Gut Hormones and Diabetes (Prof Gribble) - Revision Notes
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Course
Pharmacology
Institution
Cambridge University (CAM)
Detailed revision notes from lecture course on the pharmacology of diabetes taught by Prof Gribble, University of Cambridge, with additional reading and insights from key publications summarised.
Pancreatic Islet and Gut Hormones
Fiona Gribble
fmg23@cam.ac.uk
Essays:
Most common topics: insights into aetiology and treatment from human genetics,
monogenic diabetes, gut hormones, mechanisms of glucose sensing.
2018 (Paper 3) The future of type 2 diabetes therapeutics will be to mimic gastric bypass
surgery. Discuss.
2017 (Paper 4) Personalised medicine has revolutionised the treatment of monogenic
diabetes. Discuss.
2016 (Paper 4) Discuss current and potential future strategies for exploiting the gut
endocrine system to treat diabetes and obesity
2015 (Paper 3) What have we learnt about the role of ATP-sensitive potassium channels
from the study of human genetics?
2014 (Paper 3) What has the study of monogenic diabetes mellitus taught us about the
pathways underlying insulin secretion from human pancreatic β-cells?
2014 (Paper 4) Gut hormone-based therapies are the future for treating type 2 diabetes
mellitus. Discuss.
2013 (Paper 4) Compare the glucose-sensing mechanisms utilised by gut endocrine and
pancreatic alpha and beta cells. Discuss the physiological consequences of targeting
different glucose-sensing pathways as a therapeutic strategy for diabetes.
2012 (Paper 3) What has the study of human genetics taught us about glucose sensing
in pancreatic beta cells?
2011 (Paper 4) Discuss the role of intestinal hormones in the physiology and in the
therapy of glucose homeostasis and appetite disorders.
2010 (Paper 4) Discuss the scope for tailoring the treatment of pancreatic beta cell
defects according to an individual's genotype?
2009 (Paper 3) What is insulin-resistance? What mechanisms are targeted by drugs that
influence insulin-resistance?
2009 (Paper 3) What is the physiological basis for the ‘incretin effect’? How can it be
exploited therapeutically?
Useful Reviews:
,Lecture 1 and 2: Physiology of pancreatic islets and the gut-pancreatic axis
• Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell.
2012 148:1160-71.
• Gromada et al. GLP-1 action on beta-cell. 1998, Pflugers Arch 435:583.
• Gylfe E. Glucose control of glucagon secretion-'There's a brand-new gimmick every
year'. Ups J Med Sci. 2016;121:120-32
• Gribble FM, Reimann F. Enteroendocrine Cells: Chemosensors in the Intestinal
Epithelium. Annu Rev Physiol. 2016;78:277-99 (Also relevant for lecture 3)
• Anything by Holst and Drucker
Lecture 3: Diabetes genetics
• Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic
classification of monogenic beta- cell diabetes. Nat Clin Pract Endocrinol Metab.
2008;4:200-13.
• Prasad and Groop. Genetics of Type 2 Diabetes—Pitfalls and Possibilities. Genes
2015, 6(1), 87-123
• Rees MG, Gloyn AL Small molecular glucokinase activators: has another new anti-
diabetic therapeutic lost favour? Br J Pharmacol. 2013 ;168:335-8
• Anything by McCarthy
Lecture 4: DM treatments, focussing on Incretin-based therapies and bariatric surgery
• Dixon JB, le Roux CW, Rubino F, Zimmet P. Bariatric surgery for type 2 diabetes.
Lancet. 2012 379:2300-11.
Additional references to original manuscripts are indicated in the text
,Introduction:
• Over the last century, diabetes prevalence has been growing in developed countries,
such as UK and USA.
• High rates of diabetes coincide with age and obesity.
• Although the definition of obesity changed over time, and obesity is now is defined
as BMI (body mass index) > 30 rather than >25, which it used to be earlier, the age-
adjusted prevalence of obesity continues to rise turning into an epidemic.
• Obesity epidemic drives an increase in type 2 diabetes.
• This is a major healthcare problem because diabetes increases the risk of heart
disease, stroke, and microvascular complications such as blindness, renal failure, and
peripheral neuropathy.
• It has been shown that incidence of death (from any cause) in diabetic patients is
substantially reduced when treated with an active ingredient compared to placebo,
which speaks strongly in favour of treating type 2 diabetes in affected individuals.
Diabetes Subtypes:
• Type 1– T-cell mediated autoimmune destruction of pancreatic beta cells
(hypersensitivity IV)
• Type 2 – main focus of the lecture series
• Gestational diabetes (often precedes Type 2) – in pregnancy
• Monogenic – inherited defects in beta-cell function usually due to SNP
• Genetic defects in insulin action, e.g. insulin receptor mutations
• Mitochondrial diabetes – inherited defects in mt DNA
• Diseases of exocrine pancreas, e.g. pancreatitis, cystic fibrosis
Developing New Treatments for Type 2 DM (and obesity)
(drugs in bold discussed in the lectures)
Classic
• Sulphonylureas and glinides (block KATP channels, increase insulin secretion,
promote weight gain)
• Metformin (increases insulin sensitivity, promotes weight loss) - 1st line therapy
• Insulin (long acting, rapid acting, pumps, closed loops)
• Thiazolidinediones (PPARgamma agonists, increase insulin sensitivity, promote
weight gain) – out of favour due to side effects
Novel
• Alpha glucosidase inhibitors (e.g. acarbose) (slow digestion and absorption of
carbohydrates but little effect on lowering blood sugar or promoting incretin
secretion – high doses associated with bloating and flatulence)
• SGLT2 inhibitors (block renal glucose reabsorption)
• GLP-1 mimetics (increase insulin release, reduce appetite)
• DPP4 inhibitors (prevent GLP-1 inactivation, increase insulin release, weight neutral)
• Bariatric surgery
, Lecture 1: Gut Endocrine Cells
The Gut Endocrine System
- The gut is the largest endocrine organ in the body, composed of different cell types
including hormone-secreting enteroendocrine cells scattered throughout the
epithelium and is responsible for >50% insulin secretion.
- Most new anti-diabetic therapies target the gut:
a) GLP-1 based therapies for diabetes/obesity
b) GLP-2 based therapies for short bowel syndrome (malabsorption disorder
caused by a lack of functional small intestine)
c) Bariatric surgery for diabetes resolution
Enteroendocrine cells (EECs) along the human gut axis
- Intestinal epithelium is turned over very quickly – renewed every 5-7 days.
- Many different types of enteroendocrine cells that produce different gut hormones
in different parts of the intestine.
- Gut hormones regulate gut motility, digestion, absorption, peripheral nutrient
utilisation (by control of insulin and glucagon release), food intake.
- Enteroendocrine cells differentiate from crypt stem cells but secrete different
hormones depending on the location, e.g. in the duodenum – secrete CCK, GIP and
secretin and in the rectum – GLP-1, PYY, INSL5.
- EECs also have different morphologies, which is likely influencing communication
with neighbouring cells of the gut lining and affecting differential hormone
secretion:
1) open type that are exposed to the gut lumen (throughout the whole of
the small intestine)
2) closed type that are not exposed to the gut lumen and are unable to
detect intestinal luminal content
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