Abnormal blood sugar presentation Flashcards
Define abnormal blood sugar
Blood sugar measurement outside of the normal range 3.5 to 5.5 mmol/L
In reality hypo or hyper glycaemia are defined by large deviations from the above range (i.e 6 mmol/L is not considered hyperglycaemic)
Define hyperglycaemia
Venous or capillary blood blood glucose levels > 7mmol/L when fasting OR 11mmol/L 2 hours post prandial
define hypoglycaemia
venous of capillary blood glucose levesl < 3.3 mmol/L
What is whipple’s triad?
- Whipple’s triad –> present in cases of true hypoglycaemia:
- hypoglycaemic symptoms
- low blood glucose concentration
- resolution of symptoms after raising blood glucose concentration to normal
What are the key diagnostic factors for hypoglycaemia in history?
-
Sympathoadrenal symptoms: sympathoadrenal sx result as a decrease glucose causes sympathetic activation of adrenal glands and catecholamine release.
- Diaphoresis
- anxiety/ irritability
- hunger/ nausea
- tremor
- palpitations
- dizziness
-
Neuroglypenic symptoms:
- confusion
- drowsy
- visual disturbance/ blurred vision
- seizure
- coma
- generalised tingling
What is the pathophysiology underlying hypoglycaemia?
- Glucose = obligate fuel for the brain, to maintain proper brain function plasma glucose must be maintained within narrow range
- counterregulatory mechanisms exist to prevent/ correct hypoglycaemia:
- decreased insulin secretion
- increase in glucagon secretion
- increase in epinephrine secretion
- increase cortisol and growth hormone
- symptoms prompting food ingestion - develop after drop below 3mmol/L
What are the red flags for hypoglycaemia?
What are the risk factors/causes for/of hypoglycaemia?
Red flags –> hypoglycaemia = medical emergency, all symptoms are potentially red flags.
Risk factors:
- Middle age
- female
- insulinoma - neuroendocrine tumour that secretes insulin unregulated
- exogenous poisoning or insulin - e.g. incorrect dose, intentional overdose, correct dose but decreased food intake
- liver failure/ ethanol –> depleted glycogen stores, impaired gluconeogenesis
- intense exercise (leads to glucose uptake independent of insulin)
- adrenal insufficiency –> lack of cortisol response to low blood glucose levels, fail to counteract hypoglycaemia (significant cause in paediatric cases)
- growth hormone deficiency –> again lack of counteractive response, common in paediatric cases
- hypopituitarism –> failure of HPA, deficient growth hormone or adrenocorticotropic hormone secretion
- fibromas/sarcomas/fibrosarcomas –> large tumours that secrete insulin like growth factor unregulated
- anorexia nervosa –> chronic malnourishment leads to lack glycogen stores needed to counteract hypoglycaemia
PMH: what conditions can cause hypoglycaemia?
- adrenal insufficiency
- growth hormone insufficiency
- hypopituitarism
- fibromas/sarcoma/fibrosarcomas
- glycogen storage diseases - lack of stored glycogen hinders production of glucose to counteract hypoglycaemia
- anorexia
- malnutrition
- liver failure
- renal failure –> may impair gluconeogenesis
- ethanol consumption –> heavy alcohol consumption decreases hepatic production of glucose
- bariatric surgery –> may cause abnormalities in stomach emptying )rapid transit of carbs) can lead to hypoglycaemia
Drug history: what drugs can cause hypoglycaemia?
- Quinine and quinolones
- sulfonylurea (stimulates insulin secretion therefore increasing insulin production, also increases insulin binding to receptors so stimualtes glucose uptake)
- haloperidol (alpha adrenergic block)
- tramadol (increase risk hypoglycaemia)
- salicylates (increase in insulin response)
- beta blockers - adrenergic blockade, sustains hypoglycaemia
What examination features for hypoglycaemia?
