Pharmacological Management of Diabetes Flashcards
Which organ monitors blood glucose?
Pancreas
What happens in the event of low blood glucose?
Glucagon is released from α-cells and the upper GI tract to stimulate glycogen breakdown and gluconeogenesis in the liver.
What happens in the event of high blood glucose?
Insulin is released from β-cells to stimulate muscle and adipose tissue to uptake glucose redistributing Glut4 to the cell membrane.
How does the liver act to control glucose levels?
By gluconeogenesis and glycogen synthesis
Give a diagramatic representation of how blood glucose is controlled.
Describe type 1 diabetes mellitus.
- Genetic predisposition and exposure to environmental triggers such as viral infections, diet and vitamin D deficiency.
- Pancreatic β-cell destruction, leading to impairment of insulin secretion and deficiency.
- Clinical T1DM does not present util >80% of β-cells have been destroyed.
- Clinical course of T1DM is characterised by the rapid onset of osmotic symptoms, including polyuria, polydipsia, weight loss and fatigue along with hypoglycaemia.
- ~67% of patients present with life-threatening diabetic ketoacidosis at diagnosis (DKA).
Describe type 2 diabetes mellitus.
- Genetic predisposition and progressive loss of insulin sensitivity and defective insulin receptor signalling.
- Often due to impaired insulin receptor signalling leading to insufficient transport of glucose into tissues.
- Often associated with metabolic syndrome, which starts with energy imbalance, high food consumption along with low energy expenditure.
- Fatty deposits in visceral organs leads to altered insulin signalling, insulin resistance and β-cell damage.
- T2DM progresses when ~80-90% of β-cells fail.
Describe the progression from prediabetes to type 2 diabetes.
- There is a natural progression from prediabetes to diabetes.
- Due to disruption of an individual’s ability to metabolise glucose.
- Individuals with prediabetes have lower insulin sensitivity which results in hyperinsulinaemia.
- Diabetes progresses when the β-cells are failing, resulting in low insulin secretion in combination with low insulin sensitivity.
- >7mM fasting plasma glucose = diabetes.
At what level of fasting plasma glucose is diabetes indicated?
>7mM
How is effective T1DM usually measured?
- Effective diabetes management is usually measured by self-monitoring of blood glucose (SMBG) - sampling capillary blood after a finger prick.
- NICE guidelines:
- Fasting glucose levels above 7mM indicative of diabetes.
- OR random glucose measurement above 11.1mM.
- HbA1C measurement is also used to diagnose diabetes and evaluate glucose levels over a longer time frame.
- HbA1C provides an integrated measure of control over the lifespan of RBCs (~120 days) - levels above 7% indicate diabetes.
What fasting blood glucose level indicates diabetes?
>7.7mM
What random glucose measurement indicates diabetes?
>11.1mM
What HbA1C level indicates diabetes?
>7%
What is the aim of treatment for T1DM?
Replacement therapy to normalise glucose levels of 4-7mM (pre-prandial/fasting).
At which blood glucose level will the renal capacity be overloaded?
Blood glucose levels >10mM will overload the renal capacity and be detected in the urine.
Describe the different formulations of insulin.
- Human insulin is made by recombinant DNA technology, which allows an identical pure preparation, limiting allergic reactions.
- Designer human insulin analogues are modified insulins that produce either an extended duration of action or faster absorption.
- Insulins may be pure preparation or complexed with proteins, salts or fatty acids to alter their duration of activity.
- Durations of activity can be rapid-acting (within 15 minutes) to long-duration peakless forms (exceeding 24 hours).
Why is insulin administered parentally?
Because it is a protein that would be destroyed/digested by the gut if taken orally.
How is insulin administered?
For routine use it is given subcutaneously and by IV infusion in emergencies (only soluble forms).
Which formulations are rapid-acting soluble insulins?
- Insulin lispro
- Insulin aspart
- Insulin glulisine
- These are designer insulins that prevent dimer formation allowing more active monomers to be bioavailable.
- Rapid onset (10-20 minutes)
- Short duration (2-5 hours)
Describe isophane insulin (Neutral Protamine Hagerdorn; NPH).
- Intermediate acting insulin that precipitates into suspensions which slowly dissolve.
- Human insulin complexed with positively charged polypeptide (protamine) and zinc.
