Describe the role of insulin and the normal insulin profile
Insulin is the major controller of blood glucose and is produced by the beta cells in the islets of Langerhans. Its actions include:
- Activates GLUT4 to relocate to the cell membrane, to increase uptake of glucose into cells.
- Inhibits glycogen breakdown (glycogenolysis) and enhances uptake of glucose by muscle, liver and adipose tssue.
- Stimulates fatty acid synthesis for transport as lipoproteins and inhibits lipolysis in adipocytes.
- Inhibits proteolysis to reduce amino acid levels in the blood.
- Decreases hepatic glucose output via the inhibition of gluconeogenesis
The whole system works on a negative feedback effect whereby plasma glucose levels are always kept between 3.8-6.5mmol/L
Ideal insulin treatment would be to reinstate the normal daily insulin profile to prevent both hyperglycaemic and hypoglycaemia
Describe the importance of glycaemic control
Diabetes arises from the loss of homeostatic control through the disruption to one or more of the primary negative feedback signalling elements. Glucose is the pivotal energy intermediate for the whole body and its supply and controlunderpins the normal functioning of all body systems.
The large homeostatic resource invested in regulating glucose concentration is essential, as skeletal muscle group demand can vary at least 20-fold in a healthy individual.
Moreover, the brain is completely dependent on glucose to supply its ATP requirements and cannot use other energy intermediates. This means that plasma glucose must be kept above a minimum level to adequately support CNS activity.
Conversely, excessive levels of glucose over time result in tissue damage. This means that constant feedback has to operate to be applied to keep plasma glucose between these upper and lower limit. The normal range of plasma glucose is typically between 3.8 and 6.5 mmol/L
What is Diabetes?
Metabolic disease characterised by chronic hyperglycaemia. High glucose acutely has very little effect yet chronically does more damage; it causes macrovascular damage (increasing the risk for developing IHD, stroke, and peripheral vascular disease) and microvascular damage (increasing risk for retinopathies, neuropathies and nephropathies) with an overall increased mortality.
As a consequence, intervention is required. Type 1 diabetes is simply an absolute insulin deficiency from destruction of Beta-cells in the pancreas; as there is still normal insulin sensitivity, the condition is known as “insulin-dependent diabetes” and can be controlled with insulin analogues.
Type 2 diabetes is due to insulin resistance and progressive insulin deficiency and consequently cannot be simply treated by insulin. As a result, other management strategies are required.
How does diabetes present a growing clinical burden on the NHS?
Diabetes is a huge and growing problem, and the costs to society are high and escalating. 382 million people have diabetes. By 2035, this number will rise to 592 million.
Diabetes is a progressive disorder
- Declining beta cell function independent of changes in insulin resistance
- Deterioration of glycaemic control
- Increased risk of cardiovascular disease (Diabetes is a key cardiovascular risk factor).
Glycaemic control is directly related to exponential increases in risk of micro and macrovascular related disease, although the latter is also significantly influenced by associated hypertension or hypercholesterolaemia etc.
This burden is now rising exponentially in the UK, as a combined result of obesity, poor diet and inactive lifestyle. 90% of people with Type 2 diabetes are overweight or obese.
Insulin resistance: liver fat content decreases with low calorie dieting (increased insulin sensivity)
Some believe diabetes will become the largest single and potentially crippling demand on NHS resource within the next two decades. It currently uses 10% of the NHS budget.
Therapy for both Type 1 and Type 2 require patient education and ability to monitor results of therapy.
Describe the principle of Type 1 Diabetes therapy
Type I diabetes is characterised by autoimmune destruction of pancreatic insulin producing Beta-cells and occurs in about 5-10% of diabetic patients. Typically occurring in childhood or adolescence, it eventually leads to absolute insulin deficiency and is also known as ‘Insulin-dependent diabetes.
Once Beta-cells have fallen below 15% of their normal complement, the sufferer exhibits frank clinical signs.
The absence of this principle hormonal control signal can then only be controlled with insulin analogues.
Describe the principles of Type 2 Diabetes
Type II diabetes is due to insulin resistance and relative insulin deficiency; insulin levels may actually be higher than normal
Type II typically presents in those above 40 with obesity as a primary risk factor. Because insulin resistance develops gradually, it can frequently go undiagnosed for many years.
