DIABETES MELLITUS Flashcards
Where is insulin secreted from?
The beta cells of the islets of langerhans in the pancreas
What is secreted from the delta cells of the islets of Langerhans in the pancreas?
Somatostatin
What is secreted from the alpha cells of the islets of Langerhans in the pancreas?
Glucagon
What is secreted from the F cells of the islets of Langerhans?
Pancreatic polypeptide
In those patient’s receiving insulin treatment, what marker can be used to assess beta-cell activity?
C-peptide
What stimulates increased secretion of insulin?
Glucose diffusing into the cell causing a rise in intracellular ATP
What are the effects of insulin?
Increased uptake of metabolites (including glucose)
Conversion of metabolites to stored from (eg. glycogenesis)
Decreased breakdown of stored metabolites
Recruitment of glucose channels to the cell membranes
Use of glucose for energy over other metabolites
What is the half life of insulin?
5 minutes
What is the half life of proinsulin?
20 minutes
Where is insulin broken down?
Mainly kidney and liver
What are the effects of glucagon?
Inhibition of glucose and amino acid uptake
Breakdown of stored metabolites into useable metabolites
Use of fatty acids for energy over other metabolites
Promotes hepatic output of ketone bodies
What is the definition of hyperglycaemia?
Fasting concentration of more than 7.8 mmol/L
What is the definition of hypoglycaemia?
Blood glucose concentration of less than 2.5 mmol/L
What are the main types of primary diabetes mellitus?
Type 1 Type 2 MODY Pregnancy related diabetes Latent autoimmune diabetes of adults (LADA)
What is the cause of type 1 diabetes?
Autoimmune destruction of beta-islets of Langerhans resulting in an insulin deficiency.
What are the endocrine causes of secondary diabetes?
Cushing's syndrome Thyrotoxicosis Phaeochromocytoma Acromegaly Glucagonoma
What are the hepatic and pancreatic causes of secondary diabetes?
Cirrhosis of liver Chronic pancreatitis Pancreatectomy Haemochromatosis in the pancreas Pancreatic carcinoma Cystic fibrosis affecting pancreas
What drugs can induce diabetes?
Thiazide diuretics Corticosteroids Beta blockers Statins Anti-psychotics such as clozapine Immunosuppressants - ciclosporin
What are the genetic syndromes associated with secondary diabetes mellitus?
Friedreich’s ataxia
Dystrophia myotonica
How do type 1 diabetic patients often present?
Ketoacidotic crisis
What are the features of ketoacidosis?
Polyuria - bedwetting Excessive thirst Lethargy Anorexia Hyperventilation Ketotic breath Dehydration Vomiting Abdominal pain Coma
Is glycosuria diagnostic of diabetes?
No. About 1% of the population has renal glycosuria, an inherited autosomal trait associated with a low renal threshold for glucose.
What is the mechanism for ketoacidosis?
Body is unable to use the glucose in the blood due to lack of insulin. Fatty acids are released from adipose tissue which are converted to ketone bodies. Ketone bodies are acidic.
What infections are people with diabetes particularly prone to?
Fungal infection (pruritis vulvae and balanitis) Bacterial infections (staphylococcal skin infections)
What is impaired glucose tolerance?
A state of glucose tolerance between normal and diabetic states. Occurs in both obese and non-obese.
Are patients with a type 1 diabetic parent more likely to develop diabetes if it is their father or mother who is the diabetic?
Father
At what age is the peak incidence of disease for type 1 diabetes?
Two peaks. One in pre-school and one in teenagers.
Normally before 15 years old
What are the environmental factors thought to predispose someone to type 1 diabetes?
Hygiene Parasites Coexisting infections - TB or malaria Enteroviruses Bacteria Early exposure to cow's milk Certain toxins.
Do the autoantibodies cause type 1 diabetes?
No. They are thought to be just a marker of disease and may be used to predict onset of disease.
What is latent autoimmune diabetes of adults (LADA)?
