Insulin

Question 1

Insulin major functions and major sites of action

Answer 1

Enhance entry of glucose into cells - usually GLUT 1

Liver - enhance glycogen synthesis, protein and fatty acid synthesis. Entry via LGUT1.
Inhibition of hepatic glucose output (glycolysis and gluconeogenesis) is a main factor in maintaining euglycaemia

Sk. Muscle - enhances glucose uptake and glycogen synthesis

Adipose - enhances glucose uptake and FA synthesis

Question 2

Insulin release

Answer 2

Glucose enters B-cells via GLUT-2 receptors and is metabolised to produce ATP
The increase in the ATP/adenosine diphosphate (ADP) ratio is followed by the closure of ATP-sensitive potassium channels in the β-cell membrane, preventing potassium ions from leaving the β-cell.
This in turn causes membrane depolarization and opening of voltage-dependent calcium channels in the membrane.
The increase in cytosolic calcium then triggers insulin release

Question 3

Couter-regulatory hormones in glucose homeostasis and their function

Answer 3

Glucagon is the key counterregulatory hormone affecting recovery from acute hypoglycemia. In response to falling plasma glucose levels, glucagon is secreted by the alpha cells of the pancreatic islets into the hepatic portal circulation; it acts exclusively on the liver to activate glycogenolysis and gluconeogenesis

SNS - The adrenergic-catecholamine response to hypoglycemia plays a major role in recovery from hypoglycemia:
Epinephrine - direct and indirect effects: stimulate hepatic glycogenolysis; hepatic and renal gluconeogenesis; mobilising muscle glycogen and stimulating lipolysis (an alternative source of fuel); mobilise gluconeogenic precursors (e.g., lactate, alanine, and glycerol); and inhibit glucose utilisation by insulin-sensitive tissues

ACTH, Cortisol and GH have minimal role in the acute response to hypoglycaemia but have roles in prevention of prolonged hypoglycaemia
Cortisol facilitates lipolysis, promotes protein catabolism and the conversion of amino acids to glucose by the liver and kidney, and limits glucose utilisation by insulin-dependent tissues.
GH promotes lipolysis and antagonises the action of insulin on glucose utilisation in muscle cells

Question 4

What are incretins and what is their function

Answer 4

glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (previously called gastric inhibitory polypeptide (GIP))

GLP - enhances insulin release, suppresses glucagon release, slows gastric emptying and anorexigenic.

GIP - induces insulin secretion, protective to B-islet cells.

The reason why Oral glucose induces a more pronounced insulin secretion than glucose given intravenously.

Question 5

What is basal and bolus insulin

Answer 5

Endogenous insulin secretion can be divided into two phases: the “basal” phase, in which insulin is secreted continuously at a relatively constant rate, and the “bolus” phase, in which insulin is secreted in response to nutrients digested and absorbed from the gut.
In health, insulin secretion is constantly adjusted in response to various signals to maintain euglycaemia.

The primary role of “basal” insulin secretion is to limit lipolysis and hepatic glucose production in the fasting state. Although “basal” insulin secretion is relatively constant throughout the day, it changes over time in response to changes in insulin sensitivity; it increases when insulin resistance develops (e.g. with obesity or other diseases) and decreases when insulin sensitivity increases (e.g. with exercise)

“Bolus” insulin primarily suppresses hepatic glucose output and stimulates glucose utilisation by muscle and adipose tissue during the postprandial period, thus curbing hyperglycaemia after meals

Question 6

Difference in cat and dog bolus insulin response

Answer 6

Dog: peaks within 30 minutes at five to seven times the baseline concentration, it can remain increased for 6 to 9 hours in dogs depending on the diet

Cat: bolus” insulin secretion typically has a longer duration (6 to >12 hours) and a later and much lower peak (peaking at 1 to 8 hours and reaching 1.5 to 3 times baseline concentrations) depending on the diet fed. However, when the daily caloric intake was divided into four meals, the increase in plasma insulin was minimal and sustained throughout the 24-hour period (Camara et al. 2020). This sustained insulin requirement with no clear “bolus” phase is likely more representative of insulin requirements of cats in the clinical setting

