T1DM

Question 1

How is insulin secreted & from where?

Answer 1

Insulin secreted from beta cells of pancreatic Islets of Langerhans when they sense high glucose. Beta cells = glucose sensing + insulin secreting

1) Glucose binds to GLUT-2 transporters on beta cell membrane (low affinity transporter which only binds glucose when levels are high)

2) Glucose enters beta cells via GLUT-2 transporter & is phosphorylated to glucose-6-phosphate by hexokinase, which prevents it from leaving the cell and commits it to glycolysis. Glycolysis produces 2 net ATP per glucose.

3) ATP from glycolysis binds to ATP-dependent K+ channels, causing them to close ⇒ depolarisation of cell membrane.

4) V-G Ca2+ channels open ⇒ influx of Ca2+ causes exocytosis of insulin secretory granules.

Question 2

Which tissues are insulin sensitive?

Answer 2

Insulin-sensitive tissues = fat & muscle. They take up glucose via GLUT-4 transporters & convert it to fat & glycogen.

NOTE: Brain and erythrocytes are insulin-independent and obligately uptake glucose.

Question 3

How does glucose enter peripheral insulin-sensitive tissues?

Answer 3

Insulin promotes glucose uptake in peripheral insulin-sensitive tissues- adipose tissue and muscle.

1) Insulin binds to insulin receptor in peripheral tissues (fat & muscle).

2) Triggers Intracellular signalling cascade ⇒ GLUT 4 vesicles fuse with plasma membrane .

3) Entry of glucose into muscle and fat cells via GLUT 4 transporter. In muscle, glucose is stored as glycogen or metabolised to lactate. In adipose tissue, glucose is used as as a substrate for triglyceride synthesis.

Question 4

Why is the brain reliant on glucose?

Answer 4

Brain = major consumer of glucose INDEPENDENT of insulin, requires an uninterrupted supply of this substrate. Because FFAs (released from lipolysis) cannot cross the BBB therefore cannot undergo beta oxidation to acetyl coA → acetyl coA used in the Krebs cycle for energy production.

Question 5

Role of GLUT-2 transporters?

Answer 5

GLUT-2 = low affinity transporter in pancreatic beta cells that binds glucose when [glucose] is high. Senses blood glucose & transports glucose into beta cells to enable insulin release when blood glucose is high

Question 6

Where are GLUT-4 transporters found?

Answer 6

GLUT-4 = channel through which glucose is uptaken into peripheral tissues (muscle and adipose tissue) after insulin binds to insulin receptor on these cells.

Question 7

Effects of insulin

Answer 7

Insulin is ANABOLIC. It decreases blood glucose, AA and FA and ↑ storage of these.

• suppresses hepatic glucose output ( ↓ glycogenolysis and gluconeogenesis)
• increases glucose uptake into peripheral insulin sensitive tissues (muscle & fat- for storage as glycogen & fat) & increases glycogenesis in liver and muscle
• suppresses lipolysis and breakdown of muscle (TO SUPPRESS KETOGENESIS)

Question 8

Effects of glucagon

Answer 8

• increases hepatic glucose output (↑ gluconeogenesis and glycogenolysis)
• decreases peripheral glucose uptake
• stimulates peripheral release of gluconeogenic precursors (glycerol, AA)- by stimulating muscle breakdown and lipolysis

Question 9

General definition of diabetes

Answer 9

Group of chronic disorders characterised by inability of body to produce insulin or respond to insulin resulting in hyperglycaemia (high blood glucose levels)

Question 10

How to make a diagnosis of diabetes? (exam q)

Answer 10

Symptoms (polyuria, polydipsia, weight loss, fatigue, blurred vision) & 1 abnormal result OR 2 abnormal results needed in an asymptomatic patient:

• Raised plasma glucose:
  
  • fasting glucose ≥ 7 mmol/L
  • random plasma glucose ≥ 11.1mmol/L
• Oral glucose tolerance test (OGTT) on fasting >7 or 2h value >11.1mmol/L mol/LOGTT = after fasting, give 75g glucose drink and measure plasma glucose immediately or after 2h. Measures body’s ability to cope with carbohydrate meal. If OGTT on fasting >7 mmol/L or 2h value >11.1 mmol/L, patient has diabetes.
• HbA1c ≥ 6.5% or 48mmol/L (6.5%)
  HbA1c = glycated haemoglobin (amount of glucose attached to RBCs), reflects AVERAGE glucose levels over 3 months since RBCs have a 3 month lifespan.
• Gold standard test for diagnosing T2DM; not used in T1DM as there is a sudden onset of symptoms.

Question 11

Definition of T1DM

Answer 11

Absolute insulin deficiency due to autoimmune destruction of beta cells of pancreatic Islets of Langerhans due to a Type 4 hypersensitivity reaction.

