Residual Beta-cell Function Research Articles

Possible Ways to Improve Postprandial Glucose Control in Type 1 Diabetes.

Possible Ways to Improve Postprandial Glucose Control in Type 1 Diabetes.

Glutamic acid decarboxylase-IgG among T2DM patients with HCMV infection and HbA1c levels

Background:Prophetic immune marker glutamic acid decarboxylase (GAD) autoantibody is a distinctive diagnosis between Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus. Individuals have diagnose as Latent Autoimmune Diabetes in adults (LADA) has such autoantibody, which those patients incorrectly diagnosed as T2DM. Objective: To determines frequency of anti- GAD IgG antibody marker in LADA patients, were misdiagnosed as T2DM in relevance with a Cytomegalovirus infectin antibodies and Hemoglobine A1c levels. Patients and Methods: Ninety five patients with T2DM chosen, arranged in two groups with and without cardio vascular diseases (CVD) and a garoup of 49 individuals as healthy control matched age and gender. Samples took from subjects that attended to Hawler Cardiac Center and Diabetic Centers at Erbil city in March 2014. Sera subjected to Enzyme-Linked Immunosorbent assay (ELISA) and Glycohemoglobin assay for HbA1c. Results: GAD islet cell autoantibody was seropositive in 3.05% diabetics and 2.04% controls. There were high titers of HbA1c with low C-peptide in diabetics. A weak negative correlation was found with significant difference between anti-GAD IgG and age (r = -0.282, P < 0.017 correspondingly ). Conclusion: Appropriate diagnosis for LADA could help to preserve the residual Beta-cell function. Key words: Anti-GAD-IgG, Anti-CMC-IgG, C-peptide, HbA1c.

Beta cell function after intensive subcutaneous insulin therapy or intravenous insulin infusion at onset of type 1 diabetes in children without ketoacidosis.

Our aim was to see if IV insulin therapy at diagnosis preserves beta-cell function better than multiple subcutaneous (SC) injections. Fifty-four children 9.9 ± 3.5 years (range 2.8-14.9) without ketoacidosis were included in a 2 years, randomized multicenter study with insulin SC or 48 to 72 hours IV initially. Thirty-three (61%) were boys, 22 (41%) were pubertal. Forty-eight subjects completed 12 months follow-up and 43 completed 24 months. At 1, 6, 12, and 24 months, hemoglobin A1c (HbA1c), C-peptide and insulin/kg/24 h were measured. At 24 months, a mixed-meal tolerance test (MMTT) was performed. HbA1c at diagnosis was 10.7%, (93 mmol/mol) for IV, 10.7%, (94 mmol/mol) for SC. During the first 2 full days of insulin therapy, mean plasma glucose was 8.2 mmol/L for IV, 9.5 for SC (P = .025). Mean insulin dose was 1.5 U/kg/d for IV vs 1.0 for SC (P = .001). Sixteen (7 in IV, 9 in SC group) started with insulin pumps during the follow-up. At 24 months, we saw no significant differences: HbA1c (7.5%, 58 mmol/mol, for IV, 7.2%, 55 mmol/mol, for SC; ns), insulin doses (0.79 vs 0.88 U/kg/d; ns), fasting C-peptide (0.08 vs 0.12 nmol/L; ns), maximal MMTT response (0.19 vs 0.25 nmol/L; ns) and AUC (18.26 vs 23.9 nmol/L*min; ns). Peak C-peptide >0.2 nmol/L in the combined IV and SC groups correlated significantly with HbA1c and C-peptide at onset in a multiple regression. Residual beta cell function at 2 years seems to be independent from initial insulin regimens but related to HbA1c and C-peptide at onset.

