Investigating the metabolic and molecular regulators of diurnal insulin secretion
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Date
2022-08-15
Authors
Seshadri, Nivedita
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Abstract
ABSTRACT
Healthy β-cells secrete insulin in a rhythmic manner to maintain glucose homeostasis; however, the molecular and metabolic players remain unclear. Uncoupling protein 2 (UCP2) expressed in the β-cells negatively impacts insulin secretion; however, its physiological function remain elusive. Increased UCP2 expression was observed during starvation suggesting that UCP2-mediated insulin suppression may prevent hypoglycemia during prolonged fasting. Building on this finding we hypothesize that, in healthy β-cells, UCP2 regulates diurnal cycles of insulin secretion capacity and glucose homeostasis. We also propose that the β-cell circadian clock drives Ucp2 expression and controls daily cycles of insulin secretion.
Mouse models (Ucp2-βKO and wildtype (WT; C57BL6)) and synchronized clonal pancreatic β-cells (MIN6) were used to determine when Ucp2 is expressed daily and mechanisms controlling glucose-stimulated insulin secretion (GSIS) and glucose tolerance over 24h. Additionally, β-cell-specific Bmal1 knockout mouse model (Bmal1-βKO) and Bmal1 deficient MIN6 cells were used to address the role of β-cell clock in regulating GSIS capacities via fine tuning Ucp2 expression (refers to steady state mRNA levels throughout this thesis).
Ucp2 mRNA expression was rhythmic over 24h and inversely correlated with GSIS capacities in synchronized MIN6 cells and islets isolated from WT mice. Using both Ucp2-βKO mouse model and a pharmacological inhibitor of UCP2 (Genipin), we show that rhythms in GSIS capacities and glucose tolerance was UCP2 dependant. Rhythms in fuel oxidation capacities, glucose-stimulated Adenosine triphosphate (ATP) production and reactive oxygen species (ROS) production correlated with UCP2 dependant GSIS rhythms. Additionally, diurnal rhythms in Ldha mRNA expression suggested existence of additional metabolic regulators aligning GSIS capacities to maintain glucose homeostasis. Loss of Ucp2 and GSIS rhythms via decreased capacity for glucose-stimulated ATP production was observed in both models of circadian dysfunction. These defects were rescued by UCP2 inhibition using Genipin, suggesting that an intact β-cell clock control GSIS capacities via regulating Ucp2/UCP2 expression and activity.
The β-cell clock regulates daily cycles of Ucp2 mRNA expression, which is part of an important metabolic switch needed to align GSIS capacity in a time-of-day dependent manner, defining a novel function for UCP2 in the β-cell. This study highlights the relationship between the circadian timing system and control of insulin secretion over the daily time course.
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Keywords
Circadian rhythms, Uncoupling protein 2, Pancreatic Islets, Beta cells