Diabetes mellitus

Disease in which body doesn’t produce enough or properly

use insulin, leading to hyperglycaemia/altered glucose
metabolism!

Dr Kaustubh Garud
Scientist, Animal Sciences
Department of Veterinary Nuclear Medicine
Bombay Veterinary college
Actions of insulin on metabolism = ‘Anabolism’
• Carbohydrate metabolism
• Facilitates the transport of glucose into muscle and adipose cells
• Facilitates the conversion of glucose to glycogen for storage in the liver and
muscle.
• Decreases the breakdown and release of glucose from glycogen by the liver
• Protein metabolism
• Stimulates protein synthesis
• Inhibits protein breakdown; diminishes gluconeogenesis
• Fat metabolism
• Stimulates lipogenesis- the transport of triglycerides to adipose tissue
• Inhibits lipolysis – prevents excessive production of ketones or ketoacidosis
Deficiency of insulin..
• Hyperglycemia develops by,
• Increased gluconeogenesis
• Accelarated glycogenolysis
• Impaired glucose use by tissues
• Despite elevated glucose concentration(+ insulinopenia)  cells become
“starved” of energy
• Unavailability of glucose as substrate  cells use “free fatty acids” as
energy source
• In health, insulin inhibits “hormone sensitive lipase”  inhibit lipolysis!
• In disease: triglycerides  (lipolysis)  free fatty acids in circulation
• FFA  taken up by liver  triglycerides + ketones!!!!
 Type 1 Diabetes Mellitus

• Combination of genetic
susceptibility & immunologic
destruction of beta cells
• Progressive & eventual complete
deficiency of insulin
• Dependent on exogenous insulin
for life
 Type 2 Diabetes Mellitus
• Insulin levels may be normal,
elevated or depressed
• Characterised by,
• Insulin resistance
• Diminished tissue sensitivity to insulin
• Dysfunctional beta cells
• Control of diabetic state possible
through diet, exercise, oral
hypoglycemic drugs
• Insulin Rx necessary for patients
with severe beta cell dysfunction
IDDM Vs NIDDM
• Based on need of insulin treatment
• Cats – sometimes appear to be NIDDM, but progress to IDDM or flip
back & forth between NIDDM & IDDM
• IDDM – most common clinically recognised form of DM in dogs and
cats
• IDDM – permanent hypoinsulinemia & absolute necessity of
exogeneous insulin to maintain euglycemia
• NIDDM – often encountered in cats than dogs
• Transient DM – approx. 20% of diabetic cats  reversible suppression
of insulin secretion as a result of carbohydrate intolerance
Potential etio-pathogenetic factors
Dogs Cats
• Genetics • Islet amyloidosis
• Immune mediated • Obesity
• Pancreatitis • Pancreatitis
• Obesity • Concurrent hormonal disease
• Hyperadrenocorticism
• Concurrent hormonal disease
• Acromegaly
• Hyperadrenocorticism
• Hyperthyroidism
• Diestrous induced excess GH
• Hypothyroidism • Drugs (megestrol acetate, glucocorticoids)
• Drugs (Eg. Glucocorticoids) • Infection
• Infection • Concurrent illness (Renal/cardiac)
• Concurrent illness (Renal/cardiac) • Hyperlipidemia (?)
• Hyperlipidemia • Genetics (?)
• Islets amyloidosis (?) • Immune-mediated insulitis (?)
Signalment
• Older dogs and cats – peak prevalence @ 7-9 years in dogs and 9-11
years in cats
• Juvenile diabetes - < 1 year, uncommon!
• Dogs – females = 2X males
• Cats – neutered males
History
• Classical – polydipsia, polyuria, polyphagia and weight loss
• Brought in for evaluation – can no longer hold urine though night, and
needs to be taken out for urine OR urinates in house
• Cat owners –
• constant need to change litter and increased litter clumps
• Lethargy, decreased interaction with family members
• Lack of grooming in cats
• Dry, lustreless, unkempt or matted haircoat
• Inability to jump
• Hindlimb weakness
• Time sequence from onset of initial clinical signs to development of
complications is unpredictable – range from days to months!
Physical examination – non-ketotic patient
• No classic findings in a non-ketotic dog or a cat
• Findings depend on whether or not DKA is present, and if so – its duration
and severity.
• Many are obese, but otherwise in good physical condition
• Lethargy
• Dry, brittle, lustreless hairs
• Diabetes induced hepatic lipidosis  hepatomegaly
• Lenticular changes with cataract formation
• Inabitliy to jump, hindlimb weakness, ataxia, plantigrade posture 
diabetic neuropathy
Physical examination
Establishing diagnosis of DM
• Presence of appropriate signs
• PU/PD
• Polyphagia + weight loss
• Documentation of persistent hyperglycemia & glycosuria (Both imp)
• Concurrent documentation of ketonuria  diabetic ketosis/ketoacidosis
• Mild hyperglycemia (130-180mg/dL)  clinically silent and usually
unexpected/unsuspected finding
• Patient with mild hyperglycemia + PU/PD  explore other disorders too!
• Elevated Serum fructosamine concentration  sustained hyperglycemia
Factors causing hyperglycemia in dogs & cats
• Diabetes mellitus
• Stress – in CATS
• Postprandial effect ( high carb
diet)
• Hyperadrenocorticism
• Acromegaly in CATS
• Diestrous in BITCH
• Pheochromocytoma in DOG
• Pancreatitis
• Exocrine pancreatic neoplasia
• Renal insufficiency
• Drug therapy
• Glucocorticoids
• Progestagens
• Megestrol acetate
• Thiazide diuretics
• Dextrose containing fluids
• Parenteral nutrition
• Head trauma
Clinical presentation
• Non-ketoacidotic/uncomplicated diabetes mellitus
• HHS: Hyperglycemic hyperosmolar syndrome
• DKA: Diabetic ketoacidosis