Question 7

unique energy requirements of neurons

Answer 7

Brain cells are unique in that they do not require insulin for glucose uptake, but unlike most tissues, the brain cannot use fatty acids for energy. Instead, ketone bodies can provide the brain with two thirds of its energy needs in periods of fasting or starvation

Question 8

Pathogenesis of DKA

Answer 8

Insulinopenia (absolute or relative due to resistance) → cells use FFAs as energy substrate
Enhanced ketone body synthesis:
1) increased mobilisation of FFAs due to lipolysis (normally inhibited by insulin suppression of HSL)
2) Hepatic metabolism shifts from fat synthesis to oxidation and ketogenesis due to Increase in counterregulatory hormones - ratio of glucagon to insulin.
Increasing glucagon due to cellular demand for glucose → increased lipolysis and increased amino acid extraction → hyperglycaemia (in absence or resistance to insulin this is a vicious cycle)
Promotion of ketogenesis: shifts hepatocytes from TG to FFA production (normally inhibited by insulin)
→ FFA enter mitochondria (using carnitine carrier protein)
→ CCA is overwhelmed/not enough substrate → instead FFAs undergo B-oxidation → increasing acetoacetate and BOHB

Other than glucagon cortisol and Adr can stimulate HSL and protein catabolism further exacerbating hyperglycaemia.

Question 9

Systemic effects of DKA

Answer 9

Renal: increasing glucose and ketones surpass renal threshold for reabsorption → osmotic diuresis → dehydration (ketones have greater osmotic load) → reduced ECV, CV compromise
→ reduced renal perfusion and decline in GFR → reduced glucose/ketone excretion and accelerated accumulation
→ hyperviscosity → thrombosis
→ increased SNS and RAAS → K loss, further gluconeogenesis

Electrolytes: keto anion loss in urine necessitates Na, K, NH3, Mg and Ca loss
→ Hyponatraemia exacerbated by free water shift from osmotic effects of hyperglycaemia (movement from intercellular compartment)
→ Insulin deficiency also exacerbates Na and water loss (normal promotes retention)
→ Extracellular displacement of intracellular K and increased loss → severe intracellular deficiency
→ Intracellular shift of PO4 with correction of acidosis → unmasking of loss → haemolysis if severe.
→ Mg loss in urine and intracellular shift with acidosis resolving → lethargy, muscle weakness, seizures, fasiculations, ataxia, Further K wasting

Acid Base: ketones overwhelm buffering → increased H+ (high AG acidosis)
→ causes vomiting, diarrhoea and exacerbates dehydration

Question 10

Osmolality Calculation

Answer 10

2(Na + K) + (BG mmol/L) + (BUN mmol/L)

> 320 is hyperosmolar

Question 11

Corrected Na calculation

Answer 11

Corrected Na =
measured + 1.6(serumBG - normalBG) /5.55

Question 12

Can interstitial BGM be used in DKA

Answer 12

May be less accurate than veterinary validated glucose meters, but can detect hypoBG events that may be missed with intermittent sampling.
Working range is not a practical limitation in clinical setting - as treatment decisions depend on if <2.2 or >22.2
In sick hospitalised animals Tx decisions should be corroborated with BG, using the interstitial monitor to identify trends in BG
Check any unexpected trends against a BG.

