Week 8: Diabetes Mellitus - Insulin, other Hypoglycaemic Agents and Anti-Obesity Drugs Flashcards
what is the normal range of plasma glucose?
3.8 - 6.5 mmol/L.
why must plasma glucose be kept relatively constant?
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 be applied to keep plasma glucose beneath these upper and lower limit.
Define T1DM
Type I diabetes is characterised by autoimmune destruction of pancreatic insulin producing ß 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 ß-cells have fallen below 15% of their normal complement, the sufferer exhibits clinical signs. The absence of this principle hormonal control signal can then only be controlled with insulin analogues.
Define T2DM
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 in Type II diabetes develops gradually, it can frequently go undiagnosed for many years. Therapeutically, there are a range of treatment options employable to redress the varying degrees of loss of fine homeostatic control.
Outline normal homeostatic control of insulin in a non-diabetic
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 ß-cells. This in turn directly reflects the variations in blood glucose. Allied with a very short t1/2 of endogenous insulin of 10 minutes, normal homeostatic control of glucose is marvellously efficient.
What is the treatment for T1DM?
Insulin regimes can be tailored for individual patient requirements. Whilst some regimes utilise a ‘pre-mixed’ insulin regime to be given twice a day, with morning and evening meals, it does not provide optimized glycaemic control. Better glycaemic control can be afforded by a regime incorporating administration of an intermediate/long lasting insulin to provide a basal level that extends overnight. This should then be supplemented with fast or short acting insulins injected with meals to provide acute response, typically given three to five times daily.
Early Stages in Insulin Resistance can be managed by Diet and Lifestyle. State how this may be achieved.
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, cessation of smoking and increasing exercise complete the familiar mantra. 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.
Insulin sensitisers 1: Biguanides -General Pharmacology of Metformin
Currently, the only biguanide available for use in the UK is Metformin, which 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 and enhances skeletal and adipose glucose uptake. It also inhibits hepatic gluconeogenesis and can reduce HbA1c by up to 2%.
Whilst reducing hyperglycaemia, it does not induce hypoglycaemia. Metformin additionally reduces LDL and VLDLs. With a t1/2 of about 2-3 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.
Biguanide adverse drug reactions
GI disturbances are common, but can be ameliorated by slow dose titration. Use is contraindicated in patients with compromised HRH (heart/ renal/ hepatic) function and respiratory disease. See earlier PK lecture (HRH↓→∆ pharmacokinetics: t1/2†; CL↓→∆ pharmacodynamics).
Insulin sensitisers 2: Thiazolineinediones -General pharmacology
This group, which includes 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. TZDs can reduce HbA1c by 1-1.5%
The known pharmacological of action of Thiazolineinediones (TZDs) does not fully explain its effects. They agonistically bind to a nuclear hormone receptor site the peroxisome proliferator–activated receptor-γ (PPAR-γ). This binds with another nuclear receptor the Retinoid X receptor (RXR). The PPAR-γ/RXR complex then appear to upregulate 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-γ) 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 release into the blood.
TZDs t1/2 are ≈ 7 hrs, but metabolites can also show some degree of pharmacological activity and have prolonged t1/2 values up to 150 hrs. They 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 ≈ 99%, and would be affected by competitive binding for these sites, with knock on pharmacokinetic and pharmacodynamic consequence
Thiazolineinediones adverse drug reactions
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.
Insulin release stimulants 1: Sulphonylureas - General pharmacology
Sulphonlyureas include tolbutamide, glibencamide and glipizide.
Act by binding to and antagonizing ß-cell K+/ATP channel activity. The decrease in K+ current results in depolarization, as K+ accumulates in the ß-cell. This in turn results in increase Ca2+ entry which governs the fusion rate of insulin vesicles with the ß-cell membrane and their release into the circulation.
Tolbutamide has the shortest t1/2 of about 4 hrs and acts for up to 6-12 hrs. 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 t1/2 and duration of action for glibencamide are 10 hrs and 18-24 hrs respectively and for glipizide, 7 hrs and 16-24 hrs respectively. These will therefore provide a longer duration of negative feedback on top of any basal endogenous insulin signal. Sulphonylureas are also highly bound ≈ 90-99%, to plasma proteins. They can reduce HbA1c by between 1-2% and are given once per day.