Preserved Proinsulin Secretion in Long-Standing Type 1 Diabetes

Recent literature has reported preserved residual beta-cell function (C-peptide "microsecretion") in many individuals with long-standing type 1 diabetes (T1D). However, the concentrations of detectable insulin/C-peptide in the serum are usually very low, and beta-cell mass is typically negligible. Proinsulin is measurable in the early years after diagnosis, consistent with the presence of residual functioning beta cells. However, individuals are not expected to secrete significant amounts of proinsulin beyond the early years after diagnosis. Our primary objective was to measure the prohormone, proinsulin, in a heterogeneous cohort of individuals with long-standing T1D. We also sought to assess whether proinsulin secretion might occur in certain individuals despite the absence of measurable C-peptide. Random postmeal proinsulin concentrations were measured in 97 subjects with T1D (disease duration >3 years) recruited from within the T1D Exchange Clinic Network participants who took part in the Residual C-peptide Study. Forty-nine of these subjects had undetectable baseline and stimulated C-peptide (C-peptide [-]), and 48 of them had detectable C-peptide concentrations (C-peptide [+]). All the C-peptide (+) subjects had detectable serum proinsulin. Eight (16%) of the C-peptide (-) subjects had detectable serum proinsulin. We report the observation that proinsulin secretion persists in a proportion of individuals with long-standing T1D, even in the absence of measurable C-peptide. It is not yet clear why certain patients with T1D retain the ability to secrete proinsulin many years after diagnosis. CP = C-peptide CV = coefficient of variation ELISA = enzyme-linked immunosorbent assay IQR = inter-quartile range MMTT = mixed-meal tolerance test NIBSC = National Institute for Biological Standards and Control PI = proinsulin T1D = type 1 diabetes.

GAD65: a prospective vaccine for treating Type 1 diabetes?

ABSTRACTIntroduction: In spite of modern techniques, the burden for patients with type 1 diabetes (T1D) will not disappear and T1D remains a life-threatening disease causing severe complications and increased mortality. We have to learn how to preserve residual insulin secretion or even increase beta cell regeneration. This would give a milder disease, simpler treatment and perhaps even cure. Thus, there are good reasons to try therapies that may preserve beta cell function.Areas covered: In this review the author reviews the literature and registered ongoing trials using GAD-alum put in relation to the high number of published different immune interventions.Expert opinion: GAD-alum treatment is safe, tolerable and easy for the patients and healthcare. It seems probable that treatment with GAD65-alum 20 µg sc can preserve residual beta cell function in T1D, but efficacy needs to be improved. This may be achieved by the use of combination therapies and new approaches for administration.

Latent autoimmune diabetes in adults (LADA) in Asian and European populations.

Diabetes mellitus is a chronic disorder caused by relative or absolute insulin deficiency and characterized by chronic hyperglycaemia. It is expected that by year 2025, 80% of all type 2 diabetic patients will be living in developing or low- and middle-income countries. Among Asians, there has been an overall increase in abdominal obesity; however, the risk of diabetes in these populations starts at much lower body mass index as compared to Caucasians. A significant proportion of diabetic patients with adult-onset, initially nonrequiring insulin treatment, have diabetes-associated autoantibodies in their sera. A new subclass of diabetes with the designation of latent autoimmune diabetes of adult-onset (LADA) has been proposed for this category of subjects. Studies have demonstrated that patients with autoimmune diabetes, characterized by the presence of glutamic decarboxylase autoantibodies display a different clinical phenotype from classical type 2 diabetes without glutamic decarboxylase autoantibodies. This subset of phenotypic type 2 diabetes subjects with islet autoantibodies tend to have sulphonylurea failure and need insulin treatment earlier in the disease process. Diagnosing LADA at an initial stage will be important so that insulin can be initiated earlier, facilitating improved glycemic control sooner as well as the preservation of residual beta-cell function in adult-onset autoimmune diabetes. Because of differences in dietary habits, environmental factors, and phenotypic characteristics between European and Asian populations, there may be heterogeneity in the prevalence and other characteristics of LADA in these two populations.

Unique Challenges of Type 1 Diabetes in the Preschool Population.

