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.
Aims/hypothesis We determined whether hyperglycaemia stimulates human beta cell replication in vivo in an islet transplant model Methods Human islets were transplanted into streptozotocininduced diabetic NOD-severe combined immunodeficiency mice. Blood glucose was measured serially during a 2 week graft revascularisation period. Engrafted mice were then catheterised in the femoral artery and vein, and infused intravenously with BrdU for 4 days to label replicating beta cells. Mice with restored normoglycaemia were co-infused with either 0.9% (wt/vol.) saline or 50% (wt/vol.) glucose to generate glycaemic differences among grafts from the same donors. During infusions, blood glucose was measured daily. After infusion, human beta cell replication and apoptosis were measured in graft sections using immunofluorescence for insulin, and BrdU or TUNEL. Results Human islet grafts corrected diabetes in the majority of cases. Among grafts from the same donor, human beta cell proliferation doubled in those exposed to higher glucose relative to lower glucose. Across the entire cohort of grafts, higher blood glucose was strongly correlated with increased beta cell replication. Beta cell replication rates were unrelated to circulating human insulin levels or donor age, but tended to correlate with donor BMI. Beta cell TUNEL reactivity was not measurably increased in grafts exposed to elevated blood glucose. Conclusions/interpretation Glucose is a mitogenic stimulus for transplanted human beta cells in vivo. Investigating the underlying pathways may point to mechanisms capable of expanding human beta cell mass in vivo.
Pancreatic β-cell proliferation is infrequent in adult humans and is not increased in type 2 diabetes despite obesity and insulin resistance, suggesting the existence of inhibitory factors. Free fatty acids (FFAs) may influence proliferation. In order to test whether FFAs restrict β-cell proliferation in vivo, mice were intravenously infused with saline, Liposyn II, glucose, or both, continuously for 4 days. Lipid infusion did not alter basal β-cell proliferation, but blocked glucose-stimulated proliferation, without inducing excess β-cell death. In vitro exposure to FFAs inhibited proliferation in both primary mouse β-cells and in rat insulinoma (INS-1) cells, indicating a direct effect on β-cells. Two of the fatty acids present in Liposyn II, linoleic acid and palmitic acid, both reduced proliferation. FFAs did not interfere with cyclin D2 induction or nuclear localization by glucose, but increased expression of inhibitor of cyclin dependent kinase 4 (INK4) family cell cycle inhibitors p16 and p18. Knockdown of either p16 or p18 rescued the antiproliferative effect of FFAs. These data provide evidence for a novel antiproliferative form of β-cell glucolipotoxicity: FFAs restrain glucose-stimulated β-cell proliferation in vivo and in vitro through cell cycle inhibitors p16 and p18. If FFAs reduce proliferation induced by obesity and insulin resistance, targeting this pathway may lead to new treatment approaches to prevent diabetes.
Background: Pseudarthrosis following spinal fusion is a complication that frequently requires revision surgery. Reported rates of pseudarthrosis after surgical site infection (SSI) range from 30% to 85%, but few studies have identified infection as an independent risk factor for its development. The purpose of this study was to determine the incidence of clinically symptomatic pseudarthrosis in patient who developed SSI following lumbar fusion and to identify factors associated with its development. Methods: This was a retrospective review of a prospectively collected database. Patients who underwent spinal surgery and developed SSI between January 2005 and March 2015 with a minimum 2-year follow-up were included. Patient-specific and procedural characteristics were recorded. Presence of pseudarthrosis was determined clinically by the treating surgeon and was confirmed radiographically. All those in the Pseudarthrosis group required a revision procedure after the eradication of infection. Univariate and multivariate analyses were conducted as appropriate. Results: A total of 416 patients were included. Of these, 21 (5.0%) developed symptomatic pseudarthrosis following SSI. In this cohort, multivariate regression showed that age, Charlson Comorbidity Index, male sex, and surgical approach were not significant predictors of pseudarthrosis formation. However, number of levels fused was found to be the leading predictor for pseudarthrosis development (odds ratio [OR], 1.356/level, P , .001), followed by body mass index (OR, 1.083/point, P , .009) in this cohort. The number of levels fused was found to be a significant predictor of hardware removal (OR, 1.190/level, P , .001). Of the 21 pseudarthrosis cases, 85.7% found staphylococcal species, of which 27.8% exhibited methicillin-resistant Staphylococcus aureus. Conclusions: The number of spinal levels fused and body mass index are independent predictors of pseudarthrosis in patients who develop SSI after spinal fusion. Level of Evidence: Level 4 Clinical Relevance: This is the first known study to specifically identify risk factors for the development of symptomatic pseudarthrosis.
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