Targeting the pancreatic β-cell to treat diabetes

Key Points

  • The pancreatic β-cell is a key regulator of glucose homeostasis, sensing blood glucose levels after a meal and secreting insulin appropriately.

  • Loss of β-cell number and function feature prominently in both type 1 and type 2 diabetes.

  • Promoting β-cell regeneration, survival or function, especially with small molecules, may prove to be an effective strategy for treating diabetes.

  • β-cell regeneration can be accomplished by stimulating the division of existing β-cells. It will be important, however, to induce proliferation in a cell-specific manner to avoid oncogenic transformation.

  • Another mechanism for β-cell regeneration is through cellular reprogramming. Such transformations can occur from stem-cell-like populations (directed differentiation) or from other terminally differentiated cell types (transdifferentiation).

  • Prevention or slowing of β-cell death in the first place may avoid the loss of β-cell mass that enables the transition from insulin resistance to overt diabetes.

  • Promoting glucose-dependent induction of insulin secretion would restore hormone levels following β-cell death. Compounds exist to enhance insulin secretion, but many are not glucose-dependent.

  • Technical challenges to identifying novel compounds include a lack of many good human cell lines and the development of sophisticated techniques to measure β-cell function and number for high-throughput screening.

Abstract

Diabetes is a leading cause of morbidity and mortality worldwide, and predicted to affect over 500 million people by 2030. However, this growing burden of disease has not been met with a comparable expansion in therapeutic options. The appreciation of the pancreatic β-cell as a central player in the pathogenesis of both type 1 and type 2 diabetes has renewed focus on ways to improve glucose homeostasis by preserving, expanding and improving the function of this key cell type. Here, we provide an overview of the latest developments in this field, with an emphasis on the most promising strategies identified to date for treating diabetes by targeting the β-cell.

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Figure 1: Regulation of β-cell proliferation during ageing.
Figure 2: Signalling pathways involved in cytokine-induced β-cell apoptosis.
Figure 3: Insights into potential β-cell reprogramming targets from the development of pancreatic lineages.

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Acknowledgements

The authors would like to thank D. Altshuler and S. Schreiber for their ongoing support.

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Correspondence to Bridget K. Wagner.

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Competing interests

B.K.W. is a co-founder of KDAc Therapeutics, which is focused on some of the principles outlined in this Review.

Supplementary information

Supplementary information S1 (table)

Human genetic loci linked to type 2 diabetes and the indicated associated traits. (PDF 219 kb)

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Glossary

Genome-wide association studies

(GWASs). Studies that examine the common genetic variants across case and control populations, and determine statistical correlation with a disease or phenotypic traits. GWASs can be conducted on complex genetic diseases, such as type 2 diabetes, as well as on traits such as fasting glucose levels or insulin secretion.

Pancreatic β-cell mass

The β-cell population present in the pancreas that, under physiological conditions, results from the balance between growth (from replication, neogenesis and cell size) and cell death (from apoptosis, necrosis and autophagy).

ER stress

A physiological event activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). ER stress has two primary aims: to restore normal function of the cell by halting protein translation, and to activate the signalling pathways that lead to an increase in the production of the molecular chaperones involved in protein folding.

Oxidative stress

The effect of an imbalance between the production of reactive oxygen species and the ability of biological systems to detoxify the reactive intermediates or to repair the resulting damage.

Glucolipotoxicity

Elevated levels of glucose and fatty acids that contribute to β-cell dysfunction and death.

Zucker diabetic fatty rats

A rat model of type 2 diabetes containing a mutation of the leptin receptor.

Induced pluripotent stem cell

(iPSC). A type of pluripotent stem cell that can be generated directly from adult cells. Efforts to generate these cells have ranged from genetic to chemical, and combinations of both.

Cellular transdifferentiation

The conversion of one terminally differentiated cell state to another. This process can also be thought of as a subset of cellular reprogramming, because cells can be reprogrammed by dedifferentiation followed by directed differentiation to a new cell state.

Secretagogues

Stimuli that induce insulin secretion from β-cells. Secretagogues include small molecules, such as the sulphonylurea class of drugs, peptide growth factors and glucose itself.

Glucose-stimulated insulin secretion

The process by which β-cells sense and secrete insulin in response to a glucose challenge. β-cells are uniquely engineered to carry out this role, and this function is considered the gold standard of β-cell identity. Glucose-stimulated insulin secretion involves specialized signalling pathways and secretion machinery. In many cases of partial cellular reprogramming, this function is the one that is not fully achieved.

HOMA-B

Homeostatic model assessment of β-cell function. A method to estimate the steady-state β-cell function of an individual relative to a non-diabetic reference population, based on fasting measurements of plasma glucose and plasma insulin.

HOMA-IR

Homeostatic model assessment of insulin resistance. A method to estimate the steady-state insulin resistance of an individual relative to a non-diabetic reference population, based on fasting measurements of plasma glucose and plasma insulin.

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Vetere, A., Choudhary, A., Burns, S. et al. Targeting the pancreatic β-cell to treat diabetes. Nat Rev Drug Discov 13, 278–289 (2014). https://doi.org/10.1038/nrd4231

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