Diabetes mellitus

Epidemiology

• Type 1 (5-10%)
  • Complete insulin deficiency
  • Immune-mediated destruction of beta-cells causes 90% of cases
• Type 2 (80-90%) 
  • Insulin resistance, relative insulin deficiency or combination
  • Ketosis only occurs in presence of stressor
• Diagnosis
  • Fasting plasma glucose >7.0mmol/L (no caloric intake for >8 hours)
  • Random plasma glucose >11.1mmol/L AND symptoms of hyperglycaemia
  • 2hr plasma glucose >11.1mmol/L in OGTT
  • HbA1c > 6.5%

Aetiology

• Type 1 DM
  • Anti-islet cell (ICA)
  • Anti-glutamic acid decarboxylase (GAD)
  • Anti-insulin
  • Anti-tyrosine phosphatases
  • HLA-DR3/DR4 or both associated
• Diabetes secondary to other conditions
  • Chronic pancreatitis, carcinoma of pancreas, pancreatectomy, haemochromatosis, CF, gestational, Cushing’s, acromegaly, phaeochromocytoma and glucagonoma
• Drug-induced diabetes
  • Glucocorticoids, COCP, thiazide diuretics at high doses, tacrolimus, sirolimus, cyclosporin, pentamadine and HIV protease inhibitors

Type 2 diabetes mellitus

• Doubles mortality risk
• Pathogenesis
  • Complex heterogenous metabolic disorder with chronic elevation in plasma glucose
  • Fasting hyperglycaemia occurs due to increased hepatic glucose production, which is not suppressed because of hepatic resistance to insulin
  • Post-prandial hyperglycaemia occurs due to abnormal insulin secretion, impaired regulation of hepatic glucose production and reduced glucose uptake by peripheral tissues (particularly skeletal muscle)
• Impaired insulin secretion
  • Complex aetiology but thought to be due to glucotoxic and lipotoxic effects + amyloid deposition within islet cells
  • Glucotoxic effect = Increased exocytosis of insulin due to increased cytosolic calcium concentration as a result of beta-cell glucose metabolism
  • Lipotoxic effect = Free fatty acids may impair beta-cell function

Mechanism of chronic complications

• Microvascular complications primarily due to hyperglycaemia
• Macrovascular complications due to hyperglycaemia but also dyslipidaemia and hypertension
• Increased infection risk due to:
  • Phagocyte dysfunction (impaired adherence, chemotaxis, phagocytosis, bacterial killing and respiratory burst)
  • Nonenzymatic glycation of immunoglobulins
  • Reduced T lymphocyte populations

Clinical manifestations of T2DM

• Classically fatigue, lethargy, weakness, polyuria, polydipsia, polyphagia and blurred vision
• Frequent superficial infections and slow healing skin lesions after minor trauma

General management

• Aim is HbA1c <7.5% without frequent hypoglycaemic episodes to prevent microvascular disease
• HbA1c <6.5% in those with increased risk of arterial disease
• Target pre-prandial BSL 4.0-7.0 and post-prandial <9.0
• Strict glycaemic control prevents microvascular disease but not macrovascular

Insulins

• Ultra-short acting (onset 10-15min; peak 1-1.5hrs; duration 3-5 hours)
  • Faster-acting insulin aspart (Fiasp)
  • Insulin aspart (NovoRapid)
  • Insulin lispro (Humalog)
  • Insulin glulisine (Apidra)
• Short-acting (onset 30min; peak 2-3hrs; duration 6-8hrs)
  • Neutral insulin (Actrapid; Humulin R)
• Intermediate-acting (Onset 1-2.5hrs; peak 4-12hrs; duration 16-24hrs)
  • Isophane insulin (Humulin NPH; Protaphane)
• Long-acting (Onset 1-6hrs; No peak; Duration 24-36 hours)
  • Insulin detemir (Levemir)
  • Insulin glargine (Optisulin; Semglee; Toujeo)
• Mixed
  • Neutral insulin with isophane (Humulin 30/70; Mixtard 30/70; Mixtard 50/50)
• Mixed biphasic
  • Insulin aspart with aspart protamine (NovoMix 30)
  • Insulin lispro with lispro protamine (Humalog Mix25;Humalog Mix50)
  • Insulin aspart with degludec (Ryzodeg)

