Publications by authors named "Kathryn Aston-Mourney"

16 Publications

  • Page 1 of 1

Copper Ionophores as Novel Antiobesity Therapeutics.

Molecules 2020 Oct 27;25(21). Epub 2020 Oct 27.

Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.

The therapeutic utility of the copper ionophore disulfiram was investigated in a diet-induced obesity mouse model (C57BL/6J background), both through administration in feed (0.05 to 1% ()) and via oral gavage (150 mg/kg) for up to eight weeks. Mice were monitored for body weight, fat deposition (perigonadal fat pads), metabolic changes (e.g., glucose dyshomeostasis) and pathologies (e.g., hepatic steatosis, hyperglycaemia and hypertriglyceridemia) associated with a high-fat diet. Metal-related pharmacological effects across major organs and serums were investigated using inductively coupled plasma mass spectrometry (ICP-MS). Disulfiram treatments (all modes) augmented hepatic copper in mice, markedly moderated body weight and abolished the deleterious systemic changes associated with a high-fat diet. Likewise, another chemically distinct copper ionophore H(gtsm), administered daily (oral gavage), also augmented hepatic copper and moderated mouse body weight. Postmortem histological examinations of the liver and other major organs, together with serum aminotransferases, supported the reported therapeutic safety of disulfiram. Disulfiram specifically altered systemic copper in mice and altered hepatic copper metabolism, perturbing the incorporation of copper into ceruloplasmin (holo-ceruloplasmin biosynthesis) and subsequently reducing serum copper concentrations. Serum ceruloplasmin represents a biomarker for disulfiram activity. Our results establish copper ionophores as a potential class of antiobesity agents.
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http://dx.doi.org/10.3390/molecules25214957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672559PMC
October 2020

Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review.

J Diabetes Complications 2021 Jan 29;35(1):107640. Epub 2020 May 29.

Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India. Electronic address:

Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107640DOI Listing
January 2021

Class IIa HDACs do not influence beta-cell function under normal or high glucose conditions.

Islets 2019 21;11(5):112-118. Epub 2019 May 21.

Metabolic Research Unit, School of Medicine, Deakin University , Waurn Ponds , Australia.

Inhibiting Class IIa Histone Deacetylase (HDAC) function is a promising approach to therapeutically enhance skeletal and cardiac muscle metabolic health in several chronic diseases including type 2 diabetes. However, the importance of Class IIa HDACs in the beta-cell remains unknown. As beta-cell function is vital to maintaining glycaemia it is essential that the importance of Class IIa HDACs in the beta-cell is determined. Here we used the INS-1E cell line cultured in normal glucose (11.1 mM) or hyperglycaemic (20 mM) conditions for 48 hrs to represent cells in a normal and diabetic environment respectively. Cells cultured in high glucose showed significantly reduced insulin secretory function and increased apoptotic signalling compared to cells cultured in normal glucose. Class IIa HDACS, HDAC-4 and -5, were not regulated at the transcript or protein level under normal or hyperglycaemic conditions suggesting that they may not play a role in beta-cell dysfunction. Furthermore, overexpression of wild-type HDAC-4 and -5 or dominant negative HDAC-4 and -5 did not alter insulin secretion, insulin mRNA expression or apoptotic signalling under normal or hyperglycaemic conditions. This suggests that Class IIa Histone Deacetylases do not play an important physiological role in the beta-cell under normal or diabetic conditions. Thus, Class IIa Histone Deacetylase inhibitors are not likely to have a detrimental effect on beta-cells supporting the use of these inhibitors to treat metabolic diseases such as type 2 diabetes.
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http://dx.doi.org/10.1080/19382014.2019.1617621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773392PMC
March 2020

APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding.

J Endocrinol 2018 06 19;237(3):311-322. Epub 2018 Apr 19.

