Session 3: Diabetes

Question 1

What is T1DM vs T2DM?

Answer 1

Type 1 - Autoimmune reaction to B cells in islet of Langerhans. Number of B cells reduced, insulin not produced, hyperglycaemia. Sudden onset.

Type 2 - Pancreas makes less insulin, body becomes insulin resistant. Chronic, familial, diet related.

Question 2

What are the three stages of T1DM?

Answer 2

1: Prescence of B cell autoimmunity (2 or more B cell autoantibodies with normoglycaemia).
2: Presence of B cell autoantibodies with dysglycaemia and asymptomatic. 3: Onset of symptomatic disease.

Question 3

What is Gestational diabetes?

Answer 3

Placenta produces growth factors which causes insulin resistance. Body needs insulin for foetus. If patient already at higher risk then pregnancy can cause onset of diabetes.

Question 4

What is Maturity Onset Diabetes of the Young (MODY)?

Answer 4

• Behaves like type 1 and type 2 diabetes.
  Autosomal dominant
  Strong FHx
  Often wrongly diagnosed and treated lie type 1 (insulin) - better treated with sulfonylureas

Question 5

How does diabetic ketoacidosis occur?

Answer 5

When blood glucose is increased, insulin is utilised for glucose entry and metabolism.
Absence of insulin, glucose accumulates in the blood stream, forming fatty acids and ketone bodies. T1DM need insulin for survival.

Question 6

What are the typical pathogenic features of hyperglycaemia in T2DM?

Answer 6

1. Decreased incretin effect
2. Increased lipolysis
3. Increased glucose reabsorption
4. Decreased glucose reuptake
5. Neurotransmitter dysfunction
6. Increased hepatic glucose production
7. Increased glucagon secretion
8. Impaired insulin secretion

Question 7

What is the incretin effect?

Answer 7

Oral glucose elicits higher insulin secretory responses than IV glucose, despite inducing similar levels of glycaemia in healthy individuals. This effect is reduced in T2DM.

Question 8

What neurotransmitter dysfunction occurs in T2DM?

Answer 8

Insulin and appetite interact in the brain when neurotransmitters in the hypothalamus gland signal satiety in response to increased insulin

Question 9

Which drugs treat impaired insulin secretion?

Answer 9

Thiazolidinediones, GLP-1 analogues, DPP-4 inhibitors improve B cell function.
GLP-1 analogues, DPP-4 inhibitors, Sulfonylureas, and Meglitinides directly stimulate insulin secretion

Question 10

Which drugs treat increased lipolysis? TZDs.

Answer 10

TZDs.

Question 11

Which drugs treat increased hepatic glucose production and decreased glucose uptake?

Answer 11

TZDs and Metformin.

Question 12

What is HbA1c?

Answer 12

Glycosylated Hb. Gives mean glucose within the last 20 days.

Question 13

What complications can come with T2DM?

Answer 13

Ischaemia, peripheral arterial disease (PAD), nephropathy, neuropathy.

Question 14

What are the indications for GLP-1 analogues and DPP4 inhibitors?

Answer 14

Reduces HbA1c, reduces risk of diabetic complications such as CVD and stroke. Helps reduce weight.

Question 15

What is the MoA or GLP-1 analogues?

Answer 15

When food is digested, GI tract releases incretin hormones (GLP-1 and GIP) They enhance the glucose-dependent release of insulin from the B cells, promoting peripheral glucose uptake.

GLP-1 and GIP also bind to alpha cells, reducing glucagon secretion. Combined, these mechanisms reduce hepatic glucose output.

GLP-1 also promotes satiety reducing appetite and regulating gastric emptying.

Question 16

What are the side effects of GLP-1 analogues?

Answer 16

Pancreatitis can cause resistance. Nausea and vomiting. Weight loss

Question 17

What are the benefits of using DPP4-4 inhibitors as opposed to GLP-1 analogues.

Answer 17

Pros: Weight neutral, often well-tolerated, no resistance, no GI motility problems or decreased appetite, no hypoglycaemia when used as a monotherapy, low potency.

Question 18

What is Familial Renal Glucosuria and how does it present?