- Onset 1-2 hours
- Duration 12-20 hours
Describe insulin glargine.
- Longer acting ‘peakless’ designer insulin which has decreased solubility at neutral pH - forms aggregates that slowly dissolve into active monomers (24-36 hours).
Describe insulin detemir.
Long-acting ‘peakless’ designer insulin with a fatty acid - this confers albumin binding, which slowly dissociates prolonging circulation (24 hour duration of activity).
Describe insulin degludec.
Ultralong-acting designer insulin with a fatty-acid - this results in multi-hexamer formation at injection site with slow release (>42 hours).
Describe fixed dose insulin therapy.
- The amount of insulin taken at each meal does not vary from day to day.
- Can help to simplify understanding of blood glucose results but does not offer the flexibility of how muh carbohydrate patients choose to consume at each meal.
Describe flexible insulin therapy.
- Used for patients that really understand glucose metabolism and gives patients more control over what they eat and how they balance their blood glucose levels.
- Will take time and commitment to learn how best to adjust insulin doses.
- Patients choose how much insulin to inject at each meal and also allows doses to be varied in response to different carbohydrate quantities in meals.
What is the main adverse effect of insulin therapy?
Hypoglycaemia
How are patients who have difficulty achieving good glycaemic control managed?
These patients may have to use an insulin pump.
Describe injection insulin therapy.
- 1-3 injections per day.
- Either in the morning or at meal times.
- Suitable for T2D patients.
- Formulations:
- Rapid-acting OR
- Short-acting insulin mixed with intermediate insulin
- Meal time and content is fixed.
- Basic level of understanding required by patient.
Describe basal-bolus insulin therapy.
- Multiple injections per day.
- Injections spaced throughout the day.
- Suitable to treat T1D patients, and some T2D patients.
- Formulations:
- Intermediate or long-acting with short acting formulation.
- Meal time and content is flexible.
- High level of patient understanding is required.
Describe the use of oral hypoglycaemic agents.
- Oral hypoglycaemic tablets are used to alter glucose metabolism in T2Ds.
- The principal drug used is Metformin (a biguanide drug).
- T2Ds have some residual insulin and insulin sensitivity.
- Metformin can potentiate residual insulin by increasing insulin sensitivity.
- Acts to reduce gluconeogenesis in the liver, which is markedly increased in T2D and opposes the action of glucagon.
- Increases glucose uptake and utilisation in skeletal muscle.
- Slightly delays carbohydrate absorption in the gut.
- Increases fatty acid oxidation - reducing circulating LDL and VLDL, which can help in obesity assiciated diabetes and atherosclerosis development.
- Can encourage weight loss by suppressing apetite but can cause anorexia in rare cases.
- Can be combined with drugs that stimulate insulin release.
Describe the mechanism of action of Metformin.
- Metformin alters energy metabolism.
- it acts on the mitochondria to change the ratio of AMP to ATP.
- Increased AMP:ATP ratios activate AMP-activated protein kinases (cells metabolic master switch).
- Inhibits glucagon signalling and gluconeogenic pathways.
- AMPK increases transcription of genes important for glucose transport fatty oxidation and inhibits faty acid synthesis.
- Takes time due to regulating gene networks.
What are incretins?
- Glucagon-like peptide-1 (GLP-1) is secreted by L-cells in the gut.
- Gastric inhibitory peptide (GIP) is secreted by K-cells in the gut.
Describe the role of incretins.
- Incretins:
- stimulate insulin biosynthesis / secretion
- Inhibit glucagon secretion in the pancreas
- Delay gastric emptying
- Increase cardiac output
- Increase brain satiety signals
- Incretins also indirectly increase insulin sensitivity in the muscle and decrease gluconeogenesis in the liver.
- Incretins are rapidly degraded by an enzyme called dipeptidyl peptidase-4 (DPP-4).
Describe incretin analogs.
- Incretin analogs lower blood glucose after a meal by increasing insulin secretion and suppressing glucagon secretion.
- Used for T2D in addition of oral agents to improve control and aid weight loss.
- Given subcutaneously as peptide analogs.
- Can cause hypoglycaemia and a range of GI effects.
Name the 3 incretin mimetics.
