Diabetes basics Flashcards
What is diabetes mellitus?
An elevation of blood glucose above a diagnostic criteria
What are the 2 mechanisms of diabetes cause?
Failure to produce insulin
Sensitivity to insulin
What are some examples of disorders of insulin production?
Type I diabetes
Genetic disorders (E.g. MODY, Neonatal diabetes)
Pancreatic disease
What are some examples of disorders of insulin action?
Genetic disorders
Insulin reisstance (E.g. T2DM, Obesity, NAFLD)
Endocrinopathies
Steroids
What are some genetic disorders that cause disordered insulin action?
- Donohue sundrome
- Rabson-Mendenhall syndrome
- Familial partial lipodystrophy
- Congenital lipoatrophy
- Acquired lipoatrophy
What are some endocrinopathies that cause disordered insulin action?
- Cushing’s syndrome
- Acromegaly
- Pheochromocytoma
- Glucagonoma
What is the average blood glucose concentration?
5mmol/L
What is the fasting glucose threshold for diabetes diagnosis?
≥7mmol/L
What is the 2hr plasma glucose threshold for diabetes diagnosis?
≥11.1mmol/L
What is the HbA1c threshold for diabetes diagnosis?
≥48mmol/mol
How are the thresholds for diabetes diagnosis formed?
Based on risk of developing diabetic retinopathy
How are 2hr plasma glucose levels measured?
Having the patient drink a 75g oral glucose dose and waiting 2 hours before testing blood sugar
What is pre-diabetes?
This is the name given to impaired glucose tolerance, before the development of diabetes
What fasting plasma glucose is defined as pre-diabetic?
6.1 - 6.9 mmol/L
What 2hr plasma glucose is defined as pre-diabetic?
7.8 - 11 mmol/L
What HbA1c is defined as pre-diabetic?
6 - 6.4% or 42 - 47 mmol/mol
What is shown by C-peptide levels?
How much insulin the body is producing, even with exogenous insulin injections, as it is cleaved from insulin during its production
Why is measuring blood glucose at a single time not effective in diagnosing diabetes?
Blood glucose varies widely in response to meals and exercise throughout the day
What are the 2 ways to gain an accurate measure of long-term blood glucose changes?
HbA1c
Continuous glucose monitoring
How does continuous glucose monitoring work?
This involves continuous monitoring of glucose throughout many points during the day using a device in the arm (e.g. Free style libre)
What is HbA1c?
Glycated haemoglobin (Glucose in the blood is absorbed into erythrocytes and binds to haemoglobin)
What time-frame can HbA1c show glucose levels over?
Around 2-3 months, as this is the lifespan of a red blood cell
In what condition will HbA1c measurement not be useful or accurate?
Conditions with high red blood turnover such as haemolytic anaemia
Where is insulin produced?
In the RER of pancreatic ß-cells
Describe the formation of insulin
It is synthesised in the RER of pancreatic ß-cells as a larger, single chain pre-hormone called pre-proinsulin
This is then cleaved by Ca2+ dependant endopeptidases, PC2 and PC3 into insulin and C-peptide
Describe the release of insulin
- Glucose enters cell via GLUT2
- Increases glucokinase activity (Oxidation)
- Increased ATP release
- Closure of ATP-dependant K+ channels
- Build up of K+ in the cell
- Depolarisation of the membrane
- Opening of V-gated Ca2+ channels
- Ca2+ allows for release of insulin
What are the 2 peaks of insulin release?
1st phase in which there is a release of insulin immediately from the readily releasable pool (RRP)
2nd phase caused by preparatory action to produce more insulin
What are some other molecules that ß-cells can respond to with insulin production?
Nutrients, hormones, neurotransmitters, including leptin, GLP1, GIP, IL6, adiponectin and fatty acids
What is the region in the pancreas responsible for blood glucose control?
Islets of Langherans
What are the 5 main cells of the Islets of Langerhans?
- a-cells (10-20%)
- ß-cells (60-80%)
- ∂-cells (5%)
- PP-cells (<1%)
- e-cells
What is secreted by a-cells in the pancreas?
Glucagon
What is secreted by ß-cells in the pancreas?
Insulin
What is secreted by ∂-cells in the pancreas?
Somatostatin
What is secreted by PP-cells in the pancreas?
Pancreatic polypeptide
What is secreted by e-cells in the pancreas?
