Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes.

Objective This study aimed to report on the trends in incidence and prevalence rates of diabetes mellitus in Saudi Arabia over the last 25 years (1990–2015). Design A descriptive review. Methods A systematic search was conducted for English-language, peer reviewed publications of any research design via Medline, EBSCO, PubMed and Scopus from 1990 to 2015. Of 106 articles retrieved, after removal of duplicates and quality appraisal, 8 studies were included in the review and synthesised based on study characteristics, design and findings. Findings Studies originated from Saudi Arabia and applied a variety of research designs and tools to diagnosis diabetes. Of the 8 included studies; three reported type 1 diabetes and five on type 2 diabetes. Overall, findings indicated that the incidence and prevalence rate of diabetes is rising particularly among females, older children/adolescent and in urban areas. Conclusion Further development are required to assess the health intervention, polices, guidelines, self-management programs in Saudi Arabia.

https://opus.lib.uts.edu.au/bitstream/10453/118920/4/Incidence%20and%20prevalence%20rates%20of%20diabetes%20mellitus%20in%20Saudi%20Arabia%20An%20overview.pdf

Incidence and prevalence rates of diabetes mellitus in Saudi Arabia: An overview.

Type 2 diabetes mellitus is a complex disorder associated with multiple genetic, epigenetic, developmental, and environmental factors. Animal models of type 2 diabetes differ based on diet, drug treatment, and gene knockouts, and yet all display the clinical hallmarks of hyperglycemia and insulin resistance in peripheral tissue. The recent advances in gene-expression microarray technologies present an unprecedented opportunity to study type 2 diabetes mellitus at a genome-wide scale and across different models. To date, a key challenge has been to identify the biological processes or signaling pathways that play significant roles in the disorder. Here, using a network-based analysis methodology, we identified two sets of genes, associated with insulin signaling and a network of nuclear receptors, which are recurrent in a statistically significant number of diabetes and insulin resistance models and transcriptionally altered across diverse tissue types. We additionally identified a network of protein–protein interactions between members from the two gene sets that may facilitate signaling between them. Taken together, the results illustrate the benefits of integrating high-throughput microarray studies, together with protein–protein interaction networks, in elucidating the underlying biological processes associated with a complex disorder.

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Network-Based Analysis of Affected Biological Processes in Type 2 Diabetes Models

Summary
Background and objectives:  Foot ulcers are one of the main complications in diabetes mellitus, with a 15% lifetime risk in all diabetic patients. The rate of lower extremity amputation among diabetic patients is 17–40 times higher than in non-diabetics. A critical triad of neuropathy, minor foot trauma and foot deformity was found in > 63% of diabetic foot ulcers (DFU). Peripheral vascular disease (PVD) has been identified in 30% of foot ulcers. We present a comprehensive assessment and the treatment of DFUs. We also want to notify physicians not to ignore foot assessment and examinations in patients with diabetes.

Methods:  We conducted this study on DFU on the basis of: pathogenesis and risk factors, assessment and physical examination, paraclinic assessment, treatment, cost and mortality and prevention.

Results and findings:  Approximately 20% of hospital admissions among diabetic patients are the result of foot problems. Diabetic foot assessment should include dermatological, vascular, neurological and musculoskeletal systems. There are three basic treatments for management of DFU: (i) debridement; (ii) antibiotics and (iii) revascularization. The cost to treat one simple ulcer is $5000 to $8000.

Conclusion:  Awareness of physicians about foot problems in diabetic patients, clinical examination and paraclinical assessment, regular foot examination, patient education, simple hygienic practices and provision of appropriate footwear combined with prompt treatment of minor injuries can decrease ulcer occurrence by 50%.

Assessment and treatment of diabetic foot ulcer.

Diabetes is a disorder characterized by loss of β cell mass and/or β cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell–derived β cells recapitulate molecular-physiological phenotypes of a diabetic subject, we generated induced pluripotent stem cells (iPSCs) from subjects with maturity-onset diabetes of the young type 2 (MODY2), which is characterized by heterozygous loss of function of the gene encoding glucokinase (GCK). These stem cells differentiated into β cells with efficiency comparable to that of controls and expressed markers of mature β cells, including urocortin-3 and zinc transporter 8, upon transplantation into mice. While insulin secretion in response to arginine or other secretagogues was identical to that in cells from healthy controls, GCK mutant β cells required higher glucose levels to stimulate insulin secretion. Importantly, this glucose-specific phenotype was fully reverted upon gene sequence correction by homologous recombination. Our results demonstrate that iPSC-derived β cells reflect β cell–autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on β cell function.

Jo McEntyre

Papers

The Genetic Landscape of Diabetes

Introduction to Diabetes

Genetic Factors in Type 2 Diabetes

Other Types of Diabetes

Genetic Factors in Type 1 Diabetes