Circadian Disruption and Diet-Induced Obesity Synergize to Promote Development of β-Cell Failure and Diabetes in Male Rats.
There are clear epidemiological associations between circadian disruption, obesity, and pathogenesis of type 2 diabetes. The mechanisms driving these associations are unclear. In the current study, we hypothesized that continuous exposure to constant light (LL) compromises pancreatic β-cell functional and morphological adaption to diet-induced obesity leading to development of type 2 diabetes. To address this hypothesis, we studied wild type Sprague Dawley as well as Period-1 luciferase reporter transgenic rats (Per1-Luc) for 10 weeks under standard light-dark cycle (LD) or LL with concomitant ad libitum access to either standard chow or 60% high-fat diet (HFD). Exposure to HFD led to a comparable increase in food intake, body weight, and adiposity in both LD- and LL-treated rats. However, LL rats displayed profound loss of behavioral circadian rhythms as well as disrupted pancreatic islet clock function characterized by the impairment in the amplitude and the phase islet clock oscillations. Under LD cycle, HFD did not adversely alter diurnal glycemia, diurnal insulinemia, β-cell secretory function as well as β-cell survival, indicating successful adaptation to increased metabolic demand. In contrast, concomitant exposure to LL and HFD resulted in development of hyperglycemia characterized by loss of diurnal changes in insulin secretion, compromised β-cell function, and induction of β-cell apoptosis. This study suggests that circadian disruption and diet-induced obesity synergize to promote development of β-cell failure, likely mediated as a consequence of impaired islet clock function.
Department of Physiology and Biomedical Engineering (K.R., A.V.M.), Mayo Clinic School of Medicine, Mayo Clinic, Rochester, Minnesota 55905; and Department of Medicine (B.Y., A.V.M.) and Laboratory for Circadian and Sleep Medicine (J.Q., C.S.C.), Departments of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California 90095.
Jingyi
J
Qian
Department of Physiology and Biomedical Engineering (K.R., A.V.M.), Mayo Clinic School of Medicine, Mayo Clinic, Rochester, Minnesota 55905; and Department of Medicine (B.Y., A.V.M.) and Laboratory for Circadian and Sleep Medicine (J.Q., C.S.C.), Departments of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California 90095.
Bonnie
B
Yeh
Department of Physiology and Biomedical Engineering (K.R., A.V.M.), Mayo Clinic School of Medicine, Mayo Clinic, Rochester, Minnesota 55905; and Department of Medicine (B.Y., A.V.M.) and Laboratory for Circadian and Sleep Medicine (J.Q., C.S.C.), Departments of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California 90095.
Kuntol
K
Rakshit
Department of Physiology and Biomedical Engineering (K.R., A.V.M.), Mayo Clinic School of Medicine, Mayo Clinic, Rochester, Minnesota 55905; and Department of Medicine (B.Y., A.V.M.) and Laboratory for Circadian and Sleep Medicine (J.Q., C.S.C.), Departments of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California 90095.
Christopher S
CS
Colwell
Department of Physiology and Biomedical Engineering (K.R., A.V.M.), Mayo Clinic School of Medicine, Mayo Clinic, Rochester, Minnesota 55905; and Department of Medicine (B.Y., A.V.M.) and Laboratory for Circadian and Sleep Medicine (J.Q., C.S.C.), Departments of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California 90095.
Aleksey V
AV
Matveyenko
D050154:Adiposity; D000818:Animals; D017209:Apoptosis; D001683:Biological Clocks; D001835:Body Weight; D021081:Chronobiology Disorders / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D017930:Genes, Reporter; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008156:Luciferases; D008297:Male; D009765:Obesity / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000235:genetics; D017440:Photoperiod; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
D007328:Insulin; C539024:Per1 protein, rat; D056950:Period Circadian Proteins; D008156:Luciferases