Diabetes Flashcards
In simple terms, what is diabetes?
Diabetes mellitus is a condition associated with an elevated blood glucose.
This is a consequence of deficiency of INSULIN, or of its reduced action, or of a combination of both.
What is insulin? What role does it have in the body?
Insulin is the main hormone that regulates blood glucose – secreted by the pancreas – Beta cells in the islets of Langerhans
- Anabolic hormone – hormone of storage
- Essential for fuel storage and cell growth (mitotic action)
- Promotes uptake of glucose into cells
- Prevent breakdown of fat and protein
Where in the islets of langerhans are insulin producing cells located?
Predominant cell type – beta cells – manufacture and secrete insulin – located in centre
Alpha cells – produces glucagon – on the periphery
What is the role of somatostatin produced by delta cells in the pancreas?
Somatostatin – switches off synthesis and secretion of other hormones
What type of hormone is insulin? In what form is insulin synthesized?
Insulin is a peptide hormone
Synthesized as a pro-hormone – proinsulin – made of alpha and beta chain linked by a C-chain
Prior to release C-peptide is cleaved off by peptidases
Explain how glucose levels trigger insulin release by Beta-cells in the pancreas?
Secretion of insulin into portal circulation is directly coupled to the prevailing blood glucose level – secretion is tethered very closely to glucose levels
- Glucose enters the Beta cells via the Glut-2 transporters (don’t require action of insulin for import) – levels entering occurs in direct proportion to the level of glucose in the blood
- Glucose is then metabolized and processed by the TCA cycle producing large quantities of ATP
- ATP direct inhibits the opening of a potassium channel – channel closes - raises potassium levels in cell
- Causes membrane depolarization
- Opens a voltage gated Ca2+ channel – Ca2+ promotes the exocytosis of insulin molecules into circulation
Why is insulin release biphasic?
Prior to secretion Pro-insulin cleaved into insulin and C-peptide
Biphasic Response
1. In response to rising blood glucose – stored insulin will be released (already pre-made) - first wave.
2. Followed by increased production of newly synthesized insulin - second wave
C-peptide can be used as a measure of endogenous insulin secretion in people with diabetes that may be injecting exogenous insulin.
Does insulin act on the liver or muscles/adipose tissue first?
INSULIN from pancreas:
1. Secreted into portal vein
2. Acts first on LIVER
3. Passes through liver into systemic circulation
4. Acts on MUSCLE and FAT
What are the principle actions of insulin on the body?
Promotes
1. Liver - Increased glycogen storage
2. Muscle - Increased glucose uptake, glycogen storage, amino acid uptake and protein synthesis.
3. Fat - Increased glucose uptake and lipogenesis
Inhibits
1. Inhibits gluconeogenesis and ketogenesis
3. Inhibits apoptosis
In simple terms, how does insulin mediate its effect on cells?
Insulin binds to insulin receptor
Promotes one key final stage action – translocation of GLUT4 transporter to the plasma membrane – increasing glucose uptake
What are the different sources of glucose in the body?
- Diet
- Liver glycogen (used for blood glucose) and muscle glycogen (used for muscle)
- Liver and kidney can synthesize glucose from 3 carbon precursors - gluconeogenesis
Does insulin favour gluconeogenesis/glycogenolysis or glycogenesis?
Liver plays a very important role – constant flux in terms of the formation/breakdown of glycogen and the formation of new glucose
Insulin favors the formation of glycogen and inhibition of gluconeogenesis – glucagon is the opposite
What are some other players that influence glucose homeostasis?
Glucose homeostasis is not only controlled by insulin.
Other hormones – adrenaline and noradrenaline, growth hormone, glucocorticoids – cortisol – promote an increase in blood glucose levels
Help protect against against hypoglycemia
Why does glucose need to be tightly controlled?
In health blood glucose is maintained in very tight bands
Reason - required for the functioning of the brain as the brain has no glycogen, making it entirely dependent on blood glucose levels.
Therefore, it is important that we don’t go hypoglycemic
Other reasons…
* Maintenance of energy source for most tissues
* Integrity and health of blood vessels
What do the words “Diabetes” “Mellitus” actually mean?
Diabetes mellitus
* Syphon – polyuria
* Mellitus – honey – sweet – excess glucose
* High urine output that is sweet
What are the different types of diabetes (not just 1 and 2)?
