Treatment of diabetes mellitus Flashcards
What are the features of Diabetes Mellitus ?
Diabetes Mellitus is due to insulin deficiency (5-10%) and/or insulin insensitivity (~90%)
- 10% Type 1 (Insulin dependent)
- 85-90% Type 2 (Insulin Independent)
- 5% of pregnancies gestational diabetes
- Disrupted glucose metabolism leads to hyperglycaemia (blood glucose >11mM)
- All require intervention but depending on the disease origin, these may require different therapeutic approaches
How do we treat Diabetes?
Treatment of Diabetes Mellitus:
- Insulin discovered by Frederick Banting and Charles Best
- Insulin is essential for treating Type 1 and a component of treating Type 2 diabetes
- Aim in treating Type 1 Diabetics - replacement therapy to normalise glucose levels 4-7mM (pre-prandial/fasting)
- In normal individuals glucose level can rise higher but should be <7.8mM two hours after a meal
- Blood glucose levels >10 mM will overload renal capacity and be detected in the urine
How do we Formulate Insulin ?
Insulin Formulations;
- In the past insulin was isolated from animals such as pigs or cows
- Now, human insulin is made primarily by recombinant DNA technology, which allows an identical pure preparation, limiting allergic reactions
- Synthetic/designer human insulins modified to either prolong duration of activity or increase absorption rate (Designer insulins - Structures modified to change pharmacological properties)
- Durations of activity can be rapid-acting (peak activity ~15 min) to long-duration peak less forms (activity exceeding 24 hours)
- Insulin is administered parentally because it is a protein that would be destroyed/digested by the gut if taken orally
- For routine use it is given subcutaneously and by IV infusion in emergencies (only soluble forms)
What are the current Insulin Formulations we have and their features?
Rapid-acting soluble insulin;
- Insulin Lispro
- Insulin Aspart
- Insulin Gluslisine
- Designer insulins - prevent dimer formation and increase bioavailability of active monomers
- Rapid onset (10-20mins) and short duration (2-5 Hours)
Intermediate Acting insulin;
- Isophane Insulin (Neutral Protamine Hagedorn; NPH)
- Intermediate acting insulin that forms precipitate suspensions which slowly dissolve (8-9 hours activity time)
Longer Acting Insulin (Peakless, Basal analogues);
- Insulin Glargine, decreased solubility at neutral pH - forms aggregates that slowly dissolve (“Peakless” 24-36 hours)
- Insulin Detemir, long-acting designer insulin with a fatty acid, this confers albumin binding, slowly dissociates prolonging activity (“Peakless” 24 hours)
- Insulin Degludec, long acting designer insulin with a fatty acid, this results in multi-hexamer formation at injection site with sow release (Ultralong duration action >42 hours)
Insulin is used in type 1 diabetic patients, 1/3rd type 2 and for some women who have gestational diabetes
See table
What are the Insulin Regimes that diabetic need to adhere to ?
Fixed Doses;
- On a fixed dose insulin therapy, the amount of insulin taken at each meal will not vary from day to day
- A fixed dose therapy can help to simplify the understanding of bad glucose results but does not offer the flexibility of how much carbohydrates a patient may chose to consume at each meal (need to restrict food, make sure taking right amount carbs)
Flexible Doses;
- Flexible insulin therapy is 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 but will take time and commitment to learn how to best adjust insulin doses
- On a flexible insulin therapy 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
Main adverse effect of insulin therapy is hypoglycemia but for patients that have difficulty achieving god glycemic control they may need to use an insulin pump
What Lifestyle Modifications can we make to prevent Pre-Diabetes ?
Lifestyle Modifications to prevent Pre-Diabetes;
- Imbalance between energy intake and energy output is a key driver for the development of prediabetes and developing T2D complications
- Life-style modifications are suggested if a patient is overweight with weight loss targets between 5-10% of body weight
- Increasing exercise and having a healthy diet is key (can reverse many symptoms)
Dietary advice includes;
- Decrease intake of processes carbohydrates
- Ensure carbs come from fruit, veg and whole grains
- Eat small frequency meals to avoid glucose spikes
- Increase fibre intake and eat complex carbs (low glycemic index foods)
- Decrease alcohol consumption
What are the features of Oral Hypoglycemic agents ?
Oral Hypoglycemic agents (T2D);
- Oral hypoglycaemic tablets are used to alter glucose metabolism in T2D’s
- The principle drug is Metformin (a biguanide drug)
- T2D’s 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 type 2 diabetes and opposes the action of glucagon
- Increases fatty acid oxidation - reducing circulation LDL and VLDL, which can help in obesity associated diabetes and atherosclerosis development
- Can encourage weight loss by suppressing appetite but can cause anorexia in rare cases
- Can be combined with drugs that stimulate insulin release
What is 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 kinase (cells metabolic master switch)
- Inhibits glucagon signalling and gluconeogenic pathways
- AMPK increases transcription of genes important for glucose, transport fatty oxidation and inhibits fatty acid synthesis
Decrease level ATP so increase AMP which activates cells AMP-kinase which will inhibit fatty acid synthesis pathway, stimulates fatty acid oxidation and glucose transport giving improved insulin sensitivity
What are Insulin Secretagogues?
Insulin Secretagogues: Sulphonylureas/Meglitinides
- Sulphonylureas are an older class of orally-active hypoglycaemic drugs
- Sulphonylureas (Gliclazide, Tolbutamide, Glibenclamide) interfere with beta cell ion channels to potentiate insulin secretion (risk of hypoglycaemia)
- Well tolerated but can lead to weight gain by stimulating appetite
- Used in early stages of type 2 diabetes - as they require functional B 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, so need to monitor
- Meglitinides (Repaglinide and Nateglinide) are next sen secretagogues with similar mechanism of action (blocking K(ATP) channels to increase insulin release) - More rapid onset and short duration of activity levels leads to lower risk of hypoglycaemia (considered better)
What is the Mechanism of Action for Sulphonylureas ?
