Week 2 Flashcards
A kg increase in bodyweight leads to what % increase in the risk of developing diabetes?
A kg of weight loss a year after a diagnosis of T2DM is associated with how many months of increased survival?
4.5%
3-4 months more survival
How is Lactic Acidosis classified?
Type A
- associated with tissue hypoxaemia e.g. infarcted tissue, cardiogenic shock, hypovolaemic shock
Type B
- may occur in liver disease
- may occur in leukaemic states
- associated with diabetes
What marker is used to screen for diabetic kidney disease?
Albumin Creatine Ratio (ACR)
In managing and preventing childhood obesity, what are the 1, 2, 3, 4 steps outlined in the SIGN and NICE guidelines?
- 1 hour of physical activity a day
- less than 2 hours a day of ‘sedentary time’ i.e. TV, computer screens etc.
- Food and drink - limit foods high in fat and sugar, discourage multiple snacks and moderate portion size
- keep child’s weight within a healthy range
Thiazolidinodiones (TZDs): what do they target? Why does this make them “messy” drugs?
What is the main side effect associated with TZDs?
TZDs e.g. pioglitazone targets PPAR gamma, which is involved in the regulation of transcription of many different genes.
Because TZDs are PPAR-gamma agonists, they therefore have numerous side effects
Main side effect is weight gain, which is almost inevitable and can be quite substantial
Metformin is the 1st line drug in treating T2DM, but if a patient is not coping on this alone what other drugs could be added on?
Sulphonylureas - cheap and effective, but weight gain is a possible side effect
SGLT-2 inhibitors - better tolerated with weight fluctuation, however are (very rarely) associated with DKA
GLP-1 agonists if the above don’t work - given as an injection either daily or weekly and slow gastric emptying
How is DKA diagnosed biochemically? 3 things
- Ketonaemia > 3 mmol/L, or significant ketonuria
- Blood glucose > 11.0 mmol/L, or known Diabetes
- Bicarbonate < 15 mmol/L, or venous pH < 7.3
What newer drugs are available for the treatment of T2DM?
How do they work?
Drugs targeting the Incretin Pathway
- Incretin = Intestinal Secretion of Insulin
- GIP from K cells and GLP-1 from L cells (Exenatide)
- promote insulin secretion from the pancreas without the risk of hypoglycaemia (unlike SUs)
- Suppress glucagon
- Decreases gastric emptying, resulting in earlier satiety
- Act on the hypothalamus to cause weight loss
- DPP-IV inhibitors
- -gliptins
- less potent than GLP-1 inhibitors,
SGLT-2 Inhibitors e.g. Dapagliflozin, Canagliflozin, Empagliflozin
- prevents reabsorption of glucose by the kidneys, causing it to be excreted in the urine
- Causes weight loss, reduces CV events, death and hospitalisation from heart failure
- Increased glucose in the urine can result in increased UTIs and Thrush
Glicazide, Glibenclamide and Glimepiride are 1st/2nd gen Sulphonylureas and are long/short acting
Glicazide is the most commonly used, but when would you use Glibenclamide over it? Why?
2nd gen (1st gen are rarely used now)
shorter acting
Glibenclamide can be used in pregnancy/gestational diabetes, as it does not cross the placenta
What are the two core defects seen in T2DM?
Insulin resistance
Beta cell dysfunction
The “metabolic syndrome” refers to a series of clinical features associated with central obesity - what are these features?
Central adiposity a.k.a. ‘apple shapes’ is associated with…
- High BP
- High triglycerides
- Low HDL
- Insulin resistance
What type of drug is Metformin?
What dosage is given?
Biguanide - acts as an insulin sensitiser, primarily acts on the liver to lower glucose production
Usually start at 500mg and titrate up to 1g
Name some sulphonylurea drugs
Glimepiride
Gliclazide
Glibenclamide
Glipizide
How is DKA managed?
Replace losses
- fluids
- insulin
- potassium
Address risks
- Naso-gastric tube?
- monitor potassium
- prescribe prophylactic LMWH
How might focal neuropathy present itself?
