Endocrine Topic 2 - Diabetes Flashcards
How can T1DM development be predicted?
High lysophosphatidylcholine
How are bisphosphonates administered?
- Oral or IV administration, depending on preparation, free drug excreted by kidney
- Alendronate oral once weekly on an empty stomach with large glass of water, upright, 30 minutes before breakfast
- Zolendronate IV once weekly
How is T1DM treated?
Insulin replacement
Islet transplant
How is DKA treated?
IV fluid, insulin, potassium (cardiac monitoring), NG tube (vomiting)
Describe the normal pattern of insulin secretion
Natural insulin secretion - basal low, steady background secretion, bolus meal-time insulin
List the sources of replacement insulin
- Human - recombinant DNA technology
- Human analogues - recombinant DNA technology modified for desired kinetic characteristics
- Animal insulin - bovine or porcine (no longer initiated)
What is the diabetic response to hyperglycaemia?
- No insulin production
- No glucose uptake by cells (no GLUT 4 action)
- Blood glucose remains high
What causes insulin resistance?
- Occurs with age, exacerbated by increasing weight, due to genetic susceptibility (ethnicity, parent/1st degree relative), environmental triggers
- Adipokines have role e.g. Leptin (acts on hypothalamus to regulate fat stores), adiponectin (reduces free fatty acids, high free fatty acids disrupt insulin signalling), Resistin (increases hypothalamic stimulation of glucose production)
- Insulin receptor gene mutations
- Increased inflammatory mediators - CRP, IL6, TNF alpha
What is the normal response to hypoglycaemia?
- Descreased insulin production by beta cells - decreased glucose uptake by fat/muscle/liver
- Increased glucagon production by alpha cells - increased glycogenolysis and gluconeogenesis
List the possible mechanisms of action of drugs used to treat T2DM
- Decrease glucose absorption (GI tract)
- Increase glucose uptake (muscle/fat)
- Decreased glucose reabsorption (renal tubules)
- Increased insulin production (pancreas)
- Decreased gluconeogenesis (liver)
How is diabetic retinopathy treated?
- Glycaemic control
- Ophthalmic reveiw - laser, VEGF inhibitors (bevacizumab), vitrectomy
- Screening - annual from age 12
What are the symptoms of hypoglycaemia?
- Initital autonomic
- Sweating
- Tremor
- Palpitations
- Hunger
- Anxiety
- Later neuroglycopaenic
- Confusion
- Decreased consciousness
Give examples of bisphosphonates
End in -dronate e.g. alendronate, zolendronate
What happens to potassium concentration in reponse to hyperglycaemia?
- Increased aldosterone production to increase water retention (counteract water loss due to osmotic diuresis)
- Hyperaldosteronism - renal K+ loss
- Lack of insulin - no K+ into cells (KATP)
- Plasma K+ rises, total body K+ falls
Describe the pathophysiology of T2DM
- Increasing insulin resistance
- Initial hyperinsulinaemia to compensate (in pre-diabetes/early stage), then reduced secretion
- Glucotoxicity - impaired beta cell function
- Glucokinase defects
- Pancreatic beta cell transcription factor mutations
- Macrovascular then microvascular complications
What is the diabetic response to hypoglycaemia?
- Increased cortisol
- Increased adrenaline - tremor, sweating
- Increased acetyl choline, noradrenaline (sympathetic) - hunger
What stimulates release of mineralocorticoids?
Stimulated by angiotensin II, ACTH and potassium
How can macrovascular complications of diabetes be prevented?
BP/cholesterol control and not smoking
How do bisphosphonates function?
- Carbon substituted pyrophosphate
- Bind to bone and inhibit osteoclast activity
Compare DKA and HHS (hyperosmolar hyperglycaemic state)
- DKA - short history, HHS - insidious
- DKA - young T1DM, HHS - old T2DM
- DKA - no residual insulin, HHS - residual insulin
- DKA - hyperglycaemia, HHS - profound hyperglycaemia
- DKA - dehydration, HHS - significant dehydration
- DKA - acidosis, HHS - no acidosis (no increased in lipolysis, no ketones)
- DKA - patient usually alert, HHS - patient often drowsy
- HHS - hypernatraemia
- HHS - high mortality (comorbities)
How is an oral glucose tolerance test performed?
