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Endocrinolgy > Diabetes > Flashcards

Diabetes Flashcards

1
Q

What is diabetes mellitus?

A

An heterogenous group of conditions characterised by
- HYPERGLYCAEMIA and other abnormalities
- secondary to INSUFFICIENT INSULIN ACTION
And a risk factor for complications

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2
Q

How can diabetes be diagnosed?

A

– Typical symptoms
– Unequivocally high blood glucose concentration above 11.1 mmol/l twice
In the absence of symptoms:
• Abnormal blood glucose • Abnormally high amount of glucose on circulating proteins: • Glycated haemoglobin or HbA1c

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3
Q

What are the standard diagnostic criteria for diabetes?

A

• Symptoms and random plasma glucose >11 mmol/l
• Asymptomatic and: HbA1c ≥ 48 mmol/mol on 2 occasions Fasting plasma glucose ≥7 mmol/l and/or 2 hr post 75 g glucose load ≥11.1 mmol/l p g g ≥ mm on 2 separate occasions
High risk for diabetes, HbA1c 6.1

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4
Q

What is type 1 diabetes and what subtypes are there?

A

Beta cell destruction causes insulin dependency

  • type a - autoimmune - 70%
  • type b - idiopathic - no markers of autoimmunity
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5
Q

What is type 2 diabetes?

A

insulin resistance + some insulin deficiency OR insulin deficiency + som insulin resistance

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6
Q

What are the ‘specific’ types of insulin defficiency?

A
  • Genetic defects insulin secretion
  • Genetic defects of insulin action
  • Secondary to exocrine pancreatic disease
  • Secondary to endocrine disorders
  • Secondary to drugs or toxins
  • Secondary to infection
  • Uncommon forms of immune-mediated diabetes
  • Other genetic syndromes sometimes associated with diabetes
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7
Q

What is gestational diabetes?

A

Diagnosed in pregnancy - different diagnostic criteria
- sig. Majority - have a type which will go away after childbirth because it is being driven by pregnancy insulin resistance

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8
Q

What diseases of the exocrine pancreas can cause diabetes?

A 
Cystic fibrosis 
Haemochromatosis 
Pacreatitis 
Fibrocalculous pancreopathy 
Trauma/pancreatectomy
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9
Q

Diabetes can be secondary to which endocrine disease?

A 
Cushing's 
Acromegaly 
Phaeochromocytoma 
Glucagonoma 
Hyperthryoidism 
Somotostatinoma…..
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10
Q

What drugs and chemicals can cause diabetes?

A 
Glucocorticoids
nicotinic acid
thryoxine
thiazides
α and β adrenergic agonists
pentamidine
Interferon α…
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11
Q

What infections can cause diabetes?

A

Congenital rubella

Cytomegalovirus

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12
Q

What are the Uncommon immune mediated causes of diabetes?

A

Insulin autoimmune syndrome
Anti-insulin receptor antibodies
“Stiff man” syndrome…

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13
Q

What are the Genetic defects of β cell function that cause diabetes?

A

Neonatal diabetes : transient and permanent MODY 1 – 7 HNF4α Chr 20 glucokinase Chr 7 HNF1α Chr 12 IPF-1 HNF 1β HNF-1β Neuro D1 CarbxylEsterLipase gene Mitochondrial DNA 3243 mutation (MIDD; MELAS) deafness, short stature

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14
Q

What are the Genetic defects in insulin action that cause diabetes?

A

Type a insulin resistance
Leprechaunism
Rabson-Meldenhall syndrome
Lipoatrophic diabetes

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15
Q

What are the Other genetic syndromes that can cause diabetes?

A

Down’s; Friedrich’s ataxia, Huntington’s; Lawrence-Moon-Biedl; myotonic dystrophy; porphyria; Prader Willi; Turner’s. Wolfram’s…..

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16
Q

What are the clinical manifestations of type 1 diabetes?

A 
insulin deficient
ketosis prone
autoimmune
HLA markers
onset peak in adolescence 
weight loss
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17
Q

What are the clinical manifestations of type 2 diabetes?

A

insulin resistant & deficient
not ketosis prone
Polygenic • S Asians > Aficans & Caribbeans > Europids Increases with ageing - younger in ethnic groups with high prevalence
associated with obesity

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18
Q

Define glycolysis?

