The Endocrine Pancreas

Question 1

Discuss the base pathology for insulinoma and describe the staging of such tumours

Answer 1

• Most insulin secreting tumours are malignant carcinomas
• Most pancreatic tumours arise from the B cells within the islet of Langerhans (insulin producing cells)
• ~80% are solitary and metastasis to the local lymph nodes and liver are common at the time of diagnosis (~45-64%)

Tumour Staging:

1. Solitary pancreatic tumour
2. Pancreatic tumour with lymph node metastasis
3. Pancreatic tumour with distant organ metastasis +/- lymph node metastasis.

Question 2

Describe the physiological pathway of insulin secretion including the regulatory mechanisms.

What changes occur to this pathway with insulinoma?

Answer 2

• Glucose is the primary regulator of insulin secretion. ie. increased serum glucose will lead to insulin secretion via exocytosis
• Glucose enters the cell via GLUT transporter
• Glucose is phosphorylated to pyruvate and enters the citric acid cycle generating ATP
• ATP closes ATP-sensitive K+ channel resulting in an increased membrane polarity and subsequent depolarisation
• Membrane depolarisation activates calcium channels and there is an influx of calcium ions
• Calcium plays a role in vesicle docking to the cell membrane and exocytosis of insulin

Insulinoma:

Constitutive production and release of insulin without glucose as a trigger. In normal cells, insulin release is completely inhibited by serum glucose levels below 80 mg/dL (4.4 mmol/L)

Question 3

What are the counter-regulatory hormones secreted in response to hypoglycaemia

Answer 3

1. Glucagon
2. Catecholamines
3. Glucocorticoids
4. Growth hormone

Question 4

Discuss the mechanism of action of the 4 counter-regulatory hormones released in response to hypoglycaemia

Answer 4

1. Glucagon
   
   • Increased gluconeogenesis in the liver
   • Decreased glycolysis and increased glycogenolysis
   • Decreased lipogenesis and increased lipolysis - conversion of fatty acids to acetyl CoA or ketones
2. Catecholamines
   
   • Essentially similar effects on glucose regulation as glucagon
   • effects primarily mediated within the liver
3. Corticosteroids
   
   • Effects are widespread - liver, pancreas, muscle and fat
   • Decreased GLUT2 and glucokinase - reduced insulin uptake and metabolism by beta cells
   • Decreased insulin secretion
   • Liver - Increased gluconeogenesis and lipogenesis and decreased insulin sensitivity
   • Increased insulin sensitivty in adipose tissues with inhibition of lipolysis
4. Growth Hormone
   
   • Direct antagonism of insulin effects
   • Other effects are similar to that of glucagon.
   • Stimulates IGF-1 which stimulates the insulin receptor and provides direct counter-regulation to the effects of GH

Question 5

What clinical signs are most common with insulinoma?

Why are these clinical signs most evident?

Answer 5

• The clinical signs of insulinoma relate directly to the presence of hypoglycaemia
• Neurological signs predoiminante with weakness, ataxia, collapse, seizures, disorientation and dullness
  
  • The brain does not store significant carbohydrates, nor is it able to utilise fuels other than glucose well for energy generation. Thus the brain is most sensitive to the effects of hypoglycaemia
• Counter regulatory mechanisms including increased catecholamines may also result in clinical signs
  
  • nervousness, tremours, hunger, weakness

Question 6

Consider and note the various mechanisms of hypoglycaemia.

Provide examples of each cause for hypoglycaemia

Answer 6

1. Increased insulin or insulin-like factor production
   
   • Insulinoma
   • extra-pancreatic tumour
   • beta-cell hyperplasia
2. Decreased glucose production
   
   • Hepatic insufficiency
   • Hypoadrenocorticism
   • GH deficiency
   • Hypopituitarism
   • Glycogen storage diseases
   • Neonates and toy breeds
3. Excessive glucose consumption
   
   • Sepsis
   • Hunting dogs / extreme exercise
4. Drug related
   
   • sulfonamides, oral hypoglycaemics, insulin, salicylates, acetaminophen, ethanol, monoamine oxidase inhibitors, ACEIs, tetracycline
5. Spurious / testing error
   
   • storage with red blood cells
   • polycythaemia

Question 7

What is the expected prognosis following surgery for insulinoma in dogs?

