Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

Objective: Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.

Research Design And Methods: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months.

Reduced calcium levels and accumulation of abnormal insulin granules in stem cell models of HNF1A deficiency.

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of β-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A. HNF1A-deficient β-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation.

Reduced replication fork speed promotes pancreatic endocrine differentiation and controls graft size.

Limitations in cell proliferation are important for normal function of differentiated tissues and essential for the safety of cell replacement products made from pluripotent stem cells, which have unlimited proliferative potential. To evaluate whether these limitations can be established pharmacologically, we exposed pancreatic progenitors differentiating from human pluripotent stem cells to small molecules that interfere with cell cycle progression either by inducing G1 arrest or by impairing S phase entry or S phase completion and determined growth potential, differentiation, and function of insulin-producing endocrine cells. We found that the combination of G1 arrest with a compromised ability to complete DNA replication promoted the differentiation of pancreatic progenitor cells toward insulin-producing cells and could substitute for endocrine differentiation factors.

C-Peptide Levels in Subjects Followed Longitudinally Before and After Type 1 Diabetes Diagnosis in TrialNet.

Objective: Insulin secretion declines rapidly after diagnosis of type 1 diabetes, followed by a slower rate of change. Previous studies have demonstrated that the C-peptide decline begins before the clinical diagnosis. Changes in insulin secretion in the same individuals studied from preclinical stages through and after clinical diagnosis have not been previously reported.

Diabetes Technology Use Among Pregnant and Nonpregnant Women with T1D in the T1D Exchange.

Background: Gestational tight glycemic control is critical for women with type 1 diabetes (T1D). Limited data exist on the adoption and retention of diabetes technologies among women in different parity strata.

Methods: We compared T1D management between T1D Exchange clinic registry participants (mean age 28 ± 9 years, 84% white non-Hispanic, and median T1D duration 13 years) who were pregnant at enrollment or year 1 follow-up ("recently pregnant" between 2010 and 2013, n = 214), ever (but not recently) pregnant (n = 1540), and never pregnant (n = 2586).

Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation.

Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders.

Risk Factors Associated With Severe Hypoglycemia in Older Adults With Type 1 Diabetes.

Objective: Severe hypoglycemia is common in older adults with long-standing type 1 diabetes, but little is known about factors associated with its occurrence.

Research Design And Methods: A case-control study was conducted at 18 diabetes centers in the T1D Exchange Clinic Network. Participants were ≥60 years old with type 1 diabetes for ≥20 years.

Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience.

Objective: We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

Research Design And Methods: The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit.

Cross-sectional and Test-Retest Characterization of PET with [(18)F]FP-(+)-DTBZ for β Cell Mass Estimates in Diabetes.

Purpose: The vesicular monoamine transporter, type 2 (VMAT2) is expressed by insulin producing β cells and was evaluated as a biomarker of β cell mass (BCM) by positron emission tomography (PET) with [(18)F]fluoropropyl-dihydrotetrabenazine ([(18)F]FP-(+)-DTBZ).

Procedures: We evaluated the feasibility of longitudinal pancreatic PET VMAT2 quantification in the pancreas in two studies of healthy controls and patients with type 1 or 2 diabetes. VMAT2 binding potential (BPND) was estimated voxelwise using a reference tissue method in a cross-sectional study, followed by assessment of reproducibility using a test-retest paradigm.

Prevalence of detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes.

Objective: It is generally accepted that complete β-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown.

Research Design And Methods: The frequency of residual insulin secretion was determined by measurement of nonfasting serum C-peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration).

Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells.

The transfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistently equivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Although methods to induce pluripotent stem cells from somatic cells by transcription factors are widely used in basic research, numerous differences between induced pluripotent stem cells and embryonic stem cells have been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploid embryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematically investigated the parameters affecting efficiency of blastocyst development and stem-cell derivation.

Differences in the management of type 1 diabetes among adults under excellent control compared with those under poor control in the T1D Exchange Clinic Registry.

Objective: Optimizing glycemic control in type 1 diabetes is important to minimize the risk of complications. We used the large T1D Exchange clinic registry database to identify characteristics and diabetes management techniques in adults with type 1 diabetes, differentiating those under excellent glycemic control from those with poorer control.

Research Design And Methods: The cross-sectional analysis included 627 participants with HbA1c <6.

Evidence of a strong association between frequency of self-monitoring of blood glucose and hemoglobin A1c levels in T1D exchange clinic registry participants.

Objective: Despite substantial evidence of the benefit of frequent self-monitoring of blood glucose (SMBG) in type 1 diabetes, certain insurers limit the number of test strips that they will provide. The large database of the T1D Exchange clinic registry provided an opportunity to evaluate the relationship between the number of SMBG measurements per day and HbA1c levels across a wide age range of children and adults.

Research Design And Methods: The analysis included 20,555 participants in the T1D Exchange clinic registry with type 1 diabetes ≥1 year and not using a continuous glucose monitor (11,641 younger than age 18 years and 8,914 18 years old or older).

Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants.

Mitochondrial DNA mutations transmitted maternally within the oocyte cytoplasm often cause life-threatening disorders. Here we explore the use of nuclear genome transfer between unfertilized oocytes of two donors to prevent the transmission of mitochondrial mutations. Nuclear genome transfer did not reduce developmental efficiency to the blastocyst stage, and genome integrity was maintained provided that spontaneous oocyte activation was avoided through the transfer of incompletely assembled spindle-chromosome complexes.

Making progress: preserving beta cells in type 1 diabetes.

The clinical care of patients with type 1 diabetes (T1D) has greatly improved over the past few decades; however, it remains impossible to completely normalize blood sugar utilizing currently available tools. Research is underway with a goal to improve the care and, ultimately, to cure T1D by preserving beta cells. This review will outline the progress that has been made in trials aimed at preserving insulin secretion in T1D by modifying the immune assault on the pancreatic beta cell.

Accelerated tooth eruption in children with diabetes mellitus.

Objective: The objective of this study was to evaluate tooth eruption in 6- to 14-year-old children with diabetes mellitus.

Methods: Tooth eruption status was assessed for 270 children with diabetes and 320 control children without diabetes. Data on important diabetes-related variables were collected.

Gingival bleeding in 6- to 13-year-old children with diabetes mellitus.

Purpose: This study assessed gingival bleeding in diabetic children during the mixed dentition period.

Methods: Three hundred fifty-five 6- to 13-year-old diabetic (99% type 1) and nondiabetic control children in the mixed dentition stage were evaluated from a total cohort of 700 6- to 18-year-old children. Gingival status was assessed, and data on important diabetes-related variables were collected.

Diabetes mellitus promotes periodontal destruction in children.

Aim: The association between diabetes mellitus and periodontal attachment and bone loss is well established. Most of the prior literature has focused on adults, and studies in children have mostly reported gingival changes. Our aim was to assess the periodontal status of a large cohort of children and adolescents with diabetes.