Pharmacology - Endocrine Flashcards
Describe: Acromegaly
- Caused by excess production of growth hormone
- Most commonly affects middle-aged
- Can result in premature death
- Due to slow onset it is frequently incorrectly diagnosed
- Most common symptoms are abnormal growth of hands & feet.
Describe: Acromegaly Treatment
Aim is to reduce Growth Hormone production:
- Surgical removal of tumour, difficult due to tumour’s position within brain
- Drug therapy:
Ooctreotide & Lanreotide (somatostatin analogues, somatostatin receptor ligands SRLs)
Opegvisomant (growth hormone receptor antagonist)
Obromocriptine (dopamine agonist)
- Radiation therapy
Results of Deficit of Growth Hormone
Deficit:
- Dwarfism may be:
- general anterior pituitary dysfunction -
- specific GH deficit
- normal GH but hereditary somatomedin deficit
- Accelerated aging if loss of growth hormone occurs after adolescence
- decreased protein synthesis
Results of Excess of Growth Hormone
Excess GH
*Gigantism - early life pituitary tumour
*Acromegaly- pituitary tumour after adolescence
Dopamine agonists treat prolactinoma
Prolactin inhibiting factor (PIF) is dopamine
Dopamine acts at D2 receptors in the pituitary gland to inhibit prolactin release
Cabergoline and bromocriptine are dopamine agonists that inhibit prolactin production and can reduce the size of a prolactinoma
**Antipsychotics that are D2 receptor antagonists can cause hyperprolactinaemia
Hypopituitarism
- Rare - results from a deficiency in one or more pituitary hormones
- Panhypopituitarism – a deficiency in all anterior pituitary hormones
Multiple causes (acquired more often than congenital); tumours most common
+ traumatic, infective, vascular, autoimmune, functional (anorexia nervosa; starvation) - Symptoms mirror those of a primary deficiency in hormone secretion by the target endocrine gland
+ for example, primary and secondary hypothyroidism
+ if the deficiency is mild the patient may be asymptomatic - Managed by replacement therapy with the appropriate hormone(s)
+ e.g. recombinant GH (pituitary dwarfism); levothyroxine (2o hypothyroidism)
Describe: Hypelactinoma
Hyperlactinoma - too much prolactinoma in the blood
Benign pituitary tumours (adenomas) are the most common cause
Prolactin is the ‘milk hormone’
Common presentation:
Galactorrhoea - milky secretion from the breasts (male & female)
Amenorrhoea – females absence of periods
Hypogonadism – diminished production of sex hormones, diminished function of gonads in males & females
Erectile dysfunction - males
Vision loss, due to compression of the optic chiasm, is a common comorbidity
Explain the release and control of Growth Hormones
Hypothalamus release tropic factors into local circulation, & modified neurosecretory cells which release hormones enter the pituitary gland posterior,
The pituitary gland anterior releases primary hormones (such as prolactin & growth hormones), and trophic factors.
The GHRH (Growth Hormone Releasing hormone) stimulates the pituitary to release the GH (Growth Hormone), which is stopped by Somatostatin, a GH inhibitor.
TRH (Thyrotropin-releasing hormone) acts on the pituitary gland anterior, releasing TSH (Thyroid stimulating hormone), which acts on the Thyroid, causing the release of T3 (tri-iodothyroxine) & T4 (Thyroxine), both stimulate metabolic rate and growth, by acting at nuclear receptors to regulate gene transcription.
Describe both Hypersecretion & Hyposecretion, and the hormone whose activity results in these conditions.
Hypersecretion – too much hormones, resulting from an adenoma, a benign tumour
Hyposecretion – hormones are made against the hormone releasers, resulting from autoimmune disease.
GHRH activity results in these conditions.
The hypothalamic-pituitary axis
Hypothalamus releases TRH, causing the pituitary to release TRH onto the Thyroid, which releases T3 & T4, resulting in action within tissues. The negative feedback loop results in balance, loss of the feedback results in an unbalanced & diminished axis.
Thyroid hormone synthesis by follicle cells
TSH stimulates the Thyroid to synthesize Thyroid hormones, by stimulating iodide uptake into the cells by the transport protein Pendrin into the Follicle Lumen where TPO and TO enzymes catalyse addition of tyrosyl residues in Thyroglobulin.
When Thyroid hormones are needed the Thyroglobulin are Phagocytosed back into the cell and de-iodinated for more hormone synthesis.