Therapeutically, there are a range of treatment of options employable to redress the varying degrees of loss of fine homeostatic control.
Weight gain and hypoglycaemia are important factors in patient adherence and quality of life
Most therapies result in weight gain over time
What is the NICE target HbA1c level?
NICE targets in Type 2 diabetes: in general target for all is HbA1c 6.5 to 7.5%
- HbA1c 6.5%: diet and first 2 treatment steps
- HbA1c 7.5%: beyond this or if at risk of severe hypoglycaemia
- Common sense: limited life expectancy and co-morbid conditions
Describe how the early stages of Type 2 diabetes may be managed non-pharmacologically?
Early Stages in Insulin Resistance can be managed by diet and lifestyle
When the patient is first diagnosed and if HbAc1 and other measures allow, adequate control can be achieved with diet and lifestyle changes alone.
Losing weight by limiting fat intake, whilst increasing proportionate calories intake of complex carbohydrates is often effective at keeping HbA1c levels stable.
Reduction in alcohol and salt intake, cessation of smoking and increasing exercise also helps. Reducing CVS risk factors (such as hyperlipidaemia or hypertension) to ensure limited impact of diabetes).
In the absence of success by diet and weight control, some clinicians may now consider pharmacological intervention to treat for obesity as a second step.
Currently, there are studies to determine if earlier pharmacological intervention is beneficial.
What's the biggest advantage of oral hypoglycaemics?
Number of drug groups available. Their great advantage is that they can be taken orally unlike most insulin analogues that require injection.
What is Metformin?
Insulin Sensitiser 1: Biguanides
Currently the only biguanide available for use in the UK is Metformin.
Metformin is the first agent of choice for Type II diabetics. They appear to act by increasing sensitivity to insulin but have mixed actions, the precise sites of action are currently being characterised.
Metformin increases insulin receptor sensitivity (decreases insulin resistance) and enhances skeletal and adipose glucose uptake. It also inhibits hepatic gluconeogenesis (glucose production) and can reduce HbA1c by up to 2%.
Whilst reducing hyperglycaemia, it does not induce hypoglycaemia/ Metformin additionally reduces LDL and VLDLs. With a half life of about 2-3 hours (lusuma 1-5 hours), it is typically given two to three times a day prior to meals to provide acute negative feedback on top of a basal endogenous insulin signal.
No binding to plasma proteins so is eliminated renally directly.
Metformin is weight neutral (limited weight gain – suitable for overweight patients), cheap dose, does not cause hypoglycaemic episodes and most importantly has good effect in lowering glucose.
Can be combined with all other diabetes medications.
Decreased CVS events (UKPDS study)
What are biguanide ADRs?
GI disturbances are common but can be ameliorated by slow dose titration.
Use is contraindicated in patients with compromised HRH function and respiratory disease.
Lactic acidosis rare
Vitamin B12 deficiency uncommon
Stop of CKD < 30ml/min or significant comorbditiies
Dose range typically 500mg to 2.5g (also modified release available)
What are TZDs?
Insulin Sensitisers 2: Thiazolineinediones (Glitazones)
This group, including rosiglitazone and pioglitazone, are relative newcomers to clinical use.
They reach peak effects after 1-2 months, which include reduction of gluconeogenesis and increased glucose uptake into muscle. Glitazones increase insulin sensitivity in muscle and adipose tissue and decrease hepatic glucose output.
TZDs can reduce HbA1c by 1-1.5%
The known pharmacological action of TZDs does not fully explain its effects. They agnostically bind to a nuclear hormone receptor site, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). This binds with another nuclear receptor, the Retinoid X receptor (RXR).
The PPAR-gamma/RXR complex then appear to up-regulate a wide set of genes with products important in insulin signalling which govern glucose and lipid metabolism.
However, the tissues expressing high levels of (PPAR-gamma) are adipocytes. Muscle and liver only express this receptor at much lower levels. It is suggested that the signalling element that causes the effects observed in muscle and liver is due to a reduction of fatty acids released into the blood.
Can be used in combination with other oral agents
What are the PK and ADRs of TZDs? Are they common oral hypoglycaemics?
