Treatment of Diabetes Mellitus Flashcards
What can type 1 diabetes be due to?
- Genetic predisposition
- Viral infections (Coxsackie B)
How many Beta cells are usually destroyed before type 1 diabetes is presented?
> 80 - 90 %
- 2/3s of patients present with life-threatening diabetic ketoacidosis
What is the clinical course of type 1 diabetes characterised by?
Rapid onset of osmotic symptoms
- Including:
- Polyuria
- Polydipsia
- Weight loss
- Fatigue along with hyperglycaemia
What is metabolic syndrome?
Combination of diabetes, hypertension and obesity
What is the prediabetic stage in type 2 diabetes?
- Plasma insulin increases (compensatory hyperinsulinemia)
- Insulin sensitivity decreases
- Plasma glucose is raised
- Beta cells progressively fail - leading to diabetes with decreased plasma insulin and hyperglycaemia
What are the different levels of fasting plasma glucose in non-diabetics vs prediabetics vs diabetics?
- Normal < 6.1 mmol/L
- Prediabetes 6.1 - 6.9 mmol/L
- Diabetes > 7.0 mmol/L
How is bood glucose monitored?
Self-monitoring of blood glucose (SMBG) - samples capillary blood after a finger prick
- 4 times a day (before each meal and at bedtime)
Random glucose measurement above what number indicates diabetes?
11.1 mM (7mM if fasting)
What measurement gives a measurement of blood glucose over a long time frame (~120 days, RBC lifetime)?
HbA1c
What HbA1c levels indicate diabetes?
Above 7%
What should fasting blood glucose levels not be above?
7.8 mM (2 hours after a meal)
At what level of blood glucose would glucose be detected in the urine?
> 10 mM (will overload the renal capacity)
At what level of blood glucose would glucose be detected in the urine?
> 10 mM (will overload the renal capacity)
How is Insulin made?
Recombinant DNA technology (used to be from pigs, cows)
- Can be modified (with proteins, salts, fatty acids) to alter duration activity or increase absorption rate
How is insulin administered?
- Subcutaneously routinely
- IV in emergencies (only soluble forms)
What are examples of rapid-acting soluble insulins?
- Insulin lispro
- Insulin aspart
- Insulin glulisine
How do rapid-acting soluble insulins work? (e.g insulin lispro)
- Prevent dimer formation
- Contain amino acid substitutions that block the formation of insulin dimers allows for more active monomers to be used rapidly
- Increase bioavailability of active monomers - rapid omset (10-20 mins) and short duration (2-5 hours)
What is isophane insulin? (neutral protamine hagedoen; NPH)
- Intermediate-acting insulin
- Complexes with protamines as well as zinc
- Forms precipitate suspensions which slowly dissolve
What is insulin glargine?
A longer acting designer insulin which has decreased solubility at neutral pH - forms aggregates that slowly dissolves - prolonging activity
What is insulin detemir?
A long-acting designer insulin with a fatty acid
- Myrestic acid bound to insulin Beta chain
- This confers albumin binding, slowly dissociates prolonging activity
What is insulin degludec?
Long-acting designer insulin with a fatty acid - this results in multi-hexamer formation at injection site with slow release, 42 hours duration
What proportion of Type 2 diabetics use insulin?
1/3rd (and for some mothers with gestational diabetes)
What are basal forms of insulin?
- Activity lasts ~ 24 hours, peakless
- Insulin detemir and glargine
- Provides background amount of insulin (can be used in conjunction with a bolus which is given througout the day)
What are the advantages and disadvantages of fixed insulin doses?
- FIxed dose can help simplify understanding of blood glucose results but does not offer the flexibility of how much carbohydrates a patient may choose to consume at each meal
What are the advantages of flexible insulin therapy?
- 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 eill take time and commitment to learn how to best adjust insulin doses
- Patient chooses how much insulin to inject 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?
Hypoglycemia
What may be prescribed to patients that have difficulty achieving good glycemic control and type 1 diabetics?
Insulin pump
What are the formulations of basal-bolus insulin?
- Intermediate or long acting with short acting formulation
- > 3 injections given per day, through the day
- Requires high patient understanding
What patients are given a basal-bolus therapy?
- Patients with a high understanding of disease
- Type 1 and some type 2
How many injections are given throughout the day in an insulin pump?
Semi-automated: as needed througout day
What formulations of insulin are administered in an insulin pump?
Short acting formation
What is the first line of treatment for type 2 diabetics?
Metformin
What type of drug is metformin?
- Biguanide
- Oral hypoglycemic agent
What are the actions of metformin?
- Potentiates residual insulin by increasing insulin sensitivity
- Reduces gluconeogenesis in liver, which is markedly increased in type 2 diabetes and opposes the action of glucagon
- Increases glucose uptake and utilisation in skeletal muscle
- Slightly delays carbohydrate absorption in gut
- Increases fatty acid oxidation - reducing circulating LDL and VLDL
- Can suppress apetite
- Can be combined with drugs that stimulate insulin release
What is the mechanism of action of metformin?
- Alters energy metabolism
- Acts on mitochondria to change ratio of AMP to ATP
- Increase in AMP:ATP ratio activates 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
- Inhibits adenylate cyclase activity, decreasing cAMP, PKA and therefore glycolytic pathways, gluconeogenic pathways
- Takes time due to regulating gene networks
What does metformin enter the cell via?
SLC22A1
What is Glucagon-like peptide-1 (GLP-1) secreted by?
L-cells in gut
What is Gastric inhibitory peptide (GIP) secreted by?
K-cells in gut
What are the actions of incretins?