Question 13

Goals of DKA Tx

Answer 13

restore volume, correct dehydration
Correct electrolytes (K, Na, PO4, Mg)
Correct acid base
Decrease BG
Reduce ketones
Treat underlying condition

Question 14

Core DKA Tx

Answer 14

IVFT - LRS/Plasmalyte unless severe hypoNa <130 (then 0.9% NaCl)
→ monitor fluid resus based on CV parameters
→ supplement K+, Mg (if needed), PO4 (cannot be in Ca containing fluids)
→ ideally place central line
Monitor UOP - assess ongoing loss and titrate fluids
→ if <1-2ml/kg/hr then AKI present (oliguric or anuric)

K+ → take care not concurrent AKI causing hyperkalaemia
Monitor ECG and K+ every 4-8hr
→ 10-20mml/L if >3.5; 30-40 if 2.5-3.5; 60-80 if 2 or <2
PO4 → use KPO4 if <1.5mg/dL (cant add to LRS)
→ monitor 8-12hr, decrease if Ca lowered (hypocalcaemia can be caused by overdose)
Mg → low levels can cause refractory hypokalaemia.

Insulin - Inhibits ketone production, inhibits lipolysis, enhances ketone utilisation
Use regular insulin (though any insulin given IV has similar effects as regular insulin) - rapid onset of action and brief duration of effect
→ utilise CRI (can use IM) with adjustment of rate +/- concurrent dextrose
→ Half rate of insulin and add 2.5% dextrose when BG normalises

Question 15

ECG changes in DKA/HypoK

Answer 15

hypokalaemia causes gradual shift of repol away from systole → decrease T amplitude, prolonged QT, repolarisation (U) wave after T.

Question 16

General K+ supp guidelines in DKA

Answer 16

Maintenance fluids should be supplemented with 30 to 40 mEq/L (30–40 mmol/L) of potassium (KCl or a 50:50 combination of KCl and KPO4) from the outset

Question 17

Difference in HHS pathogenesis to DKA

Answer 17

Sufficient insulin to inhibit lipolysis → less FFAs and glycerol → no ketosis. Otherwise the underlying mechanism is similar to DKA.
Enough insulin to inhibit lipolysis and B-oxidation but still get severe hyperglycaemia from gluconeogenesis and ongoing reduced glucose utilisation

Increased osmolality of extracellular fluid → cellular dehydration (shift of fluid out of cells into intravascular/interstitial space)
→ hypernatremic dehydration (free water loss exceeds Na loss)
→ decreasing blood volume → reduced renal blood flow → reduced glucosuria → worsening hyperglycaemia
Present with neurological or respiratory signs more commonly
Often more hyperglycemic, less acidotic and more dehydrated. With lower counterregulatory hormones compared to DKA.
Absence of ketoacidosis means that vomiting and nausea are often not features of clinical picture

Question 18

Common [predisposing causes and HHS managment

Answer 18

Dogs: pancreatitis, UTI, HAC, neoplasia, pneumonia, pyelonephritis, CKD

Cats: CKD, CHF

Prognosis is poorer for animals with renal dysfunction causing symptoms.

Due to severe hyperglycemia the risk of cerebral oedema is higher in these patients and rate of BG decline needs to be monitored

IVFT and Insulin
→ correction needs to be at a rate that does not cause neuronal oedema
Use 0.9% NaCl with KCl supplementation → improve GFR, correct dehydration, stabilise BP, decrease glucose.
→ replace half of calculated deficit in 12h then the remainder over next 24h
→ insulin may be delayed a little longer in HHS to avoid sudden drop in BG that could result in cerebral oedema. And commence with a 50% dose reduction compared to DKA

Question 19

Reported longer term complications for diabetes in dogs and proposed pathogenesis