Antidiabetic drugs

• Sulphonylureas
  • Stimulate pancreatic secretion of insulin
• Biguanides e.g. metformin
  • Suppress hepatic glucose production and enhance peripheral uptake of glucose
• Alpha-glucosidase inhibitors e.g. Acarbose
  • Reduce carbohydrate metabolism and absorption
• Thiazolidinediones e.g. pioglitazone/rosiglitazone
  • Reduce insulin resistance
• DPP-4 inhibitors e.g. sitagliptin – Januvia
  • Prolong action of incretin hormones
• GLP-1 receptor antagonists e.g. Exenatide – Byetta
  • Reduce post-prandial hepatic glucose production and enhance peripheral glucose uptake
• SGLT-2 inhibitors e.g. Glifozins
  • Blocks renal glucose reabsorption

Insulin pumps

• Continuous subcutaneous insulin infusion
• Fixed dose of rapid-acting insulin at basal rate
• Reservoir needs to be refilled every few days and catheter changed by patient every 3 days
• Pump can be manually activated to provide bolus or prandial dose
• Improves HbA1c levels and reduces incidence of hypoglycaemia
• No evidence of improvement in microvascular outcomes
• Complications
  • Pump failure – Disconnection, reservoir empty, kinked catheter, priming errors
    • Can result in rapid ketosis
  • Skin infection at catheter site

Diabetic hypoglycaemia

• Type 1 diabetic particularly at risk as often very tightly controlled + lack glucagon surge  + adrenaline surge can be blunted due to neuropathy, age or autonomic dysfunction due to frequent episodes in the past
• Classically defined as:
  • Symptoms consist with hypoglycaemia
  • Measured plasma glucose <2.8
  • Symptoms resolve with glucose administration
• Symptoms likely if plasma glucose <3.5
• Precipitants include late meal, exercise, inadequate carbohydrate intake, excessive insulin use, ACS, infection, renal failure, mental stress and ethanol ingestion

• Clinical features
  • Sweating, tachycardia, drowsiness, tremor, anxiety, seizures, coma
  • Less commonly can present as hypothermia, depression and psychosis
• If safe for oral intake – 15-20g low and high glycaemic index carbohydate meals
  • Oral glucose raises serum glucose levels faster than glucagon
• If not – 50mL 50% dextrose IV or glucagon 0.5-2mg IM
  • Glucagon takes 7-10 minutes and is less effective in those with poor glycogen reserves (children and alcoholics)
• May require glucose infusion
• Beta-blockers (but not calcium channel blockers) may inhibit symptoms/signs of hypoglycaemia

Other causes of hypoglycaemia

• Insulin, sulfonylureas, salicylates, beta-blockers, quinine, chloroquine, valproate
• Ethanol
• Liver disease
• Sepsis or critical illness
• Malnourishment, especially anorexia nervosa
• GI dumping syndrome
• Adrenal insufficiency
• Hypopituitarism
• Islet cell or extrapancreatic insulin-secreting tumor
• Munchausen syndrome
• Suicide attempt

Failure to respond to glucose therapy

• Consider underlying sepsis, toxin, insulinoma, hepatic failure, adrenal insufficiency, sulfonylurea overdose or massive insulin overdose

Hyperglycaemia

• May present dehydrated, volume deplete and AKI
• Find underlying cause
  • Often underlying infection ,corticosteroids, sympathomimetics, diuretics, anticonvulsants, salicylates, beta-agonists, ACS, CVA or non-compliance
• Previously diagnosed Type 1 diabetic
  • Ensure not ketotic
  • Refer to primary care physician for alteration to insulin regime
  • Ask patient to keep diary of levels and doses
  • Can provide supplemental prandial dose  and can increase basal dose depending on degree of hyperglycaemia