- Inability to focus
- Double vision
- Aching behind the eye
- Bell’s palsy
- Pain in thigh/chest/lower back
- Pain on the outside of the foot
Name some SGLT-2 inhibitors
Dapagliflozin
Empagliflozin
Canagliflozin
Ipragliflozin
When considering a diagnosis of T2DM, what other conditions need to be ruled out?
T1DM
Pancreatic disease
LADA
Medication induced
Outline the current progression of medications for T2DM
Metformin
SUs, TZDs, DPP-4 inhibitors, SGLT-2 inhibitors
GLP-1 agonists
Insulin (unlike T1DM, this is usually given as a basal injection without a pre-meal bolus)
By what features is HHS defined?
Hypovolaemia
Hyperglycaemia (blood glucose >30 mmol/L), without significant acidosis or ketonaemia
Hyperosmolar (osmolality >320 mosmol/kg)
What are the typical features of Hyperosmolar Hyperglycaemic State (HHS)?
Usually older individuals, but may be younger individuals in non-Caucasians
High refined CHO intake pre-event
Risk associations - cardiovascular events, sepsis, medications (glucocorticoids and thiazides)
What are the three types of bariatric surgery that can be performed to tackle obesity? What are patients often prescribed following surgery?
Adjustable gastric band (lap band)
Roux-en-Y Gastric Bypass (RNY)
Verticle Sleeve Gastrectomy
Malabsorption disorders are common following these procedures, and patients are commonly prescribed vitamin supplements
HHS - typical biochemical picture
Raised blood glucose, higher than that of DKA (mean is 60 mmol/L)
Significant renal impairment
Na may be raised on admission
Significantly raised osmolality e.g. very dehydrated
What are some treatment options for painful neuropathy?
amitriptyline, duloxetine, gabapentin, pregabalin - combinations of these are not recommended
If the pain is localised and the patient wishes to avoid oral treatment, then Caspaicin cream can be applied topically
What is the Resting Metabolic Rate? How does it change in obesity and how does it contribute to maintaining weight loss?
Amount of energy expended at rest (i.e. minimum energy consumption)
Both fat mass (FM) and fat-free mass (FFM) contribute
RMR is higher in obese individuals and falls with weight loss, HOWEVER, the observed fall in RMR often exceeds that which was predicted (adaptive thermogenesis - body perceives weight loss as a threat to survival)
This makes it harder to maintain weight loss, because the lower the RMR, the harder it is to lose weight
How is osmolality calculated?
2x (Na+ plus K+) + Urea + Glucose
What hormone, produced by adipose tissue, signals our body to stop eating and tells us that our fat stores are adequate?
Leptin
What are the 4 key features of the “metabolic syndrome”?
High triglycerides
High BP
Low LDL
Insulin resistance
Name a drug that enhances glucose excretion by the kidneys
SGLT2 inhibitors e.g. empagliflozin, canagliflozin
What causes insulin resistance?
Accumulation of ectopic fat and an increase in the amount of FFAs in the circulation, as well as increased inflammatory markers (e.g. CRP) results in inhibition of insulin via serine kinases responsible for phosphorylation of Insulin Receptor Substrate-1 (IRS-1)
This leads to a reduction in the insulin-stimulated glycogen synthesis due to reduced glucose transport
Specific factors are numerous and include…
- intra-abdominal obesity
- inactivity
- genetics
- medication
- smoking
- foetal malnutrition
- PCOS
- Aging
- etc. etc.
Name each of the following drug types based on the prefix/suffix
Gli-
- tide
- gliptin
- gliflozin
Gli- = sulphonylureas (glimepiride, glibenclamide etc.)
- tide = GLP-1 agonists (exenatide)
- gliptin = DPP-4 inhibitors (vildagliptin, sitagliptin etc.)
- gliflozin = SGLT-2 inhibitors (canagliflozin, empagliflozin etc.)
Is beta cell dysfunction reversible?
Some evidence suggests yes!
