V- Conclusion

T2D develops in response to both overnutrition and lack of physical activity in subjects that are predisposed to both insulin resistance (and/or hyperinsulinemia) and β-cell dysfunction. The overworked-β-cell hypothesis proposes that lowered glucose-potentiated insulin secretory responses in diabetes are secondary to hyperstimulated insulin secretion and depletion of the β-cell insulin stores. Recent evidence shows that β-cell dysfunction appears early, long before the onset of prediabetes, when glycemia is still classified as NGT. This evolution from NGT to IGT and finally to established T2D in adult patients is accelerated in obese adolescents. This progressive failure leads to poorly functioning, dedifferentiated β cells and loss of β-cell mass from apoptosis. Research effort needs to focus on the factors that make islets susceptible to dysfunction and failure, particularly those that are acquired in early life, as these may be preventable. Even after diagnosis of T2D, β-cell function continues to worsen such that subjects progress from needing changes in diet/exercise only to requiring oral hypoglycemic agents and eventually insulin for achievement of adequate glycemic control. Future therapies will
be directed not only toward achievement of euglycemia, but also alteration of the course
of the disease by reversing the processes of β-cell failure.

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The hyperstimulated β cell: prelude to diabetes?
I- What is the role of epigenetics in insulin gene expression and insulin secretion and action
II- Impact of insulin resistance on β-cell function
III- Intrinsic hyperstimulation of β-cells
IV- Modulation of β-cell function by secretory products
V- Conclusion
Lectures during IGIS meeting