Mechanism of Action for Sulphonylureas (Meglitinides similar but different binding);
- High affinity receptors for these drugs are present in B-cell membranes
- Block ATP-sensitive potassium channels in B-cells
- Causes Beta cell depolarisation, which leads to insulin secretion
- Only work if B cells of the pancreas are functional (Useless if late stage type 2 with no insulin secretion)
What are the features of Selective Sodium Glucose Contransporter 2 (SGLT2) inhibitors ?
Empagliflozin, Canagliflozin and Dapaglifllozin
- Used in T2D as mono therapy when diet & exercise alone is not adequate for whom metformin is contraindicated or inappropriate
- Block glucose reabsorption by the proximal tubule leading to therapeutic glucosuria
- Controls glycaemia indpeendelty of insulin pathways
- Lead to reduced HbA1c up to 1.17% compared to placebo - Well tolerated, reduce weight and reduce systolic blood pressure
- Do not cause hypoglycaemia but associated with increased risk of UTI
Stop glucose from going about body
Block reabsorption glucose back into blood so patients glucose excretion is stimulates so body doesn’t have as much glucose circulating making beta cells better at handling amount of glucose
Can be combined with other drugs and have a complementary effect
What are the features of Incretins ?
- Incretins are natural gut peptides and are released in response to meal digestion, involved in gastric emptying
- Glucagon-like peptide-1 (GLP-1) is secreted by L-cells in the gut
- Gastric inhibitory peptide (GIP) secreted by K-cells in gut
- Incretins stimulate insulin biosynthesis/secretion, inhibit glucagon secretion in pancreas, delay gastric emptying, increase cardiac output and increase brain satiety signals
- Incretins indirectly increase insulin sensitivity in muscle and decrease gluconeogenesis in the liver
- Incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4) - So relatively short lived
What are the features of Incretin Mimetics ?
Incretin Mimetics are analogs of incretins and take advantage of incretins by taking control of blood glucose;
- Exenatide, Exenatide LAR and Liraglutide - analogus of extendin-4/GLP-1
- Exenatide is given twice daily, but can cause nausea (Because mimics natural gut hormone)
- Exenatide LAR is a loons-acting release formulation that is administered weekly and induces less nausea
- Liraglutide has an additional fatty side-chain that confers albumin binding and slows renal clearance (Prolonging biological variability)
- Incretin angles lowers blood glucose after a meal by increasing insulin secretion and suppressing glucagon secretion
- Used for type 2 diabetes in addition to oral agents to improve control and aid weight loss
- Given subcutaneously (SC) as peptide analogs
- Can cause hypoglycemia and range of GI effects (patient monitoring required)
Slows release from subcutaneous tissue
What are the features of DPP-4 inhibitors/Gliptins?
DPP-4 inhibitors/Gliptins;
- DPP-4 is a natural enzyme that degrades natural and some synthetic incretins
- DPP-4 inhibitors blocking enzymes and prolongs activity of natural incretins and incretin analogs
- Sitagliptin and Vildagliptin
- Enchance endogenous incretin effect by blocking DPP-4
- Lowers blood glucose by increasing first phase of insulin response after meals
- Used in type 2 diabetes in addition to other oral hypoglycaemic drugs
- Sitagliptin is well tolerated and weight neutral
- Vildagliptin is not assayable in USA - found associated with respiratory tract infections, headaches and on occasion serious pancreatitis
What are the features of Thiazolidinediones (Glitazones) ?
Thiazolidinediones (Glitazones);
- Are peroxisome proliferator activator-y (PPARy - a nuclear receptor) agonists - PPARy expressed in adipose tissue, muscle and liver
- Pioglitazone increases insulin sensitivity, lowers blood glucose and promotes esterification/storage of FFA’s in adipose tissue in T2Ds
- Reduces the amount of exogenous insulin needed by about 30%
- Promotes transcription of several genes that increase the stage of fatty acids in adipocytes, decreasing amount of circulating FFA’s
- Cells become more dependent on oxidation of carbs, reducing blood glucose levels
- Can cause weight gain and fluid retention
- Has been linked to bladder cancer, heart failure and osteoporotic fractures - withdrawn from Germany, France and India
- Rosiglitazone is another PPARy agonist recently withdrawn from UK
Increase sensitivity to insulin
Reduce circulating free fatty acids
Limits availability of free fatty acids
What is the Mechanism of Action of Poiglitazone?
Mechanism of Action of Pioglitazone;
- PPAR-y ligands promote transcription of genes important in insulin signalling: GLUT-2, glucokinase, fatty acid transporters and others
- Pioglitazone is used in the clinic as an additive to other oral hypoglycaemic drugs such as Metformin and Sulphonylureas
Ligand for natural PPA-y. Enters cell, binds to nuclear receptor, activates specific gene programs important in insulin signalling.
What are the features of a-Glucosidase inhibitors?
a-Glucosidase inhibitors;
- Acarbose - a saccharide that acts as a competitive inhibitor of intestinal a-glucosidase
- Delays carbohydrate absorption is small intestine reducing the postprandial spike in glucose (slow rate that carbohydrates are absorbed after meals)
- Used in type 2 diabetes often in combination with other hypoglycemics
- Side effects can include flatulence and diarrhoea
Inhibits enzymes with brush border in smaller intestine, increasing absorption in lower small intestine spreading out glucose absorption
