Insulin Flashcards
Insulin major functions and major sites of action
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
Insulin release
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
Couter-regulatory hormones in glucose homeostasis and their function
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
What are incretins and what is their function
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.
What is basal and bolus insulin
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
Difference in cat and dog bolus insulin response
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
unique energy requirements of neurons
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
Pathogenesis of DKA
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.
Systemic effects of DKA
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
Osmolality Calculation
2(Na + K) + (BG mmol/L) + (BUN mmol/L)
> 320 is hyperosmolar
Corrected Na calculation
Corrected Na =
measured + 1.6(serumBG - normalBG) /5.55
Can interstitial BGM be used in DKA
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.
Goals of DKA Tx
restore volume, correct dehydration
Correct electrolytes (K, Na, PO4, Mg)
Correct acid base
Decrease BG
Reduce ketones
Treat underlying condition
Core DKA Tx
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
ECG changes in DKA/HypoK
hypokalaemia causes gradual shift of repol away from systole → decrease T amplitude, prolonged QT, repolarisation (U) wave after T.
General K+ supp guidelines in DKA
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
Difference in HHS pathogenesis to DKA
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
Common [predisposing causes and HHS managment
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
Reported longer term complications for diabetes in dogs and proposed pathogenesis
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.
evidence for interstitial BGM in dogs
- 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
Proposed aetiopathogenesis factors for DM in dogs
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
Insulin options for canine DM
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.
Recommended diet for dogs with DM
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
ALIVE criteria for DM Tx goals and physiologic mechanisms by which they are achieved
- Good quality of life of pet and owner.
- Resolution of the classic clinical signs of diabetes mellitus.
- Avoidance of hypoglycaemia and ketoacidosis.
- 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.
