Bistability of Beta- Cell Mass in Type 2 Diabetes

Transcription

1 Bistability of Beta- Cell Mass in Type 2 Diabetes Arthur Sherman and Joon Ha Laboratory of Biological Modeling NIDDK, NaEonal InsEtutes of Health Bethesda, MD USA 1

2 What is Insulin? A key hormone to regulate fuel use Cells can use carbohydrate (glucose), fat or protein Secreted by pancreaec beta cells Allows muscles to consume glucose When faseng, muscles use fat When fed, muscles use glucose, fat stored in fat cells 2

3 Insulin is Secreted by b- cells in Islets in the Pancreas 3

4 What is Diabetes? Absolute or relaeve lack of insulin Absolute: Type 1 diabetes loss of beta cells RelaEve: Type 2 diabetes - insulin resistance; associated with Obesity Age Lack of exercise Inability to consume glucose results in hyperglycemia Organ damage and premature death 4

5 What We Know Obesity causes insulin resistance If beta cells compensate, no diabetes 5

6 What We Don t Know How do beta cells compensate? FuncEon (secreeon/cell)? Mass (number of cells)? What is the signal for compensaeon? Glucose? Insulin? 6

7 The Natural History of Diabetes: Starling s law of the pancreas Humans DeFronzo, Diabetes 37: (Lilly Lecture) 7

8 What We Want to Simulate: ZDF Rat Failure CompensaEon LF-fZDF ( ) HF-fZDF ( ) Topp BG et al. Am J Physiol Endocrinol Metab 2007;293:E1730-E1735 8

9 The CriEcal Experiment: Islet TransplantaEon Mass homeostasis is regulated by workload, not glucose Dadon et al, Diabetes, Obesity and Metabolism 14 Suppl 3:101-8,

10 Hypothesis: Mass homeostasis is regulated by workload (secreeon per cell) SecreEon > Metabolism: Mass increases SecreEon (per cell) Metabolic Rate Metabolism > SecreEon: Mass decreases 10

11 SecreEon is SEmulated by Glucose Metabolism Glucokinase KATP 11

12 The Model (1) Adapted from Bergman- Cobelli Minimal Model dg dt = R 0 (E G0 + S I I)G di dt = βσ ISR(M ) ki M body Conclusions: If S I decreases, normal faseng G can be maintained by proporeonally increasing I and b It is difficult to disentangle b and s. 12

13 The Model (2) Fast Slow dg dt = R 0 (E G0 + S I I)G di dt = βσ ISR(M ) ki M body dβ dt = (P A)β τ β Topp Finegood, J. Theor. Biol. 206:

14 Proposed Hierarchy of b- Cell Response Post- prandial G rise: Travel up the dose response curve. Persistent high G (days rodent, weeks - human): Shih the dose response curve to the leh (higher Ca; g) Increase efficacy of Ca (amplificaeon factor; s). Persistent high workload: Proliferate. 14

15 The Model (3) Fast Intermediate dg dt = R 0 (E G0 + S I I)G di dt = βσ ISR(M;γ) ki M body dγ dt = γ (G) γ τ γ Slow dβ dt = (P A)β τ β 15

16 The Auxiliary FuncEons γ s 16

17 CompensaEon for Insulin Resistance S I stepped down from 0.8 to 0.4 Note: Increase in G is ~10%, increase in ISR ~100%. Increase in g Increase in b GDR 17

18 How CompensaEon Happens HomeostaEc control of workload leads naturally to homeostaec control of G via increased mass Workload is a more sensieve indicator of demand for insulin than G Can also compensate by increased funceon (s) 18

19 Case Study: ZDF Rats LF-fZDF ( ) HF-fZDF ( ) Insulin peaks before mass: FuncEon (s) must decline Topp BG et al. Am J Physiol Endocrinol Metab 2007;293:E1730-E

20 The Model (4) β τ γ τ β β σ σ σ σ τ γ γ γ γ βσ ) ( ), ( ) ( ) ; ( ) ( 0 0 A P dt d ISR M dt d G dt d ki M ISR M dt di G I S E R dt dg body I G = = = = + = 20 Fast Slow Intermediate

