Residual Beta-cell Function Research Articles

Clinical Characteristics, Residual Beta-Cell Function and Pancreatic Auto-Antibodies in Thai people with Long-Standing Type 1 Diabetes Mellitus.

ObjectivesTo describe the characteristics of long-standing T1DM in Thai patients and assess residual beta-cell function with status of pancreatic autoantibodies.MethodologyThis is a cross-sectional study of Thai subjects with T1DM and disease duration ≥ 25 years seen at the Theptarin Hospital. Random plasma C-peptide and pancreatic auto-antibodies (Anti-GAD, Anti-IA2, and Anti-ZnT8) were measured. Patients who developed complications were compared with those who remained free of complications.ResultsA total of 20 patients (males 65%, mean age 49.4±12.0 years, BMI 22.5±3.1 kg/m2, A1C 7.9±1.6%) with diabetes duration of 31.9±5.1 years were studied. Half of the participants remained free from any diabetic complications while the proportions reporting retinopathy, nephropathy, and neuropathy were 40%, 30%, and 15%, respectively. HDL cholesterol was significantly higher and triglyceride concentration significantly lower in patients who were free from diabetic nephropathy but not in those who were free from other complications. The prevalence rates of anti-GAD, anti-IA2, and anti-ZnT8 were 65%, 20%, and 10%, respectively. None of the patients who tested negative for both anti-GAD and anti-IA2 was positive for anti-ZnT8. Residual beta-cell function based on detectable random plasma C-peptide (≥ 0.1 ng/mL) and MMTT was found in only 3 patients (15%). There was no relationship between residual beta-cell function and protective effects of diabetic complications.ConclusionEndogenous insulin secretion persists in some patients with long-standing T1DM and half of longstanding T1DM in Thai patients showed no diabetic complications. HDL cholesterol was significantly higher and triglyceride concentration significantly lower in patients who were free from diabetic nephropathy.

Tip 1 Diyabetli Okul Öncesi Dönem Çocuklarda Yatmadan Önce Süt İçmenin Gece Glukoz Seyrine Etkisi: Vaka Sunumları

Tip 1 diyabet (T1D) tanılı küçük çocuklar diyabet yönetimi ve glisemik değişkenlik bakımından ayrı bir yere sahiptir. Küçük çocuklar (<7 yaş), hipoglisemi ve hipergliseminin daha sık görülmesi, hipoglisemi bulgularını ifade edememeleri, rezidüel beta hücre fonksiyonunun az olması, ciddi hipoglisemi atakları ve kronik hiperglisemiye bağlı uzun dönemde nörokognitif etkilenmenin daha fazla olması gibi birçok zorlukla karşı karşıyadır. Bu zorluklar ebeveynlere endişe olarak yansımakta ve birçok ebeveyn gece hipoglisemisi korkusu nedeniyle glukoz değeri ne olursa olsun rutin bir şekilde çocuğa gece ara öğünü vermektedir. Ülkemizde çocukların gece uyumadan önce ve sabah süt içme alışkanlıkları olması sebebiyle süt sık tüketilen bir seçenek olmaktadır. Kliniğimizde izlenen küçük yaş grubu çocukların Sürekli Glukoz İzlem (SGİ) verilerinde süt içirip uyutmanın gece boyunca hiperglisemiye neden olduğu, süt vermenin bırakılması durumunda ise gece glukoz seyrinin hedef aralıkta (70-180 mg/dL) kalma oranının arttığı gözlenmiştir. Bu yazıda kliniğimizde izlenen 3-5 yaş arasındaki iki olgunun tıbbi beslenme tedavisi ve gece ara öğününde verilen sütün SGİ verilerine yansıması paylaşılacaktır.

Glutamic Acid Decarboxylase Injection Into Lymph Nodes: Beta Cell Function and Immune Responses in Recent Onset Type 1 Diabetes Patients.

