Scenario 17 Flashcards by Holly Poulson

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

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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

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What does insulin and SST do to the other pancreatic hormones?

Inhibits them

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What does glucagon do to the other pancreatic hormones?

Stimulates them

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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Doe the removal of cAMP by phodiesterase cause HSL to be active or inactive?

Inactive- TAG not broken down to glycerol and FAs

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How is the insulin signal terminated?

Dephosphorylation of the proteins using protein phospatases. Phosphorylate serine/ theonine sites of IRS rather than tyrosine

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What is cyclosporine?

An immunosuppresor which stops the activation of Th and Tc so the islets cannot be killed- risk of malignancy

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If young at diagnosis what T cells would you expect to see?

Destructive

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If older at diagnosis what T cells would you expect to see?

Mixed regulatory and destructive

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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

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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

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What are the diagnostic criterea in gestational diabetes?

2 hour plasma glucose >7.8mmmol/l

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Why do we use fluoride oxalate in plasma glucose bottles?

To stop the glucose conc falling due to glycolysis in RBCs

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How much is a normal amount of glucose in urine?

0.1%

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What is serum fructosamine?

Testing for glycated albumin over previous 2 weeks, usefull in pregnancy

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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?

1. Fluid replacement- IV saline- slowly to avoid cerebral oedema 2. Insulin replacement- 0.1 units/kg/hour 3. Potassium replacement- once fluid and insulin started must replace K as soon as it begins going back into cells 4. Identify and treat the cause 5. 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?

1. Fluid replacement 2. Insulin replacement (slower than DKA- 0.05 units/kg/hour) 3. Identify and treat cause 4. 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