Drugs act here to reduce the TPO action, limiting synthesis of Thyroid hormones.
Describe Hypothyroidism
Hypothyroidism – most common is autoimmune disease where antithyroid antibodies are made, stopping Thyroid hormone production.
A version called Hashimoto’s thyroiditis results in an enlarged thyroid gland.
Women may also get postpartum thyroiditis, but will typically recover.
May also occur from iodine deficiency.
Treated with lifelong hormone replacement.
Clinical signs & symptoms of hypothyroidism
Tiredness
Weight Gain
Cold intolerance
Goitre (large thyroid glands)
Dry thin hair
Dry skin
Mental Slowness
Slow heart rate
Slow-relaxing reflexes
Describe Hyperthyroidism (thyrotoxicosis)
Grave’s disease – autoimmune disease where antibodies act like TSH, meaning Thyroid hormones are released continuously, but can be caused by an inflammatory process or drug action.
Treated by antithyroid drugs, surgery or radiation.
Clinical features of hyperthyroidism (thyrotoxicosis) symptoms and signs
Weight Loss
Increase appetite
Tremor
Heat intolerance
Hyperkinesis
Overexcitable heart
Grave’s disease may result in bulging eyes
Hyperthyroidism treatment - 3
Treatment options:
1. Antithyroid drugs (e.g., Carbimazole): BetaBs may be coadministered for faster symptomatic relief.
2. Radioiodine: Only used for patients who have been made euthyroid first. It is contraindicated in pregnancy & breastfeeding.
3. Surgery: Reserved for patients who are euthyroid prior to the procedure.
Grave’s disease diagnosis
Graves’ disease is diagnosed with a low serum TSH & elevated T3 or T4 levels. TSH receptor antibodies are often present in cases, while thyroid peroxidase (TPO) & thyroglobulin antibodies are commonly found.
Q: What is Primary Hyperaldosteronism (Conn’s Syndrome)?
A condition caused by adrenal adenomas (benign tumours) producing excess aldosterone, leading to excessive sodium reabsorption and high blood pressure.
Q: What is the treatment for Primary Hyperaldosteronism (Conn’s Syndrome)?
A: Surgery to remove the adenoma or the use of aldosterone antagonists
Q: What is Hypoadrenalism (Addison’s Disease)?
A: A condition typically caused by autoimmune destruction of the adrenal glands, leading to insufficient production of cortisol and aldosterone.
Q: What is the treatment for Hypoadrenalism (Addison’s Disease)?
A: Hormone replacement therapy.
Q: What is Hypercortisolism (Cushing’s Syndrome)?
A: A condition caused by either endogenous (overactive adrenal glands or excess ACTH) or exogenous (glucocorticoid therapy for other conditions) factors, leading to excess cortisol production.
Q: What is the treatment for Hypercortisolism (Cushing’s Syndrome)?
A: Withdrawal of glucocorticoids or the use of cortisol synthesis inhibitors.
Q: Where is the adrenal gland located?
A: The adrenal gland is a triangular structure located on top of the kidneys.
Q: What are the two main parts of the adrenal gland?
A: The adrenal gland consists of an outer cortex and an inner medulla.
Q: What are the different zones of the adrenal cortex responsible for?
A: The cortex is zoned, with different areas responsible for synthesizing specific steroid hormones.
Q: Where is aldosterone primarily produced in the adrenal gland?
A: Aldosterone, a mineralocorticoid, is primarily produced in the outermost zone of the cortex, called the glomerulosa.
Q: Which hormone is produced in other cortical zones of the adrenal gland?
A: Glucocorticoids, like cortisol, are produced in other cortical zones.
Q: How can disorders affecting the adrenal cortex impact hormone production?
A: Disorders affecting different parts of the cortex can impact the synthesis of specific hormones, leading to various dysfunctions depending on the hormone involved.
Synthesis of aldosterone -
- Cholesterol
- to pregnenolone
- to progesterone
- to deoxycortone
- finally aldosterone.
Aldosterone - MoA
Aldosterone: primary mineralocorticoid that promotes reabsorption of sodium in the kidneys. As sodium is reabsorbed, water follows by osmosis, increasing blood volume, & raising blood pressure. Aldosterone acts by binding to mineralocorticoid receptors (MR), which are mainly found in the kidney, colon, & bladder—the organs responsible for regulating sodium.