Question 12

Aetiology

Answer 12

• Autoimmune- autoantibodies attack beta cells in pancreatic Islets of Langerhans
• Unknown, thought to be a mixture of genetic (HLA-DR3 or DLA-DR4 genes) & environmental factors (exposure to Cocksackie virus) but not fully understood.
• genetic predisposition is stronger in T2DM

Question 13

Pathophysiology

Answer 13

• Genetic abnormality in HLA genes (HLA-DR3-DQ2 or HLA-DR4-DQ8 genes) results in failure of T cell self-tolerance (elimination of T cells that recognise self antigens)
• Type IV hypersensitivity reaction - mediated by autoreactive T cells which destroy beta cells in pancreatic islets
• Autoantibodies destroy insulin-secreting beta cells in Islets of Langerhans resulting in absolute insulin deficiency. hyperglycaemia (due to continued breakdown of liver glycogen) & glycosuria (when renal threshold of 10mmol/L is reached, body eliminates glucose in urine)

Absolute insulin deficiency due to autoimmune destruction of beta cells leads to:

• hyperglycaemia (due to reduced peripheral uptake of glucose into adipose tissue & muscles via the GLUT 4 transporter, hepatic glucose output is not suppressed as glucagon high & insulin low- increased gluconeogenesis, increased glycogenolysis)
• unrestrained lipolysis and accelerated skeletal muscle breakdown ⇒ weight loss (insulin normally suppresses lipolysis & skeletal muscle breakdown)
• glycosuria (excess glucose filtered by kidneys; when renal threshold of 10mmol/L is reached kidneys cannot reabsorb glucose from filtrate) & polyuria (glucose causes osmotic diuresis)
• raised plasma ketones ⇒ ketonuria (ketones in urine)

Question 14

Explain why diabetes mellitus results in hyperglycaemia?

Answer 14

Insulin deficiency means that glucose cannot enter peripheral muscle or adipose tissue cells via insulin-dependent GLUT-4 transporters (which require insulin binding to an insulin receptor to mobilise GLUT-4 vesicles with plasma membrane). Hence not enough glucose in cells but lots in the blood causing hyperglycaemia.

Question 15

Explain why Weight loss is a symptom/sign of Diabetes Mellitus?

Answer 15

Absolute or relative insulin deficiency leads to unrestrained lipolysis (breakdown of fat) & skeletal muscle breakdown. Sudden weight loss is more common in T1DM as there is absolute insulin deficiency whereas in T2DM, there is still some insulin secretion by a depleted by beta cell mass (relative insulin deficiency & insulin resistance) so weight loss is more gradual.

• Type 1 diabetics are typically lean whereas type 2 diabetics have central obesity (a risk factor for insulin resistance).

Question 16

Explain why polyuria and glycosuria are a symptom/sign of Diabetes Mellitus?

Answer 16

Normally, all blood glucose is filtered at the glomeruli. When blood glucose levels reach 10mmol/L, maximal renal reabsorptive capacity is reached & kidneys can’t reabsorb more glucose so glucose is excreted into urine = glycosuria.

Glucose is osmotically active so draws water into urine (osmotic diuresis)- causing polyuria.

i.e. excess glucose & water are excreted in urine.

Question 17

Explain why polydipsia is a symptom/sign of Diabetes Mellitus?

Answer 17

Excess water excretion (polyuria) leaves body feeling dehydrated so thirst centre in hypothalamus is stimulated.

Question 18

Epidemiology

Answer 18

• 10% of diabetes = T1DM
• Patient is younger < 30 years. Often presents in childhood- 5-15 years but can present at any age.
• Higher prevalence in those of Northern European ancestry, especially Finnish

Question 19

Risk factors & associations

Answer 19

• Northern European- especially Finnish
• Family history
• Genetic predispositions in >90%- HLA-DR3-DQ2 or HLA-DR4-DQ8 genes (HLA (type of MHC needed for antigen presentation to T cells) genes are a family of genes on chromosome 6 that encode HLA proteins. HLA proteins present antigens to T cells. HLA genes are a phenotype- you either have them or don’t)
• Exposure to specific virus e.g. Cocksackie
• Associated with other autoimmune diseases (autoimmune hyperthyroidism-Grave’s, autoimmune hypothyroidism-Hashimoto’s thyroiditis, Coeliac disease, Addison’s disease (primary adrenal insufficiency), pernicious anaemia)

Question 20

Signs and symptoms

Answer 20

90% of beta cells destroyed before symptoms appear.

T1DM patient is leaner than T2DM patient who typically has central obesity- but both can present with weight loss.

Typically manifests in childhood. Commonly presents with DKA in newly diagnosed.

