Diabetes Flashcards
What is the target HbA1c for patients with Diabetes?
Below 48 mmol/mol (>6.5%)
What is the first line treatment for Type 2 Diabetes and QRISK of 10% or higher?
Metformin and consider SGLT-2 inhibitor (as soon as Metformin is tolerated).
What is the first line treatment for patients with Diabetes for Hypertension
An ACE inhibitor or an ARB
Why is an ACE inhibitor or an ARB ideal for patients with Diabetes?
Because they are renoprotective. They reduce the risk of reduced kidney function as a result of potential Diabetic Nephropathy
What is the WHO diagnostic blood glucose result for Type 2 Diabetes (with symptoms)?
Random venous plasma glucose ≥ 11.1 mmol/l
Fasting venous plasma glucose ≥ 7.0 mmol/l
What are the symptoms of Diabetic Ketoacidosis (DKA)?
Hyperventilation, nausea & vomiting ,
dehydration, weakness, ketone breath, reduced
consciousness
What are the symptoms of Hyperosmolar non-ketotic syndrome (HONK)?
Similar to DKA, however there is no ketosis or acidosis. It is still a medical emergency.
What are the tell-tale symptoms of Diabetes?
Polyuria, Polydipsia, Weight loss, Fatigue, Blurred vision
What are the clinical manifestations of Type 2 Diabetes?
Chronic skin infections, vaginal fungal infections, UTIs
Name some medium/long-acting Insulins
Lantus, Humulin I, Levemir
Name some rapid-acting Insulins
Novorapid, Humalog, Apidra
Name some short-acting Insulins
Actrapid, Humulin S, Hypurin Porcine Neutral
Name some mixed analogue Insulin regimes
Novomix 30, Humalog Mix 25/50
Name some mixed human Insulin regimes
Humulin M3, Insuman Comb 15/25/50, Hypurin Porcine 30/70 Mix
Tresiba
Insulin Degludec
Levemir
Insulin Determir
LAntus
Insulin GLArgine
HumaLog
Insulin Lispro
ApIdra
Insulin Glulisine
NovoRapid
Insulin Aspart
What is the pharmacological target of Sulphonylureas?
The ATP sensitive K+ channel in beta cells
What is the mechanism of action of the Sulphonylureas?
They block the K+ channel in beta cells which causes depolarisation and the activation of Ca2+ channels thus causing influx of Ca2+ and a downstream release of Insulin via secretory granules and exocytosis
Name a Sulphonylurea
Gliclazide, Glimepiride
What is the pharmacological target of GLP-1 agonists?
Glucagon-like peptide 1 receptor
What is the mechanism of action of GLP-1 agonists?
Activate the GLP-1 receptor (GPCR) and therefore decreases glucagon levels, increases glucose-dependent insulin release and delays gastric emptying which increases satiety.
Name a GLP-1 agonist
Exenatide, Liraglutide (Saxenda), Semaglutide (Ozempic)
What is the pharmacological target of DPP-4 inhibitors?
Dipeptidyl peptidase-4 (DPP-4)
What is the mechanism of action of DPP-4 inhibitors?
They decrease the breakdown of GLP-1 via inhibiting DPP-4. Therefore, GLP-1 can perform its function for longer.
Name a DPP-4 inhibitor
Alogliptin, Sitagliptin, Saxagliptin
What is the pharmacological target of Metformin?
Complex 1 in mitochondria (Liver)
What is the mechanism of action of Metformin?
Inhibition of ATP production in mitochondria in the liver, leading to a inhibition of gluconeogenesis. Increase in AMP production activates AMPK, a protein that affects the transcription of gluconeogenesis enzymes.
What is the pharmacological target of PPAR-gamma agonists?
Peroxisome proliferator-activated receptor gamma
What is the mechanism of action of PPAR-gamma agonists?
Increase insulin sensitivity by increasing the transcription of genes involved in insulin signalling which increases the effectiveness of insulin.
Name a PPAR-gamma agonist
Pioglitazone
What is the pharmacological target of SGLT-2 inhibitors?
Sodium-glucose co-transporter 2 (Kidneys)
What is the mechanism of action of SGLT-2 inhibitors?
Inhibition of the SLGT-2 co-transporter in proximal tubule, which therefore increase the excretion of glucose in urine and decrease the re-absorption of glucose.
Name a SGLT-2 inhibitor
Dapagliflozin, Empagliflozin, Canagliflozin
What is the pharmacological target of alpha-glucosidase inhibitors?
alpha-glucosidase (maltose)
What is the mechanism of action of alpha-glucosidase inhibitors?