The synthesis & secretion of aldosterone - renin system
The synthesis & secretion of aldosterone are controlled by the renin-angiotensin system. Increased sodium reabsorption is also linked to the secretion of potassium (K+) & hydrogen ions (H+). In circulation, most aldosterone is bound to proteins, and the receptor is part of the nuclear receptor superfamily (NR3C2).
Minerlocorticoids & glucocorticoid receptors - 5
- Steroid hormones like corticosterone (glucocorticoid) & aldosterone (mineralocorticoid) bind to nuclear receptors. 2. These lipophilic molecules pass bind to receptors attached to chaperone proteins.
- Upon binding, the hormone-receptor complex loses the chaperones & forms a dimer.
- This liganded dimer then translocates to the nucleus, where it binds to specific DNA sequences, called glucocorticoid receptor recognition elements.
- This binding either increases or decreases gene transcription depending on the required cellular outcome.
Aldosterone secretion: renin-angiotensin system - 8
The release of aldosterone is controlled by the renin-angiotensin system. Here’s the sequence:
1. BP drops (e.g., from bleeding).
2. Sympathetic nervous system activity increases & the Bowman’s capsule in the kidney detects the BP drop
3. This triggers the release of renin from the kidney.
4. Renin converts angiotensinogen (from the liver) to angiotensin I.
5. Angiotensin I is converted to angiotensin II in the lungs.
6. Angiotensin II acts as a vasoconstrictor, narrowing blood vessels to increase BP.
7. Angiotensin II also stimulates the release of aldosterone from the adrenal glands.
8. Aldosterone acts on the kidneys to promote sodium reabsorption, which increases blood volume & raises BP.
Clinical uses of aldosterone antagonists
Aldosterone antagonists, like spironolactone, are used to treat primary hyperaldosteronism and resistant hypertension.It competitively blocks aldosterone receptors but also affects sex hormone receptors, leading to possible side effects.
Clinical uses of exogenous antagonists
Exogenous mineralocorticoids like fludrocortisone are used in replacement therapy for conditions like Addison’s disease where both mineralocorticoid (aldosterone) & glucocorticoid (cortisol) need to be replaced. Fludrocortisone increases sodium reabsorption in the kidney’s distal tubules, while also promoting the efflux of potassium & hydrogen ions.
Spironolactone - 3
- Spironolactone is an aldosterone antagonist used to treat primary hyperaldosteronism (AKA Conn’s syndrome).
- Primary symptom of this condition is hypertension
- Spironolactone is a prodrug, which is converted into canrenone, with a half-life of 24 hours.
Primary Hyperaldosteronism (Conn’s Syndrome): - 7
- hypertension cases, but still poses significant risks like stroke, heart disease, & kidney failure.
- Diagnosis: high plasma aldosterone-to-renin ratio & plasma aldosterone levels that aren’t suppressed by saline infusion.
- Symptoms: low serum potassium (leading to muscle weakness) & increased urinary potassium.
Treatment:
5.Tissue growth: Aldosterone antagonist (spironolactone) for bilateral hyperplasia. - Unilateral, aldosterone-secreting adenoma:
- Surgical removal (usually laparoscopic/keyhole surgery) for unilateral adenoma.
Cortisol & Glucocorticoid Receptors: - 3
- Cortisol (main glucocorticoid)
- Synthesis & secretion regulated by ACTH (adrenocorticotropic hormone) from the pituitary, which stimulates cell overgrowth in the adrenal cortex.
- Synthetic glucocorticoids work by binding to nuclear receptors & regulating gene transcription, distinguishing them from more localized mineralocorticoid receptors.
Glucocorticoids - Treatment & Excessive use
- Treatment: rheumatoid arthritis, psoriasis, & eczema, where their immune-suppressive effects are beneficial.
- Excessive use: can casue disruptions in glucose regulation & lipid homeostasis, contributing to obesity & hyperglycemia.
Glucorcorticoid regulation - 3
- Increased ACTH indicates primary hyposecretion of glucocorticoids, where insufficient cortisol prevents negative feedback on ACTH production, leading to elevated levels.
- Decreased ACTH causes secondary adrenal insufficiency (low cortisol production due to insufficient ACTH release).
- Pituitary tumour can cause excess ACTH release, leading to excess glucocorticoids
Negative feedback in the HPA axis
The HPA axis involves CRH from hypothalamus triggering pituitary to release ACTH, which stimulates cortisol production by the adrenal glands. Cortisol then provides negative feedback to both the pituitary and hypothalamus to regulate the system.