Extremely young children aged ≤6 years old represent a unique population among patients with type 1 diabetes in terms of glycemic variation, diabetes management and complications. We describe distinct features of diabetes care and outcomes in preschool age children. We searched PubMed, Google Scholar, and authors' bibliographies in order to extract articles specific to type 1 diabetes in preschool age children. The preschool age group is beset by many challenges to diabetes care, including more frequent hypo- and hyperglycemia, hypoglycemia unawareness, decreased residual beta cell function, and greater long-term neurocognitive effects from severe hypoglycemia and chronic hyperglycemia. Randomized controlled trials show that equally good metabolic control can be obtained with multiple daily injections or an insulin pump. Several non-randomized trials, including an 8 year longitudinal study, show lower hemoglobin A1C and decreased hypoglycemia on insulin pumps. Sensor augmented pump therapy resulted in superior A1C as long as sensors were used regularly. In contrast to adults, continuous glucose monitoring has little to no impact on A1C, although parents appreciate the improved monitoring for hypoglycemia. Children with onset of diabetes prior to age 5 are at risk for younger onset of microalbuminuria, however do not develop earlier onset retinopathy than children diagnosed after 5 years. Both severe hypoglycemia and chronic hyperglycemia have negative impact on neurocognition. Special knowledge about this young population is helpful for practitioners and parents.

Residual beta-cell function in diabetes children followed and diagnosed in the TEDDY study compared to community controls.

To explore whether children diagnosed with type 1 diabetes during islet autoantibody surveillance through The Environmental Determinants of Diabetes in the Young (TEDDY) study retain greater islet function than children diagnosed through the community. TEDDY children identified at birth with high-risk human leukocyte antigen and followed every 3 months until diabetes diagnosis were compared to age-matched children diagnosed with diabetes in the community. Both participated in long-term follow up after diagnosis. Hemoglobin A1c (HbA1c) and mixed meal tolerance test were performed within 1 month of diabetes onset, then at 3, 6, and 12 months, and biannually thereafter. Comparison of 43 TEDDY and 43 paired control children showed that TEDDY children often had no symptoms (58%) at diagnosis and none had diabetic ketoacidosis (DKA) compared with 98% with diabetes symptoms and 14% DKA in the controls (P < 0.001 and P = 0.03, respectively). At diagnosis, mean HbA1c was lower in TEDDY (6.8%, 51 mmol/mol) than control (10.5%, 91 mmol/mol) children (P < 0.0001). TEDDY children had significantly higher area under the curve and peak C-peptide values than the community controls throughout the first year postdiagnosis. Total insulin dose and insulin dose-adjusted A1c were lower throughout the first year postdiagnosis for TEDDY compared with control children. Higher C-peptide levels in TEDDY vs community-diagnosed children persist for at least 12 months following diabetes onset and appear to represent a shift in the disease process of about 6 months. Symptom-free diagnosis, reduction of DKA, and the potential for immune intervention with increased baseline C-peptide may portend additional long-term benefits of early diagnosis.

Assessment of preservation of beta-cell function in children with long-standing type 1 diabetes with „ultrasensitive c-peptide” method

Type 1 diabetes mellitus is a disease caused by the autoimmune destruction of pancreatic beta-cells. It was previously believed that the loss of the endocrine function of the pancreas is total and inevitable. With the rise of new knowledge and new methods allowing to reliably measure c-peptide in the low plasma concentration range, we have learned otherwise. Some residual function of the beta-cells can be present even after decades of the course of the disease. The aim of the study was to evaluate the c-peptide level with routine laboratory and ultrasensitive methods in children with long-standing type 1 diabetes in relation to clinical characteristics. We recruited 178 consecutive children with type 1 diabetes mellitus lasting at least 1 year, mean diabetes duration was 5.6 years. Basic anthropometric measurements were performed and blood samples were drawn. From patients history records we gathered data regarding the course of the disease and laboratory results previously acquired. Laboratory tests performed on the blood samples included HbA1c levels and c-peptide level measurement using classic (n=178) and ultrasensitive (n=160) method (Mercodia). Clinically relevant c-peptide level was set at 0.23 ng/ml according to the DCCT recommendations. Clinically relevant c-peptide was found in 54 of 160 (33.75%) patients. Patients with preserved c-peptide were older at the time of diagnosis, had longer clinical remission, and required lower total and basal doses of insulin. Significantly lower mean HbA1c from the last year, but higher HbA1c at the time of the diabetes diagnosis were found in the group with higher c-peptide levels. The comparison of the classic and ultrasensitive c-peptide tests revealed that both yield similar results. Our observation shows that 34% of young patients with long-standing type 1 diabetes have prolonged c-peptide secretion. We confirm the long-standing assumption that residual beta-cell function is beneficial for metabolic control of the patients. Classic method of the c-peptide measurement can be just as useful in clinical practice as the ultrasensitive one.

