Journal of Diabetes Investigation最新文献

Impaired insulin secretion from pancreatic islet β-cells is a major cause of metabolic dysregulation and type 2 diabetes mellitus. Complete transcriptomic characterization of islets in patients with type 2 diabetes mellitus has yet to be completed, and it remains challenging to link insulin secretion dysfunction with precise changes in gene expression. There are several ongoing initiatives aimed at enabling the discovery of regulatory molecules that might contribute to insulin secretion dysfunction and whole-body glucose homeostasis impairment. In one such line of research, Bacos et al.¹ obtained evidence suggesting that the gene PAX5 might play an important role in impaired insulin secretion in human islets (Figure 1).

Given the established differences between mouse and human islets, type 2 diabetes mellitus candidate genes that were identified in mice might not have the same regulative effects on human islets. There is an unmet need for powerful transcriptomic analyses that can be applied to human islets isolated from individuals with type 2 diabetes mellitus and nondiabetic controls. Due to the difficulties associated with obtaining human islets, most human islet transcriptomic studies thus far have involved small cohorts and have lacked functional validation. Bacos et al.¹ generated a ribonucleic acid sequencing (RNA-Seq) resource bank from the large Lund University Diabetes Center pancreatic islet cohort. It is one of the largest existing type 2 diabetes mellitus human islet cohorts in existence, providing an extensive gene expression resource based on 309 islet preparations in total from individuals with type 2 diabetes mellitus and nondiabetic controls. They then identified 395 differentially expressed genes (DEGs) from the Lund University Diabetes Center cohort, and further performed some functional validation of DEGs in vitro.

The utility of transcriptomic resources can be affirmed by robust replication of DEGs across studies and databases. To date, few DEG replication studies in type 2 diabetes mellitus human islets have been reported, and the various studies in the literature showing replication have been relatively small, including the work by Bacos et al.¹ Unsurprisingly, the variance in demographic and pathophysiological profiles among sample donors affects DEG overlap across study cohorts. There remains a need to analyze human islets from a more diverse donor pool, and larger cohorts to clarify whether islet gene expression differs among individuals with type 2 diabetes mellitus in relation to demographic and pathophysiological variables. Another important factor affecting DEG overlap is the particular screen technology applied. RNA-Seq, microarray analysis and other screening technologies have been used to identify genes with altered expression in type 2 diabetes mellitus human islets, generating transcriptiona

The term laminopathies refers to a group of congenital diseases characterized by accelerated degeneration of human tissues. Mutations in LMNA, LMNB, ZMPSTE24, and other genes lead to structural and functional abnormalities associated with lamins. One subtype of laminopathy is the generalized lipodystrophy-associated progeroid syndrome (GLPS), which occurs in patients with heterozygous mutations of the LMNA gene c.29C>T(p.T10I). This paper reports the first case of GLPS in China and compares the clinical features of other GLPS patients with literature reports. A 16-year-old male patient was treated for diabetic ketoacidosis, presenting with premature aging appearance, systemic lipodystrophy, severe fatty liver, and decreased bone density. After peripheral blood DNA extraction and second-generation sequencing, a heterozygous mutation of exon 1 of the LMNA gene c.29C>T(p.T10I) was detected. This case of GLPS may provide a diagnostic and therapeutic basis for potential patients.

Diabetes mellitus is still expanding globally and is epidemic in developing countries. The combat of this plague has caused enormous economic and social burdens related to a lowered quality of life in people with diabetes. Despite recent significant improvements of life expectancy in patients with diabetes, there is still a need for efforts to elucidate the complexities and mechanisms of the disease processes to overcome this difficult disorder. To this end, the use of appropriate animal models in diabetes studies is invaluable for translation to humans and for the development of effective treatment. In this review, a variety of animal models of diabetes with spontaneous onset in particular will be introduced and discussed for their implication in diabetes research.