Metabolic Research UnitSchool of Medicine and Centre for Molecular and Medical Research, Deakin University, Geelong, Victoria, Australia

The amyloid precursor protein (APP) generates a number of peptides when processed through different cleavage mechanisms, including the amyloid beta peptide that is implicated in the development of Alzheimer's disease. It is well established that APP via its cleaved peptides regulates aspects of neuronal metabolism. Emerging evidence suggests that amyloidogenic processing of APP can lead to altered systemic metabolism, similar to that observed in metabolic disease states. In the present study, we investigated the effect of APP deficiency on obesity-induced alterations in systemic metabolism. Compared with WT littermates, APP-deficient mice were resistant to diet-induced obesity, which was linked to higher energy expenditure and lipid oxidation throughout the dark phase and was associated with increased spontaneous physical activity. Consistent with this lean phenotype, APP-deficient mice fed a high-fat diet (HFD) had normal insulin tolerance. However, despite normal insulin action, these mice were glucose intolerant, similar to WT mice fed a HFD. This was associated with reduced plasma insulin in the early phase of the glucose tolerance test. Analysis of the pancreas showed that APP was required to maintain normal islet and β-cell mass under high fat feeding conditions. These studies show that, in addition to regulating aspects of neuronal metabolism, APP is an important regulator of whole body energy expenditure and glucose homeostasis under high fat feeding conditions.
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http://dx.doi.org/10.1530/JOE-18-0051DOI Listing
June 2018

Metformin, beta-cell development, and novel processes following beta-cell ablation in zebrafish.

Endocrine 2018 02 22;59(2):419-425. Epub 2017 Dec 22.

Metabolic Research Unit, School of Medicine, Deakin University, 75 Pigdons Rd, Waurn Ponds, VIC, 3216, Australia.

Purpose: Type 1 and 2 diabetes are characterized by a loss of insulin-producing beta-cells. Current treatments help maintain blood glucose levels but cannot provide a cure. As such, a vital target for the cure of diabetes is a way to restore beta-cell mass. The drug metformin can protect cultured beta-cells/islets from hyperglycemia-induced dysfunction and death. Further, treatment of pregnant mice with metformin results in an enhanced beta-cell fraction in the embryos; however, whether this occurs via a direct effect is unknown.

Methods: We utilized the external embryogenesis of the zebrafish to determine the direct effect of metformin treatment on the pancreas of the developing embryo and following beta-cell ablation.

Results: During development metformin did not alter beta-cell or alpha-cell mass but had a small effect to increase delta-cell mass as measured by in situ hybridization. Further metformin significantly increased beta-cell number. Following beta-cell ablation, both glucagon and somatostatin expression were upregulated (>2-fold). Additionally, while metformin showed no effect to alter beta-cell mass or number, somatostatin expression was further increased (>5-fold).

Conclusions: We showed that direct exposure to metformin during embryogenesis does not increase insulin-expressing area but does increase beta-cell number. Further, we identified novel consequences of beta-cell ablation to alter the expression of other pancreatic hormones that were enhanced by metformin. Therefore, this study provides a greater understanding of the beta-cell development/regenerative processes and the effect of metformin, bringing us closer to identifying how to increase beta-cells in humans.
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http://dx.doi.org/10.1007/s12020-017-1502-3DOI Listing
February 2018

Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice.

Diabetes Obes Metab 2017 07 3;19(7):936-943. Epub 2017 Mar 3.

Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.

Aim: To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity.

Materials And Methods: Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function.

Results: Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function.

Conclusion: These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.
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http://dx.doi.org/10.1111/dom.12896DOI Listing
July 2017

Gene expression signature: a powerful approach for drug discovery in diabetes.

J Endocrinol 2017 02 7;232(2):R131-R139. Epub 2016 Dec 7.

