title: Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression.
abstract: Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced β-cell mass (11, 62). Therapies aimed at expanding β-cell mass may be useful to treat T2D (14). Although feeding rodents a high-fat diet (HFD) for an extended period (3-6 mo) increases β-cell mass by inducing β-cell proliferation (16, 20, 53, 54), evidence suggests that adult human β-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human β-cells, are not known. To develop a model to identify early drivers of β-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The β-cell proliferative response also began within the first week of HFD feeding. Intriguingly, β-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory β-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse β-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human β-cell proliferation.
authors.affiliation: Division of Diabetes, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Stamateris
authors.forename: Rohit B
authors.initials: RB
authors.lastname: Sharma
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Hollern
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000235:genetics* / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology*; D002149:Energy Intake / Q000502:physiology; D018149:Glucose Intolerance / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015430:Weight Gain / Q000502:physiology
chemical_list: D001786:Blood Glucose; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D004041:Dietary Fats; D007328:Insulin
keywords: diet-induced obesity; islet replication; overnutrition; pancreatic β-cell mitosis; short-term high-fat diet