It is crucial to develop practical and noninvasive methods to assess the functional beta-cell mass in a donor pancreas, in which monitoring and precise evaluation is challenging. A patient with type 1 diabetes underwent noninvasive imaging following simultaneous kidney–pancreas transplantation with positron emission tomography/computed tomography (PET/CT) using an exendin-based probe, [¹⁸F]FB(ePEG12)12-exendin-4. Following transplantation, PET imaging with [¹⁸F]FB(ePEG12)12-exendin-4 revealed simultaneous and distinct accumulations in the donor and native pancreases. The pancreases were outlined at a reasonable distance from the surrounding organs using [¹⁸F]FB(ePEG12)12-exendin-4 whole-body maximum intensity projection and axial PET images. At 1 and 2 h after [¹⁸F]FB(ePEG12)12-exendin-4 administration, the mean standardized uptake values were 2.96 and 3.08, respectively, in the donor pancreas and 1.97 and 2.25, respectively, in the native pancreas. [¹⁸F]FB(ePEG12)12-exendin-4 positron emission tomography imaging allowed repeatable and quantitative assessment of beta-cell mass following simultaneous kidney–pancreas transplantation.

The possible mechanism of increased urinary C-peptide due to neprilysin inhibitors is investigated. Neprilysin inhibition blocks degradation of natriuretic peptides, and elicits a natriuretic and antihypertensive effect. Neprilysin inhibition might similarly block degradation of C-peptides in the kidney and thus increase the urinary C-peptide level.

Subjects with diabetes develop marked disturbances in amino acid metabolism and the concentration in plasma and tissues. Most consistently, the levels of branched-chain amino acids (BCAAs) and aromatic amino acids are increased, and the levels of l-serine and glycine are decreased¹. Aberrant nonessential amino acid metabolism is involved in the pathogenesis of diabetes. Elevated levels of plasma BCAAs have been associated with insulin resistance and type 2 diabetes since the 1960s². A cluster of obesity-associated changes in the specific amino acid, acylcarnitine, and organic acid metabolites in obese compared with lean subjects was also associated with insulin resistance. Although it is also speculated that disturbances in aminoacidemia play a role in the development of diabetic complications, their pathogenesis has not been sufficiently elucidated in detail.

Diabetic peripheral neuropathy (DPN) is the most frequent complication among diabetic patients. Its symptoms are pain, hyperalgesia, hypoalgesia, and paralysis, which can decrease the quality of life of patients. In diabetic peripheral neuropathy, peripheral nerve fibers are affected from the prediabetic stage. Because diabetic peripheral neuropathy is a retrograde-type neuropathy, small nerve fibers located in the epidermis or cornea are first degraded. Small nerve fibers consist of myelinated Aδ fibers and unmyelinated C fibers. Small fiber neuropathy is a disorder of these nerve fibers, manifesting as spontaneous pain or loss of pain sensation with reduction of their density. As diabetic peripheral neuropathy progresses, large myelinated fibers are also decreased with segmental demyelination and microvascular changes, such as thickening of the vascular wall and stenosis of intraneuronal vessels. Without proper treatment, these patients develop paralysis or ulcer formation on the foot. To date, diabetic peripheral neuropathy is thought to be caused by aberrant glucose metabolism in neuronal cells, Schwann cells and endothelial cells in the peripheral nervous system. Abnormal glycemic metabolism elicits nerve dysfunction with activation of the polyol pathway, protein kinase C, advanced glycation end products and its receptor, the receptor for advanced glycation end product (RAGE) pathway, oxidative stress, and inflammation. Clinically, in addition to hyperglycemia, metabolic syndrome, including dyslipidemia, obesity and hypertension, is well known to be a contributor to the pathogenesis of diabetic peripheral neuropathy. In addition to glucose and fatty acid metabolism, recent metabolomics studies have revealed the involvement of another metabolite, glucosamine, in the pathogenesis of diabetic peripheral neuropathy. Lower baseline amino acid levels such as asparagine and glutamine were correlated with cardiovascular autonomic neuropathy in a small sample of subjects with type 1 diabetes³. Thus, to