Classic triad = polyuria, polydipsia, sudden unexplained weight loss +/ ketosis (raised ketones in blood or urine)

Symptoms

• polyuria (increased urination) and nocturia- when blood glucose reaches 10mmol/L kidneys cannot reabsorb any more from filtrate so excess glucose is excreted in urine. Glucose is osmotically active causing water to be excreted in urine (osmotic diuresis).
• polydipsia (increased thirst due to dehydration)
• weight loss (patient is in CATABOLIC STATE due to insulin deficiency- due to accelerated breakdown of skeletal muscle (proteolysis) & lipolysis)
• polyphagia (hunger)- (lack of usable energy source, lots of glucose in blood but this can’t enter cells via insulin-dependent GLUT 4 transporter)
• fatigue- due to losing glucose in urine, cells don’t have usable energy source (lots of glucose in blood but this can’t enter cells via insulin-dependent GLUT 4 transporter)
• Blurred vision (reduced visual acuity because of glucose and therefore water uptake into the lens)
• Recurrent infections- vaginal candidadis, chest/skin infections

Signs

• glycosuria (glucose in urine due to increased urinary losses. Above 10mmol/L glucose in blood, kidneys can’t reabsorb glucose from filtrate)
• Ketones in urine

Question 21

Which features are suggestive of type 1 diabetes as opposed to type 2?

Answer 21

• onset in childhood/adolescence (typically presents 5-15 years)
• lean body (whereas type 2 diabetics have central obesity)
• short history of severe symptoms
• Classic triad: polyuria, polydipsia, sudden unexplained weight loss
• prone to ketoacidosis (although this can rarely occur with T2DM)

Question 22

What are the clinical features of newly diagnosed T1DM?

Answer 22

• short history of severe symptoms
• weight loss
• ketones in urine (do urine dipstick)

Any 2 of these 3 features indicate type 1 diabetes.

Question 23

Diagnosis

Answer 23

In symptomatic patient: symptoms of DM (fatigue, polyuria, polydipsia, blurred vision, polyphagia, sudden weight loss) AND

Raised plasma glucose detected once- fasting plasma glucose ≥ 7mmol/L or random plasma glucose ≥ 11.1 mmol

In asymptomatic patient, patient must show raised glucose on 2 separate occasions:

Fasting plasma glucose ≥ 7mmol/L OR random plasma glucose ≥ 11.1 mmol OR

OGTT fasting value ≥7mmol/L and 2 hr value ≥ 11.1mmol/L

Question 24

Treatment

Answer 24

Monitoring

• Monitoring blood glucose levels on waking, at each meal and before bed
• Monitoring dietary carbohydrate intake

Long term management

• Subcutaneous BASAL BOLUS insulin regimen
  
  • combination of background, long-acting insulin (BASAL) injected once daily & short acting insulin (BOLUS) injected 30 mins before meals
  • Example of long-acting insulin = insulin detemir
  • Example of short-acting insulin = insulin lispro/ insulin aspart

Question 25

Complication of insulin therapy? (3)

Answer 25

• Lipodystrophy/lipohypertrophy- subcutaneous fat hardens so patient does not absorb insulin properly. To counteract this site of insulin injection should be cycled.
• Hypoglycaemia
• Hypokalaemia- because insulin drives K+ into cells via the Na+/K+ ATPase pump. Hypokalemia can lead to fatal arrythmias.

Question 26

What electrolyte imbalance are type 1 diabetics at risk of?

Answer 26

When treatment with insulin starts, patients can develop severehypokalaemia (low serum potassium) very quickly as insulin transports K+ into cells via the Na+/K+ ATPase pump so there is less K+ in the serum, this can lead to fatalarrhythmias.

Question 27

Complications of T1DM

Answer 27

Failure to treat with insulin therapy leads to diabetic ketoacidosis- a medical emergency:

Low insulin results in HIGH circulating glucagon (no paracrine feedback between alpha cells in Islets of Langerhans) ⇒ unrestrained lipolysis releasing FFA ⇒ increased FFA oxidation to acetyl coA ⇒ acidic ketone bodies (acetoacetate, beta hydroxybutyrate, acetone) produced ⇒ acidosis (blood pH < 7.35)

Question 28

General complications of diabetes

Answer 28

Chronic exposure to hyperglycaemia damages endothelium resulting in vascular complications. Also supresses immune system, resulting in recurrent opportunistic infections e.g. vaginal candidiasis.

Microvascular

• retinopathy- causes vision loss
• nephropathy (kidney disease) especially glomerulosclerosis- leading cause of end-stage renal disease
• peripheral neuropathy

Macrovascular

• peripheral ischemia causes ulcers and ‘diabetic foot’ (gangrene)- peripheral vascular disease
• ischaemic stroke
• coronary artery disease/ischeamic heart disease- can cause unstable angina, NSTEMI or STEMI

Question 29

What do C-peptide levels indicate?

Answer 29

C-peptide is cleaved from proinsulin when endogenous insulin is produced. If C-peptide is high, it indicates T2DM as some insulin still present. If C-peptide is low, it indicates T1DM as T1 diabetics have absolute insulin deficiency.