Diabetes Flashcards

Question

What is Leprechaunism (Donohue Syndrome)?

Answer 1

- Rare autosomal genetic trait involving mutations in the insulin receptor - Severe insulin resistance and developmental abnormalities e.g. growth retardation, abscence of SC fat, caused by defects in insulin binding or insulin receptor signalling

Answer 2

- Rare autosomal recessive trait which presents with severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia - Other clinical features include developmental abnormalities and acanthosis nigricans - Patients have fasting hypoglycaemia (due to hyperinsulinaemia) - Patients are very prone to diabetic ketoacidosis - Severe cases linked to mutations in the insulin receptor that reduce sensitivity

Answer 3

- Risk factors can be reviewed by heath providers - If at risk, blood glucose levels should be checked for pre-diabetes/diabetes - The hyperinsulinemic-euglycemic clamp is the gold standard for the measurement of insulin sensitivity

Answer 4

- Overweight - 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

Answer 5

Results from a combination of insulin resistance and less severe insulin deficiency

Answer 6

- Accounts for 90-95% of diabetes - Greatest prevalence is in lower and middle income countries - T2DM is thought to be polygenic - contribution of environmental influences, usually the development of insulin resistance and obesity

Answer 7

- Usually occurs later in life (> 45 years) - β-cell function declines with age - Genetics - polygenetic disease with 400 genetic variants identified to date ('common complex disease') - Ethnicity - individuals of South Asian, African and Afro-Carribean descent are at greater risk

Answer 8

- Obesity - 9 out of 10 people with T2DM are overweight/obese (BMI of 25 or above) - Diet - high dietary fat, particularly saturated fat, red and processed meat, fried food, increased intake of white rice and sugary drinks - Physical inactivity and sedentary behaviours

Answer 9

- Autoimmune destruction of the beta-cell does not occur - Patients do not have any other known cause for their diabetes - Ranges from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance

Answer 10

- Insulin action is diminished in T2DM through the development of insulin resistance - Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes and adipocytes - Increased tyrosine kinase activity in liver, fat and skeletal muscle cells → decreased activation of downstream proteins → decreased expression of GLUT channels → decreased cellular glucose uptake - Insulin resistance occurs in genetically susceptible individuals due to modifiable lifestyle related factors - Insulin resistance occurs when fat can no longer be stored in subcutaneous adipose tissue causing spill over of FFA to the viscera, which explains why not everyone with obesity develops diabetes - People with 'healthy' obesity are able to safely store lots of fat, whereas others have a low fat storage threshold and these are the people who develop T2DM

Answer 11

- As insulin resistance develops, the body's response is to increase insulin secretion and so early T2DM is often associated with insulin hypersecretion - An early sign is the loss of the first phase of the normal biphasic insulin secretion - The compensatory increased insulin is still insufficient to restore glucose homeostasis, so hyperglycaemia persists - Hyperglycaemia and the increased levels of FFAs and adipokines are toxic to the β-cells - The hyperglycaemia and lipid excess damage the β-cells → decrease in insulin production - People with increased genetic risk of T2DM have β-cells which are less able to cope with the lipotoxicity and glucotoxicity - another explanation for why not all obese people are diabetic

Answer 12

- gradual onset, majority of patients are asymptomatic - symptoms of complications may be first clinical sign of disease - when symptomatic → thirst, polyuria, blurred vision, weight loss, recurrent infections and tiredness - **acanthosis nigricans** - insulin-driven epithelial growth seen in hyperinsulinemia states

Answer 13

**Symptomatic patients** can be diagnosed on the basis of one positive result (but may wish to perform a second test to confirm) In **asymptomatic patients**, the diagnosis of diabetes should never be based on a single abnormal HbA1c or fasting plasma glucose level. A last one additional abnormal HbA1c or plasma glucose level is essential. **Other:** - BP - Ketones - if random blood glucose > 15mM - cholesterol - pancreatic autoantibodies