- Exenatide
- Exenatide LAR
- Liraglutide
Describe Exenatide
- Analog of exendin-4/GLP-1
- Given twice daily
- Can cause nausea
Describe Exenatide LAR
- Analog of exendin-4/GLP-1
- Long-acting release formulation that is administered weekly
- Induces less nausea
Describe Liraglutide
- Analog of exendin-4/GLP-1
- Has an additional fatty side-chain tht confers albumin binding and slows renal clearance.
Give 2 examples of DPP-4 Inhibitors (Gliptins).
- Sitagliptin
- Vildagliptin
Describe the function of DPP-4 Inhibitors (Gliptins).
- Enhance endogenous incretin effects by blocking DPP-4.
- Lowers blood glucose by increasing the first phase of insulin response after meals.
- Used in T2D in addition to other oral hypoglycaemic drugs.
- Sitagliptin is well tolerated and weight neutral.
- Vildagliptin is not available in the USA - found associated with respiratory tract infections, headache and on occasions serious pancreatitis.
Describe sulphonylureas.
- Insulin secretagogues
- An older class of orally-active hypoglycaemic drugs.
- Sulphonylureas interfere with β-cell ion channels to potentiate insulin secretion.
- Well tolerated but can lead to weight gain by stimulating apetite.
- Used in early stages of T2D, as they require functional β-cells.
- Can be combined with Metformin and Glitazones.
- But can interact with other drugs to produce severe hypoglycaemia due to competition for metabolising enzymes, plasma binding proteins and excretory pathways.
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Sulphonylureas:
- Tolbutamide
- Chlorpropamide
- Gilbenclamide
- Glipizide
Describe meglitinides.
- Insulin secretagogue
- Next generation secretagogues with a similr mechanism of action (blocking KATP channels to increase insulin release) - short duration of activity leads to lower risk of hypoglycaemia.
-
Meglitinides:
- Repaglinide
- Nateglinide
Describe the mechanism of action of sulphonylureas.
- High affinity receptors for these drugs are present in β-cell membranes.
- Block ATP-sensitive potassium channels in β-cells.
- Causes β-cell depolarisation, which leads to insulin secretion.
- Only work if β-cells of the pancreas are functional.
Give examples of selective sodium glucose cotransporter 2 (SGLT2) inhibitors.
- Canagliflozin
- Dapagliflozin
- Empagliflozin
When are SGLT2 inhibitors used?
Used in T2D as monotherapy when diet and exercise alone is not adequate for whom metformin is contraindicated or inappropriate.
Describe the mechanism of action of SGLT2 inhibitors.
- Block glucose reabsorption by the proximal convoluted tubule leading to theraputic glucossuria.
- Controls glycaemia independently of insulin pathways.
- Lead to reduced HbA1C up to 1.17% compared to placebo.
- Well tolerated.
- Reduce weight.
- Reduce systolic blood pressure.
- Do not cause hypoglycaemia but associated with increased risk of urinary tract infections.
What are thiazolidinediones (glitazones)?
- Peroxisome proliferator activated receptor - ɣ (PPARɣ - a nuclear receptor) agonists.
- PPARɣ expressed in adipose tissue, muscle and liver.
What are the actions of Pioglitazone (a thiazolidinedione (glitaozone))?
- Pioglitazone:
- Increases insulin sensitivity and lowers blood glucose in T2Ds.
- Reduces the amount of exogenous insulin needed by ~30%.
- Increases glucose uptake into muscle in response to insulin.
- Reduces blood glucose and free fatty acid concentrations.
- Promote transcription of several genes with products that are important in insulin signalling but take months to work.
- Can cause weight gain and fluid retention.
- Has been linked to bladded cancer, heart failure and osteoporotic fractures - withdrawn from Germany, France and India.
Describe the mechanism of action of Pioglitazone. What is it used for?
- PPAR-ɣ ligands promote transcription of genes important in insulin signalling: lipoprotein lipase, fatty acid transporters, Glut-4 and others.
- Pioglitazone is used in the clinic as an additive to other oral hypoglycaemic drugs such as Metformin and Sulphonylureas.
Describe the function of an α-glucosidase inhibitor.
- Acarbose - a saccharide that acts as a competitive inhibitor of intestinal α-glucosidase.
- Delays carbohydrate absorption in the small intestine reducing the postprandial spike in glucose.
- Used in T2D often in combination with other hypoglycaemics.
- Side effects can include flatulence and diarrhoea.