Answer 18

Presentation: Glucosuria: 1-170g/day. Asymptomatic.
Bloods: Normal blood glucose, no hypoglycaemia or hypovalaemia.
Kidney/bladder: no tubular dysfunction. Normal histology and function.
Complications: No increased risk of CKD, diabetes or urine infection.

Question 19

How is glucose handled by the kidneys?

Answer 19

SGLT2 receptors are responsible for glucose reabsorption. The SGLT2 receptor is defective in patients with familial renal glucosuria.

Question 20

What is the 1st choice medication for T2DM and what lifestyle advice is given?

Answer 20

Metformin.
Weight reduction and calorie restricted diabetes diet.

Question 21

What needs to be considered when prescribing Metformin and why?

Answer 21

Renal function. Avoid metformin if eGFR < 30. Risk of accumulation leading to lactic acidosis.

Question 22

How should metformin be introduced?

Answer 22

Gradually increase the dose of standard-release metformin over several weeks to minimise the risk of GI side effects.

Question 23

What are the side effects of metformin?

Answer 23

Common: Abdominal pain, anorexia, diarrhoea, nausea, taste disturbance. vomiting
Rare: decreased B12 absorption, erythema, lactic acidosis, pruritis, urticaria. (swollen hives)

Question 24

What is the MOA of metformin?

Answer 24

Oral metformin is absorbed by the hepatocytes from the portal vein through plasma membrane transporters, including the organic cation transporter (OCTI).
inside the cell, metformin inhibits mitochondrial respiratory-chain complex I resulting in reduced ATP levels and increased AMP.
Increased AMP activates adenosine monophosphate-activated protein kinase (AMPK), which contributes to the lowering of glucose production by at least 2 pathways.

Question 25

What are the two pathways that contribute to the lowering of glucose production through increased AMPK?

Answer 25

1. increased AMPK phosphorylation of CBP and CRTC2 transcription factors, inhibiting genes involved in the production of glucose. 2. increased AMPK inhibits g; glycerol-3-phosphate dehydrogenase leading the an increase in cytosolic NAPDH, which stimulates the conversion of pyruvate to lactate and decreases gluconeogenesis.

Question 26

What is the MOA of sulfonylureas and glinides?

Answer 26

A rise in plasma glucose level associated with a meal results in increased glucose uptake, followed by intracellular metabolism increasing intracellular metabolism increasing intracellular ATP. this inhibits ATP-sensitive K channels resulting in membrane depolarisation, and activating Ca channels. A rise in intracellular calcium promotes the fusion of vesicles containing insulin with the cell membrane and subsequent release of insulin. sulfonylureas and glinides bind to the site on the sulfonylurea receptor channel substrate, inhibiting K channels, and leading the the release of insulin.

Question 27

What is the difference between Sulfonylureas and Glinides?

Answer 27

Glinides bind with lower affinity than sulfonylureas, and as a result have a much shorter duration of action. To be effective, glinides have to be given with each meal, while sulfonylureas can be given once a day.

Question 28

What are the downsides of Sulfonylureas?

Answer 28

Can cause hypoglycaemia, weight gain, and GI side effects

Question 29

What is the MoA of TZDs? e.g. Pioglitazone

Answer 29

TZDs, or insulin sensitizers, are synthetic compounds that activate PPARy, a transcription factor expressed in various tissues including muscle, fat, and liver. Activation of PPARy by TZDs enhances the expression of genes involved in glucose and lipid metabolism, insulin signalling, and fat cell development. One way TZDs lower blood sugar is by increasing the expression of GLUT4, a glucose transporter, which improves glucose uptake into cells in response to insulin. Pioglitazone, a TZD, also activates PPARy, leading to lipid-lowering effects.

Question 30

What risks are associated with Thiazolidinediones TZDs?

Answer 30

Weight gain, oedema, heart failure (especially when given with insulin), small bone fractures (especially in women), small increased risk of bladder cancer

Question 31

What are SGLT2 inhibitors and examples?

Answer 31

A class of drugs that lower your blood sugar levels by preventing your kidneys from reabsorbing sugar that is created by your body and the extra sugar leaves through in your urine. e,g, dapagliflozin

Question 32

What is the MOA of SGLT2 inhibitors?