Answer 14

- Metformin + lifestyle management first line in all patients with T2DM - Diabetic patients with atherosclerotic CVD (e.g. previous MI) should be given metformin + GLP-1 receptor antagonist - Diabetic patients with heart failure or chronic kidney disease should be given metformin + an SGLT2i as first line (GLP-1 receptor antagonist second line) - Others: DPP4i, SUs, TZDs,

Answer 15

- A target of HbA1c target of 7.0% (53 mmol/mol) among people with type 2 diabetes is reasonable to reduce the risk of microvascular and macrovascular disease - Targets should be set with individuals in order to balance benefits with harms, in particular hypoglycaemia and weight gain

Answer 16

Weight loss in people BMI >30 reduces risk of developing T2DM significantly

Answer 17

Early onset (usually before age 25) of non-insulin dependent diabetes

Answer 18

- Single gene mutation (monogenetic) which is dominantly affected and predominantly affects β-cell function - Most common form of monogenetic diabetes

Answer 19

- Common clinical features to both type 1 and type 2 diabetes - Genetic defective glucose sensing in the pancreas and/or loss of insulin secretion - At least 150 different mutations (6 genes) have been identified - 3 types of mutation: - **Glucokinase (14%)** - Glucokinase activity impaired, resulting in a glucose sensing defect - blood glucose threshold for insulin secretion is increased - Everything else about the β-cell is normal - **Transcription factors (75%)** - The main transcription factor mutations are HNF-1⍺, HNF-1β, HNF-4⍺ - Play key roles in pancreas foetal development and neogenesis - Also regulate β-cell differentiation and function - glycolytic flux, expression of GLUT2 transports, insulin secretion etc. - **MODY X (11%)** - Unknown causative gene

Answer 20

**Glucokinase Mutations:** - onset at birth - stable hyperglycaemia **Transcription factor mutations:** - adolescence/ Young adult onset - progressive hyperglycaemia

Answer 21

**Oral Glucose Tolerance Test:** - Patients with a glucokinase mutation will have a high fasting blood glucose (~7 mmol) but bring their glucose down very well when given oral challenge - Patients with a transcription factor mutation will have a normal fasting blood glucose but don't respond well to glucose challenge **Genetic Screening:** - Can be used to confirm type of mutation

Answer 22

**Glucokinase Mutations:** Not associated with an increased risk of microvascular disease and can be managed with diet alone **Transcription Factor Mutations:** - Diet + treatment with insulin or sulphonylureas - Respond very well to sulphonylureas (~4 x more sensitive than patients with T2DM) as MODY patients usually have β-cell function available - Patients previously misdiagnosed as T1DM who are on insulin can safely switch to low dose SUs - Complications frequent

Answer 23

Rare form of monogenic diabetes much of which is caused by mutations in the glucose sensing mechanism e.g. in the ATP sensitive K channel

Answer 24

- Monogenic mutation - Many genes responsible, 35 genes can explain up to 82% of neonatal diabetes

Answer 25

- The KATP channel consists of: - An inward rectifier (pore) subunit (KIR) - Kir6 - A sulphonylurea receptor (regulatory subunit) - SUR1 - Both are required to form a functional channel - In humans, Kir6.2 mutations can lead to neonatal diabetes - Due to constitutively activated KATP channels or increase in KATP numbers

Answer 26

- Diabetes diagnosed < 6 months (chance of T1DM at this age is >1%) - Polydipsia, polyuria - Dehydration - DKA

Answer 27

Blood glucose

Answer 28

- In many of these patients the β-cells are responsive to sulphonylureas which inhibit KATP - recover euglycaemia fairly quickly - Patients previously misdiagnosed as T1DM who are on insulin can safely switch to high dose SUs

Answer 29

- Some Kir6.2 or SUR1 mutations lead to congenital hyperinsulinism - Congenital hyperinsulinism is characterised by inappropriate and unregulated insulin secretion, which results in severe, persistent hypoglycemia in newborn babies, infants, and children - Management: diazoxide stimulates KATP so can help inhibit insulin secretion if channels are still getting to the membrane