21 Proposed Mechanism for FuncEon Defect ISR M 21

22 Hypothesis: The only difference between LFD and HFD rats is rate and extent of fall in S I 22

23 SimulaEons of ZDF Rats Note: Insulin peaks before mass 23

24 How Failure Happens Increased workload increases mass If mass fails to increase rapidly enough, funceon declines Decline of funceon leads to beta- cell death To maintain normoglycemia, need b to increase as fast as S I falls 24

25 Starling s law of the pancreas Humans Rats (SimulaEon) 25

26 Recall: The Fast G- I Subsystem Adapted from Bergman- Cobelli Minimal Model dg dt = R 0 (E G0 + S I I)G di dt = βσ ISR(M ) ki M body 26

27 Curves of constant G Progressive ReducOon of S I Slow reduceon of S I : b increases, G mildly elevated (constant disposieon index) Rapid reduceon of S I : b Eventually decreases, G rises (decreased disposieon index)

28 Dynamics of the Disposition Index in ZDF Rats Falling off the DI curve corresponds to the Starling peak Topp B G et al. Am J Physiol Endocrinol Metab 2007;293:E1730-E by American Physiological Society

29 Reversing Diabetes: Look Ahead Trial Goal: Lose 7% of body weight through moderate calorie reduceon and exercise Only about 10% experienced remission first year, many relapsed over the next few years In contrast, a similar interveneon in pre- diabetes reduced conversion to diabetes 56% Gregg et al, JAMA 308:

30 Intensive Lifestyle IntervenEon: Early and Rapid Succeed, Late Fails 30

31 Bariatric Surgery hmp:// 31

32 Rapid Reversal of DM by Bariatric Surgery Increase S i, reduce R 0, increase s 32

33 P 0.04 A G G P, A P A, AMmax=0.55 A, AMmax=0.3 P-A G G

34 The Central Principle ISR- based homeostasis plus a threshold explains everything 34

35 Lifestyle IntervenEon: Must be Early and Rapid 35

36 Rapid Reversal of DM by Bariatric Surgery 36

37 The Heart of the Model: Threshold and Bistability [300] Disease G mg/dl [150] [125] Acute caloric restriceon [100] Health b- cell Mass Defect

38 The Full Slow Dynamics 38

39 Important: S i can t change b, G steady states but can shih the trajectory across thresholds 39

40 The Heart of the Model: Threshold and Bistability [300] Disease G mg/dl [150] [125] Acute caloric restriceon [100] Health b- cell Mass Defect

41 Is There Evidence for a Threshold? 41

42 Longitudinal Two-Hour Glucose Measurements in 55 Pima Indians Mason et al., Diabetes 2007;56: Copyright 2011 American Diabetes Association, Inc.

43 Is There Evidence for Bistability? 43

44 Partial Pancreatectomy Results in Bimodal Glycemia Experiment, Laybum et al, JBC, 2003 SimulaEon 60 Percentage of Diabetes 30 Model tells us: Bimodality results from Bistability 70% Ptx 90% Ptx Model PredicEon 44

45 Monostable Model No rapid reversal of diabetes 45

46 Conclusions No one cause, but dynamic balance of mass, funceon and insulin resistance Workload, not G per se, drives compensaeon to insulin resistance Diabetes results when resistance worsens faster than secreeon rises Model is bistable with a threshold: Below threshold, mass increases; above, mass decreases Peak in Starling s law of the pancreas corresponds to crossing the threshold Explains why preveneon is easier than cure Explains why bariatric surgery works: Improves insulin sensievity rapidly 46

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48 Don t Pop the Champaign Cork Yet Model reinforces emphasis on preveneon but we don t have drugs safe enough to give to people who are not yet sick. Clinical researchers want to know what molecules to target model can t tell them that. Concern that it doesn t apply to humans. 48

49 [300] Gordon Weir, Susan Bonner- Weir, Five Stages of b- Cell DysfuncEon, Diabetes 53, Supp. 3, Dec Severe DecompensaOon irreversible G mg/dl [150] [125] 4 Stable DecompensaOon frank diabetes 3 Transient DecompensaOon G rises rapidly [100] 1 CompensaOon normal G 2 Stable AdaptaOon reduced mass and funcoon, G starts to rise b- cell Defect 49

50 Five Stages of Progression of Diabetes Weir G C, and Bonner-Weir S Diabetes 2004;53:S16-S21 Copyright 2011 American Diabetes Association, Inc. 50