causes of diabetes

Question 1

insulin secretion

Answer 1

• increased uptake and metabolism of glucose leads to an increase in ATP-ADP ratio
• increased ATP-ADP leads to closure of ATP-sensitive K+ channels and membrane depolarisation
• depolarisation of membrane leads to opening of voltage-gated Ca2+ channels
• resulting increase in cytosolic Ca2+ promotes secretion of insulin via exocytosis of insulin granules

Question 2

insulin signalling pathways

Answer 2

• binding of insulin to insulin receptor (IR) leads to receptor auto-phosphorylation
• phosphorylated residues on the IR act as binding sites for insulin receptor substrate (IRS) proteins
• IR phosphorylates 4 tyrosine residues in IRS proteins
• the lipid kinase, phosphoinositide 3 kinase binds to phosphorylated residues on IRS proteins and converts PIP2 to PIP3
• binding to PIP3 activates PDK1 which then phosphorylates and activates kinases such as PKB/Akt
• activated PKB/Akt can then diffuse through cell and activate processes such as glucose transport and glycogen synthesis

Question 3

glucose transport into adipocytes/skeletal muscle

Answer 3

• glucose transporter GLUT4 is contained inside cell in storage vesicles
• the protein AS160 acts to retain these vesicles in the cell
• activated PKB phosphorylates AS160 and inactivates it
• allowing GLUT4 vesicles to fuse with plasma membrane leading to increased levels of glucose transporter at cell surface
• this is how insulin stimulates glucose uptake into adipocytes/muscle

Question 4

insulin inhibiting gluconeogenesis

Answer 4

• insulin signalling leads to activation of PKB
• PKB phosphorylates Fox01
• phosphorylation of Fox01 prevents it from entering the nucleus leading to a loss of expression of gluconeogenic genes and hence a loss of glucose production

Question 5

Fox01

Answer 5

synthesised in the cytosol but is targeted to the nucleus where it regulates expression of genes that mediate gluconeogenesis

Question 6

genetic risk factors for type 1 diabetes

Answer 6

• risk of T1D is 15x higher for first degree relatives of someone with type 1
• HLA (human leukocyte antigen) region is critical susceptibility locus for T1D
• contains genes that encode components of major histocompatibility complex (MHC)

Question 7

autoantibodies

Answer 7

• presence of autoantibodies against beta cell antigen is a risk factor for developing T1D
  examples:
• glutamic acid decarboxylase-65 (GAD-65)
• insulin
• IA-2 (islet antigen 2)
• AnT8 (zinc transporter 8)

Question 8

enteroviruses and T1D

Answer 8

striking similarity between the 2C protein of coxsackie virus and GAD-65 suggests molecular mimicry might be involved of aetiology of T1D

Question 9

auto-immune destruction of beta cells

Answer 9

• the islets of langerhans contain several cell types secreting distinct hormones, each cell expresses different tissue-specific proteins
• in T1D an effector T-cell recognises peptides from a beta cell specific protein and kills the beta cell
• glucagon and somatostatin are still produced by alpha/beta cells but insulin cannot be made

Question 10

mechanisms that inhibit insulin signalling pathway

Answer 10

• protein tyrosine phosphatase 1B dephosphorylates the insulin receptor IR leading to a loss of IRS binding
• PTEN (phosphate and tensin homologue) dephosphorylates PIP3 back to PIP2
• IRS proteins are inactivated by phosphorylation of serine residues by PKC which prevents IR from phosphorylating tyrosine residues on IRS

Question 11

obesity affecting insulin resistance

Answer 11

• a consequence of obesity is that the amount of triacylglycerols exceeds the storage capacity of adipose cells as a result fat starts to accumulate in other tissues such as liver and muscle
• excess fat leads to increased levels of intracellular lipid signalling intermediates diacylglycerol (DAG) and ceramide (component of sphingolipids) in the cytoplasm of cells, both formed from fatty acids

Question 12

adiponectin

Answer 12

secreted from adipocytes and promotes insulin sensitivity

Question 13

adipokines and insulin resistance

Answer 13

• insulin-sensitising effects of adiponectin are related to its effects on sphingolipid metabolism
• adiponectin secretion is decreased in obesity which contributes to insulin resistance

Question 14

obesity

Answer 14

• pro-inflammatory condition in which hypertrophied adipocytes and adipose-resident immune cells contribute to increased circulating levels of pro-inflammatory cytokines
• in obesity more inflammatory cytokines are released such as TNFa (tumour necrosis factor alpha)

Question 15

increased TNF and insulin resistance

Answer 15

• induces expression of PTP1B which can dephosphorylate the insulin receptor
• activates JNK (jun-N-terminal kinase) which causes serine phosphorylation and inactivation of IRS proteins

Question 16

loss of insulin secretion in type 2 diabetes

Answer 16

• dysregulation of insulin secretion linked to accumulation of fat in pancreas
• over time beta cell mass decreases
  25% decrease 5 years after diagnosis
  50% decrease >15 years after diagnosis

Question 17

beta cell destruction

Answer 17

• beta cells respond to prevailing insulin resistance by synthesising more insulin
• this puts endoplasmic reticulum under stress and cells can no longer fold and process new insulin
• activates unfolded protein response (UPR)
• eventually results in apoptosis and beta cell death