Addison’s Disease (Primary Adrenal Insufficiency):
- 5
- Caused by autoimmune diseases
- Symptoms: Chronic fatigue, loss of appetite, generalized weakness, hypotension.
- Pathophysiology: Reduced production of adrenal steroids
- Diagnosis: Increased ACTH levels due to lack of cortisol feedback, leading to hyperpigmentation of the skin & vitiligo.
- Secondary features: Increased melanocyte-stimulating hormone (MSH) due to ACTH excess causes skin changes.
Secondary Adrenal Insufficiency - 4
- Cause: Often results from impaired ACTH release, commonly due to long-term corticosteroid use for non-endocrine conditions like rheumatoid arthritis, asthma, or ulcerative colitis.
- Management: Gradual withdrawal of corticosteroids is essential to avoid adrenal insufficiency.
- Less common causes: Pituitary tumours (non-ACTH secreting), infections, or pituitary ablation (radiation or surgery).
- Mechanism: Exogenous glucocorticoids suppress ACTH production through negative feedback, leading to adrenal insufficiency.
Acute management of adrenal insufficiency - 4
Urgent treatment is required to correct the following:
Hypotension
Hypokalaemia,
Hypoglycaemia
Dehydration
Long-term Management of Adrenal Insufficiency: - 2
- Treatment: Requires replacement therapy with both glucocorticoids (e.g., hydrocortisone) & mineralocorticoids (e.g., fludrocortisone).
- Patient Guidance: Patients should wear a medic-alert bracelet, carry a steroid card, & keep hydrocortisone at home for emergency injection if oral therapy is not possible.
Congenital Adrenal Hyperplasia (CAH):
- 2
- Pathophysiology: Leads to decreased cortisol secretion, increased plasma ACTH, & adrenal hyperplasia.
- Most Common Cause: 90-95% of cases are due to CYP21A2 steroid hydroxylase deficiency, affecting steroid hormone synthesis & impacting childhood development.
Cushing’s syndrome - 3
Cushing’s Syndrome:
1. Primary Cause: Overactivity of the adrenal g;and due to cortisol-secreting adrenal tumours or nodular hyperplasia, leading to suppression of ACTH secretion.
2. Secondary Cause: Pituitary gland tumour or ACTH-dependent overproduction, often due to a pituitary adenoma.
3. Differential Diagnosis: Tests like plasma ACTH levels (low) & dexamethasone suppression test
Exogenous Cushing’s Syndrome: - 2
- Cause: Long-term use of glucocorticoids
- Administration Route: Less likely with topical or inhaled glucocorticoids.
Signs & Symptoms of Cushing’s Syndrome: - 3
- Fat Redistribution: “moon face” & fat belly
- Purple or red stretch marks on the skin.
- Hypertension: Caused by excess aldosteronism
Dexamethasone Suppression Test for Cushing’s Syndrome Diagnosis: - 3
- Dexamethasone, a synthetic glucocorticoid, is given at 11:00 PM
- Blood sample taken next morning when cortisol levels would normally be elevated (circadian rhythm)
- In cases of adrenal dysfunction, the negative feedback may be disrupted, leading to insufficient suppression or excessive suppression of cortisol, helping diagnose adrenal issues.
Management of Cushing’s Syndrome - 5
- Untreated Cushing’s Syndrome has a poor prognosis, with morbidity mainly from hypertension, MI, infections, & heart failure.
- Cortisol hypersecretion must be controlled before surgery or radiotherapy.
- Pharmacological options include: Metyrapone, Ketoconazole
- Monitoring: Plasma cortisol levels
- Alternative approach: Gradually tapering or withdrawing glucocorticoid treatment
Regulation of Blood Glucose by Insulin & Glucagon
Insulin: released by pancreas in response to high blood glucose levels (e.g., after eating). Facilitates uptake of glucose to be stored as glycogen. Also regulates protein & fat metabolism by promoting storage of amino acids & fatty acids.
Glucagon: released when blood glucose levels are low (e.g., between meals). Promotes breakdown of glycogen into glucose. Also stimulates release of free fatty acids & ketones for energy when glucose is scarce & can convert amino acids into glucose through gluconeogenesis.
Diabetes Mellitus:
Diabetes Mellitus: characterized by hyperglycemia (high blood glucose levels), fasting blood glucose level greater than 7 mmol/L (normal is between 4.5-5 mmol/L).