Answer 32

- A sodium-glucose low affinity and high capacity co-transporter expressed in the proximal renal tubule. reabosrbs 905 of filtered glucose. SGLT1 assists SGLT2. preventing glucose from appearing in urine. Inhibitors of SGLT2 reduce glucose reabsorption, leading to more glucose excreted in urine and lower blood glucose levels, without relying on insulin.

Question 33

Pros and cons of SGLT-2

Answer 33

Pros: No hypoglycaemia as monotherapy, weight neutral (may aid weight loss)< good glucose lowering effects Cons: UTI and candidiasis, hypovolaemia (uncommon), DKA (rare), fourniers gangrene (rare)

Question 34

What features are required to diagnose diabetic ketoacidosis (DKA)?

Answer 34

1. Ketonaemia >3mmol/L OR ketonuria (+2 urine stick) 2. Blood glucose>11mmol/L (hyperglycaemia) OR known DM 3. Bicarbonate (HCO3-) <15mmol/L AND/OR venous ph <7.3 (acidosis)

Question 35

What is the immediate management of DKA?

Answer 35

Within 1hr: 1. IV fluids -If patient in shock, 0.9%NaCl 500mls over 15 mins Repeat is BP still <100mmHg. If patient not shocked, 1L over 1hr. 2. After fluids, fixed rate IV insulin infusion (50 units actrapid in 49.5ml 0.9% NaCl) 3. Monitoring regime specific to each patient, generally: hourly blood glucose, hourly ketones, 2 hourly potassium and bicarbonate for 6 hours. 4. Clinical and biochemical assessment of patient.

Question 36

What are the characteristics of a person with Hyperosmolar hyperglycaemic state?

Answer 36

Hypovalaemia and marked hyperglycaemia (<30mmol/L), without significant hyperketonaemia (<3mmol/L) or acidosis (>7.3mmol/L, bicarbonate >15mmol/L), and osmality >320mosmol/kg.

Question 37

How is HHS managed differently to DKA?

Answer 37

1. IV fluids before insulin essential 2. No IV insulin until glucose stops falling by 5mmol/L using IV fluids 3. If IV insulin needed then use low dose (0.5 units/kg/hr) 4. Need for thromboprophylaxis 5. Look for infection and treat it 6. Foot care

Question 38

How is hypoglycaemia managed in Adults who are conscious, orientated and able to swallow?

Answer 38

Give 15-20g quick acting carbohydrate of the patient's choice where possible e.g. 5-7 Dextrosol tabs (or 4-5Glucotabs) 1 bottle (60ml) Glucojuice 150-200ml pure fruit juice 3-4 heaped teaspoons sugar dissolved in water

Question 39

How would you manage hypoglycaemia if patient was conscious but confused, disorientated, unable to cooperate or aggressive but are able to swallow?

Answer 39

Either 1.5-2 tubes 40% glucose gel squeezed into mouth between teeth and gums OR give glucagon 1mg IM (may be less effective in patients prescribed sulfonylureas or patients under the influence of alcohol)

Question 40

How would you manage hypoglycaemia in adults who are unconscious and/or having seizures and/or are very aggressive?

Answer 40

Three options in hospital: 1. If IV access available, 75-100ml of 20% glucose over 15 mins (300-300ml/hr) 2. If IV access available, 150-200ml 10 glucose (600-800ml/hr) 3. If no IV access, 1mg glucagon IM.

Question 41

How are patients with diabetes managed in preoperative care?

Answer 41

Depends on surgery (major vs minor) Day surgery may only need reduction in insulin dose or omission/continuation of oral drug Use of variable insulin infusion and glucose Prevention of hyper and hypoglycaemia Transition back to usual diabetes regimen

Question 43

What are the sick day rules for T1DM?

Answer 43

Always continue insulin. Consume sugar-free fluids to avoid dehydration (1ml/hr). Consider insulin correction doses. If blood glucose is 10-13mmol/L, increase insulin by 10% and monitor every 4 hours. If ineffective after 24 hours, increase by another 10%. If blood glucose exceeds 13mmol/L, increase insulin by 10% and administer rapid-acting insulin every 2-4 hours. Test for ketones; if moderate or large, test every 2 hours until normal.