One study…
- 11 people with T2DM
- 2 months reduced food intake of 800 calories a day
- 10 retested after 3 months, 7 classed as free of diabetes
- Exhibited near normal post-prandial insulin production
What medications can cause erectile dysfunction?
Anti-hypertensive drugs - commonly thiazides and beta blockers, uncommonly CCBs, ACEIs
CNS drugs - antidepressants/tricyclics/SSRIs, tranquilizers, sedatives, analgaesics
What are some of the microvascular complications of diabetes?
Retinopathy
Nephropathy
Neuropathy
Erectile dysfunction
What are the short term complications of Diabetes?
Mainly Type I - hypoglycaemia, DKA
Mainly Type II - Hyperosmolar Hyperglycaemic State (HHS)
Sulphonylureas: side effects
Hypoglycaemia
Weight gain
GI upset, headaches
SUs should be conisdered as an add-on therapy to Metformin, or as a first line T2DM treatment in those who are underweight/cannot tolerate Metformin
What are some of the severe complications associated with DKA?
ARDS
Severe cerebral oedema
Acute gastric dilation, resulting in possible aspiration
Hypokalaemia
Where are SGLT-2 receptors found?
In the proximal convoluted tubule in the kidney. Inhibiting them means glucose cannot be reabsorbed and is passed out in the urine
What drug helps with weight loss when given as an adjunct to diet modifications? What is the common side effect?
Orlistat - inhibits the action of lipases and blocks the absorption of dietary fat
This leads to steatorrhoea, as up to 1/3 of dietary fat is excreted in faeces
What are the different types of eye pathology seen in diabetic patients?
Diabetic retinopathy
Cataracts - clouding of the lens
Glaucoma - increase in fluid pressure in the eye, leading to damage of the optic nerve
Acute hyperglycaemia - (reversible) visual blurring
What are some common precipitating factors of DKA?
Infection
Illicit drugs and alcohol
Non-adherence with treatment (main cause)
Newly diagnosed diabetes
DKA pathophysiology: the activation of stress hormones due to absolute/relative insulin deficiency results in what 4 events?
What does this lead to?
- Increased lipolysis, resulting in acidosis
- Decreased glucose utilisation, 3. Increase proteolysis, and 4. Increased glycogenolysis, all resulting in Hyperglycaemia
Lactic Acidosis: clinical and laboratory findings
Clinical
- Hyperventilation
- Mental confusion
- Stupor or coma if severe
Biochemical
- reduced bicarbonate
- raised anion gap [(Na + K) - (HCO3 + Cl)]
- glucose - variable, may often be raised
- raised phosphate
- no ketonaemia
What is MODY? What is it commonly misdiagnosed as?
Maturity Onset Diabetes in the Young
- autosomal dominant mutations resulting in impaired insulin production
- non-insulin dependant
- age of onset usually <25 years old
- multiple types, but two distinct forms (GCK (MODY2) and Transcription Factor (MODY3)). HNF1A are sensitive to SUs, and GCKs don’t require treatment
Commonly misdiagnosed as T1 or T2 DM
What are some of the longer term micro and macrovascular complications associated with Diabetes?
Macrovascular
- TIAs and stroke
- Angina, MIs and cardiac failure
- Peripheral vascular disease
Microvascular
- Diabetic retinopathy
- non-proliferative
- proliferative
- macular oedema
- Microalbuminuria, Macroalbuminuria, Endstage renal disease
- Erectile dysfunction
- Autonomic neuropathy
- Peripheral neuropathy
- Osteomyelitis
- Amputation
DKA - classical biochemical presentation
Glucose
- median around 40 mmol/L (normal should be under 6)
- anywhere from 10 to 100 (lower range known as euglycaemic ketosis)
Potassium
- usually raised above 5.5 mmol/L
- beware the low normal - K is taken into cells when insulin is given
Creatine
- Often raised
Sodium
- Often low
Lactate
- Very commonly raised
Blood ketones
- usually raised above 5 mmol/L
- blood measure is beta-hydroxybutarate
- urine is acetoacetate
Bicarbonate
- above 10 mmol/L in most severe cases
Amylase
- Very frequently rasied - does not necessarily mean pancreatitis
Name some drugs that decrease insulin resistance and reduce hepatic glucose output
Metformin
TZDs (pioglitazone)
Name some drugs that increase the release of insulin
Sulphonylureas
Incretin mimetics i.e. GLP-1 agonists
DPP-4 inhibitors
What is the immediate treatment of a hypoglycaemic episode?
consume 15-20grams of glucose or simple carbohydrate
recheck blood glucose after 15 mins. If hypoglycaemia persists, repeat above.
