Bisphenol A, Obesity, and Type 2 Diabetes Mellitus: Genuine Concern or Unnecessary Preoccupation?

Bisphenol A or BPA is a ubiquitious industrial chemical found in a variety of plastic containers intended for food storage and in the epoxy resin linings of metal food and beverage cans, where it is used to prevent corrosion, food contamination, and spoilage. BPA has been recently linked to a wide variety of medical disorders and is known to have estrogenic activity with genomic as well as non-genomic estrogen-receptor mediated effects. Given rapidly increasing prevalence rates of metabolic disorders like obesity and Type 2 diabetes, BPA has recently come under intense scrutiny in scientific and lay communities as a potential endocrine disrupting compound with diabetogenic effects. The purpose of this review is to critically examine available literature investigating the link between BPA and alterations in metabolic health. Here, we discuss typical levels of exposure to BPA in daily life and analyze both epidemiological human data and mechanistic preclinical studies that have tested associations between BPA and obesity and diabetes. Finally, we summarize the current policies and views of national and international regulatory agencies regarding the safety of BPA use

Nucleic Acid Biomarkers of β Cell Stress and Death in Type 1 Diabetes

Purpose of the review The purpose of this review is to summarize recent advances in the development of nucleic acid-based biomarkers in type 1 diabetes (T1D). Recent findings Recent rodent and human studies have identified new roles for stress pathways intrinsic to the β cell during the development of T1D. As such, methods to identify an authentic nucleic acid signature of β cell stress and/or death may improve our ability to predict T1D at earlier timepoints, allowing for optimal timing of immunomodulatory interventions. To this end, both targeted and unbiased approaches have begun to identify changes in microRNA expression patterns in T1D. Moreover, a number of groups have developed distinct assays that quantitatively detect circulating unmethylated insulin DNA, which is thought to primarily emanate from dying β cells. Summary Here we highlight unique blood and urine miRNA signatures identified in T1D cohorts, compare differences between first, second, and third generation assays that detect circulating unmethylated insulin DNA, and review recent technological advances that have the capacity to improve T1D biomarker development

Type 1 diabetes

Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care

Pancreatic and Islet Development and Function: The Role of Thyroid Hormone

A gradually expanding body of literature suggests that Thyroid Hormone (TH) and Thyroid Hormone Receptors (TRs) play a contributing role in pancreatic and islet cell development, maturation, and function. Studies using a variety of model systems capable of exploiting species-specific developmental paradigms have revealed the contribution of TH to cellular differentiation, lineage decisions, and endocrine cell specification. Moreover, in vitro and in vivo evidence suggests that TH is involved in islet β cell proliferation and maturation; however, the signaling pathway(s) connected with this function of TH/TR are not well understood. The purpose of this review is to discuss the current literature that has defined the effects of TH and TRs on pancreatic and islet cell development and function, describe the impact of hyper- and hypothyroidism on whole body metabolism, and highlight future and potential applications of TH in novel therapeutic strategies for diabetes

Translational implications of the β-cell epigenome in diabetes mellitus

Diabetes mellitus is a disorder of glucose homeostasis that affects more than 24 million Americans and 382 million individuals worldwide. Dysregulated insulin secretion from the pancreatic β cells plays a central role in the pathophysiology of all forms of diabetes mellitus. Therefore, an enhanced understanding of the pathways that contribute to β-cell failure is imperative. Epigenetics refers to heritable changes in DNA transcription that occur in the absence of changes to the linear DNA nucleotide sequence. Recent evidence suggests an expanding role of the β-cell epigenome in the regulation of metabolic health. The goal of this review is to discuss maladaptive changes in β-cell DNA methylation patterns and chromatin architecture, and their contribution to diabetes pathophysiology. Efforts to modulate the β-cell epigenome as a means to prevent, diagnose, and treat diabetes are also discussed

Combination Immunotherapy for Type 1 Diabetes

Purpose of Review Type 1 diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T cell or B cell inhibition, regulatory T cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D. Recent Findings Combination immunotherapies have had mixed results in improving short-term glycemic control and insulin secretion in recent-onset T1D. Summary A handful of studies have successfully reached their primary end-point of improved insulin secretion in recent-onset T1D. However, long-term improvements glycemic control and the restoration of insulin independence remain elusive. Future interventions should focus on strategies that combine immunomodulation with efforts to alleviate β-cell stress and address the formation of antigens that activate autoimmunity

