Diabetes Mellitus

Question 1

T1DM. Insulin preparations.

Answer 1

Human Insulin Analogues Short-acting insulins Intermediate/long-acting insulins

Question 2

T1DM. Human Insulin analogues. Use.

Answer 2

Modified insulin peptides (insulin lispro and insulin aspart) - have a rapid onset but short duration of action. May be injected before a meal/ when necessary after a meal. Increases flexibility and are useful for patients prone to pre lunch hypoglycaemia, and those who tend or eat late in the evening and may be at risk of nocturnal hypoglycaemia.

Question 3

T1DM. Short acting Insulins. Use.

Answer 3

Soluble insulins. Relatively short acting effects of 6-8hours, with peak at 2-5hours. Given approximately 15-30 minutes before meals.

Question 4

T1DM. Intermediate/ long acting insulins. Use.

Answer 4

Insulin + protamine = isophane insulin, INTERMEDIATE acting. Insulin + zinc = INTERMEDIATE to LONG acting insulin. Insulin + protamine + zinc = LONG acting insulin. Crystalline zinc insulin suspensions = LONG a acting. Biphasic preparations contain: INTERMEDIATE acting agent (e.g. Isophane insulin) With a SHORTER acting form (e.g. Soluble insulin).

Question 5

T1DM Regimens.

Answer 5

Can be adopted for individual needs. TWICE DAILY 2 daily injections - of short and longer acting insulins in combo 1x 30 minutes before breakfast (2/3 dose) 1x before the evening meal Most common regimen. MULTIPLE DOSING REGIMENS 1x medium-acting insulin given at bedtime Doses of short acting insulin given 30 minutes before each meal Allows flexibility with meal times “Basal Bolus” regimen. OR Short acting mixed + intermediate acting insulin given before breakfast Short acting given before evening meal Intermediate acting given at bedtime SINGLE DAILY REGIMENS 1x intermediate acting (+/- short acting) before breakfast/ at bedtime Rarely used For patients with T2DM, unable to control blood glucose with anti-diabetic drugs.

Question 6

What factors increase insulin requirements?

Answer 6

Stress Infection Accidental/ surgical trauma Puberty (GH effects) Later two trimesters of pregnancy

Question 7

What factors reduce insulin requirements?

Answer 7

Coeliac disease Renal/ hepatic impairment Endocrine disorders e.g. Untreated Addison’s

Question 8

Routes of insulin administration

Answer 8

INTRAVENOUS INFUSION Reliable Used in hospital/ acute care, bring DM under control Amount needed gives an indication of future daily requirements SUBCUTANEOUS INJECTION Use disposable syringe (in which insulins can be mixed) Conventional route Method has been overtaken by injection pens and biphasics. May lead to changes in the skin Site of repeated injections –> lipohypertrophy –> unpredictable insulin absorption. Important to rotate injection sites INSULIN PUMPS continuous subcutaneous administration Useful in difficult diabetes Advantage - continuous, can be increased at meal times Disadvantages - expensive, not available on prescription.

Question 9

What is the “honeymoon period”

Answer 9

In early stages of DM, patients experience a period where less insulin is required.

Question 10

T2DM features

Answer 10

Increased insulin resistance - loss of beta cells (but they still produce insulin) - tissues become less responsive - leads to increased blood levels Strong family association, late onset >40 Associated diseases: obesity/ HTN/ hyperlipidaemia Patient may have condition for several years (prediabetic phase) without recognition.

Question 11

T2DM Management initially

Answer 11

Mild/ initial disease –> dietary modification. - reduce amount of simple carbohydrates in diet - limit intake of mono and disaccharides - increase non- starch polysaccharides - reduce fat intake (reduce atherosclerosis risk) so that fat is 30-35% calorific intake and carbs are 50-55% - weight loss for obese - increased exercise If dietary changes alone are insufficient after 3 months then anti diabetic drugs are used.