- Type 1
- Type 2
- Secondary Diabetes
Monogenic Diabetes
* MODY
* Diabetes & Syndromes
On a mechanistic level what are the two main causes of diabetes?
- Insulin Deficiency - Absolute deficiency occurs in the context of toxic insults to the islets (auto-immune insult, alcohol insult, or surgical insult)
- Insulin Resistance - more complicated interactions in signalling cascade in cells.
Or a combination of both
What are examples of severe insulin resistance syndromes?
Specific insulin resistance syndromes that are related to specific gene defects - usually in the insulin receptor or very proximal downstream secondary messengers
Cause very profound insulin resistance – very rare
Dark pigmentation in axillae and skin folds – feature of severe insulin resistance
Examples…
* Leprechaunism
* Rabson-Mendenhall syndrome
* Type A insulin resistance
What type of fat is associated with insulin resistance?
Central adiposity (visceral fat) – more common in men – associated with increasing levels of insulin resistance
Visceral fat is more metabolically active
Mechanism not fully understood by adipose tissue secretes various messengers/hormones - e.g. adipokines
Apart from central obesity, what other conditions could increase insulin resistance?
Other causes of insulin resistance – GH, adrenaline and cortisol – impair the action of insulin – boost sugar levels
Pathogenic states of elevated GH, adrenaline and cortisol will cause insulin resistance such as…
- Acromegaly – GH overproduction
- Pheochromocytoma – tumour of the adrenals - increase adrenaline
- Cushing disease - increase cortisol
What does the scale for fasting blood glucose look like - including normal, impaired fasting glycaemia and diabetes.
In epidemiological terms the ranges are defined when complications arise – specifically microvascular complications
Fasting glucose…
Below 6 - normal
Between 6-7 - pre-diabetic
Above 7 - diabetic
What are the definitions of diabetes based on fasting blood glucose, 2hr Glucose following OGTT or random plasma glucose and HBa1c?
- Fasting plasma glucose – equal or greater than 7
- 2hr plasma glucose in Oral glucose tolerance test (OGTT) and random plasma glucose (unsure of fed state) – cut off at equal or greater than 11.1
- HbA1c – increasingly using glycated hemoglobin – greater or equal to 48 is considered diagnostic
If the patient is asymptomatic, the same test should be repeated to confirm the diagnosis of diabetes
What is HbA1c?
Measure of average glycemia – glucose will bind to hemoglobin in a directly proportional rate depending on ambient glucose concentrations
Average red blood cell has a life exp. of 120 days
Hence, HBA1c gives you an average of blood glucose over the last 3-4 months
Measured at any time of day independent of food consumption
Note - not only used as a diagnostic tool but also as a monitoring tool.
What are situations when HbA1c should not be used in a diagnostic manner?
- Rapid onset of diabetes – not immediately translate into a rise in HbA1c - type 1, children and drug-induced – can not be used as a diagnostic!
- Pregnancy – glucose rise rapidly – HbA1c does not keep up
- Conditions where RBC survival decreases also impact HbA1c – disconnect between average glucose and HbA1c
- Conditions where RBC survival increases
- Renal dialysis
- Iron and vitamin B12 deficiency
What is the oral glucose tolerance test?
- Used to assess state of glucose tolerance
- 75g oral glucose load
- No restriction or modification of carbohydrate intake for preceding three days
- Fast overnight
- Test is performed in morning – seated; no smoking
- Blood samples for plasma glucose taken at 0hrs and 2 hrs
Used in pregnancy or when HbA1c is not appropriate.
How can we diagnose someone with impaired glucose tolerance or impaired fasting glucose?
Both considered pre-diabetic states
Impaired Glucose Tolerance
* Fasting Below 7 and OGTT 2 hour glucose value between 7.8-11.1
Impaired Fasting Glucose
* Fastign Plasma glucose - 6.0-6.9
Note - can also used HbA1c to identify pre-diabetic state - HbA1c 42-47
Increases risk of CVD and future diabetes
Can have a combination of impaired fasting glycemia and impaired glucose tolerance – even higher risk group
What is the most common type of diabetes?
Type 2 Diabetes
* Most common form of diabetes
* 85% of all diabetes in people of European heritage
* 95% of all diabetes in other ethnic groups
What are some risk factors for developing diabetes?
- Genetics - Ethnicity (south asian, Polynesian and Arabic countries)
- Increasing age - beta cell function decreases with age plus diabetes increases with age.