In spite of intensive treatment Type 1 diabetes leads to serious complications. Preservation of residual beta cell function makes the disease milder, facilitates treatment, prevents complications and increase survival. So far immune interventions have had limited effect, and some serious adverse events and risks. In an open pilot trial we aimed to improve efficacy of GAD-alum treatment using lymph-node administration in combination with oral vitamin D. Here we report the clinical effect and focus on biomarkers for response to treatment. Patients (n = 12) aged 12 to 24 years with recent onset of Type 1 diabetes received 4 μg GAD-alum into lymph-node at day 30, 60, and 90, and oral Vitamin D 2000 U/d, days 1 to 120. Beta cell function was estimated by Mixed Meal Tolerance Tests. GADA, GADA subclasses, GAD65-induced cytokines and proliferation, and T cells markers were analyzed. The treatment was tolerable with no adverse events. Fasting C-peptide and insulin requirement remained stable at 15 months, while HbA1c was lower than baseline. Stimulated C-peptide showed no change at 6 months but declined after 15 months (81% of baseline). Eleven patients remained in partial remission (IDAAC < 9). Patients (n = 9) with better clinical outcome had reduced proportion of IgG1 and increased IgG2, IgG3, and IgG4, increased IL-10 secretion, and reduction of proliferation and CD8+ T cells activation. Patients with poorer clinical response had higher baseline levels of GAD65-induced cytokines and T-cell activation, and an increased ratio of effector/central memory T cells. Intra-lymphatic GAD treatment combined with Vitamin D might preserve beta cell function and improve clinical course in T1D. Patients with less benefit have a different quality of immune response both before and after treatment.Clinical Trial Registration clinicaltrials.gov, identifier NCT02352974.

Functional changes in beta cells during ageing and senescence.

Insulin secretion from beta cells is crucial for maintaining euglycaemia and preventing type 2 diabetes, a disease correlated with ageing. Therefore, understanding the functional changes that beta cell function undergoes with age can reveal new therapeutic targets and strategies to delay or revert the disease. Herein, a systematic review of the literature agrees that, as humans age, their beta cell function declines, independently of peripheral insulin resistance, BMI and waist circumference. Rodent studies reveal that, with age, basal insulin secretion increases with either no change or an increase in stimulated insulin secretion, but the biological significance of this is unclear. The accumulation of senescent beta cells could explain some of these functional changes: transcriptional analysis of senescent and aged beta cells revealed parallel downregulation of several steps along the pathway linking glucose stimulation and insulin secretion. Moreover, specific deletion of senescent cells (senolysis) improved residual beta cell function, gene expression profile and blood glucose levels. In conclusion, cellular senescence could underlie the functional decline of beta cells during ageing and could represent a novel and promising approach for recovering insulin secretion. Graphical abstract.

Preserved C-peptide secretion in patients with type 1 diabetes and incipient chronic complications is associated with lower serum resistin and higher uric acid levels.

Previous studies suggested that long-term perseverance of beta-cell function in patients with type 1 diabetes (T1DM) is associated with lower incidence of microvascular complications. The objective of this study was to evaluate preserved C-peptide secretion in patients with T1DM without overt chronic complications and to explore associations with resistin and uric acid as biomarkers of microvascular complication pathogenesis. We assessed residual beta-cell function in 164 T1DM patients (male/female = 91/73; age/diabetes duration range = 18-70/1-30years) using an ultrasensitive C-peptide ELISA assay with detection limit of 2.5pmol/L and total coefficient of variation (CV) 5,8% (Mercodia, Sweden). Serum level of uric acid was measured by enzymatic method (AU680, Beckman Coulter, USA) while resistin concentration was determined by the ELISA assay (Biovendor, Czech Republic). C-peptide secretors had shorter diabetes duration (5.1 vs. 16years; p< 0,001), lower resistin (4.53 vs. 4.93mg/mL p= 0.045), and higher uric acid (259 vs 238μmol/L, p= 0.048) level than T1DM patients with no detectable C-peptide levels, while no differences in routine anthropometric and laboratory variables, including HbA1c, were observed. Although the proportion of C-peptide secretors significantly decreased across categories of diabetes duration (70%, 38%, 17% and 15% for <5, 5-10, 10-20 and 20-30years of duration, respectively; p< 0,001), detectable C-peptide was found in 5/23 T1DM patients who were diagnosed with T1DM more than 20years ago. The results of our study revealed that patients with detectable C-peptide had lower resistin and higher uric acid level compared to patients with undetectable C-peptide.

