Diabetes Flashcards
What is diabetes mellitus?
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 are the actions of insulin?
Promotes uptake of glucose into cells for energy
Prevents breakdown of fat and protein
What do islets of langerhans look like histiologically?
What are the different cells contained within the islets of langerhans?
Rich blood supply so hormones can be released
What is the function of somatostatin hormone?
In your pancreas, somatostatin inhibits the release of pancreatic hormones, including insulin, glucagon and gastrin, and pancreatic enzymes that aid in digestion
How is glucose secretion from beta cells controlled?
Glucose enters beta cells directly via GLUT2 transporters. It is a permissive process that is directly related to the amount of glucose in the blood
Glucose is then metabolised (glycoloysis) then pyruvate enters TCA cycle
The ATP produced directly inhibits a K+ channel opening, so intracellular K+ levels rise which causes a membrane depolarisation which opens a voltage gated Ca+ channel, allowing Ca+ to come into beta cell. That promotes exocytosis of insulin molecules
What is the difference between endogenous and exogenous insulin produced?
In the body, endogenous pro-insulin is converted to insulin and C peptide
C-peptide can be used as a measure of endogenous insulin secretion in people with diabetes
This is because exogenous insulin manufactered by companies does not have C peptides
What tissues does insulin act on and what are the principle actions?
Increased Glucose uptake in FAT and MUSCLE and Glycogen storage in LIVER and MUSCLE
Increased Amino Acid uptake in MUSCLE and Protein Synthesis
Increased Lipogenesis in ADIPOSE TISSUE
Decreased Gluconeogenesis from 3-Carbon precursors and Ketogenesis (in LIVER)
Increased Cell proliferation
Decreased Apoptosis
What is the basic action of insulin?
Binds to a cell membrane receptor
Many pathways after this that lead to transformation of GLUT4 transporters from the cytoplasm to the surface of the cell in fat and muscle
This allows insulin-dependent glucose uptake into cells
What substances can gluconeogenesis occur from?
Glycerol
Lactate
Pyruvate
Alanine (protein)
What hormones increase the levels of blood glucose?
Adrenalin, noradrenalin, glucocorticoids, growth hormone and glucagon
Why is Blood Glucose Maintained within a Narrow Range by Homeostatic Mechanisms?
- Optimal functioning of brain
- Maintenance of energy source for most tissues
- Integrity and health of blood vessels
What can cause a deficiency in insulin?
Toxic insults to pancreas- chemical, surgery, autoimmune= absolute deficiency in insulin
What are conditions that can cause a severe resistance to insulin and what can occur in these conditions?
- Leprechaunism
- type A insulin resistance
- Rabson-Menderhall syndrome
Due to single gene mutations in receptors or proximal downstream messengers. Cause profound resistance and are rare
Can develop catnthosis nigricans, dry, dark patches of skin that usually appear in the armpits, neck and groin
What type of obesity is associated with increased insulin resistance?
Central adiposity
Visceral fat produces hormones- these can affect insulin. Likely to be part of the cause
What endocrine conditions can cause insulin resistance?
GH, cortisol and adrenalin can stop insulin actions in fight or flight. Pathogenic states of these will cause insulin resistance e.g. acromegaly, phaeochromocytoma or cushings disease
What are the cut off levels of blood fasting glucose in diabetes?
Lines are drawn where complications (microvascular) of diabetes occur- these shown are fasting blood glucose. > 7 mmol/L
Between 6-7= pre-diabetic state
What are the definitions of diabetes in biochemical results?
Oral glucose tolerance test- give a measured dose of glucose then measure after 2 hours
What is glycated haemoglobin?
Rate of formation of glycated haemoglobin is directly proportional to ambient blood glucose concentration
Reflects integrated blood glucose (BG) concentrations during lifespan of erythrocyte (120 days)
Blood sample can be taken at any time of day, irrespective of food consumption
When should HbA1c not be used as a diagnostic test for diabetes?
- Rapid onset
- Pregnancy
- Conditions where RBC survival may be impacted
- Renal dialysis
- Iron and vit 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
What are pre-diabetic states?
Intermediate state between normal glucose metabolism and diabetes
Increased risk of vascular complications
Increased mortality from cardiovascular disease (doubled)
Weight loss can help
What are risk factors for type 2 diabetes?
Genetics
Ethnicity
Increasing age
Central obesity
Low birth weight
What is the genetic component of type 2 diabetes?
Genome-wide association studies have identified >400 gene variants associated with an increased risk of Type 2 diabetes
Most relate to beta cell function or mass, rather than obesity/insulin resistance
40% of the overall risk of Type 2 diabetes is determined by genetic factors-
What ethnicities have a higher prevalence of type 2 diabetes?
