Diabetes Flashcards
2 types of T1DM
Type 1a: immune mediated (95%)
Type 1b: idiopathic (<5%)
Pathophysiology of T1DM
Autoimmune cell mediated destruction of pancreatic beta cells
Age of onset and rate of B cell destruction is quite variable. Generally rapid in infants and children, and slow in adults i.e. latent autoimmune diabetes of adulthood
Diagnosis of T1DM
Acute onset hyperglycaemia ≥11.1 mmol/L (polydipsia, polyuria, weight loss), ketosis +/- acidosis
HbA1c not used in diagnosis
Low or undetectable plasma C peptide level supports the diagnosis
Other clinical clues
- Personal or FHx of autoimmune disorders
- No FHx of T2DM
- No features of metabolic syndrome (central obesity, HTN, ^lipids)
- Failure to respond to non-insulin treatment options
Autoantibodies not routinely tested but may be positive
- GAD 65
- Insulin (AA)
- Tyrosine phosphatases (IA-2 &IA-2B)
- Zinc transporter 8 (ZnT8)
What’s latent autoimmune diabetes of adulthood (LADA)?
Subtype of T1DM
Slow progressive autoimmune destruction of beta cells
Age of onset >30
Positive titre for at least 1 T1DM antibody
May respond to oral agents initially. However starting insulin early may help preserve beta cell function.
Less likely to have metabolic syndrome
More likely to have FHx or personal history of autoimmune disease
What’s idiopathic T1DM (Type 1b)?
Accounts for <5% of T1DM
No evidence of B cell autoimmunity
Strongly inherited but not HLA associated
Africans and Asians
Permanent insulinopenia (low or undetectable plasma c peptide level) Prone to ketoacidosis
Associated conditions of autoimmune T1DM
Autoimmune thyroid disease e.g. Grave’s
- Monitor TSH, thyroid antibodies every 2 years
Addison’s disease
Coeliac disease
- Monitor coeliac ab every 2 years
Vitiligo
Autoimmune hepatitis
Myasthenia gravis
Autoimmune gastritis –> pernicious anaemia
- Monitor B12 every 2 years
What’s the typical starting dose for insulin?
0.5IU/kg/day (50% should be administered as bolus with meals)
Why should we rotate the areas of insulin administration?
To avoid lipohypertrophy and atrophy = erratic insulin absorption
Rotate between abdomen, thighs, buttock, upper arms
How does insulin analogues compared to human analogues?
Insulin analogues have less hypoglycaemia, less weight gain, achieve lower HbA1c
How does continuous subcutaneous insulin infusion (CSII) compared to multiple daily injections?
Less severe hypoglycaemia
More HbA1c lowering
What’s insulin sensitivity factor?
How much BSL is lowered in 2-4 hours with 1 unit of rapid acting insulin?
What’s insulin carbohydrate index?
How many grams of carbohydrate is covered by 1 unit of insulin?
List treatment options other than insulin for T1DM
Whole pancreas transplant
Islet transplant
Both require lifelong immunosuppression to prevent graft rejection
Downsides to HbA1c
Measures average BSL over 3/12
Doesn’t tell you glycaemic variability or hypoglycaemia
Affected by RBC turnover, blood loss, Hb variants, time in hypoglycaemia
Management of hypoglycaemia
15g glucose (2-3 tsp honey or sugar/100ml soft drink/glucose tab)
Glucagon
Who is at risk of hypoglycaemia unawareness?
Increasing age Long diabetes duration Aggressive glycaemic control Frequent hypoglycaemia Autonomic neuropathy Medications e.g. beta blockers
What’s continuous glucose monitoring?
Measures interstitial glucose level every 1-5 minutes
Correlates well with plasma glucose level
Provides glucose trends over 24h period
Can be connected to mobile or pump
Reduces time in hypoglycaemia without compromising HbA1c, improves HbA1c, improves in target range
What’s continuous subcutaneous insulin infusion (CSII) pump therapy?
Advantages?
Disadvantages?
Insulin is infused continuously to mimic normal basal secretion, and boluses with meals or when BSL is high
Advantages: can lower HbA1c, reduce severe hypoglycaemia rates, less injections, less variable insulin absorption
Disadvantages: $$$, infection risk, pump failure/needle dislodgement (ketoacidosis), need to wear an external pump
What to do with CSII during DKA?
Switch it off (probably pump failure)
Do normal DKA management
Criteria for DKA
Ketosis
BSL >14
Venous pH <7.3 and/or bicarb <20
Features of severe DKA
Ketones >6 pH <7.1 or bicarb <5 K <3.5 GCS <12 SpO2 <92% SBP <90 HR <60 or >100
Criteria for HHS
BSL >30
Minimal ketosis
Serum osmol >320mOsm/kg
Coma present in 1 in 3
DKA vs HHS
A lot of overlap!!