Exenatide extended release in patients with type 1 diabetes with and without residual insulin production.

To test whether a long-acting GLP-1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function. We performed a randomized placebo-controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C-peptide. Seventy-nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C-peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24 weeks. Participants were followed for another 6 months off study drug. At week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C-peptide. Those treated with exenatide ER lost weight at 12 and 24 weeks compared to those treated with placebo (P <0.001 and P = 0.007). The total insulin dose was lower, but not when corrected for body weight, and was not affected by residual insulin production. Adverse events were more frequent with exenatide ER, but hypoglycaemia was not increased. Treatment with exenatide ER may have short-term benefits in some individuals with T1D who are overweight or who have detectable levels of C-peptide, but short-term improvements were not sustained.

Adverse events associated with immune checkpoint inhibitors: a new era in autoimmune diabetes.

To summarize a new form of autoimmune diabetes as an adverse event of specific cancer immunotherapies. Immune checkpoint inhibitors are revolutionary treatments in advanced cancers; however, they can cause type 1 diabetes following treatment with these state-of-the-art therapies. A review of the literature showed that this new form of autoimmune diabetes has significant similarities with childhood-onset type 1 diabetes but also some distinctions. It frequently presents with severe diabetic ketoacidosis and almost half of the patients have type 1 diabetes-associated antibodies at presentation. Rapid loss of residual beta-cell function with a lack of honeymoon phase is typical. Certain human leukocyte antigen risk genes for prototypical type 1 diabetes that develops in children and young adults are also commonly found in patients with immune checkpoint inhibitor-induced type 1 diabetes. Immune checkpoint inhibitor-induced type 1 diabetes presenting with diabetic ketoacidosis is a life-threatening adverse event of cancer immunotherapy. Healthcare providers should be aware of this adverse event to prevent morbidity and mortality related to diabetic ketoacidosis. Developing guidelines to identify and monitor risk groups are of utmost importance.

SAT-688 Rare Case of 48 XXYY Syndrome with Suspected Type 1 Diabetes Mellitus

BACKGROUND: 48 XXYY syndrome is a rare aneuploidy characterized by the presence of an extra X and Y chromosome in males. Patients share features of Klinefelter syndrome such as tall stature, hypogonadism, congenital malformations and neurocognitive issues. Hypogonadism may cause abdominal adiposity hence increasing risk of insulin resistance and type 2 diabetes mellitus (DM). Klinefelter syndrome has been associated with certain autoimmune diseases however there is no autoimmune disease link described with XXYY syndrome. We present a patient with XXYY polysomy with insulin requiring DM.Clinical Case: A 26-year-old intellectually disabled male with history of XXYY polysomy presented with seizures and was evaluated for DM management. At age 18, he was noted to have hyperglycemia while undergoing dental extractions for brittle enamel leading to the diagnosis of DM. He was initiated on oral medications for a short period of time and transitioned to insulin due to significant hyperglycemia. Endocrine evaluation at the time also revealed hypergonadotropic hypogonadism and evaluation for Klinefelter syndrome revealed 48 XXYY aneuploidy.Patient’s history was significant for poorly controlled hyperglycemia with HbA1C ranging in 12–14% range in the last few years. History was negative for diabetic ketoacidosis (DKA) as per his primary endocrinologist, despite being noncompliant with his insulin therapy. History was negative for retinopathy, nephropathy or macrovascular complications, although he did have distal extremity paresthesia. On exam, he was noted to be edentulous with tall stature, BMI 21.7, facial dysmorphism, pes planus and 5th-digit clinodactyly bilaterally. Family history was positive for type 2 DM in father and prediabetes in mother.He presented with seizures and was diagnosed with brain abscess. Hyperglycemia was initially managed with IV insulin, followed by basal/bolus therapy. Fasting labs 20 hours after receiving insulin glargine showed glucose of 284 mg/dL, C-peptide 0.6 ng/mL (ref range: 0.8–3.5), proinsulin less than 1.6 pmol/L (less than 8.0), insulin 4 uIU/mL (3–19) suggestive of type 1 DM. Anti-GAD65 and anti-ICA antibody levels were negative. Additional antibody evaluation for type 1 DM (islet antigen 2, insulin autoantibody, micro-insulin and zinc transporter 8) is currently pending at the time of writing.Conclusion: Prevalence of XXYY syndrome is 1:18 000–1:40 000 in males. There are few case reports describing the association of type 2 DM with this syndrome. Our patient’s low BMI, low insulin and C-peptide with hyperglycemia indicate type 1 DM, although the absence of DKA in the setting of noncompliance suggests residual beta cell function or maturity onset diabetes of the young (MODY). Neither T1DM nor MODY has been reported with 48XXYY previously. Clinicians should be aware of this association as it has implications in terms of management of DM.