- Central obesity - metabolic syndrome (HBP, high trigly, low HDL, etc.)
- Low birth weight
Is there a strong genetic component to type 2 diabetes?
Genetic component is strong - 40% risk
Polygenic inheritance – multiple genes – over 400 different gene variants
Most relate to beta cell function or mass rather than obesity or insulin resistance (gene relating to this are present but less important)
Inherit a pancreas that functions less well – in practice if you gain weight and become insulin resistant your pancreas is less able to cope resulting in diabetes
Explains why people with a lower BMI (25-30) have diabetes and people with very high BMI that don’t have diabetes, where the pancreas is in overdrive
Type 2 diabetes – balance between beta-cell function and insulin resistance
What are the different stages that lead us to type 2 diabetes?
What are the classical presenting features of type 2 diabetes?
Type 2 diabetes is commonly asymptomatic at diagnosis – people with risk factors are screened
Symptoms
* Osmotic symptoms - Thirst and polyuria
* Malaise and chronic fatigue
* Infections – hyperglycemia has an immunosuppressive effect and high glucose promotes germ growth – genital thrush, UTIs and skin/soft tissue infections all are more common
* Blurred vision – causes glycosylation of the lens of the eye – swelling of the lens – blurred vision
* Complication of diabetes – retinopathy or neuropathy
What are examples of other medical disoders associated with type 2 diabetes?
- Obstructive Sleep Apnoea
- Polycystic Ovarian Disease
- Hypogonadotrophic Hypogonadism in men
- Non-Alcoholic Fatty Liver Disease
What are the symptoms on presentation for type 1 diabetes?
- Osmotic symptoms - Polyuria and polydipsia
- Fatigue and malaise
- Weight loss – more common in type 1 (in type 2 it is possible on presentation) - because of insulin deficiency and osmotic diuresis weight loss is marked in type 1
- Blurred vision
- Nausea and vomiting
- DKA can occur – life threatening – associated with nausea and vomiting on presentation
How do type 1 diabetic patients normally present? What is the typical story?
- Usual presentation is in childhood, adolescence or young adulthood
- But can present at any age
- Short history (weeks) of florid osmotic symptoms and rapid weight loss; Ketonuria/ketonaemia is usually present
- High risk of metabolic decompensation - ketoacidosis
What is the underlying pathogenesis behind type 1 diabetes?
Strong genetic element – HLA haplotypes as risk alleles – auto-immunity
Environmental trigger for the auto-immune process in genetically susceptible individuals (latency between trigger and onset) – thought to be viral and chemical
Activates an autoimmune process that destroys beta cells – measure auto-antibodies in the blood to GAD, IA2 and ZnT8 – these biomarkers are not pathogenic but rather a consequence of beta cell destruction
What are the stages of development for type 1 diabetes?
Stages of development
Normal individuals - inherited a polygenic susceptibility
- Stage 1 – biomarkers are present – auto-antibodies – auto-immune process undergoing – inflammatory infiltrate in the islets – blood glucose remains normal
- Stage 2 – progression of the auto-immune dysfunction – progressive deficiency of insulin – blood glucose levels are no longer normal – pre-diabetic
- Stage 3 – islets destruction continues – stage 3 – symptomatic diabetes
What are other autoimmune disorders associated with type 1 diabetes?
Associated with other HLA mediated autoimmune disorders – Thyroid disease, pernicious anaemia, coeliac disease , Addison’s and vitiligo
How can type 1 diabetes imapct patients?
- Life-long treatment with insulin – risk of hypoglycemia – impacts on driving and employment – not allowed to drive heavy good vehicles, military deployment
- Risk of diabetic ketoacidosis
- Negative impact during pregnancy
- Impact on children and adolescence – difficulties with treatment
- Complications – increased risk of macrovascular complications but not to the same extent as type 2 – main complications are microvascular – more prevalent in type 1 because people are living with type 1 for 50,60 or 70 years
What are examples of different genes affecting in MODYs?
Genes implicated in MODY – all have different phenotype
- Glucokinase – leads to mild dysglycemia – can be exacerbated during pregnancy
- Transcription factors - HNF1alpha – can be associated with cystic formation in the kidneys, early onset kidney failure and insulin requiring diabetes
- Mitochondrial DNA mutations – associated with deafness – maternally inherited diabetes and deafness
- MODY-X - genetic cause still unknown
What are the differences/similarities between type 1 and 2 diabetes?
