Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The Childhood Diabetes in Finland Study Group.

Röder, Michael; Knip, Mikael; Hartling, Svend G; Karjalainen, J.; Åkerblom, H. K.; Binder, Christian

doi:10.1210/jcem.79.6.7989457

Cited by 32 publications

(28 citation statements)

References 24 publications

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“…Islet cell antibodies (ICA) have been observed to be associated with increased PIM concentrations (9), but most of the first-degree relatives in previous studies tested negative for ICA (1,2,9). However, in some siblings we found increased PIM concentrations or PIM/C-peptide ratios associated with decreased B cell function and later progression to IDDM (10).…”

Section: Introductionmentioning

confidence: 51%

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland

Hartling

Knip²,

Röder³

et al. 1997

European Journal of Endocrinology

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Objective: To follow proinsulin immunoreactive material (PIM) in healthy siblings from the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) in the proband, for at least 2 years. Design and methods: The study comprised 148 siblings representing 112 families. The siblings were recruited from the nationwide 'Childhood Diabetes in Finland' study and tested for immunological markers. If a sibling was found positive for islet cell antibodies (ICA) or insulin autoantibodies (IAA), PIM sampling was extended beyond 2 years. Results: Of the 148 siblings, 12 developed IDDM 3-53 months after the diagnosis in the proband. Eleven of these siblings exhibited initially normal PIM concentrations. In nine siblings, samples were available both more than 6 months and during the last 6 months before the diagnosis of IDDM; PIM concentrations increased in seven, remained unchanged in one, and decreased in one in the period up to the diagnosis of IDDM (P < 0.05). Median PIM concentration did not change significantly during the examination period of 2 years in the 136 siblings who did not contract IDDM. Constantly increased PIM concentrations were found in 12 of the 136 siblings who did not develop IDDM. These 12 siblings were all ICA negative. Conclusion: In healthy siblings of IDDM patients exhibiting an initially low PIM concentration, an abrupt increase in PIM seems to precede the clinical manifestation of IDDM within 0-6 months. However, there were too few patients available to close follow-up to allow calculation of any predictive value of this increase. Persistently increased PIM concentrations were present in some healthy siblings who did not develop IDDM. The reason for that finding remains unclear, but it could be associated with previous B cell damage.

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Section: Introductionmentioning

confidence: 51%

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland

Hartling

Knip²,

Röder³

et al. 1997

European Journal of Endocrinology

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“…Age, gender, BMI and 5′ INS genotype (K. Decochez, unpublished)-all known to influence the risk of diabetes [3,18,20,22]could not improve the prediction of diabetes so far in this group, but demonstration of their possible added value would require follow-up of larger study groups for longer periods. Disease prediction may further benefit from the assessment of the persistence of antibodies, changes in antibody levels and SDS-BMI over time and, most likely, from the repeated assessment of beta cell function and insulin resistance [22,24,[37][38][39][40][41][42]. The most standardised functional tests (intravenous glucose tolerance test, clamps) are, however, more difficult to implement on a larger scale in non-diabetic risk groups.…”

Section: Discussionmentioning

confidence: 99%

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Decochez

Truyen²,

Auwera

et al. 2005

Diabetologia

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Aims/hypothesis: Prevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset. Methods: Antibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40. Results: On first sampling, 11.1% of the siblings presented at least one antibody type (p<0.001 vs other relatives). During follow-up (median 52 months) 43 subjects developed type 1 diabetes (31 siblings, ten offspring of a diabetic father, two offspring of a diabetic mother). Using Kaplan-Meier survival analysis and Cox regression, IA-2A conferred the highest 5-year diabetes risk (>50%) irrespective of the number of antibodies present. In initially IA-2A-positive relatives (n=58) progression to hyperglycaemia depended more on HLA DQ status than on type of kinship (84% progression in the presence of DQ2/DQ8 vs 32% in its absence; p<0.003). In IA-2A-negative relatives (n=4,531) 5-year progression to diabetes increased with the number of other antibodies (ICA, GADA and/or IAA) (p<0.001) but overall did not exceed 10% even for two or more antibodies. Among relatives initially positive for one or more antibody type other than IA-2A (n=315), there was significantly more progression to diabetes (overall still <10%) in carriers of DQ2 (p<0.001 vs no DQ2), regardless of DQ8 status. Conclusions/interpretation: These observations suggest that the HLA-DQ-inferred risk of diabetes can proceed through two distinct pathways distinguished by IA-2A status. Combined positivity for DQ2/DQ8 and IA-2A defines a more homogeneous high-risk population for prevention trials than those used so far.

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“…This underlines the important point that the proinsulin:insulin ratio is not a reliable index of beta-cell function under conditions of altered hepatic insulin clearance, and under such circumstances, the proinsulin:C-peptide ratio should be used. Certainly a close and inverse relationship has been demonstrated between the proinsulin:C-peptide ratio and first phase insulin secretion as an index of beta-cell function [40].…”

Section: Discussionmentioning

confidence: 99%

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

et al. 1997

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Non-insulin-dependent diabetes mellitus (NIDDM) is a complex metabolic condition characterised by both impaired insulin secretion and insulin resistance [1]. It is also recognised that elevated circulating proinsulin levels are an important and consistent feature of NIDDM [2][3][4][5], and may represent a specific defect of pancreatic beta-cell function. There is continuing debate as to whether insulin deficiency or insulin resistance represents the primary abnormality which predisposes to the development of NIDDM [6], although it is clear that comparative insulin deficiency is a sine qua non for NIDDM to develop [7].In an attempt to identify the early fundamental abnormalities, non-diabetic first degree relatives of NIDDM patients have been studied, as they have a 40 % lifetime risk of progressing to diabetes [8]. However, such an approach has so far failed to clarify matters, as some studies have found a principal defect of insulin secretion [9-13], several have suggested that Diabetologia (1997Diabetologia ( ) 40: 1185Diabetologia ( -1190 Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families Summary Non-diabetic first degree relatives of noninsulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3 %, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pairmatched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and Cpeptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion. [Diabetologie (1997[Diabetologie ( ) 40: 1185[Diabetologie ( -1190

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Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The Childhood Diabetes in Finland Study Group.

Cited by 32 publications

References 24 publications

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

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