Treatment of Diabetes Flashcards
What monitors blood glucose?
Pancreas
What is central to controlling all glucose levels?
The liver
Where is glucagon released from and what is its purpose?
Glucagon is released from α cells + upper GI if blood glucose is low to stimulate glycogen breakdown + gluconeogenesis in the liver
Where is insulin released from and what is its purpose?
Insulin is released from β cells if blood glucose is high to stimulates the liver, adipose and muscle to take up glucose
What occurs in diabetes?
Diabetes occurs when regulation of blood glucose is disrupted
Describe the common differences between Type 1 and Type 2 diabetes.
TYPE 1:
- Often diagnosed in childhood
- Not associated with excess body weight
- Often associated with higher than normal ketone levels at diagnosis
- Treated with insulin injections or insulin pump
- Cannot be controlled without taking insulin
TYPE 2:
- Usually diagnosed in over 30 year olds
- Often associated with excess body weight
- Often associated with high blood pressure and/or cholesterol levels at diagnosis
- Is usually treated initially without medication or with tablets
- Sometimes possible to come off diabetes medication
Why does the occur progressing from pre diabetes to diabetes occur?
This is due to a disruption of an individual’s ability to metabolise glucose.
Might not yet appear to have diabetes but may have hyperinsulinemia due to lower insulin sensitivity
Full diabetes progresses when beta-cell failure surpasses a critical threshold usually ~90%
Describe the aim of insulin in treating Type 1 diabetes.
Aim in treating Type I diabetics - replacement therapy to normalize glucose levels 4-7 mM (pre- prandial/fasting).
What are normal glucose levels two hours after a mean?
In normal individuals glucose level can rise higher but should be <7.8 mM two hours after a meal.
When will glucose be detected in urine?
Blood glucose levels >10 mM will overload the renal capacity and be detected in the urine.
How is insulin made?
human insulin is made by recombinant DNA technology, which allows an identical pure preparation, limiting allergic reactions.
How is insulin administered and why?
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.
What are designer insulins?
Altering the amino acids in the insulin structure can usefully alter insulin kinetics – these modified human insulins are called designer insulins
Describe and name rapid-acting soluble insulin.
Insulin Lispro or Insulin Aspart, designer insulins that prevent dimer formation allowing more active monomers to be bioavailable and used rapidly.
Describe and name an intermediate-acting insulin.
Neutral Protamine Hagedorn/Isophane Insulin is an intermediate-acting insulin that precipitates insulin into suspensions which slowly dissolve.
Describe and name a longer acting designer insulin.
Insulin Glargine is a longer acting designer Insulin which has decreased solubility at neutral pH - forms aggregates that slowly dissolve.
Describe and name a long-acting designer insulin with a fatty acid.
Insulin Detemir is a long-acting designer insulin with a fatty acid – this confers albumin binding, which slowly dissociates prolonging circulation.
What type of insulin is often used in T1D?
T1Ds require insulin replacement so an intermediate-acting preparation or a more long-acting analogue is often combined with a short-acting analogue taken before meals.
Describe the duration of activity and formulation/structural changes of Insulin Lispro.
Rapid acting
Human insulin with penultimate lysine and proline reversed in beta chain
What do structural changes in Insulin Lispro prevent?
Structural changes prevents insulin dimers and hexamers increasing availability of active monomers
Describe the duration of activity and formulation/structural changes of Insulin Aspart.
Rapid acting
Human insulin with Proline 28 switched to Aspartic acid in beta chain
What do structural changes in Insulin Aspart prevent?
Structural changes prevents insulin dimers and hexamers increasing availability of active monomers
Describe the duration of activity and formulation/structural changes of Neutral Protamine Hagedorn/ Isophane Insulin.
Intermediate acting
Human insulin complexed with positively charged polypeptide (protamine) and zinc
Describe the slow dissolving of Neutral Protamine Hagedorn/ Isophane Insulin.
Aggregates in suspension that slowly dissolve from injections site; “Isophane” insulins were (initially made with porcine insulin but now use recombinant human insulin)
Describe the duration of activity and formulation/structural changes of Insulin Detemir.
Long acting “peakless" Fatty acid (myristic acid) added to Lys29 of beta chain
Describe the features of absorption and dissociation of Insulin Detemir.
Rapidly absorbed but FA side-chain confers binding to albumin. Slowly dissociates from complex
Describe the duration of activity and formulation/structural changes of Insulin Glargine.