• Undiagnosed diabetic
  • Can make diagnosis of diabetes if meeting criteria
  • Can admit for initiation of insulin if likely Type 1 diabetic or refer for urgent outpatient assessment by primary care physician
• If started on steroids and insulin-dependent
  • Advise to more accurately record BSL’s and increase prandial dosing as required (increasing basal dosing not required)
• Somogyi effect
  • Excessive nocte insulin results in overnight hypoglycaemia with subsequent rebound hyperglycaemia in the morning

Chronic complications

• Vascular
  • Microvascular – Nephropathy, peripheral neuropathy, retinopathy
  • Macrovascular – CVA, ACS, PVD
• Non-vascular
  • Infections
  • Dermatologic changes
  • Urinary tract involvement
  • Sexual dysfunction
  • GI (gastroparesis, diarrhoea)
  • Cataract/glaucoma

Cardiovascular complications

• Risk of coronary artery disease is 2-4 fold and prognosis is worse
• Silent ischaemia is common in diabetic patients
• MI often presents atypically
• Medically unrecognised MI 40% (vs. 25% in general population)
• Heart failure 2-5 fold risk
• Diabetic cardiomyopathy
  • Changes in myocardium that make it more susceptible to ischaemia and less able to recover after ischaemic insult
• Stroke 3-fold and worse outcomes
• Peripheral vascular disease 2-4 fold

Renal complications

• Diabetic nephropathy seen in 5-40% of patients
• Found in 7% of cases at time of diagnosis
• More common in Type 1 DM (but majority are Type 2)
• Triad of hypertension, proteinuria and ultimately renal impairment
• UTI and papillary necrosis also seen
• Renal papillary necrosis can be asymptomatic through to pyelonephritis-type presentation

Neurological complications

• Presence of symptoms and/or signs of peripheral nerve dysfunction in diabetics in the absence of another cause
• Can be non-specific 
• Need to rule out chronic inflammatory demyelinating polyneuropathy, B12 deficiency, hypothyroidism, uraemia
• Defined as:
  • Subclinical neuropathy
    • 50% of patients asymptomatic
  • Diffuse clinical neuropathy
    • Usually presents as chronic sensorimotor distal symmetric polyneuropathy and autonomic neuropathy
  • Focal neuropathy
    • Mainly mononeuropathy and entrapment syndromes

• Diffuse clinical neuropathy
  • Typically presents as burning, stabbing sensation, paraesthesia, hyperaesthesia, deep aching
  • Vibriosense, pressure, pain and temperature usually lost
  • Glove and stocking
  • Foot ulceration is the greatest risk
• Mononeuropathy
  • Usually sudden onset and painful
  • Can affect large peripheral nerves, cranial nerves (due to microvascular infarcts)
  • Can be difficult to differentiate from TIA or CVA
  • Incidence of carpal tunnel is increased in diabetics

• Autonomic neuropathy
  • Resting tachycardia, exercise intolerance, orthostatic hypotension, diarrhoea, constipation, gastroparesis, erectile dysfunction and neurogenic bladder
  • Autonomic diarrhoea defined as at least 3 weeks of diarrhoea with no other cause
• Proximal motor neuropathy
  • Resultant weakness in proximal lower limb musculature
  • Spontaneous and/or percussion-provoked muscle fasciculations

Infectious complications

• S. aureus and M. tuberculosis more common in pneumonia
• Candida more common in UTI
• Malignant otitis externa (almost only seen in diabetics)
• Emphysematous cholecystitis and pyelonephritis
  • Consider in unexplained fever in diabetics (with/without abdominal pain)
  • Mostly Clostridial, strep, E. coli and Pseudomonas
• Rhinocerebral mucormycosis
  • Invasive fungal infection of nasal and paranasal sinuses
  • Onset is sudden and rapidly progressive
  • May have black eschar on nasal mucosa or hard palate due to ischaemia
  • May have proptosis and CN involvement/seizures if progresses

Lower limb complications

• Diabetic foot ulceration
  • Combination of peripheral neuropathy, peripheral vascular disease, excessive plantar pressure, repetitive trauma and poor wound healing
  • S. aureus is predominant 
  • Gram-negative rods seen in chronic infections or those with recent antibiotic therapy
  • Ischaemia or gangrene predisposes to obligate anaerobic bacteria
  • Should probe all ulcers to ascertain bone/tendon/sinus tract involvement
  • Purulence and inflammation suggest infection
  • If wound probed to bone = osteomyelitis
  • X-ray may show Charcot joints, osteomyelitis, subcutaneous gas and FB
  • Bone scan and MRI can help rule out osteomyelitis

