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.)