Answer 19

Long term complications: all relate to overproduction of superoxide by the mitochondrial electron transport chain
Increased intracellular advanced glycation end products
Aldose reductase pathway → sorbitol
Activation of protein kinase C
Increased shunting of glucose into hexosamine pathway
Hypoglycemia: due to overdosage, increased sensitivity, excessive overlap
Ocular - cataracts (intracellular sorbitol accumulation)
→ lens induced uveitis
Corneal ulceration (reduced sensitivity)
Retinopathy - retinal haemorrhage and microaneurysms
Neuropathy - segmental demyelination, remyelination and axonal degeneration (uncommon in dogs unless prolonged diabetes)
Nephropathy - membranous glomerulonephropathy → microalbuminuria and eventual increase in UPCR. thickening of the glomerular and tubular basement membrane and increase in mesangial matrix, glomerular fibrosis and glomerulsclerosis.
→ progressive proteinuria and GFR reduction (often not life limiting in dogs as takes a long time to progress)
→ can prolong duration of insulin effect and cause insulin resistance, creates unpredictable fluctuations in glycemic control
Microvascular disease - progressive narrowing and occlusion of vascular lumina → hypertension and inadequate perfusion
→ hypertension prevalence of 46% (development associated with duration of DM and presence of proteinuria)
Gastroparesis - loss of NO synthase in neurons (smooth muscle relaxant) → reduced motility.

Question 20

evidence for interstitial BGM in dogs

Answer 20

• JVIM 2020: prospective study compared to portable Vet BGM → better detection of hypoBG
• JVIM 2021 identified 3 dogs with nocturnal hypoBG indicating individual circadian variability
• JVIM 2021: rapidly induced hypoBG and hyperBG assessed with blood and FGM → failed to detect hypoglycaemia (but not a typical clinical scenario for what would be occurring)
• demonstrated to be effective at monitoring BG in DKA - but corroborate decision making BG with blood sample

Question 21

Proposed aetiopathogenesis factors for DM in dogs

Answer 21

permanent hypoinsulinemia (type I) due to loss of beta cell function. Pancreatic tissue shows reduced number and size of B islets with beta cell degeneration, vacuolation and enlargement.
Underlying cause of Beta cell loss not been identified, multifactorial with genetic and immune mediated destruction theorised.

Risk factors include: genetics, pancreatitis, concurrent hormonal disease (HAC, dioestrus, hypoTH), glucocorticoids, Progestagens, CKD, hyperlipidemia
→ immune mediated insulitis has been described and Ab against various targets identified in diabetic dogs → unclear as yet if this precedes development of hyperglycemia like it does in humans

Breeds: Aust Terrier, Elkhound, Samoyed

Question 22

Insulin options for canine DM

Answer 22

Insulin (Jsap 2021 review) - ideally would mimic basal and bolus release of insulin seen in health, but often not practical.
- Basal: need to have low within day variation, degludec and glargine U300
Degludec can have duration of ~24h.
U300 seems to offer more stable diabetic control, less day-to-day variation. Seems to control 50% with SID but did require higher doses - can increase dose daily if nadir >20.
→ switch to BID if poor control for roughly half of day
→ alternatively change diet (lower carb, reduced frequency) or ad meal time bolus insulin (NPH) if post-prandial peak
JVIM 2021 comparison study showed similar variability of degludec and U300. Lente intra-day variability was lower because of less pronounced postprandial peak.

Intermediate such as PZI or NPH, peak 3-6h post injection which may be later than meal BG peak creating incongruency b/w required and delivered insulin. Substantial day to day variability increasing risk of hypoglycemia.
Lack of side by side comparison trials of intermediate to long acting basal insulins are rare.
- One comparing Lent to degludec and Toujeo - found no difference in mean daily BG or hypoglycemia frequency
- JVIM 2021: degludec and U300 had lower day to day variability than lente (hypoglycaemia was not different). Prospective purpose bred experimental study.
- JAVMA 2023: determir improved glycaemic control in 7 dogs compared to intermediate insulin use (dogs had failed treatment with those). Retrospective.

Question 23

Recommended diet for dogs with DM

Answer 23

weight loss if obesity present, optimise body weight
Insoluble fibre, low in fat and low caloric density
Ideally provide calories as complex carbohydrates→ low glycemic index
Fibre forms a viscous gel that impairs convective transfer of glucose and water to the absorptive surface.
Avoid high fat diet as this worsens hyperlipidemia and can cause insulin resistance

Question 24

ALIVE criteria for DM Tx goals and physiologic mechanisms by which they are achieved

Answer 24

1. Good quality of life of pet and owner.
2. Resolution of the classic clinical signs of diabetes mellitus.
3. Avoidance of hypoglycaemia and ketoacidosis.
4. Normalisation of body conditions score.

