Insulin & Hypoglycaemics

Question 1

Blood Glucose and Energy

Answer 1

Ubiquitous energy source
Most tissue can utilize non-glucose molecules as substitutes
CNS cannot substitute glucose; delivery is therefore critical

Question 2

Blood Glucose Values

Answer 2

10mmol/L if sustained - hyperglycaemia

Question 3

Glucosuria

Answer 3

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

Question 4

The Homeostasis of Hyperglycaemia

Answer 4

Food Intake / Endogenous Glucose Production
Rise in Blood Glucose – Hyperglycaemia
Insulin Release: Pancreatic β-Cells
Insulin Action: Liver, Muscle, Adipocytes, CNS
Lowers Blood Glucose

Question 5

The Homeostasis of Hypoglycaemia

Answer 5

Fasting
Fall in Blood Glucose - Hypoglycaemia
Glucagon Release: Pancreatic α-Cells
Endogenous Glucose Production: Liver, Muscle, Adipocytes
Raises Blood Glucose

Question 6

Pancreatic Islets of Langerhans

Answer 6

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

Question 7

Glucose-Stimulated Insulin Release

Answer 7

Food intake 
Digestion 
Glucose uptake by β-cells
Inhibition of KATP Channels
Depolarization of the cell
Ca2+ Influx
Insulin Release

Question 8

Insulin Secretagogues

Answer 8

Molecules which close the K-channel and mimic the actions of glucose and are used to treat type 2 diabetes

Question 9

Hyperglycaemia-inducing drugs

Answer 9

Molecules which open the K-channel inhibit the actions of glucose and are used to treat CHI.

Question 10

Functional Effects of Insulin

Answer 10

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

Question 11

The Mode of Action of Insulin

Answer 11

Receptor Activation
Signal Transduction
Signalling Cascades Mediated by IRS2
Functional effects

Question 12

Diabetes Mellitus

Answer 12

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

Question 13

Broad Treatment plans

Answer 13

T1DM: lifelong insulin, healthydiet, regular exercise.
T2DM: lifestyle changes (diet, weight, activity).
T2DM: hypoglycaemic therapy and/or insulin.

Question 14

Insulin Therapy

Answer 14

Short Duration; rapid onset of action
Intermediate Action
Longer Lasting: slower in onset and lasts for long periods

Question 15

Short Duration Insulin

Answer 15

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.

Question 16

Intermediate Action Insulin

Answer 16

Isophane insulin; can be porcine, human or bovine (s.c.)
onset 1-2 hours
peak action 4-12 hours
duration 16-35 hours

Question 17

Longer Lasting Insulin

Answer 17

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

Question 18

Biphasic Insulin Preparations

Answer 18

Mixture of intermediate and fast acting 
rapid onset 
long-lasting actions
biphasic insulin aspart
biphasic insulin lispro 
biphasic isophane insulin
(NOVI MIX)

Question 19

Insulin Administration

Answer 19

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

Question 20

Glucagon Therapy

Answer 20

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

Question 21

Glucagon promotes :

Answer 21

Glycogenolysis (glycogen to glucose)
Gluconeogenesis (glucose formation)
Lipolysis (fat to FAs)

Question 22

T2DM Therapies – Secretagogues

Sulphonylureas

Answer 22

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

Question 23

T2DM Therapies – Secretagogues

Meglitinides

Answer 23

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

Question 24

T2DM Therapies – Secretagogues
incretin mimetic
Exenatide
Liraglutide

Answer 24

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

Question 25

T2DM Therapies – Secretagogues 
incretin mimetic
Gliptins
e.g. Sitagliptin
Vildagliptin

Answer 25

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

Question 26

Incretin mimetics / GLP-1 analogues

Answer 26

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.

Question 27

Hyperglycaemic Therapies - Diazoxide

Answer 27

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

Question 28

hypertrichosis

Answer 28

excessive hair growth over and above the normal for the age, sex and race of an individual

Question 29

Insulin Sensitizers

Answer 29

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

Question 30

Biguanides - Insulin Sensitizers - modes of action?

Answer 30

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

Question 31

Thiazolidinediones / glitazones - Insulin Sensitizers

Answer 31

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®

Question 32

Acarbose
α-Glucosidase Inhibitors
Acarbose, GlucobayT

Answer 32

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.

Question 33

SGLT2 Inhibitors

Answer 33

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

Question 34

SGLT2

Answer 34

Sodium-coupled glucose transporter.