Scenario 17 Flashcards
How can you diagnose diabetes?
Symptoms and blood glucose >11.1mmol/l or no symptoms and HbAC1>48mmol/l or 6.5% on two occasions and fasting plasma glucose >7mmol/l and 2 hours after glucose 11.1mmol/l on 2 occasions
What proportions of the islets secrete each hormone?
60-80% are insulin secreting beta cells. 20-40% are glucagon secreting alpha cells and somatostatin secreting delta cells
What does insulin and SST do to the other pancreatic hormones?
Inhibits them
What does glucagon do to the other pancreatic hormones?
Stimulates them
How is insulin secreted?
Glucose enters the cell via GLUT-2 converted to pyruvate- TCA and ox phos creating ATP which binds to Katp closing the channel causing a build up of K in the cell, depolarising the membrane activating voltage dependent Ca channels allowing it to enter the cell facilitating exocytosis of the secretory granules from the cell
Other factors which affect insulin secretion
Incretins released from GI tract in response to food potentiate secretion and NA inhibits secretion as does Adr whereas Acetylcholine stimulates secretion
What is the role of glucagon?
Codes for GLP-1 in gut L cells. Stimulated by low blood glucose and acts on receptors linked to adenylate cyclase to break down glycogen to glucose especially in the liver
What is normal metabolism in the fed state?
Glucose to liver to be stored as glycogen excess stored as VLDLs in adipose tissue, muscles and adipose take up glucose using GLUT-4. AAs taken up by tissues for protein synthesis
What is metabolism in the fasting state?
Glycogen from the liver is degraded to glucose, brain and RBCs still use glucose but muscle uses FA instead of glucose. After time muscle protein is degraded to ketone bodies whihc can be used by the brai and muscles. AA breakdown causes increased urea
What is metabolism in type 1 diabetes?
Glucose from gluconeogenesis even if blood glucose is high. Muscle breakdown is uncontrolled, TAG broken down, ketone and glucose in the urine and blood
What are the cellular effects of insulin?
Increased glycogen synthesis, glucose uptale in lier and muscle, FA synthesis in the liver, DNA replication and protein synthesis
What is the mechanism for a insulin receptor?
Insulin binds to the tyrosine kinase receptor causing phosphorylation of the tyrosine of protein and can then phosphorylate other proteins causing either the PI3-K pathway (immediate metabolism, increases glut-4 on muscle and adipose) or MAP kinase pathways (cell growth and differentiation through ras and raf)
Does phosphorylating glycogen synthase kinase activate or inactivate it?
Inactivate- cant phosphorylate the glycogen synthase so it remains active allowing the translocation of GLUT 4 to the membrane
Doe the removal of cAMP by phodiesterase cause HSL to be active or inactive?
Inactive- TAG not broken down to glycerol and FAs
How is the insulin signal terminated?
Dephosphorylation of the proteins using protein phospatases. Phosphorylate serine/ theonine sites of IRS rather than tyrosine
What is cyclosporine?
An immunosuppresor which stops the activation of Th and Tc so the islets cannot be killed- risk of malignancy
If young at diagnosis what T cells would you expect to see?
Destructive
If older at diagnosis what T cells would you expect to see?
Mixed regulatory and destructive
Why is there metabolic alkalosis in diabetes?
Pulmonary compensation- ketones produced are acidic so hydrogen ions increase and shift equilibrium left so increased CO2- Kaussmaul breathing
Renal compensation- inability for kidney to buffer H- Na and K lost in the urine
Why is potassium lost in diabetes?
Normally insulin causes glucose to be taken up and K follows but this doesnt happen and K is excreted as too much in the blood
What are the diagnostic criterea in gestational diabetes?
2 hour plasma glucose >7.8mmmol/l
Why do we use fluoride oxalate in plasma glucose bottles?
To stop the glucose conc falling due to glycolysis in RBCs
How much is a normal amount of glucose in urine?
0.1%
What is serum fructosamine?
Testing for glycated albumin over previous 2 weeks, usefull in pregnancy
Ketone testing disadvantage on strips
Doesnt detect beta-hydrocubutyric acid
Blood ketone testing range
<0.6 normally, >1.5 DKA
Normal urine protein
<100mg over 24 hours
What is microalbuminuria defined as?
30-300mg over 24 hours- 20x risk of diabetic renal disease and progression of CVD
How do you diagnose DKA?