Long acting “peakless” basal analogue
Glycine for Asparagine substitution at N21 and 2 arginine amino acids added to the end of beta chain
What makes Insulin Glargine less soluble, what is the purpose?
Shift isoelectric point making it less soluble at neutral pH creating aggregates which slowly dissolve into active monomers
Why is fixed dose therapy useful?
A fixed dose therapy can help to simplify the understanding of blood glucose results but does not offer the flexibility of how much carbohydrate patients choose to consume at each meal
When is flexible insulin therapy used?
Flexible insulin therapy is used for patients that really understand glucose metabolism and gives patients more control of what they eat and how they balance their blood glucose levels but will take time and commitment to learn how best to 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.
Once daily regimen: Number of injections? Time of injections? Suitability? Meal time and content: Required patient understanding?
Number of injections: 1
Time of injections: Morning
Suitability: T2D
Meal time and content: Less flexible
Required patient understanding: Basic
Describe the formulations used in the once daily insulin regimen.
long acting (Glargine) or Intermediate (e.g. NPH)
Twice daily regimen: Number of injections? Time of injections? Suitability? Meal time and content: Required patient understanding?
Number of injections: 2
Time of injections: Morning + Evening
Suitability: T1D and T2D
Meal time and content: Less flexible
Required patient understanding: Basic
Describe the formulations used in the twice daily insulin regimen.
Short acting mixed with intermediate formulation
Basal-Bolus regimen: Number of injections? Time of injections? Suitability? Meal time and content: Required patient understanding?
Number of injections: Multiple
Time of injections: Throughout day
Suitability: T1D, some T2D
Meal time and content: Flexible
Required patient understanding: High
Describe the formulations used in the Basal-Bolus insulin regimen.
Intermediate or long acting with short acting formulation
Insulin Pump regimen: Number of injections? Time of injections? Suitability? Meal time and content: Required patient understanding?
Number of injections: Semi-automated: as needed
Time of injections: Throughout day
Suitability: T1D
Meal time and content: Flexible
Required patient understanding: Medium/High
Describe the formulations used in the Insulin Pump insulin regimen.
Short acting insulin formulation
What is the principal oral hypoglycemic agent.
Metformin (a biguanide drug)
When are oral hypoglycemic tablets used?
- used to alter glucose metabolism in T2Ds
- T2Ds have some residual insulin and insulin sensitivity: metformin can potentiate residual insulin by increasing insulin sensitivity
What is the aim of metformin?
Acts to reduce gluconeogenesis in the liver, which is markedly increased in type 2 diabetes and opposes the action of glucagon.
What does metformin do?
- 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 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.
Describe the mechanism of action of Metformin.
- Metformin alters energy metabolism
- It acts on the mitochondria to change the ratio of AMP to ATP
- ↑ AMP:ATP ratios activate AMP- activated protein kinase (cells metabolic master switch) - Inhibits glucagon signaling and gluconeogenic pathways
- AMPK increases transcription of genes important for glucose transport fatty oxidatin and inhibits fatty acid synthesis
- Takes time due to regulating gene networks
What are insulin secretagogues?
Sulphonylureas/Meglitinides:
Sulphonylureas are an older class of orally-active hypoglycemic drugs
Meglitinides are next gen secretagogues
What do Sulphonylureas do?
interfere with beta cell ion channels to potentiate insulin secretion
Give examples of Sulphonylureas.
Tolbutamide
Chlorpropamide
Glibenclamide
Glipizide
Describe the tolerance of Sulphonylureas.
Well tolerated but can lead to weight gain by stimulating appetite.
When are Sulphonylureas used?
Used in early stages of type 2 diabetes – as they require functional b cells
What can Sulphonylureas be combined with?
Metformin and Glitazones
Describe drug interactions of Sulphonylureas.
But can interact with other drugs to produce severe hypoglycaemia due to competition for metabolising enzymes, plasma binding proteins, and excretory pathways.
Give examples of meglitinides.
Repaglinide and Nateglinide
Describe the mechanism of action of meglitinides.
similar mechanism of action (blocking KATP channels to ↑insulin release) – short duration of activity leads to lower risk of hypoglycaemia
Describe the mechanism of action of Sulphonylureas.
- 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
What does Pioglitazone do?