An autoimmune form of diabetes which is often misdiagnosed as type II diabetes due to the late onset of the disease.
What are the risk factors associated with developing type 2 diabetes?
Genetic markers Female gender Increasing age Diet - Westernisation of diet Sedentary lifestyle Obesity Stress Low weight at birth and at 12 months
What is the mechanism of disease in type 2 diabetes?
Resistance to the normal actions of insulin by cell membrane receptors
What is the association between polycystic ovary syndrome and type 2 diabetes?
PCOS leads to insulin resistance. As a consequence, the patient develops hyperinsulinaemia which may stimulate androgen production by acting as a gonadotrophin.
What are the criteria for testing someone who is asymptomatic but over the age of 45 for prediabetes?
Any of the following: First degree relative with diabetes Overweight or obese Previous gestational diabetes Polycystic ovary syndrome Essential hypertension Hypertriglyceridaemia Low HDL cholesterol High-risk ethnic group Premature cardiovascular disease Therapy with corticosteroids, thiazides or beta-blockers Primary hyperuricaemia or gout Cushing's syndrome Acromegaly Turner's syndrome Down syndrome
How long after the development of symptoms of type 1 diabetes are the autoantibodies detectable?
Before symptoms. Months to years before symptoms.
What are the autoantibody markers associated with type 1 diabetes?
Islet cell antibodies (ICA)
Insulin autoantibodies (IAA)
Glutamate decarboxylase (GAD)
Insulinoma-related antigen 2 (1A-2)
Which is associated with a higher risk of developing type 2 diabetes? Impaired fasting glucose or impaired glucose tolerance.
Impaired glucose tolerance
What is the form of management of impaired glucose tolerance to prevent it progressing to type 2 diabetes?
Lifestyle changes
What is the single most common cause of limb amputations?
Diabetes mellitus
What is the single most common cause of blindness in middle aged adults in developed countries?
Diabetes mellitus
What is the single most common cause of renal failure in middle aged adults in the developed world?
Diabetes mellitus
What are the main groups of complications of diabetes mellitus?
Macrovascular disease Microvascular disease Hyperglycaemia and DKA Increased susceptibility to infection Pregnancy related complications Psychosocial complications
What are the main macrovascular complications of diabetes mellitus?
Stroke
Cardiovascular disease
Renovascular disease
Peripheral vascular disease
What are the three main sites affected by diabetic microvascular disease?
Retina (retinopathy) Renal glomerulus (nephropathy) Nerve sheaths (neuropathy)
Within how many years of diagnosis do diabetic patients tend to develop macrovascular complications?
10-20 years
What is the hallmark indicator of nephropathy?
Proteinuria
What are the molecular consequences of hyperglycaemia?
Development of advanced glycation end products (AGEs)
Increased production of reactive oxygen species
Activation of NFκB (an intracellular transcription factor that mediate proinflammatory responses)
Sorbitol accumulation
Activation of protein kinase Cβ
What is the normal range for percentage of haemoglobin that is glycated (HbA1c)?
4-5.9% (20-41 mmol/mol)
How long does HbA1c reflect?
Roughly 2-3 months (half life of a red blood cell)
What is the HbA1c used for?
To measure average diabetes control over a 2-3 month period.
In a diabetic patient with a haemoglobinopathy or who is pregnant, what measurement can be used instead of HbA1c?
Glycated plasma proteins (fructosamine) levels
Glycated albumin levels
In what patients is HbA1c not particularly useful?
In those where haemoglobin turnover is changeable:
Haemoglobinopathy
Pregnancy
What are the changes to blood flow seen in the microvasculature of diabetics?
Increased blood viscosity Increased shear stress Plugging of capillaries with activated leucocytes Closure of capillaries Proliferation of new vessels
What are the major modifiable factors marcovascular and microvascular disease in diabetes?
High blood glucose
Hypertension
Dyslipidaemia
Cigarette smoking
What are the main patterns of diabetic neuropathy?
