10 Insulin & Hypoglycaemics Flashcards
Learning Outcomes From This Lecture …
Demonstrate an understanding of the physiological basis of glucose homeostasis and the actions of insulin.
Demonstrate an understanding of the different forms of diabetes mellitus and the complications of these diseases.
Demonstrate an understanding of the applied pharmacology of insulin for the treatment of type 1 diabetes mellitus.
Demonstrate an understanding of the applied pharmacology of hypoglycaemics the management of type 2 diabetes mellitus
Blood Glucose
Energy
Ubiquitous energy source
Most tissue can utilize non-glucose molecules as substitutes
CNS cannot substitute glucose; delivery is therefore critical
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; thirst , 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 Hyperglycaemia
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 per pancreas;
Represent 1-2% of the mass of the pancreas
Distributed throughout the pancreas
Contain different cell types
Associate with the vasculature
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 b-Cells Inhibition of KATP Channels Depolarization of the cell Ca2+ Influx Insulin Release
Molecules which close this K-channel mimic the actions of glucose and are used to treat type 2 diabetes. Insulin Secretagogues
Molecules which open this K-channel inhibit the actions of glucose and are used to treat CHI. Hyperglycaemia-inducing drugs
Glucose Homeostasis; Integration with Digestion
Food Intake Digestion Release of Gut Hormones Rise in Serum GLP-1 Activation on the GLP-1 Receptor Cell Signalling Insulin Release
Oral glucose load produces a faster insulin response than intravenous glucose
Incretin Hormones -
Glucagon-Like Peptide-1
Gastric Inhibitory Peptide
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
People with diabetes have a spectrum of problems associated with glucose homeostasis
GDM: Gestational diabetes mellitus
NDM: Neonatal Diabetes Mellitus
MODY: Maturity onset diabetes of the young
The Diabetes Mellitus “Time Bomb”
Diabetes UK (2009); Report: 7 million people in the UK currently may have pre-diabetes; Impaired Glucose Regulation (IGR). People with IGR are 15 times more likely to develop T2DM
J Clin Endo Met (2011) 96: 2354-66. 79 million people in the USA currently may have pre-diabetes; 40-50% will progress to T2DM
Diabetes Mellitus (DM)
In people with DM blood glucose is elevated because the body cannot utilize it properly
DM has a graded severity
In people with Type 1 DM, insulin-producing cells are destroyed and insulin must be provided
In people with Type 2 DM, insulin-producing cells are “failing”, tissues are “insensitive” to insulin or both
Treatment options for T2DM are varied and reflect the complexity of glucose sensing and insulin signalling
The level and type of intervention will be determined by the severity of disease, and patient lifestyle & compliance
Diabetes Mellitus (DM)
T1DM
Most cases present in childhood
Accounts for 5 -15% of DM
Caused by destruction or damage to β-cells
An autoimmune disease
Not genetically predetermined, but susceptibility may be inherited
Detected by the presence of anti-islet antibodies
The incidence is rising steadily
Genetic susceptibility Environmental Triggers Cytotoxic T-Cell and Antigen Presenting Cell Involvement B cell autoantibodies Epitope Spreading Clinical diabetes
T2DM
T2DM
Can progress to insulin-dependency
Accounts for between 85 - 95% DM
A disorder of epidemic proportions
Risk factors include ageing, obesity, ethnicity, family history
Genetic & environmental predisposition
Polygenic disorder, but the genes have yet to be identified
The Treatment of Diabetes
Objectives
achieve normoglycaemia
return blood pressure & cholesterol levels to normal
adopt a healthy lifestyle to protect against long-term complications.
Broad Treatment plans
T1DM: lifelong insulin, healthydiet, regular exercise.
T2DM: lifestyle changes (diet, weight, activity).
T2DM: hypoglycaemic therapy and/or insulin.
Insulin Therapy
3 Basic Insulin preparations:
Short Duration; rapid onset of action
Soluble insulin & the rapid-acting human insulin analogues; insulin aspart, insulin glulisine, and insulin lispro (s.c.; i.v.)