Answer 7

• Approximately 80% of dogs become euglycaemic immediately following surgery
• Median period of normoglycaemia is ~ 14 months
• Median survival in a recent retrospective study was 2 years / 746 days
• ~ 8 month survival following hypoglycaemia relapse
• Stage is the major predictor of survival

Question 8

Discuss the use of imaging in the diagnosis of insulinoma

Answer 8

• Radiographs are typically normal or unremarkable.
• Abdominal ultrasound has a variable sensitivity and specificity in the detection of insulinoma.
  
  • Old reports suggest a sensitivity of ~ 50-60% with abdominal ultrasound
  • Nodular hyperplasia may be over-interpreted
  • Metastatic disease may or may not be identified
  • US guided fine needle aspiration can be useful at identifying metastatic disease or primary insulinoma
• MRI has been described with good sensitivty but variable appearance of insulinoma
• CT - Triple phase CT is recommended as there is variable hpyo- and hyper-attenuation during the arterial and pancreatic/tissue phases. Sensitivity is very good but correct identification of left or right lobe is not perfect.
• As there is no pathognomonic imaging findings for canine insulinoma, the interpretation must incorporate the clinical and clinicopathological findings.

Question 9

Discuss the acute management of clinical hypoglycaemia secondary to insulinoma

Answer 9

• Clinical hypoglycaemia typically manifests with neurological signs including weakness, collapse, mental dullness and seizure
  
  • The signs are primarily caused by neuroglyopenia
  • The problem is most often slowly progressive and chronic
• An initial dextrose bolus followed by a CRI of 2.5-5% dextrose is typically effective at rapidly resolving the clinical signs
• The dextrose administration should stop with resolution of clinical signs even if mild hypoglycaemia persists
• As neoplastic beta cells continue to response to glucose normally, provision of glucose can lead to increased insulin release and paradoxical hypoglycaemia may ensue
• Glucagon CRI following a glucagon bolus can be effective - single case report in 2000, 20 dogs reported more recently across 2 studies.
• If dextrose fails to resolve signs, then dexamethasone or octreotide may be beneficial. Glucagon is likely indicated prior to octreotide

Question 10

Discuss the definitive and longer term management of dogs with insulinoma

Answer 10

• Surgery is recommended for all dogs with stage I and II disease. Surgery is likely to be beneficial for dogs with stage III disease also, though the prognosis is worse and return to eugylcaemia less likely.
• ~ 10% of dogs will develop diabetes mellitus for a variable period of time following surgery. Insulin therapy is required for a variable period as a result
• Persistent or recurrent hypoglycaemia is most often managed initially with prednisolone starting at a dose of ~ 0.5 mg/kg/day
• Dietary management with small frequent meals and a high protein, moderate fat and high complex carbohydrates (low simple carbohydrates) is recommended
• Other medications of potential benefit or to reduce the prednisolone requirement include:
  
  • diazoxide
  • octreotide

Question 11

Describe the mechanism of action, indications and adverse effects of diazoxide.

Answer 11

• Diazoxide is a benzothiadiazine derivative
• Inhibits closure of beta-cell ATP-dependent K+ channels
  
  • Inhibits cellular depolarisation
  • Inhibits opening of the calcium channel
• Reduced calcium influx reduces the rate of insulin exocytosis
• Diazoxide also increased glycogenolysis and gluconeogenesis within the liver
• Tissue uptake of glucose is inhibited
• Responses are variable with ~70% of dogs responding to doses of 10-40 mg/kg/day
• Adverse effects are uncommon and include vomiting anorexia and ptyalism.

Question 12

Discuss the potential primary causes of diabetes mellitus in dogs

Answer 12

• The underlying cause of beta cell dysfunction in dogs is not fully established and many possible causes have been identified
• Protective and susceptible genotypes have been identified
  
  • Mutations in the MHC II genes - DLA (dog leukocyte antigen) have been identified
• Mutations have been identified in the canine insulin gene
• Most often the histological changes include:
  
  • Reduced beta cell number within islets
  • Reduced pancreatic islet size and number
  • Beta cell enlargement, vacuolisation and degeneration
  • Occasionally lymphocytic infiltates have been reported together with antibodies directed against islet cells, insulin and proinsulin.
• The role of autoimmunity has not been fully established

Question 13

Note the potential causes of secondary diabetes mellitus in dogs.