Answer 30

Cystic fibrosis DIDMOAD or Wolfram syndrome Barget-Biedl Syndrome Autoimmune conditions such as: **Relatively common** - Thyroid disease - Coeliac disease - Pernicious anaemia - Addison's disease - IgA deficiency **Rare/very rare** - Autoimmune polyglandular syndromes - AIRE mutations - IPEX syndrome

Answer 31

damage to the retina

Answer 32

- Early stages of retinopathy, rated from mild-severe (with severe being last stage before proliferative retinopathy) - Damage to the wall of small vessels cause microaneurysms and then intraretinal haemorrhages (dot, blot, flame) - Leaked blood leaves behind hard exudates (lipid breakdown products) - Micro-infarcts (ischaemia) due to occluded vessels cause cotton wool spots - Laser therapy in severe NPDR may help prevent long-term visual loss

Answer 33

- Blockage of blood vessels leads to areas of non-perfusion and ischaemia - Ischaemia in these areas cause the release of vascular growth factors e.g. VEGF which cause new blood vessels to grow in the retina (neovascularisation) - IRMA - abnormalities of blood vessels/precursor to neovascularisation but blood vessels are patent (not leaking) - Vitreous haemorrhage can occur of the new blood vessels leading to sudden loss of vision - Lifetime risk of developing proliferative retinopathy in a diabetic patient is ~35%

Answer 34

- Laser - panretinal photocoagulation - Reduces oxygen requirement of the retina so reduces the ischaemia that is driving the retinopathy - Vitrectomy in a vitreal haemorrhage

Answer 35

disease affecting the macula

Answer 36

- Macular oedema involves clinically significant retinal thickening and oedema involving the macula, hard exudates and macula ischaemia - May occur in all stages of NPDR and PDR

Answer 37

Fundus photo Optical Coherence Tomography

Answer 38

Intravitreal anti-VEGF (anti-vascular endothelial growth factor)

Answer 39

- **Cataract** - clouding of the lens, develops earlier in people with diabetes - Increased sugar contents in lens - Conversion of glucose to sortbitol - Altered osmotic gradients → swelling and fibre disruption - **Glaucoma** - increase in fluid pressure in the eye leading to optic nerve damage, 2x more common in diabetes - Rubeotic glaucoma - new vessel formation forming angle (rare and late complication) - Acute hyperglycaemia causes **visual blurring** (reversible)

Answer 40

Progressive kidney disease caused by damage to the capillaries in the glomeruli

Answer 41

- It is characterised by proteinuria and diffuse scarring of the glomeruli - Also known as Kimmelsteil-Wilson Syndrome or Nodular Glomerulosclerosis

Answer 42

1. If ACR <30 or PCR <50 = microalbuminuria 1. Repeat twice as false positive readings are common 2. Established microalbuminuria if 2/3 positive 3. Microalbuminuria will not show up as protein++ on urine dipstick 2. If ACR >30 or PCR >50 = proteinuria (overt nephropathy) 1. Repeat on EMU 2. Proteinuria will show up on a urine dipstick

Answer 43

- Presence of microalbuminuria requires treatment with ACEi/ARB - Dilate renal arterioles so decrease filtration pressure → decrease proteinuria (also decreases GFR - allow up to 20% deterioration in GFR) - Diabetic patients with microalbuminuria should be started on an SGLT2i (irrespective of HBA1c) - Manage other vascular complications e.g. discourage smoking, assess fasting lipid profile, screen for cardiovascular disease and hypertension - Target BP is <140/80 mmHg for all patients with diabetes - Aggressive treatment of blood pressure, glycaemia and use of ACEi/AGLT2i can prevent decline in renal function

Answer 44

Good glycaemic control (53mmol/mol) in patients with T2DM should be maintained to reduce the risk of developing diabetic neuropathy (depending on age and other risk factors

Answer 45

- Development of hypertension - Relentless decline in renal function - Reduction in GFR of 1ml/min/month if untreated - Accelerated vascular disease - Microalbuminuria is a sign of damage to the glomeruli causing protein leak - Marker of 'high risk' of other vascular problems