A

GLYCOLYSIS - pathway for breakdown of glucose to pyruvate

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19
Q

Define gluconeogenesis

A

GLUCONEOGENESIS - neo-formation of glucose from non-carbohydrate precursors

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20
Q

What do you know about the Islets of Langerhans?

A
  • The islets comprise 1-2% of the pancreas. There are 250,000 islets in a human pancreas
  • The cellular composition is:
  • 70% B cells making insulin
  • 25% A cells making glucagon
  • 5% D cells making somatostatin
  • The B cells tend to be at the core of the islet.
  • This islet is an endocrine unit, showing paracrine regulation of hormone secretion
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21
Q

Are beta cells actively innervated?

Roughly how many beta cells are there in the pancreas?

A

Yes

3000-4000

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22
Q

What factors regulate insulin secretion?

A

Glucose is the key regulator of insulin secretion
• Many other factors can also influence secretion.
- neural control plays a small role
• Enteroinsular axis hormones esp. Gastric Inhibitory Peptide (GIP), and Glucagon - Like Peptide-1 (GLP-1) potentiate glucose stimulated secretion and may promote B cell proliferation.
• Adrenaline inhibits insulin secretion.

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23
Q

What are Insulinomas?

A

Insulin Secreting tumours
• Rare
• Drive down blood glucose levels through uncontrolled secretion of insulin

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24
Q

What are the treatments of Insulinomas?

A

• Treat by surgery or with Diazoxide which opens K-ATP channels on B cells and inhibits secretion

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25
Q

What are the B cell defects in Type 2 diabetes?

A

• B cell mass is reduced by 20-40%, A and D cells are normal.
• Insulin response to glucose may be reduced by 80%, suggesting a functional defect.
• This defect can be overcome by use of insulin releasing sulphonlyureas, suggesting that it is glucose sensing mechanisms
Islet amyloid polypeptide (IAPP) is deposited outside the B cells. Is this cause or effect?
• Glucotoxicity?
• Lipotoxicity?

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26
Q

What is the precursor and what are the products of this precursor?

A

• It is synthesised via a single chain precursor, proglucagon. Products include GLP 1 and GLP 2 as well as glucagon.

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27
Q

What is the main stimulus for glucagon secretion and what type of receptor does it act on and where?

A
  • Fall in blood glucose is the major stimulus to glucagon secretion.
    • Glucagon acts via receptors linked to adenylate cyclase to break down glycogen to glucose, especially in the liver.
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28
Q

What is insulin’s mechanism of action?

A
  • Insulin binds the receptor
  • The receptor is autophosphorylated
  • IR catalyses tyrosine phosphorylation of insulin receptor substrates IRS
  • IRS-1 activates several signalling pathways,
  • the PI(3)K (phosphatidyl inositol 3 OH kinase) pathway is involved in protein carbohydrate and fat metabolism
  • the MAP (mitogen activated protein) kinase pathway is involved in cell growth and differentiation through ras.
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29
Q

Effects of insulin receptor activation on growth and proliferation?

A
  • ras is an oncogene product, a small GTPase
  • it is a signal transduction protein
  • it activates a number of pathways
  • MAP kinase pathways particularly important
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30
Q

What are the metabolic effects of activation of insulin receptors?

A
  • IRS-1 binding and phosphorylation and subsequent activation of PI3-K lead to:
  • an increase in the glucose trasporter (Glut 4) molecules on the plasma membrane of insulin-sensitive tissues e.g. muscle and adipose tissue
  • Glut 4 is transported from cellular vesicles to the cell surface
  • increased uptake of glucose from blood
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31
Q

Where are GLUT4 transporters found?

A

GLUT4 transporters are in vesicles in the interior of the cell in the absence of insulin. In the presence of insulin the vesicles take the transporters to the plasma membrane

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32
Q

How is the insulin signal terminated?

A
  • Sustained insulin action would be detrimental to the system
  • A number of mechanisms to end the signalling
  • Protein phosphatases and phosphoinositide phosphatases inhibit at several points in the signalling pathway
  • Phosphorylation of IRS on serine/threonine sites is another mechanism for switching off
  • emerging as an important link in the aetiology of insulin resistance
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33
Q

What is Insulin resistance?

