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.

Metabolism Regulates Exposure of Pancreatic Islets to Circulating Molecules In Vivo

“…This paradigm has the advantage of preventing the hormonal changes occurring during gestation. As anticipated (13)(14)(15), animals fed HFD were heavier and more glucose intolerant than their standard chow-fed counterparts, whereas basal and glucosestimulated insulin secretion were not significantly modified ( Fig. 3A-E).…”

“…However, a contribution of the latter to the measures detailed here cannot be ruled out. This notwithstanding, alterations to molecule exposure might provide a mechanism to downregulate insulin signaling during gestation, helping to maintain the hyperglycemia required to support the energy requirements of fetal growth, and may partly explain the impaired insulin secretion detected in mice in vivo 1 week after commencing HFD (13)(14)(15), despite improved b-cell function in isolated islets (41). Importantly, this demonstrates that molecule diffusion is a dynamic process modulated by physiological state.…”

“…Failure to compensate for increased insulin demand contributes to gestational diabetes mellitus and type 2 diabetes (T2D) in genetically predisposed individuals (10). b-Cell adaption during gestation and high-fat diet (HFD) is widely studied (11)(12)(13)(14)(15), and vessel properties are modified during these highly proliferative phases. For instance, islet blood flow varies during acute and chronic blood glucose concentration changes (4,(16)(17)(18), insulin resistance states (19), and pregnancy in the rat (20).…”

Insulin demand regulates β cell number via the unfolded protein response

“…jci.org Volume 125 Number 10 October 2015 relationship was absent in unstressed normoglycemic mice (saline infusion, Figure 3H). To learn whether this observation was unique to the hyperglycemic environment or might be a feature of increased insulin demand, we repeated the experiment in a second model of β cell adaptation, the high-fat diet-fed mouse (HFD-fed mouse) (28). β cell proliferation was more frequent in cells with active UPR in these mice, as well ( Figure 3I), despite having normal blood glucose (control diet 144 ± 8 mg/dl, high-fat diet 127 ± 11 mg/dl), suggesting that increased proliferation in β cells with active UPR may be a general feature of insulin-demand compensation.…”

Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

“…This inbred mouse strain is known to expand b-cell mass in response to diet-induced obesity (Stamateris et al 2013), so it is a good candidate for testing the effects of other potential stimuli of b-cell proliferation. Several studies in young C57BL/6 mice (!12 weeks of age) demonstrated that exenatide (administered by daily injections or a constant s.c. infusion over a period of up to 3 weeks) increased the proportion of proliferating b-cells, as identified by markers such as bromodeoxyuridine (BrdU) incorporation and Ki67 immunopositivity (Li et al 2003, Park et al 2006, Rankin & Kushner 2009, Tschen et al 2009).…”