Polynesian countries, Arabic, south Asia
In part relates to genetics, in part relates to lifestyle
South Asian- lay down more visceral fat than those of European even if they have the same BMI
Why does age affect the prevelance of type 2 diabetes increases with age?
Beta cell function reduces with age
Obesity increases with age
What is the classical presentation of type 2 diabetes?
Asymptomatic- found on routine screening
Thirst, polyuria (osmotic symptoms)
Malaise, chronic fatigue
Infections e.g. thrush and boils
Blurred vision
Complication (e.g. retinopathy, neuropathy) as presenting problem
What are the features of metabolic syndrome?
- Central obesity
- High blood pressure
- High triglycerides
- Low HLD- cholesterol
- Insulin resistance
What other medical disorders are associated with type 2 diabetes?
Obstructive Sleep Apnoea
Polycystic Ovarian Disease
Hypogonadotrophic Hypogonadism in men
Non-Alcoholic Fatty Liver Disease
What are the symptoms of type 1 diabetes?
Polyuria, thirst
Fatigue, malaise
Weight loss
Blurred vision
Nausea and vomiting
Usually presents in younger people
What is the pathogenesis of type 1 diabetes?
Autoimmune condition that is triggered by the HLA system
May be an environmental trigger years before such as viral infection or chemical toxin
Causes destruction of pancreatic beta cells
What are the different stages in the development of type 1 diabetes?
Stage 1- emergence of biomarkers (auto antibodies). Inflammatory infiltrate in the islets. Blood glucose levels normal
Stage 2- progressive deficiency and blood glucose levels not normal. Prediabetic state
Stage 3- 80% of islets destroyed. Symptomatic diabetes
What is the prevalence of type 1 diabetes across the globe?
Geographical variation- more prevalent in the Northern and Southern latitudes
What are some of the autoimmune disorders associated with type 1 diabetes?
Thyroid disease
Pernicious anaemia
Coeliac disease
Addison’s disease
Vitiligo
How does type 1 diabetes have an impact on life?
Hypoglycaemia can affect driving and employment
Risks of diabetic ketoacidosis
Complications- microvascular and macrovascular
What is secondary diabetes?
Diabetes secondary to other health problems
What are some causes of secondary diabetes?
Pancreatectomy
Trauma
Tumours
Pancreatitis e.g. due to alcohol intake
Iron overload
Endocrine disorders
Drugs
What drugs an exacerbate insulin resistance?
High dose prednisolone or dexamethasone to treat inflammatory conditions such as IBS
What is monogenic diabetes?
Single inhertied gene defects that lead to diabetes
What is MODY?
Maturity onset diabetes of the young
Caused by a gene defect altering beta-cell function - not insulin dependant but instead resistant to insulin
Develop diabetes at a young age but not type 1
What are the overlapping clinical features between type 1 and type 2 diabetes?
What is hypoglycaemia?
Low blood sugar- commonest diabetic emergency
The cause is too much insulin or sulphonylureas
What are the common causes of hypoglycaemia?
Patient error- too much insulin, too little carbs, missed/late meal or exercise
Alcohol
Decreased insulin requirements e.g. weight loss
Liver disease
Conditions associated with type 1 diabetes- coeliac, Addison’s disease, hypothyroidism
Complications of diabetes- renal failure, autonomic neuropathy
What are sulphonylureas ?
This family of tablets mainly works to stimulate the cells in the pancreas to make more insulin and to make insulin work more effectively in the body.
E.g. gliclazide, glipizide
What is the mechanism of action of sulfonylurea?
They bind to sulfonylurea receptors 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 happens in the body when there is hypoglycaemia?
Pancreas decreases insulin output and increases glucagon output
Adrenalin is also secreted by adrenal gland, tells liver and kidney to produce more glucose
Adrenalin also acts to stop insulin secretion and stops muscles from using too much glucose
When adrenalin and glucagon fail to raise sugar levels, GH and cortisol are released
What are the warning signs of hypoglycaemia?
Children often manifest behavioural change
Elderly can hve neurological symptoms e.g. mimics stroke
What happens to levels of counter-regulatory hormones in type 1 diabetes?
They decrease over time- get deficiencies
What is the vicious cycle of hypoglycaemia?
What is the diagnosis of hypoglycaemia based on?
Whipple’s triad- 2 out of 3
- Typical symptoms
- Biochemical conformation- no agreed cut off but usually 4mmol/L
- Symptoms resolve with carbohydrates
What is the managment of hypoglycaemia?