Non-
ketoacidotic
DM HSS DKA
Non-ketoacidotic diabetes mellitus
• Diseases like Hyperadrenocorticism  carbohydrate intolerance
• Carbohydrate intolerance  disease like bacterial cystitis
• CBC – typically normal
• Neutrophilic leucocytosis, toxic neutrophils if pancreatitis or infection is present
• Hyperglycemia
• Hypercholestremia
• Hypertriglyceroidemia (lipemia)
• Increased SGPT/SGOT
• Urine Sp Gr >1.025
• Glycosuria
• Variable ketonuria
• Proteinuria
Rx for non-ketotic patient
• Primary goal of Rx  elimination of owner observed signs!
• Persistence of clinical signs and development of chronic complications
α severity and duration of hyperglycemia
• Proper insulin therapy
• Diet
• exercise
• oral hypoglycemic drugs (cats)
• Prevention and control of concurrent inflammatory, infectious,
neoplastic and hormonal disorders!
Initial insulin therapy
• Establishment of diagnosis of DM  consider IDDM
• Dogs: Intermediate acting/recombinant human insulin/NPH/Lente
@0.25U/kg twice daily
• Cats: Lente or PZI(beef/pork origin) @ 1-2U/kg twice daily

Insulin Onset of Tmax (Hr) Duration of action (Hr)

Route
type action
Dog Cat Dog Cat

NPH SC ½-2 hrs 2-10 2-8 6-18 4-12

Lente SC ½- 2 hrs 2-10 2-10 8-20 6-18

PZI SC ½- 4 hrs - 4-14 - 6-20

Dietary recommendations
• Dogs:
• Prevent obesity + maintain consistency in timing and caloric intake + minimize
postprandial increase in glucose
• Correct obesity & increased fibre  improved control of glycemia
• More viscous soluble fibres like gums and pectins  slower glucose diffusion
• Side effects: excess frequency of defecation
• Hills w/d
• Cats:
• High protein, low carb, low fibre
• Hills w/d
• Purina DM
Oral hypoglycemic drugs (NIDDM)
• Sulfonylurea(Eg. Glipizide), meglitidines: Stimulate pancreatic insulin
secretion
• Biguinides(Eg. Metformin), thiazolidinediones : enhance tissue
sensitivity to insulin
• Alpha glucosidase inhibitors (eg. Acarbose, miglitol): slow
postprandial intestinal glucose absorption