Answer 46

pain/loss of feeling in feet and hands in a distal symmetrical or sensorimotor neuropathy

Answer 47

- Increased length of diabetes - Poor glycaemic control - More common in T1DM - High cholesterol/lipids - Smoking - Alcohol - Genetics - Mechanical injury

Answer 48

- Numbness/insensitivity - Tingling/burning - Sharp pains or cramps - Sensitivity to touch - Loss of balance and coordination

Answer 49

Painless trauma Charcot foot Foot ulcer Claw foot and callus formation Argyll Robertson pupil

Answer 50

- Complication of severe neuropathy that occurs in a well-perfused foot **Pathophysiology** 1. Acute onset of a hot, swollen foot +/- pain 2. Bony destruction - if treatment is delayed, the foot can become deformed as bone is destroyed 3. Radiological consolidation and stabilisation - after 6-12 months

Answer 51

MRI can differentiate between Charcot foot and infection

Answer 52

- Aim is to prevent/minimise bony destruction by keeping pressure off the foot - non-weight bearing, total contact cast or aircast boot - Any resulting deformity can alter the pressure distribution across the foot and predisposes the foot to future ulceration

Answer 53

- Small bilateral pupils that do not constrict when exposed to bright light but do constrict when focused on a nearby object - Highly specific sign of neurosyphilis but may also be a sign of diabetic neuropathy

Answer 54

- Sensation unimpaired, foot pulses present - Requires annual screening by health-care professional

Answer 55

- Sensation unimpaired, foot pulses present OR - Inability to self-care for feet - Requires annual assessment by podiatrist

Answer 56

- Sensation unimpaired, foot pulses present with skin callus or foot deformity OR - Sensation impaired, foot pulses absent OR - Previous foot ulcer/amputation - Requires annual assessment by podiatrist

Answer 57

- Current foot ulcer, gangrene, critical ischaemia, infection, or unexplained red, hot swollen foot - Requires urgent referral to specialist team

Answer 58

- Amitriptyline, duloxetine, gabapentin or pregabalin - Topical capsaicin cream can be used for localised neuropathic pain in patients who do not want or can't tolerate oral treatments

Answer 59

- Affects the nerves regulating heart rate and blood pressure as well as control of internal organs such as those involved in GI motility, respiratory function, urination, sexual function and vision - Usually in those with a long history of very poor diabetes control - Can be intractable - recurrent admissions with vomiting or collapse

Answer 60

- Improved glycaemic control - Diet - smaller more frequent meals, low fat, low in fiber, if severe may need liquid meals - Promotility dugs e.g. metoclopramide - Anti-nausea medications e.g. prochlorperazine, and serotonin antagonists e.g. ondansetron - Analgeisia: NSAIDs, low dose tricyclic antidepressants, gabapentin, tramadol and fentanyl for abdominal pain - Severe cases: consider botulinum toxin, gastric pacemaker

Answer 61

- Caused by damage to the nerves of the lumbosacral plexus - Involves pain in the buttocks, hips, thighs or legs which is then followed by variable weakness in the proximal muscles of the lower limbs and then muscle wasting - Rare, more commonly in elderly T2DM - Often associated with weight loss

Answer 62

e.g. sudden weakness in one nerve or a group of nerves causing muscle weakness or pain e.g. carpal tunnel syndrome, cranial nerve palsy

Answer 63

- Occurs when more insulin is injected than is needed - Irregular eating habits, unusual exertion and alcohol excess may precipitate a hypoglycaemic episode - Insulin errors and variation in insulin absorption e.g. as a result of lipohypertrophy are also important - The times of greatest risk are before meals, during the night and during or after exercise

Answer 64

- Pallor - Sweating - Tremor - Palpitations - Confusion - Nausea - Hunger - Cognitive impairment - Coma

Answer 65

- 15-20g oral glucose - Severe hypoglycaemia (confusion, coma) is managed with IM glucagon or IV glucose

