Insulin & Hypoglycaemics Flashcards
Blood Glucose and Energy
Ubiquitous energy source
Most tissue can utilize non-glucose molecules as substitutes
CNS cannot substitute glucose; delivery is therefore critical
Blood Glucose Values
10mmol/L if sustained - hyperglycaemia
Glucosuria
Elevated glucose levels saturate the glucose-reuptake mechanisms in the kidney
Diagnostic of underlying pathology – diabetes mellitus
Leads to osmotic diuresis; increased thirst, increased urine production; dehydration; unconsciousness; death
The Homeostasis of Hyperglycaemia
Food Intake / Endogenous Glucose Production
Rise in Blood Glucose – Hyperglycaemia
Insulin Release: Pancreatic β-Cells
Insulin Action: Liver, Muscle, Adipocytes, CNS
Lowers Blood Glucose
The Homeostasis of Hypoglycaemia
Fasting Fall in Blood Glucose - Hypoglycaemia Glucagon Release: Pancreatic α-Cells Endogenous Glucose Production: Liver, Muscle, Adipocytes Raises Blood Glucose
Pancreatic Islets of Langerhans
Human pancreas; approx. 1.5 million islets of langerhans per pancreas; Represent 1-2% of the mass of the pancreas Distributed throughout the pancreas Contain different cell types β-cells; release insulin α-cell; release glucagon δ-cells; release somatostatin ε-cells; release ghrelin PP-cells; release pancreatic polypeptide
Glucose-Stimulated Insulin Release
Food intake Digestion Glucose uptake by β-cells Inhibition of KATP Channels Depolarization of the cell Ca2+ Influx Insulin Release
Insulin Secretagogues
Molecules which close the K-channel and mimic the actions of glucose and are used to treat type 2 diabetes
Hyperglycaemia-inducing drugs
Molecules which open the K-channel inhibit the actions of glucose and are used to treat CHI.
Functional Effects of Insulin
Increases Glucose -> Glycogen (liver, skeletal muscle)
Increases Glucose -> Fat (adipose tissue)
Increases Amino Acids -> Protein (muscle)
Increases Glucose and Amino Acid transportation into cells
increases gene expression and growth
increases triglyceride synthesis
increases protein synthesis
increases glucose uptake, storage and utilization
decreases glycogen breakdown
decreases gluconeogenesis (glucose formation)
decreases proteolysis
decreases Lipolysis and Lipid Oxidation
The Mode of Action of Insulin
Receptor Activation
Signal Transduction
Signalling Cascades Mediated by IRS2
Functional effects
Diabetes Mellitus
Diabetes is a chronic disease, which occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. This leads to an increased concentration of glucose in the blood - hyperglycaemia
Broad Treatment plans
T1DM: lifelong insulin, healthydiet, regular exercise.
T2DM: lifestyle changes (diet, weight, activity).
T2DM: hypoglycaemic therapy and/or insulin.
Insulin Therapy
Short Duration; rapid onset of action
Intermediate Action
Longer Lasting: slower in onset and lasts for long periods
Short Duration Insulin
Soluble insulin & the rapid-acting human insulin analogues; insulin aspart, insulin glulisine, and insulin lispro (s.c.; i.v.)
Rapid in onset; 30-60 mins
peak action 2-4 hours
duration 8 hours
Injected just before, with or just after food and only lasts long enough for the meal at which it is are taken.
Intermediate Action Insulin
Isophane insulin; can be porcine, human or bovine (s.c.)
onset 1-2 hours
peak action 4-12 hours
duration 16-35 hours
Longer Lasting Insulin
Protamine zinc insulin; insulin zinc suspension - porcine, human, bovine (s.c.)
Insulin detemir; insulin glargine - recombinant human(s.c.)
onset 1-2 hours
peak action 4-12 hours
duration 16-35 hours
Biphasic Insulin Preparations
Mixture of intermediate and fast acting rapid onset long-lasting actions biphasic insulin aspart biphasic insulin lispro biphasic isophane insulin (NOVI MIX)
Insulin Administration
Injection -
Subcutaneous 3-4 times daily
Device: syringe and needles, pens
Device: portable infusion pump
Short-acting insulins by continuous subcutaneous infusion
Pumps deliver a continuous basal insulin and patient-activated bolus doses at meal times
Closed-loop system
Glucagon Therapy
Hyperglycaemia-Inducing
First-aid treatment for severe hypoglycaemia when oral glucose is not possible or desired
Route: injection; intramuscular, intravenous or subcutaneous
Must be reconstituted prior to use
Acutely raises plasma glucose levels
side effects: head ache and nausea
Glucagon promotes :
Glycogenolysis (glycogen to glucose)
Gluconeogenesis (glucose formation)
Lipolysis (fat to FAs)
T2DM Therapies – Secretagogues
Sulphonylureas
Boost insulin release; enhance the normal physiology of glucose-stimulated insulin secretion.