Metabolic Research UnitSchool of Medicine, Deakin University, Geelong, Australia

Type 2 diabetes (T2D) is increasing in prevalence at an alarming rate around the world. Much effort has gone into the discovery and design of antidiabetic drugs; however, those already available are unable to combat the underlying causes of the disease and instead only moderate the symptoms. The reason for this is that T2D is a complex disease, and attempts to target one biological pathway are insufficient to combat the full extent of the disease. Additionally, the underlying pathophysiology of this disease is yet to be fully elucidated making it difficult to design drugs that target the mechanisms involved. Therefore, the approach of designing new drugs aimed at a specific molecular target is not optimal and a more expansive, unbiased approach is required. In this review, we will look at the current state of diabetes treatments and how these target the disease symptoms but are unable to combat the underlying causes. We will also review how the technique of gene expression signatures (GESs) has been used successfully for other complex diseases and how this may be applied as a powerful tool for the discovery of new drugs for T2D.
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http://dx.doi.org/10.1530/JOE-16-0515DOI Listing
February 2017

One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice.

Am J Physiol Endocrinol Metab 2013 Aug 4;305(4):E475-84. Epub 2013 Jun 4.

Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington;

The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve β-cell mass. However, sitagliptin also increases β-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is cosecreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated β-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing β-cell secretory demand and could therefore offset sitagliptin's potential proamyloidogenic effects. Sitagliptin treatment has also been reported to be detrimental to the exocrine pancreas. We investigated whether long-term sitagliptin treatment, alone or with metformin, increased islet amyloid deposition and β-cell toxicity and induced pancreatic ductal proliferation, pancreatitis, and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and nontransgenic littermates were followed for 1 yr on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, β-cell mass, insulin release, and measures of exocrine pancreas pathology were determined. Relative to untreated mice, sitagliptin treatment did not increase amyloid deposition, despite increasing hIAPP release, and prevented amyloid-induced β-cell loss. Metformin treatment alone or with sitagliptin decreased islet amyloid deposition to a similar extent vs untreated mice. Ductal proliferation was not altered among treatment groups, and no evidence of pancreatitis, ductal metaplasia, or neoplasia were observed. Therefore, long-term sitagliptin treatment stimulates β-cell secretion without increasing amyloid formation and protects against amyloid-induced β-cell loss. This suggests a novel effect of sitagliptin to protect the β-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas.
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http://dx.doi.org/10.1152/ajpendo.00025.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891222PMC
August 2013

Adipocytokines as features of the metabolic syndrome determined using confirmatory factor analysis.

Ann Epidemiol 2013 Jul 25;23(7):415-21. Epub 2013 Mar 25.

Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System, Seattle, WA 98108, USA.

Purpose: Confirmatory factor analysis (CFA) was used to test the hypothesis whether adipocytokines are associated with the risk factor cluster that characterizes the metabolic syndrome (MetS).

Methods: Data from 134 nondiabetic subjects were analyzed using CFA. Insulin sensitivity (SI) was quantified using intravenous glucose tolerance tests, visceral fat area by computed tomography and fasting high-density lipoprotein, triglycerides, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA), tumor necrosis factor (TNF)-α, adiponectin, resistin, leptin, interleukin (IL)-6, C-reactive protein (CRP), and plasminogen activator inhibitor (PAI)-1 were measured.

Results: The basic model representing the MetS included six indicators comprising obesity, SI, lipids, and hypertension, and demonstrated excellent goodness of fit. Using multivariate analysis, MCP-1, SAA, and TNF-α were not independently associated with any of the MetS variables. Adiponectin, resistin, leptin, CRP, and IL-6 were associated with at least one of the risk factors, but when added to the basic model decreased all goodness-of-fit parameters. PAI-1 was associated with all cardiometabolic factors and improved goodness-of-fit compared with the basic model.

Conclusions: Addition of PAI-1 increased the CFA model goodness of fit compared with the basic model, suggesting that this protein may represent an added feature of the MetS.
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http://dx.doi.org/10.1016/j.annepidem.2013.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778191PMC
July 2013

Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide.

J Biol Chem 2013 Feb 10;288(5):3553-9. Epub 2012 Dec 10.

Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA.

Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but nontransgenic islets do not, a broad spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.
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http://dx.doi.org/10.1074/jbc.M112.438457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561574PMC
February 2013

β-cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition.

Am J Pathol 2011 Jun;178(6):2632-40

Division of Metabolism, Endocrinology and Nutrition, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington, USA.

Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased β-cell area, and increased β-cell apoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition (r = -0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes.
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http://dx.doi.org/10.1016/j.ajpath.2011.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123989PMC
June 2011

Neprilysin impedes islet amyloid formation by inhibition of fibril formation rather than peptide degradation.

J Biol Chem 2010 Jun 16;285(24):18177-83. Epub 2010 Apr 16.

Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108, USA.

Deposition of islet amyloid polypeptide (IAPP) as islet amyloid in type 2 diabetes contributes to loss of beta-cell function and mass, yet the mechanism for its occurrence is unclear. Neprilysin is a metallopeptidase known to degrade amyloid in Alzheimer disease. We previously demonstrated neprilysin to be present in pancreatic islets and now sought to determine whether it plays a role in degrading islet amyloid. We used an in vitro model where cultured human IAPP (hIAPP) transgenic mouse islets develop amyloid and thereby have increased beta-cell apoptosis. Islet neprilysin activity was inhibited or up-regulated using a specific inhibitor or adenovirus encoding neprilysin, respectively. Following neprilysin inhibition, islet amyloid deposition and beta-cell apoptosis increased by 54 and 75%, respectively, whereas when neprilysin was up-regulated islet amyloid deposition and beta-cell apoptosis both decreased by 79%. To determine if neprilysin modulated amyloid deposition by cleaving hIAPP, analysis of hIAPP incubated with neprilysin was performed by mass spectrometry, which failed to demonstrate neprilysin-induced cleavage. Rather, neprilysin may act by reducing hIAPP fibrillogenesis, which we showed to be the case by fluorescence-based thioflavin T binding studies and electron microscopy. In summary, neprilysin decreases islet amyloid deposition by inhibiting hIAPP fibril formation, rather than degrading hIAPP. These findings suggest that targeting the role of neprilysin in IAPP fibril assembly, in addition to IAPP cleavage by other peptidases, may provide a novel approach to reduce and/or prevent islet amyloid deposition in type 2 diabetes.
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http://dx.doi.org/10.1074/jbc.M109.082032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881741PMC
June 2010

Fructose-1,6-bisphosphatase overexpression in pancreatic beta-cells results in reduced insulin secretion: a new mechanism for fat-induced impairment of beta-cell function.

Diabetes 2008 Jul 28;57(7):1887-95. Epub 2008 Mar 28.

Department of Medicine, Heidelberg Repatriation Hospital, University of Melbourne, Heidelberg Heights, Victoria, Australia.

Objective: Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is upregulated in islets or pancreatic beta-cell lines exposed to high fat. However, whether specific beta-cell upregulation of FBPase can impair insulin secretory function is not known. The objective of this study therefore is to determine whether a specific increase in islet beta-cell FBPase can result in reduced glucose-mediated insulin secretion.

Research Design And Methods: To test this hypothesis, we have generated three transgenic mouse lines overexpressing the human FBPase (huFBPase) gene specifically in pancreatic islet beta-cells. In addition, to investigate the biochemical mechanism by which elevated FBPase affects insulin secretion, we made two pancreatic beta-cell lines (MIN6) stably overexpressing huFBPase.

Results: FBPase transgenic mice showed reduced insulin secretion in response to an intravenous glucose bolus. Compared with the untransfected parental MIN6, FBPase-overexpressing cells showed a decreased cell proliferation rate and significantly depressed glucose-induced insulin secretion. These defects were associated with a decrease in the rate of glucose utilization, resulting in reduced cellular ATP levels.

