Papers by Grace Fergusson
The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. Previo... more The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. Previously we observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat islets to HB-EGF stimulated β-cell proliferation, whereas inhibition of EGFR or HB-EGF blocked the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in islets blocked β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels were increased in β-cells in response to glucose in a carbohydrate response eleme...
American Journal of Physiology-Endocrinology and Metabolism
The pancreatic β-cell responds to changes in the nutrient environment to maintain glucose homeost... more The pancreatic β-cell responds to changes in the nutrient environment to maintain glucose homeostasis by adapting its function and mass. Nutrients can act directly on the β-cell and also indirectly through the brain via autonomic nerves innervating islets. Despite the importance of the brain-islet axis in insulin secretion, relatively little is known regarding its involvement in β-cell proliferation. We previously demonstrated that prolonged infusions of nutrients in rats provoke a dramatic increase in β-cell proliferation in part because of the direct action of nutrients. Here, we addressed the contribution of the autonomic nervous system. In isolated islets, muscarinic stimulation increased, whereas adrenergic stimulation decreased, glucose-induced β-cell proliferation. Blocking α-adrenergic receptors reversed the effect of epinephrine on glucose + nonesterified fatty acids (NEFA)-induced β-cell proliferation, whereas activation of β-adrenergic receptors was without effect. Infusi...
The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. Previo... more The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. Previously we observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat islets to HB-EGF stimulated β-cell proliferation, whereas inhibition of EGFR or HB-EGF blocked the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in islets blocked β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels were increased in β-cells in response to glucose in a carbohydrate response eleme...
Journal of Visualized Experiments, 2013
Chronic exposure to excessive levels of nutrients is postulated to affect the function of several... more Chronic exposure to excessive levels of nutrients is postulated to affect the function of several organs and tissues and to contribute to the development of the many complications associated with obesity and the metabolic syndrome, including type 2 diabetes. To study the mechanisms by which excessive levels of glucose and fatty acids affect the pancreatic beta-cell and the secretion of insulin, we have established a chronic nutrient infusion model in the rat. The procedure consists of catheterizing the right jugular vein and left carotid artery under general anesthesia; allowing a 7-day recuperation period; connecting the catheters to the pumps using a swivel and counterweight system that enables the animal to move freely in the cage; and infusing glucose and/or Intralipid (a soybean oil emulsion which generates a mixture of approximately 80% unsaturated/20% saturated fatty acids when infused with heparin) for 72 hr. This model offers several advantages, including the possibility to finely modulate the target levels of circulating glucose and fatty acids; the option to co-infuse pharmacological compounds; and the relatively short time frame as opposed to dietary models. It can be used to examine the mechanisms of nutrient-induced dysfunction in a variety of organs and to test the effectiveness of drugs in this context.
Molecular Metabolism, 2014
The C57Bl/6J (Bl/6J) mouse is the most widely used strain in metabolic research. This strain carr... more The C57Bl/6J (Bl/6J) mouse is the most widely used strain in metabolic research. This strain carries a mutation in nicotinamide nucleotide transhydrogenase (Nnt), a mitochondrial enzyme involved in NADPH production, which has been suggested to lead to glucose intolerance and beta-cell dysfunction. However, recent reports comparing Bl/6J to Bl/6N (carrying the wild-type Nnt allele) under normal diet have led to conflicting results using glucose tolerance tests. Thus, we assessed glucose-stimulated insulin secretion (GSIS), insulin sensitivity, clearance and central glucose-induced insulin secretion in Bl/6J and N mice using gold-standard methodologies. GSIS was measured using complementary tests (oral and intravenous glucose tolerance tests) and hyperglycemic clamps. Whole-body insulin sensitivity was assessed using euglycemic-hyperinsulinemic clamps. Neurally-mediated insulin secretion was measured during central hyperglycemia. Bl/6J mice have impaired GSIS compared to Bl/6N when glucose is administered intravenously during both a tolerance test and hyperglycemic clamp, but not in response to oral glucose. First and second phases of GSIS are altered without changes in whole body insulin sensitivity, insulin clearance, beta-cell mass or central response to glucose, thereby demonstrating defective beta-cell function in Bl/6J mice. The Bl/6J mouse strain displays impaired insulin secretion. These results have important implications for choosing the appropriate test to assess beta-cell function and background strain in genetically modified mouse models.
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Papers by Grace Fergusson