A
  • Condition in which normal amounts of insulin are inadequate to maintain normal concentrations of blood glucose
  • both insulin and glucose are high
  • often associated with obesity
34
Q

What are the physiological features of insulin resistance?

A
  • in muscle cells reduces glucose uptake
  • therefore, reduces glycogen synthesis and storage
  • in liver cells it reduces storage of glycogen
  • Both result in high blood glucose conc
  • High plasma levels of insulin and glucose due to insulin resistance often lead to metabolic syndrome and type 2 diabetes
35
Q

What are the effects of insulin resistance on fat cells?

A
  • in fat cells it reduces the effects of insulin

* results in lipolysis and increased fatty acid concentrations in the blood

36
Q

What are the causes of insulin resistance?

A

• Insulin receptors are down-regulated because of the high conc of circulating insulin - simplest explanation but not enough
• Interference with insulin signalling pathway seems to be an important cause
• Inflammation also contributes to insulin resistance.
- Recent work points to a complex interaction between products of adipose tissue and defective insulin signalling
- A number of these adipose tissue produced hormones and metabolites may inhibit Insulin hormones and inhibit Insulin Receptor Substrate (IRS) activation
- the switching off mechanisms may be activated

37
Q

What is the role of adipose tissue in insulin resistance?

A
  • Plays crucial role in development of insulin resistance
  • It produces a number of metabolites/hormones/cytokines which modulate metabolism
  • Visceral adipose tissue mainly implicated in insulin resistance
38
Q

What Adipose derived metabolites/hormones/cytokines do you know about?

A
  • Good: • Leptin increases insulin sensitivity - obese often leptin resistant
    • Adiponectin which increases insulin sensitivity is decreased in obesity
  • bad: • FFA can impair insulin sensitivity by interfering with IRS activation • Are they the ‘nutrient sensor’? • glucose? glucosamine?
    • TNFα also interferes with IRS activation
    • Resistin controversial: some studies show increased secretion in abdominal adiposity some do not
39
Q

What are the direct effects of lipids in insulin resistance?

A

Lipid stimulated insulin resistance in muscle not from defect in insulin stimulated glucose metabolism but defects in insulin stimulated glucose transport in insulin stimulated glucose transport
• In muscle and liver intracellular accumulation of lipids such as DAG triggers activation of protein kinases which impair insulin signalling

40
Q

What are acute diabetic crisis that occur in the absence and relative insufficiency of insulin?

A

• Absolute insulin deficiency:
- Diabetic ketoacidosis (DKA) - A medical emergency
• Relative insulin deficiency:
(HHS) - Hyperosmolar Hyperglycaemic State

41
Q

What is the central equation involved in pH balance in the blood?

A

CO2 + H2O ← H2CO3 → H+ + ↓ HCO3-

42
Q

Why are pulmonary and renal compensation inadequate in metabolic acidosis?

A

Inefficient because of the high concentration of
• Acetoacetate
• Β hydroxybutyrate

• pKa 3.5-4, so at blood pH they are in the dissociated form which increases the H+ conc in blood

43
Q

What is the Henderson-Hasselbalch equation?

A

pH = pKa + log ( [conjugate base] / [acid] )

44
Q

How is an assessment of acid-base status carried out?

A

By measuring H+, bicarbonate and pCO2

Conjugate base is bicarbonate
Acid is proportional to pCO2

45
Q

Why is there hyperventilation in DKA?

A
  • ‘Kussmaul’ breathing
  • Rapid hyperventilation accompanies DKA
  • Loss of HCO3-
46
Q

What happens when renal compensation is overcome in DKA?

A
  • Insufficient ability of the kidney to buffer H+ as ammonium and phosphate
  • Na+ and K+ ions are lost in the urine
47
Q

What causes dehydration in DKA?

A

• From osmotic diuresis - loss of water and electrolytes

- frequent vomiting accentuates the loss of water and electrolytes

48
Q

See notes on insulin action and resistance for diagram of cycle of DKA

A

-

49
Q

What happens to potassium balance in DKA?