• Glipizide@2.5mg PO BID in non-ketotic and relatively healthy cats

• Acarbose@12.5-25mg per dog at each meal
Monitoring
• Glycated protein levels: Fructosamine & glycosylated hemoglobin
• markers of mean glucose concentration and their amount is proportional to
the blood glucose concentration
Fructosamine
• Advantages of measuring fructosamine
• Distinguishes hyperglycemic, non-diabetic dogs from diabetics with chronic
hyperglycemia.
• Does not appear to be influenced by transient hyperglycemia.
• Useful in evaluating longer-term control and owner compliance with insulin
treatment.
• Limitations of fructosamine measurements
• Unable to detect short-term or transient abnormalities in the blood glucose
concentration, eg, transient daily episodes of hypoglycemia. This would require serial
measurement of blood glucose concentrations.
• Albumin and fructosamine concentrations are highly correlated in dogs. Dogs with
hypoalbuminemia also have a decreased fructosamine concentration (false
negative)—the laboratory performing the analysis should be consulted as to whether
a correction is required and whether or not this has been done.
Glycosylated hemoglobin (GHb/HbA1c)
• GHb is produced by the non-enzymatic, irreversible binding of glucose to
hemoglobin in erythrocytes.
• Advantages of GHb measurements
• Unaffected by stress-related or postprandial hyperglycemia.
• Useful in long-term monitoring of diabetic dogs over the previous 2–4 months.
• Limitations of GHb measurements
• Test not widely available for dogs.
• Not the most effective test due to the relatively long erythrocyte lifespan
(approximately 110 days in dogs).
• Less effective for short-term monitoring than fructosamine because hyperglycemia
must be present for at least 3 weeks before increased values are detectable.
• Affected by hemoglobin concentrations: may be increased or decreased due to
polycythemia or anemia, respectively.
Complications of insulin therapy
• Hypoglycemia
• Stress hyperglycemia
• Recurrence or persistence of clinical signs
• Insulin underdosage
• Insulin overdosage & glucose counter regulation (SOMOGYI phenomenon)
• Short term insulin effect
• Prolonged duration of insulin effect
• Inadequate or impiared insulin absorption
• Circulating insulin antibodies
• Concurrent disoders causing insulin resistance
Complications of DM in dogs & cats
COMMON
• Iatrogenic hypoglycaemia
• Persistent PU/PD & weight loss
• Cataracts (dogs)
• Bacterial UTI
• Pancreatitis
• Ketoacidosis
• Hepatic lipidosis
• Peripheral neuropathy (cats)
UNCOMMON
• Peripheral neuropathy (dogs)
• Glomerulonephropathy/sclerosis
• Retinopathy
• EPI
• Gastric paresis
• Diabetic diarrhoea
• Diabtic dermatopathy (dogs)
Clinical presentation
• Non-ketoacidotic/uncomplicated diabetes mellitus
• HHS: Hyperglycemic hyperosmolar syndrome
• DKA: Diabetic ketoacidosis