Acute sensory disorders - usually asymmetric mononeuropathies
Chronic sensory nerve disorders - symmetrical polyneuropathies
Acute motor neuropathies - uncommon
Autonomic neuropathy - most common manifestation is erectile dysfunction
What is the early histological change that occurs as part of diabetic neuropathy?
Segmental demyelination caused by damage to Schwann’s cells
What are the early clinical signs of diabetic chronic sensory polyneuropathy?
Loss of vibration
Loss of pain
Loss of temperature sensation
What are the complications of diabetic chronic sensory polyneuropathy?
Unrecognised trauma including ulceration, blistering, callus formation and infection.
What is the characteristic appearance in terms of stance of a person with diabetic chronic sensory neuropathy?
High arched foot with clawed toes
What joint is most affected by neuropathic arthropathy (Charcot’s joint) in diabetics?
Ankle
What is Charcot’s joint?
Progressive degeneration of a weight bearing joint, a process marked by bony destruction, bone resorption, and eventual deformity. Precipitated by diabetes. Can lead to amputation.
What are the clinical features associated with acute sensory neuropathies in diabetics?
Burning or crawling pains in the feet, shins and anterior thighs, and muscular leg cramps.
Symptoms worse at night
Even pressure from bedclothes can be intolerable (allodynia).
Can happen after sudden impovement in glycaemic control.
Usually resolves spontaneously
What are the cranial nerves most often affect by acute neuropathies in diabetics?
III
VI
What is the characteristic feature of diabetic third cranial nerve palsy?
Pupillary reflexes are retained.
What are the features of erectile dysfunction that would lean you towards thinking that the cause was psychogenic as opposed to an organic cause?
Sudden onset Specific situations Normal nocturnal and early morning erections Relationship problems Problems during sexual development
On examination, what would you look for in the hands of a diabetic patient?
Liver related changes (palmar erythema)
Lipid related changes (nodules)
Peripheral neuropathy
Nicotine staining
On examination, what would you look for in the arms of a diabetic patient?
Injection sites
Blood pressure
Pulse
On examination, what would you look for in the neck of a diabetic patient?
Carotid bruits
On examination, what would you look for in the eyes of a diabetic patient?
Lipid related changes (corneal arcus, xanthelasma)
On examination, what would you look for in the chest of a diabetic patient?
Signs of heart failure
History of angina
On examination, what would you look for in the abdomen of a diabetic patient?
Hepatomegaly
Insulin injection site
On examination, what would you look for in the genitalia of a diabetic patient?
Haemochromatosis associated with hypogonadism
On examination, what would you look for in the legs of a diabetic patient?
Peripheral neuropathy - sensation using microfilament, reflexes
Peripheral pulses
Injection sites
On examination, what would you look for in the feet of a diabetic patient?
Shape and deformities Test vibration and temperature sensation Reflexes Weakness Sweating Distended veins Pulses Oedema Cold feet
What are the infections commonly seen in diabetic patients?
Staphylococcal skin infection - boils, abscesses, carbuncles
Fungal infections - mouth, skin, nails, folds
Mucocutaneous candidiasis
Chronic peridontitis (tissue around teeth)
UTI
Pyelonephritis
Pneumococcal pneumonia
TB
What drugs can be used to treat erectile dysfunction in a diabetic patient?
Phosphodiesterase type 5 inhibitors - sildenafil
Prostaglandin E1 preparation - alprostadil (tablet inserted in urethra)
What are the non-medical ways of managing erectile dysfunction in a diabetic patient?
Vacuum devices
Surgery to insert semi-rigid plastic rods
What proportion of lower limb amputations are accounted for by diabetes?
50%
What are the three pathological factors that increase the likelihood of amputation in a diabetic patient?
Peripheral neuropathy
Peripheral arterial disease
Infection secondary to trauma or ulceration
In a diabetic patient, why is it important to distinguish between an ischaemic ulcer and a neuropathic ulcer of the foot?
