Paper 3
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Paper 3 Bariatric Surgery in Obese Rats
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Paper 3. Bariatric Surgery in Obese Rats. Regulation of Energy Balance. Mainly controlled in the hypothalamus Integration of hormonal and nutrient stimuli from periphery ANOREXIGENIC Eat less, increase energy expenditure OREXIGENIC Eat more, less energy expenditure. - PowerPoint PPT Presentation
Transcript of Paper 3
Paper 3
Bariatric Surgery in Obese Rats
Regulation of Energy Balance
• Mainly controlled in the hypothalamus– Integration of hormonal and nutrient stimuli from
periphery
• ANOREXIGENIC– Eat less, increase energy expenditure
• OREXIGENIC– Eat more, less energy expenditure
Gut– Brain Communication Short Term Signals – hunger and satiation
ghrelin
pancreatic polypeptide
(PP)
cholecystokinin (CCK)
peptide YY (PYY)
glucagon Like Polypeptide-1
(GLP-1)
ANOREXIGENIC
ANOREXIGENIC
ANOREXIGENIC
ANOREXIGENIC
OREXIGENIC
PYY
• High after feeding– Secreted as N-truncated form PYY3-36
• ANOREXIGENIC– Decreases appetite• Increases sensation of fullness
– About 30% reduction in feeding in buffet tests– Similar effects in both lean and obese• But obese have lower fasting and post-prandial rises
GLP-1• Glucagon-like peptide-1
– From pro-glucagon peptide, several different variations• Amidation, splicing
– Made in intestinal L-cells – distal small bowel• ANOREXIGENIC
– High after feeding – secretion stimulated by nutrients in gut– Slows gastric emptying
• INCRETIN effect– Stimulates insulin secretion
• Insulin is an important anorexigenic factor itself– Obese subjects have lower levels and faster gastric emptying
• Trialed as both anti-obesity and anti-diabetic agent – Quickly degraded by peptidase in serum (2 min half-life)– Resistant analogs (exendin)– Inhibitors of the peptidase
GIP• Glucose dependent insulinotropic peptide
– Made in intestinal K-cells – duodenum– Previously known as gastric inhibitory peptide– Slows gastric emptying
• INCRETIN effect– High after feeding – secretion stimulated by glucose– NIDDM subjects lower response
• Note that incretins cause oral glucose to give larger insulin response to intravenous glucose
Lifestyle Managementdiet and physical activity
• How much weight loss is appropriate to aim for?• ‘ideal’ weight probably unachievable– MAINTAIN (don’t put on more)• this may be the best option
– LOSE 5-10%• even this results in 20% less mortality, 10 mmHg drop
in blood pressure, 15% lowering of lipids/cholesterol, etc
Dietary Therapy for Obesity: An Emperor With No Clothes Hypertension. June 2008;51:1426-1434
“In an era when we pride ourselves on practicing evidence-based medicine, why then does dietary and behavioral therapy still reign?”
“Over 5 decades, it has been demonstrated repeatedly that dietary therapy fails…”
Bariatric Surgery
• Manipulation of the Digestive system–Malabsorbtive• shorten the digestive tract• by-pass the small intestine or parts of it
–Restrictive• reduce the size of the stomach
http://www.bariatricsurgeons.com/options.htm
Before and after
Banding
Laproscopic adjustable gastric band (LAGB)
Minimally invasive
Adjustable (even reversible)
O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al
Banding
• Convenient– 35 min operation– Inexpensive, Not permanent
• Safe – 0.05% deaths– Late complications common (15%)
• Slippage, infection, stomach erosion, leakage
• Relatively slow weight loss– But >50% excess weight (EW) loss over 2 years
• Some lose 120% EW– But easy to ‘cheat’
Small Bowel By-Pass
O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al
Stapling & Biliopancreatic By-Pass
O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al
Still 250 ml stomach
Roux en Y (Gastric Bypass)• Small stomach, less digestive juice
– Restriction and malabsorbtion• 80% excessive weight loss• Stop diabetic medication
– 85% cure from Type II diabetes– IN TWO DAYS!!!!– “Metabolic Surgeons”
• All other obesity related problems affected– Angina, hypertension, sleep apnoeas, arthiritis
• Skin excess a big disadvantage– Also hair thinning, gall stones
• 90 min operation, 0.5% deaths– Cutting and joining… Leak 2% – Cheating still possible if force stomach to stretch!
Diabetes Reversal
• Very rapid– Within a few days– Even before any significant weight loss– Same applies to sleep apnoea
• Mechanism?– Food-gut interactions affecting incretin secretion?– Intestinal gluconeogenesis?• Cell Metab 2008 Sep 8(3):201-11
– But still not clear how the communication works
N Eng J Med 357;8 (2007)
Sustained Weight Loss
N Eng J Med 357;8 (2007)
Short vs Long term costs?
Costs of Surgery soon Recouped
• Diabetes Care 2009;32:567-574 and 580-584.
• Randomised controlled study in Melbourne• Looking at Type 2 diabetes in obese patients– Surgery vs drug/diet interventions
• Surgically induced weight loss is cost-effective relative to conventional therapy – in the short term (2 years)– projected over a patient's lifetime
Bariatric Surgery in Australia
• 1996 frequency was 1.2 per 100,000– In 2006 it was 36 per 100,000
• In 2008 12,000 banding operations performed• Many see as the ONLY option– Ensures compliance– Reversal of diabetes
• Can we persevere with lifestyle therapy?• Surely this can’t be the answer….– And would we recommend it for children?!
Why is Bariatric Surgery so Effective?
• Changes even before weight loss has occurred• Not all types of surgery so rapid in effect• Adipokines?– Surely not... No change in adipocyte size
• Gut hormones?– Seems much more likely!
Roux-en-Y in Zucker rats• Zuckers– fa/fa – defect in leptin receptors– Hyperphagic obesity– All the usual hallmarks of insulin resistance
• Measure– Insulin sensitivity
• Tolerance tests, euglycemic clamp– Fat stores (subcutaneous, visceral)– Fuel metabolism– Hormones
• GLP-1, GIP, glucagon, PYY
Surgery
• Don’t worry about surgical details• Sham surgery groups• Pair feeding• Solid food commenced on Day 3 after surgery– Post-operative day 3 (POD 3)
Oral Glucose Tolerance
• OGTT on POD 21– Given by gavage– Blood by tail snipping
• HOMA and QUICK– Ways of gauging insulin sensitivity from fasting
glucose and insulin
Fat Measurements
• Before surgery and POD 28– Magnetic resonance imaging– Very specialised analysis• Hard for us to judge if it has been done properly
Indirect Calorimetry
• Oxygen consumption – measure of metabolic rate– ATP use = fuel oxidation = O2 consumption
• Carbon dioxide production– Also measure of metabolic rate
• CO2 produced:O2 consumed ratio – Respiratory quotient (RQ)– Tells us if fat or carbohydrates are being burnt
• RQ is 1 carbs• RQ is 0.7 fatty acids
Euglycemic Clamp
• Explained before– WebCT developer has done animation
• Involves even more surgery– To implant cannulae
• Infusion of [3-3H] glucose– Bolus followed by continuous infusion– Label lost as glucose is used
Hormones
• Radioimmunoassay– Don’t worry about details– Similar in principle to that in prac.
Weight Loss