A
  • Insulin increases K+ uptake by cells
  • Lack of insulin leads to release of K+ by cells esp. muscle
  • Osmotic diuresis leads to K+ excretion by the kidney
  • Most patients K+ depleted although blood K+ may seem normal because of dehydration
50
Q

What are two of the most important factors in the development of long term complications in diabetes?

A
  • Glycation of proteins

* Abnormalities in the polyol pathway

51
Q

What is the state if the islets of Langerhans type 1 diabetes?

A

•Pseudoatrophic islets; small, devoid of beta cells, but retaining alpha and delta cells

52
Q

What do you see if you examine an islet of Langerhans close to type 1 diagnosis?

A

Insulitis: immune cell infiltration:

T cells, B cells, macrophages and activated dendrites

53
Q

What are the criteria for classing a disease as directly autoimmune?

A

Evidence of loss of immunological tolerance to self components components
Direct evidence/major criteria
•Passive transfer of disease by immune effectors (eg T cells, antibodies)
•Clinical responsiveness to immune suppression, or re-establishment of tolerance
•Genetic predisposition

54
Q

Are type one and type two diabetes associated with the same genetic factors?

A

Type 1 and 2 diabetes - completely different genetic predisposition
2 - beta cell focused disease
1 - HLA1 and 2, immune focused disease, CD25, CTLA4 (dampens immunity), IFIH1(sensor for viruses- viruses a trigger?), InS VNTR (expression of insulin in the thymus, how well you get rid of auto reactive T cells)

55
Q

What are 4 main autoantibody targets in type 1 diabetes?

A

Insulin (and proinsulin)
Glutamic acid decarboxylase (GAD65)
Insulinoma-associated antigen-2 (IA-2)
Zinc Transporter 8 (ZnT8) (Formation of insulin secretion granules)

56
Q

Antibodies in Type 2 diabetes Antibodies in Type 2 diabetes?

A
  • 10% of patients initially diagnosed with Type 2 diabetes have anti-GAD65 antibodies;
  • Very few have antibodies to Insulin or IA-2;
  • 90% of GAD65-Ab positive Type 2 patients require insulin within 6 year follow up;
  • GAD65-Ab marker of slowly progressing Type 1 diabetes or ‘latent autoimmune diabetes in adults (LADA)’.
57
Q

Is it the existence of autoreactive T cells or their phenotype which important in type 1 diabetes?

A

Everybody has autoreactive T cells - same numbers
- but sub-type - primed activated and pro inflammatory in phenotype. INFgamma and CD8 cells are activated
- balance of cells - if and when you will develop type 1 diabetes
T regs dominant in normal case

58
Q

Are babies of mothers with type 1 diabetes born with diabetes?

A

Babies of Type 1 DM mothers are not born with diabetes diabetes
(Can measure serum autoantibodies for 6-9 months of life but no evidence of beta cell damage or autoimmune cascade)

59
Q

What evidence is there that T cells cause type 1 diabetes?

A

It can be transmitted by bone marrow transplant - memory T cells

60
Q

At what % of original beta cell mass does clinical type 1 diabetes appear

A

10-30%

61
Q

What are the effects of cyclosporine in diabetes and why is it not available for treatment?

A

Cyclosporine increases the length of the Cyclosporine increases the length of the ‘honeymoon period’ in type 1 diabetes
- but it is dangerous, - malignancy, low immunity, kidney damage

62
Q

What Is the concordance of type 1 diabetes in identical twins?
What does this demonstrate?

A
  • 50% concordance with identical twin

- genetics v. Important but also environmental triggers

63
Q

What is the effect of cows milk on the stances of getting type 1 diabetes when taken in early life?
What is the likelihood of developing type 1 diabetes if you are born to a positive mother?

A

Introduce cows milk before 6 months of age - twice the risk

Born to a positive mother gives 5pc chance

64
Q

Can Bone Marrow transplants treat type 1 diabetes?

A

BM transplant - destroyed immune system and rebooted it

  • extraordinary success rate
  • some insulin independant for 46 months
  • will revert
  • Infections, hypothyroidism, hypogonadism……
65
Q

What is meant by Targeted Immunosuppression in T1Diabetes treatment?