The physiological mechanisms through which these aims are achieved include:
1. Decreasing hepatic glucose output.
2. Improving insulin sensitivity.
3. Ensuring appropriate insulin availability.
4. Reducing postprandial hyperglycaemia.
5. Attending underlying causes or comorbidities.

Question 25

ALIVE consensus on measures of DM success

Answer 25

1. Systematic and standardised assessment of classic clinical signsof diabetes mellitus ideally incorporating a scoring system.
2. Assessment of glycaemic parameters in blood, interstitium, and/or urine.
3. There is no prospective high level evidence that setting a specificglycaemic goal is correlated with a specific treatment outcome,including remission.
4. Glycaemic parameters within the reference interval of non-diabetic animals commonly indicates diabetic remission or insulin overdosing and therefore implies possibility of episodes of hypoglycaemia in a treated diabetic patient.

Question 26

Evidence for insulin pens over syringe

Answer 26

JSAP review: Multiple studies have found various advantages to using insulin dosing pens over the traditional combination of multi-dose vial and syringe-needle, including increased patient adherence

injection pens are consistently shown to have better dosing accuracy and precision compared to insulin syringes

The relative imprecision of vial-syringe method can be critical in contributing to increased day-to-day variability which subsequently makes monitoring more complicated and more expensive

Priming of the needle (“air shot”) with 1 to 3 U is recommended before every injection. This might also make the use of a pen less economical. After priming once when starting a new pen to verify that the pen works, one of the authors who is based in the USA (CG) does not recommend routine priming of pens.

Most pens are lim-ited to delivery of 1 U increments with no 0.5 U option. While this might seem like a disadvantage, compared to the traditional vial-syringe approach, one needs to take into account the very low precision and accuracy of insulin syringes for administration of 0.5 U dose increments

Question 27

Different insulin types, pros and cons

Answer 27

Short acting (lispro, aspart) - mimic normal insulin if given sc. Duration is 5-9 h.

Suspensions (lente = caninsulin; NPH and PZI) - intermediate acting, the Zn and/or protamine form precipitates with the insulin that slowly dissociate resulting in slower b/d of insulin and slower absorption.
Lente - peak 3-6h and 11h. Mix of 35% semi and 65%ultra-lente
Deprecipitation can be variable, (need to resuspend before use)
Time action profiles may not be congruent with biological needs –> more incongruence and higher intra day variability

Insulin solutions/recombinant analogues= long acting insulins. Amino acid substitutions to alter tendency to crystalise or form hexamers dependent on pH.
The higher concentration (U300) formulations reduce the droplet size further slowing absorption.
- do not need resuspending
- less erratic absorption
- determir requires lower dose in dogs (not cats)

Question 28

Mechanism of new novel insulin-Ab

Answer 28

The resulting insulin-Fc fusion protein is a ligand to the insulin receptor but also binds to the host neonatal Fc receptor (FcRn). In contrast to other sc formulations, the prolonged duration of action of insulin-Fc does not rely on slowing absorption of insulin from the sc tissue but rather on intracellular circulation

The FcRn is ubiquitously expressed-in epithelia, endothelia, cells of haematopoietic origin and other cells. Upon binding to the FcRn, insulin-Fcis pinocytosed and eventually exocytosed. While inside the cell,insulin-Fc is protected from proteolysis like other ligands of theFcRn (Pyzik et al. 2019). This intracellular recycling extends the half-life of the insulin-Fc to 5 to 7 days, allowing for once weekly administration and minimal intra-day variability, making-it an ideal “basal” insulin. Preliminary data suggest that insu-lin-Fc is a promising formulation in both cats and dogs