Sulphonylurea ADRs
The increased t1/2and potency of the latter two agents 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.
Insulin release stimulants 2: Meglitidines - General pharmacology
p include repaglinide and nateglinide. They also act as K+/ATP channel antagonists and are equal in efficacy to the Sulphonylureas. They have a shorter t1/2≈1-3 hrs, like tolbutamide. They are taken before meals for shorter term control of post meal glucose elevation. They can result in reductions in HbA1c by about 1%.
Meglitidine ADRs
They 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.
GLP-1 analogues, DPP4 inhibitors and α - Glucosidase inhibitors - general pharmacology
GLP-1 analogues and DPP4 inhibitors are relatively new agents and not considered in detail here. GLP stands for ‘Glucagon Like Peptide’ (although it is not glucagon like in action!). GLP-1 increases insulin levels and decreases glucagon levels. It also decreases appetite and slows gastric emptying and needs to be injected. ‘Dipeptidyl peptidase-4’ or DPP4, inhibits the DPP enzyme, which breaks down GLP-1, therefore decreasing glucose levels.
Acarboseis an example of an -Glucosidase inhibitor used to delay carbohydrate absorption by the gut, thus decreasing post prandial glucose peak levels. They have some clinical utility, either alone or in combination therapy and can decrease HbA1c by 1%. The ADR GI profile of flatulence, runny stools and abdominal pain allied with variable efficacy means they are not first agents of choice.
Type II treatment: Combination therapy
The treatment options for Type II diabetes are much wider and begin with no drug therapy starting with diet, exercise and lifestyle changes.
Drug therapy usually starts with the biguanide Metformin. Over time if HbA1c levels go above 7%, then a sulphonylurea (K+/ATP antagonist) is added to therapy.
With this regime, if HbA1c levels over time go above 7.5%, then the clinician may choose to add a TZD (PPAR-γ 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.
General diabetic Drug-Drug Interactions (DDIs)
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. Previous comments about DDIs should also be taken into consideration i.e. drugs affecting protein binding – both sulphonylureas and TZDs are heavily bound to plasma proteins.
Note also 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.
Anti-Obesity drugs
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 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.
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, its use is associated with increased heart rate and BP – cardiovascular risk factors present and being treated in obese diabetics!
Mechanism of Atherosclerosis
There are a number of stages underlying the aetiology, the primary one involving endothelial dysfunction which leads to infiltration and entrapment of LDL in the arterial wall. LDL oxidation leads to further pro-inflammatory changes. Over time this leads to deposition of connective tissue components and the formation of a fibrous cap over a lipid rich core. Rupture of the plaque provides a substrate for thrombosis.
Prevention of Atherosclerosis – Lipid lowering drugs
Drug treatments apart, exercise change in dietary and other habits can reduce LDL and increase HDL. The main agents of clinical choice are: Statins; Cholesterol Absorption Inhibitors; Fibrates; Bile Acid Sequestrants; Niacin. Use of the latter two will be covered in brief.
Why does blood glucose rise?
Simply put….
• Inability to produce insulin due to beta cell failure
and / or
• Insulin production adequate but insulin resistance
prevents insulin working effectively
• Knowing that these are the 2 principle mechanisms helps understand the treatment options available
How do we treat diabetes?
Type 1
o Lifestyle plus insulin – many formulations o More in Lecture 3.2
• Type 2
o Lifestyle plus non-insulin therapies
o Biguanides eg metformin, sulphonylureas,
thiazolidinediones, DPP4 inhibitors, α- Glucosidase inhibitors, SGLT2s, GLP1 analogues and Insulin
• Both require patient education and ability to monitor results of therapy
Challenges for patients with Type 2 diabetes
• Weight gain and hypoglycaemia are important factors in patient adherence and quality of life
• Why ?
• Drug stimulates more insulin release → more insulin (anabolic)
leads to weight gain and hypoglycaemia