Include the mechanism of action of each cause in the answer

Answer 13

• The most common cause of secondary pancreatitis is the destruction of normal pancreatic islets by acute or chronic severe pancreatitis
  
  • Pancreatits has been identified in 30-40% of newly diagnosed diabetic dogs
  • Though, this may be more a trigger for DKA, than the initiating event causing pancreatits
• Diestrus elevations in progesterone can contribute to diabetes mellitus
  
  • Diestrus results in elevated progesterone
  • Progesterone stimulates release of GH from the mammary tissue
  • Both Progesterone and GH antagonise the effects of insulin
  • This condition of insulin resistance can lead to overt DM
  • Reversiblity of DM relies on early diagnosis and removal of the source of progesterone (ovohysterectomy)
• Glucocorticoid use can result in transient insulin resistance and diabetes. This is usually transient and resolves with cessation of the exogenous glucocorticoids

Question 14

Describe the pathophysiological effects of insulin deficiency

Answer 14

• Decreased tissue utilisation of glucose, amino acids and fatty acids
• Accelerated glyogenolysis and gluconeogenesis
  
  • End result is hyperglycaemia
• Catabolic state with increased proteolysis and muscle breakdown
• As glucose absorption continues as normal, hyperglycaemia leads to glycosuria as the renal resorption of glucose threshold is reached.
  
  • Osmotic diuresis and water loss
  • Secondary increases in osmolarity and stimulation of thirst receptors in the hypothalamus (mediated by ATII)
• Increased catabolism and decreased energy utilisation triggers hunger resulting in polyphagia
• Leptin levels are decreased in the absence of insulin, releasing hunger inhibition

Question 15

Note the pathophysiological consequences of insulin deficiency

Answer 15

• Cachexia due to catabolism
• Increased hunger as a result of negative energy balance and inadequate utilisation of calories
• Increased lipolysis
  
  • increased free fatty acids undergo metabolism to form acetyl CoA to supply citric acid cycle
  • increased ketones via metabolism of excess acetyl-CoA
• Increased fatty acid synthesis leads to increased hepatic uptake of fatty acids
  
  • Increase synthesis of triglycerides and VLDL
  • Hyperlipidaemia and hepatic lipidosis

Question 16

Discuss the progression from mild transient hyperglycaemia through to diabetic ketoacidosis in newly diabetic dogs.

Include reference to urinalysis results in the answer

Answer 16

• Stress induced hyperglycaemia is rare in dogs
• Mild hyperglycaemia can be caused by DM or concurrent disease that antagonises the effect of insulin
• Mild to moderate and persistent hyperglycaemia is necessary to establish a diagnosis
  
  • Glycosuria must be present to establish the diagnosis
  • Glycosuria in the absence of hyperglycaemia suggests a renal tubular disease
    
    • Fanconi syndrome, primary renal glyucosuria, AKI, nephrotoxin
• With persistent moderate hyperglycaemia and low insulin, ketogenesis occurs and ketosis will be seen. Ketosis will lead to ketouria
  
  • Low to moderate 3-beta hydroxybutyrate suggests diabetic ketosis
  • Moderate to high 3BH together with ketouria and a metabolic acidosis is consistent with DKA

Question 17

Discuss the essential diagnostic tests to establish a diagnosis of diabetes mellitus.

What additional tests may be useful to completely investigate a newly diagnosed diabetic dog?

Answer 17

Diagnosis:

• Hyperglycaemia and glucosuria are necessary to establish a diagnosis
  
  • Other changes on biochemical testing may be seen due to secondary hepatic vacuolar change or with concurrent disease

Additional Tests:

• The need for additional testing largely depends on the clinical presentation of the dog. An otherwise healthy dog with PU/PD or an “incidental” diagnosis on routine testing may not require further tests
• Urine culture is generally recommended at the outset
• Abdominal ultrasound is indicated when DKA is present or with additional systemic signs of illness (vomiting/diarrhoea, abdominal pain)
• cPL may be recommended with suspected pancreatitis
• Special considerations should be given to intact females - assessment for pyometra, ovarian cysts, increased progesterone

Question 18

Discuss the dietary recommendations for dogs with diabetes mellitus

Answer 18

1. Feed two equal sized meals at 12 hour intervals around the time of insulin administration
   
   • timing of insulin administration can be variable and dependent on individual appetites and eating behaviour
2. Meals must be complete and balanced and CONSISTENT
3. Aim for a caloric intake that maintains a near ideal weight
   
   • weight loss diets should be considered for obese dogs to help minimise insulin resistance
4. Majority of calories from complex carbohydrate and protein
5. Minimise fat content of diet to limit increases in cholesterol, free fatty acids, triglycerides and glycerol
   
   • Fat restricted diets are essential if there is a pancreatitis history
6. Some studies suggest high fibre diets help to regulate glycaemic control
7. The diet should also consider concurrent conditions and balanced appropriately - eg. food intolerance/IBD, renal disease

Question 19

Briefly describe the recommended exercise regime for dogs with diabetes mellitus, noting the physiological reasons for benefit.