Cardiovascular concerns with Rosiglitazone
Pioglitazone still available but concerns regarding weight gain, fluid retention and heart failure, effects on bone metabolism (fractures in post-menopausal women?) and bladder cancer.
Glitazones are rarely used these days.
The half life of TZDs are approximately 7 hours but metabolites can also have some degree of pharmacological activity and have prolonged half lives of up to 150 hours.
TZDs are given once per day for prolonged control of glucose levels and do not offer as fine glycaemic control as metformin. Notably, they are very heavily bound by plasma proteins (approximately 99%) and would be affected by competitive binding for these sites, with knock on pharmacokinetic and pharmacodynamics consequences.
- Whilst associated with weight gain, they do not induce hypoglycaemia.
- Other ADRs include oedema and some increases in LDL and HDL.
- Their use is contraindicated in heart failure.
What are Sulphonylureas? Give specific examples
Insulin Release Stimulants 1: Sulphonylureas
First used in the 1950s and both first and second generation drugs are in use in the UK. These include tolbutamide, glibencamide and glipizide.
They vary in their pharmacokinetic and pharmacodynamics and are chosen for use to supplement endogenous insulin accordingly.
Extensive experience – decreased microvascular risk (UKPDS study)
They act by binding to and antagonising Beta-cell K+/ATP channel activity. The decrease in K+ current results in depolarization, as K+ accumulates in the Beta-cell. This in turn results in increased Ca2+ entry which governs the fusion rate of insulin vesicles within the B-cell membranes and their release into the circulation (increased rate of insulin secretion through stimulating beta cells).
Tolbutamide has the shortest half life of about 4 hours and acts for up to 6-12 hours. Tolbutamide offers better short-term post-prandial control of glucose and is given about 30 minutes before eating.
Glibencamide and glipizide are far more potent than tolbutamide by a factor of about 100, but are not necessarily therapeutically superior.
The half life and duration of action for glibencamide are 10 hours and 24 hours respectively, and for glipizide, 7 hours and 16-24 hours respectively. These will therefore provide a longer duration of negative feedback on top of any basal endogenous insulin signal.
Sulphonylureas are also highly bound – approximately 90-99% to plasma proteins. They can reduce HbA1c by between 1-2% and are given once per day.
Commonly used include Gliclazide (modified release too) (hepatic metabolism so can be used in renal impairment), Glimepiride
What are Sulphonylurea ADRs?
The increased half life and potency of glibencamide and glipizide result in a greater incidence of hypoglycaemia, especially in the elderly.
With glibencamide, secondary metabolites are also active, so even modest renal deficit can result in iatrogenic hypoglycaemia.
Common ADRs are GI disturbance.
Additionally, weight gain is a problem which limits their use in the particularly obese patient.
What are Meglitidines?
Insulin Release Stimulants 2: Meglitidines
Two agents in UK use from this group include repaglinide and nateglinide. They also act as K+/ATP channel antagonists and are equal in efficacy to the Sulphonylureas but distinct receptors.
They have a shorter half life (approximately 1-3 hours) like tolbutamide but more rapid action than sulphonylureas – known as rapid acting insulin secretagogues
They are taken immediately before meals for shorter term control of post-meal glucose elevation.
They can result in reductions in HbA1c by about 1%.
- The agents are associated with a relatively lower risk of hypoglycaemia, and are not associated with weight gain, which extends their utility in treating obese patients.
What are GLP-1 analogues? Consider the physiological action of GLP-1
GLP-1 analogues (Glucagon-Like Peptide) increases insulin levels and decreases glucagon levels. It also decreases appetite and slows gastric emptying. It needs to be injected.
Exenatide GLP1 agonist has shown sustained HbA1c reductions and reduced body weight in long term studies.
What are the actions of GLP-1 agonist Exenatide? Adverse side effects and NICE guidelines?
- Gastrointestinal symptoms, nausea, loose stools or diarrhoea
- Gastrooesophageal reflux
- Low risk of hypoglycaemia
- Occasional painful to inject
- ? Pancreatitis and pancreatic carcinoma
- NICE and FDA have found no evidence of pancreatitis in the reported studies
- Generally perceived to be safe and well tolerated agents
- Widely used
NICE and Exenatide
- Continue Exenatide (and similar agents) only if a beneficial metabolic response occurs and is maintained
- HbA1c reduction at least 1% at 6 months
- Weight loss of at least 3% at 6 months
What are DPP4 inhibitors?
