Transcript Hepatic insulin resistance
The endocrinological: insulin resistance-deficit secretion, incretins, intestinal hormones and microbiota
Dr Alexander Miras NIHR Clinical Lecturer Diabetes and Endocrinology [email protected]
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hyperinsulinaemic clamps • Before and after 1 week of LCD • 1 week after Endobarrier • RCT starting Miras et al, unpublished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 • University of Surrey • Prof Margot Umpleby • Prof David-Rusell Jones • Dr Fariba Shojaee-Moradie • Dr Roselle Herring • Dr Nicola Jackson [email protected]
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
• Bypass: ↓/↑/ →
Fasting Ghrelin
• Band: → /↑ • Sleeve: ↓ Chambers A et al., Gastroenterology 2013
Postprandial GIP
Glucose-Dependent Insulinotropic Polypeptide • Bypass: ↑/↓/ → • Band: → • Sleeve: ↑/→ Yamada Y, Diabetes, 2006
Postprandial Glucagon
• Bypass: temporary ↑ • Band: → • Sleeve: temporary ↑
Postprandial Oxyntomodulin
• Bypass: ↑ • Band: ?
• Sleeve: ?
Laferrere B, JCEM, 2010
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/m 2 cut-off
Microvascular complications Retinopathy Albuminuria Miras et al, Diabetes Care in press