Endocrine Flashcards
Human insulin preparations (NPH = Neutral Protamine Hagedorn, and regular insulin) do not replicate endogenous insulin due to the time to peak and duration of action. Why does this occur?
They form subcutaneous hexamers and polymers, which delay absorption and delay action.
How are rapid-acting insulin analogues different from human insulin preparations?
To produce an insulin preparation with a faster onset and shorter duration of action than regular insulin, modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action.
Rapid-acting insulin analogs (insulin lispro, aspart, and glulisine) have an onset of action within 5 to 15 minutes, peak action at 45 to 75 minutes, and a duration of action of two to four hours.
Long-acting insulin analogues include insulin glargine. How is this different from human insulin preparations?
Glargine is produced by modifications to the human insulin molecule that result in a change in the pH.
After subcutaneous administration glargine precipitates in the tissue forming hexamers, which delays absorption and prolongs duration of action.
Glargine has no appreciable peak and a duration of action that usually lasts 24 hours. Glargine CANNOT BE MIXED WITH RAPID-ACTING INSULINS as the kinetics of both the glargine and rapid-acting insulin will be altered.
Name the ultra-short acting insulin analogues.
List time to onset, time to peak effect and duration of action.
These “don’t LAG”
L: Insulin Lispro = Humalog
A: Insulin Aspart = Novorapid
G: Insulin Glulisine = Apidra
(HNA)
Onset: 0.25 hours
Peak: 1 hour
Duration: 4-5 hours
Give immediately before a meal.
Name the short-acting insulins.
List time to onset, time to peak effect and duration of action.
Neutral:
Actrapid,
Humulin R,
Hypurin Neutral
Onset: 0.5 hours
Peak: 2-3 hour
Duration: 6-8 hours
Give during 30mins pre-meal.
Long-acting insulin analogues include insulin detemir.
How does this differ from human insulin?
Insulin detemir is an acylated insulin; the fatty acid side chain allows albumin binding and results in prolongation of action.
- has a noticeable peak (compared with glargine)
- rarely lasts 24 hours
- BD injections necessary for optimal glycemic control
Detemir CANNOT BE MIXED WITH RAPID-ACTING INSULINS as the kinetics of both the detemir and rapid-acting insulin will be altered.
Name the long-acting (intermediate-acting) insulins and the mixes available.
List time to onset, time to peak effect and duration of action.
- Isophane:
Humulin NPH
Protaphane
Hypurin Isophane.
Onset: 1 - 2.5 hours
Peak: 4-12 hour
Duration: 16-24 hours
Unlike the long-acting insulin analogues, isophane insulin can be mixed with more rapidly-acting insulins and insulin analogues. These “biphasic insulins” are given once or twice daily.
List these mixes.
(a) mixed with short acting insulin:
Humulin 30/70
Mixtard 30/70
Mixtard 50/50
(b) mixed with ultra-short acting insulin analogues: NovoMix 30 (isophane and aspart) Humalog Mix25 (isophane and lispro) Humalog Mix50 (isophane and lispro)
Why does glycaemic control deteriorate in T2DM over time? Does this signal a switch to T1DM?
Decreasing insulin secretion.
No, there is not an absolute loss of insulin secretion and the pathology is different.
Pathology of T2DM: both INSULIN RESISTANCE (IR) and HYPOSECRETION OF INSULIN.
Most studies:
IR precedes an insulin secretory defect.
Diabetes develops only when insulin secretion becomes inadequate.
- Primary defect controversial
- Type 2 DM likely encompasses a range of disorders with common phenotype of hyperglycemia.
Neuropathic arthropathy is an uncommon complication of diabetes. Which joints are most commonly affected?
- tarsus and tarsometatarsal joints (ie. midfoot)
- MTPJs (metatarsophalangeal joints) and ankle joint
- upper limb joints (unusual)
Association with charcot arthropathy (collapse of arch of midfoot).
Usually in longstanding diabetes.
Features of virilisation / hyperandorgenism:
Hirsutism (Ferriman-Gallwey Score >8, or >2 in Asian women) Irregular menses / amenorrhoea Acne Frontal balding Deepening of voice Clitorromegaly Increased muscle mass
Approach to differentials for hirsutism - what to rule out and what’s common.
Need to rule out serious causes:
- Androgen-secreting tumors (ovarian or adrenal) - rare (particularly premenopause) 0.3% hirsute women.