75g anhydrous glucose, blood glucose concentration taken every 30-60 minutes
Describe the 3rd line treatment of T2DM
- Add different oral agent or injectable agent
- BMI > 30 - GLP1 agonist
- BMI < 30 - basal insulin
What treatments are used for osteoporosis other than bisphosphonates?
- Calcium and Vitamin D - essential for bone formation
- Denosumab - monoclonal antibody, inhibits RANK ligand which signals to osteoclasts, therefore reduces resorption, subcutaneous injection every 6 months
- Teriparatide - recombinant parathyroid hormone, binds to osteoblasts to increase bone formation, requires subcutaneous injection as it is a peptide
- Strontium ranclate stimulates osteoblasts and inhibits osteoclasts
- HRT for menopause related bone loss
- SERMs - bind to oesteogen receptor and decreases bone resorption
What is the function of DPP-4?
Breaksdown GLP-1
List the types of diabetes mellitus
- Type 1
- Type 2
- Maturity onset diabetes of the young (MODY)
- Gestational
- Secondary - pancreatitis, cystic fibrosis, haemachromatosis, steroid induced
List the types of diabetic neuropathy
- Peripheral neuropathy
- Autonomic neuropathy
- Mononeuritis multiplex - painful motor/sensory, 2+ nerves
- Diabetic amyotrophy - painful proximal neuropathy (thigh/buttock)
What causes MODY?
- Autosomal dominant
- Mutations - HNF1 alpha, glucokinase, HNF4 alpha, HNF1 beta, neonatal (K+ channel deficiency)
- Insulin produced but not secreted by beta cells
Describe the pharmacokinetics and pharmacodynamics of thiazolidinediones
- Pharmacokinetics
- Rapidly absorbed
- Extensive hepatic metabolism
- Pioglitazone excreted in bile
- Pharmacodynamics
- PPAR alpha agonists - increase transcription of insulin sensitising genes
- PPAR alpha is a nuclear receptor expressed in adipose tissue, muscle and liver
- Increased insulin sensitivity over weeks-months
How is MODY treated?
Sulphonylureas e.g. Glicazide
Which drugs are used to treat T2DM by increasing insulin secretion by the pancreas?
Insulin, sulphonylureas, meglitinides, GLP-1 receptor agonists, DPP4 inhibitors
Describe the clinical features of DKA
- Metabolic acidosis (pH < 7.3, bicarbonate < 15mmol/L)
- Usually hyperglycaemia (>13.9 mmol/L)
- Ketosis
- Dehydration
How must insulin be administered? Why?
- Injected - subcutaneous, usually into abdomen or outer thigh/buttocks
- Peptide hormone - inactivated by GI enzymes, can’t be given orally
Describe the 1st line treatment of T2DM
- Lifestyle and metformin/sulphonyurea
- Targe = <7% HbAlc
List the genes which cause type 1 diabetes susceptibility
- HLA - DR3/4 and DR2/8 - largest genetic effect
- Protein tyrosine phosphatase PTPN 22
- CTLA-4 - cytotoxic T lymphocyte associated protein 4
How does bone resorption occur?
Preosteoclasts –> osteoclasts –> acid and lysosome secretion –> bone resorption at ruffled membrane
List the risk factors for T2DM
- Age >40 (or 25 if south Asian)
- Parent/1st degree relative with T2DM
- Overweight/obese
- South Asian, Chinese, Afrocaribbean or black African origin
- Hypertension
- High waist circumference
- Schizophrenia, bipolar illness, depression or treatment with anti-psychotic medication
- Women with polycystic ovaries, gestational diabetes or baby weighing >10 lbs
Describe the types of insulin replacement regimens
- Basal-bolus insulin regimens - 1/2 daily long or intermediate-acting insulin with bolus
- Mixed biphasic - short and intermediate, short-acting before meals
- Continuous subcutaneous insulin infusion (pump) - continuous short acting
How is hypoglycaemia treated?
- Mild (blood glucose < 4 mmol/L)
- 15-20g fast-acting carbohydrate
- Retest 15-20 minutes later
- Severe (requiring help from another person)
- 15-20g fast-acting carbohydrate, retest 15-20 minutes later
- If decreasing consciousness - IM glucagon, IV dextrose
- Retest
- Follow with long-acting carbohydrate