Dipeptidyl peptidase-4 or DPP4 inhibitors, inhibit the DPP4 enzyme which rapidly breaks down GLP-1, therefore decreasing glucose levels.
Gliptins are DPP4 inhibitors and inhibits the breakdown of incretins and thereby increases active incretin levels.
Gliptins include Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin
They inhibit DPP4 activity, increasing post prandial active GLP-1 concentraitons
- Side effects include GI symptoms, ? pancreatitis
- Low risk of hypoglycaemia
- Weight neutral
- Modest HbA1c reduction
NICE and DPP4 inhibitors (Sitagliptin and Vildagliptin)
- Consider adding 2nd line to Metformin or sulphonyulrea with HbA1c>6.5% if:
- Patient at significant risk of hypoglycaemia and its consequences (e.g. older people, living alone and certain occupations)
- Patient does not tolerate a sulphonylurea (or it is contraindicated)
- Can be used as triple therapy
- Continue only if HbA1c reduction >0.5% is achieved and maintained over 6 months
Acarbose is an example of an alpha-Glucosidase inhibitor used to delay carbohydrate absorption by the gut, thus decreasing post prandial glucose peak levels. It inhibits breakdown of carbohydrates to glucose by blocking action of the enzyme alpha-Glucosidase – delays glucose load into blood. They have some clinical utility, either alone or in combination therapy and can decrease HbA1c by ~0.5-1%. It is excreted unchanged in gut. High doses are associated associated with elevation of ALT. The ADR GI profile of flatulence, runny stools and abdominal pain allied with variable efficacy means they are not first agents of choice. Rarely if ever used nowadays.
Describe Sodium Glucose Co-Transporter 2 Inhibitors
Sodium-Glucose Co-Transporter 2 inhibitors
- Normal renal glucose handling: majority of glucose is reabsorbed by SGLT2 (90%) in the proximal tubule whilst the remaining glucose is reabsorbed by SGLT1 (10%)
- Dapagliflozin is a novel insulin-independent approach to remove excess glucose as it selectively inhibits SGLT2 in the renal proximal tubule – excrete glucose in urine = calories
- Long term studies lacking
- Can be used for patients with Type 1 and Type 2 diabetes as add-on therapy
- Dapagliflozin, Canagliflozin and Empagliflozin are available
- Side effects includes increased risk of lower urinary tract symptoms including genital and urinary infections especially in women (5%) e.g. thrush. Polyuria is also an adverse side effect. Hypoglycaemia risk is low.
What types of insulins are available?
The therapeutic use of mammalian insulin analogues began shortly after the elucidation of its role in the 1920s. Porcine or bovine derivatives were the pharmaceutical agents of choice up until the 1990s. Extensive research over the last two decades has led to the large scale manufacture of synthetic human insulin using recombinant DNA technology.
Types of insulin available:
- Animal Porcine and Bovine (NB: some older patients may be still on this insulin – they may have been taking it for 60 years etc)
- Recombinant DNA technology
- Human short acting insulins
- Human rapid acting insulin analogues
- Isophane intermediate acting insulin
- Long acting basal analogue insulins
- Very long acting basal analogue insulins
The resultant exogenous insulins use variation in both pharmaceutical preparation and single amino acid substitutions to provide a range of effective glycaemic controllers.
Give examples of how recombinant technology has allowed the development of insulin analogues?
Recombinant DNA technology has allowed for the development and production of analogues – the insulin molecule structure is modified to alter the pharmacokinetic properties, primarily affecting the absorption characteristics of the drug from subcutaneous tissue (amino acids in the B26-30 region is altered).
With rapid-acting insulins such as Aspart, substitutions occurs e.g. Proline is exchanged for Aspartate which makes molecule more negatively charged so the molecules become monomers in solution – increases rate of reabsorption.
With longer-acting insulins like Glargine, clumping or coalescing occurs (hexamers instead of monomers form) which need to be broken down prior to absorption hence slows down the rate of reabsorption.
Describe the ideal insulin drug
The pharmaceutical formulation of these insulin means that the rate of uptake following subcutaneous injection can be varied allowing gradation of glycaemic control.