Answer 66

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 e.g. glucagon, adrenaline, cortisol and growth hormone

Answer 67

- Serious complication of type 1 diabetes and, much less commonly, of type 2 diabetes **Insulin deficiency** - Initial presentation of unknown diabetes - Non-adherence to insulin/poor self-management **Increased insulin demand** - Infections: pneumonia, UTIs, cellulitis - Inflammatory: pancreatitis, cholecystitis - Intoxication: alcohol, cocaine, salicylate, methanol - Infarction: acute MI, stroke - Iatrogenic: steroids, surgery

Answer 68

- Formed in liver mitochondria (mainly acetoacetate and 3 hydroxybutyrate) from acetyl-CoA (which is from beta oxidation of fats) - Diffuse into the bloodstream and to peripheral tissues - Ketones are important molecules of energy metabolism for heart muscle and renal cortex - Converted back into acetyl-CoA, which enters TCA cycle - If supply of pyruvate/oxalonacetate is limited (e.g. if glycolysis is reduced, limiting glucose) the excess acetyl-CoA is diverted to ketones

Answer 69

- Insulin normally inhibits lipolysis, reducing risk of ketone body overload - In T1DM, DKA is a danger if insulin supplementation is missed and hyperglycaemia ensues - amount of glucose taken up from the blood into tissues and amount of glycolysis will reduce, so body switches to fatty acid oxidation - DKA is more rare in T2DM where there is still some inhibition of lipolysis, but can occur as insulin resistance and deficiency increases, alongside increase in glucagon - Ketoacidosis can also occur in starvation - oxaloacetate is consumed for gluconeogenesis and when glucose is not available fatty acids are oxidised to provide energy; the excess acetyl-CoA will be converted into ketones

Answer 70

- Excessive accumulation of ketone bodies can lead to acidosis - High glucose excretion creates an osmotic diuresis, resulting in electrolyte loss and dehydration; this decreases renal function and exacerbates acidosis - Can lead to coma, death

Answer 71

- thirst - polyuria - dehydration - flushed - vomiting - abdominal pain - increased respiratory rate - Kussmaul’s respiration → deep, rapid breathing pattern associated with severe metabolic acidosis - distinctive smell on breath (not present in all individuals) - associated with underlying sepsis and gastroenteritis

Answer 72

Diagnosis is confirmed by demonstrating hyperglycaemia with ketonaemia or heavy ketonuria, and acidosis: - Ketonaemia ≳3 mmol/L, or significant ketouria (≳2 on standard urine stick) - Blood glucose > 11.0/L or known DM - Euglycaemic DKA is possible if a patient has given themselves some insulin, but not enough to switch off ketogenesis - Euglycaemic DKA is also a rare complication of SGLT2i - Bicarbonate <15 mmol/L and/or venous pH <7.3 **Other biochemistry** - Potassium often >5.5 mmol/L but drops as soon has insulin is given - can cause hypokalaemia - Insulin promotes co-transport of potassium along with glucose into cells - Creatinine often raised - Sodium often low or low end of normal - Amylase often raised (rarely pancreatitis, origin can be salivery) - White cell count raised (median 25) - does not always equate infection, sign of inflammatory response

Answer 73

**Replace fluid losses** - 1000mL NaCl 0.9% in the first hour - 20000mL NaCl by end of hour 2 - 30000mL NaCl by end of hour 4 - Once blood-glucose concentration falls below 14 mmol/litre, IV glucose 10% should be given in addition to the sodium chloride 0.9% infusion **Replace electrolyte losses** - NaCl 0.9% as above - IV Potassium - Phosphate rarely replaced

Answer 74

**Restoration of acid-base balance** - Bicarbonate rarely replaced as once the circulating volume is restored the metabolic acidosis is rapidly compensated **Insulin replacement** - IV insulin 0.1 units/kg per hour to suppress ketogenesis, lower the glucose and correct the electrolyte disturbance - Continue 'usual' SC daily basal insulin - Continue IV insulin until ketoacidosis has been resolved; to prevent hypoglycaemia give 10% glucose IV alongside the 0.9% NaCl once blood-glucose concentration falls below 14 mmol/L

