The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, "The ...Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.
Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its ...genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.
We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (
= 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (
= 2,454 vs. 968) and type 2 diabetes (
= 2,779 vs. 10,396).
The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring
, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.
Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.
Adult-onset autoimmune diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive autoimmune process and a mild metabolic decompensation at onset compared ...with young-onset type 1 diabetes mellitus (T1DM). The majority of patients with adult-onset autoimmune diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent autoimmune diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset autoimmune diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset autoimmune diabetes and highlight the similarities and differences with classic T1DM and type 2 diabetes mellitus.
Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors
, including complex genetic elements
, patient exposures
and ...the gut microbiome
. Viral infections
and broader gut dysbioses
have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts
and a T1D mouse model
, these data support the protective effects of short-chain fatty acids in early-onset human T1D.
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 Ségalat 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.
It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These ...complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.
Diabetes mellitus (DM), a chronic metabolic disease characterised by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM have been ...increasing over the years. The complications of DM represent a serious health problem. The long‐term complications include macroangiopathy, microangiopathy and neuropathy as well as sexual dysfunction (SD) in both men and women. Erectile dysfunction (ED) has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5‐fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity and increased caloric consumption. Although lifestyle changes may help improve sexual function, specific treatments are often needed. This study aims to review the definition and prevalence of ED in DM, the impact of DM complications and DM treatment on ED and, finally, the current and emerging therapies for ED in patients with DM.
Context and Aim
Continuous glucose monitoring (CGM) is becoming widely accepted as an adjunct to diabetes management. Compared to standard care, CGM can provide detailed information about glycaemic ...variability in an internationally standardised ambulatory glucose profile, enabling more informed user and clinician decision making. We aimed to review the evidence, user experience and cost‐effectiveness of CGM.
Methods
A literature search was conducted by combining subject headings ‘CGM’ and ‘flash glucose monitoring’, with key words ‘type 1 diabetes’ and ‘type 2 diabetes’, limited to ‘1999 to current’. Further evidence was obtained from relevant references of retrieved articles.
Results
There is a strong evidence for CGM use in people with type 1 diabetes, with benefits of reduced glycated haemoglobin and hypoglycaemia, and increased time in range. While the evidence for CGM use in type 2 diabetes is less robust, similar benefits have been demonstrated. CGM can improve diabetes‐related satisfaction in people with diabetes (PWD) and parents of children with diabetes, as well as the clinician experience. However, CGM does have limitations including cost, accuracy and perceived inconvenience. Cost‐effectiveness analyses have indicated that CGM is a cost‐effective adjunct to type 1 diabetes management that is associated with reduced diabetes‐related complications and hospitalisation.
Conclusions
Continuous glucose monitoring is revolutionising diabetes management. It is a cost‐effective adjunct to diabetes management that has the potential to improve glycaemic outcomes and quality of life in PWD, especially type 1 diabetes.
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