Review of Diabetic Studies最新文献

In comparison to procedures used for the separation of individual cell types from other organs, the process of human pancreatic islet isolation aims to digest the pancreatic exocrine matrix completely without dispersing the individual cells within the endocrine cell cluster. This objective is unique within the field of tissue separation, and outlines the challenge of islet isolation to balance two opposing priorities. Although significant progress has been made in the characterization and production of enzyme blends for islet isolation, there are still numerous areas which require improvement. The ultimate goal of enzyme production, namely the routine production of a consistent and standardized enzyme blend, has still not been realized. This seems to be mainly the result of a lack of detailed knowledge regarding the structure of the pancreatic extracellular matrix and the synergistic interplay between collagenase and different supplementary proteases during the degradation of the extracellular matrix. Furthermore, the activation of intrinsic proteolytic enzymes produced by the pancreatic acinar cells, also impacts on the chance of a successful outcome of human islet isolation. This overview discusses the challenges of pancreatic enzymatic digestion during human islet isolation, and outlines the developments in this field over the past 5 decades.

Transplantation of pancreatic islets encapsulated within immuno-protective microcapsules is a strategy that has the potential to overcome graft rejection without the need for toxic immunosuppressive medication. However, despite promising preclinical studies, clinical trials using encapsulated islets have lacked long-term efficacy, and although generally considered clinically safe, have not been encouraging overall. One of the major factors limiting the long-term function of encapsulated islets is the host's immunological reaction to the transplanted graft which is often manifested as pericapsular fibrotic overgrowth (PFO). PFO forms a barrier on the capsule surface that prevents the ingress of oxygen and nutrients leading to islet cell starvation, hypoxia and death. The mechanism of PFO formation is still not elucidated fully and studies using a pig model have tried to understand the host immune response to empty alginate microcapsules. In this review, the varied strategies to overcome or reduce PFO are discussed, including alginate purification, altering microcapsule geometry, modifying alginate chemical composition, co-encapsulation with immunomodulatory cells, administration of pharmacological agents, and alternative transplantation sites. Nanoencapsulation technologies, such as conformal and layer-by-layer coating technologies, as well as nanofiber, thin-film nanoporous devices, and silicone based NanoGland devices are also addressed. Finally, this review outlines recent progress in imaging technologies to track encapsulated cells, as well as promising perspectives concerning the production of insulin-producing cells from stem cells for encapsulation.

Diabetes, type 1 and type 2 (T1D and T2D), are diseases of epidemic proportions, which are complicated and defined by genetics, epigenetics, environment, and lifestyle choices. Current therapies consist of whole pancreas or islet transplantation. However, these approaches require life-time immunosuppression, and are compounded by the paucity of available donors. Pluripotent stem cells have advanced research in the fields of stem cell biology, drug development, disease modeling, and regenerative medicine, and importantly allows for the interrogation of therapeutic interventions. Recent developments in beta-cell differentiation and genomic modifications are now propelling investigations into the mechanisms behind beta-cell failure and autoimmunity, and offer new strategies for reducing the propensity for immunogenicity. This review discusses the derivation of endocrine lineage cells from human pluripotent stem cells for the treatment of diabetes, and how the editing or manipulation of their genomes can transcend many of the remaining challenges of stem cell technologies, leading to superior transplantation and diabetes drug discovery platforms.

Background: Adiponectin is a hormone secreted by adipose tissue. It regulates glycolysis and lipolysis and is involved in the pathophysiology of diabetes and related disorders. Its activity is mainly mediated by the transmembrane receptors AdipoR1 and AdipoR2, which are encoded by ADIPOR1 (1q32.1) and ADIPOR2 (12p13.33) genes, respectively. In genetic association studies, single nucleotide polymorphisms (SNPs) in or near these genes have been associated with metabolic alterations. However, these relationships are still controversial.

Aim: The aim of this work was to analyze possible associations between ADIPOR1/2 and diabetes and other metabolic disorders.

Methods: A genetic association study was carried out in an admixed Latin American population. A sample of 200 adults was analyzed. Clinical and serum-biochemical characteristics were measured to diagnose obesity, abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, low HDLc, insulin resistance (HOMA-IR), and diabetes. Three SNPs were genotyped in ADIPOR1 (rs10494839, rs12733285, and rs2275737) and ADIPOR2 (rs11061937, rs11612383, and rs2286383). For the association analysis, an additive model was assessed through logistic regression. An admixture adjustment was performed using a Monte-Carlo-Markov-Chain method, assuming a three-hybrid substructure (k = 3).

Results: Two SNPs in ADIPOR1 were associated with diabetes: rs10494839 (OR = 3.88, adjusted p < 0.03) and rs12733285 (OR = 4.72, adjusted p < 0.03). Additionally, rs10494839 was associated with hypertriglyceridemia (OR = 2.16, adjusted p < 0.01). None of the SNPs in ADIPOR2 were associated with metabolic disorders.

Conclusions: ADIPOR1 was consistently associated with diabetes and hypertriglyceridemia. This association was maintained even after adjusting for genetic stratification. There were no significant associations involving ADIPOR2.

Background: Low-grade inflammation is involved in the development of diabetes and cardiovascular disease (CVD). Inflammation can be modulated by dietary factors. Dairy products are rich in saturated fatty acids (SFA), which are known to possess pro-inflammatory properties. However, different fatty acid compositions may exert different effects. Other components such as milk proteins may exert anti-inflammatory properties which may compensate for the potential negative effects of SFAs. Generally, the available data suggest a neutral role of dairy product consumption on inflammation.

Aim: To investigate the effects of, and potential interaction between, a dietary supplementation with whey protein and milk fat, naturally enriched in medium-chain SFA (MC-SFA), on inflammatory markers in abdominal obese adults.

Methods: The study was a 12-week, randomized, double-blinded, intervention study. Sixty-three adults were equally allocated to one of four groups which received a supplement of either 60 g/day whey or 60 g/day casein plus 63 g/day milk fat either high or low in MC-SFA content. Fifty-two subjects completed the study. Before and after the intervention, changes in plasma interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), high-sensitive C-reactive protein (hsCRP), adiponectin, and monocyte chemoattractant protein-1 (MCP-1) were measured. Changes in inflammatory genes in the subcutaneous adipose tissue were also documented.

Results: There were no differences in circulating inflammatory markers between protein types or fatty acid compositions in abdominally obese subjects, with the exception of an increase in adiponectin in response to high compared to low MC-SFA consumption in women. We found that combined dairy proteins and MC-SFAs influenced inflammatory gene expression in adipose tissue, while no effect was detected by dairy proteins or MC-SFA per se.

Conclusion: Whey protein compared with casein and MC-SFA-enriched milk fat did not alter circulating markers of low-grade inflammation in abdominally obese subjects, except for an increase in circulating adiponectin in response to high MC-SFA in abdominally obese women.