Arginine Metabolism Is Altered in Adults with A-ß + Ketosis-Prone Diabetes.

Background: A-ß + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible ß cell dysfunction of unknown etiology. Plasma metabolomic analysis indicates that abnormal arginine metabolism may be involved. Objective: The objective of this study was to determine the relation between gut microbiome and arginine metabolism and the relation between arginine availability and ß cell function in KPD patients compared with control participants. Methods: Kinetics of arginine and related metabolites were measured with stable isotope tracers, and insulin secretory responses to arginine and glucose were determined under euglycemic and hyperglycemic conditions in 6 KPD patients and 6 age-, gender-, and body mass index-matched control participants. Glucose potentiation of arginine-induced insulin secretion was performed in a different set of 6 KPD and 3 control participants. Results: Arginine availability was higher in KPD patients during euglycemia [53.5 ± 4.3 (mean ± SEM) compared with 40.3 ± 2.4 µmol · kg lean body mass (LBM)-1 · h-1, P = 0.03] but declined more in response to hyperglycemia (Δ 10.15 ± 2.6 compared with Δ 3.20 ± 1.3 µmol · kg LBM-1 · h-1, P = 0.041). During hyperglycemia, ornithine flux was not different between groups but after an arginine bolus, plasma ornithine AUC trended higher in KPD patients (3360 ± 294 compared with 2584 ± 259 min · µmol · L-1, P = 0.08). In both euglycemia and hyperglycemia, the first-phase insulin responses to glucose stimulation were lower in KPD patients (euglycemic insulin AUC 282 ± 108 compared with 926 ± 257 min · µU · mL-1, P = 0.02; hyperglycemic insulin AUC 358 ± 79 compared with 866 ± 292 min · µU · mL-1, P = 0.05), but exogenous arginine restored first-phase insulin secretion in KPD patients to the level of control participants. Conclusion: Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response.

Type 1 Diabetes Genetic Risk Score Differentiates Subgroups of Ketosis-Prone Diabetes.

OBJECTIVE: To determine whether genetic risk for type 1 diabetes (T1D) differentiates the four Aß subgroups of ketosis-prone diabetes (KPD), where A+ and A- define the presence or absence of islet autoantibodies and ß+ and ß- define the presence or absence of ß-cell function. RESEARCH DESIGN AND METHODS: We compared T1D genetic risk scores (GRS) of patients with KPD across subgroups, race/ethnicity, ß-cell function, and glycemia. RESULTS: Among 426 patients with KPD (54% Hispanic, 31% African American, 11% White), rank order of GRS was A+ß- > A+ß+ = A-ß- > A-ß+. GRS of A+ß- KPD was lower than that of a T1D cohort, and GRS of A-ß+ KPD was higher than that of a type 2 diabetes cohort. GRS was lowest among African American patients, with a similar distribution across KPD subgroups. CONCLUSIONS: T1D genetic risk delineates etiologic differences among KPD subgroups. Patients with A+ß- KPD have the highest and those with A-ß+ KPD the lowest GRS.

Serum C-peptide and osteocalcin levels in children with recently diagnosed diabetes.

BACKGROUND: We explored the association of C-peptide (marker of secreted insulin), proinsulin and proinsulin /C-peptide ratio (PI/C) (markers of beta-cell endoplasmic reticulum [ER] stress) with undercarboxylated (uOC) and carboxylated osteocalcin (cOC) and their ratio (uOC/cOC) in children with recently diagnosed type 1 (T1D) or type 2 diabetes (T2D), and the correlation of these variables with partial remission (PR) in children with T1D. METHODS: Demographic and clinical data of children with new-onset diabetes (n = 68; median age = 12.2 years; 33.8% non-Hispanic White, 45.6% Hispanic/Latino, 16.2% African American and 4.4% other) were collected at diagnosis and during the first (V1), second (V2) and third clinical visits at 9.0, 32.0 and 175.7 weeks, respectively. Serum proinsulin, C-peptide, uOC and cOC values were measured 7.0 weeks after diagnosis. PR was defined as insulin dose-adjusted HbA1c (IDAA1c) ≤9. RESULTS: In children with new-onset T1D with DKA (33.3%) or T2D (29.4%), Spearman's correlation coefficient revealed a positive association between the C-peptide levels and both uOC and uOC/cOC ratio. In T1D (n = 48), both higher serum C-peptide levels and low PI:C ratio were associated with higher BMI percentile (ß = 0.02, P = .001; ß = -0.01, P = .02, respectively) and older age at diagnosis (ß = 0.13, P = .001; ß = -0.12, P = .001, respectively). Furthermore, in children with T1D, C-peptide levels at V1 correlated with IDAA1c ≤ 9 at V1 (P = .04). CONCLUSION: C-peptide levels are associated with a higher uOC and uOC/cOC ratio in paediatric diabetes. In new-onset T1D children, older age and higher BMI were associated with lower beta-cell stress and higher preserved function, which was predictive of PR on follow-up.

Autoantibodies to the IA-2 Extracellular Domain Refine the Definition of "A+" Subtypes of Ketosis-Prone Diabetes.

OBJECTIVE: Autoantibodies directed against tyrosine phosphatase IA-2 antibody (IA-2 Ab) are diagnostic for autoimmune type 1 diabetes. Conventional assays target the intracellular domain of IA-2. Among patients with ketosis-prone diabetes (KPD), characterized by presentation with diabetic ketoacidosis (DKA), >60% of adults lack three classic islet autoantibodies-IA-2, GAD65, and ZnT8 Abs-associated with type 1 diabetes. We aimed to determine whether apparently autoantibody-negative ("A-") KPD patients possess occult IA-2 Ab directed against full-length IA-2 (IA-2FL) or its extracellular domain (IA-2EC). RESEARCH DESIGN AND METHODS: We developed an assay that targets IA-2FL and IA-2EC and used it to analyze 288 subjects with A- KPD. RESULTS: Ten A- KPD patients were positive for IA-2EC Ab (3.5%), and three were also positive for IA-2FL Ab (1.0%), similar to frequencies in type 1 and type 2 diabetes. CONCLUSIONS: Measurement of IA-2FL Ab and IA-2EC Ab improves the accuracy of the Aß classification of KPD patients.

Elevated unmethylated and methylated insulin DNA are unique markers of A+ß+ ketosis prone diabetes.

A+ß+ ketosis prone diabetes (KPD) is associated with slowly progressive autoimmune beta cell destruction. Plasma unmethylated and methylated insulin DNA (biomarkers of ongoing beta cell damage and systemic inflammation, respectively) were elevated in A+ß+ KPD compared to all other KPD subgroups.