• Mild acute wound infections
  • <2cm surrounding cellulitis, not systemically unwell
  • Oral antibiotics (Augmentin) and outpatient management
  • Consider anaerobic cover (metronidazole)
• Complicated
  • Deep ulcers, >2cm surrounding cellulitis, systemic toxicity, ulcer with lymphangitis, purulent/malodourous discharge, necrotic/gangrenous tissue, associated limb ischaemia without pulses, deep abscess or suspicion of osteomyelitis
  • IV PipTaz and admission
• Always check vascular supply

Ophthalmological complications

• Diabetic retinopathy
  • Non-proliferative
    • Retinal vessel vasodilatation, microaneurysm and leakage
    • Hard exudates (lipid in outer plexiform layer)
    • Flame haemorrhages in nerve fibre layer
    • Dot haemorrhages in deeper layers of retina
    • Cotton wool spots (soft exudates from microinfarctions in retina)
    • Venous tortuosity and beading in advanced stages
  • Proliferative
    • Neovascularisation across retinal surface and optic disc
    • Easily bleed into vitreous as very fragile
    • Of note, this is NOT a contraindication to thrombolysis as bleeding into the eye is extremely rare in this setting
    • Neovascularisation into iris (rubeosis iridis) and can lead to glaucoma
    • Tractional retinal detachment can occur via contraction of fibrous tissue in the setting of neovascularisation
• Recurrent styes, blepharoconjunctivitis, xanthelasma
• Impaired corneal sensitivity can increase risk of bacterial corneal ulcers, neurotropic ulcers
• Cataracts and all forms of glaucoma are more common in diabetics
• Recurrent styes, blepharoconjunctivitis, xanthelasma
• Impaired corneal sensitivity can increase risk of bacterial corneal ulcers, neurotropic ulcers
• Cataracts and all forms of glaucoma are more common in diabetics

Dermatological complications

• Non-infectious
  • Acanthosis nigricans – Hypertrophic, hyperpigmented plaques in skin folds
  • Necrobiosis lipoidica – Oval violaceous patch with red border and yellow-brown central area. Prominent telangiectasia.
  • Diabetic dermopathy – Lower extremity 4-5 dull red macules, 5-12mm in diameter with hyperpigmented scarring
  • Scleroderma – Asymmetric nonpitting induration of skin on posterolateral neck, shoulders, back
  • Granuloma annulare – Ring of small, firm, flesh-coloured papules on hands/feet
  • Carotenodermia – Yellow skin due to deposition of carotenoids
  • Diabetic bullae – Tense blisters on plantar surfaces of feet
  • Skin tags

• Infectious
  • Erythrasma – Pruritic red-brown patch in axilla or groin. Corynebacterium minutissimum
  • Necrotising fasciitis
  • Rhinocerebral mucormycosis 
  • Malignant external otitis
• Resulting from treatment
  • Lipoatrophy
  • Lipohypertrophy

Insulin treatment for hospitalised adults with diabetes

Do NOT give sliding scale insulin without basal insulin as greatly increases risk of fluctuations in glucose and subsequent hypoglycaemia/hyperglycaemia events

Type 1 diabetics

• Basal insulin should NEVER be withheld
• Fasting patients need to receive ongoing carbohydrates to reduce development of ketones
• If persistent hyperglycaemia, clinically unwell or fasting >24 hours -> Measure ketones regularly
• Fasting patients who are unwell are best managed on insulin/dextrose infusions
• Best if patient can continue to self-manage with carbohydrate and BSL monitoring
• Those on a pump need endocrine input -> Cessation leads to rapid falls in insulin levels as only contain rapid-acting insulin with high risk of development of DKA
• Basal-bolus regime should be started in all non-critically ill hospitalised adults with hyperglycaemia (>10mmol/L)
  • Once or twice daily basal dosing + boluses with meals and BSL measured before each meal
  • Boluses include a preprandial supplemental dose based on the pre-meal BSL
  • Bolus should not be withheld if hypoglycaemia pre-meal if going to eat
  • If already on insulin, total daily dose should be divided 50:50 between long- and rapid-acting insulin
  • Normal supplemental doses are:
    • BSL 8.1-12: Extra 1U rapid-acting insulin
    • BSL 12.1-16: Extra 3U ”
    • BSL 16.1-20: Extra 4U “
    • BSL >20: Extra 6U “
    • Higher doses required if insulin resistant and normally on high doses of insulin