DKA usually has lower BSLs, while HHS BSLs >56!
DKA presents earlier due to ketosis symptoms (dyspnoea) and are generally younger (able to excrete glucose better)
HHS presents in older people –> poor renal function so can’t excrete the glucose
DKA is due to absolute insulin deficiency –> body reverts to lipolysis –> increased FFHA –> ketogenesis –> acidosis
Alot more fluid in HHS (8-10L) compaerd to DKA (3-6L)
HHS
Decreased insulin or resistance –> decreased glucose utilisation in skeletal muscle –> increased fat and muscle breakdown –> increase in glucagon, cortisol and catecholamines + increase in hepatic gluconeogenesis –> increased BSL –> glycosuria + osmotic diuresis (further aggravate dehydration)
Causes of ketosis
DKA
Ketotic hypoglycaemia (occurs in children after a night of fasting)
Starvation ketosis
Alcoholic ketosis
Symptoms and signs of DKA
EARLY
Nausea, vomiting, abdo pain, hyperventilation
Symptoms of hyperglycaemia - polyuria, polydipsia, weight loss
LATE
Lethargy, focal deficits, obtundation, seizure, coma
Precipitants of DKA
Infection Inadequate insulin - new onset diabetes, lack of insulin increase with sick day, non-compliance Myocardial ischaemia, stroke Drugs e.g. steroids Endocrine - hyperthyroidism, Cushing's Pancreatitis Trauma ETOH excess, illicit drugs
Management of DKA in the first hour
Hour 1
x2 IVCs
1) 1L normal saline over 1/24 (cannula 1)
2) If K>3, start IV novorapid 0.1 unit/kg/hr (max starting dose 10 units/hr) (cannula 2)
If K<3, replace K (cannula 2)
3) Other
- Septic screen +/- abx
- Fluid balance chart
- Neuro obs
- Remove CSII pump
- Cardiac monitoring
- DVT prophylaxis
- Give patient’s usual long-acting insulin
4) Monitor
- Do BSL and ketones at the end of hour 1
Management of DKA hour 2-4
1) Continue IVT (cannula 1)
- 500ml/hr for hour 2
- 500ml/hr for hour 3
- 250ml/hr for hour 4
2) Give K infusion over 1 hour via “Y’ site (cannula 1)
If serum K>5 or patient anuric - withhold
If serum K 3.5-5, give 10mmol/100ml
If serum K<3.5, give 20mmol/100ml
3) Insulin + glucose (cannula 2)
- Continue initial insulin rate (novorapid 0.1IU/kg/hr) if BSLs decreasing and pH increasing, and ketones decreasing
- Increase insulin rate if pH is not increasing or if BSLs are not decreasing
- When BSL <14, give 10% glucose 100ml via “Y” site
- Maintain BSL 9-14
- May need to reduce or cease insulin infusion if becoming hypokalaemic
4) Monitor Hourly BSLs UECs and VBG at end of hour 2 and 4 Ketones at end of hour 4 Fluid balance chart (catheter if oliguric)
Subsequent management of DKA after hour 4
1) Continue IVT
- Normal saline 125ml/hr until patient is fluid replete or eating/drinking
2) Continue K replacement to maintain within reference range (cannula 1)
3) Insulin
- Continue insulin at variable rate to maintain BSL 9-14
- Allow oral intake if no clinical evidence of ileus, bowel obstruction or acute abdomen.
- If eating but still requiring IV insulin, consider giving mealtime subcut insulin
4) Monitor
Hourly BSL until insulin infusion ceased
UEC and VBG at end of hour 8 and 12
Ketone at end of hour 6 then Q4H until ketones <0.6
When to transit people from DKA protocol to subcut insulin?
Patient well and eating/drinking Anion gap is normal <12 Ketones <0.6 Long-acting insulin has been given at least 2h ago (or pump recommenced) pH >7.3 and bicarb >18
Anion gap and bicarb take hours-days to normalise
Ignore mild persistent acidosis if above criteria are met and there is hyperchloraemia
Complications of DKA
Dehydration + electrolyte disturbance –> circulatory instability and arrhythmias
Vascular thrombosis (DVT prophylaxis!) - Coronary, bowel, cerebral, DVT/PE, limb
Sepsis
Aspiration
ARDS
Cerebral oedema
- Mainly Children
- High mortality
- Gradually lower the glucose (3mmol/hr) and Na+ especially when BSLs have been 30+ for weeks (HHS)
Best marker for resolution of DKA
resolution of ketones
Acidosis takes time to resolve
What’s the role of bicarbonate in DKA?
May be used in severe DKA pH <7
Low level balance
What’s the role of phosphate replacement in DKA?
