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Purpose of Review: Insulin therapy alone fails to achieve target glycemic control in the majority of individuals with type 1 diabetes (T1D), motivating the investigation of additive medications. This review focuses on the recent findings on the use of adjunctive pharmacotherapy in T1D., Recent Findings: Metformin and glucagon-like peptide-1 receptor agonists have been associated with weight reduction and decrease in daily insulin requirements without sustainable improvement in glycemic control. Sodium-glucose cotransporter (SGLT)-2 inhibitors, dual SGLT-1/2 inhibitors, and pramlintide have been shown to reduce hemoglobin A1c, induce weight loss, and lower insulin dose. The benefits of dipeptidyl peptidase-4 inhibitors, thiazolidinediones, and alpha glucosidase inhibitors appear to be more limited. Gastrointestinal symptoms and increased hypoglycemia are adverse effects of certain classes. Although not devoid of side effects, additive pharmacotherapies in T1D can improve glycemic control and lower body weight and insulin requirement. Longer studies are needed before consideration for widespread clinical care.

Objective: Current data are limited on the course of type 1 diabetes (T1D) in children and adolescents through the first few years of diabetes. The Pediatric Diabetes Consortium T1D new onset (NeOn) Study was undertaken to prospectively assess natural history and clinical outcomes in children treated at 7 US diabetes centers from the time of diagnosis. This paper describes clinical outcomes in the T1D NeOn cohort during the first 3 years postdiagnosis., Results: A total of 1048 participants (mean age 9.2 years, 49% female, 65% non-Hispanic White) were enrolled between July 2009 and April 2011. Mean glycated hemoglobin (HbA1c) (±SD) was 7.2% (55 mmol/mol) at 3 months, followed by a progressive rise to 8.4% (68 mmol/mol) at 36 months postdiagnosis, with only 30% of participants achieving target HbA1c<7.5% (58 mmol/mol). The percentage of participants in partial remission estimated by insulin dose adjusted HbA1c [HbA1c % + (4×insulin dose unit/kg/24 h)] ≤9 sharply declined from 23% at 12 months to 7% at 36 months. The percentage of participants developing diabetic ketoacidosis (DKA) was 1% in the first year after diagnosis, increasing to 6% in years 2 and 3., Conclusions: These results demonstrate the gradual decline in glycemic control due to waning residual endogenous insulin secretion with increasing duration of T1D in children and adolescents. These data indicate the need to translate recent advances in automated insulin delivery, new insulin analogs, and adjunctive pharmacologic agents into novel treatment strategies to maintain optimal glycemic control even early in the course of T1D., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To evaluate mini-dose glucagon in adults with type 1 diabetes using a stable, liquid, ready-to-use preparation., Research Design and Methods: Twelve adults with type 1 diabetes receiving treatment with insulin pumps received subcutaneous doses of 75, 150, and 300 μg of nonaqueous glucagon. Plasma glucose, glucagon, and insulin concentrations were measured. At 180 min, subjects received insulin followed in ~60 min by a second identical dose of glucagon., Results: Mean (±SE) fasting glucose concentrations (mg/dL) were 110 ± 7, 110 ± 10, and 109 ± 9 for the 75-, 150-, and 300-μg doses, respectively, increasing maximally at 60 min by 33, 64, and 95 mg/dL (all P < 0.001). The post-insulin administration glucose concentrations were 70 ± 2, 74 ± 5, and 70 ± 2 mg/dL, respectively, with maximal increases of 19, 24, and 43 mg/dL post-glucagon administration (P < 0.02) at 45-60 min., Conclusions: Subcutaneous, nonaqueous, ready-to-use G-Pen Mini glucagon may provide an alternative to oral carbohydrates for the management of anticipated, impending, or mild hypoglycemia in adults with type 1 diabetes., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To identify determinants of hemoglobin A1c (HbA1c) levels 1 yr after the diagnosis of type 1 diabetes (T1D) in participants in the Pediatric Diabetes Consortium (PDC) T1D New Onset (NeOn) Study., Research Design and Methods: Diabetes-specific as well as socioeconomic factors during the first year following diagnosis were analyzed in 857 participants (mean age 9.1 yrs, 51% female, 66% non-Hispanic White) not participating in an intervention study who had an HbA1c value at 12 months., Result: Mean ± SD HbA1c at 1 yr was 62 ± 16 mmol/mol (7.8% ± 1.5). In univariate and multivariate analyses, clinical center, non-Hispanic White race, private health insurance, living with both parents, higher frequency of self-monitoring of blood glucose (SMBG), and lower insulin requirements were associated with lower HbA1c concentrations at 1 yr (p < 0.01). No association was found with gender, age, Tanner stage, body mass index (BMI), diabetic ketoacidosis (DKA) at onset, number of positive autoantibodies or HbA1c at onset, or number of visits to diabetes physician during the first year., Conclusions: White race, higher socioeconomic status, two-parent household, more frequent SMBG, and low insulin requirements are associated with lower HbA1c concentration 1 yr after the onset of T1D in children., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Increasing numbers of children and adolescents with type 1 diabetes (T1D) have been placed on insulin pump therapy. Nevertheless, data are limited regarding patterns of pump use during the first year of treatment and the clinical and socioeconomic factors associated with early use of pump therapy. Therefore, we sought to determine factors associated with pump therapy within the first year of diagnosis in youth enrolled in the Pediatric Diabetes Consortium (PDC) T1D New-Onset (NeOn) Study., Subjects and Methods: The NeOn Study includes youth <19 years old at T1D diagnosis who have been followed from the time of diagnosis at seven U.S. pediatric diabetes centers. Cox regression was used to determine factors associated with transition from injection to pump therapy during the first year of T1D in 1,012 participants., Results: Twenty-seven percent (n=254) of participants began pump therapy within the first year of diagnosis, ranging from 18% to 59% among the seven centers. After adjusting for center effect, factors associated with pump use in multivariate analysis included private health insurance (37% vs. 7%; P<0.001), having annual household income over $100,000 (50% vs. 15%; P<0.001), and non-Hispanic white race (36% vs. 11%; P<0.001). The hemoglobin A1c level did not appear to influence the decision to initiate pump use., Conclusions: Participants of non-Hispanic white race and higher socioeconomic status were more likely to be placed on pumps during the first year. Further investigations are needed to gain a better understanding of barriers to use of pumps in youth with T1D, especially in disadvantaged and minority families.