<11mmol or know diabetes, ketones >3mmol or >2+ ketonuria, bicarbonate <15 or venous pH <7.3
What is DKA?
Hyperglycaemia, hyperketonaemia and metabolic acidosis
What are the causes of DKA?
Infection, poor compliance, newly diagnosed, failure of care
What are the signs and symptoms of DKA?
Polyuria, polydipsia, weight loss, blurred vision, vomiting abdominal pain, weakness, leg cramps, confusion
Kaussmaul respiration, ketotic factor, dehydration, hypotension, tachycardia, drowsiness, coma
What is the treatment for DKA?
- Fluid replacement- IV saline- slowly to avoid cerebral oedema
- Insulin replacement- 0.1 units/kg/hour
- Potassium replacement- once fluid and insulin started must replace K as soon as it begins going back into cells
- Identify and treat the cause
- Venous thromboembolism prophylaxis
What is HHS?
State of severe uncontrolled diabetes but enough insulin to suppress ketogenesis- type 2
What is HHS characterised by?
Hypervolaemia, hypoglycaemia (>30mmol/l), hyperosmolality (>320mosmol/kg) no significant ketonaemia or acidosis
Complictions of HHS
Life threatening, develops over days and metabolic disturbance is more severe than DKA, cerebral oedema, central pontine myelinolysis, seizures, thrombosis, co-morbidity likely
What is the treatment for HHS?
- Fluid replacement
- Insulin replacement (slower than DKA- 0.05 units/kg/hour)
- Identify and treat cause
- Venous thromboembolism prophylaxis
What is hypoglycaemia defined as?
Blood glucose <3.5mmol/l
What is an example of a biguanides?
Metformin
What does metformin do?
Absorbed in SI (half life 3 hours), decreased blood glucose by decreasing hepatic glucose production and potentiatinf insulin action, stimulate glycolysis
Does metformin cause hypoglycaemia?
No (or weight gain)
What are the side effects of metformin?
Diarrhoea, nausea, metallic taste, decreased absorption of folate and B12
What are sulphonlyureas and s/e?
Activate K channel independent of glucose so more insulin is released. Side effects mainly hypoglycaemia
What is the action of thiazolidineodines?
Activates insulin responsiveness genes that contorl carb and lipid metabolism- reduces glucose production by liver and uotake in muscle and liver. Eg Proglitazone- can cause weight gain and fluid retention
What are meglitinides?
Repaglinide and Nateglinide- half life 1 hour, close K ATP channels on beta cells
What are incretins?
Stimulates insulin release by acting on incretin receptor also suppresses glucagon secretion, reduces appetite and weight
What are DPP4 inhibitors?
Stop breakdown of incretins
What are alpha-glucosidase inhibitors?
Inhibit intestinal brush border alpha-glucosidase, inhibit carb breaksown and reduce post prandial blood glucose increase (in both types) S/E flatulance and diarrhoea
How do S-GLUT2 inhibitors work?
Inhibit glucose reuptake in the kidney
What are amyline analogues?
Decrease gastric emptying, inhibits glucagon release (type 1 or 2)
What treatment can be used for retinopathy?
Laser Photocoagulation
What is the role of VEGF in retinopathy?
Tries to produce new bood vessels
What is GFR by end stage renal disease?
<10ml/min
What is the average amount of time until ESRD?
23 years
How many men with long standing diabetes get erectile dysfuntion?
50%
Is the risk of complications the same for everyone with similar sugar control?
No it is also genetically influenced
What is glycosylation?
Glucose binding non-enzymatically to free AA residues- lysine
What damage can glycosylation cause to proteins?
Complex cross-linking, loss of flexibiltiy and functionality
Where does glycosylation occur?
Kidney, eye lens, arterial collagen, nerve myelin proteins, circulating LDL
What do glycated proteins form?
AGEs- basis for oxidative stress hard to turn over proteins
What does oxidative stress result in?
Increased free radicals which cause endothelial damage and decrease NO availability causing vasoconstriction and damage to blood vessels
What is the result of increased TGFbeta?
Scarring in kidney and eye, less ECM breakdown, BM of glomerulus thickens
What affect can diabetes have on the arterioles in the glomerulus?
Paralysis of tone which is much bigger in the afferent so much wider than efferent so more blood enters glomerulus increasing GFR- use RAAS inhibitor to lower pressure
