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

CONTROL OF GLYCEMIA Insulin glucose Endogenous Glucose Production liverIntestinekidney

Glucose-6 phosphatase : the key enzyme of EGP

EVIDENCE for its EXPRESSION In the INTESTINAL MUCOSA Gastroenterology, 1999

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

WHAT’S HAPPENING IN THE DIABETIC STATE ?

CONTROL OF GLYCEMIA - DIABETES Insulin glucose Endogenous Glucose Production liverIntestinekidney

normal diabetic Insulin tolerance test

2) This results in glucose intolerance Time (mn) % basal glucose ** normal diabetic glucose tolerance test

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:

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

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

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.

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

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

Pair-fed sham band EGA Days Food intake (g/d) Surgery Daily food intake Days Body weight (g) Surgery Body weight on pair-feeding Decreased food intake No malabsorption EGA Band

Time (mn) Pair-fed shamGLBEGA A Time (m n) % basal glucose * * $ $ glucose tolerance Insulin secretion EGA

SDHFDPair-fed sham GBEGA GLP-1 (pmol/l) T0 T40 $ # § * GLP-1 plasma levels during OGTT

Time (mn) % basal glucose § § § ITT Pair-fed shamEGA There is also a marked increase in insulin sensitivity after bypass EGA

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

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

CONTROL OF GLYCEMIA - DIABETES Insulin glucose Endogenous Glucose Production liverIntestinekidney

HFD Sham GLBEGA Segment n°4 G6Pase (arbitrary units) * G6Pase actin HFD Sham GLBEGA Segment n°4 * actin PEPCK PEPCK (arbitrary units) Segment n° HFDSham GLBEGA G6Pase activity (µmol/min/g) * HFDSham GLBEGA Segment n°3 G6Pase activity (µmol/min/g) * HFDSham GLBEGA Segment n°4 G6Pase activity (µmol/min/g) Ileum Duodenum Esophagus Proximal Jejunum Stomach Distal Jejunum

HFDPair-fed shamGLB EGA Micromole / min/g NS $ * Hepatic G6Pase activity

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

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

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?