Publications by authors named "Anne W Thorburn"

4 Publications

  • Page 1 of 1

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice.

J Endocrinol 2016 Jan 22;228(1):61-73. Epub 2015 Oct 22.

Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.

Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with β-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a ∼211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving β-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to β-cell dysfunction in T2D.
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http://dx.doi.org/10.1530/JOE-15-0290DOI Listing
January 2016

The therapeutic potential of leptin.

Expert Opin Investig Drugs 2003 Mar;12(3):373-8

Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Victoria 3050, Australia.

Many studies have reported the difficulty most subjects have in maintaining weight loss. Leptin is a cytokine-like protein made in adipose tissue and is transported into the brain by the blood-brain barrier where it inhibits food intake by altering the expression of hypothalamic neurotransmitters. The discovery of leptin raised the hope that a natural compound had been found that could cause weight loss without adverse effects. However, the majority of obese people have high levels of circulating leptin and it is not surprising that clinical trials published so far have shown that leptin only works effectively to suppress food intake in subjects who are hyperphagic as a result of low leptin levels. Obesity secondary to leptin deficiency is rare, most being associated with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels in the CNS may be required. However, there is evidence that the leptin transport mechanism is saturated at low plasma leptin concentrations, limiting the effectiveness of peripherally-administered hormone. It is concluded that for leptin to have therapeutic potential, it either needs to be modified or the transport system by which leptin enters the brain needs to be upregulated to allow leptin to enter the brain more easily. To achieve effective weight loss, it may also be necessary to overcome central leptin insensitivity by developing agents that act downstream of leptin action.
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http://dx.doi.org/10.1517/13543784.12.3.373DOI Listing
March 2003

Effect of low-glycemic-index dietary advice on dietary quality and food choice in children with type 1 diabetes.

Am J Clin Nutr 2003 Jan;77(1):83-90

Department of Nutrition and Food Services, Royal Children's Hospital, Melbourne, Parkville, VIC, Australia.

Background: The practicality of diets with a low glycemic index (GI) is controversial. Theoretically, low-GI diets may limit food choice and increase dietary fat intake, but there is little objective evidence to support such a theory.

Objective: The objective was to determine the effect of low-GI dietary advice on dietary quality and food choice in children with diabetes.

Design: Children aged 8-13 y with type 1 diabetes (n = 104) were recruited to a prospective, randomized study comparing the effects of traditional carbohydrate-exchange dietary advice (CHOx) with those of more flexible low-GI dietary advice (LowGI). We determined the effect on long-term macronutrient intake and food choice with the use of 3-d food diaries.

Results: There were no differences in reported macronutrient intakes during any of the recording periods. After 12 mo, intakes of dietary fat (33.5 +/- 5.6% and 34.2 +/- 6.7% of energy, P = 0.65), carbohydrate (48.8 +/- 5.4% and 48.6 +/- 6.5% of energy, P = 0.86), protein (17.6 +/- 2.5% and 17.3 +/- 3.7% of energy, P = 0.61), total sugars, and fiber did not differ significantly between the CHOx and LowGI groups, respectively. The average number of different carbohydrate food choices per day also did not differ significantly. Subjects in the lowest-GI quartile consumed less carbohydrate as potato and white bread, but more carbohydrate as dairy-based foods and whole-grain breads than did subjects in the highest-GI quartile.

Conclusion: Children with diabetes who receive low-GI dietary advice do not report more limited food choices or a diet with worse macronutrient composition than do children who consume a traditional carbohydrate-exchange diet.
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http://dx.doi.org/10.1093/ajcn/77.1.83DOI Listing
January 2003

Comparison of insulin secretory function in two mouse models with different susceptibility to beta-cell failure.

Endocrinology 2002 Jun;143(6):2085-92

University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

Type 2 diabetes is characterized by a susceptibility to beta-cell failure. However, subjects at risk of developing type 2 diabetes, such as those with obesity or a family history of diabetes, have been shown to display hyperinsulinemia. Although this hyperinsulinemia may be an adaptive response to insulin resistance, the possibility that insulin hypersecretion may be a primary defect has not been thoroughly investigated. The DBA/2 mouse is a model of pancreatic islet susceptibility. Unlike the resistant C57BL/6 mouse strain, the DBA/2 mouse islet fails when stressed with insulin resistance or when exposed to chronic high glucose concentrations. The aim of this study was to compare insulin secretory function in the DBA/2 and C57BL/6 strains in the absence of insulin resistance or high glucose. Insulin secretion was assessed in vivo using the iv glucose tolerance test and in vitro using isolated islets in static incubations. It was shown that DBA/2 mice hypersecreted insulin in vivo, compared with C57BL/6 mice, at 1 d and at 4 and 10 wk of age. This hypersecretion was not attributable to insulin resistance (as assessed by the insulin tolerance test) or increased parasympathetic nervous system outflow. Insulin hypersecretion was also demonstrated in vitro. This was associated with higher glycolysis and glucose oxidation, and elevated activity (but not protein levels) of islet glucokinase and hexokinase. Furthermore, GLUT2 protein levels were higher, which may explain an increase in glucokinase activity in DBA/2 mouse islets. In summary, the DBA/2 mouse, a model of islet failure, has increased glucose-mediated insulin secretion from a very early age, which is associated with an increase in glucose utilization. Further studies will determine whether there is a link between insulin hypersecretion and subsequent beta-cell failure.
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http://dx.doi.org/10.1210/endo.143.6.8859DOI Listing
June 2002