Because a neuropathic ulcer can heal whereas an ischaemic one will not and needs to treated/debridement.
How do you treat infection of a diabetic foot?
X-ray foot to check for osteomyelitis Broad based antibiotics High dose Given often in excess of a month May require excision of bone
How do we assess blood supply to a diabetic foot?
Look for pulses using doppler
What are the different types of eye disease that can affect a diabetic patient?
Retinopathy
Cataracts
Glaucoma
Ocular nerve palsy
What is the early clinical sign of diabetic retinopathy?
Dot haemorrhages on the retina from capillary microaneurysms
Scattered exudates
What might you seen in retinal screening of a diabetic patient who had retinopathy that had slightly progressed beyond the early stages of dot haemorrhages?
Cotton wool spots representing oedema
What are the signs of proliferative retinopathy when photographing the retina of a diabetic patient?
New fragile branching vessels
How is diabetic eye disease managed?
Tight control of blood glucose and blood pressure
Quit smoking as the increases the rate of retina disease
Severe retinopathy can be treated using laser photo coagulation
Cataracts surgery
What are the three ways that diabetes affects the kidney?
Glomerular damage
Ischaemia hypertrophy of afferent and efferent arterioles
Ascending infections
How are diabetics screened for kidney disease?
Urine analysis looking for proteinuria and some centres look for microalbuminuria
What are the three main causes for someone experiencing a ketoacidotic attack?
Undiagnosed diabetes
Stopping insulin therapy
Intercurrent illness
What are the symptoms of ketoacidosis?
Vomiting Thirst Polyruria Weight loss Abdominal pain
What are the clinical signs of ketoacidosis?
Dehydration Tachycardia Hypotension Warm, dry skin Hyperventilation (Kussmaul breathing) Acetone on breath Confusion, coma
What investigations would be ordered for someone suspected of being ketoacidotic?
Blood tests: BM, U+Es, Ketones, FBC ABG Urine dipstick Bacteriology from blood and urine (MSU) ECG - looking for hypo- or hyper-kalaemia Chest X-ray - infection CT or MRI - if cerebral oedema is suspected Exclude other causes of coma
What are the principles of management of ketoacidosis?
Replace insulin Replace fluid loss Replace electrolyte loss Restore acid-base balance Seek underlying cause - eg infection
What are the early complications of ketoacidosis?
Coma
Cerebral oedema
Hypotension
Hypothermia
What is the level you are aiming to bring the blood glucose down to in a ketoacidotic patient?
Below 10 mmol/L
Which group of diabetic patients are more commonly affected by hyperglycaemic non-ketotic hyperosmolar state (HONK)?
Type 2 adults, often with previously undiagnosed diabetes
How do people in a hyperglycaemic non-ketotic hyperosmolar state usually present?
Severe dehydration
Stupor
Coma
What are the main complications of hyperglycaemic non-ketotic hyperosmolar state (HONK)?
Arterial thrombosis leading to stroke, MI or arterial insufficiency in lower limbs
How do you manage hyperglycaemic non-ketotic hyperosmolar state (HONK)?
Osmolality adjustment
Fluid replacement
Careful insulin use
Antithrombotic prophylaxis with aspirin
What is the WHO criteria for the diagnosis of diabetes?
a) symptoms of hyperglycaemia and one off blood test of raised glucose (either a random test of over 11 mmol/L or a fasting test of over 7mmol/L)
b) No symptoms but two blood tests showing raised glucose (either random of over 11 mmol/L or fasting test of over 7 mmol/L)
c) Oral glucose tolerance test - 2 hours value of over 11 mmol/L
d) HbA1c of over 48 mM (6.5%) - not excluded if under this amount.
What is the diagnostic definition of impaired fasting glucose?
Fasting glucose of 5.6-6.9 mmol/L
What is the diagnostic definition of impaired glucose tolerance?
Oral glucose tolerance test - 2 hour value of between 7.8 and 11 mmol/L with a fasting glucose of less that 7.