There are over 20 different types of insulin in use in various strengths and forms (vials, cartridges, disposable pens). This is very confusing and liable to prescribing errors.
In normal non-diabetics, the rate of insulin production is continuous and very fine, governed by the ATP/ADP ratio in the Islet of Langerhans Beta-cells. This in turn directly reflects the variations in blood glucose. Allied with a very short half life of endogenous insulin of 10 minutes, normal homeostatic control of glucose is marvellously efficient. In the absence of this properly functioning control system, the optimal way to attempt to mimic this is to utilise a mixture of insulins with varying absorption properties from their subcutaneous injection sites and half-lives.
What are the 5 Main Insulin Categories and describe Short Acting
There are 5 main insulin categories. Absorption into bloodstream is via subcutaneous injection and the formulation of insulin influences the rate of absorption. NB: once the insulin is injected, it’s all the same!
Very long acting
- Starts to work 30 to 60 minutes
- Need to inject at least 15 to 30 minutes before eating
- Peaks at 2 to 3 hours
- Duration 8 to 10 hours
- Needs to be injected several times daily to cover meals
- Labelled regular on the graph. Risk of hypoglycaemia due to peaks so advise patients to snack between meals.
Describe Rapid Acting and Intermediate Acting Insulins
Rapid Acting insulins
- Rapid onset of action 5 to 15 minutes
- Inject just before eating (or even just afterwards in children)
- Peaks 30 to 90 minutes (less need to snack between meals)
- Duration 4 to 6 hours
- Labelled Aspart, lispro on graph
Intermediate acting insulin (NPH)
- Slower onset 2 to 4 hours
- Peaks 4 to 8 hours
- Duration up to 12 to 10 hours
- 2x a day – e.g. one before lunch, one before dinner
- Peaks are quite high – risk of nocturnal hypoglycaemia so advise patients to snack before bedtime but weight gain is a problem.
Describe Long and Very Long Acting Insulins
Slow onset 2 to 6 hours
Duration up to 24 horus
Very long up to 50+ hours (DEGLUDEC insulin => stable background, supplement with short acting insulins. Less risk of hypoglycaemia particularly nocturnal episodes). Peak-less - so there is less need for snacking, gives patients more freedom and more control about when to take their insulin
What are the adverse effects of insulin?
Hypoglycaemia (=> release of adrenaline => shaky, sweaty, increasing confusion)
Lipodystrophy – lipohypertrophy (due to anabolic nature of insulin – need to make sure patients are not injecting into the same site every time) or lipoatrophy (more of a problem with animal insulins)
Painful injections – can change to a different company, different preservatives
Describe Type 1 treatment
Type I treatment: can be tailored individual patient requirements but the main management plan for Type 1 diabetes is insulin subcutaneous injections.
Whilst some regimes utilise a ‘pre-mixed’ insulin regime to be given twice a day with morning and evening meals, it does not provide optimised glycaemic control.
Better glycaemic control can be afforded by a regime incorporating administration of intermediate/long-lasting insulin to provide a basal level that extends overnight. This should then be supplemented with first or short acting insulins injected with meals to provide acute response, typically given three to five times daily
The pharmacological formulation of these insulins means that the rate of uptake following a SC injection can be varied allowing for gradation of glycaemic control.
Rapid onset involves administration of a insulin-hexamer, which peaks around 20in after injected and so can be given just before a meal.
Intermediate onset comprises of a crystalloid form, which allows for a slightly more prolonged peak.
Long-acting analogues can have prolonged levels so can become very long lasting.
Describe two insulin regimens and their advanteges
Due to the absence of properly functioning control systems, the best way to mimic the optimal actions of insulin is to utilise mixtures of analogues. There are 2 main mixtures used:
Basal Bolus Regimen involves utilising a long-acting insulin as background and then a fast acting insulin with meals. This involves injecting around 5 times a day yet does provide good flexibility.
Pre-mixed Insulin Regime involves administration of both fast and slow-acting insulin twice a day. Whilst this does not provide optimised glycaemic control, it involves less injecting for the patient.
Describe Combination Therapy in Type II treatment
The treatment options for Type II are much wider and begin with no drug therapy starting with diet, exercise and lifestyle changes.
