The endocrinological: insulin resistance-deficit secretion, incretins,
intestinal hormones and microbiota
Dr Alexander Miras
NIHR Clinical Lecturer
Diabetes and Endocrinology
a.miras@nhs.net
Mechanisms of weight loss after Bypass
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Increase fullness
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Gut hormones
Increase DIT
? Gut hormones
? Bile acids
? Bacteria
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Change in food choices
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Miras A & le Roux CW, Nature Reviews Gastroenterology, 2013
? Gut hormones
Post-ingestive effects (dumping)
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
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Liver
• glucose output
• Responds predominantly to caloric
restriction
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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
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10 patients with T2DM
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3 euglycaemic hyperinsulinaemic clamps
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Before and after 1 week of LCD
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1 week after Endobarrier
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RCT starting
Miras et al, unpublished
RCT at Imperial and Southampton
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Endobarrier vs. medical care
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24 months
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Mechanistic studies
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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
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Increase in early insulin secretion
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Decrease in peripheral insulin
resistance
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incretins
? bile acids
weight loss
Decrease in hepatic insulin
resistance before weight loss
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Miras A & le Roux CW, Nature Reviews Gastroenterology, 2013
? caloric restrictions
? altered nutrient sensing
? bile acids
Acknowledgements
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Imperial College London
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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
•University of Surrey
•Prof Margot Umpleby
•Prof David-Rusell Jones
•Dr Fariba Shojaee-Moradie
•Dr Roselle Herring
•Dr Nicola Jackson
Medical Research Council/CSC
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Prof Jimmy Bell
Dr Tony Goldstone
Dr Samantha Scholtz
a.miras@nhs.net
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
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Bypass: ↓/↑/ →
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Band: → /↑
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Sleeve: ↓
Chambers A et al., Gastroenterology 2013
Postprandial GIP
Glucose-Dependent Insulinotropic Polypeptide
Yamada Y, Diabetes, 2006
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Bypass: ↑/↓/ →
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Band: →
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Sleeve: ↑/→
Postprandial Glucagon
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Bypass: temporary ↑
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Band: →
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Sleeve: temporary ↑
Postprandial Oxyntomodulin
Laferrere B, JCEM, 2010
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Bypass: ↑
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Band: ?
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Sleeve: ?
Summary: Mechanisms after Bypass
Miras A & le Roux,
Nature Reviews Gastroenterology, in press
Mechanisms of Diabetes improvement
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Weight loss
Decreased Insulin Resistance
Increased Insulin production
Distal intestinal hypothesis
Proximal intestine bypass
Altered bile flow
Hot topics in metabolic surgery
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Lack of trials on its effects on complications
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Preoperative management of glycaemia
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Postoperative management of the patient
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When to operate? What about hypos?
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Lowering the random 35kg/m2 cut-off
Microvascular complications
Retinopathy
Albuminuria
Miras et al, Diabetes Care in press