How do you manage impaired fasting glucose or impaired glucose tolerance?
Lifestyle changes - diet, exercise
Structured education program
Control blood pressure
How would you medically manage the blood glucose of someone who has just been diagnosed with type 2 diabetes?
Metformin - 500mg BD after food
Dose can be titrated up from 250 mg originally
How does metformin work (broadly)?
It sensitizes cells to insulin and promotes weight loss
Can metformin use lead to a hypoglycaemic event?
Theoretically no because it only sensitises the body to insulin that would otherwise be there rather than actually increasing inappropriate amount of insulin or insulin equivalents.
What are the side effects of metformin?
Abdominal pain
Nausea
Diarrhoea
Lactic acidosis
In what group of patient should metformin be avoided?
Renal failure patients (those with a eGFR of under 36 ml/min)
Why should metformin be avoided in renal failure patients?
Because of the risk of lactic acidosis
As well as starting on metformin, what other management will a recently diagnosed type 2 diabetic need?
Lifestyle advice - diet and exercise Statins Control BP Yearly retinal screening Foot care State a target for the HbA1c Teach about capillary glucose analysis
What is the target HbA1c for a type 2 diabetic?
Less than 6.5% (48 mmol/mol)
What might make you decide to change the blood glucose controlling medication regime in a type 2 diabetic currently on metformin?
16 weeks after starting medication the HbA1c is over 53 mmol/mol (7%)
What class of drug might you choose to give a type 2 diabetic if you decided that metformin wasn’t working well enough?
Sulphonylurea OD
Name 4 examples of sulphonylureas.
Gliclazide Glipizide Glipenclamide Glycopyramide Glibornuride Glimepiride
How do sulphonylureas work (broadly)?
Stimulates insulin release by inhibiting ATP sensitive K channels.
What are the side effects of sulphonylurea?
Hypoglycaemia
Skin rashes
Weight gain
Renal impairment (applies only to those not excreted by the liver)
What are the drug interactions involved with sulphonylurea?
The drug interaction is caused by the fact that sulphonylurea binds to circulating albumin and may therefore displace or be displaced by other drugs that compete for the same binding spot. One such drug is warfarin.
If sulphonylurea was causing a problem in terms of hypoglycaemia or weight gain in a type 2 diabetic, what might you consider changing them to (in addition to their metformin)?
DPP-4 inhibitor/Gliptins
How do DPP-4 inhibitors work?
They inhibit the breakdown of GLP-1. GLP-1 is an incretin that increases insulin release and inhibits release of glucagon. They also reduce appetite.
Can DPP-4 inhibitors cause hypoglycaemia?
No. GLP-1 is only released when you eat so will correspond to glucose levels rising in the blood.
Name the 2 DPP-4 inhibitors approved in Europe.
Sitagliptin
Vildagliptin
What are the adverse effects associated with DPP-4 inhibitors such as sitagliptin?
Nasopharyngitis Headache Nausea Heart failure Skin reactions
If after 6 months of treatment, with metformin plus sulphonyurea or a gliptin, the patient’s HbA1c was still over 57 mmol/mol, what might you decide to start the patient on?
Glitazone (thiazolidinediones) eg Pioglitazone
GLP-1 analogue eg Exenalide
Sulphonlyurea receptor binders eg Nateglinide
Gliflozins (SGLT-2 inhibitors) eg Canagliflozin
Insulin
What are the side effects of Pioglitazone (a glitazone used in the management of diabetes)?
Hypoglycaemia
Fractures
Fluid retention
Raised LFTs
What are the side effects of Exenalide (a sulphonylurea receptor binder used in the management of diabetes)?
Hypoglycaemia
Name the rapid acting insulin used in the management of diabetes.
Insulin aspart
Insulin lispro
Name the intermediate acting insulin used in the management of diabetes.
Isophane detemir
Name a long acting insulin used in the management of diabetes.
Insulin glargine
