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Pancreatic Islet and Gut Hormones - Coggle Diagram

- - - - At the top of the axis (near stomach) they secrete CCK, GIP and secretin
      - At the bottom they secrete GLP-1, PYY and INSL5
      - Most are open-type and have a lifespan of 5 days (preventing them from getting damaged directly, but stem cells can be), these secrete GLP-1, PYY, GIP and CCK
      - Some are closed-type, which is much more common in the stomach, these secrete somatostatin and ghrelin
      - These were originally investigated using cell lines and dyes, before moving into transgenic mice models
        
        More recently mouse organoids (Goldspink, 2018) and human organoids have come into use
      - Transcriptomic studies by Habib, Reimann, Gribble et al (2012) found that K and L cells ~produce the same chemicals under the right conditions and that they are effectively the same, it is their location that determines what they are secreting in vivo
      - Signalling in EECs involves Gq and Gs coupled receptors, nutrient transporters and ion channels
        
        Each nutrient has a separate transporter/receptor
    - - Discovered by Nauck (Diabetologica, 1986) using glycolycemic doses and shown to be impaired in D2M patients
      - Secretion of GLP-1 and GIP by gut cells is driving this, faulty GIP secretion in D2M patients is thought to be to blame for their lack of glucose response
      - GLP-1 is produced by alternative processing of proglucagon
        
        In pancreatic alpha cells only an inert form is produced. In L cells proglucagon is processed into GRPP, oxyntomodulin, (Gilcentin), GLP-1 (cutting at position 7 by prohormone convertase 1/3) and GLP-2
        
        Production of GIP and GLP-1 is delayed from eating a meal
      - Experiments have shown that sugars must be absorbed by a cell for the incretin effect to be initiated (Na+ is also required) by using phloridzin to inhibit SGLT1 (and no incretins being secreted as a result)
      - Theories
        
        1 - 'sweet taste' receptors localised on the basolateral side
        There is no evidence for this though. Sglt1 KO mouse cells do not have a response to glucose even when it is added to the basolateral side (Nauck, Regul Peptides, 2004), additionally no evidence of them on primary L cells (Reimann, Cell Metab, 2008 - countered by Jang, PNAS, 2007)
        
        2 - Sugar is sensed inside the cell
        Blocking GLUT does not reduce GLP1 response, this is the main transporter of glucose so inhibiting it would reduce the amount of glucose that can be in the cell
        
        3 - Sensing is directly linked to transport
        Sodium entry alongside glucose causes a small membrane depolaristaion which then triggers CaVs to open and trigger secretion of incretin granules. It was shown that SGLT1 was responsible for glucose-stimulated incretin release by inhibiting it and showing that glutamine could still cause calcium influx (Parker, Diabetologica, 2012)
        
        It has been theorised that K ATP channels may modulate responses to small SGLT1 current and aid propagation of the AP
        
        It is not known why but SGLT1 KO impairs early GLP-1 secretion but increases late secretion. Was postulated by Powell to be the result of microbial glucose fermentation to short chain fatty acids which can then stimulate GLP-1 release through detection by FFA1
        
        FFA1 signalling recruits TRPC3 currents, an unusual pathway for a Gq coupled receptor (Goldspink, 2018)
      - long chain FAs are transported through the endothelium by chylomicrons and then act on basolateral FFA1 to stimulate incretin secretion (Psichas, DIabetologica, 2017)
        Such secretion also involves GPR119 (GsPCR - responds to OEA)
      - Peptones can also rigger incretin secretion, via the CASR. This is dependent on CaV action, suggesting a membrane depolarisation event occurs - shown by inhibiting CASR and CaV (Pais, peptides, 2016)
      - Glucose, amino acids and fatty acids stimulate this process
      - Action in the body
        
        Unclear how physiologically relevant the action of incretins on glucagon is
        
        Is also thought that this may be the result of GLP-1 stimulation of somatostatin
        
        High doses of GLP-1 but not GIP stimulate insulin release and suppress glucagon levels in D2M patients (Nauck, 1993, J Clin Invest)
        
        How GLP1 suppresses food intake is currently unclear. GLP1Rs are expressed in afferent vagus (could detect in the intestines), brainstem, hypothalamus (but can GLP-1 penetrate these nuclei?) and mesolimbic reward areas (again, can GLP-1 penetrate this deep?)
        
        Mouse model studies seem to suggest that the BBB is leaky to GLP-1, which suggests that GLP-1 could be acting in the brainstem or elsewhere (Cork, 2015, Mol Metab)
  - - - Beta cell function
        
        IVGTT - pancreatic response (clamp is ~gold standard)
        OGTT - combined gut and pancreatic response
        Intraperitoneal tolerance test (animals) - bypasses gut so ~IVGTT
      - Insulin sensitivity
        
        HOMA - prediction from fasting plasma glucose and insulin
        Hyperinsulinaemic euglycaemic clamp
        Insulin tolerance test (in animals)
    - - T2DM results from failure of beta cells or resistance to glucose
        Is known now to be due to beta cell failure
      - Does glucose stimulate insulin secretion by being sensed or metabolised
        Now known that it is the result of metabolism - non-metabolisable sugars are ineffective and secretion is prevented by metabolism inhibitors (the reasons this was resisted is that the cell is sensing changes in [ATP], which is ordinarily kept constant
    - - GLUT2 draws glucose in, which is metabolised to produce ATP. This blocks K+ATP channels, causing a small depolarising current, which stimulates CaV channels and subsequent insulin release
      - K+ATP channel modulators have different affinities for SUR1&2, most used clinically seem to have some action on SUR2 but avoid CV side effects
        