Inhibition of maltose, which therefore reduces glucose absorption and in turn decreases the blood glucose concentration after a meal.
Name an alpha-glucosidase inhibitor
Acarbose
What are the micro-vascular complications of Diabetes?
Retinopathy, Nephropathy, Neuropathy
What are the macro-vascular complications of Diabetes?
Hypertension and Hyper-lipidaemia
Why are the eyes, kidneys and nerves vulnerable to damage?
Because the endothelial cells of the retina, kidneys and peripheral nervous system allow glucose to enter the cells even in the absence of insulin.
What is a common symptom of Diabetic Nephropathy?
Protienuria. This is the presence of proteins (primarily Albumin) in the urine.
What are the blood pressure targets for under 80 year olds?
<140/90 mmHg in clinic. <135/85 mmHg on ABPM/HBPM
What are the blood pressure targets for over 80 year olds?
<150/90 mmHg in clinic. <145/85 mmHg on ABPM/HBPM
What can cause ‘Diabetic Foot’
A small wound that is affected by peripheral vascular disease (reduced blood flow) and/or peripheral neuropathy (cessation of localised pain)
What drug at what dose should be offered to patients who are over 40 in Diabetes?
Atorvastatin 20mg
What are the conditions for a Diabetes patient aged 18-39 to receive statin treatment?
Retinopathy, Nephropathy with persistent microalbuminuria, persistent poor glycaemic control (HbA1c of >9% or 75mmol/mol), Elevated BP needing antihypertensive therapy, Serum cholesterol of >6 mmol/L
What should be done if a patient is hypoglycaemic (<3 mmol/L blood glucose)?
Mild: 15-20g of rapidly absorbed sugar
Medium: 2 tubes of glucogel, or IM glucagon (1mg)
Severe: IM glucagon (1mg) or IV glucose (150ml of 10% glucose over 10-15 mins)
What lifestyle advice should be offered to patients with Type 2 Diabetes?
Dietary changes (lower saturated fats in diet), Exercise (30 mins a day, 5 days a week), less/no alcohol and stop smoking
What therapeutic monitoring parameters should be considered with Metformin treatment?
Blood glucose levels and HbA1c
What toxic monitoring parameters should be considered with Metformin treatment?
GI disturbances and Renal function
Why is Metformin an ideal drug for treating Type 2 Diabetes?
Its mechanism of action does not affect insulin and therefore does not cause hypoglycaemia as a result of its use.
What is the WHO diagnostic blood glucose result for Type 2 Diabetes (without symptoms)?
Two separate measurements of either random ≥ 11.1 mmol/l or fasting ≥ 7.0 mmol/l or from 2 hrs post GTT.
What is Glycogen?
The stored version of glucose. It is stored in the liver.
What is Gluconeogenesis?
The formation of glucose from Pyruvate
What is Glucagon?
A hormone that is antagonistic to Insulin. It increases glucose and fatty acid concentration. It does this by increasing glycogenolysis and gluconeogenesis, and decreasing glycogenesis.
What is Glycogenolysis?
The breakdown of Glycogen into Glucose.
What is Glycogenesis?
The formation of Glycogen from glucose.
What is protein CATAbolism?
The process in which proteins are broken down into amino acids.
What is protein ANAbolism?
The process in which amino acids are used to form proteins.
How does HbA1c work?
Glucose naturally binds to haemoglobin in the blood, so this gives an accurate measurement of how much glucose has bound to haemoglobin over a period of time (2-3 months).
How does Ketosis occur?
Little to no insulin causes increased hydrolysis of triacylglycerides (TAGs), which leads to increased fatty acid levels which are then catabolised into Acetyl-CoA. The excess Acetyl-CoA is converted into ketone bodies (Acetone and D-beta-hydroxybutyrate). Acetone is the breath ketone, acetoacetate is the urine ketone and D-beta-hydroxybutyrate is the blood ketone.
What is the first-line treatment for Type 2 Diabetes who is not at a high CVD risk?
Metformin (up-titrate from 500mg OD to 500mg TDS)
What is the first line treatment for Type 2 Diabetes and chronic heart failure?
Metformin and offer SGLT-2 inhibitor (Dapagliflozin 10mg OD, as soon as Metformin is tolerated).
What is second-line in Type 2 Diabetes if Metformin becomes contraindicated?
SGLT-2 inhibitor and potentially the addition of a Sulphonylurea, a DPP-4 inhibitor or Pioglitazone.
What does a multiple insulin regime consist of?