Once BG is under control, eat a small snack if the next planned meal is more than 1-2 hours away
If severe:
- 1 mg Glucagon injected into buttock/arm/thigh
Of all the approaches to take when trying to lose weight, what appears to be the single most effective in terms of total weight lost?
Diet
DKA - clinical presentation
Osmotic related
- Thirst and polyuria
- Dehydration
Ketone body related
- Flushing
- Vomiting
- Abdo pain and tenderness
- Breathlessness - Kussmaul’s breathing
- Ketone-smelling breath (in some)
Associated conditions
- underlying sepsis
- gastroenteritis
How is beta cell dysfunction brought about?
Initially beta cells compensate for increasing insulin resistance, however eventually their function declines over time and blood glucose levels increase
Insulin resistance leads to glucotoxicity (hyperglycaemia) and lipotoxicity (excess FFAs, TGs etc.), both of which result in a decline in beta cell function
Describe the “therapy staircase” of T2DM management
1st step - diet and exercise
2nd step - oral monotherapy
3rd step - oral combination of therapies
4th step - injectable and oral therapy
As well as leptin, name some other substances that arise from adipose tissue
- adiponectin
- CRP
- TNF alpha
- IL-6
- PAI-1
- Oestrogen
- Cortisol
- FFAs
Compare DKA and HHS in terms of the following:
- Age
- Cause
- Type of Diabetes
- Precipitant
- Mortality
- Treatment
DKA
- younger individuals
- insulin deficiency
- Type 1 DM
- Insulin omission
- <2%
- Insulin
HHS
- older individuals
- Diuretics and/or steroids. Also fizzy drinks
- Type 2 DM
- new diagnosis, infection
- 10 to 50%
- Diet/OHA/Insulin(may not require insulin)
Lactic Acidosis: treatment
Treat underlying condition - fluids and antibiotics
Withdraw offending medication if this is the cause
What is the name of the cell type that provides a lot of the same functions as macrophages but is found in fat tissue?
Adipocytes
What are the 4 types of neuropathy? Give an example of each
Peripheral - pain/loss of feeling in feet, hands, sensitivity to touch, loss of balance etc. (associated with Charcot’s foot)
Autonomic - changes in bowel/bladder function, sexual response, sweating, heart rate, BP etc.
Proximal - pain in the thighs, hips or buttocks leading to leg weakness
Focal neuropathy - sudden weakness in one nerve or group of nerves causing muscle weakness/pain
Define diabetic ketoacidosis (DKA)
DKA is a disordered metabolic state that usually occurs in the context of an absolute or relative insulin deficiency, accompanied by an increase in the counter-regulatory hormones i.e. glucagon, adrenaline, cortisol and growth hormone.
By definition, DKA can occur in both T1DM and T2DM, however more commonly occurs in T1
How are ketones monitored?
Blood ketone testing for beta-hydroxybutarate
Urinary ketone testing for acetoacetate
Explain the general concept of Insulin resistance in comparison to normal insulin activity
Normal activity - insulin binds to receptors triggering the production of glucose transport proteins and allowing glucose into the cell
Insulin resistance - receptors aren’t as responsive to insulin, meaning less glucose is brought into cells and instead remains in the blood stream
Metformin is a brilliant drug! BUT! What side effects does it have?
How are these avoided?
GI side effects (most common, seen in up to 25% of patients) - anorexia, nausea, vomiting, diarrhoea, abdo pain
Interference with Vit B12 and folic acid absorption
Lactic acidosis - 1/100,000, but can be fatal
Liver failure - also v. rare
Rash
“Start low, go slow”