A

Humanized monoclonal antibodies:
anti-CD3 targets T cells,
anti-CD20 targets B cells
(more subtle ways to renew immune system than the transplant method
- but only appears to work in a sub group so far
- maybe only works if enough beta cells remain)

66
Q

Is increasing T reg activity an area of research for the treatment of type 1 diabetes?

A

Yes -
•Phase Ia safety study, single PI peptide in long standing T1D
•Increased number of regulatory T cells in treatment group
•Induction associated with reduced HbA1c
•Phase Ib safety study, started Aug 2012
- Stop the destruction process - may be enough for some regeneration

67
Q

What are the two types of diabetic emergency?

A

DKA – Diabetic Ketoacidosis

HONK – Hyperosmolar non-ketotic state or
HHS – Hyperosmolar Hyperglycaemic state

68
Q

What is Diabetic Ketoacidosis?

A
  • acute, potentially life-threatening metabolic acidosis complicating Type 1 DM
  • Absolute or relative deficiency of insulin
  • hyperglycaemia, dehydration, ketonaemia, metabolic acidosis
  • Attempts at clinical criteria suggest: HCO311, pH3
69
Q

How can insulin deficiency result in diabetic ketoacidosis DKA?

A
  • reduced tissue glucose utilisation
  • increased hepatic glucose production • HYPERGLYCAEMIA
  • increased circulating fatty acids
  • fatty acids converted to ketones • RAISED BLOOD and URINE KETONES
  • DEHYDRATION and ACIDOSIS
70
Q

Does DKA occur in type 1 or type 2 diabetes?

A

Type 1

71
Q

What is the incidence and mortality of DKA?

A
  • Incidence 1 - 8 % of diabetic patients /yr • little change in incidence over time
  • Mortality @ 5-10 % with little change since 1949
72
Q

What are the precipitating factors of DKA?

A

-

73
Q

What are the symptoms like to be in the history of a of DKA patient?

A
  • Polyuria, polydipsia, thirst
  • Weight loss
  • Blurred vision
  • Vomiting
  • Abdominal pain (rigid stomach - always check blood glucose)
  • Weakness, cramps
  • Breathless
  • Altered sensation
  • Altered conscious level - coma
74
Q

What are the signs of DKA?

A
  • Tachycardia, tachypnoea, furred tongue
  • Hypotension
  • Kussmaul breathing – Air Hunger
  • Altered mental state
  • Acetone foetor
  • ‘surgical’ abdomen
  • Of precipitant?
75
Q

What investigations are done for a DKA presentation?

A
  • Blood Glucose
  • Urinary/serum ketones
  • ABG/ venous bicarbonate
  • FBC, Electrolytes - pre-renal failure?
  • Cultures
  • CXR
  • ECG
76
Q

What are the goals of therapy for DKA?

A
  • Improve circulating volume
  • Reduce plasma glucose and osmolality
  • Normalise electrolytes
  • Clear serum ketones - to reverse acidosis
  • Identify and treat the cause
77
Q

What are the 4 principles of management in DKA?

A
  • insulin replacement
  • fluid replacement
  • potassium replacement
  • supportive care - airway - nasogastric tube / catheter - psychological support
78
Q

What are the fluids given in DKA?

A

6-8 Litre fluid deficit- replace with 0.9% saline over 24 hours
Add in / change to 5 or 10% dextrose when glucose <14mmol/L

Caution in old/ young, heart/ kidney disease - Can precipitate cerebral oedema if you are not careful and go to fast

79
Q

How is insulin therapy used in DKA?

A
  • Continuous rate IV insulin infusion to clear ketones not just normalise hyperglycaemia
  • Reduce blood glucose by no more than 5mmol/l/hr
  • Restart normal insulin regime of s/c insulin when patient eating + drinking (and ketone free)
80
Q

What are the principles of monitoring in DKA patient?

A

Check hourly
• Essential to ensure no iatrogenic complications:
• Vital signs
• Blood/Urinary ketones
• Capillary blood glcose
• Bloods: electrolytes, venous bicarbonate • Urine output
(Hypokalaemia risk
Fluid overload - acute pulmonary odaema
Risk of cerebral oedema from changes being to fast)

Endocrinolgy (8 decks)

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