- Diaphoresis
- tremor
- tachycardia
- unexplained weight gain –> w hypoglyaemic symptoms may suggest insulinoma
- unexplained weight loss –> may suggest adrenal insufficiency
- hyperpigmentation –> typically in folds/ scars notexposed to sun, may suggest adrenal insufficiency –> lack of cortisol response to low serum glucose fails to counteract hypoglycaemia (common in paediatric)
- hypotension –> adrenal insufficiency
- short stature –> growth hormone deficiency (typically in paediatrics)
What is the cause of hypoglycaemia in a known diabetic?
- Most common cause in diabetic = insulin or sulfonylurea use (accidental or non accidental oversode, or non adjustment of dose depending on activity level and/or food intake)
- T2DM –> post prandial (reactive) hypoglycaemia can occur within 4 hours of eating a high carbohydrate meal
What are the causes of hypoglycaemia in non diabetics?
EXPLAIN causes
EX –> exogenous drugs –> insulin or hypoglycaemics (alcohol, aspirin, beta blockers, quinine, sulfonlyureas (increase release insulin from pancreas))
P –> Pituitary insufficiency
L –> Liver failure, rare inherited enzyme diseases
A –> Addison’s disease
I –> Islet cell tumour (insulinoma) and immune hypoglycaemia (Anti-insulin receptor Ig in Hogkin’s disease)
N = non pancreatic neoplasma e.g. fibrosarcomas that produce insulin like growth factor 2 or tumours with high metabolic demand utilising free glucose
What is the pathophysiology behind:
exogenous drugs causing hypoglycaemia?
1) Insulin overdose/ incorrect dosing for food intake –> insulin binds insulin receptor on cells leading to expression of GLUT4 in the outer membrane of skeletal and liver cells, activation of glycogenesis and lipogenesis in adipose tissue, inhibition proteolysis/gluconeogenesis —> leads to increase uptake of glucose from the blood.
Excess insulin or IGF-2 from tumours act via the same mechanism
Sulphoylureas –> close the ATP sensitive K+ channels in beta ells, causing constant depolarisation and insulin release unregulated
Pathophysiology: HPA axis problems?
- Normally the hypothalamus detects hypoglycaemia and secretes corticotrophin releasing hormone (CRH) –> stimulates the pituitary gland to secrete adrenocorticotrophic hormone which in turn stimulates the adrenal gland to secrete cortisol and other molecules
- Cortisol stimulates gluconeogeneis (pyruvate –> glucose) in order to increase blood glucose levvels
- Tissues at any point in this axis can lead to hypoglycaemia, as the body cannot respond to dropping glucose levels e..g pituitary insufficiency and addison’s disease (adrenal insufficiency, lack of adrenal hormones/ glucocorticoids).
Pathophysiology: liver failure
Liver = major site of gluconeogenesis, thus damage = inability to correct hypoglycaemic state
overall result –> blood glucose levels drop such that the HPA axis is stimulated –> leads to cortisol and adrenaline secretion –> leads to sympathoadrenal symptoms of hypoglycaemia (diaphoresis, tachycardia, anxiety, tremor) at levels usually around 3.6 mmol/L and below
At levels below 2.8 mmol/L, neuroglycopenic symptoms (blurred vision, dizziness, confusion, coma) result due to an inability of the brain to function in abscence of sufficient glucose (glucose = primary energy source for brain, unable to store therefore needs constant supply via vasculature).
Diagnosis: Hypoglycaemia
What bedside/ lab investigations need to be done and why?
- Do a capillary blood sugar on all patients with any suggestion of hypoglycaemia
- Further investigations are needed is presentation of Whipples triad (symptoms of hypoglycaemia, low blood sugar, reversed by raising serum glucose).
