Endocrinology 3 - diabetes 🍫

• what are the two main hormonal regulators of blood glucose?


  glucagon and insulin
• what are the effects of insulin?what does an increase in insulin aim to prevent?

  • glucose uptake
  • glucose usage
  • glucose storage

  lowers blood glucose levels -> prevents hyperglycemia
• what are the effects of glucagon and what do they aim to prevent?


  • gluconeogenesis
  • glycogenolysis
  • lipolysis

  causes a raise in blood pressure -> prevents hypoglycemia
• the pancreas has both cells in islets of Langerhans (endocrine function) and acinar cells (exocrine function), Which cells make up the endocrine portion of the pancreas and what do they release?


  • alpha cells -> glucagon
  • beta cells -> insulin
  • delta cells -> somatostatin
  • PP cells -> pancreatic polypeptides

  
• what is the function of somatostatin? how does it affect insulin and glucagon?


  Somatostatin produces predominantly neuroendocrine inhibitory effects across multiple systems. It is known to inhibit GI, endocrine, exocrine, pancreatic, and pituitary secretions, as well as modify neurotransmission and memory formation in the CNS.

  somatostatin inhibits insulin and glucagon
• describe the structure of insulin


  • make of and A and B-chain and a C-peptide connecting the two chains
  • 3 disulphide bonds -> 2 disulphide bonds connect A and B chains, 1 disulphide bond as an intrachain bond on chain A
  • half life of 4-6 mins

  
• how is insulin formed from preproinsulin?


  1. preproinsulin -> A and B chain, C-peptide, Signal sequence
  2. preproinsulin is cleaved of the signal sequence in the endoplasmic reticulum
  3. becomes proinsulin
  4. In the golgi apparatus -> the C-peptide is removed and insulin is free (A- and B-chain)
• how is insulin formed from preproinsulin?


  1. preproinsulin -> A and B chain, C-peptide, Signal sequence
  2. preproinsulin is cleaved of the signal sequence in the endoplasmic reticulum
  3. becomes proinsulin
  4. In the golgi apparatus -> the C-peptide is removed and insulin is free (A- and B-chain)

  
• How does high blood glucose lead to insulin release?


  1. beta cells take up glucose by GLUT-2 -> glucokinase converts this into glucose 6-P -> which is used in oxidative metabolism for ATP formation
  2. high level of ATP -> higher ATP:ADP ratio -> causes closing of ATP-sensitive K channels
  3. this causes membrane depolarisation which causes the opening of voltage gated Ca channels -> influx of calcium channels
  4. high intracellular calcium channels cause the release/exocytosis of granules containing insulin and c-peptides (1:1)
• outline the anabolic effects of insulin

  promotes:

  • glucose uptake - in muscle and adipose tissue
  • lipogenesis - liver and adipose tissue
  • glycolysis
  • glycogen synthesis - liver and muscles
  • protein synthesis

  prevents:

  • gluconeogenesis
  • glycogenolysis
  • lipolysis
  • ketogenesis
  • proteolysis
• outline how insulin is synthesised in beta cells from the transcription of genes encoding for insulin


  1. transcription of genes encoding for insulin onto mRNA
  2. mRNA moves to cytosolic ribosomes and begins translation
  3. N-terminal signal sequence is formed and elongation of the chain occurs -
• outline how insulin is synthesised in beta cells from the transcription of genes encoding for insulin


  1. transcription of genes encoding for insulin onto mRNA
  2. mRNA moves to cytosolic ribosomes and begins translation
  3. N-terminal signal sequence is formed and elongation of the chain occurs - the polypeptide chain then has to move into the RER due to the length -> this forms preproinsulin
  4. signal sequence is cleaved to form proinsulin
  5. proinsulin is cleaved into insulin and CC-peptide in the golgi apparatus
  6. packaged into secretory granules to be exocytosed

  
• which of the following is false?

  C because high ATP concentration causes the closing of ATP-sensitive K channels

  
• how does activation of the insulin receptor affect target cells?


  target cells = on liver, adipose and muscle

  1. insulin binds to insulin receptor which is a tyrosine kinase receptor
  2. insulin binds to the alpha subunit of the receptor and causes autophsophorylation
  3. this activates two pathways -> MAP kinase signalling and PI-3K signalling pathway
  4. MAP kinase signalling -> cell growth, proliferation and gene expression
  5. PI-3K signalling -> cell proliferation and survival, synthesis of glycogen, lipids and protein, opening of the GLUT-4 channels to allow for the movement of glucose in

  
• what is the difference between the fasted and fed states?

  fasted:

  • low glucose availability
  • hepatic glucose production
  • other tissues use alternate fuels (FFAs and ketones)

  fed :

  • high availability of glucose
  • hepatic glucose is no longer needed
  • no alternative fuels needed
  • excess glucose diverted to energy storage
• which receptor does insulin use to activate the cell?

  tyrosine kinase receptor
• which of the following is a potent inhibitor of glucagon?