Assessing the effect of closed-loop insulin delivery from onset of type 1 diabetes in youth on residual beta-cell function compared to standard insulin therapy (CLOuD study): a randomised parallel study protocol

IntroductionManagement of newly diagnosed type 1 diabetes (T1D) in children and adolescents is challenging for patients, families and healthcare professionals. The objective of this study is to determine whether continued...

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route.

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

Distinction of cardiometabolic profiles among people \u226575\u2009years with type 2 diabetes: a latent profile analysis

BackgroundOlder patients with type 2 diabetes mellitus represent a heterogeneous group in terms of metabolic profile. It makes glucose-lowering-therapy (GLT) complex to manage, as it needs to be individualised according to the patient profile. This study aimed to identify and characterize subgroups existing among older patients with diabetes.MethodsRetrospective observational cohort study of outpatients followed in a Belgian diabetes clinic. Included participants were all aged ≥75 years, diagnosed with type 2 diabetes, Caucasian, and had a Homeostasis Model Assessment (HOMA2). A latent profile analysis was conducted to classify patients using the age at diabetes diagnosis and HOMA2 variables, i.e. insulin sensitivity (HOMA2%-S), beta-cell-function (HOMA2%-β), and the product between both (HOMA2%-βxS; as a measure of residual beta-cell function). GLT was expressed in defined daily dose (DDD).ResultsIn total, 147 patients were included (median age: 80 years; 37.4% women; median age at diabetes diagnostic: 62 years). The resulting model classified patients into 6 distinct cardiometabolic profiles. Patients in profiles 1 and 2 had an older age at diabetes diagnosis (median: 68 years) and a lesser decrease in HOMA2%-S, as compared to other profiles. They also presented with the highest HOMA2%-βxS values. Patients in profiles 3, 4 and 5 had a moderate decrease in HOMA2%-βxS. Patients in profile 6 had the largest decrease in HOMA2%-β and HOMA2%-βxS. This classification was associated with significant differences in terms of HbA1c values and GLT total DDD between profiles. Thus, patients in profiles 1 and 2 presented with the lowest HbA1c values (median: 6.5%) though they received the lightest GLT (median GLT DDD: 0.75). Patients in profiles 3 to 5 presented with intermediate values of HbA1c (median: 7.3% and GLT DDD (median: 1.31). Finally, patients in profile 6 had the highest HbA1c values (median: 8.4%) despite receiving the highest GLT DDD (median: 2.28). Other metabolic differences were found between profiles.ConclusionsThis study identified 6 groups among patients ≥75 years with type 2 diabetes by latent profile analysis, based on age at diabetes diagnosis, insulin sensitivity, absolute and residual β-cell function. Intensity and choice of GLT should be adapted on this basis in addition to other existing recommendations for treatment individualisation.