Intermediate Action
Isophane insulin; can be porcine, human or bovine (s.c.)
Longer Lasting: slower in onset and lasts for long periods
Protamine zinc insulin; insulin zinc suspension - porcine, human, bovine (s.c.)
Insulin detemir; insulin glargine - recombinant human(s.c.)
In people with Type 1 DM, insulin-producing cells have no b-cells and insulin must be provided
Insulin Therapy
Short Duration 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.
insulin aspart, insulin glulisine, insulin lispro (s.c.; i.v.)
Insulin Therapy
Intermediate / Longer Duration
Onset; 1-2 hours
Peak action: 4-12 hour
Duration: 16-35 hours
Insulin detemir insulin glargine insulin zinc suspension isophane insulin protamine zinc insulin
Insulin Therapy
Biphasic Insulin Preparations
Mixture of intermediate & fast acting
Rapid onset
Long-lasting actions
biphasic insulin aspart
biphasic insulin lispro
biphasic isophane insulin
Insulin Administration
Injection subcutaneous often 3-4 times daily. Device: syringe & needle, ‘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
Common side-effects include headache and nausea
Glucagon promotes :
Glycogenolysis (glycogen to glucose)
Gluconeogenesis
Lipolysis (fat to FAs)
Hypoglycaemic Therapies - Overview
Patients Type 2 Diabetes Rarer forms of Diabetes Mellitus Route of Administration Oral: oral antihyperglycaemic agents. Injectable; Newer “peptide” agents Variety Different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and patient compliance Mode of Action Stimulate insulin release by β-cells; “secretagogues” Improved insulin sensitivity: “sensitizers” Slow the rate of glucose absorption Enhance glucose loss
∴ several groups of drugs are effective & some can work in combinations
Current Therapy for Diabetes Mellitus
Islet/Pancreas Transplantation
T1DM -
Prevention: Immune-Mediated Destruction of β-Cells
Insulin Therapy
T2DM - KATP channel Inhibitors Sulphonylureas/ Meglitinides Thiazolidinediones Biguanides α-glucosidase Inhibitors SGLT2 inhibitors GLP-1 Receptor Agonists DPP4 Inhibitors
T2DM Therapies – Secretagogues I
Food Intake
Digestion
Glucose Uptake by b-Cells
Inhibition of KATP Channels -
Sulphonylureas
Meglitinides
Depolarization of the cell
Ca2+ Influx
Insulin Release
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
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 the elderly
T2DM Therapies – Secretagogues II
Food Intake
Digestion
Release of Gut Hormones
Rise in Serum GLP-1
Activation on the GLP-1 -
Exenatide
Liraglutide
Receptor
Cell Signalling
Insulin Release
Incretin Mimetic
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
Required Knowledge of the Therapy for Diabetes Mellitus
Insulin Sensitizers Thiazolidin -ediones Sulphonylureas/Meglitinides SGLT2 inhibitors α-glucosidase Inhibitors Biguanides GLP-1 Receptor Agonists DPP4 Inhibitors
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
The Mode of Action of Biguanides
Agonist of AMP-activated protein kinase (AMPK)
Inc.Glucose Uptake, Storage & Utilization inc. Protein Synthesis dec. Proteolysis inc. Triglyceride Synthesis dec. Lipolysis and Lipid Oxidation Inc. Gene Expression & Growth
Receptor Activation
Signal Transduction
Signalling Cascades Mediated by IRS2
Functional Effects
Insulin Sensitizers
Biguanides
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
Metformin - Combinational Therapies
Available in combination:
- pioglitazone (Actoplus Met)
- glipizide (Metaglip)
- glibenclamide (Glucovance),
- sitagliptin (Janumet),
- repaglinide (PrandiMet)
Formulation of metformin / rosiglitazone are under review
Insulin Sensitizers
Thiazolidinediones / glitazones
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
T2DM Therapies; Modifying Glucose Breakdown
Acarbose
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
T2DM Therapies; Enhancing Glucose Release
SGLT2 Inhibitors
SGLT2 = Sodium-coupled glucose transporter.
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