What should be avoided?

If strenuous exercise is expected, should the insulin dose be adjusted?

Answer 19

• Regular and consistent exercise is to be encouraged.
• Exercise helps with glycaemic control in many ways
  
  • increases glucose utilisation, limiting hyperglycaemia
  • Increases blood flow and thus distribution of insulin
  • Stimulates translocation of the glucose transporter GLUT-4 in muscle cells
• Sporadic and strenuous exercise should be avoided if possible - ie. no walks during the week, and hard work on the weekend
• Owners should consider reducing the insulin dose if strenuous exercise is anticipated. Monitor for signs of hypoglycaemia or PU/PD.

Question 20

List the various insulin types that may be utilised for canine diabetes mellitus.

Identify the duration of effect of each

Answer 20

1. Lente insulin - Porcine - intermediate acting
   
   • Caninsulin: 8-14 hours
2. NPH - recombinant human - intermediate acting
   
   • Humulin
   • Duration of effect: 4-10 hours
3. Protamine Zinc Insulin (PZI) - recombinant human - long acting
   
   • ProZinc
   • Duration of effect: 10-16 hours
4. Glargine / Detemir - recombinant human - long acting
   
   • Duration of effect: 8-16 hours
   • Designed to maintain basal insulin requirements in humans
   • A few small studies have suggested adequate control with a flat or peakless curve

Question 21

Describe the mechanism of action that enables prolonged activity of both insulin glargine and insulin detemir

Answer 21

Glargine:

• Structure: asparagine replaces glycine at A21 and two positively charged arginine molecules are added to C-terminus of the B chain
  
  • Complete solubility at pH 4, low aqueous solubility at neutral pH
• SC injection - neutral milieu - forms insulin analogue microprecipitates - slows absorption
• pH dependent, so cannot be mixed / diluted

Detemir:

• Structure threonine removed from B30 and a 14 carbon fatty acid bound to the B29 lysine
• The added fatty acid chain allows the insulin to bind reversibly to albumin
• Albumin binding slows the absorption and prolongs the metabolic activity of the insulin
• Significantly more potent (~4 x) than other insulin preparations in dogs

Question 22

Discuss the mechanisms by which insulin may be less effective in the presence of concurrent conditions

Note an example of a condition that could contribute to each

Answer 22

1. Alterations in insulin metabolism (pre-receptor)
   
   • Development of insulin auto-antibodies
2. Alterations in insulin receptor binding (receptor)
   
   • Reduced binding affinity
   • Reduced receptor number
     
     • Obesity - in normal animals results in a state of hyperinsulinism and subsequent down-regulation of insulin receptors. However maximal insulin effect is maintained until the insulin receptor number is reduced > 90% from normal
3. Interference with the signalling cascade (post-receptor)
   
   • The same antagonistic conditions that result in reduced receptor number likely also affect insulin signal transduction

Question 23

Discuss the interaction between and inhibitory effects of growth hormone on the effects of insulin

Answer 23

• The interaction between growth hormone and insulin is complex
• GH induces IGF-1 release, which has insulin like activities
  
  • lack of GH causes an insulin resistance type state due to lack of IGF-1 effects
• GH suppresses the expression of GLUT4 transporter on the cell membrane
  
  • via upregulation of a molecule that inhibits translocation
• GH increases lipolysis and free fatty acid production
  
  • FFA inhibit the effect of the insulin receptor
  • FFA promotes hepatic lipid oxidation and production of acetyl-CoA
    
    • Precursor to gluconeogenesis via citric acid cycle
  • Lipid intermediates from triglyceride production (from FFA) impede insulin signalling pathways

Question 24

What is fructosamine?

How do fructosamine levels relate to glycaemic control?

How is fructosamine helpful in monitoring diabetes mellitus in dogs?

Answer 24

• Fructosamines are glycated proteins produced by irreversible, non-enzymatic reactions between glucose and plasma proteins.
• Fructosamines are therefore a marker of the average blood glucose over the lifetime of the particular plasma protein
• The variable binding proteins lead to variable estimates on the time frame reflected by fructosamine
• An estimate of 1-3 weeks is often suggested
• Low fructosamine suggests prolonged periods of hypoglycaemia over the previous 1-3 weeks
• Elevated fructosamine suggests prolonged periods of hyperglycaemia over the previous 1-3 weeks
• Fructosamine can be used in place of blood glucose curves in stressed patients that do not tolerate repeated blood draw.
• I would suggest that glucose sensor information reduces the issues of hospital / needle associated stress and reduces the utility of fructosamine monitoring.

