The underlying cause of type 1 diabetes, loss of β-cell function, has become the therapeutic target for a number of interventions in patients with type 1 diabetes. Even though insulin therapies continue to improve, it remains difficult to achieve normal glycemic control in type 1 diabetes, especially long term. The associated risks of hypoglycemia and end-organ diabetic complications remain. Retention of β-cell function in patients with type 1 diabetes is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. To facilitate the development of therapies aimed at altering the type 1 diabetes disease process, an American Diabetes Association workshop was convened to identify appropriate efficacy outcome measures in type 1 diabetes clinical trials. The following consensus emerged: While measurements of immune responses to islet cells are important in elucidating pathogenesis, none of these measures have directly correlated with the decline in endogenous insulin secretion. HbA1c is a highly valuable clinical measure of glycemic control, but it is an insensitive measure of β-cell function, particularly with the currently accepted standard of near-normal glycemic control. Rates of severe hypoglycemia and diabetic complications ultimately will be improved by therapies that are effective at preserving β-cell function but as primary outcomes require inordinately large and protracted trials. Endogenous insulin secretion is assessed best by measurement of C-peptide, which is cosecreted with insulin in a one-to-one molar ratio but unlike insulin experiences little first pass clearance by the liver. Measurement of C-peptide under standardized conditions provides a sensitive, well accepted, and clinically validated assessment of β-cell function. C-peptide measurement is the most suitable primary outcome for clinical trials of therapies aimed at preserving or improving endogenous insulin secretion in type 1 diabetes patients. Available data demonstrate that even relatively modest treatment effects on C-peptide will result in clinically meaningful benefits. The development of therapies for addressing this important unmet clinical need will be facilitated by trials that are carefully designed with β-cell function as determined by C-peptide measurement as the primary efficacy outcome.

/pdf/c-peptide-is-the-appropriate-outcome-measure-for-type-1-3vamg4vfh2.pdf

C-Peptide Is the Appropriate Outcome Measure for Type 1 Diabetes Clinical Trials to Preserve β-Cell Function: Report of an ADA Workshop, 21–22 October 2001

Background. Cow's milk has been implicated as a possible trigger of the autoimmune response that destroys pancreatic beta cells in genetically susceptible hosts, thus causing diabetes mellitus. Studies in animals have suggested that bovine serum albumin (BSA) is the milk protein responsible, and an albumin peptide containing 17 amino acids (ABBOS) may be the reactive epitope. Antibodies to this peptide react with p69, a beta-cell surface protein that may represent the target antigen for milk-induced beta-cell—specific immunity. Methods. We used immunoassays and Western blot analysis to analyze anti-BSA antibodies in the serum of 142 children with insulin-dependent diabetes mellitus, 79 healthy children, and 300 adult blood donors. Anti-ABBOS antibodies were measured in 44 diabetic patients at the time of diagnosis, three to four months later, and one to two years later. Results. All the diabetic patients had elevated serum concentrations of IgG anti-BSA antibodies (but not of antibodies to other ...

A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus.

Background Cow's milk has been implicated as a possible trigger of the autoimmune response that destroys pancreatic beta cells in genetically susceptible hosts, thus causing diabetes mellitus. Studies in animals have suggested that bovine serum albumin (BSA) is the milk protein responsible, and an albumin peptide containing 17 amino acids (ABBOS) may be the reactive epitope. Antibodies to this peptide react with p69, a beta-cell surface protein that may represent the target antigen for milk-induced beta-cell--specific immunity. Methods We used immunoassays and Western blot analysis to analyze anti-BSA antibodies in the serum of 142 children with insulin-dependent diabetes mellitus, 79 healthy children, and 300 adult blood donors. Anti-ABBOS antibodies were measured in 44 diabetic patients at the time of diagnosis, three to four months later, and one to two years later. Results All the diabetic patients had elevated serum concentrations of IgG anti-BSA antibodies (but not of antibodies to other milk proteins), the bulk of which were specific for ABBOS: The mean (+/- SE) concentration was 8.5 +/- 0.2 kilofluorescence units (kfU) per microliter, as compared with 1.3 +/- 0.1 kfU per microliter in the healthy children. IgA antibodies were elevated as well, but not IgM antibodies. The antibody concentrations declined after diagnosis, reaching normal levels in most patients within one to two years. The initial decline involved anti-ABBOS--specific antibodies almost exclusively. Much lower serum concentrations of anti-BSA antibodies were found in all 379 control subjects, but only 2.5 percent of them had small amounts of ABBOS-specific IgG. Conclusions Patients with insulin-dependent diabetes mellitus have immunity to cow's-milk albumin, with antibodies to an albumin peptide that are capable of reacting with a beta-cell--specific surface protein. Such antibodies could participate in the development of islet dysfunction.

