In Pancreatic Islets from Type 2 Diabetes Patients, the Dampened Circadian Oscillators Lead to Reduced Insulin and Glucagon Exocytosis
Background: Type 2 Diabetes Mellitus (T2D) is a disease resulting from decreased insulin sensitivity within the body mainly due to lifestyle choices related to diet and exercise.1 T2D seems to mainly stem from lifestyle, with a high caloric and high glycemic diet with insufficient exercise increasing the rate of incidence in individuals. Obese individuals are much more likely to suffer from the disease.1 Patients with T2D have been observed to have dysregulation in pancreatic alpha and beta cells that could be related to certain circadian clock genes like Bmal1. Circadian oscillators connected to the alpha and beta cells in the pancreas could be seen as potential methods of treatment in individuals with the disease, due to the fact that individuals with T2D have been studied to have impacted circadian genes.
Objective: In this narrative review, I explored the ways that circadian genes are affected in type 2 diabetic cells and their systemic impact on the patient.
Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “type 2 diabetes”, “circadian rhythms”, “beta islet cells”, “pancreas”.
Results: Studies indicated that circadian clock genes present in pancreatic islet cells were dampened in cells taken from type 2 diabetes affected patients.4 The circadian clock genes, particularly Bmal1, showed a reduction in overall responsiveness to normal circadian patterns, which led to decreased ability of the alpha and beta cells to synchronize and work with each other.4 The alpha and beta cells within the pancreas also showed a decreased tendency to respond to other endogenous molecules that normally work to help regulate them such as adrenaline and octreotide.4 Specifically, knockdown of Bmal1 in alpha and beta cells led to a decrease in glucagon and insulin secretion respectively during the early morning hours.3 However, the circadian oscillations can be corrected and insulin secretion enhanced by the receptor-related orphan receptor (ROR) agonist Nobiletin, restoring some of the functionality lost due to downregulation of certain circadian genes.4
Conclusions: Studies have found that through the stimulation or Bmal1, CLOCK, Per1, and Per2 genes within pancreatic cells that functionality that was previously lacking in T2D patients can be restored.2 Through certain agonization of receptors via the compound nobiletin, circadian rhythmicity can be restored and protection generated for pancreatic cells from reactive oxygen species.4 These therapeutics combined with certain lifestyle controls of sleep regulation and helping to identify risk factors like shift work can be essential in the future treatment of type 2 diabetes.4
- Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature Reviews Endocrinology. 2017;14(2):88-98. doi:10.1038/nrendo.2017.151
- Rakshit K, Matveyenko AV. Induction of Core Circadian Clock Transcription Factor Bmal1 Enhances β-Cell Function and Protects Against Obesity-Induced Glucose Intolerance. Diabetes. 2020;70(1):143-154. doi:https://doi.org/10.2337/db20-0192
- Petrenko V, Saini C, Giovannoni L, et al. Pancreatic α- and β-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression. Genes & Development. 2017;31(4):383-398. doi:https://doi.org/10.1101/gad.290379.116
- Petrenko V, Gandasi NR, Sage D, Tengholm A, Barg S, Dibner C. In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis. Proceedings of the National Academy of Sciences. 2020;117(5):2484-2495. doi:10.1073/pnas.1916539117