294-OR: Type 1 Diabetes Patients with Residual Beta-Cell Function Display Improved Time in Euglycemia and Less Glycaemic Fluctuation after Exercise

Aims: Exercise can disrupt glycemia in individuals with type 1 diabetes (T1D). A large inter-individual variability in the glucose responses to exercise exists. It is not known how residual beta-cell function in long duration T1D influences glycaemia around exercise. Methods: Individuals with T1D completed a postprandial urine C-peptide creatinine ratio test (UCPCR), and 25 participants (M/F 14/11, 39.4±12.4 years, HbA1c 58.8±9.3 mmol/mol-1, BMI 25.6±4.0 kg/m2, diabetes duration 21.4±13.7 years) with a range of UCPCR were recruited. Participants were split into undetectable, microsecretors and clinically significant C-peptide groups (&amp;lt;0.001, 0.001-0.2 and &amp;gt;0.2 nmol/mmol, respectively). After a maximum exercise test, participants attended the second visit whereby they completed 45 minutes of walking at 60%VO2peak. Participants then left the laboratory, with the remainder of the trial under free-living control. Blinded continuous glucose monitoring (CGM) was captured for 12 hours before exercise and for 3 days afterwards. Data (mean±SD) were analysed by one way ANOVA with significance accepted at p ≤0.05. Results: CGM data were successfully captured for 22/25 participants. In the 12 hours prior to exercise, there was no significant differences in CGM between groups. In the first 12 hours post-exercise, the clinical C-peptide group spent significantly more time (83.7±23.2%) in time in euglycemia (3.9-10 mmol/l) compared to the microsecretors (38.8±16.9%, p =0.002) and undetectable participants (40.5±23.3%, p =0.005). The clinical group had lower post exercise SD (1.95±1.26) than the microsecretors (3.56±1.09 p =0.045) and tended to be lower than the undetectable (3.54±1.10 p =0.07). Conclusion: Residual beta-cell function may offer protection against exercise induced dysglycemia. C-peptide could potentially be a method of stratifying the amount of exercise related support patients need to manage glucose around exercise. Disclosure G.S. Taylor: None. K. Smith: None. J. Scragg: None. A. Bashir: None. R.A. Oram: Other Relationship; Self; Randox Laboratories Ltd. T.J. McDonald: None. E.J. Stevenson: None. J.A. Shaw: Advisory Panel; Self; Sanofi. Other Relationship; Self; Novo Nordisk A/S. D.J. West: Research Support; Self; Arla Foods Ingredients, Dexcom, Inc. Funding Diabetes Research &amp; Wellness Foundation

59-OR: Liraglutide Preserved Insulin Secretion in Adults with Newly Diagnosed Type 1 Diabetes: The NewLira Trial

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion in adults with type 1 diabetes and residual beta-cell function. This randomized, double-blind, placebo-controlled, 52-week trial evaluated the efficacy of liraglutide 1.8 mg QD added to insulin treatment in adults diagnosed with type 1 diabetes within 6 weeks prior to screening. At randomization, at end-of-treatment (week 52) and at follow-up (week 58), a 240-min. liquid mixed meal test (237 kcal Nestlé BOOST) was conducted to evaluate the C-peptide response. In total, 65 adults (age 18-40 years) with newly diagnosed type 1 diabetes, stimulated C-peptide ≥200 pmol/L and BMI &amp;gt;20 kg/m2 were randomized (1:1) to liraglutide or placebo added to insulin treatment. Baseline characteristics were similar between groups (mean±SD) age 27±5 years, fasting C-peptide 359±226 pM and diabetes duration 4.4±1.2 weeks. At end-of-treatment, liraglutide sustained stimulated C-peptide secretion and reduced insulin dose compared with placebo (Table). At 6 weeks post-treatment, stimulated C-peptide levels and total insulin dose did not differ between the groups. No difference was found between groups in HbA1c or BMI (Table). No events of severe hypoglycemia or ketoacidosis were reported. In conclusion, liraglutide preserved postprandial insulin secretion one year after diagnosis of type 1 diabetes. The effects had disappeared 6 weeks post-treatment. Disclosure T.F. Dejgaard: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim International GmbH. C.S. Frandsen: None. U. Kielgast: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Sanofi. H.U. Andersen: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Nordic Infucare. Stock/Shareholder; Self; Novo Nordisk Inc. B. Thorsteinsson: None. T. Krarup: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None. Funding Novo Nordisk

Role of vitamin D and vitamin D receptor gene polymorphisms on residual beta cell function in children with type 1 diabetes mellitus.