https://www.nejm.org/doi/pdf/10.1056/NEJM199207303270502

Objectives To determine whether human aorta lengthens with aging and to evaluate the impact of the hypothesized aortic elongation on pulse wave velocity (PWV) measurements. Background Although it is generally thought that the aorta becomes tortuous with aging, there has been no systematic study to date in healthy adults to determine if this is so. Such age-related aortic elongation may be a confounding factor for the PWV measurement in elderly people. Methods Arterial lengths were computed by the 3-dimensional transverse magnetic resonance image arterial tracing of the aorta and carotid and iliac arteries in 256 apparently healthy adults (age 19 to 79 years). Results The ascending aorta was greater with advancing age (r = 0.72), whereas the lengths of the descending aorta and carotid and iliac arteries were not associated with age. The elongation of the ascending aorta was associated with the corresponding increases in aortic PWV (beta = 0.50) and brachial/aortic pulse pressure ratio (beta = 0.24), which is an index of pulse wave amplification. The straight distance between carotid and femoral sites (car-fem), the most popular arterial length measurement, overestimated the aortic length measured with the magnetic resonance image by ∼25%. The most accurate arterial length estimation was the distance obtained by subtracting carotid length from the car-fem, with Conclusions The aorta lengthens with age, even in healthy humans, due primarily to the elongation of the ascending aorta. Age-related aortic elongation has little impact on PWV measurements, as the ascending aorta, which undergoes lengthening with age, is not included in the arterial length measurements.

Age-Associated Elongation of the Ascending Aorta in Adults

The incidence rate of insulin-dependent (Type I) diabetes mellitus is bimodal: one peak occurs close to puberty, and the other in the fifth decade. To evaluate possible differences in these forms of the disease, we examined the clinical, biochemical, autoimmune, and genetic features of 82 children and adolescents (1.3 to 18.2 years old) and 44 adults (20.0 to 55.8 years old) when they presented with Type I diabetes. The mean (+/- SEM) duration of symptoms before diagnosis was longer in the adults (7.5 +/- 1.0 vs. 3.9 +/- 0.4 weeks; P less than 0.001), and their serum C-peptide concentrations at diagnosis were higher (0.29 +/- 0.03 vs. 0.17 +/- 0.01 nmol per liter; P less than 0.001), suggesting that they had more residual beta-cell function. There were no significant differences between the two groups in sex ratio, blood glucose levels, hemoglobin A1 values, degree of metabolic decompensation, or frequency of Type I diabetes in first-degree relatives. Thirty-four of 80 children tested (42.5 percent) were positive for insulin autoantibodies, as compared with only 1 of 26 adults (3.8 percent; P less than 0.001). However, the frequencies of islet-cell autoantibodies were similar in the adults and children (conventional autoantibodies, both 81 percent; complement-fixing autoantibodies, 46.2 percent and 60 percent). More children than adults were heterozygous for both HLA-Dw3/4 antigens (26.6 percent vs. 9.8 percent; P less than 0.05) and HLA-DR3/4 antigens (36.6 percent vs. 12.5 percent; P less than 0.05). We conclude that Type I diabetes that begins in adulthood is characterized by a longer symptomatic period before diagnosis, better preservation of residual beta-cell function, and lower frequencies of insulin autoantibodies and HLA-D3/D4 heterozygosity than Type I diabetes that begins in childhood or adolescence.

A Comparison of Childhood and Adult Type I Diabetes Mellitus

To test the hypothesis that insulin-binding antibodies (IBAs) appearing in the circulation before insulin treatment are markers of β-cell damage, we studied the prevalence of IBAs and both conventional (IF-ICAs)- and complement (CF-ICAs)-fixing cytoplasmic islet cell antibodies in 60 newly diagnosed diabetic children with a mean age of 9.5 yr. Seventeen (28.3%) had an insulin binding exceeding the upper range (2.8%) of that observed in 68 age-matched controls. The IBA-positive subjects were characterized by a younger age of onset [6.2 ± 4.0 (SD) vs. 10.8 ± 3.2 yr; P < 0.001], lower glycosylated hemoglobin A, levels (14.1 ± 3.1 vs. 16.0 ± 3.0%; P < 0.05), lower serum C-peptide concentrations (0.12 ± 0.07 vs. 0.20 ± 0.17 nmol/L; P < 0.05), and an increased frequency of HLA-Dw4 (9/13 vs. 11/37; P < 0.05). There was no significant relation between IBAs and serum C-peptide concentrations after age adjustment by multiple regression analysis. Forty-three children (75%) were positive for IF-ICA and 38 (63.3%) for CF-ICA. Twelve IBA-positive diabetics (70.6%) had IFICA as well as CF-ICA in their serum. No association could be observed between IBA and either IF-ICA or CF-ICA, however. The results suggest that IBAs developing before diagnosis serve as an indicator of clinical and genetic heterogeneity within IDDM rather than as a marker of autoimmune β-cell destruction.