If alert, give a sweet drink or dextrose tabet
If not alert, give 20% dextrose IV
If cannot get IV access, give 1mg intramuscular glucagon
Follow up with slow release carbs
What drinks are recommended to give to a patient having a hypo?
Previously lucozade, but glucose content has now been reduced
Tea with suagr or fruit juice still fine
What does the DVLA say about drivers with insulin-treated diabetes?
Drivers should carry glucose meters and rescue carbohydrates
Check glucose levels before driving and every 2 hours
Carry ID saying you have diabetes in case of accident
What does the DVLA advice to drivers who experiance a hypo while driving?
If you have a hypo while driving
- Stop vehicle as soon as safe
- Switch off engine and remove keys from ignition
- Get out of driver’s seat
- Wait 45 mins after blood glc normal before driving
When must drivers inform the DVLA about their diabetes?
Drivers must inform DVLA if:
>1 severe hypo whilst awake within last yr (need for assistance)
If you or your carer feel you are at high risk of developing hypo
Develop impaired hypo awareness
Suffer hypo while driving
What hyperglycaemic emergenies can occur in type 1 and type 2 diabetes?
Type 1= diabetic ketoacidosis
Type 2= more usual to develop hyperosmolar hyperglycaemic state
What is the pathogenesis of DKA?
Glucose builds up in the body but is unable to be used
Free fatty acids, fats are broken down and these can be used through ketonegenesis as an alternate energy source
Ketones build up which causes ketoneuria and metabolic acidosis
Can lead to electrolyte imbalances, reduced consciousness and death eventually
What acids build up in DKA?
These build up- acetone, beta-hydroxybutyrate and acetoacetate
Main ketone bodies= 3 beta H
What exacerbates hyperglycaemia in type 1 diabetes?
There is an increase in hepatic glucose production as glucose is not being used and gluconeogenesis occurs from amino acids
Causes glucose levels to rise
Why is there higher glucose levels in type 1 and 2 diabetes?
Lack of insulin= no inhibition of gluconeogenesis or breakdown of glycogen
Insulin resistance= cells do not react to insulin and gluconeogenesis and breakdown of glycogen occurs
What does DKA do to the kidney?
The hypovolaemia and osmotic diuresis causes a decreased glomerular filtrating rate due to kidney injury
This means glucose stops being secreted as fast and hyperglycaemia gets worse
How do you manage DKA?
FLUIDS= rehydrate
IV insulin= to switch off ketone body production
Monitor potassium
Seek the precipitant
Why do you want to monitor potassium in patients recovering from DKA?
In metabolic acidosis, K+ shifts to the extracellular space
As you give more insulin, K+ moves into cells
What are the symptoms of DKA?
Polyuria, polydipsia
Hypovolaemia- decreased JVP, BP, increased HR
Sigificant electrolyte deficit
Abdominal pain, nausea and vomiting
Kussmal breathing, ketotic breath (fruity)
Muscle cramps
What hyperosmolar hyperglycaemic syndrome?
Usual finding is MARKED hyperglycaemia, raised osmolality and mild/no ketoacidosis
Affects middle-aged or elderly type 2 DM
Diagnosis=
Hyperglycaemia, serum osmolality, no/mild ketoacidosis, serve dehydration and pre-renal failure are common
What can Hyperosmolar Hyperglycaemic Syndrome cause?
- Profound dehydrattion
- Coma, confusion and fits
- Hypercoagualbility
- Nausea and vomiting
How is Hyperosmolar Hyperglycaemic Syndrome managed?
- Prolonged rehydration
- Anticoagulation is vital
- Seek the precipitant (infection, MI, ect)
Does metformin cause lactic acidosis?
Evidence that MF causes lactic acidosis is poor
Review of cases of MF-associated lactic acidosis 1995-2000 showed that no cases were caused solely with MF
When should metformin be stopped?
Stop MF if eGFR <30 (or worsening fast)
Withdraw during tissue hypoxia but can reinstate later e.g. in ‘Shock’, MI, Sepsis, Dehydration, Acute renal failure
Withdraw for 3 days after iodine-containing contrast medium given. Check U/E before reinstating 48h later
Withdraw 2 days before general anaesthetic and reinstate once renal function stable
What are the different complications that can arise due to diabetes?
What is macrovascular disease?
It refers to disease of any large blood vessel, including coronary arteries, aorta and sizable arteries in the brain or limbs
Can translate in stroke, MI, ischaemic heart diease, cerebrovascular disease, vascular dementia and peripheral vascular disease
What is microvascular disease?
