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OBJECTIVE Proteomic profiling can identify useful biomarkers. Monozygotic (MZ) twins discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well-characterized cohorts. RESEARCH DESIGN AND METHODS A broad, multiplex analysis of 4,068 proteins in serum samples from MZ twins concordant (n = 43) and discordant (n = 27) for type 1 diabetes identified major differences that were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n = 39) and discordant (n = 42) for type 1 diabetes, individuals at risk for (n = 195) and with (n = 990) type 1 diabetes, as well as individuals with non–insulin-requiring adult-onset diabetes diagnosed as either autoimmune (n = 96) or type 2 (n = 291). RESULTS Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite a strong correlation between twins, whether concordant or discordant for type 1 diabetes (P < 0.01 for both). In validation experiments, trypsin(ogen) levels were lower in twins with diabetes than in the co-twin without diabetes (P < 0.0001) and healthy control participants (P < 0.0001). In recently diagnosed participants, trypsin(ogen) levels were lower than in control participants across a broad age range. In at-risk relatives, levels CONCLUSIONS Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and nongenetically determined factors. Exocrine/endocrine interactions are important underinvestigated factors in type 1 diabetes.

Aims/hypothesis It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes and non-autoimmune type 2 diabetes, especially as type 1 diabetes presents in adulthood. Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune type 1 diabetes, but the clinical value of GADA by current standard radiobinding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes. Methods Two cohorts were analysed including 771 diabetic participants, 30–70 years old, from the Action LADA study (n = 6156), and 2063 diabetic participants, 20–45 years old, from the Diabetes in Young Adults (DiYA) study. Clinical characteristics of participants, including requirement of early insulin treatment, BMI and development of multiple islet autoantibodies, were analysed according to the status of RBA-GADA and ECL-GADA, respectively, and compared between these two assays. Results GADA was the most prevalent and predominant autoantibody, >90% in both cohorts. GADA positivity by either RBA or ECL assay significantly discriminated clinical type 1 from type 2 diabetes. However, in both cohorts, participants with ECL-GADA positivity were more likely to require early insulin treatment, have multiple islet autoantibodies, and be less overweight (for all p Conclusions/interpretation Detection of GADA by ECL assay, given technical advantages over RBA-GADA, identified adult-onset diabetes patients at higher risk of requiring early insulin treatment, as did clinical phenotype, together allowing for more accurate clinical diagnosis and management. Graphical abstract

Hypoglycemia is common in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) and constitutes a major limiting factor in achieving glycemic control among people with diabetes. While hypoglycemia is defined as a blood glucose level under 70 mg/dL (3.9?mmol/L), symptoms may occur at higher blood glucose levels in individuals with poor glycemic control. Severe hypoglycemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions to assure neurologic recovery. Hypoglycemia is the most important safety outcome in clinical studies of glucose lowering agents. The ADA Standards of Medical Care recommends that a management protocol for hypoglycemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan. A tailored approach, using clinical and pathophysiologic disease stratification, can help individualize glycemic goals and promote new therapies to improve quality of life of patients. Data from recent large clinical trials reported low risk of hypoglycemic events with the use of newer antidiabetic drugs. Increased hypoglycemia risk is observed with the use of insulin and/or sulfonylureas. Vulnerable patients with T2D at dual risk of severe hypoglycemia and Cardiovascular (CV) outcomes show features of ?frailty?. Many of such patients may be better treated by the use of GLP-1 receptor agonists or SGLT2 inhibitors rather than insulin. CGM should be considered for all individuals with increased risk for hypoglycemia, impaired hypoglycemia awareness, frequent nocturnal hypoglycemia and with history of severe hypoglycemia. Patients with impaired awareness of hypoglycemia (IAH) benefit from real-time continuous glucose monitoring (CGM). The diabetes educator is an invaluable resource and can devote the time needed to thoroughly educate the individual to reduce the risk of hypoglycemia and integrate the information within the entire construct of diabetes self-management. Conversations about hypoglycemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycemia among patients with diabetes and their family members. Optimizing insulin doses and carbohydrate intake, in addition to a short warm up before or after the physical activity sessions may help avoiding hypoglycemia. Several therapeutic considerations are important to reduce hypoglycemia risk during pregnancy including administration of rapid-acting insulin analogs rather than human insulin, pre-conception initiation of insulin analogs, and immediate postpartum insulin dose reduction. This article is protected by copyright. All rights reserved.

Over a century ago, there was diabetes and only diabetes. Subsequently, diabetes came to be much more discretely defined (1) by age at onset (childhood or adult onset), clinical phenotype (lean or obese), treatment (insulin dependent or not insulin dependent), and, more recently, immune genotype (type 1 or type 2 diabetes). Although these categories broadly describe groups, they are often insufficient to categorize specific individuals, such as children having non–insulin-dependent diabetes and adults having type 1 diabetes (T1D) even when not requiring insulin. Indeed, ketoacidosis at presentation can be a feature of either T1D or type 2 diabetes. That heterogeneity extends to the origins and character of both major types of diabetes. In this issue of Diabetes Care , Redondo et al. (2) leverage the TrialNet study of subjects with a single diabetes-associated autoantibody at screening in order to explore factors determining progression to multiple autoantibodies and, subsequently, the pathogenesis of T1D. T1D is initiated by presumed nongenetic event(s) operating in children with potent genetic susceptibility. But there is substantial heterogeneity even within the origins of this disease. Those nongenetic events evoke different autoantibodies such that T1D patients with insulin autoantibodies (IAA) have different features from those with GAD autoantibodies (GADA) (3,4). The former, in contrast with the latter, are younger both at seroconversion and at development of clinical diabetes, the two groups having different genetic risk and those with IAA having greater insulin secretory loss (3,4) (Fig. 1). These observations hint at distinct disease-associated networks leading to T1D, perhaps induced by distinct nongenetic events. Such disease-associated pathways could operate in unison, especially in children with T1D, who often have multiple autoantibodies. Figure 1 The incidence of insulin-treated T1D in the first 35 years of life. Cases with multiple autoantibodies have different features (as illustrated) than those with …