Diabetes - clinical cases Flashcards
Describe diabetes, T1D and T2D, and hyperglycaemic disorders in pregnancy
- Diabetes is a complex metabolic disorder characterized by persistent hyperglycemia.
- Blood glucose is controlled primarily by insulin action; therefore
- Diabetes results from defects in insulin secretion, its action, or both.
Type 1 and Type 2 Diabetes
### Type 1 Diabetes
- Autoimmune disease in which islet beta-cells are destroyed by the immune system.
- Disease of insulin deficiency.
Type 2 Diabetes
- Develops in insulin-resistant subjects (often obesity-associated) when islet beta-cell compensation for insulin resistance fails.
- Defects in both insulin action and insulin secretion.
Hyperglycemic Disorders in Pregnancy
- Diabetes in pregnancy: pre-existing diabetes worsened by pregnancy, as pregnancy puts physiological stress on glucose regulatory system
- Gestational diabetes mellitus (GDM)
Discuss T1D: natural history and immune destruction of islets
* Natural history of T1D:
* Born with 100% ß cell function, but have genetic predisposition to T1D
* Environmental modifiers may trigger autoimmune process
* e.g. low vitamin D, viral infections (particularly gut viruses)
* Infect islets and cause them to become stressed ∴ produce abnormally formed proteins that trigger immune system
* Autoantibodies appear in blood once autoimmune process starts
* Autoantibodies to insulin, glutamic acid decarboxylase (GAD65) and islet antigen 2 (IA2)
* Once autoantibodies are +ve, progressive destruction if islet ß cells and loss of ß cell function → diabetes
-
Immune destruction of islets.
- Normal islets have no lymphocytes accumulating around or within islets
- Early insulitis: peri-islet lymphocyte accumulation
- Progression to invasion of lymphocytes and replacement of islet tissue
- Antibodies don’t directly damage the tissue, but T cell mediated destruction causes loss of ß cells
Discuss the importance of insulin
Importance of Insulin
- Insulin binds → receptor dimer conformation changes → TK activation → phosphorylation cascade → PI3K activated → AKT phosphorylated → GLUT4 transported to plasma membrane → glucose enters
- The purpose of insulin is to regulate blood glucose concentration.
- Uptake into peripheral tissues
- Activation of glucose-metabolizing enzymes and pathways
- Inhibition of glucose-producing enzymes and pathways
- Also inhibits lipolysis
- In T1D (insulin absent), hormone-sensitive lipase in fat cells is activated
* Results in hydrolysis of stored TAGs into glycerol and fatty acids
* Glycerol available for gluconeogenesis
* ß oxidation of FAs in hepatocyte mitochondria results in excess formation of KBs → metabolic acidosis
Discuss the T1D case
- 20yo F presents with increasing thirst and passing large volumes of urine for 2-3 weeks with weight loss of ~5kg
- Weight loss from ongoing catabolism (fat and protein breakdown)
On examination:
* Sweat/sour breath noted - ketones give acetone smell on breath
* Shaky, dehydrated, afebrile
* Glycosuria drags water with it (osmotic effect) - polyuria and thirst to keep up
* BP 80/60 mmHg, HR 100 bpm, RR 30
* Hypotensive and tachycardia because of dehydration
* High respiratory rate to compensate for metabolic acidosis
* Urine dipstick: glucose +++, ketones +++
* Capillary blood glucose level high
Investigations
* Na 127 L - osmotic diuresis from glucose causes negative salt balance
* K 4.9 H
* HCO3 3 very L
* pH 7.1 L - metabolic acidosis
* Creatinine 0.29 H - pre-renal renal impairment from dehydration and hypotension causing ↓ renal perfusion
* Glucose 26.5 H
* Acetoacetate and ß hydroxybutyruate H
* Capillary ketones 5.8 H - not enough insulin to stop KB production
Discuss DKA and treatment
Diabetic ketoacidosis (DKA)
* Ketones lose a proton in normal blood pH ∴ ↑ [H+]
* H+ combines with bicarbonate (HCO3-) to form carbonic acid (H2CO3), which then breaks down into water and CO2
* ↑ H+ = ↑ CO2
* Kussmaul breathing - deep, high volume respiration to breathe off excess CO2 (respiratory compensation)
* Significant mortality (3-5%)
* Precipitants
* Infection
* MI, trauma, other major stress - activate counter-regulatory hormones (cortisol, adrenaline) THAT activate lipolysis (↑ risk
of ketosis)
* Insulin resistance may also occur with intercurrent trauma
* New cases of T1DM
* Insulin omission/non-compliance
Treatment of DKA:
* Insulin - usually IV infusion of actrapid
* IV fluid therapy
* Monitoring/correction of electrolyte imbalance (especially K+)
* Investigation/treatment of underlying cause (infection, MI, pneumonia, etc.)
