1. The new discoveries of Basic Researchers: bile acids, oxygen radicals, intestinal glucose metabolism reprogramming, others? Gilles Mithieux « Nutrition and Brain » Inserm U855, university of Lyon, France

2. CONTROL OF GLYCEMIA Insulin glucose Endogenous Glucose Production liverIntestinekidney

3. Glucose-6 phosphatase : the key enzyme of EGP

4. EVIDENCE for its EXPRESSION In the INTESTINAL MUCOSA Gastroenterology, 1999

5. PRODUCTION OF GLUCOSE – FASTING Normal state  15%  80%  5% Fasting state  20%  45%  35% G6PC PEPCK Diabetes, 2001

6. WHAT’S HAPPENING IN THE DIABETIC STATE ?

7. CONTROL OF GLYCEMIA - DIABETES Insulin glucose Endogenous Glucose Production liverIntestinekidney

8. normal diabetic Insulin tolerance test

9. 2) This results in glucose intolerance 0 100 200 300 400 0204060 Time (mn) % basal glucose ** normal diabetic glucose tolerance test

10. 3) Endogenous glucose production is increased 1) Peripheral glucose utilization is decreased 4) End-point: fasting plasma glucose is increased, when insulin secretion becomes insufficient to compensate insulin resistance 2) Insulin secretion is increased, partly compensating insulin resistance A probable sequence of events is:

11. WHAT ARE THE MODIFICATIONS OBSERVED AFTER OBESITY SURGERY? especially after bypass procedures…

12. In morbid obese: - marked decrease in appetite (hunger sensations) - modifications of liking for some foods In diabetic obese: - dramatic and rapid amelioration of diabetes

13. The rationale the most often put forward to account for this amelioration is based on the restoration of postprandial secretion of incretin hormones (e.g.GLP-1), promoting a restored secretion of insulin.

14. Ileum Duodenum Esophagus Proximal Jejunum Stomach Distal Jejunum Ileum Esophagus Proximal Jejunum Stomach Distal Jejunum bandingbypass = EGA What’s happening in obese diabetic mice (HF-HS diet) ? restrictive procedure malabsorptive procedure

15. The differential efficiency of the various gastric surgeries is an early event

16. Pair-fed sham band EGA 0 1 2 3 4 -6-4-20246810 Days Food intake (g/d) Surgery Daily food intake 15 20 25 30 35 40 45 -6-4-20246810 Days Body weight (g) Surgery Body weight on pair-feeding Decreased food intake No malabsorption EGA Band

17. Time (mn) Pair-fed shamGLBEGA A 0 100 200 300 400 0204060 Time (m n) % basal glucose * * $ $ glucose tolerance Insulin secretion EGA

18. 0 5 10 15 20 25 SDHFDPair-fed sham GBEGA GLP-1 (pmol/l) T0 T40 $ # § * GLP-1 plasma levels during OGTT

19. 0 20 40 60 80 100 015304560 Time (mn) % basal glucose § § § ITT Pair-fed shamEGA There is also a marked increase in insulin sensitivity after bypass EGA

20. Which is the function improved in terms of insulin sensitivity after bypass? EGP of peripheral glucose utilization?

21. sham mg/kg/mn Glucose infusion rate (GIR) Endogenous Glucose Production (EGP) Peripheral glucose utilization (Rd) 0 10 20 30 40 50 60 SDHFDPair-fedGLBEGA * * * § $ $ $ Euglycemic hyperinsulinemic clamps reveals improved suppression of EGP by insulin, and no effect on glucose utilization

22. CONTROL OF GLYCEMIA - DIABETES Insulin glucose Endogenous Glucose Production liverIntestinekidney

23. 0 0.5 1.0 HFD Sham GLBEGA Segment n°4 G6Pase (arbitrary units) * G6Pase actin 0 0.5 1.0 HFD Sham GLBEGA Segment n°4 * actin PEPCK PEPCK (arbitrary units) Segment n°1 0 5 10 HFDSham GLBEGA G6Pase activity (µmol/min/g) * 0 5 10 HFDSham GLBEGA Segment n°3 G6Pase activity (µmol/min/g) * 0 5 10 HFDSham GLBEGA Segment n°4 G6Pase activity (µmol/min/g) Ileum Duodenum Esophagus Proximal Jejunum Stomach Distal Jejunum

24. 0 5 10 15 20 25 HFDPair-fed shamGLB EGA Micromole / min/g NS $ * Hepatic G6Pase activity

25. PRODUCTION OF GLUCOSE – BYPASS Before surgery  5% After bypass  15-20%  45%  35%  15-20%  80%  50%  30%

26. Early after bypass in mice: there is a dramatic change in whole body glucose metabolism - recovery of insulin sensitivity (of EGP) - recovery of pancreatic function (GLP-1and insulin secretions) - amelioration of glucose tolerance - no change in basal EGP, but a new repartition among the 3 gluconeogenic organs, with an increased participation of the gut

27. Hayes et al, OBES SURG (2011) 21:759–762 Is Intestinal Gluconeogenesis a Key Factor in the Early Changes in Glucose homeostasis following Gastric Bypass?