After the onset of type 1 diabetes mellitus (T1DM), preservation of the residual ß-cell function can help good metabolic control. The aim of this study was to evaluate the effect of vitamin D and its receptor gene polymorphisms on residual ß-cells function. One hundred and one children with T1DM (new cases) older than 5 years were selected. Vitamin D receptor (VDR) gene polymorphisms, vitamin D (VD), fasting and stimulated C-peptide (FCP and SCP) levels were measured within 1.5 and 4.5 month after the diagnosis of disease. Kruskal-Wallis and Mann-whitney U test were used for comparing the study groups. Generalized estimating equation (GEE) model was used for the estimation of association between VD and VDR gene polymorphisms with FCP and SCP after adjustment for comorbid variables. The most frequent genotypes and alleles in TaqI, FokI, BsmI and ApaI polymorphisms were TT (50%) and allele T (68.88%), FF (59.2%) and allele F (77.04%), Bb (41.8%) and allele b (61.73%), and Aa (53.1%) and allele A (63.29%) respectively. In children with higher VD levels, the C-peptide (CP) levels were elevated. Also we observed: the tt genotype associated with increasing SCP levels compared with TT genotype; the bb and Bb genotypes were associated with increasing both FCP and SCP in comparison to BB; and the aa and Aa genotypes were associated with decreasing FCP in comparison to the AA genotype. Sufficient levels of VD (more than 30 ng/ml) can preserve residual ß-cells and insulin secretion.

Plasma lipid species at type 1 diabetes onset predict residual beta-cell function after 6 months

IntroductionThe identification of metabolomic dysregulation appears promising for the prediction of type 1 diabetes and may also reveal metabolic pathways leading to beta-cell destruction. Recent studies indicate that regulation of multiple phospholipids precede the presence of autoantigens in the development of type 1 diabetes.ObjectivesWe hypothesize that lipid biomarkers in plasma from children with recent onset type 1 diabetes will reflect their remaining beta-cell function and predict future changes in beta-cell function.MethodsWe performed targeted lipidomic profiling by electrospray ionization tandem mass spectrometry to acquire comparative measures of 354 lipid species covering 25 lipid classes and subclasses in plasma samples from 123 patients < 17 years of age followed prospectively at 1, 3, 6 and 12 months after diagnosis. Lipidomic profiles were analysed using liner regression to investigate the relationship between plasma lipids and meal stimulated C-peptide levels at each time point. P-values were corrected for multiple comparisons by the method of Benjamini and Hochberg.ResultsLinear regression analysis showed that the relative levels of cholesteryl ester, diacylglycerol and triacylglycerol at 1 month were associated to the change in c-peptide levels from 1 to 6 months (corrected p-values of 4.06E−03, 1.72E−02 and 1.72E02, respectively). Medium chain saturated and monounsaturated fatty acids were the major constituents of the di- and triacylglycerol species suggesting a link with increased lipogenesis.ConclusionThese observations support the hypothesis of lipid disturbances as explanatory factors for residual beta-cell function in children with new onset type 1 diabetes.

Capturing residual beta cell function in type 1 diabetes.

