Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes

in Pediatric Diabetes (2012), 13(1), 51-58

Objective: Proinsulin is a marker of beta-cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim ... [more ▼]

Objective: Proinsulin is a marker of beta-cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim was to assess the relationship between proinsulin, insulin dose-adjusted haemoglobin A1c (IDAA1C), glucagon-like peptide-1 (GLP-1), glucagon, and remission status the first year after diagnosis of type 1 diabetes. Methods: Juvenile patients (n = 275) were followed 1, 6, and 12 months after diagnosis. At each visit, partial remission was defined as IDAA1C ≤9%. The patients had a liquid meal test at the 1-, 6-, and 12-month visits, which included measurement of C-peptide, proinsulin, GLP-1, glucagon, and insulin antibodies (IA). Results: Patients in remission at 6 and 12 months had significantly higher levels of proinsulin compared to non-remitting patients (p < 0.0001, p = 0.0002). An inverse association between proinsulin and IDAA1C was found at 1 and 6 months (p = 0.0008, p = 0.0022). Proinsulin was positively associated with C-peptide (p < 0.0001) and IA (p = 0.0024, p = 0.0068, p < 0.0001) at 1, 6, and 12 months. Glucagon (p < 0.0001 and p < 0.02) as well as GLP-1 (p = 0.0001 and p = 0.002) were significantly lower in remitters than in non-remitters at 6 and 12 months. Proinsulin associated positively with GLP-1 at 1 month (p = 0.004) and negatively at 6 (p = 0.002) and 12 months (p = 0.0002). Conclusions: In type 1 diabetes, patients in partial remission have higher levels of proinsulin together with lower levels of GLP-1 and glucagon compared to patients not in remission. In new onset type 1 diabetes proinsulin level may be a sign of better residual beta-cell function. © 2011 John Wiley & Sons A/S. [less ▲]

The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

in BMC Medical Genetics (2011), 12(41),

BACKGROUND: The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be ... [more ▼]

BACKGROUND: The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes. METHODS: The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset. RESULTS: A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03). CONCLUSIONS: The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children. [less ▲]

Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

in BMC Endocrine Disorders (2010), 10

Background: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA ... [more ▼]

Background: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.Materials and methods: In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.Results: Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c(P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.Conclusion: GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes. © 2010 Pörksen et al; licensee BioMed Central Ltd. [less ▲]

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

in Clinical Immunology (2008), 128(1), 57-65

Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing ... [more ▼]

Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated longitudinally circulating concentrations of CCR5 ligands of 256 newly diagnosed patients with type 1 diabetes. CCR5 ligands were differentially associated with beta-cell function and clinical remission. CCL5 was decreased in remitters and positively associated with HbA1c suggestive of a Th1 associated progression of the disease. Likewise, CCL3 was negatively related to C-peptide and positively associated with the beta-cell stress marker proinsulin but increased in remitters. CCL4 associated with decreased beta-cell stress shown by negative association with proinsulin. Blockage of chemokines or antagonism of CCR5 by therapeutic agents such as maraviroc may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes. [less ▲]

Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: Reduced insulin antibody titres and preserved beta cell function

in Diabetologia (2006), 49(1), 71-74

Aims/hypothesis: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin ... [more ▼]

Aims/hypothesis: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin gene (INS). We investigated the association between INS VNTR class III alleles (-23HphIA/T) and both insulin antibody presentation and residual beta cell function during the first year after diagnosis in 257 children with type 1 diabetes. Materials and methods: To estimate C-peptide levels and autoantibody presentation, patients underwent a meal-stimulated C-peptide test 1, 6, and 12 months after diagnosis. The insulin -23HphIA/T variant was used as a marker of class III alleles and genotyped by PCR-RFLP. Results: The insulin antibody titres at 1 and 6 months were significantly lower in the class III/III and class I/III genotype groups than in the class I/I genotype group (p = 0.01). Class III alleles were also associated with residual beta cell function 12 months after diagnosis and independently of age, sex, BMI, insulin antibody titres, and HLA-risk genotype group (p = 0.03). The C-peptide level was twice as high among class III/III genotypes as in class I/I and class I/III genotypes (319 vs 131 and 166 pmol/l, p=0.01). Furthermore, the class III/III genotype had a 1.1% reduction in HbA1c after adjustment for insulin dose (p = 0.04). Conclusions/interpretation: These findings suggest a direct connection in vivo between INS VNTR class III alleles, a decreased humoral immune response to insulin, and preservation of beta cell function in recent-onset type 1 diabetes. © Springer-Verlag 2005. [less ▲]