TY - JOUR
T1 - Disruption of circadian rhythms accelerates development of diabetes through pancreatic beta-cell loss and dysfunction
AU - Gale, John E.
AU - Cox, Heather I.
AU - Qian, Jingyi
AU - Block, Gene D.
AU - Colwell, Christopher S.
AU - Matveyenko, Aleksey V.
N1 - Funding Information:
This work was supported by the Larry Hillblom Foundation and by grants from the National Institutes of Health (DK089003 and DK063491 to A.V.M.). We thank Ryan Galasso, Larry Hillblom Islet Research Center at University of California, Los Angeles, for excellent technical support. We are indebted to William Larkin, University of California, Los Angeles, for help with building environmentally controlled circadian chambers. We also thank Dr. Peter Butler, Larry Hillblom Islet Research Center at the University of California, Los Angeles, for insightful comments and critical discussions.
PY - 2011/10
Y1 - 2011/10
N2 - Type 2 diabetes mellitus (T2DM) is complex metabolic disease that arises as a consequence of interactions between genetic predisposition and environmental triggers. One recently described environmental trigger associated with development of T2DM is disturbance of circadian rhythms due to shift work, sleep loss, or nocturnal lifestyle. However, the underlying mechanisms behind this association are largely unknown. To address this, the authors examined the metabolic and physiological consequences of experimentally controlled circadian rhythm disruption in wild-type (WT) Sprague Dawley and diabetes-prone human islet amyloid polypeptide transgenic (HIP) rats: a validated model of T2DM. WT and HIP rats at 3 months of age were exposed to 10 weeks of either a normal light regimen (LD: 12:12-h light/dark) or experimental disruption in the light-dark cycle produced by either (1) 6-h advance of the light cycle every 3 days or (2) constant light protocol. Subsequently, blood glucose control, beta-cell function, beta-cell mass, turnover, and insulin sensitivity were examined. In WT rats, 10 weeks of experimental disruption of circadian rhythms failed to significantly alter fasting blood glucose levels, glucose-stimulated insulin secretion, beta-cell mass/turnover, or insulin sensitivity. In contrast, experimental disruption of circadian rhythms in diabetes-prone HIP rats led to accelerated development of diabetes. The mechanism subserving early-onset diabetes was due to accelerated loss of beta-cell function and loss of beta-cell mass attributed to increases in beta-cell apoptosis. Disruption of circadian rhythms may increase the risk of T2DM by accelerating the loss of beta-cell function and mass characteristic in T2DM.
AB - Type 2 diabetes mellitus (T2DM) is complex metabolic disease that arises as a consequence of interactions between genetic predisposition and environmental triggers. One recently described environmental trigger associated with development of T2DM is disturbance of circadian rhythms due to shift work, sleep loss, or nocturnal lifestyle. However, the underlying mechanisms behind this association are largely unknown. To address this, the authors examined the metabolic and physiological consequences of experimentally controlled circadian rhythm disruption in wild-type (WT) Sprague Dawley and diabetes-prone human islet amyloid polypeptide transgenic (HIP) rats: a validated model of T2DM. WT and HIP rats at 3 months of age were exposed to 10 weeks of either a normal light regimen (LD: 12:12-h light/dark) or experimental disruption in the light-dark cycle produced by either (1) 6-h advance of the light cycle every 3 days or (2) constant light protocol. Subsequently, blood glucose control, beta-cell function, beta-cell mass, turnover, and insulin sensitivity were examined. In WT rats, 10 weeks of experimental disruption of circadian rhythms failed to significantly alter fasting blood glucose levels, glucose-stimulated insulin secretion, beta-cell mass/turnover, or insulin sensitivity. In contrast, experimental disruption of circadian rhythms in diabetes-prone HIP rats led to accelerated development of diabetes. The mechanism subserving early-onset diabetes was due to accelerated loss of beta-cell function and loss of beta-cell mass attributed to increases in beta-cell apoptosis. Disruption of circadian rhythms may increase the risk of T2DM by accelerating the loss of beta-cell function and mass characteristic in T2DM.
KW - beta-cell
KW - beta-cell mass
KW - circadian disruption
KW - constant light
KW - insulin secretion
KW - insulin sensitivity
KW - type 2 diabetes
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U2 - 10.1177/0748730411416341
DO - 10.1177/0748730411416341
M3 - Article
C2 - 21921296
AN - SCOPUS:80755130246
SN - 0748-7304
VL - 26
SP - 423
EP - 433
JO - Journal of biological rhythms
JF - Journal of biological rhythms
IS - 5
ER -