Although a variety of effective treatment options are available for patients with type 1 or type 2 diabetes, many patients in the United States have difficulty reaching their glycemic goals. Patient adherence to insulin therapy, which often involves self-administered subcutaneous injections of insulin using either a vial and syringe or an insulin pen device, is often poor. Various factors associated with the type of injection device have been shown to influence the rate of patient adherence to insulin therapy. This article reviews patient-reported outcome (PRO) evidence from pediatric and adult studies that compared insulin pen devices with vial and syringe use. In a majority of these cases, patients preferred the pen devices over vial and syringe, stating advantages such as ease of use, convenience, greater confidence in their ability to properly administer the drug, and a greater perceived social acceptance. The pens were considered less painful than syringes and were associated with less needle fear. In addition, PRO evidence has directed pen technology design, leading to development of more advanced insulin pen devices. By appreciating the correlation between adherence to insulin regimens and a patient's device preference, clinicians can make improved treatment recommendations to facilitate achievement and maintenance of glycemic targets., (© 2011 Diabetes Technology Society.)

Type 1 diabetes of both the NOD mouse and man is associated with autoimmunity directed against insulin which is the only beta cell specific autoantigen identified to date. One can use autoantibodies to insulin to predict diabetes, use insulin peptides to create insulin autoantibodies, insulitis and diabetes, and use insulin or its peptides in animal models to prevent diabetes. An expanding set of resources are now available for the development and testing in man of therapies to prevent type 1 diabetes, and a number of trials utilizing insulin peptides are now underway.