Ghrelin
What is meant by exocrine secretion?
Release of secretions into ducts
What is meant by endocrine secretion?
Release of secretions into the blood
What is meant by paracrine secretion?
Release of secretions into neighbouring cells
What is meant by autocrine secretion?
Release of secretions into the same cell (Itself)
What is meant by juxtacrine secretion?
Release of secretions onto the cell surface as a receptor
What is secreted when BCG increases?
Insulin
What is secreted when BCG decreases?
Glucagon
What are some of the functions of insulin?
Inhibits gluconeogenesis in the liver
Promotes glycogenesis in muscle, liver and adipose tissue
What are some of the functions of glucagon?
Increased gluconeogenesis
Stimulation of lipolysis (Fat breakdown)
How does exercise cause increased lipolysis and glucose production
Exercise leads to production of adrenaline and cortisol, which cause glucagon release from the pancreas
How is glucagon formed?
The glucagon gene is one gene but codes for many hormones forming pre-proglucagon
This can then be cleaved into a number of hormones, depending on where it is cleaved
This depends on which enzyme is cleaving it, either PSCK2 or PCSK1
How is glucagon secreted?
- Glucose enters cell via GLUT2
- Increases glucokinase activity (Oxidation)
- Increased ATP release
- Closure of ATP-dependant K+ channels and opening of Na+ channels
- No depolarisation of the membrane
- Closure of V-gated Ca2+ channels
- No secretion of glucagon
- Lower glucose, means less opening of Na+ channels so depolarisation means secretion of glucagon
What is meant by insulin resistance?
The reduced ability to respond to physiological insulin levels
What are some causes of insulin resistance?
Obesity
Excess caloric intake
Sedentary lifestyle
Genetic conditions
What are some diseases that can occur as a result of insulin resistance?
- Diabetes
- Hypertension
- Neurodegenerative disease
- Liver disease
- Sleep apnoea
- Acne
- Polycystic ovarian disease
- Cancer
- Hyperlipidaemia
How can insulin resistance lead to impaired memory in Alzheimer’s disease?
Insulin signalling in the brain is responsible for synaptic plasticity and thus memory, therefore insulin resistance can lead to synaptic dysfunction
What are some risk factor for developing insulin resistance?
- Physically inactive
- FHx of diabetes
- Genetics
- Race (African Americans, Hispanic/Latinos)
- PCOS
- Gestational diabetes
- High blood pressure
- Low HDL
- High blood triglyceride
- Heart disease
- Smoking
How does skeletal muscle insulin resistance occur?
In insulin resistant patients, skeletal muscle insulin receptors undergo decrease in tyrosine kinase activity
This causes a decrease in IRS1, PI3K and AKT phosphorylation, leading to a decrease in glycogen synthesis and a decrease in GLUT4 translocation, meaning less glucose is taken into the cell and even less is stored as glycogen
How does adipose and muscle tissue insulin resistance occur?
Obesity-induced inflammation occurs with JNK and NF-kB activation in adipocytes, causing release of pro-inflammatory cytokines and free fatty acids, leading to local insulin resistance of the adipose tissue, and systemic inflammation of the skeletal muscle and liver
Inflammation leads to increased collagen levels on the cell membrane, with increased extra-cellular matrix receptor signalling, resulting in muscle insulin resistance
How does hepatic insulin resistance occur?
In hepatic insulin resistance, there is a decrease in uptake of glucose, leading to lower levels of glycogenesis
Increased FFA and glycerol, means more is available in the liver fr gluconeogenesis (Formation of more glucose), as well as release of VLDL, therefore causing hyperglycaemia and hyperlipidaemia
What are some ways in which insulin resistance can be reversed?
- Eating less
- Moving more
- Medication
How is insulin resistance measured?
Hyperinsulinaemic-eugycaemic clamp
What is another name for Donoghue syndrome?
Leprechaunism
Describe the genetics of Donoghue syndrome
Rare autosomal genetic trait involving mutations in the insulin receptor
How does Donoghue syndrome present?
Severe insulin resistance
Developmental abnormalities:
- Growth retardation
- Abscence of SC fat
Is Rabson Medenhall sydrome autosomal dominant or recessive?
Autosomal recessive
How does Rabson Medenhall syndrome present?
Severe insulin resistance
Hyperglycaemia
Compensatory hyperinsulinaemia
Developmental abnormalities
Acanthosis nigricans