-
1) Serum Glucose:
- When symptoms present OR during 72 hour fast = < 2.8 mmol/L. If fasting, if glucagon administration at conclusion shows >1.4 mmol/L glucose increase = Insulinoma or IGFII secretion
- 2) LFT’s to rule out hepatic cause
- 3) Renal function testing - to rule out renal cause e.g congestive HF, chronic renal failure or hepatorenal syndrome.
-
4) Serum insulin
- should be undetectable when <3.3 mmol/L glucose. If high (>21pmol/L) = exogenous insulin, sulphonylurea or insulinoma
- 5) C - peptide (from cleavage of proinsulin into mature insulin and C peptide) : to distinguish between endogenous and exogenous insulin. If high (> 200pmol/L) insulin is endogenous e.g. insulinoma or sulphonylurea induced hypoglycaemia.
- 6) serum beta hydroxybutyrate –> measured at time of symptoms or end of 72 hour fast, excessive insulin or insulin like growth factor ii inhibits ketogenesis –> lowers beta hydroxybutryrate (supports diagnosis of tumour). Need Beta hydroxybutryrate < 2.7 mmol/L
- 7) Serum sulfonylurea –> presence indicates iatrogenic hypoglycaemia, usually done in urine or serum. If positive know medication induced
- 8) Thyroid stimulating hormones –> to rule out thyroid dysfunction
- 9) serum cortisol –> low level to indicate adrenal glands or hypopituitarism as source of adrenal insufficiency.
What is the purpose of testing serum C peptide in hypoglycaemia?
C - peptide (from cleavage of proinsulin into mature insulin and C peptide) :
to distinguish between endogenous and exogenous insulin.
C peptide is a useful marker of insulin production.
High concentrations indicate high insulin (insulinoma, excessive insulin production e.g. reactive hypoglycaemia which indicates insulin resistance early), hypokalaemia, pregnancy, cushing’s, kidney disease.
Low conc of C peptide when insuffient insulin is produced by beta cells or production is suppressed by injected insulin.
What two further tests could be considered in the hypoglycaemic patient?
- 48-72 observed fast –> indicated in adults if presence of hypoglycaemic symptoms but blood glucose > 2.8 mmol/L. Blood glucose levels checked every 6 hours, once below 3.3 mmol/L then checked every hour w serum proinsulin, c peptide and insulin. Test ends with sympathoadrenal or neuroglypenic symptoms/ 72 hours passes or blood glucose drops below 2.8 mmol/L
- Oral glucose tolerance test –> performed to rule of diabetes mellitus, late reactive hypoglycaemia occuring within 3/5 hours after meal can occur in patients with prediabetes or impaired glucose tolerance/ pregnancy.
What is the treatment/ management of hypoglycaemia?
- If consious and orientated, give 15-20 g fast acting carbohydrate e.g. 200ml orange juice and repeat blood sugar monitoring every 15 minutes. Repeat snack up to 3 times.
- If conscious and non-cooperative, squirt glucose gel between teeth and gums
- If unconcious or above measures do not work:
- 10% or 50% dextrose IV
- Glucagon IV or IM (not appropriate in malnourshed patients)
- Once patient’s symptoms have recovered and glucose =. 4 mmol/L give long acting carbohydrate orally e.g. toast/ sandwich
- If overdose, consider psychiatric referral
- If insulinoma, or IGF2 secreting tumour, surgically excise and give glucaogn injections/ IV glucose.
- for renal failure/liver failure/ sepsis or other endocrinopathy treatment should focuse on management of underlying organ dysfunction. Support with glucose infusion may be necessary until condition resolves.
Glucose homeostasis: what are the actions of insulin?
- Insulin acts on insulin receptors on adipocytes/muscle cells to activate insulin receptor substrate 1 –> activates PI3K (phosphatidyly kinase) –> PIP2 converted to PIP3 –> activates AKT –> leads to transportation of GLUT4 vesicles to PM and activates glycogen synthase
- increase in glycogen synthesis
- increase in lipogenesis
- increase protein synthesis
- inhibit ketogenesis
- ultimately leads to lowering of blood glucose levels.