Relation Between Insulin Antibody and Complement-Fixing Islet Cell Antibody at Clinical Diagnosis of IDDM

SUMMARY To test the hypothesis that insulin-binding antibodies (IBAs) appearing in the circulation before insulin treatment are markers of p-cell damage, we studied the prevalence of IBAs and both conventional (IF-ICAs)and complement (CF-ICAs)-fixing cytoplasmic islet cell antibodies in 60 newly diagnosed diabetic children with a mean age of 9.5 yr. Seventeen (28.3%) had an insulin binding exceeding the upper range (2.8%) of that observed in 68 age-matched controls. The IBA-positive subjects were characterized by a younger age of onset [6.2 ± 4.0 (SD) vs. 10.8 ± 3.2 yr; P < 0.001], lower glycosylated hemoglobin A, levels (14.1 ± 3.1 vs. 16.0 ± 3.0%; P < 0.05), lower serum C-peptide concentrations (0.12 ± 0.07 vs. 0.20 ± 0.17 nmol/L; P < 0.05), and an increased frequency of HLA-Dw4 (9/13 vs. 11/37; P < 0.05). There was no significant relation between IBAs and serum C-peptide concentrations after age adjustment by multiple regression analysis. Forty-three children (75%) were positive for IF-ICA and 38 (63.3%) for CF-ICA. Twelve IBA-positive diabetics (70.6%) had IFICA as well as CF-ICA in their serum. No association could be observed between IBA and either IF-ICA or CF-ICA, however. The results suggest that IBAs developing before diagnosis serve as an indicator of clinical and genetic heterogeneity within IDDM rather than as a marker of autoimmune p-cell destruction. DIABETES 1986; 35:620-22.

Rapid Publication Relation Between Insulin Antibody and Complement-Fixing Islet Cell Antibody at Clinical Diagnosis of IDDM

We studied 178 diabetic children and adolescents diagnosed during the period 1962-79 to find out the occurrence and duration of the postinitial remission, factors favoring a remission and the prognostic value of the remission. A postinitial remission occurred in 113 children (64%) being complete in only three boys (2%). The duration ranged from one month to 4.8 years, the mean being 8.4 months. The boys had a remission more often and of longer duration than the girls. The duration of diabetes was longer in the children without remission. The children with remission had lower blood glucose, milder hyperketonemia and ketonuria, higher pH and PCO2 at onset than those without remission. Hemoglobin A1 (HbA1) during 1979 were lower in the children with a positive remission history. The children with a remission lasting more than one year had a subsequently higher glucosuria index, lower HbA1 and higher C-peptide when compared to those without remission or to those with a short remission. The remission frequency increased from 1962 to 1979. Male sex and mild metabolic derangement at onset favor a postinitial remission, which results in a persisting residual beta-cell function and better metabolic control beyond the remission.

Postinitial remission in diabetic children--an analysis of 178 cases.

Forty-four children with Type 1 (insulin-dependent) diabetes (aged 0.7–16.7 years) were observed from diagnosis for cytoplasmic islet cell antibodies and serum C-peptide concentrations. Islet cell antibodies were analysed by indirect immunofluorescence for both conventional IgG and complement-fixing antibodies. Thirty-seven children (84%) were found to be positive for conventional islet cell antibodies at diagnosis, and 21 (48%) remained positive over the observation period. Twenty-six patients (59%) were positive for complement-fixing antibodies at diagnosis and eight remained so during the follow-up period. The serum C-peptide concentrations increased significantly during the first 3 months after diagnosis, after which there was a gradual decrease in the levels. Those children who remained positive for complement-fixing antibodies over the observation period had significantly higher serum C-peptide concentrations on several occasions during the second year and had also a higher integrated serum C-peptide concentration over the initial 2 years than those who became negative for complement-fixing antibodies. These observations suggest that the continuous production of complement-fixing islet cell antibodies in those patients who are positive for these antibodies at diagnosis presupposes the preservation of a sufficient amount of functioning β cells for antigenic stimulation. These results support the view that the complement-fixing islet cell antibodies reflect ongoing destructive processes in the β cells.

/pdf/evidence-of-delayed-beta-cell-destruction-in-type-1-insulin-2x81dmtfbs.pdf

Evidence of delayed beta-cell destruction in type 1 (insulin-dependent) diabetic patients with persisting complement-fixing cytoplasmic islet cell antibodies.

The physical working capacity (PWC170) of 84 children and adolescents with insulin-dependent diabetes mellitus (IDDM) and of 94 non-diabetic subjects was measured by a submaximal progressive exercise test. The age of the diabetic subjects ranged from 6.3 to 18.8 years and that of the control subjects from 8.5 to 18.8 years. The PWC170 of diabetic boys was lower than that of non-diabetic boys (p less than 0.01) while no difference was observed between diabetic and non-diabetic girls. PWC170 was inversely related to age (p less than 0.01) and concentration of hemoglobin A1 (p less than 0.025) in diabetic boys but not in diabetic girls. No relationship was observed between PWC170 and duration of diabetes in either boys or in girls. The results indicate that good physical fitness in boys is associated with a better metabolic control. Hence the study indirectly supports previous observations that physical activity improves the metabolic control of IDDM.

Physical fitness of children and adolescents with insulin-dependent diabetes mellitus.

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