Reversing type 2 diabetes: pancreas composition and function during return to normal glucose tolerance

Transcription

1 Reversing type 2 diabetes: pancreas composition and function during return to normal glucose tolerance Dr Sarah Steven Clinical Research Fellow to Professor Roy Taylor

2 Observations from bariatric surgery Type 2 diabetes is widely believed to be inevitably progressive However, bariatric surgery can reverse diabetes The reversal of diabetes occurs before any significant weight loss occurs Guidone et al. Diabetes 2006 Could the reversal of diabetes relate to energy restriction alone? 7 weeks of moderate calorie restriction has been shown to be associated with improvement in FPG Petersen et al. Diabetes 2005

3 Fat and the beta cell Intra-organ fat accumulation is central to the pathophysiology of type 2 diabetes Taylor Diabetologia 2008 The transition from abnormal glucose tolerance to overt type 2 diabetes is determined by a decrease in insulin secretory capacity Clear in vitro evidence that exposure to fatty acid impairs acute insulin release Morgan Curr Opin Clin Nutr Metab Care 2009 The pancreas is the least studied organ in type 2 diabetes

4 Using MR Spectroscopy to examine pancreas fat 1.9% 6.6% Repeatability is no better than 15% When patient breathes in deeply, visceral fat is included in measurement

5 New development: the 3 point Dixon MR technique fat fat percentage water

6 Counterpoint Study Lim et al. Diabetologia 2011; 54 (10): Aims 1) Can a very low calorie diet normalise the abnormalities in the pancreas and liver seen in type 2 diabetes? 2) What is the time course of these changes?

7 Counterpoint Study 11 subjects with T2DM (BMI 33.6±1.2 kg/m 2 ) and 9 controls 8 week Optifast diet: 600kcal + 3 portions of non-starchy vegetables Metabolic studies at baseline, 1, 4 and 8 weeks of VLCD a) Pancreas: beta cell function using an incremental insulin secretion test b) Liver: insulin sensitivity by isoglycaemic hyperinsulinaemic clamp c) Liver and pancreatic fat levels: 3 point Dixon MR method Follow-up OGTT 3 months after completing diet

8 Plasma glucose 9.2 ± ± 0.4 mmol/l; p = Fasting plasma glucose (mmol/l) Week

9 % Insulin suppression of HGP CON: 68 ± 5% DM: 43 ± 4% (p = 0.001) Marked after 1 week of diet (74 ± 5%, p = 0.003) 0 Week 0 Week 1 Week 4 Week 8 20 Liver fat content (%) Week 0 Week 1 Week 4 Week 8 CON: 8.5 ± 1.9% DM: 12.8 ± 2.4% Reduced by 30% during 1 st week; 70% by 8 weeks

10 Insulin secretion rates Normal controls c Diabetes: Baseline T2DM - baseline ISR (nmol/min/m 2 ) Time (min) T2DM - Week 1 T2DM - Week 8

11 First phase insulin response (nmol/min/m 2 ) Pancreas fat content (%) Week Insulin secretion steadily At 8 weeks, similar to control values Pancreatic fat content fell gradually over 8 weeks

12 Follow-up 3 month follow-up after general lifestyle advice Mean weight gain 3.1 ± 1 kg Fasting plasma glucose 6.1 ± 0.2 mmol/l IGT 3 NGT T2D Unavailable

13 Aetiology of Type 2 Diabetes: Twin Cycle Hypothesis Positive calorie balance ++ Pre-existing insulin resistance liver fat Liver cycle Resistance to insulin suppression of HGP VLDL triglyceride basal insulin secretion plasma glucose Pancreas cycle islet triglyceride acute insulin response to food Taylor, Diabetologia 2008

14 Translation to clinical practice Worldwide public interest in the diet Information for people with diabetes and healthcare practitioners provided via website Feedback of personal experiences: - 70 individuals with T2DM: 59M, 11F - Diabetes reversal: 57%

15 Metabolic effects of calorie restriction 4 days post RYGB or post bypass diet Weight loss RYGB 1.4 ± 5.3kg 1 ± 3.4% Post-bypass diet 2.2 ± 1kg 2.2 ± 1% Fasting glucose -6% -20% Insulin levels -25% -27% HOMA-IR -25% -30% Isbell et al. Diabetes Care % weight loss following RYGB (3.4 weeks) and LCD (8.1 weeks) Plum et al. Obesity day VLCD in T2DM with BMI>40kg/m 2 : 3.58kg weight loss, FPG 7.66 to 6.9mmol/l Malandrucco et al. Am J Clin Nutr 2012

16 Hypothesis of PANCREAS study The changes in the pancreas and liver that underlie the normalisation of blood glucose after bariatric surgery are the same as those that occur after a very low calorie diet

17 Specific aims To compare the effect of bariatric surgery with that of very low calorie diet upon fasting plasma glucose, beta cell response to glucose and pancreatic fat content, liver insulin sensitivity and liver fat content To examine whether secretion of incretin hormones changes principally in response to change in calorie intake or as a specific response to bariatric surgery

18 Protocol Usual presurgery diet VLCD Post-surgery diet 18 subjects with T2D Usual pre-surgery diet Postsurgery diet Post-surgery diet nondiabetic weight matched Usual pre-surgery diet Post-surgery diet Weeks -2-1 Surgery +1 +8

19 Expected outcomes Improve our understanding of how diabetes can be reversed Develop acceptable and durable non-surgical approaches to the reversal of type 2 diabetes Allow further developmental work on the technique to accurately image the pancreas

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