List and describe the effects of DKA
Effects of DKA
* Hyperglycaemia
* Insulin deficiency: ↑ hepatic glucose output and ↓ peripheral glucose uptake
* Ketonaemia (urinary, capillary, venous)
* Insulin deficiency: ↑ hormone-sensitive lipase → ↑ FA → oxidised in liver→ KBs
* Acidosis
* KBs: strong organic acids that generate ↑ H+ at physiological pH → Kussmaul breathing to compensate
* KBs cause nausea and vomiting
* Serum sodium/hyponatraemia
* Dilution of sodium due to osmotic water movement out of cells
* Glycosuria-induced osmotic diuresis resulting in water and electrolyte loss (dehydration, thirst and polyuria)
* Elevated creatinine (probably pre-renal due to dehydration)
* Hyperkalaemia
* Metabolic acidosis ∴ exchange of H+ into cells and K+ out
* Insulin promotes transport of K+ into cells with glucose
* When insulin low, K+ doesn’t enter cells
* But, whole body potassium deficit due to:
* Increased urinary losses
* GI losses e.g. vomiting
* ∴ need to generously replace K+ to prevent cardiac arrhythmia/death
* When insulin replaced, this will rapidly push K+ back into cells as acidosis will be corrected
* K+ can plummet in bloodstream ∴ risk of arrhythmia when K+ deplete
Briefly describe T2 diabetes
- Insulin resistant patients when islet ß cell compensation (↑ insulin
production) fails
* Can be obese and have insulin resistance but not have diabetes - Progressive disease → islet ß cell function progressively worsens
- ↑ hepatic glucose production + failed suppression in fed state → hepatic insulin resistance
- Impaired glucose clearance into peripheral tissues → peripheral insulin resistance
- No insulin signalling cascade ∴ no GLUT4 transported to membrane, etc
Describe the insulin profile in T2D
-
Classic profile of insulin in blood:
- Always some fasting insulin level
- Base level of insulin needed to halt hepatic glucose production (w/o insulin, default setting of liver is to pump out
lots of glucose) - With each meal, there is meal-stimulated insulin release
-
T2D:
- Elevated fasting insulin but this doesn’t work well in suppressing hepatic glucose production
- Very poor meal-stimulated insulin secretion
- ß cells don’t respond to nutrient signals
- T2D need oral hypoglycaemic agents e.g. metformin, sulfonylurea
- Pancreatic islet ß cell volume ↓
- Pre-diabetes have increased ß cell mass to compensate for need to produce more insulin in obese
- Increased ß cell apoptosis in T2D
Describe how diabetes is diagnosed
- Random blood glucose ≥ 11.1mmol/L with symptoms
- OGTT
- Impaired fasting glucose (IFG): fasting blood glucose ≥ 7.0mmol/L
- Impaired glucose tolerance (IGT): 2h blood glucose ≥ 11.1mmol/L
- HbA1c ≥ 6.5% - indicates fraction of Hb that is glycosylated over 3 month period
* Hb turnover every ~3 months and gradually gets glycosylated
Describe diabetes in pregnancy
- Pre-existing diabetes (T1D or T2D)
- Hyperglycaemia detected in pregnancy
- Diabetic fetopathy
- Plethoric - high Hb
- ↑ adiposity because high glucose from mother crosses placenta and feeds baby too much - makes lots of fat
- Baby’s lungs mature slowly - often sluggish
- W/o glucose from mother, glucose can crash post-birth
- Higher rates of perinatal mortality
- Higher rates of congenital malformation (T2D worse outcomes than T1D)
Describe gestational diabetes mellitus
- Glucose intolerance with onset or first recognition in pregnancy
* May or may not resolve after pregnancy - Can develop at any stage along the T2D continuum, but usually in the earlier stages of disease progression
* Pregnancy makes insulin resistance worse, so ß cells have to work harder - Treatment of GDM can improve adverse outcomes
* Birth weight, LGA, macrosomia, pre-eclapmsia, SGA, NICU admissions, etc. - Risk of developing T2D is 10x higher in GDM compared to normal
- Offspring of GDM mothers have a higher prevalence of T2D/pre-diabetes and of metabolic syndrome
Describe the diagnosis of GDM
- Screen pregnant women with Oral Glucose Challenge Test at 24-28 weeks
- No 2 days of high carbohydrate diet
- Fasting overnight
* 75g OGTT - glucose cut-points are lower than for diabetes outside of pregnancy- Fasting glucose ≥ 5.1mmol/L
- 1 hour glucose ≥ 10mmol/L
- 2 hour glucose ≥ 8.5mmol/L
- High risk patients
- Asian, Indian, Aboriginal, Torres Strait islander, Pacific Islander, Maori, Middle Eastern, non-white African
- Previous GDM
- Previously elevated blood glucose level
- Maternal age ≥ 40 years
- Family history DM (1st degree relative with DM or sister with GDM)
- BMI > 35kg/m2
- Previous macrosomia (baby with birthweight > 4500g or > 90th percentile)
- PCOS
- Medications: corticosteroids, antipsychotics
Compare and contrast type 1 and type 2 diabetes
Age of onset: type 1 diabetes emerges in children, adolescents and young adults, less often in older persons;type 2 diabetes emerges usually in older adults, but prevalence in adolescents and young adults is increasing in association with increasing obesity rates
Body habitus: type 1 diabetes patients are usually lean, overweight subjects are increasingly being seen; type 2 diabetes body habitus is usually overweight or obese, but can occur in lean subjects
Endogenous insulin production: there is no or negligible endogenous insulin production in type 1 diabetes, whereas in type 2 diabetes endogenous insulin production is low, normal or high, depends on the stage of disease process
Genetic susceptibility: multiple loci are associated with increased risk in T1D, strongest associations are with HLA alleles DR3/4 and DQ8; family history is strongly associated in T2D, inheritance is polygenic, large number of gene polymorphisms that have small effect
Autoantibodies at diagnosis: There are autoantibodies at T1D diagnosis, usually islet autoantibodies e.g. islet antigen-2 Ab (IA2 Ab), glutamic acid decarboxylase Ab (GAD Ab. No autoantibodies at diagnosis in type 2 diabetes
Risk for diabetic ketoacidosis: risk for T1D, uncommon but can occur for T2D