Does Vitamin D Supplementation Improve Glycaemic Control In Children With Type 1 Diabetes Mellitus? - A Randomized Controlled Trial.

Vitamin D endocrine system is a potential immune system modulator and has been implicated in the pathogenesis of several autoimmune diseases including Type 1 Diabetes Mellitus (T1DM). Studies have demonstrated an inverse risk relationship between T1DM and Vitamin D levels and also, shown a reduced risk of the disease with its supplementation. To evaluate the role of Vitamin D as an adjuvant in improving glycaemic control and residual pancreatic beta-cell function. Primary outcome was the mean change in HbA1c levels over a period of six months. This double-blinded randomized controlled trial was done in a tertiary care hospital, Southern India and included 52 children aged 1-18 years with T1DM, with 26 participants each in the intervention and standard of care arm. Oral Vitamin D therapy was administered once a month for six months in addition to insulin in intervention arm while only insulin was continued for other arm. Plasma HbA1c, serum 25-Hydroxy vitamin D (25OHD), insulin dose and C-peptide were measured at baseline and repeated after 6 months. Prevalence of Vitamin D deficiency was as high as 63.5% i.e., 33 of total 52 children with T1DM. The mean C-peptide levels were significantly high in intervention arm as compared to standard of care after six months. However, there was no significant difference in HbA1c, and insulin requirement at six months between the two groups. No adverse events due to Vitamin D therapy were noted. Oral Vitamin D may serve as an adjuvant to insulin therapy for children with T1DM by augmenting residual beta-cell function and improving insulin secretion. However, a significant decrease in HbA1c level and requirement for exogenous insulin was not achieved in our study.

Circulating microRNA levels predict residual beta cell function and glycaemic control in children with type 1 diabetes mellitus.

We aimed to identify circulating microRNA (miRNA) that predicts clinical progression in a cohort of 123 children with new-onset type 1 diabetes mellitus. Plasma samples were prospectively obtained at 1, 3, 6, 12 and 60months after diagnosis from a subset of 40 children from the Danish Remission Phase Cohort, and profiled for miRNAs. At the same time points, meal-stimulated C-peptide and HbA1c levels were measured and insulin-dose adjusted HbA1c (IDAA1c) calculated. miRNAs that at 3months after diagnosis predicted residual beta cell function and glycaemic control in this subgroup were further validated in the remaining cohort (n = 83). Statistical analysis of miRNA prediction for disease progression was performed by multiple linear regression analysis adjusted for age and sex. In the discovery analysis, six miRNAs (hsa-miR-24-3p, hsa-miR-146a-5p, hsa-miR-194-5p, hsa-miR-197-3p, hsa-miR-301a-3p and hsa-miR-375) at 3months correlated with residual beta cell function 6-12months after diagnosis. Stimulated C-peptide at 12months was predicted by hsa-miR-197-3p at 3months (p = 0.034). A doubling of this miRNA level corresponded to a sixfold higher stimulated C-peptide level. In addition, a doubling of hsa-miR-24-3p and hsa-miR-146a-5p levels at 3months corresponded to a 4.2% (p < 0.014) and 3.5% (p < 0.022) lower IDAA1c value at 12months. Analysis of the remaining cohort confirmed the initial finding for hsa-miR-197-3p (p = 0.018). The target genes for the six miRNAs revealed significant enrichment for pathways related to gonadotropin-releasing hormone receptor and angiogenesis pathways. The miRNA hsa-miR-197-3p at 3months was the strongest predictor of residual beta cell function 1year after diagnosis in children with type 1 diabetes mellitus.

