats with DKA, what is the effect of a lispro insulin CRI vs a regular insulin CRI?

A

Shorter time to BG <250 (7 vs 12.5 hours); no difference in hospitalization time

74
Q

What ketone is detected on urine Ketostix?

A

Acetoacetate

75
Q

Which ketone increases first in DKA?

A

Beta-hydroxybutyrate - not detected on Ketostix, which makes them insensitive for DKA

76
Q

What is the protocol for using glargine to treat DKA (rather than regular insulin)?

A
  • Give 1-2U/cat SQ q12 (normal long acting dose)
  • Then give 0.5-1U/cat IM q4 hours or longer, as needed to regulate glucose between 180-250 mg/dL
77
Q

What is the equation for correcting low bicarbonate in patients with metabolic acidosis?

A

NaHCO3 (mEq) = (desired HCO3 - patient HCO3) x 0.3 x body weight

78
Q

Is waiting to start insulin therapy until the patient is rehydrated beneficial?

A

Not in the JVECC study - starting insulin within 6 hours of hospitalization led to shorter time to DKA resolution with no increase in complications

79
Q

In a study comparing regular insulin CRI to IM glargine for the management of feline DKA, what variables improved with the IM glargine protocol?

A

Shorter median time to resolution of ketonemia, short time to improvement of hyperglycemia (2h vs 6 h), and shorter hospitalization (140 vs 173h)

80
Q

What gene mutation is associated with food motivation and obesity in Labs? Was the gene associated with the development of DM in these dogs?

A
  • Base pair deletion in canine pro-opiomelanocortin (POMC)
  • Not associated with DM development
81
Q

In what breed has DM been shown to be heritable (heritability 0.62)? What is the mode of inheritance?

A

American Eskimo Dogs
Likely polygenic with no single gene identified

82
Q

What insulins have lower day to day variability in dogs compared to porcine lente insulin?

A

Glargine and degludec (ultra long acting)

83
Q

In a prospective study, what was the agreement between Freestyle data and BG in diabetic cats? When did the agreement change?

A
  • r = 0.93 with 100% clinical accuracy
  • However, in the 30 minutes after an IV bolus of glucose, when BG was rising rapidly, interstitial glucose increased slowly and there was poor agreement
84
Q

In a prospective study, what was the agreement between Freestyle data and BG in diabetic dogs?

A

r = 0.94
Libre was 93, 99, and 99% accurate at low, normal, and high BGs

85
Q

Does DKA affect the accuracy of Freestyle Libre data in dogs?

A

No - metabolic variables did not affect agreement
r = 0.88 before and 0.93 after DKA

86
Q

What are the most common complications with Freestyle Libres in cats?

A

Most common - early sensor detachment (15%)
Mild dermatologic changes (erythema, crusts - 12%)
Skin erosions/abscess were rare, but occurred in 2 cats

87
Q

Is the Freestyle useful to detect hypoglycemia in healthy dogs given insulin?

A

No - limited agreement with BG, proportions of readings not likely to affect clinical outcome was only 80%

ACVIM Specialty 2023 (38 decks)

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