Question 25

List the causes for ineffective control of diabetes mellitus

Answer 25

1. Insulin / technical issues
   
   • Denatured insulin / incorrect handling
   • Draw up / injection technique
2. Insulin underdose
3. insulin overdose and Somogyi response
   
   • Caused by either hypoglycaemia or a rapid drop in blood glucose
4. Short duration of insulin effect
5. Prolonged duration of insulin effect
6. Development of insulin antibodies
   
   • Uncommon with canine/porcine/human insulin
   • Common with beef based insulin
7. Concurrent disorder causing insulin resistance

Question 26

List the common concurrent disorders that contibute to insulin resistance and poor glycaemic control

Answer 26

Any inflammatory, infectious, neoplastic or endocrine disorder could cause insulin resistance

1. Hyperadrenocorticism
   
   • Including iatrogenic HAC due to iatrogenic corticosteroid use
2. Diestrus
3. Hypothyroidism
4. Chronic pancreatitis
5. Chronic kidney disease
6. Infection
   
   • urinary tract / oral
7. Neoplasia
8. Hyperlipidaemia
9. Obesity

Question 27

List the potential mechanisms for development of Type 2 DM in cats

Answer 27

1. Insulin resistance
   
   • Obestiy if the major cause of insulin resistance in cats
   • Insulin sensitivity is to some degree genetically determined
   • Cats with DM are ~ 6 times less sensitive to insulin - increased hepatic glucose production, decreases tissue utilisation of glucose
2. Reduced insulin secretion
   
   • beta cell failure may be related to the chronic inflammatory state of obesity - immune cells can be found in tissue involved in energy homeostasis (liver, pancreas, muscle, fat)
   • Increased expression of IL-1b has been documented
3. Islet amyloid polypeptide (IAPP or Amylin)
   
   • Amylin is secreted with and modulates the effects of insulin
   • Increase amylin secretion in idividuals with insulin resistance
   • Amylin may fold into beta-pleated sheets forming toxic intracellular aggregates and fibrils
     
     • Trigger for inflammation and beta cell death
4. Oxidative damage
   
   • Pancreatic beta cells have limited antioxidant activity and are susceptible to oxidative damage
   • Glucotoxicity and lipotoxicity increase cellular respiration in beta cells leading to increased production of reactive oxygen species
   • Oxidative stress down regulates insulin and amylin and upregultes inflammatory or apoptotic pathways

Question 28

Describe the glucose tolerance test together with interpretation of test results

Answer 28

• In humans, there are well established guidelines for assessment of blood glucose following oral glucose bolus
  
  • The test is indicated when routine BG and urine screening are not consistent with a diagnosis of DM
• In cats, an IV glucose bolus (0.5 mg/kg or 1.0 mg/kg) is administered with monitoring of the blood glucose at 2 and 3 hours post administration depending on the size of the glucose bolus
• Normal cats should have a BG < 9.8 mmol/L at 2 hours
• Normal cats should have a BG < 6.5 mmol/L at 3 hours

Elevated results can suggest pre-diabetes.

Question 29

Define the difference between DK and DKA.

At what point do DK and DKA become evident after the onset of overt diabetes mellitus in cats

Answer 29

• DK is the presence of increased blood ketones - b-hydroxybutyrate with normal blood pH. Ketouria may or may not be present.
• DKA is the progression from a state of DK to metabolic acidosis. This is most often triggered by a concurrent disease process
• Ketosis will generally develop within 10-30 days of a cat becoming insulinopenic (diabetic)
  
  • Ketosis will not develop unless the BG is > 17 mmol/L
• Ketouria developed after a meas of 23 days of persistent marked hyperglycaemia in one study with wide variation

Question 30

Diabetic remission is the hope when initiating treatment of a new diabetic cat.

What factors have been associated with an increased chance of achieving diabetic remission?

Answer 30

1. Use of a low carbohydrate diet
2. Use of long acting insulin - glargine or detemir
3. Tight glycaemic control within first 6 months of tx
4. Older cat (likely slower progression to over disease)
5. Recent corticosteroid tx (likely unmaksing pre-diabetic condition
6. Absence of neuropathy
7. Lower mean blood glucose (milder disease)
8. Lower cholesterol

Question 31

Discuss the dietary risk factors for the development of diabetes mellitus in cats.