National Differences in Remission of Type 2 Diabetes Mellitus After Roux-en-Y Gastric Bypass Surgery-Subgroup Analysis of 2-Year Results of the Diabetes Surgery Study Comparing Taiwanese with Americans with Mild Obesity (BMI 30\u201335\xa0kg/m2)

BackgroundThe purpose of this study is to compare effects of different nations on Roux-en-Y gastric bypass (RYGB) vs. intensive medical management (IMM) in achieving remission of type 2 diabetes mellitus (T2DM).Materials and MethodsBetween April 2008 and December 2011, this randomized, controlled clinical trial was conducted at four teaching hospitals in the United States and Taiwan involving 71 participants with mild obesity (BMI 30–35 kg/m2). Thirty-six of 71 participants were randomly assigned to the RYGB group, and the others were in IMM group. Partial or complete remission of T2DM was defined as blood HbA1c < 6.5 % (48 mmol/mol) or <6 % (42 mmol/mol) without any antihyperglycemic medication for at least 1-year duration, respectively.ResultsAt baseline, Taiwanese participants had a lower BMI, younger age, and shorter duration of T2DM than American participants. At 24 months, weight loss was greater in the RYGB group in both populations than in the IMM group. No IMM participant of either population had partial or complete remission of T2DM. In the RYGB group, a substantial proportion of the subjects achieved complete or partial remission (57 % in Taiwanese and 27 % in American participants, P = 0.08). Logistic regression revealed stimulated C-peptide (Odds ratio 2.22, P = 0.02) but not nationality as a significant predictor of diabetes remission.ConclusionAdding RYGB to lifestyle and medical management was associated with a greater likelihood of remission of T2DM in both Taiwanese and American subjects with mild obesity with type 2 diabetes. Residual beta-cell function at baseline appears to be the major factor predicting remission of T2DM.Trial registry number: clinicaltrials.gov Identifier: NCT00641251

Beta cell function and ongoing autoimmunity in long-standing, childhood onset type 1 diabetes.

Aims/hypothesisThis study aimed to determine the frequency of residual beta cell function in individuals with long-standing type 1 diabetes who were recruited at diagnosis, and relate this to baseline and current islet autoantibody profile.MethodsTwo hour post-meal urine C-peptide:creatinine ratio (UCPCR) and islet autoantibodies were measured in samples collected from 144 participants (median age at diagnosis: 11.7 years; 47% male), a median of 23 years (range 12–29 years) after diagnosis. UCPCR thresholds equivalent to mixed meal-stimulated serum C-peptide >0.001 nmol/l, ≥0.03 nmol/l and ≥0.2 nmol/l were used to define ‘detectable’, ‘minimal’ and ‘residual/preserved’) endogenous insulin secretion, respectively. Autoantibodies against GAD (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) were measured by radioimmunoassay.ResultsEndogenous C-peptide secretion was detectable in 51 participants (35.4%), including residual secretion in seven individuals (4.9%) and minimal secretion in 14 individuals (9.7%). In the 132 samples collected more than 10 years after diagnosis, 86 participants (65.2%) had at least one islet autoantibody: 42 (31.8%) were positive for GADA, 69 (52.3%) for IA-2A and 14 of 104 tested were positive for ZnT8A (13.5%). The level of UCPCR was related to age at diagnosis (p = 0.002) and was independent of diabetes duration, and baseline or current islet autoantibody status.Conclusions/interpretationThere is evidence of ongoing autoimmunity in the majority of individuals with longstanding diabetes. Endogenous insulin secretion continues for many years after diagnosis in individuals diagnosed with autoimmune-mediated type 1 diabetes above age 5. These findings suggest that some beta cells are protected from continued autoimmune attack in longstanding type 1 diabetes.