Non-
ketoacidotic
DM HSS DKA
Physical examination – in ketoacidotic patient
• Dehydration
• Depression
• Weakness
• Tachypnoea
• Strong odor of acetone to breath
• Severe metabolic acidosis
• Slow deep breathing – kussmaul’s respiration
• GI signs – vomiting, abdominal pain, distension
• Those with severe hyperosmoality extremely lethargic, may be
comatose!
 HSS Vs DKA
HSS DKA
• Profound hyperglycemia • Hyperglycemia
(>600mg/dL) • Glycosuria
• Hyperosmolality • Ketonemia
(>320mOsm/kg)
• Ketonuria
• pH > 7.3
• Metabolic acidosis (pH<7.3 &
• No significant or detectable Bicarb <15mmol/L)
ketonemia or ketonuria
How DKA is different from Uncomplicated DM
• Relative lack of Insulin + increase in counter-regulatory hormones
• Glucagon, cortisol, epinephrine and growth hormone
• Increased “Glucagon:Insulin” in DKA  enhanced gluconeogenesis
• DKA events precipitated by period of relative insulin resistance,
brought about by secondary disease process/counter-regulatory
hormones
• DKA  electrolyte and acid base imbalance
Rx management of severe DKA
Goals of treatment for a severely ill, ketoacidotic diabetic pet:
1. To provide adequate amounts of insulin to normalize intermediary
metabolism
2. To restore water and electrolyte losses
3. To correct acidosis
4. To identify precipitating factors for currant illness
5. To provide carbohydrate substrate when required by insulin
treatment
Fluid therapy
• 0.9% Normal saline @ 60-100ml/kg/24hrs  adjust based on
hydration, urine O/P and persistence of fluid losses
• Potassium supplementation
• Based on serum potassium
• If unknown  add 40mEq of KCl to each liter of fluid
• Phosphate supplementation
• If serum phosphorus < 1.5mg/dL IV infusion @0.01-0.03mmol/kg/hr in
calcium free fluids
• Dextrose supplementation
• NOT INDECATED until blood glucose approaches 250mg/dL  begin D5%
infusion!
Bicarbonate therapy
• If plasma bicarb < 12mEq/L OR total CO2 is < 12mmol/L
• Add to Iv fluids and give over 6 hrs
• Do not give infusion
• Bicarb amount to be given =
= Body weight (kg) X 0.4 X (12- patient’s bicarb) X 0.5
• If patient’s bi carb is unknown –use 10 in place of (12-patient’s bicarb)
• Retreatment – only if plasma bicarb remains < 12 mEq/L after 6 hrs of
therapy
Insulin Therapy
• Regular or crystalline insulin
• Intermittent i/m technique:
• Initial dose 0.2U/kg IM  followed by  0.1U/kg IM hourly until blood
glucose approaches 250mg/dL  then switch to SC regular insulin every 6-8
hrs
• Low dose IV technique:
• Initial rate @0.05 – 0.1U/kg/hr diluted in 0.9% NS and administered via
infusion or syringe pump ( separate line)  adjust rate based on hourly
glucose levels  once it approaches 250mg/dL  switch to SC every 6-8 hrs
• If patient is hypokalemic at presentation  reduce rate of infusion
• GOAL: decline in glucose @75mg/dL/hr until  250mg/dL
Ancillary therapy
• Concurrent pancreatitis is common with DKA  NBM + aggressive
fluids
• Concurrent infections are common with DKA  Judicious antibiotics
• Additional therapy as needed, for concurrent diseases
Patient monitoring
• BGL every 1-2 hrs initially  adjust insulin and begin dextrose 5%,
when glucose approaches 250mg/dL
• Hydration status, respiration and pulse – every 2-4 hrs  adjust fluids
accordingly
• Lytes and venous CO2 – every 6-12 hrs  adjust bicarb accordingly
• Urine O/P, glycosuria, ketonuria – every 1-4 hrs  adjust fluids
accordingly
• Body weight, PCV, Temp and blood pressure – DAILY
• Additional monitoring depending on concurrent diseases
Initiation of longer acting insulin
• Should not be done until dog/cat is stable, eating , maintaining fluid
balance without any Ivs and is no longer acidotic, azotemic or
electrolyte deficient
• Initial dose – similar to regular insulin used just before switch!