T1D - 5
Type 1 Diabetes:
1. Immune system destroys pancreatic beta cells, leading to an inability to produce insulin.
2. Treatment requires insulin injections.
3. The body is unable to produce any insulin
4. Previously known as insulin dependent diabetes mellitus (IDDM), juvenile diabetes
5. Sudden onset
T2D
Type 2 Diabetes: Associated with obesity & sedentary lifestyles, characterized by insulin resistance (or impaired insulin secretion). Treatment focuses on enhancing insulin secretion or improving insulin sensitivity.
Gestational diabetes
Gestational Diabetes: Develops during pregnancy & is typically temporary. However, if untreated, it can cause serious health risks for both the mother & the baby.
Symptoms of T1DM - 7
- Increased urination
- Increased thirst
- Weight loss (in spite of increased appetite)
- Fatigue
- Nausea, vomiting
- Coma
- Patients often diagnosed in an emergency setting as symptoms develop over a short period of time
T1DM is an autoimmune disease - 3
- Characterized by immune-mediated destruction of the insulin-secreting b cells of the pancreas
- T-cell mediated autoimmune disease with circulating autoantibodies to various islet cell antigens.
- Caused by: Genetic risk factors (HLA), Environmental factors e.g. viral infection
Islet cell transplantation for T1DM Risks 3vs Benefits 2
Risks:
1. Transplantation surgery risk
2. Immunosuppressant drugs side effects
3. Need 2-3x transplants
Benefits:
1. Live without insulin injections
2. Improved blood glucose control
Type 2 diabetes mellitus (T2DM) - 3
- The body cannot produce enough insulin OR the body cannot respond to insulin = “insulin resistance”
- Previously known as non-insulin dependent diabetes mellitus, adult-onset diabetes
- Can go undiagnosed for a long time
Symptoms of T2DM - 8
- Increased urination
- Increased thirst
- Increased appetite
- Fatigue
- Blurred vision
- Slow-healing infections
- Impotence in men
- Slower onset than T1DM, symptoms develop over a long period of time and may go unnoticed
Risk factors for T2DM - 8
- Your family history
- > 45 yrs
- Ethnicity
- Weight
- BP – more at risk if you’ve ever had high BP
- High cholesterol levels
- Sedentary life style
- Gestational diabetes or delivering a baby > 9lbs
Consequences of Insulin Resistance - 4
- Causes: excess weight, a sedentary lifestyle, & genetic factors.
- Early Intervention: diet & exercise, pre-diabetic or early stages can manage their symptoms
- Elevated Blood Sugar: When insulin resistance occurs, glucose cannot be taken up by cells, leading to high blood sugar levels. This also affects the kidneys, increasing urination & thirst.
- Fat Metabolism Disruption: Insulin resistance impairs fat metabolism, leading to: Increased release of triglycerides, Elevated fats in the bloodstream, Decreased “good” cholesterol.
Insulin resistance: Long-term Health Risks – 4
Atherosclerosis: Hardening and narrowing of blood vessels, raising the risk of blockages and cardiovascular disease.
Hypertension: Increased risk of high blood pressure.
Liver Inflammation: Potential for liver damage.
Metabolic Syndrome: Includes conditions like polycystic ovary syndrome (PCOS) and other metabolic issues.