  1. hypoglycemia
  2. arginine
  3. lysine
  4. hyperglycemia
• in which of the following tissues is glucose transport into the cells insulin-dependent?

  1. adipose
  2. brain
  3. liver
  4. red blood cells

  adipose - adipose and skeletal muscle cells have GLUT-4 which allows for the influx of glucose
• which of the following is true?


  B

  
• what is the structure of glucagon?


  • peptide hormone
  • single polypeptide chain
  • formed as proglucagon
  • in alpha/a-cells the proglucagon is cleaved into secretory vesicles
• regulation of glucagon: what activates, enhances and inhibits the release of glucagon?

  activates - low blood glucose/ hypoglycemia

  enhances - Amino acids (arginine and alanine), stress hormones (epinephrine and noradrenaline)

  neural input - sympathetic stimulation during stress

  inhibited - by glucose and insulin
• where are glucagon receptors found, what happens when they are activated in response to glucagon 


  found - hepatocytes and renal cortex

  1. binds to glucagon receptor which is a GPCR
  2. causes the activation of Adenylyl cyclase
  3. casues production of cAMP
  4. cAMP binds to the 2 regulatory subunits on PKA
  5. PKA catalytic subunits separate and the PKA is activated
  6. active PKA can phosphorylate enzymes in the cells

  
• what are glucagon's actions on the body?


  liver:

  • glycogenolysis + inhibition of glycogen synthesis
  • gluconeogenesis + inhibition of glycolysis
  • beta-oxidation of and ketone body synthesis
  • synthesis of FFAs and cholesterol

  renal cortex - gluconeogenesis, inhibition of glycolysis

  fat cells - TAG/triglyceride degradation
• list pathologies associated with insulin:


  • Type 1 – Can result from atrophy or destruction of b-cells of pancreas due to an immune response or viral infection
  • Type 2 –  insulin resistance - more insulin than normal is needed for the insulin receptors to respond. Subsequent beta cell failure
  • Maturity-onset diabetes of the young
  • Secondary diabetes (Acromegaly, Cushing’s syndrome, Haemochromatosis, Pancreatitis)
  • Gestational DM
• what happens in T1DM? what are the symptoms? what is a worrying complication? how is it treated?


  caused by the autoimmune destruction of beta cells

  insulin levels - very low/ little

  starts in childhood/adolescence

  history of osmolar symptoms - polyuria, thirst, lethargy, weight loss

  complication - diabetic ketoacidosis (DKA)

  tx - insulin lifelong

  
• what are risk factors for T2DM and how is it tx?

  •Risk factors - Obesity, Sedentary lifestyle, strong familial tendency and aging

  target tissues are no longer responsive to circulating insulin (insulin resistance) and this causes a decrease in insulin secretion

  tx: initially lifestyle -> medications (metformin) -> insulin
• what are the three Ps/ diabetic triad?


  • polyuria
  • polydysia
  • polyphagia

  more common in type 1
• what are common signs and symptoms of diabetes?


  • Polyphagia, Polydipsia, & Polyuria - more common in type 1
  • Extreme fatigue
  • Blurry vision
  • Repeated infection
  • Slow wound healing
  • Weight loss
  • Numbness in hands and feet
• what are major micro and macrovascular complications of diabetes mellitus?


  • retinopathy
  • nephropathy - requires VB12 prescription
  • neuropathy

  
• what are the different clinical tests that can be used to dx cancer?

  • Fasting plasma glucose > 126 mg/dL  (7.0 mmol/L). Screening test – 8 hours after meal
  • Random plasma glucose >200mg/dL (11.1 mmol/L) with one of symptoms
  • Elevated HbA1c levels >6.5% (48 mmol/mol)
  • Oral glucose tolerance test (OGTT): Evaluates the ability to regulate glucose metabolism, Considered as the ‘gold standard test’, Used to identify patients with ‘prediabetes’ and gestational diabetes
  • 2-hour plasma glucose >200mg/dL after 75 gms of glucose (OGTT)
• what is HbA1 and why is it important?


  • Non-enzymatic glycation of hemoglobin (depends on plasma glucose levels) Indicator of long-term glucose control (Over previous 3-4 months)
  • Poor blood glucose control (high HBA1c), higher risk of complications (microvascular and macrovascular)
  • Optimal blood glucose control reduces risk of complications in diabetes
  • Used for diagnosis of diabetes mellitus – greater than 6.5%