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The endocrinological: insulin resistance-deficit secretion, incretins, intestinal hormones and microbiota
Dr Alexander Miras
NIHR Clinical LecturerDiabetes and Endocrinology
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Miras et al, unpublished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 [email protected]
•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