Question 29

Evidence for Flash glucose monitoring in cats (4)

Answer 29

JVIM 2021 - good agreement b/w IG and BG, r=0.93
Analytical accuracy not achieved but clinical accuracy was good. IG increased slowly after IV glucose compared to BG levels.
JVIM 2023 - using clamps, strong correlation of IG and Alphatrak 2 in stable glycemia and moderately at all rates of change. Underestimates BG through most of range but overestimates BG when marked hypoglycemia.
JVIM 2021 - use in 15 client owned cats. Excellent correlation with BG. Median sensor duration 7 days
JFMS 2022 - 41 client owned DM cats. Good correlation (r=0.88)
Overall good correlation for at home monitoring compared to BG. May underestimate severity of some hypoglycemic events - correlate with CS and overall picture. Clinical decision making is sufficient.

Question 30

Oral Hypoglycemics and MOA (5)

Answer 30

Bexagliflozin (Bexacat) - proximal renal tubule Na/glucose transporter inhibitor. Inhibits glucose reabsorption by the kidney
2022- proof of concept study, 5 cats with poorly controlled DM. 3 persistent clinical signs, 2 resolution. Reduced insulin doses. 1 cat achieved long term remission with Bex.
JVIM 2023 Manufacturer pilot study - 84 cats (historical controls) initial trial then 6 month follow up. NON BLINDED, NO CONTROL
Reduced CS and BG/fructosamine of newly diagnosed DM cats, no hypoglycemia. 84% considered successfully treated
Durable effect on mean BG over duration of study - Effectiveness was based on the change from baseline in serum fructosamine concentration,mean BGC results over 8 hours, change in body weight, and owner assessments of clinical signs (not the best measures)
3 developed euglycemic DKA, 5 removed from study due to serious adverse effects
Vomiting and diarrhoea were common adverse effects
Can induce ketosis in healthy cats with concurrent dehydration
AEs: vomiting, elevated BUN and USG, dehydration, diarrhoea, hyporexia/anorexia. Multiple serious AEs in extended safety study - can develop euglycemic DKA

Exanetide - GLP1 analogue (insulin secretion, B cell proliferation and survival, glucagon suppression), increases insulin secretion and sensitisation
2 placebo controlled studies found no significant effect on glycemic control but did promote weight loss and reduced insulin requirement.
JVIM 2021 - extended release formulation, placebo controlled trial.
Reduced glucose variability in Tx group,

Glipizide - sulfonylurea that stimulates insulin release from B cells (ie must have residual B cell function for them to work). Useful in mild or pre-clinical DM in cats. Often loses efficacy with prolonged use.
Can cause hypoglycemia.

Meglinides - insulin secretagogues, used to counteract post-prandial hyperglycemia. Short lived duration of effect. Again need functioning B cells.

Acarbose - reduce brush border enzyme degradation of carbohydrates → slowing absorption → useful if concurrent CKD limits use of high protein diet (not as useful if already on low carb diet)

Question 31

REcommended Diet for Diabetic cat

Answer 31

Diet: Carbohydrates <12% ME; AAHA Guidelines
Higher protein (40-50% of ME) normalises fat metabolism; arginine stimulates insulin secretion. Adequate protein also prevents loss of lean body mass
Canned diets - lower carb, more water = lower caloric density
2006 Study comparing low-carb, low fibre diet to moderate carb high fibre diet found that conversion to non-insulin dependence was significantly higher in the LC-LF group (68 to 41%) as well as better control in those cats not in remission
Weight loss: aim for 1% per week, reduce caloric intake by 10-15% weekly if not improving

Question 32

Insulin recommendations in cats (JSAP 2021)