Answer 31

• Obesity is the single largest risk factor for the development of diabetes in cats
  
  • Cats fed high fat diets (eg. wet food) had a 3 times greater risk of diabetes
  • Cats fed a high carbohydrate diet (>50% ME from carb) had a 2 times greater risk of diabetes
• High carbohydrate diets carry the risk of significant post-prandial hyperglycaemia
  
  • Significant increase with 47% carbohydrate food versus high protein (46% protein, 27% carbohydrate
• Insulin levels follow the post-prandial hyperglycaemia
  
  • Regularly elevated glucose and insulin can lead to obesity, insulin resistance, and decreased beta cell function
• The magnitude and duration of post-prandial hyperglycaemia is exacerbated by weight gain - ie. obesity contributes to insulin resistance and persistent hyperglycaemia
  *

Question 32

Discuss the recommendations for maintenance of cats at risk of diabetes or in a pre-DM state

Answer 32

• In a young, healthy and lean adult cat, a moderate carbohydrate diet is likely to be safe and well tolerated. Excessive intake leading to obesity should obviously be avoided
• High carbohydrate diets (>50%) are unlikely to contain sufficient protein and are not recommended
• For cats with an increased risk of diabetes, carbohydrate content should be < 12%
• Older cats or cats with conditions that could predispose to diabetes (breed, corticosteroid use, obesity) would also benefit for low carbohydrate diets

Question 33

Discuss the dietary recommendations for cats with diabetes mellitus with reference to the aim of achieving diabetic remission

Answer 33

• The highest remission rates (~80%) have been achieved in cats fed a fiet where < 6% of metabolizable energy was derived from carbohydrates.
• Remission rates between cats fed a 12% CHO (low fibre) food and 26% CHO (moderate fibre) food were 68% and 41% respectively - Bennet et al 2006
• Systematic review in 2014 suggested CHO restriction was beneficial but no single factor was identified that predicted diabetic remission

Question 34

List the basic mechanisms of action of oral hypoglycemic medications

Answer 34

1. Reduce or slow glucose absorption from the intestine
2. Increase insulin secretion
3. Increase insulin sensitivity

Question 35

List the classes of oral hypoglycemic drugs the have been assessed in cats.

Give an example of each

Answer 35

1. Sulfonylureas
   
   • Glipizide
     
     • Binds to ATP dependent potassium channel - closure of which triggers depolarisation and calcium influx - insulin release
2. Meglitinides
   
   • Nateglinide
     
     • Similar action to the sulfonylureas but bind to different sites on the ATPase
3. Biguanides
   
   • Metformin
     
     • Insulin sensitizer, mechanism of action not fully known
4. Thiazolidinedione
   
   • Darglitazone
     
     • Binds in the nucleus and improves insulin sensitivity in muscle, adipose and liver. Reduces gluconeogenesis
5. Alpha-glucosidase inhibitors
   
   • Acarbose
     
     • Inhibits membrane bound brush border enzymes in the SI
     • Useful when administered with a high carbohydrate food, but this combination was not as good as a low carbohydrate food alone.

Question 36

What are incretins?

Answer 36

• Incretins are hormones produced within the gastrointestinal tract that are rapidly release in response to food intake.
  
  • Glucagon-like peptide
  • Gastric inhibitory peptide
• They have numerous effects that synergise to stimulate insulin release, reduce hyperglycaemia and limit glucose intake

Question 37

What are three potential therapeutic options to optimise incretin activity

Answer 37

• Primary incretin therapy - often utilised in an extended release form due to rapid degradation by dipeptidylpeptidases (DPP-4)
• GLP-1 agonist drugs - resistant to DPP-4 degradation
• DPP-2 inhibitors - extend the activity of naturally occuring GLP-1

Question 38

Discuss the evidence for the use of extended release exenatide in cats with newly diagnosed diabetes mellitus

Answer 38

• The drug can be administered as a long-acting once weekly or new once monthly SC injection
  
  • Previous short acting versions were twice daily
• The drug is a GLP-1 receptor agonist
• Shown to reduce weight gain after commencing diabetes treatment with insulin
• Reduced the dose of insulin required for adequate glycemic control
• Generally well tolerated, though vomiting and decreased appetite was reported
  
  • Both would be expected given the mechanism of action - increases nausea and satiety
• A placebo controlled study in 2016 revealed a tendency for increased weight loss in obese cats, but insulin requirement unchanged.