An intermediate/long acting basal once at night and multiple short acting bolus doses at meal times, e.g. Lantus ON and NovoRapid PC
What does a ‘twice daily’ insulin regime consist of?
A short and intermediate acting pre-mixed twice daily, e.g. Novomix 30, Humulin M3.
What does a ‘once daily’ insulin regime consist of?
An intermediate/long acting basal once daily at night, e.g. Lantus ON.
What should a patient with type 1 or 2 diabetes do if they are sick/ill?
Do not stop taking insulin or tablets, test blood more often (>=4x times a day), test for ketones, drink fluids.
What does basal refer to?
A constant low level to maintain body tissues and prevent fat and protein metabolism.
What does bolus dose refer to?
A response to a dramatic increase in glucose, e.g. after a meal
What are the two things that make up the SAR of a Sulphonylurea?
p-substituent on aromatic ring, cannot be amine as to avoid antibacterial activity. Also, alkyl substituent needed on urea group.
How does oxidative stress occur?
- Increased glycolysis leads to higher production of NADH/FADH2. Increased NADH/FADH2 leads to overactivity of the ETC. Oxygen is converted into superoxide (ROS), instead of water.
- Increased DHAP is converted into methylglyoxal (toxic biproduct), increases AGE products by binding to Lysine side chains on proteins to create imines.
- Increased activity of PKC pathway as excess DHAP is converted into DAG which activates PKC (increases NADPH oxidases, increases ROS levels).
What is glycolysis?
The metabolic process in which glucose is catabolised into pyruvate.
What happens in the body during hyperglycaemia with respect to Ketosis/Acidosis?
Lack of insulin leads to decreased TAG synthesis and increased lipolysis (hydrolysis of TAGs). The concentration of fatty acid increases inside the body. These fatty acids are catabolised through beta-oxidation into Acetyl-CoA. As well as this, fatty acids react with DHAP which can be anabolised back into Glucose through gluconeogenesis (hyperglycaemia). Excess Acetyl-CoA is converted into ketone bodies like Acetone which give rise to Ketosis. Acidosis occurs as there are too many fatty acids due to decreased TAG synthesis.
What is DHAP?
A intermediate that is formed in glycolysis. It can also be formed from fatty acids. It can be catabolised into pyruvate or anabolised into glucose. Can tautomerise into GAP.
Why are ROSs like superoxide bad for the body?
It damages proteins, and disrupts biochemical processes causing cardiac and nerve tissue damage in the long term. It also oxidises nucleic acids causing DNA damage.
What functional group is key for irreversible DPP-4 inhibitors and why?
The cyanopyrrolidine group. It is a pyrrole like nitrogen ring with a cyano group (C≡N). It covalently binds to DPP-4 via the Serine active site. Steric shielding in Vildagliptin and Saxagliptin has improved its stability.
Why should longer acting sulphonylureas be avoid in the elderly.
Long acting sulphonylureas like Glimepiride should be avoided as they can cause prolonged hypoglycaemia in the elderly.
What removes/breaks down methylglyoxal?
Glutathione detoxifies methylglyoxal through the Glyoxalase pathway into Lactic Acid. As well as this, it is also detoxified via the Polyol pathway which can decrease levels of NADPH and decreases the body’s ability to regenerate Glutathione.
What cells in the Islet of Langerhans secrete Glucagon?
alpha-cells
What cells in the Islet of Langerhans secrete Insulin?
beta-cells
What type of receptor does Insulin act at?
A receptor Tyrosine Kinase
What type of receptor does Glucagon act at?
A GPCR coupled to G-alpha-S (cAMP)
What is the Polyol pathway?
A pathway used to create Fructose when there is increased Glucose. ROSs are reduced into inactive alcohols by Aldose reductase. As well as this, Glucose is reduced into Sorbitol. Sorbitol is then oxidised by Sorbitol dehydrogenase into Fructose, using NAD+ as a co-factor. This process relies on NADPH being reduced into NADP+, however it uses up a lot of NADPH. This means that the body’s ability to regenerate Glutathione is reduced.
How does Glucose entering the cell cause Insulin to be released?
Glucose enters in through the GLUT2 transporter in beta-cells. The influx of Glucose stimulates Glucose metabolism which in turn causes an increase in ATP concentration. This increased ATP inhibits the ATP-sensitive K+ channel, which causes membrane potential to become more positive leading to activation of the Ca2+ channel. This activation causes an influx of Ca2+. The elevated Ca2+ leads to exocytosis of secretory granules containing Insulin.