Answer 32

U300 glargine is close to meeting the standard required for a basal insulin with relatively constant activity throughout the day. Due to residual B cell function use of a basal insulin may be enough to normalise BG (if residual function is enough to make up the bolus) - especially in cats with peakless postprandial insulin requirement.
Emerging evidence U300 is superior to U100 glargine for in maintaining glycemic control and reducing risk of hypoglycemia (as in ppl). Though duration of action often not long enough for once daily admin.
Not necessary to match injection times with feeding (though those with no B cell function may be prone to more intra-day variability)
Once daily injection of U300, PI or detemir may be effective in cats with residual B cell function
JFMS 2019 - U300 longer duration and flatter time action profile than any other insulin. In healthy cats
JFMS 2021 - safe and effective in diabetic cats
Lente and NPH insulins have shorter duration of action in cats compared to determir, degludec and glargine U100
Both determir and degludec had glucose clamp profiles more consistent with intermediate acting insulin.
JFMS 2022 - 13 cats with U300 prospective clinical trial.
4 cats achieved remission, 12.5% occurrence of hypoglycemia with no clinical signs. Still need larger long term studies
L Fleeman reports can adjust U300 insulin more daily provided nadir is >20mmol/L, then if <19 monitor for 3-5 days

Question 33

Pathogenesis of feline DM

Answer 33

Type 2 disease characterised by combination of B cell failure and increased insulin resistance. Cannot develop diabetes with insulin resistance alone, there has to be concurrent B cell dysfunction (as otherwise would compensate)
Causes of B cell damage:
→ currently thought that primary defect is genetic predisposition (polygenetic) and env/diet/health factors amplify the genetic damage
→ Islet amyloid polypeptide cosecreted with insulin to modulate its action and elevated in insulin resistance. Amyloid deposits in B cells have been demonstrated in both DM and healthy cats → misfolding may result in aggregates that are cytotoxic
→ Oxidative stress:seen with glucotoxicity or lipotoxicity, B cell capacity to cope is low.
→ Pancreatitis: prevalence is not well defined, previously reported as 20-50%, more recently lower levels possibly more severe acute pancreatitis is more common
Glucotoxicity - role in the progression of B cell dysfunction with chronic hyperglycaemia → progressive B cell dysfunction (perpetuating cycle)
May be reversible with prompt treatment
Obesity (avg 33%): visceral adipose tissue secretion of adiponectin decreases (anti-inflammatory and insulin sensitising hormone)
→ increased NEFA → accumulation of intermediates in liver interfering with insulin signalling
(30% decline for each kg increase in BW)
→ reduced expression of GLUT4 which is insulin sensitive expression and affects glucose uptake by muscle, liver and adipose (unlike GLUT1 whose expression is not insulin sensitive and remains unchanged)
→ nutrient excess and calorie overconsumption may contribute to B cell damage (glucotoxicity
→ reversible effects if weight loss is instigated
→ reduced responsiveness to GLP1 (incretin released with meal) → ?less suppression of glucagon

• No evidence that it is immune mediated (Ab have not been demonstrated and no lymphocytic infiltration)

Question 34

Different long acting insulins

Answer 34

Degludec - changes to structure allow multi-hexamers to form in tissues → peakless time action profile

Determir - insulin molecules have strong hydrophobic interactions b/w fatty acids.
Considered lower potency in people.
Also binds albumin buffering its concentration in the blood and likely achieves higher concentrations in liver than other insulins (not proven to occur in dogs/cats) more intermediate acting used at similar doses to glargine.

Glargine (lantus) - protein modified to precipitate at neutral pH (injected at pH 4)
→ slow absorption
Not ‘long acting in dogs due to pronounced peak at 7-9h
(increasing dose will prolong duration of effect but also increase peak)
Published evidence of efficacy not as good as other insulins.
Used as intermediate acting insulin

Toujeo is 3x the concentration of Glargine - smaller droplet size of deliver = even slower absorption
Meets the requirements of a basal insulin as its action is roughly the same throughout the day
Preferred in cats - meets the requirement of basal insulin with low day-today variation

In dogs - Intra-day variability higher than with lente due to postprandial hyperglycemia