The endocrinological: insulin resistance-deficit secretion, incretins, intestinal hormones and microbiota

Dr Alexander Miras

NIHR Clinical LecturerDiabetes and Endocrinology

a.miras@nhs.net

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

Insulin release

Bradley D et al, JCI 2013

Post - prandial GLP-1

Salehi M et al., Diabetes 2011

GLP-1 receptor inhibition effect on insulin

Jimenez A et al., Diabetes Care 2013

GLP-1 receptor inhibition effect on glucose

Jimenez A et al., Diabetes Care 2013

Glucagon and GIP

Jimenez A et al., Diabetes Care 2013

Beta cell glucose sensitivity

Camastra S et al., Diabetes 2013

Insulin resistance: hepatic vs. peripheral

• Liver• glucose output• Responds predominantly to caloric

restriction

• Muscle & fat • glucose uptake• Responds predominantly to weight loss

Hepatic insulin resistance early after surgery(is it just the calories?)

le Roux, Pournaras et al Ann of Surg 2010

EndoBarrier ®

Early and longer term effects

De Jonge et al., Obesity Surgery, 2013

Duodenal-jejunal bypass

Breen et al, Nature Medicine, 2012

Teff K et al, Physiology & Behavior, 2013

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Miras et al, unpublished

RCT at Imperial and Southampton

• Endobarrier vs. medical care

• 24 months

• Mechanistic studies• Insulin clamps• Eating behaviour

Peripheral insulin resistance

Miras and le Roux, Lancet Diabetes & Endocrinology 2014

Mingrone et al, NEJM 2012

Peripheral insulin resistance

Castagneto and Mingrone, Curr Ath Rep 2012

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

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

Hormonal responses

De Jonge et al., Obesity Surgery, 2013

Hepatic insulin resistance(is it just calories?)

Miras and le Roux, Lancet Diabetes & Endocrinology 2014

Hepatic glucose output

Reprogramming of glucose uptake-RYGB rats

Saeidi et al, Science, 2013

Fasting Ghrelin

• Bypass: ↓/↑/ →

• Band: → /↑

• Sleeve: ↓

Chambers A et al., Gastroenterology 2013

Postprandial GIP Glucose-Dependent Insulinotropic Polypeptide

Yamada Y, Diabetes, 2006

• Bypass: ↑/↓/ →

• Band: →

• Sleeve: ↑/→

Postprandial Glucagon

• Bypass: temporary ↑

• Band: →

• Sleeve: temporary ↑

Postprandial Oxyntomodulin

Laferrere B, JCEM, 2010

• Bypass: ↑

• Band: ?

• Sleeve: ?

Summary: Mechanisms after Bypass

Miras A & le Roux, Nature Reviews Gastroenterology, in press

Mechanisms of Diabetes improvement

• Weight loss• Decreased Insulin Resistance• Increased Insulin production

• Distal intestinal hypothesis• Proximal intestine bypass• Altered bile flow

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/m2 cut-off

Microvascular complications

Retinopathy Albuminuria

Miras et al, Diabetes Care in press