Optimizing Glycemic Outcomes for Children with Type 1 Diabetes.

Changes in physical growth, neurocognitive development, and pubertal maturation are some of the challenges to achieving blood glucose targets in children with type 1 diabetes mellitus. To optimize glycemic outcomes, a comprehensive approach is crucial to address psychosocial needs, expand the use of diabetes technology, and diminish health inequities.

Structure-Function Analysis of p57KIP2 in the Human Pancreatic Beta Cell Reveals a Bipartite Nuclear Localization Signal.

Mutations in CDKN1C, encoding p57KIP2, a canonical cell cycle inhibitor, underlie multiple pediatric endocrine syndromes. Despite this central role in disease, little is known about the structure and function of p57KIP2 in the human pancreatic beta cell. Since p57KIP2 is predominantly nuclear in human beta cells, we hypothesized that disease-causing mutations in its nuclear localization sequence (NLS) may correlate with abnormal phenotypes. We prepared RIP1 insulin promoter-driven adenoviruses encoding deletions of multiple disease-associated but unexplored regions of p57KIP2 and performed a comprehensive structure-function analysis of CDKN1C/p57KIP2. Real-time polymerase chain reaction and immunoblot analyses confirmed p57KIP2 overexpression, construct size, and beta cell specificity. By immunocytochemistry, wild-type (WT) p57KIP2 displayed nuclear localization. In contrast, deletion of a putative NLS at amino acids 278-281 failed to access the nucleus. Unexpectedly, we identified a second downstream NLS at amino acids 312-316. Further analysis showed that each individual NLS is required for nuclear localization, but neither alone is sufficient. In summary, p57KIP2 contains a classical bipartite NLS characterized by 2 clusters of positively charged amino acids separated by a proline-rich linker region. Variants in the sequences encoding these 2 NLS sequences account for functional p57KIP2 loss and beta cell expansion seen in human disease.

Papillary Thyroid Carcinoma in a Pediatric Patient With ß-Thalassemia.

ß-Thalassemia is characterized by the abnormal synthesis of ß-hemoglobin chains resulting in hemolytic anemia. Treatment involves frequent blood transfusions, which leads to deposition of iron in many organs, including endocrine glands. To date, several cases of papillary thyroid cancer (PTC) in patients with ß-thalassemia have been reported in the adult literature, but there have been none in pediatrics. Here we report on an female adolescent with ß-thalassemia who initially presented for evaluation of secondary amenorrhea. On examination, her thyroid gland was asymmetric, firm in consistency, with palpable lymph nodes along the right anterior cervical chain. A thyroid ultrasound revealed an enlarged right lobe containing 3 focal hypoechoic masses with calcific foci. Biopsy was consistent with PTC. She underwent total thyroidectomy and histological examination confirmed the diagnosis. Her postoperative course was uncomplicated and she was started on replacement therapy with levothyroxine. This is the first reported case of PTC in a pediatric patient with ß-thalassemia. The incidence of thyroid cancer in patients with ß-thalassemia is currently unknown; however, there may be utility in routine surveillance of this patient population.

Disrupting the DREAM complex enables proliferation of adult human pancreatic ß cells.

Resistance to regeneration of insulin-producing pancreatic ß cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human ß cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and ß cell transcriptomic databases seeking to understand why ß cells in insulinomas proliferate, while normal ß cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human ß cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human ß cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges.

A quantitative deficiency of normally functioning insulin-producing pancreatic beta cells is a major contributor to all common forms of diabetes. This is the underlying premise for attempts to replace beta cells in people with diabetes by pancreas transplantation, pancreatic islet transplantation, and transplantation of beta cells or pancreatic islets derived from human stem cells. While progress is rapid and impressive in the beta cell replacement field, these approaches are expensive, and for transplant approaches, limited by donor organ availability. For these reasons, beta cell replacement will not likely become available to the hundreds of millions of people around the world with diabetes. Since the large majority of people with diabetes have some residual beta cells in their pancreata, an alternate approach to reversing diabetes would be developing pharmacologic approaches to induce these residual beta cells to regenerate and expand in a way that also permits normal function. Unfortunately, despite the broad availability of multiple classes of diabetes drugs in the current diabetes armamentarium, none has the ability to induce regeneration or expansion of human beta cells. Development of such drugs would be transformative for diabetes care around the world. This picture has begun to change. Over the past half-decade, a novel class of beta cell regenerative small molecules has emerged: the DYRK1A inhibitors. Their emergence has tremendous potential, but many areas of uncertainty and challenge remain. In this review, we summarize the accomplishments in the world of beta cell regenerative drug development and summarize areas in which most experts would agree. We also outline and summarize areas of disagreement or lack of unanimity, of controversy in the field, of obstacles to beta cell regeneration, and of challenges that will need to be overcome in order to establish human beta cell regenerative drug therapeutics as a clinically viable class of diabetes drugs.

Vitamin D supplementation and upper respiratory tract infections in adolescent swimmers: a randomized controlled trial.

Observational studies identified associations between vitamin D insufficiency (serum 25(OH)D < 30ng·ml-1) and risk of upper respiratory infection (URI). Swimmers are highly prone to URIs, which might hinder their performance. The aim of this study was to examine if vitamin D3 supplementation reduces URI burden in vitamin D-insufficient swimmers. Fifty-five competitive adolescent swimmers with vitamin D insufficiency were randomized to receive vitamin D3 (2,000IU·d-1) or placebo for 12 winter weeks. A URI symptom questionnaire was completed weekly. Serum 25(OH)D concentrations were measured by radio-immunoassay before and after supplementation. We used linear regression to examine the relation between the change in 25(OH)D concentrations during the trial, and the duration and severity of URIs. There were no between-group differences in the frequency, severity, or duration of URIs. Exploratory analyses revealed that in the placebo group only, the change in 25(OH)D concentrations during the trial was highly associated with the duration of URIs (r = -0.90,p < .001), and moderately associated with the severity of URIs (r = -0.65,p = .043). The between-group differences for duration were highly significant. Vitamin D3 supplementation in adolescent swimmers with vitamin D insufficiency did not reduce URI burden. However, larger decreases in serum 25(OH)D concentrations were associated with significantly longer and more severe URI episodes.