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Diabetes - Gribble

Ashcroft and Rorsman 2012 Review: glucose in gut lumen = GLP-1 secr = insulin secr via raised cAMP. Oral glucose more effective at raising insulin than IV due to gut hormones. PKA independent cAMP induced insulin incr acts through Epac2 (target for sulphonylureas).
Hosker et al 1989 TII diabetes causes loss of primary peak of insulin secretion and second peak is reduced, restored by drug therapy.
Rosengren et al 2010 Found gene locus linked to diabetes in rats led to overexpression of alpha2 Adrenoceptor mediating adrenergic insulin suppression. Found human polymorph in the a2AR gene reducing basal and gluc stim insulin, predisposes to diabetes (through a2AR incr).
Butler et al 2003 Incr no of beta cells in non-diab obesity, may be genetic or adaptive, 50% incr in number. Decreased number in diabetes regardless of treatment, parallels decr in insulin secr. B cell apoptosis may be more freq in diabetes (trend, not sig in all groups).
Del Guerra et al 2005 Shows decreased insulin secretion from isolated islets of human pancreata (mentioned in notes on Butler et al 2003)
Menge et al 2008 No pancreas regeneration in humans (but 4 of 13 were post chemo) unlike that seen in rats. Other studies have shown pancreas can compensate a bit in children. Removing 50% of pancreas caused incr in fasting gluc ('small' according to A&R'12, I disagree).
Kashyap et al 2003 Infusion of triglyceride emulsion decreased insulin secretion only in patients who had a first degree relative with T2DM despite all having normal baseline levels. Constant infusion over two days, designed to mimic diabetic lipidaemia.
Hoppa et al 2009 In humans:Chronic palmitate exposure (>72hr) causes diffusion of calcium entry as shown by indicator and incr sensitivity to buffers. Global rises stim by uncaging are unaffected. Effects may be miRNA. Disconnection of Ca channels from secretory granules.
Lee et al 1994 Rat study: Islet triglycerides and more noticeably plasma FFA rose a few weeks before blood glucose in a rat diabetes model (zucker diabetic fatty).
Kebede et al 2009 Review: Novel G-protein agonists have been found which may stimulate the β cell or incretin producing cells via different receptors.
Mandrup-Poulsen et al 2010 IL-1 antagonists improve glycaemic control and β cell function and are entering trials. May be of use in TI and TIIDM, particularly if the latter includes beta cell death and inflammation (cell death evidence - Butler 2003)
Karra et al 2010 Surgery better than predicted based on reduced intake. May cause incr delivery to ileal L-cells making incretins, foregut bypassed. Rerouting food through ileum then foregut (ileal transposition) has no effect on length/absorption but better for diabetes.
Westlund 1966 (only author) The effects of surgery are mimicked by calorie restriction, this is paralleled by a drop in newly diagnosed diabetes during WWII, rising afterward (Westlund 1966) as well as similar better documented changes in the Balkan war (Kulenovic 1996)
Kulenovic et al 1996 Effects of surgery mimicked by calorie restriction, shown by improvement in diabetes patients during the Balkan War. Glycaemic control and blood pressure (of diabetics) improved despite stress and reduced medical intervention of war.
Reimann, Ward & Gribble 2006 (et al if you're struggling) Review: GLP1. Cell cultures indicate that majority of KATP channels are closed at physiological glucose, this would seem reasonable as small currents are being used to depolarise. DPP4, the enzyme cleaving GLP-1, is CD26 & has a role in cleaving cytokines
Moore et al 1906 Acid extracts of duodenal mucosa can treat diabetes, given to three patients with beneficial effects (two of them children (TIDM?) treatment was stopped in a young boy and yet no sugar in urine for 1 month min). 1st signs of the incretin effect.
Deacon et al 1995 (needs Reimann et al 2006 citation too as I only read abstract) Circulating GLP-1 has a half-life of 30 secs in circulation as it is quickly degraded by DPP4
Reimann et al 2005 Depolarisation and Ca entry are necessary for GLP-1 release, glucose stimulated GLP release is insensitive to tetrodotoxin and so does not require Na channels but reduced by nifedipine indicating a role for L-type channels.
Gribble et al 2003 Pharmacological inhibition of the SGLT blocks the release of GLP-1 in response to non-metabolisable glucose and reduces the response to glucose.
Ritzel et al 1997 Fructose entering through GLUT5 has also been shown to stimulate secretion in an Na independent manner so SGLT may not be the whole story
Sampedro et al 2003 Uses transfected cells, transfection doesnt create a glucose conductance as measured by radiolabelled glucose uptake but does cause a depolarising movement of Na as shown by patch clamp and no current in the absence of Na. All blocked by SGLT blocker
Reimann & Gribble 2002 Diazoxide found to inhibit action potentials and hyperpolarise – used 360micromol/l, seems like a large amount as I've seen beta cell studies using less (200M)? Should be small given the theory that the KATP channels are largely inactive
Bokvist et al 1995 speed of exocytosis indicates colocalisation with Ca channel as it occurs before global Ca rise. Shows using Ca imaging that short depolarisations can cause insulin release even though Ca hasn’t spread more than 1-2um below the membrane (cell is 10-20um)
Reimann et al 2004 Glutamine potentiates GLP1 secr even when electrogenic effects are neutralised by KCl and diazoxide, a-haemolysin was used to bypass the transporter. Glutamine’s effect occured with constant Ca rise, indicating a downstream effect, not just electrogenic.
Peterson & Sullivan 2001 Human test of glucagon antagonist, shown to attenuate the response to glucagon. Demonstrates safety in humans although no real indication of real-world effectiveness
Yan et al 2009 Despite fears that glucagon antagonists would cause alpha cell hyperplasia (do in mice) shows successful test in monkeys indicating this wouldnt be an issue in humans.
Walker et al 2011 Review: Glucagon secretion is max suppressed by concs of glucose with no effect on somatostatin/insulin. Zinc is co-rel with insulin and stims glucagon secr. Diabetics respond to glucose challenge by briefly upregulating glucagon before normal reduction.
Yusta et al 2006 GLP-1 receptor ligands improve b cell survival following ER stress. ER stress gene mRNA and protein levels assayed. Survival of cells incr by forskolin (cAMP & PKA) or GLP-1 agonist. Stress induced by thapsigargin (non-comp SERCA inh)
Zhang et al 2009 Sulphonylureas bind Epac2 to activate it through a site independent of cAMP (cAMP analogue didn’t inhibit). Epac KO removed sulphonylurea activation of rap, re-expression rescued this activity. Epac KO animals less sensitive to sulphonylureas.
Created by: Jonmassie



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