Glycosylated haemoglobin (HbA1c) - 6
- When glucose attaches to proteins, they become glycated (glycosylated)
- HbA1c is a test that measures glycated haemoglobin
- Biomarker of disease and treatment response
- Preferred method of assessing how well blood glucose levels are being controlled
- HbA1c level of 6.5% (48mmol/mol) or above indicates T2DM
- HbA1c level of 6-6.4% (42-47 mmol/mol) indicates a high risk of developing diabetes
Testing for diabetes: Fasting plasma glucose test (FPG) - 2
- Fast for 8 h, blood sample taken,
- Blood sugar > 7 mmol/l in fasted state = diabetes
Testing for diabetes: Oral glucose tolerance test (OGTT) - 3
- Fast for 8h, blood sample taken, drink sugary drink, 2h later blood sample taken
- Blood glucose 7.9 – 11 mmol/l = impaired glucose tolerance (IGT)
- Blood glucose > 11 mmol/l = diabetes
Testing for diabetes: Glycosuria - 3
- Quick & simple “dipstick” test
- Less accurate than HbA1c or GTT
- Kidney normally reabsorbs glucose into the body, but there is a “tubular maximum” capacity for transport, so blood glucose leads to glucose appearing in urine
Testing for diabetes: Ketone bodies - 3
- Quick and simple “dipstick” test
- Body can switch from using glucose to using fats to provide cellular energy & produce ketones
- Ketones can change blood pH leading to diabetic ketoacidosis particularly in T1DM
Hypoglycaemia
Hypoglycaemia (low blood glucose) caused by not eating enough carbohydrates, taking too much insulin, exercising too much
Hyperglycaemia
Hyperglycaemia (high blood glucose) caused by eating too much sugary food, drinking alcohol, not taking medication, not exercising
Diabetic ketoacidosis in T1DM:
Diabetic ketoacidosis in T1DM: when glucose not available for energy generation, body uses fat and ketones are a by-product of fat metabolism, lowers plasma pH – pear drops breath
Hyperosmolar hyperglycaemic state (HHS)
Hyperosmolar hyperglycaemic state (HHS) in T2DM (without ketoacidosis): associated with dehydration - can occur in older patients, especially with concomitant infection – can life-threatening emergency
Microvascular complications - 3
- Common microvascular modification is a thickening of the capillary basement membrane resulting in the classic diabetic microangiopathy
- Thickening alters blood vessel function, directly promoting hypertension, reduced wound healing, & tissue hypoxia
- Later stages, a loss of micro vessels occurs leading to: Retinopathy, Nephropathy, Neuropathy
Consequences of Hypoglycaemia on Blood Vessels - 5
- Hypoxia & Oxidative Stress: Low blood glucose can cause hypoxia (lack of oxygen) in tissues, leading to oxidative stress & production of reactive oxygen species, which may trigger apoptosis (cell death).
- Impaired Blood Vessel Function: Hypoglycaemia can inhibit endothelial nitric oxide synthase, reducing blood vessel relaxation & impairing proper circulation.
- Protein Glycation: Excess sugar in the blood leads to the attachment of sugar residues to proteins, forming advanced glycation end products (AGEs).
- Advanced Glycation End Products (AGEs): These stable & rigid molecules bind together, making blood vessels stiff & less flexible, impairing their ability to circulate blood effectively.
- Microvascular Damage: Accumulation of AGEs in tissues can be a major contributor to microvascular damage, affecting smaller blood vessels.
Diabetic Retinopathy & Vision Loss - 3
- Background Retinopathy: Tiny bulges develop in the blood vessels, which may bleed slightly but typically don’t affect vision.
- Pre-Proliferative Retinopathy: More severe changes in the blood vessels occur, including significant bleeding into the eye.
- Proliferative Retinopathy: Scar tissue & weak, easily bleeding new blood vessels form on the retina, leading to more severe vision problems.
Diabetic Nephropathy (Kidney Damage) - 3
- Damage to capillaries in the glomerulus causes breakdown of the filtration barrier, allowing more protein to leak into the urine.
- Hypertension, common in diabetes, exacerbates this process.
- The condition develops slowly over time, & as kidney function declines, it may eventually lead to chronic kidney failure.
Diabetic neuropathy - 4
- Peripheral nerve dysfunction
- Capillary damage can lead to nerve damage & loss of sensation, particularly extremities
- Begins as loss of sensation e.g. in the toes & leads to injury
- e.g. ulcers, gangrene, “diabetic foot
Atherosclerosis & Macrovascular Complications in Diabetes - 3
- Atherosclerosis is primary cause of macrovascular complications in diabetes.
- It results from chronic inflammation & injury to the arterial walls, particularly in the peripheral or coronary vascular systems.
- Type 2 diabetes (T2DM) also increases platelet adhesion & hypercoagulability, raising the risk of vascular occlusion & cardiovascular events.
Insulin Treatment in Diabetes: - 2
- Type 1 Diabetes (T1DM): Insulin is essential as no insulin is produced.
- Type 2 Diabetes (T2DM): Insulin is used when other methods fail to control blood glucose effectively
Types of Insulin - 3
- Short-acting insulins: Administered before meals.
- Intermediate-acting insulins: Given once or twice daily, before meals.
- Long-acting insulins: Taken once or twice daily, before meals.
Duration of action depends on factors such as insulin crystal size, pH, and protein content.
Insulin Regulation of Blood Glucose - 3
- Goal: Maintain blood glucose levels between 4-9 mmol/L.