Answer 75

**Monitoring** - Monitor blood-ketone and blood-glucose concentrations hourly - Blood gas and electrolytes every 2-4 hours **Other measures** - Seek underlying cause e.g. infection if suspected - Patient may aspirate vomit so consider NG tube - Dehydration, increased blood viscosity and coagulability of DKA increase risk of thromboembolism - all patients should receive prophylactic LMWH

Answer 76

**Prevention of recurrence** - Education and support before discharge - Provide patient with ketone meter - Arrange DSN follow-up and inform GP

Answer 77

- Cerebral oedema - mostly happens in children/YAs - Hypokalaemia can cause cardiac arrest and paralytic ileus - Aspiration pneumonia - ARDS

Answer 78

Severe hyperglycaemia without significant ketosis; the characteristic metabolic emergency of T2DM

Answer 79

- People present in middle or later life, often with previously undiagnosed diabetes - Common precipitating factors include consumption of glucose-rich fluids, concurrent medication such as thiazide diuretics or steroids, and intercurrent illness

Answer 80

- Pathophysiology is similar to DKA, but HHS, there are still small amounts of insulin being secreted by the pancreas - This is sufficient to prevent DKA by suppressing lipolysis and, in turn, ketogenesis, but level is not high enough to lower blood glucose to a safe level - HHS is characterized by symptoms of marked dehydration (and loss of electrolytes) due to the predominating hyperglycaemia and osmotic diuresis (hyperosmolar urine)

Answer 81

- Dehydration due to polyuria - Polydipsia - Nausea and vomiting - Stupor/coma - Impaired consciousness is directly related to degree of osmolarity

Answer 82

HHS is characterised by: - Profound hyperglycaemia (glucose >33.3mmol/L) - Hyperosmolality (serum osmolarity >320mmol/kg) - Can be measured directly or calculated as (2 x Na+) + glucose + urea - Volume depletion in the absence of ketoacidosis (pH >7.3 and bicarbonate >15mmol/L) **Other features** - Significant renal impairment - Sodium often high normal or raised

Answer 83

- Assess severity of dehydration and use 0.9% saline for fluid replacement WITHOUT insulin - fluids alone will reduce osmolarity - Be aware of increased risk of fluid overload - Sodium - avoid rapid fluctuations, if dropping too quickly consider 0.45% saline - Monitor and chart BG, osmolarity and sodium - Start low dose IV insulin only if significant ketones (>1) or BG falling at a slow rate - Comorbidities more likely - Screen for vascular event e.g. silent MI - LMWH for all patients (unless contraindicated) - High risk of feet complications

Answer 84

Metabolic acidosis caused by increased production of ketone bodies with normal or low glucose levels resulting from the combined effects of alcohol and starvation on glucose metabolism

Answer 85

- Most commonly occurs in malnourished individuals with AUD - Associated with recent episodes of binge drinking complicated by poor food intake, dehydration, and vomiting

Answer 86

Accumulation of ketone bodies as a result of: - Depleted glycogen stores in the liver from malnutrition/decreased carbohydrate intake - Increased lipolysis and FFA release - Volume depletion from e.g. vomiting, poor oral fluid intake which impairs renal perfusion and decreases ability to excrete ketone bodies

Answer 87

- Nausea, vomiting - Abdominal pain - Increased respiratory rate - Dehydration

Answer 88

- Ketonaemia >3 mmol/L, or significant ketonuria (2+ on standard urine stick) - Bicarbonate usually <15 mmol/L or venous pH <7.3 in severe cases - Glucose usually normal, may be low

Answer 89

- IV pabrinex - high dose vitamins including thiamine to prevent Wernicke encephalopathy - IV fluid - 5% dextrose in 0.9% NaCl - IV anti-emetics - Insulin may be required on occasion **Further management** - Address alcohol dependency