A case of extragastrointestinal stromal tumor complicated by severe hypoglycemia: a unique presentation of a rare tumor

BACKGROUND: Non-Islet Cell Tumor Hypoglycemia (NICTH) is a rare paraneoplastic cause of hypoglycemia arising from excess tumor production of insulin-like growth factor. The objective of this report is to describe an unusual case of Extragastrointestinal Stromal Tumor (EGIST) associated NICTH. CASE PRESENTATION: A 64 year-old African female was brought to the emergency room with a 1-month history of recurrent syncope, weight loss, and abdominal bloating. Serum blood glucose was discovered to 39 mg/dL, when insulin, proinsulin, and C-peptide were suppressed. Computed tomography scan revealed a diffuse extraintestinal metastatic disease process, and a biopsy confirmed the diagnosis of an Extragastrointestinal Stromal Tumor (EGIST). IGF-I and II levels were 27 ng/ml and 262 ng/ml respectively, and the ratio of IGF-II to IGF-I was calculated as 9.7:1, suggestive of IGF-II-mediated NICTH. Acutely, the patient's hypoglycemia resolved with dextrose and glucagon infusion. Long-term euglycemia was achieved with prednisone and imatinib therapy. CONCLUSIONS: NICTH should be considered when hypoglycemia occurs in the setting of low serum insulin levels. Whereas definitive treatment of EGIST involves surgical resection, immunotherapy with tyrosine kinase inhibitors and corticosteroids have been shown to alleviate hypoglycemia in cases where surgery is delayed or not feasible

A case of calciphylaxis in a patient with hypoparathyroidism and normal renal function

OBJECTIVE: To present the case of a patient with a history of thyroid cancer, postsurgical hypoparathyroidism, chronic calcitriol use, and normal renal function who presented with painful skin lesions secondary to calciphylaxis. METHODS: We describe the history, biochemistry, histopathology, evaluation, and management of this patient. RESULTS: A 47-year-old female with hypoparathyroidism, chronically treated with calcitriol and calcium, presented with exquisitely painful skin ulcerations. Four months prior to the onset of symptoms, she had initiated warfarin therapy for atrial fibrillation. Review of laboratory data from the past year revealed elevated calcium and phosphorus levels. A diagnosis of calciphylaxis was made based upon pathologic evaluation of a skin biopsy. Management included titration of calcitriol and calcium to maintain serum calcium and phosphate levels in the low-normal range. Sodium thiosulfate was administered at a dose of 25 mg intravenously 3 times a week with some resolution in the patient's pain. Unfortunately, the patient battled recurrent bacteremia and sepsis, presumably related to her calciphylaxis wounds, and ultimately succumbed to complications from sepsis. CONCLUSION: Although calciphylaxis is typically associated with renal insufficiency and secondary hyperparathyroidism, we highlight the case of a patient with normal renal function and hypoparathyroidism. Patients treated with chronic calcitriol should have serum calcium and phosphorus monitored closely and may benefit from non-calcium-based phosphate binders if hyperphosphatemia becomes unavoidable. This is especially important in the presence of other risk factors for calciphylaxis, including warfarin use

Profiling of RNAs from Human Islet-Derived Exosomes in a Model of Type 1 Diabetes

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing islet β cells. Biomarkers capable of identifying T1D risk and dissecting disease-related heterogeneity represent an unmet clinical need. Toward the goal of informing T1D biomarker strategies, we profiled coding and noncoding RNAs in human islet-derived exosomes and identified RNAs that were differentially expressed under proinflammatory cytokine stress conditions. Human pancreatic islets were obtained from cadaveric donors and treated with/without IL-1β and IFN-γ. Total RNA and small RNA sequencing were performed from islet-derived exosomes to identify mRNAs, long noncoding RNAs, and small noncoding RNAs. RNAs with a fold change ≥1.3 and a p-value <0.05 were considered as differentially expressed. mRNAs and miRNAs represented the most abundant long and small RNA species, respectively. Each of the RNA species showed altered expression patterns with cytokine treatment, and differentially expressed RNAs were predicted to be involved in insulin secretion, calcium signaling, necrosis, and apoptosis. Taken together, our data identify RNAs that are dysregulated under cytokine stress in human islet-derived exosomes, providing a comprehensive catalog of protein coding and noncoding RNAs that may serve as potential circulating biomarkers in T1D