- Ovarian hyperthecosis: severe hyperandrogenism and insulin resistance, mostly postmenopausal women
Evaluate for most common cause:
3. PCOS = 75-80% of women presenting with hirsutism
Other causes to check if suggestive features:
- Congenital Adrenal Hyperplasia - classic or nonclassic (ie. 21-hydroxylase [or CYP21A2] deficiency, especially in Ashkenazi Jewish population)
- Cushing’s syndrome
- Hyperprolactinaemia
- Idiopathic hirsutism (if other causes ruled out) - may be of emotional / psychological consequence, even if not pathological
Investigations for hirsutism:
** Pregnancy test if menstrual irregularities
1. serum testosterone (total)
2. DHEAS
3. 17-hydroxyprogesterone
(raised in 21-hydroxylase [or CYP21A2] deficiency = non classic (late-onset) CAH. Can be confirmed with ACTH / cosyntropin stimulation test)
4. Imaging:
- Ovarian USS
- CT adrenal glands if adrenal source suggested
5. Selective venous sampling (combined ovarian and adrenal vein sampling):
To show left to right gradient in androgen secretion between pairs of glands, to localise tumour.
Sometimes performed if high serum testosterone but negative USS and CT (suspect ovarian tumour as adrenal tumours almost always visualised on CT, but small ovarian tumour may not be seen on USS).
But technically difficult and interpretation can be difficult.
Interpretation of serum testosterone in hirsutism:
Serum testosterone (total):
- > 5.2 nmol/L requires further investigation for testosterone-secreting tumour (ovarian or adrenal) or ovarian hyperthecosis
- In PCOS may be <2.1). Degree of testosterone elevation correlates with metabolic features, but not degree of hirsutism
- free testosterone would be more sensitive for hyperandrogenism, but current assays inaccurate
Interpretation of serum DHEA-S levels in hirsutism:
> 18.9 µmol/L requires further evaluation.
Raises suspicion for an adrenal tumor, most importantly adrenal carcinoma (<10% adrenal carcinomas present with virilization alone, but the presence of virilization in a patient with an adrenal neoplasm suggests an adrenal carcinoma rather than an adenoma).
Presentation of adrenal carcinoma - proportions presenting with hormonal overproduction or glucocorticoids or androgens (or both):
45% Cushing’s syndrome alone
25% Mixed Cushing’s and virilisation syndrome
<10% Virilisation alone
Presence of virilisation with an adrenal neoplasm suggests an adrenal carcinoma rather than an adenoma.
PCOS diagnosis:
- hyperandrogenism (clinical or biochemical)
- ovulatory dysfunction (oligomenorrhoea / amenorrhoea)
- polycystic ovaries (by USS criteria)
+ Exclusion of other disorders
(thyroid disease, nonclassic congenital adrenal hyperplasia, hyperprolactinemia, and androgen-secreting tumors)
Controversy over which guidelines to use:
(a) Rotterdam criteria (2003): 2/3
(b) Androgen Excess Society (2008): 1 + either 2 or 3 + exclusion of other disorders
De Quervain’s (subacute) thyroiditis is associated with which HLA type?
HLA Bw35
Effect of amiodarone on pituitary?
Blocks deiodination in liver and pituitary - pituitary cannot read T4, only T3. Therefore thinks T4 is low - increased TSH release
How does the thyroid respond to iodine administration (–> iodide)?
Pre-existing iodine deficiency: Iodine administration with increase the production of thyroid hormones (resulting in normalisation of TSH).
High dose exogenous iodine (with pre-existing normal iodine levels):
- Wolff-Chaikoff effect: Transient inhibition of thyroid hormone synthesis by inhibiting iodination of tyrosine. However, may only last 8-10 days, after which the iodine transport system adapts to higher concentrations of iodine –> potential exacerbation of thyrotoxicosis.
- Reduces symptoms of hyperthyroidism in 1-2 days (blocks release of thyroid hormones from thyroid)
- Decrease in size and vascularity of the gland (over 10-14 days).
- Lugol’s iodine (oral solution of potassium iodide):
Used prior to surgical resection in hyperthyroid patients, or in thyroid storm.
Main systemic effects of thyroid hormones:
- Metabolic effects:
- increased metabolism of carbohydrate, protein, fat, mainly by actions on other hormones (insulin, glucagon, glucocorticoids, catecholamines).
- increased basal metabolic rate
- increased heat production and oxygen consumption
- increased HR and increased propensity to dysrhythmias (eg. AF) - Growth and development:
- direct actions on tissues
- indirectly: influences GH production and increases its effect
- moderates response to PTH and calcitonin
- skeletal development
- CNS growth and maturation