Since the 1970s, C-peptide has been used as a surrogate marker for monitoring the progression of type 1 and type 2 diabetes and to determine the effects of interventions designed to preserve or improve residual beta cell function. C-peptide measurement is a well-established surrogate of residual beta cell activity and of clinical significance as it is associated with HbA1c, risk for microvascular complications and the incidence of hyperglycaemia in longitudinal studies. Measurement of C-peptide after a mixed meal tolerance test is considered the gold standard of measuring beta cell function in type 1 diabetes, but the method is laborious and inconvenient. In this issue of Diabetologia, Wentworth et al ( https://doi.org/10.1007/s00125-018-4722-z ) report an algorithm for estimating C-peptide (CPEST) based on six routine clinical measures. These do not include stimulated C-peptide measurement and outperform other prevailing algorithms for estimating residual beta cell function. Going forward it is very likely that this new algorithm will serve as a simple measure of beta cell function in routine practice and as a more acceptable primary outcome measure in future trials of disease-modifying therapies.

Temporal dynamics of serum let-7g expression mirror the decline of residual beta-cell function in longitudinal observation of children with type 1 diabetes.

In type 1 diabetes mellitus (T1DM), the introduction of insulin is typically followed by a brief remission period, with subsequent gradual decline in beta-cell function. Several studies described altered profile of circulating miRNAs (microRNAs) in T1DM patients and proposed them as biomarkers of associated pathologic processes. Serum miRNA expression profile reflects residual beta-cell function and autoimmunity in T1DM. The profiling group included patients with: GCK-MODY (N = 13), T1DM (N = 9), and 10 healthy controls. The longitudinal group included 34 patients with samples collected at diagnosis of T1DM and first, third, and fourth to eighth year since diagnosis. We reanalyzed data from the profiling group for miRNAs differentially expressed between patients with T1DM, other types of diabetes and controls. Afterward, we shortlisted miRNAs on the basis of this reanalysis and literature review and quantified their expression with quantitative polymerase chain reaction. Additionally, we measured the levels of anti-islet antibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, IA2 antibodies, and ZnT8A) and C-peptide concentrations across the four timepoints in the longitudinal group. miR-24 and let-7g serum expression differed significantly between GCK-MODY, controls, and HbA1c-matched T1DM patients; P < 0.05, false discovery rate < 0.05. Autoantibodies levels showed decreasing linear trend in repeated timepoints (all P < 0.0001). C-peptide concentration peaked during the first year after diagnosis, corresponding to remission phase, and declined in consecutive measurements. This dynamic was evidenced for let-7g expression levels (P = 0.0058). The pattern of let-7g expression change during the course of diabetes mirrors that of C-peptide levels, hinting at this microRNA's association with the residual mass of the beta cells in patients with T1DM.

Identification of a distinct phenotype of elderly latent autoimmune diabetes in adults: LADA China Study 8.

Latent autoimmune diabetes in adults (LADA) exhibits significant clinical heterogeneity, but the underlying causes remain unclear. The aim of this study was to investigate whether age of onset of LADA contributes to the observed clinical heterogeneity by comparing the clinical, metabolic, and immunogenetic characteristics between elderly and young LADA patients. The cross-sectional study included a total of 579 patients with LADA which was further divided into elderly LADA (E-LADA) group (n=135, age of onset ≥60years) and young LADA (Y-LADA) group (n=444, age of onset <60years). Age-matched subjects with type 2 diabetes were served as control (E-T2D group, n=622). Clinical characteristics, serum autoantibodies, and HLA-DQ haplotypes were compared among these groups. Compared with patients with Y-LADA, patients with E-LADA have better residual beta-cell function and higher level of insulin resistance (both P<.01), more metabolic syndrome characteristics, similar proportion of islet autoantibody positivity, and strikingly different HLA-DQ genetic background. In comparison with E-T2D patients, E-LADA patients tend to have similar metabolic syndrome prevalence, comparable C-peptide levels, and insulin resistance levels and share similar HLA-DQ genetic characteristics. Elderly LADA differs phenotypically and genetically from Y-LADA but has a clinical and genetic profile more similar to that of E-T2D. These distinct phenotypes could potentially help physicians better manage patients with E-LADA.

