Bistability of Beta Cell Mass in Diabetes

Arthur Sherman (August 27, 2013)

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Slides

0:04 Bistability of Beta-Cell Mass in Type 2 Diabetes
0:17 What is Insulin?
2:19 Insulin is Secreted by b-cells in Islets in the Pancreas
4:03 What is Diabetes?
5:24 What we know
5:53 What Don't We Know
6:44 The Natural History of Diabetes
8:33 What we want to simulate
11:17 The Critical Experiment: Islet Transplantation
12:59 Hypothesis: Mass homeostasis is regulated by workload (secretion per cell)
16:23 The Model(1)
20:17 The Model(2)
22:28 Proposed Hierarchy of b-Cell Response
25:11 The Model (3)
25:49 The Auxiliary Functions
28:16 Compensation for Insulin Resistance
31:22 How Compensation Happens
31:45 Case Study: ZDF Rats
33:04 The Model (4)
33:17 Hypothesis: The only difference between LFD and HFD rats is rate and extent of fall in S1
33:38 Simulations of ZDF Rats
34:08 How Failure Happens
34:51 Starling's law of the pancreas
35:15 Recall: The Fast G-I Subsystem
36:14 Progressive Reduction of S1
37:38 Dynamics of the Disposition Index of ZDF Rats
38:04 Reversing Diabetes: Look Ahead Trail
39:35 Intensive Lifestyle Intervention: Early and Rapid Succeed, Late Fails
41:14 Bariatric Surgery
42:45 Rapid Reversal of DM by Bariatric Surgery
43:45 Rapid Reversal of DM by Bariatric Surgery (cont)
45:13 The Central Principle
46:41 The Heart of the Model
48:53 The Full Slow Dynamics
49:27 The Full Slow Dynamics (cont)
50:35 The Heart of the Model
51:18 Is There Evidence for a Threshold?
51:25 Longitundinal Two-Hour Glucose Measurements
51:59 Is there Evidence for Bistability
52:01 Partial Pancreatectomy Results
53:18 Monostable Model
54:10 Conclusions

Abstract

Insulin is the master hormone that controls fuel usage by body tissues. After a meal, glucose is plentiful and stimulates insulin secretion, which allows muscle and fat to take up glucose. When blood glucose falls, insulin falls as well and tissues revert to using fat as a fuel. Obesity causes insulin resistance, meaning that more insulin is needed to produce a given amount of glucose uptake. If the number of insulin-secreting pancreatic beta cells, or secretion per cell, increases sufficiently, this excess demand for insulin can be met. If expansion of mass is inadequate, type 2 diabetes, a rise in glucose to levels that are harmful to cells, results. Diabetes leads to cardiovascular disease, blindness, kidney failure and premature death. We update the seminal model of Topp et al (J. Theor. Biol. 2001) for the regulation of beta-cell mass by glucose and present a comprehensive picture of how diabetes develops and may either be avoided or reversed. Although many details of the model are in doubt, we show that any successful model results in a bistable bifurcation structure, with normal and elevated glucose levels separated by a threshold. This simple picture unifies and explains a striking diversity of experimental data, including why prevention is much easier than cure and why bariatric surgery is able to reverse longstanding diabetes within a week.