The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

Objective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).Research Design and Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant.Results: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar.Conclusions: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity. [ABSTRACT FROM AUTHOR]

This document is a reply to a correspondence on a review about the heterogeneity and endotype of type 1 diabetes mellitus. The authors agree with the correspondents that slowly progressive type 1 diabetes mellitus (SPIDDM) may not necessarily involve obesity or other diabetogenic mechanisms characteristic of type 2 diabetes mellitus. They also note that the definition of SPIDDM may differ in different populations. The relationship between SPIDDM and the endotype referred to as T1DE2 remains unclear, and the authors propose that T1DE2 is the predominant endotype of type 1 diabetes among the adolescent-onset and adult-onset population in Western countries. They also discuss the differences between SPIDDM and fulminant type 1 diabetes mellitus (FT1DM) and the potential role of MDA5 in SPIDDM. The authors agree with the correspondents that a deeper understanding of type 1 diabetes mellitus endotypes is important for effective therapeutic intervention. [Extracted from the article]

Type 1 diabetes (T1D) results from immune‐mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non‐HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus ( T1DM) is the archetypal example of a T cell-mediated autoimmune disease characterized by selective destruction of pancreatic β cells. The pathogenic equation for T1DM presents a complex interrelation of genetic and environmental factors, most of which have yet to be identified. On the basis of observed familial aggregation of T1DM, it is certain that there is a decided heritable genetic susceptibility for developing T1DM. The well-known association of T1DM with certain human histocompatibility leukocyte antigen ( HLA) alleles of the major histocompatibility complex ( MHC) was a major step toward understanding the role of inheritance in T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (e.g., HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/ DQ alleles [e.g., DRB1*03- DQB1*0201 ( DR3/ DQ2) or DRB1*04- DQB1*0302 ( DR4/ DQ8)]. In addition, the HLA allele DQB1*0602 is associated with dominant protection from T1DM in multiple populations. A concordance rate lower than 100% between monozygotic twins indicates a potential involvement of environmental factors on disease development. The detection of at least two islet autoantibodies in the blood is virtually pre-diagnostic for T1DM. The majority of children who carry these biomarkers, regardless of whether they have an a priori family history of the disease, will develop insulin-requiring diabetes. Facilitating pre-diagnosis is the timing of seroconversion which is most pronounced in the first 2 yr of life. Unfortunately the significant progress in improving prediction of T1DM has not yet been paralleled by safe and efficacious intervention strategies aimed at preventing the disease. Herein we summarize the chequered history of prediction and prevention of T1DM, describing successes and failures alike, and thereafter examine future trends in the exciting, partially explored field of T1DM prevention. [ABSTRACT FROM AUTHOR]

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Twin studies help to elucidate the contribution of genes and environment to type 1 diabetes (T1DM). The Diabetes Prevention Trial-1 (DPT-1) tested for anti-islet autoantibodies: 34,765 non-diabetic non-twin siblings of patients with T1DM, and 896 non-diabetic potential twins of patients with T1DM. Zygosity (being monozygotic [MZ] or dizygotic [DZ]) was unknown except for 357 non-diabetic subjects with opposite gender to their diabetic twin, who must be DZ. Expression of cytoplasmic islet cell (ICA), GAD65, ICA512 and insulin autoantibodies in 357 different-sex (DZ) potential non-diabetic twins of T1DM patients was, respectively, 4.5%, 4.7%, 3.0% and 2.4%, which was lower than in 539 same-sex potential non-diabetic twins (including MZ and DZ) of T1DM patients for ICA (7.8%, p<0.05), GAD65 (13.4%, p<0.0001) and ICA512 (6.5%, p<0.03). In contrast, expression of ICA, GAD65, ICA512 and insulin autoantibodies was not significantly different in different-sex (DZ) potential twins versus all siblings (respectively, 4.2%, 4.8%, 2.2%, 2.5%), different-sex siblings (3.9%, 4.9%, 2.2%, 2.5%) or same-sex siblings (4.4%, 4.7%, 2.2%, 2.5%) of T1DM patients. In conclusion, anti-islet autoimmunity is not increased in non-diabetic DZ twins of T1DM patients compared to non-diabetic siblings of T1DM patients, suggesting that the greater environmental sharing by twins does not increase risk of anti-islet autoimmunity. [Copyright &y& Elsevier]