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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 non-fasting 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). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control. RESULTS The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time from diagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with ≤18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing. CONCLUSIONS The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 or more years from type 1 diabetes diagnosis. The frequency of residual C-peptide decreases with time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide. [ABSTRACT FROM AUTHOR]

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. Here we show that improvements to the oocyte activation protocol, including the use of both kinase and translation inhibitors, and cell culture in the presence of histone deacetylase inhibitors, promote development to the blastocyst stage. Developmental efficiency varied between oocyte donors, and was inversely related to the number of days of hormonal stimulation required for oocyte maturation, whereas the daily dose of gonadotropin or the total number of metaphase II oocytes retrieved did not affect developmental outcome. Because the use of concentrated Sendai virus for cell fusion induced an increase in intracellular calcium concentration, causing premature oocyte activation, we used diluted Sendai virus in calcium-free medium. Using this modified nuclear transfer protocol, we derived diploid pluripotent stem-cell lines from somatic cells of a newborn and, for the first time, an adult, a female with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Diabetes is a disorder characterized by loss of β cell mass and/or β cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell-derived β cells recapitulate molecular-physiological phenotypes of a diabetic subject, we generated induced pluripotent stem cells (iPSCs) from subjects with maturity- onset diabetes of the young type 2 (MODY2), which is characterized by heterozygous loss of function of the gene encoding glucokinase (GCK). These stem cells differentiated into β cells with efficiency comparable to that of controls and expressed markers of mature β cells, including urocortin-3 and zinc transporter 8, upon transplantation into mice. While insulin secretion in response to arginine or other secretagogues was identical to that in cells from healthy controls, GCK mutant β cells required higher glucose levels to stimulate insulin secretion. Importantly, this glucose-specific phenotype was fully reverted upon gene sequence correction by homologous recombination. Our results demonstrate that iPSC-derived β cells reflect β cell–autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on β cell function. [ABSTRACT FROM AUTHOR]

The exchange of the oocyte's genome with the genome of a somatic cell, followed by the derivation of pluripotent stem cells, could enable the generation of specific cells affected in degenerative human diseases. Such cells, carrying the patient's genome, might be useful for cell replacement. Here we report that the development of human oocytes after genome exchange arrests at late cleavage stages in association with transcriptional abnormalities. In contrast, if the oocyte genome is not removed and the somatic cell genome is merely added, the resultant triploid cells develop to the blastocyst stage. Stem cell lines derived from these blastocysts differentiate into cell types of all three germ layers, and a pluripotent gene expression program is established on the genome derived from the somatic cell. This result demonstrates the feasibility of reprogramming human cells using oocytes and identifies removal of the oocyte genome as the primary cause of developmental failure after genome exchange. [ABSTRACT FROM AUTHOR]

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. Material and Methods: We examined 350 children with diabetes (cases) and 350 non-diabetic controls (6–18 years of age). Using three different case definitions for periodontal disease, which incorporated gingival bleeding and/or attachment loss findings, multiple logistic regression analyses adjusting for age, gender, ethnicity, frequency of prior dental visits, dental plaque, and examiner were performed. Results: Subjects with diabetes had increased gingival inflammation and attachment loss compared with controls. Regression analyses revealed statistically significant differences in periodontal destruction between cases and controls across all disease definitions tested (odds ratios ranging from 1.84 to 3.72). The effect of diabetes on periodontal destruction remained significant when we separately analysed 6–11 and 12–18 year old subgroups. Conclusions: These findings demonstrate an association between diabetes and an increased risk for periodontal destruction even very early in life, and suggest that programmes to address periodontal needs should be the standard of care for diabetic youth. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the levels of subgingival plaque bacteria and serum IgG responses in patients with type 1 diabetes and non-diabetic controls of comparable periodontal status. Material and Methods: Fifty type 1 diabetes patients (mean duration 20.3 years, range 6–41) were age-and gender-matched with 50 non-diabetic individuals with similar levels of periodontal disease. Full-mouth clinical periodontal status was recorded, and eight plaque samples/person were collected and analysed by checkerboard hybridization with respect to 12 species. Homologous serum IgG titres were assessed by checkerboard immunoblotting. In a sub-sample of pairs, serum cytokines and selected markers of cardiovascular risk were assessed using multiplex technology. Results: Among the investigated species, only levels of Eubacterium nodatum were found to be higher in diabetic patients, while none of the IgG titres differed between the groups, both before and after adjustments for microbial load. Patients with diabetes had significantly higher serum levels of soluble E-selectin ( p=0.04), vascular cell adhesion molecule-1 (VCAM-1; p=0.0008), adiponectin ( p=0.01) and lower levels of plasminogen activator inhibitor-1 (PAI-1; p=0.02). Conclusions: After controlling for the severity of periodontal disease, patients with type 1 diabetes and non-diabetic controls showed comparable subgingival infection patterns and serum antibody responses. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the level of oral disease in children and adolescents with diabetes.Research Design and Methods: Dental caries and periodontal disease were clinically assessed in 182 children and adolescents (6-18 years of age) with diabetes and 160 nondiabetic control subjects.Results: There were no differences between case and control subjects with respect to dental caries. Children with diabetes had significantly higher plaque and gingival inflammation levels compared with control subjects. The number of teeth with evidence of attachment loss (the hallmark of periodontal disease) was significantly greater in children with diabetes (5.79 +/- 5.34 vs. 1.53 +/- 3.05 in control subjects, unadjusted P < 0.001). When controlling for age, sex, ethnicity, gingival bleeding, and frequency of dental visits, diabetes remained a highly significant correlate of periodontitis, especially in the 12- to 18-year-old subgroup. In the case group, BMI was significantly correlated with destruction of connective tissue attachment and bone, but duration of diabetes and mean HbA(1c) were not.Conclusions: Our findings suggest that periodontal destruction can start very early in life in diabetes and becomes more prominent as children become adolescents. Programs designed to promote periodontal disease prevention and treatment should be provided to young patients with diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To evaluate the level of oral disease in children and adolescents with diabetes. RESEARCH DESIGN AND METHODS -- Dental caries and periodontal disease were clinically assessed in 182 children and adolescents (6-18 years of age) with diabetes and 160 nondiabetic control subjects. RESULTS -- There were no differences between case and control subjects with respect to dental caries. Children with diabetes had significantly higher plaque and gingival inflammation levels compared with control subjects. The number of teeth with evidence of attachment loss (the hallmark of periodontal disease) was significantly greater in children with diabetes (5.79 ± 5.34 vs. 1.53 ± 3.05 in control subjects, unadjusted P < 0.001). When controlling for age, sex, ethnicity, gingival bleeding, and frequency of dental visits, diabetes remained a highly significant correlate of periodontitis, especially in the 12- to 18-year-old subgroup. In the case group, BMI was significantly correlated with destruction of connective tissue attachment and bone, but duration of diabetes and mean HbA[sub 1c] were not. CONCLUSIONS -- Our findings suggest that periodontal destruction can start very early in life in diabetes and becomes more prominent as children become adolescents. Programs designed to promote periodontal disease prevention and treatment should be provided to young patients with diabetes. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "iPSC-derived β cells model diabetes due to glucokinase deficiency" which appeared in the previous issue.