1. The endocrinological: insulin resistance-deficit secretion, incretins, intestinal hormones and microbiota Dr Alexander Miras NIHR Clinical Lecturer Diabetes and Endocrinology a.miras@nhs.net

2. Mechanisms of weight loss after Bypass Increase fullness Gut hormones Increase DIT ? Gut hormones ? Bile acids ? Bacteria Change in food choices ? Gut hormones Post-ingestive effects (dumping) Miras A & le Roux CW, Nature Reviews Gastroenterology, 2013

3. Insulin release Bradley D et al, JCI 2013

4. Post - prandial GLP-1 Salehi M et al., Diabetes 2011

5. GLP-1 receptor inhibition effect on insulin Jimenez A et al., Diabetes Care 2013

6. GLP-1 receptor inhibition effect on glucose Jimenez A et al., Diabetes Care 2013

7. Glucagon and GIP Jimenez A et al., Diabetes Care 2013

8. Beta cell glucose sensitivity Camastra S et al., Diabetes 2013

9. Insulin resistance: hepatic vs. peripheral Liver glucose output Responds predominantly to caloric restriction Muscle & fat glucose uptake Responds predominantly to weight loss

10. Hepatic insulin resistance early after surgery (is it just the calories?) le Roux, Pournaras et al Ann of Surg 2010

11. EndoBarrier ®

12. Early and longer term effects De Jonge et al., Obesity Surgery, 2013

13. Duodenal-jejunal bypass Breen et al, Nature Medicine, 2012 Teff K et al, Physiology & Behavior, 2013

14. Pilot Study 10 patients with T2DM 3 euglycaemic hyperinsulinaemic clamps Before and after 1 week of LCD 1 week after Endobarrier RCT starting Miras et al, unpublished

15. RCT at Imperial and Southampton Endobarrier vs. medical care 24 months Mechanistic studies Insulin clamps Eating behaviour

16. Peripheral insulin resistance Miras and le Roux, Lancet Diabetes & Endocrinology 2014 Mingrone et al, NEJM 2012

17. Peripheral insulin resistance Castagneto and Mingrone, Curr Ath Rep 2012

18. Mechanisms of diabetes improvement after Bypass Increase in early insulin secretion incretins ? bile acids Decrease in peripheral insulin resistance weight loss Decrease in hepatic insulin resistance before weight loss ? caloric restrictions ? altered nutrient sensing ? bile acids Miras A & le Roux CW, Nature Reviews Gastroenterology, 2013

19. Acknowledgements Imperial College London Prof Steve Bloom Prof Carel le Roux Dr Tricia Tan Mr Torsten Olbers Mr Ahmed Ahmed Mr Sanjay Purkayastha Mr Florian Seyfried Dr Ling Ling Chuah Dr Christina Prechtl Miss Sabrina Jackson Miss Werd Al-Najim Medical Research Council/CSC Prof Jimmy Bell Dr Tony Goldstone Dr Samantha Scholtz a.miras@nhs.net University of Surrey Prof Margot Umpleby Prof David-Rusell Jones Dr Fariba Shojaee-Moradie Dr Roselle Herring Dr Nicola Jackson

20. Hormonal responses De Jonge et al., Obesity Surgery, 2013

21. Hepatic insulin resistance (is it just calories?) Miras and le Roux, Lancet Diabetes & Endocrinology 2014

22. Hepatic glucose output

23. Reprogramming of glucose uptake-RYGB rats Saeidi et al, Science, 2013

24. Fasting Ghrelin Bypass: ↓/↑/ → Band: → /↑ Sleeve: ↓ Chambers A et al., Gastroenterology 2013

25. Postprandial GIP Glucose-Dependent Insulinotropic Polypeptide Yamada Y, Diabetes, 2006 Bypass: ↑/↓/ → Band: → Sleeve: ↑/→

26. Postprandial Glucagon Bypass: temporary ↑ Band: → Sleeve: temporary ↑

27. Postprandial Oxyntomodulin Laferrere B, JCEM, 2010 Bypass: ↑ Band: ? Sleeve: ?

28. Summary: Mechanisms after Bypass Miras A & le Roux, Nature Reviews Gastroenterology, in press

29. Mechanisms of Diabetes improvement Weight loss Decreased Insulin Resistance Increased Insulin production Distal intestinal hypothesis Proximal intestine bypass Altered bile flow

30. Hot topics in metabolic surgery Lack of trials on its effects on complications Preoperative management of glycaemia Postoperative management of the patient When to operate? What about hypos? Lowering the random 35kg/m 2 cut-off

31. Microvascular complications Retinopathy Albuminuria Miras et al, Diabetes Care in press