- Stimulate insulin biosynthesis / secretion
- Inhibit glucagon secretion in pancreas,
- Delay gastic emptying,
- Increase cardiac output
- Increase brain satiety signals
- Indirectly increase insulin sensitivity in the muscle and decrease gluconeogenesis in liver
What are incretins degraded by?
Dipeptidyl peptidase-4 (DPP-4)
What are incetin mimetics?
- Exenatide
- Exenatide LAR (long-acting release formulation)
- Liraglutide
Analogs of exedin-4/GLP-1 - Used with oral agents for type 2 diabetes
What is a side-effect of exenatide?
Nausea, hypoglycaemia, other GI effects
How often is exenatide given?
2x daily (LAR administered weekly)
What is the main advantage of exenatide LAR?
Induces less nausea than exenatide
What is the structure of liraglutide, how does this benefit it?
Additional fatty side-chain that confers albumin binding and slows renal clearence
How are incretin mimetics (e.g Exenatide, liraglutide) administered?
Subcutaneously as peptide analogs
How do incretin mimetics work?
Lower blood glucose after a meal by increasing insulin secretion and suppressing glucagon secretion
What protein is exenatide and liraglutide like in the body?
GLP-1
How does exenatide vary in order to confer resistance to cleavage by DPP4?
Changes amino acids
Addition of zinc to aan incretin mimetic results in what?
Delays absorption from subcutaneous tissues (e.g taspoglutide)
WHat incretin mimetic has an attachement of a fatty acid side chain to confer noncovalent albumin binding?
Liraglutide
What drug can couple to biodegradable polymer microspheres to confer protracted release from subcutaneous tissue?
Exenatide-LAR
What drugs can have a covalent conjugation with large molecules such as albumin and IgG to retard renal elimination?
- Albiglutide
- Dulaglutide
How do sitagliptin and vildagliptin work?
Enhance endogenous incretin effects by blocking DPP-4
What are examples of DPP-4 inhibitors?
- Sitagliptin
- Vildagliptin
What are the side-effects of vildagliptin?
- Associated with:
- Respiratory tract infections
- Headache
- Serious pancreatitis
Not available in USA
What are examples of Sulphonylureas?
- Tolbutamide
- Chlorpropamide
- Glibenclamide
- Glipizide
When are sulphonylureas used?
Early stages of type 2 - as they require functional Beta cells
What can sulphonylureas be combined with?
Metformin and Glitazones
What are side-effects of sulphonylureas?
- Weight gain, appetite increase
Can iteract with other drugs to produce: - Severe hypoglycaemia due to cometition with metabolizing enzymes, plasma binding proteins, and excretory pathways
What are examples of meglitinides (types of insulin secretagogues)?
- Repaglinide
- Nateglinide
What is the mechanism of action of meglitinides?
- Block K+ATP channels to increase insulin release
- Short duration of activity leads to lower risk of hypoglycaemia
What is the mechanism of action of sulphonylureas?
- High affinity receptors present in Beta-cell membranes
- Block ATP-sensitive K+ channels in Beta cells
- Causes beta cell depolarisation - leads to insuin secretion
- Only works if Beta cells of the pancreas are functional
What are examples of Selective sodium glucose transporter 2 inhibitors (SGLT2)?
- Canagliflozin
- Dapaglifozin
- Empaglifozin
When are SGLT2 inhibitors recommended?
Type 2 diabetes as monotherapy when diet and exercise alone not adequate for whom metformin is contraindicated or inappropriate
How do SGLT2 inhibitors work?
Block glucose reabsorption by the proximal tubule leading to therapeutic glucosuria - controls glycaemia independantly of insulin pathways
- Well tolerated, reduce weight and reduce systolic BP
How much does SGLT2 inhibitors reduce HbA1c compared to placebo?
1.17%
What is a side-effect of SGLT2 inhibitors (canaglifozin, dapaglifozi , empaglifozin)?
- Increased risk of UTIs
- Do NOT cause hypoglycaemia
How do thiazolidinediones (glitazones) work?
- Peroxisome proliferator activated receptor - gamma (PPARgamma - anuclear receptor) agonist - PPARgamma expressed in adipose tissue, muscle and liver
How does pioglitazone work?
- Increases insulin sensitivity
- Lowers blood glucose and promotes esterfication/storage of free fatty acids in adipose tissue in type 2 diabetes
- Promotes transcription of several genes that increase the storage of fatty acids in adipocytes, decreasing amount of circulating FFAs
- Cells become more dependant on oxidation of carbs, reducing blood glucose levels
- Can cause weight gain and fluid retention
How much does pioglitazone reduce exogenous insulin by?
~ 30%
What are side-effects / links of piglitazone?
- Bladder cancer
- Heart failure
- Osteoporotic fractures
Withdrawn from Germany, france, India
What is an example of a PPARgamma agonist other than Pioglitazone?
Rosiglitazone (recently withdrawn from UK)
What is the mechanism of action of pioglitazone?
- Mimics PPAR-gamma ligands by binding to PPAR-gamma receptors complexes with retinoid X receptor forming heterodimer which binds to DNA to promote transcription of genes important in insulin signalling: lipoprotien lipase, fatty acid transporters, GLUT-4 and others
- Can take a few weeks to work
What is an example of an alpha-glucosidase inhibitor?
Acarbose
What is a side-effect of acarbose?
Flatulence and diarrhoea (increased glucose lower down in GI tract)
What is acarbose used in?
Type 2 diabetes often in combination with other hypoglycemics
How does acarbose (alpha-glucosidase) work?
- A saccharide that acts as a competitive inhibitor of intestinal alpha-glucosidase (brush border enzymes)
- Delays carbohydrate absorption in the small intestine (upper portion) reducing the postprandial spike in glucose