What is the counterregulatory hormone to insulin?
What are its actions?
- Glucagon: synthesised and released from alpha cells in islets of langerhans
- main stimulation for release is HYPOglycaemia, also stimulated by loss of suppression of insulin (when glucose low, no insulin release, no inhibition of glucagon release)
- ACTIONS:
- promotes gluconeogenesis
- glyogenolysis in muscle and liver
- inhibits lipogenesis and glucose uptake in adipose tissue
- promotes lipolysis and release of free fatty acids
- promotes ketogenesis and proteolysis (production of alternative energy substrates)
What is the pathophysiology of type 1 diabetes?
- autoimmunue destruction occurs subclinically for months/ years until 80-90% of beta cells are lost
- at this point hyperglycaemia develops due to absolute deficiency of insulin
- leads to decreased upatke and utilisation of glucose in muscel and adipose tissues leading to glucagon release –> increased proteolysis, lipolysis, glycogenolysis and gluconeogenesis
- patients often present with diabetic ketoacidosis: acidosis, ketosis and hyperglycaemia
Explain the underlying pathophysiology of diabetic complications:
Toxicity of glucose?
- Hyperglycaemia leads to increased glucose intracellularly, especially in cells with insulin- independent glucose uptake mechanisms
- cells which take up glucose independently of insulin = endothelial, renal, retinal, peripheral neurones.
- High glucose leads to increase in ROS, and activation of 4 main pathways: hexosamine, PKC/DAG, Polyol, and AGE p/w
- increase in DAG/hexosamine p/w leads to increase in vascular permeability and thrombogenesis
- polyol p/w leads to endothelial damage and AGE p/w leads to vascular inflammation & endothelial damage.
- this leads to vascular damage, and atheroma formation –> micro and macrovascular damage
LO: explain pathophysiology of diabetic complications
Retinopathy
- retinal damage due to chronic microvascular leakage and occlusion.
- can be non proliferative or proliferative
- ultimately leads to visual disturbance or loss
- Process:
- increased glucose uptake in retinal endothelial cells leading to increased ROS formation and activation of glucose pathways –> increased vascular permeability, inflammation, thrombogenesis and vascular damage
- increased vascular permeability –> leads to aneurysms, haemorrhage, oedema and cholesterol deposition
- Thrombogenesis –> leads to vessel occlusion and ischaemia/ infarction
- ischaemia –> can lead to angiogenesis (becomes proliferative retinopathy), fibrosis and retinal detachment
- Signs on examination:
- Cotton wool spots (nerve damage, accumualation of nerve cytoplasm- ischaemia )
- microaneurysms - discrete red spots
- macular thickening
- new vessel formation
- haemorrhages (red with less definable edges)
*
LO: explain pathophysiology of diabetic complications:
Neuropathy
Signs of this complication?
Neuropathy = peripheral nerve dysfunction with or without autonomic dysfunction
Process:
- Hyperglycaemia causes increase in ROS and AGE’s in peripheral nerve fibres
- Ultimately leads to damage and loss of schwann cells and peripheral neurones, particularly those which transmit PAIN and Temp input.
Presentation:
- Loss of sensation described as “glove and stocking” distribution.
- sensation loss is often patchy therefore examine multiple sites
- Presence if neuropathic deformity –> Charcot joint, pes cavus (high arch deformity), claw toes (fixed flexion), loss of transverse arch (flat arch at metatarsals).
- Ulceration –> usually painless
What is the pathophsiology of insulin resistance?
- high levels of fatty acids in blood leads to interference with insulin signalling pathway
- fatty acids in blood enter adipocytes/muscle cells and convert to ceramide which inhibits AKT2 (serine/threonine kinase). Also activates PKC which inhibits IRS1 (insulin receptor substrate 1), prevents GSK activation and GLUT4 translocation
- Hyperglycaemia persists