It refers to disease of the smaller blood vessels, including those supplying the retina, kidneys, and nerve endings
Can manifest in retinopathy, neuropathy or peripheral neuropathy
What reduces cardiovascular risk in diabetes?
Lowering glucose and controlling it has proven to reduce complications of diabetes and increased life expectancy
What is the target of HbA1c for those with type 2 diabetes?
58 mmols/mol
What is the central pathological mechanism of macrovascular disease in diabetes?
Atherosclerosis arises due to chronic inflammation and injury to the arterial wall
Blockage can lead to ischaemia or acute injury due to complete blockage
What occurs in atherosclerosis?
In response to endothelial injury and inflammation, oxidized lipids from LDL particles accumulate in the endothelial wall of arteries.
Angiotensin II may promote the oxidation of such particles
Monocytes then infiltrate the arterial wall and differentiate into macrophages, which accumulate oxidized lipids to foam cells
Once formed, foam cells stimulate macrophage proliferation and attraction of T lymphocytes, in turn inducing smooth muscle proliferation in the arterial walls and collagen accumulation.
The net result is the formation of a lipid rich atherosclerotic lesion with a fibrous cap.
What can cause macrovascular disease in diabetes?
Atheroma formation
Increased platelet adhesion
Hypercoagulability
What can cause macrovascular disease in diabetes?
Atheroma formation
Increased platelet adhesion (impaired nitric oxide generation, increased free radical formation and altered calcium regulation)
Hypercoagulability
Elevated levels of plasminogen activator inhibitor type 1 may also impair fibrinolysis
Metabolic syndrome= also has risk factors of CVD
How does diabetic foot occur in diabetics?
Lack of feeling in feet due to peripheral neuropathy
May hit or damage their feet, but lack the pain to alter behaviour
May get infected and there is delayed wound healing due to hyperglycaemia
What is the management of diabetic foot?
Antibiotics for infection
Debridement to take away some of infection
Off loading to take pressure off foot
Improved glycaemic control
What is the pathophysiology of microvascular disease?
Aldose reductase may participate in the development of complications
It is an enzyme in the pathway that converts glucose into glucose alcohol. High glucose= high glucose alcohol and osmotic stress from this causes microvascular disease
ALSO High gluc levels can stimulate free radical production and reactive oxygen species formation
What growth factors have been posulated to have important roles?
Vacular endothelial growth factor
Transforming growth factor B
What is the pathophysiology of diabetic nephropathy?
Initial constriction of the efferent arterioles and dilation of the afferent
Results in glomerular pressure rises and hyperfiltration
Gradually changes to hypotension through time
Glomerular filtration eventually shuts offd
How do you halt diabetic nephropathy?
Good blood pressure control
Improving glycaemic control
ACEi
Where is protein, carbohydrate and fat digested and uptaken in the digestive tract?
What does pancreatic lipase require in order to break down fat?
Requires the prescence of detergents such as bile acids and salts
What does pepsin in the stomach break protein into?
Pepsin breaks protein into peptides, not fully into amino acids
What digests carbs in the small intestine and where are they made?
Pancreas secretes amylase, isomaltase, sucrase and lactase on the SI wall
What is the function of alpha-amylase?
Breaks alpha(1-4) links in starch
What is the dietary, transport, storage and mobilised form of protein, carbs and fat?
What enzymes change in concentration after feeding and fasting?
What happens to carbohydrate, fat and protein after a meal? (overview diagram)
How does glucose metabolism in muscle work? (diagram)
What increases the conversion of glycogen to G-1-P?
Glucagon
Adrenalin
AMP
What enzyme breaks down glycogen and what is it activated by?
Glycogen phosphorylase
Activated by phosphorylation (through a pathway activated by ACh or adrenalin) or by AMP activation
What is the overview of metabolism in anaerobic exercise?
Lactate can be circulated to the liver and reconverted to glucose
Does the concentration of ketone bodies rise during exercise?
No- unsure of the mechanism why
What is the overview of metabolism in aerobic exercise?
What is the overview of metabolism during fasting?
How are triacylglycerides stored, transported and digested?
MAG= monoacylglycerol
What is the graph that shows the different sources of glucose during starvation and what fuel the brain is using?
What substances can enter the TCA cycle but not be converted to glucose?
Ketogenic aminoacids
Fatty acids
Ethanol
What are the metabolic effects of insulin on the liver, muscle and adipose tissue?
What does metformin do?
Activates AMP-activated protein kinase which has a range of effects:
How does tissue injury affect glucose levels?
Get an increase in cortisol, catecholamines and cytokines which raise blood glucose levels
What are the different drugs used to manage type 2 diabetes?