Not routinely replaced
Consider in cardiac dysfunction or respiratory depression if PO4 <1mmol/L
How long should subcut and IV insulin overlap in DKA/HHS management?
2 hours
Complications of hyperglycaemia
Dehydration + electrolyte disturbance
Lactic acidosis (major surgery + metformin)
DKA
Infection
Long-term: CV disease
BSL target in hospital
5-10
What to do with these pre-op?
1) Metformin
2) Sulphonylureas
3) Glitazones (thiazolinediones)
4) Acarbose
5) GLP1 agonist or DPP4
6) SGLTi
7) Long-acting insulin
8) Bolus insulin
1) Withhold day of surgery (or 24h for major surgery)
2) Withhold day of surgery
3) Withhold day of surgery
4) Withhold day of surgery
5) Withhold day of surgery
6) Withhold at least 2 days before surgery and day of surgery
7) Give normal insulin day before
1/2 basal insulin day of surgery
Monitor BSLs Q2H from 1st missed meal to surgery
IV 5% dextrose if BSL <10
Give PRN short acting insulin if BSL >10
8) Withhold short-acting insulin while fasting
Where is glucose reabsorbed in kidneys?
SGLT1+2 transporters in the PCT
Adverse effects of SGLT2i
Increased urogenital infections
Euglycaemic DKA
Urinary frequency
Hypovolaemia (especially if on concurrent diuretics) and hypotension
Increased risk of LL amputation and fracture
How does SGLT2i cause euglycaemic DKA?
Rapid fall in serum glucose –> fall in plasma insulin –> rise in plasma glucagon –> low insulin:glucagon ratio stimulates lipolysis –> mild ketosis –> when combined with severe insulin deficiency e.g. fasting –> ketoacidosis
Precipitants
- Prolonged fasting
- Reduction in insulin when starting on SGLT2i
- Sepsis
- Significant ETOH intake
- Exercise
Mechanism of action of DPP4 inhibitors ‘gliptins’
Eat –> release of active incretins GLP1 and GIP from GI tract –> stimulate beta cells to increase insulin and inhibit glucagon release from alpha cells
Delays gastric emptying –> less nutrients being delivered rapidly to the bowel and gives insulin more time
Acts on hypothalamus to suppress appetite
DPP4 enzymes degrade GLP1 and GIP. By inhibiting DPP4, you get increase in insulin and decrease in glucagon
Do DPP4 inhibitors cause hypoglycaemia?
No unless compared with insulin or SU
They stimulate beta cells to secrete insulin 24/7
Which DPP4 inhibitor can we use in renal impairment?
Linagliptin
Excreted in bile and gut
Mechanism of action of GLP1 agonist
Eat –> release of active incretins GLP1 and GIP from GI tract –> stimulate beta cells to increase insulin and inhibit glucagon release from alpha cells
Delays gastric emptying –> less nutrients being delivered rapidly to the bowel and gives insulin more time
Acts on hypothalamus to suppress appetite
Similar to DPP4 inhibitors
Benefits of DPP4 inhibitors other than BSL effects
Weight loss
No CV benefits
If atherosclerotic CV disease predominates but HbA1c is suboptimal despite metformin, what’s the next drug that should be added?
GLP-1 agonist preferred or SGLT2i as 2nd line (if eGFR adequate)
If further therapy needed consider adding DPP4i, basal insulin, TZD, sulphonylurea
(Relative) Contraindications to SGLT2i
eGFR <30 (may be used but lacking data)
Genital thrush infections
Recurrent UTIs or IDC
Ketosis prone
Dehydration - need to drink lots to make up for polyuria (can be difficult in HF patients with FR)
Low BP - may need to reduce antihypertensives/diuretics
Low BMD + frequent falls = high risk of #
If HF or CKD predominates but HbA1c is suboptimal despite metformin, what’s the next drug that should be added?
Particularly HFrEF with LVEF <45% or CKD eGFR 30-60ml/min or UACR >30mg/g (particularly >300mg/g)
SGLT2i preferred (if eGFR adequate) or GLP1 agonist as 2nd line
If further therapy needed, consider adding DPP4i, basal insulin, sulphonylurea
Avoid TZD
Which OHG to avoid in HF?
TZD
Pathophysiology of T2DM
What happens during the course of T2DM from diagnosis to late stage?
In early T2DM, there is insulin resistance –> high glucose despite hypersecretion of insulin by a depleted beta cell mass –> glucotoxicity destroys more beta cells –> absolute insulin deficiency –> requires insulin therapy
What’s the criteria for remission of T2DM
1) Previous diagnosis of T2DM
2) Off anti-diabetic medication for 2 months
3) HbA1c <6.5 OR
Fasting BSL <7 AND 2-hour glucose <11