It is a Thiazolidinediones (glitazones):
increases insulin sensitivity and lowers blood glucose in type 2 diabetics.
What do Thiazolidinediones (glitazones) do?
- Reduces the amount of exogenous insulin needed by about 30%.
- Increases glucose uptake into muscle in response to insulin.
- Reduces blood glucose and free fatty acid concentrations.
- Are peroxisome proliferator activated receptor – g ( PPARg - a nuclear receptor) agonists – PPARg expressed in adipose tissue, muscle and liver.
- Promote transcription of several genes with products that are important in insulin signalling but take months to work.
What are the side effects of Thiazolidinediones (glitazones) ?
Can cause weight gain and fluid retention.
Has been linked to bladder cancer, heart failure, and osteoporotic
fractures - withdrawn from Germany, France and India
What is Rosiglitazone?
another PPARy agonist recently withdrawn from UK
What is the mechanism of action of Pioglitazone?
- PPAR-γ 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
What is Acarbose?
inhibitor of intestinal a-glucosidase
What does acarbose do?
Delays carbohydrate absorption in the small intestine reducing the postprandial spike in glucose.
When is acarbose used?
Used in type 2 diabetes often in combination with other hypoglycemics
What are the side effects of acarbose?
Side effects can include flatulence and diarrhoea
Give examples of Selective sodium glucose cotransporter 2 (SGLT2) inhibitors.
Canagliflozin
Dapagliflozin
Empagliflozin
When are Selective sodium glucose cotransporter 2 (SGLT2) inhibitors used?
Used in T2D as monotherapy when diet & exercise alone is not adequate for whom metformin is contraindicated or inappropriate.
What do Selective sodium glucose cotransporter 2 (SGLT2) inhibitors do?
- Block glucose reabsorption by the proximal tubule leading to therapeutic glucosuria
- Controls glycaemia independently 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 urinary tract infections
Give examples of incretins?
Glucagon-like peptide-1 (GLP-1) is secreted by L-cells in the gut
Gastric inhibitory peptide (GIP) secreted by K-cells in gut
What do incretins do?
- Incretins directly stimulate insulin biosynthesis and secretion, inhibit glucagon secretion in the pancreas, delay gastric emptying, increase cardiac output and increase satiety signals in the brain.
- Incretins also indirectly increase insulin sensitivity in the muscle and decrease gluconeogenesis in the liver
How are incretins degraded?
Incretins are rapidly degraded by an enzyme called dipeptidyl peptidase-4 (DPP-4).
Give examples of incretin mimetic - analogs of exendin-4/GLP-1.
Exenatide
Exenatide LAR
Liraglutide
Describe Exenatide.
given twice daily, but can cause nausea
Describe Exenatide LAR.
a long-acting release formulation that is administered weekly and induces less nausea
Describe Liraglutide.
has an additional fatty side-chain that confers albumin binding and slows renal clearance
What do incretin analoges do?
Incretin analogs lowers blood glucose after a meal by increasing insulin secretion and suppressing glucagon secretion.
When are incretin analoges used?
Used for type 2 diabetes in addition to oral agents to improve control and aid weight loss.
How are incretin analoges given?
Given subcutaneously (SC) as peptide analogs.
What are the side effects of incretin analoges?
Can cause hypoglycemia and a range of gastrointestinal effects
Give examples of DPP-4 Inhibitors - Gliptins.
Sitagliptin and vildagliptin
What do DPP-4 Inhibitors - Gliptins do?
Enhance endogenous incretin effects
by blocking DPP-4
Lowers blood glucose by increasing first phase of insulin response after meals.
When are DPP-4 Inhibitors - Gliptins used?
Used in type 2 diabetes in addition to other oral hypoglycaemic drugs.
Describe Sitagliptin.
well tolerated and weight neutral
Describe Vildagliptin.
is not available in the USA - found associated with respiratory tract infections, headache and on occasion serious pancreatitis.
What are the symptoms of diabetes?
- Always tired
- Frequent urination
- Sudden weight loss
- Wounds that won’t heal
- Always hungry
- Sexual problems
- Blurry vision
- Vaginal infections
- Numb or tingling hands or feet
- Always thirsty
What is a normal FPG?
< 6.1 mmol/L
What is a pre-diabetes FPG?
6.1 - 6.9 mmol/L
What is a diabetes FPG?
> 7.0 mmol/L
