Diabetes is a disease characterized by a relative or absolute lack of insulin, leading to hyperglycaemia. There are two main types of diabetes: type 1 diabetes and type 2 diabetes. Type 1 diabetes is due to an autoimmune destruction of the insulin-producing pancreatic beta cells, and type 2 diabetes is caused by insulin resistance coupled by a failure of the beta cell to compensate. Animal models for type 1 diabetes range from animals with spontaneously developing autoimmune diabetes to chemical ablation of the pancreatic beta cells. Type 2 diabetes is modelled in both obese and non-obese animal models with varying degrees of insulin resistance and beta cell failure. This review outlines some of the models currently used in diabetes research. In addition, the use of transgenic and knock-out mouse models is discussed. Ideally, more than one animal model should be used to represent the diversity seen in human diabetic patients.

LINKED ARTICLES

Animal Models

This paper is the latest in a series of publications on the use of animal models in pharmacology research. Readers might be interested in the previous papers.

Robinson V (2009). Less is more: reducing the reliance on animal models for nausea and vomiting research.

Holmes AM, Rudd JA, Tattersall FD, Aziz Q, Andrews PLR (2009). Opportunities for the replacement of animals in the study of nausea and vomiting.

Giacomotto J and Segalat L (2010). High-throughput screening and small animal models, where are we?

McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL (2010). Guidelines for reporting experiments involving animals: the ARRIVE guidelines.

Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG (2010). The ARRIVE guidelines.

Emerson M (2010). Refinement, reduction and replacement approaches to in vivo cardiovascular research.

Berge O-G (2011). Predictive validity of behavioural animal models for chronic pain.

Vickers SP, Jackson HC and Cheetham SC (2011). The utility of animal models to evaluate novel anti-obesity agents.

Percie du Sert N, Holmes AM, Wallis R, Andrews PLR (2012). Predicting the emetic liability of novel chemical entities: a comparative study.

The complete series including future publications, as they occur, can be found at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1476-5381/homepage/animal_models.htm.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2012.01911.x

The use of animal models in diabetes research

Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

Metabolic Signaling in Fuel-Induced Insulin Secretion

Background: Changes in gene expression in pancreatic beta-cells from type 2 diabetes (T2D) should provide insights into their abnormal insulin secretion and turnover. Methodology/Principal Findings: Frozen sections were obtained from cadaver pancreases of 10 control and 10 T2D human subjects. Beta-cell enriched samples were obtained by laser capture microdissection (LCM). RNA was extracted, amplified and subjected to microarray analysis. Further analysis was performed with DNA-Chip Analyzer (dChip) and Gene Set Enrichment Analysis (GSEA) software. There were changes in expression of genes linked to glucotoxicity. Evidence of oxidative stress was provided by upregulation of several metallothionein genes. There were few changes in the major genes associated with cell cycle, apoptosis or endoplasmic reticulum stress. There was differential expression of genes associated with pancreatic regeneration, most notably upregulation of members of the regenerating islet gene (REG) family and metalloproteinase 7 (MMP7). Some of the genes found in GWAS studies to be related to T2D were also found to be differentially expressed. IGF2BP2, TSPAN8, and HNF1B (TCF2) were upregulated while JAZF1 and SLC30A8 were downregulated. Conclusions/Significance: This study made possible by LCM has identified many novel changes in gene expression that enhance understanding of the pathogenesis of T2D.

/pdf/gene-expression-profiles-of-beta-cell-enriched-tissue-2in4qqhlu5.pdf

Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes.

Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. During postprandial periods an elevated level of plasma glucose rapidly stimulates insulin secretion to decrease hepatic glucose output and promote glucose uptake into other tissues, principally muscle and adipose tissues. Beta cell mitochondria play a key role in this process, not only by providing energy in the form of ATP to support insulin secretion, but also by synthesising metabolites (anaplerosis) that can act, both intra- and extramitochondrially, as factors that couple glucose sensing to insulin granule exocytosis. ATP on its own, and possibly modulated by these coupling factors, triggers closure of the ATP-sensitive potassium channel, resulting in membrane depolarisation that increases intracellular calcium to cause insulin secretion. The metabolic imbalance caused by chronic hyperglycaemia and hyperlipidaemia severely affects mitochondrial metabolism, leading to the development of impaired glucose-induced insulin secretion in type 2 diabetes. It appears that the anaplerotic enzyme pyruvate carboxylase participates directly or indirectly in several metabolic pathways which are important for glucose-induced insulin secretion, including: the pyruvate/malate cycle, the pyruvate/citrate cycle, the pyruvate/isocitrate cycle and glutamate-dehydrogenase-catalysed α-ketoglutarate production. These four pathways enable ‘shuttling’ or ‘recycling’ of these intermediate(s) into and out of mitochondrion, allowing continuous production of intracellular messenger(s). The purpose of this review is to present an account of recent progress in this area of central importance in the realm of diabetes and obesity research.