Conclusions: Taken together, these results suggest that upregulation of FBPase in pancreatic islet beta-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.
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http://dx.doi.org/10.2337/db07-1326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453625PMC
July 2008

Differential effect of inbred mouse strain (C57BL/6, DBA/2, 129T2) on insulin secretory function in response to a high fat diet.

J Endocrinol 2005 Oct;187(1):45-53

University of Melbourne, Department of Medicine, Heidelberg Repatriation Hospital, Heidelberg Heights, Victoria 3081, Australia.

The increasing production of genetically-modified mouse models has necessitated studies to determine the inherent physiological characteristics of commonly used mouse strains. In this study we examined insulin secretory function in response to an intravenous bolus of glucose or glucose plus arginine in anesthetized C57BL/6, DBA/2 and 129T2 mice fed either a control or high fat diet for 6 weeks. The results show that 129T2 mice had higher fasting plasma glucose levels and lower fasting plasma insulin levels compared with C57BL/6 and DBA/2 mice regardless of diet. Furthermore, 129T2 mice were glucose intolerant and secreted significantly less insulin in response to glucose and glucose plus arginine irrespective of diet compared with the other two strains of mice. DBA/2 mice hypersecreted insulin in response to glucose and glucose plus arginine compared with C57BL/6 and 129T2 mice. Moreover while first phase insulin secretion was appropriately increased in response to the high fat diet in C57BL/6 and 129T2 mice, this was not the case for DBA/2 mice. Mean islet area was decreased in response to a high fat diet in DBA/2 mice, while there was no dietary effect on the other two strains. This study highlights the inherent genetic differences that exist among seemingly normal strains of mice that are commonly used to make transgenic and knockout mice. Understanding these differences will provide researchers with the information to choose the appropriate genetic background on which to express their particular genetic alteration.
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http://dx.doi.org/10.1677/joe.1.06333DOI Listing
October 2005

Investigational agents that protect pancreatic islet beta-cells from failure.

Expert Opin Investig Drugs 2005 Oct;14(10):1241-50

Department of Medicine (AH/NH), Heidelberg Repatriation Hospital, University of Melbourne, Heidelberg Heights, Victoria 3081, Australia.

Type 2 diabetes is associated with insulin resistance and reduced insulin secretion, which results in hyperglycaemia. This can then lead to diabetic complications such as retinopathy, neuropathy, nephropathy and cardiovascular disease. Although insulin resistance may be present earlier in the progression of the disease, it is now generally accepted that it is the deterioration in insulin-secretory function that leads to hyperglycaemia. This reduction in insulin secretion in Type 2 diabetes is due to both islet beta-cell dysfunction and death. Therefore, interventions that maintain the normal function and protect the pancreatic islet beta-cells from death are crucial in the treatment of Type 2 diabetes so that plasma glucose levels may be maintained within the normal range. Recently, a number of compounds have been shown to protect beta-cells from failure. This review examines the evidence that the existing therapies for Type 2 diabetes that were developed to lower plasma glucose (metformin) or improve insulin sensitivity (thiazolidinediones) may also have islet-protective function. Newer emerging therapeutic agents that are designed to increase the levels of glucagon-like peptide-1 not only stimulate insulin secretion but also appear to increase islet beta-cell mass. Evidence will also be presented that the future of drug therapy designed to prevent beta-cell failure should target the formation of advanced glycation end products and alleviate oxidative and endoplasmic reticulum stress.
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http://dx.doi.org/10.1517/13543784.14.10.1241DOI Listing
October 2005

High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction.

J Mol Endocrinol 2005 Aug;35(1):39-48

University of Melbourne, Department of Medicine, Heidelberg Repatriation Hospital, 300 Waterdale Road, Heidelberg Heights, Victoria 3081, Australia.

Type 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2.8 mM glucose) insulin release was increased in both DBA/2 and C57BL/6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BL/6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.
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http://dx.doi.org/10.1677/jme.1.01720DOI Listing
August 2005