C-peptide – measure of endogenous insulin production – usually low in type 1 and high in type 2 – but differences can be present
How can we increase our ability to pick up on diabetic retinopathy?
Proactively screening using retinal photography
Usually asymptomatic especially in the earlier stages – important to pick up early
What is the mechanism underlying sulphonylureas (e.g. glicazide)?
- Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic beta-cells.
- This binding effectively closes these K+ion channels.
- This decreases the efflux of potassium from the cell which leads to the depolarization of the cell.
- This causes voltage dependent Ca2+ion channels to open increasing the Ca2+influx.
- The raise in calcium ultimately leads to exocytosis of insulin vesicles leading to insulin release
What are some other causes of hypoglycemia?
Outline the mechanisms the body uses to prevent hypoglycemic episodes?
Be aware of the conter-regulation
- Pancreas decreases insulin production and produces glucagon instead from alpha cells – tells liver to release more glucose (break down glycogen and gluconeogenesis)
- Adrenal glands – release epinephrine – signals to the liver and kidneys to produce more glucose + also prevent muscles from up taking too much glucose and acts to reduce insulin secretion
- If body fails to increase blood glucose – body releases cortisol and GH – attempts to increase blood glucose
At what blood glucose level is endogenous insulin secretion inhibited? What point to other mechanisms kick in?
Lower than 4 – inhibition of endogenous insulin
Thereafter – counterregulatory hormones – glucagon and adrenaline are released
What are the symptoms of a hypoglycemic epsiode?
- These are most common symptoms in young adults
- Children often manifest behavioural change
- Elderly can have neurological symptoms (eg mimic stroke)
- Symptoms are idiosyncratic and may change with time
What happens to the counterregulatory responses the longer someone lives with diabetes?
Counterregulatory hormones decrease with increasing duration of diabetes
Important to be aware of as it helps to explain why people lose their hypoglycemic awareness - counterregulatory mechanisms are important in telling us that we are in a hypo state (e.g. adrenaline stimulates an autonomic response)
So if counterregulatory mechanisms kick in later, we potentially only become aware of our hypoglycemic at a later stage.
Forms a vicious cycle were lack of awareness drives more hypoglycemic episodes which increase our lack of awareness.
Outline the pathogenesis underlying DKAs?
- Lack of insulin – unable to utilize glucose
- Leads to glucose accumulation in the blood causing hyperglycemia
- Leads to FFA mobilization – lipolysis
- Leads to ketone body production – energy source – acetone, 3-beta-hydroxy-butyrate (main) and aceto-acetate
- Leading to ketonemia – ketone bodies are weak acids – but if levels increase – leads to metabolic acidosis & Ketonuria
- Raised glucose levels leads to osmotic diuresis and profound hypovolemia – exacerbated by vomiting – lead electrolyte derangement, LOC and death
Outline the pathogenesis of hyperosmolar hyperglycaemic syndrome?
- Inability to use blood glucose
- Leads to excess levels of glucagon
- Resulting in increased glycogenolysis and gluconeogenesis (e.g. from muscle proteinolysis)
- Raises serum glucose even further
- Drives osmotic diuresis and hypovolemia
- Due to hypovolemia we see a drop in the GFR (renal impairment) which drives up glucose levels further
- Ultimately resulting in electrolyte derangement, LOC and death
How do these variables differs between type 1 and 2 diabetes?
How do the symptoms between type 1 and 2 diabetes differ? What diagnostic test(s) is used for both?
How can be prevent the occurence of macrovascular and microvascular complications in diabetics?
Improving blood sugar control/levels!
What are the different drugs that are used for treating type 2 diabetes? Which ones are 1st, 2nd and 3rd line?
Important to forget that technically first line is diet and exercise for 6 months (variable)!
First line - Metformin
Second Line - Sulphonylureas
Third line - Thiazolidinediones/Glitazones
Other popular drugs…
* Incretin mimics (satiety, increase insulin release and inhibit glucagon release) - also help with weight management
* SGLT-2 inhibitors - also help with kidney and CVD
How do the main groups of drugs for type 2 diabetes influence the liklihood of hypoglycemia and weight? What are other side effects to remember?
What are vascular, neurological, drugs/substances, psychological and endocrine causes of erectile dysfunction?
What are potential treatments for erectile dysfunction?
What are the main players that increase or decrease glucose?