The clinical potential of low-level C-peptide secretion

ABSTRACTIntroduction: In all forms of diabetes, especially so in Type 1 diabetes (T1D), beta cell function is crucial for the course. The interest for residual beta cell function has been meagre, but increased in recent years with interventions to preserve function.Areas covered: Importance and clinical use of C-peptide in Type 1 diabetes. Data for this review were identified by searches of PubMed, and references from relevant articles using the search terms: “type 1 diabetes”, “C-peptide”, “beta cell function”, “HbA1c”, quality of life”, “complications”. s and reports from meetings were not included.Expert commentary: C-peptide may help to get a correct diagnosis, and it is of practical clinical value to know degree of residual insulin secretion to diminish the risk of severe hypoglycaemia and ketoacidosis. Evidence shows that even a quite reduced beta cell function may play an important role for quality of life, for metabolic balance/control, possibility to avoid complications and even for long-term survival. Furthermore, the evidence is increasing for C-peptide being a hormone per se.

JDRF's vision and strategy for prevention of type 1 diabetes

The increasing incidence and lower threshold of developing type 1 diabetes (T1D) increases the urgency of its prevention. Insights from past and current natural history studies have provided the framework for a compelling strategy for primary and secondary prevention. Primary prevention of T1D should target the general childhood population with vaccines (viral or tolerogenic) or by altering microbiota-induced immunoregulation. Secondary prevention will likely require combination therapies (anti-inflammatories, immunomodulatory agents, beta cell survival agents, and/or agents improving glucose control) used sequentially or simultaneously to preserve residual beta cell function and prevent symptomatic disease. Critical gaps and challenges for prevention of T1D include an incomplete understanding of disease pathogenesis and heterogeneity, the lack of cost-effective risk screening and validated biomarkers for precise staging of disease and optimizing design of shorter and smaller prevention clinical trials, and the lack of appreciation of the impact and burden of T1D and the potential for its prevention. A comprehensive and concerted effort of funders, academia, industry, regulatory authorities, payers, government bodies, health care providers, and the T1D community will be required to deliver on JDRF's vision and strategy for prevention of T1D.

The “Unusual Suspects” in Allograft Rejection: Will T Regulatory Cell Therapy Arrest Them?

Several trials with adoptively transferred T regulatory cells (TRegs) have shown to be safe and—in some instances—to be effective in patients with hematological malignancies after allogeneic hematopoietic stem cell transplantation (to prevent graft-versus-host disease), with type 1 diabetes (to preserve residual beta cell function), and with refractory Crohn’s disease (to control the disease). In solid organ transplantation, TReg-cell therapy trials with TReg-supportive immunosuppression are currently being undertaken to control the well-documented T effector cells responsible for allograft rejection. Emerging reports show that many “unusual suspects” are involved in allograft rejection as well. Whether TReg-cell therapy will also target them remains to be investigated. In this review, we will shed some light on these underscored cells, the role TRegs would potentially have in controlling these unusual suspects, and the immune-monitoring strategies that would address potential TReg-cell therapy efficacy.

Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ∼80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans.

Ketoacidosis at diagnosis in childhood-onset diabetes and the risk of retinopathy 20 years later

AimsTo investigate on the relationship between severity of ketoacidosis, an important risk factor for C-peptide preservation, and long-term microvascular complications in childhood-onset type 1 diabetes mellitus (T1DM). Methods230 childhood-onset diabetic patients (177 pre-pubertal), aged 7.0±3.8years followed for at least 15years after their diagnosis, were enrolled. Clinical and laboratory data at diagnosis, and C-peptide levels in a subset of patients, were compared with the severity of retinopathy and nephropathy, after a mean of 19.6±3.8years of disease. Digital retinal photographs were taken in all patients, and centrally graded. Repeated measurements of HbA1c and microalbuminuria for the whole duration of diabetes were collected in over half of the cases. ResultsOut of 230 patients, those with the lowest age at diagnosis had the most severe DKA and clinical conditions (p<0.05), and lower C-peptide levels (p<0.0001) at diagnosis. There was a significant relationship between pH and clinical severity (r=−0.783, p<0.0001), and between pH and C-peptide levels (r=0.278, p<0.05). The severity of ketoacidosis had no relationship with subsequent lifetime HbA1c values and long-term microvascular complications. In logistic regression analysis, the only variables that independently influenced severity of retinopathy were lifetime HbA1c (B=0.838, p<0.001), duration of disease (B=0.208, p<0.005) and age at diagnosis (B=0.116, p<0.05). ConclusionsThe degree of metabolic derangement at diagnosis is not associated with retinopathy and nephropathy in childhood-onset T1DM. Age at diagnosis seems to be an important variable to be considered when evaluating the long-term effects of residual beta-cell function.

Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM).

Whether the titer of glutamic acid decarboxylase antibodies (GADAs), especially a low titer, is a marker of progression of beta cell dysfunction in patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) is unclear. Patients were subdivided as follows: patients with high GADA titers [≥10U/ml (≥180 WHOU/ml): high GADA] (group 1, n=37); those with low GADA titers [<10 U/ml (<180 WHO U/ml): low GADA] (group 2, n=33); those without GADA and with islet cell antibodies (ICA) (group 3, n=8); those without both GADA and ICA and with insulinoma-associated antigen 2 antibodies (IA-2A) (group 4, n=6). We also allocated 198 type 2 diabetic patients without any GADA, ICA or IA-2A as group 5. Serum C-peptide responses to annual oral glucose tolerance tests (OGTTs) were followed up for a mean of 107months from entry. The proportion of patients progressing to an insulin-dependent state in groups 1, 2, 3 and 4 was significantly higher than in group 5. C-peptide responses in OGTTs of patients in groups 1 and 2 were decreased at a significantly higher rate than in group 5. Multivariate Cox proportional hazard analysis revealed that factors including high GADA, low GADA, onset age <45years, duration of diabetes <24months, body mass index (BMI) <22.0kg/m2, low degree of preserved beta cell function and ICA were independent risk factors for progression to an insulin-dependent state. SPIDDM patients with low GADA titers have a significantly higher risk of progression to an insulin-dependent state than type 2 diabetic patients, suggesting that the presence of GADA, irrespective of the titer, is a hallmark of beta cell failure. Other risk factors for further progression to an insulin-dependent state in SPIDDM patients were ICA, onset age, duration of diabetes, BMI and residual beta cell function.

Changes in beta cell function during the proximate post-diagnosis period in persons with type 1 diabetes.

Prior studies examining beta-cell preservation in type 1 diabetes have predominantly assessed stimulated C-peptide concentrations approximately 10 wk after diagnosis. We examined whether earlier assessments might aid in prediction of beta cell function over time. Using data from a multi-center randomized trial assessing the effect of intensive diabetes management initiated within 1 wk of diagnosis, we assessed which clinical factors predicted 90-min mixed-meal tolerance test (MMTT) stimulated C-peptide values obtained 2 and 6 wk after diagnosis. We also studied associations of these factors with C-peptide values at 1- and 2-year post-diagnosis. Data from intervention and control groups were pooled. Among 67 study participants (mean age 13.3 ± 5.7 yr, range 7.8-45.7 yr) in multivariable analyses, C-peptide increased from baseline to 2 wks and then 6 wk. C-peptide levels at these times were significantly correlated with 1- and 2-yr C-peptide concentrations (all p < 0.001), with the strongest observed associations between 6-wk C-peptide and the 1- and 2-yr values (r = 0.66 and r = 0.61, respectively). In multivariable analyses, greater baseline and 6-wk C-peptide, and older age independently predicted greater 1- and 2-yr C-peptide concentrations. C-peptide assessments close to diagnosis were predictive of subsequent C-peptide production. Our data demonstrate a clear increase in C-peptide over the initial 6 wk after diabetes diagnosis followed by a plateau. Our data do not suggest that MMTT assessments performed closer to diagnosis than 6 wk would improve prediction of subsequent residual beta cell function.