Effects of walking on residual beta cell function and glycemic control in patients with type 1 diabetes mellitus

Objective To explore the effect of walking on residual beta cell function and glycemic control in patients with type 1 diabetes mellitus. Methods A total of 117 type 1 diabetes mellitus patients who usually walked less than 5000 steps per day were given health education about exercise and divided into three groups according to their self-estimates of the number of walking steps they had taken daily in the previous 4 months: an absent exercise group ( 10000 steps/day). Among them, 34 were in absent group (23.5% for males), 45 were in basis exercise group (40.0% for males) and 38 were in active exercise group (52.6% for males). Fasting C-peptide, postprandial C-peptide, and postprandial C-peptide to glucose ratio were used to evaluate the residual beta cell function, while glycated hemoglobin A1c (HbA1c) and insulin dose-adjusted HbA1c (IDAA1c) were used to evaluate their glycemic control. Results The beta cell function and glycemic control showed a tendency to improve with increases in the number of walking steps. Fasting C-peptide, postprandial C-peptide and the postprandial C-peptide to glucose ratio also increased significantly, while HbA1c and IDAA1c decreased significantly. After balancing the initial difference in the analysis of covariance, significant differences were still found among the 3 groups in the subjects′ beta cell function and glycemic control during the follow-up. Linear regression showed that a large number of steps independently predicted better beta cell function. Conclusions In patients with type 1 diabetes mellitus, walking exercise may be effective for improving residual beta cell function and glycemic control. Key words: Walking; Diabetes mellitus, type 1; Glycemic control; Beta cells; C-peptide

Residual Beta-Cell Function in Long Duration Type 1 Diabetes (T1D)

We investigated residual beta cell function in participants from the DCCT/EDIC study with an average of 35 (range 27, 48) years duration of T1D. Between 2015-2017 after 22-24 years of follow-up in EDIC, a 4-hour mixed meal tolerance test was administered to 944 participants and 7 timed plasma specimens were collected and assayed for C-peptide using a chemiluminescent immunoassay (Roche). We defined a significant post-stimulus response as a peak C-peptide concentration &amp;gt;0.03 nmol/L, based on an earlier DCCT study which demonstrated that the risk of microvascular disease progression was markedly higher among participants who entered the trial with values below this concentration. Overall, 71 (7.5%) participants were classified as “responders” with a median peak C-peptide of 0.10 nmol/L (IQR 0.06, 0.15). Among the 873 participants classified as “non-responders”, 46 had detectable peak C-peptide between 0.003 (limit of detection) and 0.029 nmol/L. Responders were slightly older than non-responders (58.5 ± 6.2 vs. 56.5 ± 6.8 y; p=0.02), yet had similar age of onset of diabetes (22.5 ± 7.0 vs. 21.4 ± 7.8 y) and duration of diabetes (35.9 ± 5.1 vs. 35.0 ± 4.9 y). Compared to non-responders, responders had lower HbA1c values (8.6 ± 1.7 vs. 8.9 ± 1.5%; p=0.01) and higher stimulated C-peptide (0.22 ± 0.14 vs. 0.11 ± 0.11 nmol/L; p&amp;lt;0.0001) at DCCT baseline; and had lower insulin requirements both at DCCT baseline (0.54 ± 0.18 vs. 0.67 ± 0.24 units/kg/day; p&amp;lt;0.0001) and throughout DCCT follow-up (0.61 ± 0.20 vs. 0.69 ± 0.19 units/kg/day; p=0.0008). Significantly fewer responders experienced severe hypoglycemia [requiring assistance] throughout the DCCT/EDIC study (45% of responders vs. 70% of non-responders; p&amp;lt;0.0001). Both the initial episode and recurrent episodes of severe hypoglycemia were less frequent with increasing C-peptide concentrations. In conclusion, beta cell function persists in some very long duration T1D patients and is associated with clinically meaningful reductions in the frequency of severe hypoglycemia. Disclosure R. Gubitosi-Klug: None. B. Braffett: None. S.M. Hitt: None. V. Arends: None. M. Steffes: None. A.K. Saenger: Advisory Panel; Self; Alere Inc. J. Lachin: Board Member; Self; AbbVie Inc., Celgene Corporation. J.P. Palmer: None.