Sick day management

Type 1 DM

• The basal insulin requirement usually increases during intercurrent illness
• Key is regular (1-4 hourly) BSL and ketone monitoring
• In some illnesses (e.g. gastroenteritis), patients may be at risk of hypoglycaemia and as such need their bolus dosing and potentially basal dosing reduced during this period
• If unable to eat enough carbohydrates, patients should drink glucose-containing fluids and if unable to achieve this, seek urgent medical attention

Type 2 DM

• If insulin-dependent, similar management to T1DM
  • May need to consider switch to basal-bolus regime if on mixed regime as difficult to manage mixed regimes with fluctuant oral intake
• Metformin may need to be withheld due to risk of accumulation in AKI and exacerbation of nausea
• SGLT2 inhibitors need to be withheld if acutely unwell
• GLP-1 receptor agonists can be temporarily withheld if acute illness causes nausea, vomiting or anorexia as may worsen these
• Sulfonylureas can be continued but should be withheld if hypoglycaemic
• DPP4 inhibitors can be continued

Peri-procedural management

• Endoscopy
  • Morning list
    • No tablets night before or morning of
    • Hourly BSL’s all morning
    • Insulin night before but none morning of
  • Afternoon list
    • Tablets night before but not morning of
    • Insulin night before and 1/3 normal dose in the morning
    • Hourly BSL’s all day

• Colonoscopy
  • Morning list
    • No diabetes tablets from night before clear fluid bowel prep starting (~36 hours prior)
    • 1/3 normal insulin dose from start of clear fluids only prep phase and none on morning of procedure
  • Afternoon list
    • No diabetes tablets from morning before starting clear fluid phase
    • 1/3 normal insulin dosing from start of clear fluids phase including the morning of the procedure
  • Check BSL regularly during bowel prep phase and hourly on day of procedure

Peri-operative management

• All T1DM need dextrose and insulin infusions
• Subcut sliding scale not recommended
• Cease metformin 1 day prior and 1 day after any contrast delivery
• Diet-controlled
  • QID BSL pre-operatively and hourly perioperatively
  • Insulin/dextrose infusion if BSL persistently >12
• Oral hypoglycaemic agent
  • Omit all tablets morning of procedure
  • If taken nocte diamicron XR or glimepiride, need IV dextrose pre-operatively due to long half-life
  • If BSL persistently >12, start insulin/dextrose infusion
• Consider witholding SGLT2 inhibitors in unwell adults as risk of euglycaemic DKA is greatly increased

• Insulin treated
  • Minor surgery (delay in meal 2-3 hours)
    • Morning list
      • Usual insulin evening prior
      • BSL 2 hourly from 7am
      • If BSL <7, start dextrose infusion
      • Give usual breakfast insulin before late breakfast
    • Afternoon list
      • Half morning dose insulin with light breakfast
      • Usual lunchtime insulin with late lunch
  • Minor surgery (miss one meal)
    • Morning list
      • Usual insulin night before
      • Half morning insulin dose
      • Start dextrose infusion
    • Afternoon list
      • Half morning insulin dose with light breakfast
      • Half lunchtime dose with dextrose infusion
    • If BSL >12, insulin/dextrose infusion

• Major surgery (missing 2 meals)
  • Morning list
    • Usual insulin night before
    • Withold normal morning insulin and start insulin/dextrose infusion
  • Afternoon list
    • Half morning insulin dose with light breakfast
    • Withold lunchtime insulin and start insulin/dextrose infusion

Last Updated on October 6, 2021 by Andrew Crofton