        KO of Kir6.2 abolishes insulin secretion, SUR1 KO effectively does the same, although there is a slight response (Miki, 1998, PNAS & Seghers, 2000, J Biol Chem)
    - - GPCRs act through Gq proteins to activate IP3Rs, PKC and (somehow)TRPC3 and through Gs proteins to increase [cAMP]
      - Insulin release is potentiated by GqCPR pathways and GsPCR pathways, the latter pathway is stimulated by incretins (Rosselin, 1998, Endocrine)
        
        GLP-1 triggered insulin secretion is dependent on glucose because without it there is no signal to potentiate. Hence GLP-1 therapies carry low risks of hypoglycaemia
        
        Sulphonylureas can trigger insulin secretion at any glucose secretion, potentially causing hypoglycaemia (particularly in older thinner people)
        
        Sulphonylureas are used for treatment of patients with open K+ATP channels and show a good response to oral but not i.v. glucose (Pearson, 2006, New Eng J Med) as it allows beta cells to respond to gut hormones
- - - - MODY2 = glucokinase mutations
        Can be heterozygous or homozygous, the former causes MODY, the latter causes neonatal diabetes (Njolstad, 2001, NEJM)
        Activating mutations rarely cause dominant persistent hyperinsulinism
        
        M210K causes MODY if heterozygous and neonatal diabetes if homozygous
      - Insulin mutations are typically either:
        Processing mutations - misfolded protein accumulates and causes ER stress and apoptosis, hence these need only be heterozygous for an effect
        Biosynthesis mutations - decreased [insulin] due to faulty transcription or mRNA processing, need to be homozygous for an effect
        MODY7 = insulin mutations
      - HNF1alpha mutations alter metabolism in mature beta-cells by reducing glycolysis and ATP generation. This has been shown to reduce insulin, GLUT2, pyruvate kinase etc expression and increase UCP2 mRNA and protein (Wang, 2000, EMBO J)
    - - Activating mutations in Kir6.2 and SUR1 subunits are common
      - Disease severity is determined by ATP sensitivity of the mutant channels (ND alone, iDEND or DEND)
      - K+ATP channels in other areas of the body are that to cause DEND syndrome (neurons = SUR1 + Kir6.2, skeletal & cardiac muscle = SUR2A & Kir6.2, smooth muscle = SUR2B + some Kir6.1)
        
        Mutations in muscle results in weakness and in neurons it results in decreased muscle stimulation, shown by looking at V59M mutation in mice (Clark, 2010, Science)
  - - - These findings have mainly informed pharmacoepignomics rather than triggered a wave of new therapies
  - - - SUR1 mutations cause truncated or misfolded protein, reduced surface expression or partially functional channels
        Some mutations (K67N in Kir6.2) have no effect on the channel in vitro
- - - - However GLP-1 is a poor therapy as it is rapidly degraded by DPP4 in vivo
    - - Liraglutide binds to albumin, protecting it from DPP4. This is also now used in the treatment of obesity
      - Semaglutide is also available orally (one of few as these are peptides)
      - Dulaglutide has a much longer half life and means that treatment is only needed once per week
      - Exenatide has shown weight loss effects on D2M patients as a long acting molecule and as a short acting molecule (Drucker, 2008, Lancet)
  - - - Initial trials were successful but the genotype can still influence the benefit received from these drugs (Pearson, 2006, NEJM)
        
        Benefit is largely derived from sensitivity of K+ATP channels
  - - - Roux-en-Y GB seems to be the most effective for diabetes, followed by sleeve gastroectomy
        
        RYGB has shown clear improvements in glucose tolerance and a reemergence of the incretin effect after 1 week (Joergensen, Am J Phys, 2012)
        
        Stomach exclusion seems to be key to this, duodenal exclusion has a role but only occurs in RYGB so cannot be the major factor
        
        Experiments have shown that gastrectomy improvements in insulin secretion are mediated by improvements in GLP-1 secretion by inhibiting GLP1R with exendin-9, the result is an abolition of improvements seen after RYGB (Larraufie, Cell Reports, 2019)
        
        GLP-1 drives hypoglycaemia when patients lose a lot of weight post-surgery and can be treated with exendin-9
    - - 78.1% of patients in the Buchwald 2009 study (Am J Med) had complete resolution of D2M, which increased to 80.3% for those with RYGB
    - - There are no transcriptional or hormone biosynthetic changes in each cell following bariatric surgery. However the make up of cells has changed as many have been removed, meaning overall peptide production has shifted (Larraufie, Cell Reports, 2019)
      - The changes reflect altered nutrient flow, there is now a higher [glucose] at the site of L cells (Roberts, 2019, Diabetes)
      - PYY's role
        
        Is at low levels in obesity and PYY (3-36) is related to food intake (Batterham, 2003, NEJM)
        
        Is known to contribute to decreased food intake after RYGB. Inhibiting GLP1R and Y2R with exendin and sitagliptin reduces food intake showing that they both have a role in the reduction in food intake post-bariatric surgery
    - - Also the pathway of post-surgical weight loss is not understood. GLP1R and PYY do not seem to be relevant (Boland, Mol Metab, 2019) but FXR may be (Seeley, Nature, 2014) although mice were lighter to start with which may have prevented weight loss
- - - - May be achieved by reducing proximal absorption using SGLT1 inhibitors, slowing digestion with orlistat or increasing dietary fibre to trap nutrients in complex structures
      - Small molecules targeting GPCRs that ordinarily respond to aas, LCFAs, bile acids and SCFAs are in the clinic
    - - Glucagon reduces food intake so on balance seems to favour weight loss
      - Cotadutide (GLP-1/glucagon agonist) recently underwent PhIIa trial and showed positive results (Parker, 2019, J Clin Endocrin Metab)
      - Tirzepatide (GIP/GLP-1 agonist) is now in PhIII trials after passing PhII (Frias, 2018, Lancet)