Question 12

T2DM Drugs?

Answer 12

Sulphonylureas Meglitinide analogues Biguanides Thiazolindiediones (Glitazones)

Question 13

Sulphonylureas - examples and MOA

Answer 13

e.g. Glibenclamide, Gliclazide, Tolbutamide Increase insulin secretion Inhibit ATP sensitive K+ channels Normally…. Glucose leads to ATP production which inactivate the K+ channels, leading to cellular depolarisation, which results in calcium influx and insulin secretion. When glucose is low, ATP levels fall and ADP rises, K+ channels open, causing membrane hyperpolarisation and this decreases insulin resistance. Sulphonylureas…. Bind to a receptor associated with K+ATPase channels, resulting in channel closure, which leads to insulin release.

Question 14

Sulphonylureas. Side effects

Answer 14

Cause weight gain ( and increase insulin resistance), avoid in obesity. Awareness may be lost when using beta blockers (I.e. Beta blockers delay awareness of sulphonylurea induces hypo) Associated with causing hypoglycaemia, especially - in the elderly - with long acting agents such as glibenclamide - missing meals

Question 15

Meglitinide analogues. MOA and Examples.

Answer 15

E.g. nateglinide, repaglinide These also act on beta cells (but at a distinct site from the sulphonylurea receptor) to cause closure of the K+ATPase channels, leading to depolarisation and insulin release. Rapid rate of onset. Given at meal times to stimulate post prandial insulin secretion, which is relatively short lived. Their effects may be enhanced by the patient having a meal and they are referred to as prandial glucose regulators (PGRs).

Question 16

Biguanides. Example and MOA

Answer 16

E.g. Metformin Action less clear May activate AMP-kinase Drug choice for obese patients - does not cause weight gain Should no be used in renal impairment Does not cause hypoglycaemia

Question 17

Thiazolindiediones - “Glitazones”, example and MOA

Answer 17

E.g. Pioglitazone Activate nuclear peroxisome-proliferator-activated-receptor-gamma (PPAR-gamma), which alters gene expression and results in insulin-like effects. “Insulin sensitisers” which work by enhancing glucose utilisation in tissues, and so reduce insulin resistance. Effects include: - reduced haptic glucose output - increased glucose transporters (GLUT) in skeletal muscle with increased peripheral glucose utilisation - increased fatty acid uptake into adipose cells

Question 18

Thiazolindiediones “Glitazones” - Cautions

Answer 18

Liver function should be monitored May be used alone NICE 2003 - should not be used as second line their pay unless patient cannot tolerate metformin plus a sulphonylurea - or when either metformin/ sulphonylurea is not tolerated

Question 19

Diabetic complications - CVS

Answer 19

Increase risk CV mortality through IHD & stroke (70% patient deaths) BP regulation essential, British HTN society recommend >140/80 - ACEIs often first choice in DM patients. - reduce complications/ development of DM - Thizaides/ beta blockers/ Ca channel blockers all equally effective, BP lowering most important Heart protection study demonstrated in DM patients that SIMVASTATIN protects against CV events.

Question 20

Diabetic complications - Nephropathy

Answer 20

Long term consequence, may result in end stage renal failure. All with T1DM and microalbuminuria should receive ACEI. NICE 2002: Renal disease in T2DM - diabetic nephropathy likely in patients with albuminuria and/or increased plasma creatinine (accompanied by retinopathy) - for these patients, aim for good glycemic control below 6.5-7.5% - aim for BP >135/75 - and ACEI for renal and cardiovascular protection - AT1R antagonists may substitute for ACEIs if they are not tolerated

Question 21

T2DM, Treatment pathway

Answer 21

Pic

Question 22

T1DM Features

Answer 22

Destruction beta cells following viral infection/ autoimmune process. Inability of beta cells to produce insulin, fatal if untreated. Replace insulin in attempt to decrease blood glucose to normal and prevent complications.