Biguanides
Sulphonylureas
Thiazolidinediones
Incretin mimetics
SLGT2 inhibitors
Lowers blood sugar levels
What are biguanides (side effects too)?
- e.g. metformin- reduces hepatic glucose output
- Does not cause hypoglycaemia
- No increase in weight- may help people to lose weight (used in PCOS to help with metabolic effects)
- Side effect- Possible nausea, can also get lactic acidosis so if GFR drops you need to withhold metformin
What are Sulphonylureas (and the side effects)?
- e.g. gliclazide, glibenclamide which stimulates insulin secretion.
- Can cause hypoglycaemia- important to educate patients
- Can cause weight increase
What are Thiazolidinediones (and what are the side effects)?
- e.g. pioglitazone, reduces insulin resistance. Currently 3rd line but its use is increasing. Cause fluid retention, can cause heart failure. Because the drug is long lasting can stop taking it and still have effects for 6 months
- Does not cause hypoglycaemia
- Causes weight increase
- Contraindicated in those with ischaemic heart disease
What are incretin mimetics (and what are the side effects)?
- e.g. exenatide, liraglutide and gliptins. Physiological mode of action to enhance incretin secretion
- When you eat food- incretins released such as glucagon-like peptide. This causes insulin release
- Does not cause hypoglycaemia
- Causes weight loss
What is the recommended level of HbA1c in diabetic patients?
< 48 mmol/L
At what level does the DVLA recommend not driving for blood sugar levels?
DVLA recommends not driving when you have a blood glucose level < 4 mmol/L
What ages do the peaks of diagnosis of type 1 and type 2 diabetes?
- Type 1 diagnosis- any age, peaks around 2 years and 14 years
- Type 2- typically 40+ but we not test younger age groups
What are the different diagnostic tests for type 1 and type 2 diabetes?
Diagnotic tests- type 1
- High blood glucose
- DKA (ketones in urine and blood)
- May show antibodies, elevated HbA1c
Diagnostic tests- type 2
- High blood glucose
- OGTT- oral glucose tolerance test
- Elevated HbA1c
What are the values of blood sugar 2 hours after a oral glucose tolerance test?
< 7.8= normal, 7.8-11.1 impaired glucose tolerance, > 11.1 diabetes
What are SLGT2 inhibitors and what are the side effects they cause?
- E.g. Empagliflozin
- Inhibits sodium glucose co-transporters in the nephron
- Do not cause hypoglycaemia
- Cause weight loss
- Increased genital thrush and UTI risk- due to excess glucose in the urine
What are the different causes of erectile dysfunction?
Vascular causes= atheroma, blood vessel damage
Neurological= nerve damage
Drugs/substances= antihypertensives, alcohol, tobacco and narcotics
Psychological= (performance) anxiety, depression
Endocrine= hypogonadotrophic hypogonadism
What is the treatment of erectile dysfunction?
- Mechanical ⇒ Vacuum mediated pump
- Pharmaceutical ⇒ Local vasodilators e.g. viagra can be given orally or injection, Available over the counter. Also hormone replacement
- Prosthetic ⇒ Rigid- surgically implanting a rod into the penis so it is constantly a rod. Also get inflatable types
What antibodies are present in type 1 diabetes?
Anti IA2, GAD and ZNT8
What is needed to make a diagnosis of diabetes?
2 out of the 3 of
- Random blood glucose > 11
- Fasting blood glucose > 7
- Symptoms
Why is HbA1c mainly used for diabetes type 2 diagnosis?
Type 1 can occur rapidly and the HbA1c may not always reflect this
What are the most common mutations that can cause MODY?
HNF1-alpha and glucokinase mutations
What proves a patient has type 1 diabetes?
C peptide < 300
Not used for diagnosis
What is latent autoimmune diabetes of adults?
Latent autoimmune diabetes in adults (LADA) is a slow-progressing form of autoimmune diabetes. Like the autoimmune disease type 1 diabetes
People who have LADA are usually over age 30. Because they’re older when symptoms develop than is typical for someone with type 1 diabetes and because initially their pancreases still produce some insulin, people with LADA are often misdiagnosed with type 2 diabetes
What injection technique can cause too much or too little insulin in the body?
Repeat injection sites- if patients inject in same place fatty deposits may build up and can end up absorbing too much or too little
When is laser eye surgery given to diabetic patients?
when the patient has proliferative retinopathy- new vessels forming which are prone to bleeding and causes blinding
What is anti-VEGF medication used for in diabetes?
Anti-VEGF medicines stop the abnormal blood vessels leaking, growing and then bleeding under the retina