- Type 1 Diabetes Treatment: Insulin is administered externally to regulate blood glucose, aiming to keep levels within a healthy range without causing hypoglycaemia.
- The oral glucose tolerance test was referenced to understand normal blood glucose fluctuations (blue line).
Exogenous Insulin Action - 3
- Exogenous insulin activates the receptor tyrosine kinase and the PI3 kinase pathway.
- This triggers metabolic effects, including the increased expression of glucose transporters on the cell membrane.
- As a result, glucose is more efficiently taken up into the cell
Insulin-Stimulated Glucose Transport - 4
- Glucose transporters are stored inside the cell in a “storage microzone.”
- When glucose levels rise after eating, insulin is released.
- Insulin binds to receptor, triggering release of these glucose transporters to the cell surface.
- This increases the number of transporters available, facilitating greater glucose uptake into the cells.
Hoe does insulin affect metabolism - 3
- Insulin receptor (IR) activation triggers a cascade of phosphorylation events.
- This activation leads to the activation of phosphoinositide 3 kinase (PI3K), which generates membrane-bound phosphatidylinositol (3,4,5)-triphosphate (PIP3).
- PIP3 activates Akt: mediates insulin’s effects by regulating the expression & activity of transcription factors & enzymes involved in metabolic processes.
How does insulin affect metabolism - 5
- Insulin promotes glycolysis & glycogenesis.
- It upregulates transcription of enzymes involved in glycolysis, e.g. glucokinase, phosphofructokinase, & pyruvate kinase.
- Insulin activates glycogen synthase, adding glucose units to form glycogen, & by inactivating glucose synthase kinase 3 (GSK-3), which inhibits glycogen synthase.
- Insulin inhibits glucose production by suppressing gluconeogenesis & glycogenolysis.
- It inactivates glycogen phosphorylase, an enzyme responsible for breaking down glycogen into glucose monomers.
a-glucosidase inhibitors - 3
- For T2D, Acarbose reduces the digestion of complex carbohydrates & slows their absorption from the gut, leading to reduced postprandial glycaemia.
- S/Es flatulence, diarrhoea
- Acarbose is an oligosaccharide metabolized in the intestines by enzymes & bacteria, rather than the liver. Typically used when hypoglycaemics are not tolerated.
SGLT2 Inhibitors & Glucose Reabsorption in the Kidney:
- 2
- SGLT2 Inhibitors: Block glucose reabsorption at PCT, prevents glucose reabsorption, causing it to stay in the nephron & be excreted in the urine.
- Effect in Diabetic Patients: In diabetes or when on SGLT2 inhibitors, glucose appears in the urine (glucosuria), used as a marker for treatment effectiveness.
SGLT2 Inhibitors MoA - 2
- Sodium-potassium ATPase pumps sodium out of the tubule cells, creating a gradient that allows sodium & glucose to enter the cell via the sodium-glucose cotransporter.
- The glucose then moves into the bloodstream through the glucose transporter.
SGTL2i S/Es - 3
- Hypoglycemia: Not a side effect of SGLT2 inhibitors.
- Kidney Function: No significant negative impact observed on kidney function.
- Potential Risks: Increased risk of urinary tract infections due to excess glucose in the urine.
Key Mechanisms Affected in Type 2 Diabetes - 4
- Liver: Increased hepatic glucose production.
- Muscles: Reduced glucose uptake due to insulin resistance.
- Adipose Tissue (Fat): Increased breakdown of fats leading to elevated triglyceride levels in the blood.
- Pancreas: Impaired insulin secretion, can be addressed by stimulating insulin release through medications like sulfonylureas and incretin mimetics.
Sulfonylureas Oral Antidiabetic Drugs (Oral Hypoglycemic Drugs) for Type 2 Diabetes:
- 3
- Sulfonylureas Function: Stimulate insulin secretion from the pancreas, helping to lower blood glucose levels.
- First-Generation Drugs: Tolbutamide (short-acting).
- Second-Generation Drugs: Gliclazide, (longer-acting, higher risk of hypoglycaemia).
Sulfonylureas & Melitanides MoA:
Sulfonylureas & Melitanides MoA:
These drugs block the potassium channel, causing depolarization & triggering calcium-dependent insulin release, bypassing the normal glucose-sensing process.
Adverse Side Effects of Sulfonylureas & Glitinides - 5
- Hypoglycaemia:
- Weight Gain:
- Secondary Pancreatic Beta-Cell Failure: Prolonged use may lead to beta-cell failure.
