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.
Supplementary Materials
Timecodes
- 00:05
- Bistability of Beta-Cell Mass in Type 2 Diabetes
- 00:17
- What is Insulin?
- 02:20
- Insulin is Secreted by b-cells in Islets in the Pancreas
- 04:04
- What is Diabetes?
- 05:24
- What we know
- 05:53
- What Don't We Know
- 06:45
- The Natural History of Diabetes
- 08:34
- What we want to simulate
- 11:18
- The Critical Experiment: Islet Transplantation
- 13:00
- Hypothesis: Mass homeostasis is regulated by workload (secretion per cell)
- 16:24
- The Model(1)
- 20:17
- The Model(2)
- 22:29
- Proposed Hierarchy of b-Cell Response
- 25:11
- The Model (3)
- 25:49
- The Auxiliary Functions
- 28:17
- Compensation for Insulin Resistance
- 31:23
- How Compensation Happens
- 31:46
- 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
- 34:09
- How Failure Happens
- 34:51
- Starling's law of the pancreas
- 35:15
- Recall: The Fast G-I Subsystem
- 36:15
- Progressive Reduction of S1
- 37:38
- Dynamics of the Disposition Index of ZDF Rats
- 38:05
- Reversing Diabetes: Look Ahead Trail
- 39:36
- Intensive Lifestyle Intervention: Early and Rapid Succeed, Late Fails
- 41:15
- 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
- 46:42
- The Heart of the Model
- 48:54
- The Full Slow Dynamics
- 49:28
- The Full Slow Dynamics (cont)
- 50:36
- 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