Drug therapy usually starts with biguanide Metformin. Over time if HbAc levels go about 7%, then a sulphonylurea (K+/ATP antagonist) is added to therapy.
With this regime, if HbA1c levels over time go about 7.5%, then the clinical may choose to add a TZD (PPAR-gamma agonist), one of the newer hypoglycaemics OR start Insulin therapy.
With this regime, if HbA1c levels over time come back up and go above 7.5%, then doses will be titrated upwards to regain adequate glycaemic control.
Describe general drug-drug interactions in diabetes
The principle therapeutic interaction is the combined use of these agents to lower hyperglycaemia.
The main ADR of this combination is hypoglycaemia possibly leading to diabetic coma.
Also consider individual drug interactions e.g. drugs affecting protein binding – both sulphonylureas and TZDs are heavily bound to plasma porteins.
Any other drug affecting hepatic metabolism of oral hypoglycaemics can cause either hyperglycaemia if they induce the CYP enzymes that metabolise them, or hypoglycaemia if they inhibit the CYP enzymes that metabolise them.
Describe clinical and self-monitoring of diabetes
In patients with advanced diabetes, regular monitoring several times a day is required to determine their dosing level with insulin.
The regime with other non-insulin therapies is frequently determined by dietary habit. Along with carefully controlling their diet, patients can avoid excessive excursions above and below their normal 3.5-6.5 mmol/L glycaemic limits.
Chronic clinical monitoring of diabetic severity and progression is carried out by measuring glycohaemoglobin, or HbA1c. Gradually over time glucose non-enzymatically irreversibly glycosylates haemoglobin, the rate of which is proportional to glucose levels. Therefore, HbA1c acts as an integral measure of overall glucose levels and provides a stable clinical marker.
Normal baseline HbA1c is usually about 6%, when it rises about 7% the risk of vascular complications arises exponentially.
The rises of HbA1c determines the therapeutic steps to be taken.
Because of the potential damage across body systems, it is also necessary to monitor renal, hepatic, cardiovascular and neurological function to detect early onset of any microvascular disease e.g. retinal neuropathy and peripheral neuropathy. This also goes to inform drug management strategy.
Education is also required with diabetes education programme (DAFNE for type 1 diabetes and DESMOND for type 2 diabetes). Home monitoring of own diabetes via urine testing or capillary blood glucose, as well as HbA1c checks regularly.
Clinical Trials Show Progression of Disease with All Therapeutic Strategy Groups - what does this mean?
The 1998 UKPDSG (Prospective Diabetic Study Group) trials showed that across a range of newer therapies, initial overall reduction in HbA1c by about 1% was achieved over the first 1-2 years of monotherapy, compared to conventional therapy.
After this initial drop, the HbA1c levels gradually increased at the same rate as with conventional therapy. This increase in HbA1c means that multiple drug intervention is likely to be required to offset the increasing risk of vascular and neuropathology.
Describe Anti-Obesity therapy
Orlistat is a gastric and pancreatic lipase inhibitor so reducing (up to about 30%) dietary fat conversion to fatty acids and glycerol. Combined with a low calorie diet, a modest average of about 3% body weight reduction was obtained, although some subjects achieved a 10% loss. It has been effective with helping obese diabetics keep weight down.
- The major limitation of its use is broad GI disturbance, most notably soft fatty stools, which increases the risk of flatus with unpleasant faecal discharge or faecal incontinence alone.
- Prescribe only as part of overall plan in BMI 28 or more with diabetes
- Continue longer if 5% weight loss
Sibutramine is a noradrenaline and serotonin re-uptake inhibitor. This has potential mixed effects including appetite suppression and some additional reduction in hyperglycaemia and rate of glucose metabolism which may be related to increased thermogenesis.
- Sibutramine use resulted in a mean 5% weight loss with an upper limit of about 15%. However, it’s use is associated with increased heart and BP – cardiovascular risk factors present and being treated in obese diabetics
Rimontadine is a endocannainoid antagonist.
What kind of errors are there in diabetes
In UK 4 to 5% population has diabetes
30 to 40% treated with insulin
Insulin errors are very common in UK with approximately prescribing errors in ~20% cases
Why? Too much will lead to hypoglycaemia and too little to hyperglycaemia