/pdf/regulation-of-insulin-secretion-role-of-mitochondrial-q3ofh28yle.pdf

Regulation of insulin secretion: role of mitochondrial signalling

Although insulin independence is maintained in most islet recipients at 1 yr after transplant, extended follow-up has revealed that many patients will eventually require insulin therapy. Previous studies have shown that islet autografts are prone to chronic failure in large animals and humans, suggesting that nonimmunological events contribute to islet graft functional decay. Early intervention with therapies that promote graft stability should provide a measurable benefit over time. In this study, the efficacy of the long-acting glucagon-like peptide-1 analog liraglutide was explored in a porcine marginal mass islet autograft transplant model. Incubation with liraglutide enhanced porcine islet survival and function after prolonged culture. Most vehicle-treated (83%) and liraglutide-treated (80%) animals became insulin independent after islet autotransplantation. Although liraglutide therapy did not improve insulin independence rates or blood glucose levels after transplant, a significant increase in insulin secretion and acute-phase insulin response was observed in treated animals. Surprisingly, no evidence for deterioration of graft function was observed in any of the transplanted animals over more than 18 months of follow-up despite significant weight gain; in fact, an enhanced response to glucose developed over time even in control animals. Histological analysis showed that intraportally transplanted islets remained highly insulin positive, retained alpha-cells, and did not form amyloid deposits. This study demonstrates that marginal mass porcine islet autografts have stable long-term function, even in the presence of an increasing metabolic demand. These results are discrepant with previous large animal studies and suggest that porcine islets may be resistant to metabolic failure.

Porcine Marginal Mass Islet Autografts Resist Metabolic Failure Over Time and Are Enhanced by Early Treatment with Liraglutide

Traditionally, studies of cells and tissues have been performed on isolated primary cells or immortalized cell lines by culturing them in 2D culture dishes or flasks. However, a caveat regarding 2D culture is that the cells poorly recapitulate their in vivo counterparts, mainly due to a lack of 3D cell-cell and cell-extracellular matrix interactions. In recent years, the development of in vitro organoids as 3D culture has gained substantial attention as a model to study different tissues. In adults, pancreatic ductal cells are considered as a source of stem or progenitor cells, so developing new methods to study ductal cells would be useful. Here, we provide a protocol to isolate mouse pancreatic ductal cells and a cost-effective protocol to generate 3D organoid structures from such ductal cells. Additionally, we have devised a protocol for immunostaining of intact whole organoids without sectioning. © 2018 by John Wiley & Sons, Inc.

/pdf/generation-of-pancreatic-ductal-organoids-and-whole-mount-2ydmgc4imq.pdf

Generation of Pancreatic Ductal Organoids and Whole-Mount Immunostaining of Intact Organoids

Aims/hypothesis
The pyruvate–malate shuttle is a metabolic cycle in pancreatic beta cells and is important for beta cell function Cytosolic malic enzyme (ME) carries out an essential step in the shuttle by converting malate to pyruvate and generating NADPH In rat islets the pyruvate–malate shuttle may regulate insulin secretion and it has been shown to play a critical role in adaptation to obesity and insulin resistance However, ME has not been demonstrated in mouse islets and three reports indicate that mouse islets contain no ME activity If mouse islets lack ME, rat and mouse islets must regulate insulin secretion by different mechanisms

https://link.springer.com/content/pdf/10.1007%2Fs00125-008-1155-0.pdf

Malic enzyme is present in mouse islets and modulates insulin secretion

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Porcine Marginal Mass Islet Autografts Resist Metabolic Failure Over Time and Are Enhanced by Early Treatment with Liraglutide

Generation of Pancreatic Ductal Organoids and Whole-Mount Immunostaining of Intact Organoids

Malic enzyme is present in mouse islets and modulates insulin secretion