Small molecule antagonists of the KATP Channel
Oral agents: Once or twice daily with or shortly before a meal
Short Lasting Formulations: gliclazide (Diamicron); tolbutamide (Orinase)
Long-Lasting Formulations: chlorpropamide (Diabinese); glibenclamide; glipizide (Glucotrol); glimepiride (Amaryl)
Combined with other therapies
Risk of hypoglycaemia with sulphonylureas
T2DM Therapies – Secretagogues
Meglitinides
Boost insulin release; enhance the normal physiology of glucose-stimulated insulin secretion.
Small molecule antagonists of the KATP Channel
Oral agents: Once or twice daily with or shortly before a meal
Short Acting
Repaglinide (Prandin®)
Nateglinide (Starlix®)
May have a decreased the risk of hypoglycaemia compared to SUs, particularly in the elderly
T2DM Therapies – Secretagogues
incretin mimetic
Exenatide
Liraglutide
Boost insulin release by enhancing the normal physiology of incretin-mediated insulin secretion.
Peptide-Agonists of the GLP-1 Receptor and not broken down by dipeptydylpeptidase-4 (DPP-4)
Injectable agents, s.c.
Combined with other therapies
Much reduced risk of hypoglycaemia compared to sulphonylureas
Side-effects: gastro-intestinal disturbances including nausea, vomiting, diarrhoea, dyspepsia, abdominal pain and distension, gastro-oesophageal reflux disease, decreased appetite; headache, dizziness, agitation, asthenia; increased sweating, injection-site reactions; antibody formation
T2DM Therapies – Secretagogues incretin mimetic Gliptins e.g. Sitagliptin Vildagliptin
Boost insulin release by enhancing the normal physiology of incretin-mediated insulin secretion.
Inhibitors of dipeptydylpeptidase-4 (DPP-4); raises the half-life of serum GLP-1
Tablet – Oral
Can be combined with other medications; novel formulations e.g. Eucreas®, Janume® - gliptins+metformin
Side-effects vomiting, dyspepsia, gastritis; peripheral oedema; headache, dizziness, fatigue; upper respiratory tract infection, urinary tract infection, gastroenteritis, sinusitis, nasopharyngitis; hypoglycaemia, myalgia; less commonly dyslipidaemia, hypertriglyceridaemia, erectile dysfunction, arthralgia; also reported rash
Incretin mimetics / GLP-1 analogues
This type of medication works by increasing the levels of hormones called ‘incretins’. These hormones help the body produce more insulin only when needed and reduce the amount of glucose being produced by the liver when it’s not needed. They reduce the rate at which the stomach digests food and empties, and can also reduce appetite.
Hyperglycaemic Therapies - Diazoxide
Diazoxide (Eudemine®) is used to treat congenital hyperinsulinism in infancy, insulinomas, severes cases of transient hypoglycaemia.
Small molecule agonist of the KATP Channel
Oral administration, given with chlorothiazide
Side effects:
anorexia, nausea, vomiting, hyperuricaemia,
hypotension, oedema, tachycardia, arrhythmias,
extrapyramidal effects; hypertrichosis on prolonged treatment
hypertrichosis
excessive hair growth over and above the normal for the age, sex and race of an individual
Insulin Sensitizers
Insulin Sensitizers improve the sensitivity of target organs to insulin
Insulin Sensitizers act in different ways,
e.g. activating enzymes – biguanides
e.g. modifying the transcription of genes - thiazolidinediones
Biguanides - Insulin Sensitizers - modes of action?
Two modes of action;
(i) prevents hepatic production of glucose,
(ii) overcomes insulin resistance by improving insulin sensitivity
Metformin® (also marketed as Glucophage®) is the most widely prescribed antidiabetic drug in the world; >48 million prescriptions in USA (2010), and the drug of choice for T2DM in children and teenagers
Up to 3 times a day with, or immediately after a meal
Does not cause weight gain and may be the best choice for patients who also have heart failure
Thiazolidinediones / glitazones - Insulin Sensitizers
Oral; One / two times daily
Activate PPARγ, a regulatory protein involved in the transcription of insulin-sensitive genes which regulate glucose and fat metabolism
Principal target; adipocytes
Rosiglitizone (Avandia®) [also combined with metformin (Avandamet®) or glimepiride (Avandaryl®)]
Pioglitazone is marketed as Actos®
Acarbose
α-Glucosidase Inhibitors
Acarbose, GlucobayT
α-glucosidase converts oligosaccharides to glucose
Acarbose inhibits this enzyme.
Absorption of starchy foods is slowed, thereby slowing-down rises in blood glucose following a meal
In patients, this provides a closer alignment of [impaired] insulin output with glucose uptake
Undesirable effects: Flatulence, diarrhoea, abdominal pain, nausea, vomiting, indigestion, liver function problems, oedema, blood disorders, allergic skin reaction, intestinal problems.
SGLT2 Inhibitors
Physiological role: glucose reabsorption
SGLT2 inhibitors cause excess glucose to be eliminated in the urine; reducing hyperglycaemia
Potential Advantages: weight loss, insulin independent, low risk of hypoglycaemia, osmotic diuresis reduces hypertension
SGLT2 inhibitors: Dapagliflozin*, canagliflozin, empagliflozin
SGLT2
Sodium-coupled glucose transporter.