- Use with Caution: liver or kidney dysfunction
- Pregnancy - drugs cross the placenta.
GLP-1 (Glucagon-like peptide-1) - 3
- Stimulates insulin secretion from pancreas in response to elevated blood glucose.
- Inhibits glucagon release, preventing production of more glucose.
- Enhances insulin secretion under hyperglycaemic conditions, inhibits glucagon release, & reduces food intake
GLP1 agonists - Incretin mimetics - 3
- Analogues of incretin – glucagon-like peptide-1 (GLP-1) – bind to GLP-1 receptor e.g. liraglutide
- Main adverse effect is nausea which deters use
- GLP-1 therapy is aimed at overweight T2DM patients
Gliptins – DPP-4 inhibitors - 6
- DPP-4 responsible for the rapid breakdown of GLP-1 & GIP.
- Blockade of DPP-4 enhances effects of endogenous GLP-1, which helps:
- Increase insulin secretion,
- Suppress glucagon secretion,
- Slow down gastric emptying, contributing to satiety & reduced food intake.
- Examples of DPP-4 inhibitors: e.g. Sitagliptin
Metformin’s Main Actions:
Decrease Hepatic Glucose Production:
- 3
Decrease Hepatic Glucose Production:
1. Inhibits gluconeogenesis by reducing uptake of needed substrates in liver
2. Inhibits mitochondrial respiratory chain complex 1, reducing ATP synthesis & energy status, which in turn decreases gluconeogenesis.
3. AMP-activated protein kinase (AMPK) is the key target. AMPK acts as a “fuel gauge” & switches cell from an anabolic to a catabolic state when activated by a higher AMP:ATP ratio.
Metformin Additional Actions - 3
- Insulin Sensitizing: Stimulates insulin receptor expression & tyrosine kinase activity
- Enhances glucose uptake in skeletal muscle.
- Incretin Effect: Increases GLP-1 levels acutely & stimulates incretin receptor gene expression.
Adv of Metformin compared to Sulfonylureas:
- 6
- No Weight Gain
- No Increase in Plasma Insulin: reducing the risk of hypoglycaemia.
- Persistent Efficacy
- Improved Lipid Profile: Metformin leads to decreased triglycerides (TGs) and increased HDL (good cholesterol).
- BP Reduction
- Delay in Insulin Use
S/E of Metformin - 3
- Acute GI Effects: e.g. diarrhea, nausea, vomiting. Taking with or after food can help reduce these effects.
- Lactic Acidosis
- May DDI in kidney with other drugs
Thiazolidinediones (TZDs) – MoA - 6
e.g. pioglitazone & rosiglitazone
1. TZDs bind to & activate PPAR-γ. PPAR-γ is a transcription factor that regulates genes involved in glucose & lipid metabolism.
2. Activation of PPAR-γ enhances insulin sensitivity
3. Reduces hepatic glucose production
Bonus effects:
4. Promotes fat storage, improving insulin sensitivity.
5. PPAR-γ activation reduces inflammatory cytokine production, can reduce insulin resistance
6. Increase HDL cholesterol, may reduce CV risks of T2D
PPARγ has two mechanisms of action: - 2
- Transactivation – activates gene expression.
- Transrepression – represses gene transcription, including NFkB, providing anti-inflammatory effects.
Potential adverse effects of thiazolidinediones - 3
- Minimal hypoglycaemia risk
- Hence of drug-induced hepatoxicity with rosiglitazone and pioglitazone (but problem for troglitazone)
- Weight gain major
Metabolic syndrome
Metabolic syndrome: group of health problems that puts you at higher risk ofdiseases of the heart and blood vessels
7 features of metabolic syndrome
- Insulin resistance
- Elevated fasting glucose
- Hypertension
- Reduced HDL, elevated LDL
- Endothelial dysfunction
- Systemic inflammation
- Inflamed adipose tissue
Metabolic syndrome:
Risk factors - 8
- Visceral obesity
- Age
- Weight
- Race (higher in Afro-Caribbean, Asian)
- Non-alcoholic fatty liver
- History of gestational diabetes
- Polycystic ovary syndrome
- Smoking
Metabolic syndrome: Treatment - 7
- Diet
- Exercise
- Smoking cessation
- Pharmacology
e.g. Cholesterol lowering drugs, Antihypertensives, Insulin sensitizers - Gastric bypass
- Faecal transplant
