An online tool using clinical factors to estimate the probability of partial clinical remission of adult-onset Type 1 diabetes.

A type 1 diabetes (T1D) diagnosis is often followed by a period of reduced exogenous insulin requirement, with acceptable glucose control, called partial clinical remission (pCR). Various criteria exist to define pCR, which is associated with better clinical outcomes. We aimed to develop formulae and a related online calculator to predict the probability of pCR at 3- and 12-months post-T1D diagnosis. We analysed data from 133 adults at their T1D diagnosis (mean ± SD age: 27 ± 6 yrs., HbA1c 11.1 ± 2.0 %, 98 ± 22 mmol/mol), 3- and 12-months later. All patients were enrolled in the prospective observational InLipoDiab1 study (NCT02306005). We compared four definitions of pCR: 1) stimulated C-peptide >300 pmol/l; 2) insulin dose-adjusted HbA1c ≤9 %; 3) insulin dose <0.3 IU/kg/24 h; and HbA1c ≤6.4 % (46 mmol/mol); and 4) insulin dose <0.5 IU/kg/24 h and HbA1c <7 % (53 mmol/mol). Using readily available demographics and clinical chemistry data exhaustive search methodology was used to model pCR probability. There was low concordance between pCR definitions (kappa 0.10). The combination of age, HbA1c, diastolic blood pressure, triglycerides and smoking at T1D onset predicted pCR at 12-months with an area under the curve (AUC) = 0.87. HbA1c, triglycerides and insulin dose 3-mths post-diagnosis had an AUC = 0.89. A related calculator for pCR in adult-onset T1D is available at http://www.bit.ly/T1D-partial-remission.

Partial Clinical Remission of Type 1 Diabetes in Swedish Children: A Longitudinal Study from the Swedish National Quality Register (SWEDIABKIDS) and the Better Diabetes Diagnosis (BDD) Study.

Aims/Hypotheses: To investigate the frequency and characteristics of partial remission in Swedish children with type 1 diabetes and whether the insulin delivery method, that is, continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDIs), affects incidence and duration of this period, 2007-2011. Factors that increase the proportion of subjects who enter partial remission and extend this period can improve long-term metabolic control and reduce the risk of severe hypoglycemia, improve quality of life, and, in the long run, reduce late complications. Methods: Longitudinal data from 2007 to 2020 were extracted from the Swedish National Quality Register (SWEDIABKIDS) with all reported newly diagnosed children. Data on C-peptide from the participants in the Better Diabetes Diagnosis study from 2007 to 2010 were used. The definition of partial remission was insulin dose-adjusted HbA1c: HbA1c (%) + [4 × total daily insulin dose (U/kg/day)] ≤9. Results: Of the 3887 patients, 56% were boys. More boys than girls were in partial remission throughout the follow-up period until 24 months after diabetes onset. Fewer children 0-6 years old had partial remission at 3 and 12 months but not at 24 months compared with older age-groups. A larger proportion of patients using CSII at 12 and 24 months remained in partial remission compared with those with MDI (37% vs. 33%, P = 0.02 and 31% vs. 27%, P = 0.01, respectively). The level of C-peptide was higher in the group with partial remission and mean HbA1c was lower (both P < 0.001). Partial remission at 12 months after diabetes onset was associated with CSII (odds ratio [OR]: 1.39, confidence interval [CI]:1.13, 1.71), shorter diabetes duration (OR: 0.80, CI: 0.76, 0.84), and male sex (OR: 1.23, CI: 1.04, 1.46). Conclusions/Interpretation: Insulin through MDI, longer duration of diabetes, and female sex were associated with lower frequency of partial remission. Use of CSII seems to contribute to longer partial remission among Swedish children with type 1 diabetes.

Muscle-to-fat ratio in children and adolescents with type 1 diabetes in predicting glycaemic control and partial clinical remission.

BACKGROUND: Advances in treatment could mitigate the expected adverse changes in the body composition of children and adolescents with type 1 diabetes (T1D). OBJECTIVES: To examine the evolution of weight status and body composition and their association with glycaemic control and partial clinical remission in youth with T1D. METHODS: Ninety-nine participants with T1D (median age 9.5 years [interquartile range 7.3, 12.9], 59.6% boys) were longitudinally followed for 3 years since diagnosis. Data at seven pre-determined time points were extracted from medical files. Outcome measures included body mass index (BMI) z-scores, muscle-to-fat ratio (MFR) z-scores, haemoglobin A1c (HbA1c) levels, continuous glucose monitoring metrics, and insulin dose-adjusted HbA1c (IDAA1c) levels. RESULTS: The BMI z-scores increased significantly (p < 0.001) for both sexes, with no significant change in MFR z-scores over time. The girls had higher BMI z-scores (p < 0.001) and lower MFR z-scores than the boys (p = 0.016). The mean HbA1c levels decreased during the first month and at 3 months since diagnosis (p < 0.001), then plateaued and achieved a median overall HbA1c of 7.1% for the entire cohort. At 12 months, 37 participants (37.6%) were in partial clinical remission, as evidenced by IDAA1c ≤ 9. The odds of partial clinical remission at 2 years increased by 2.1-fold for each standard deviation increase in the MFR z-score (p < 0.001). Higher MFR z-scores were associated with better metabolic control. CONCLUSIONS: Integration of body composition assessments could mitigate adverse body changes in paediatric patients with T1D.

Guidance for high-dose vitamin D supplementation for prolonging the honeymoon phase in children and adolescents with new-onset type 1 diabetes.

The publication of our recent randomized controlled trial (RCT) showing that vitamin D could protect the ß-cells during the honeymoon phase of type 1 diabetes (T1D) has led to calls for guidance for vitamin D supplementation during the critical phase of type 1 diabetes. Prolonging the partial clinical remission (PR) phase of TID improves glycemic control and reduces long-term complications of T1D. This RCT randomized 36 children and adolescents to either receive vitamin D2 (ergocalciferol, given as 50,000 international units per week for 2 months and then every other week for 10 months) or a placebo. The results showed that vitamin D significantly decreased the temporal rise in both hemoglobin A1c at a mean rate of changes of 0.14% every 3 months versus 0.46% every 3 months for the placebo group (p=0.044); and in the functional marker of PR, the insulin-dose adjusted A1c at a mean rate of change of 0.30% every 3 months versus 0.77% every 3 months for the placebo group, (p=0.015). We recommend a baseline estimation of 25(OH)D concentration at the time of diagnosis of T1D, and to begin vitamin D supplementation if serum 25(OH)D concentration is <30 ng/mL, to maintain serum 25(OH)D concentrations between 30-60 ng/mL. If serum 25(OH)D concentration is >30 ng/mL, monitor vitamin D status with serial 25(OH)D estimations; and initiate vitamin D supplementation if serum 25(OH)D concentrations drop to <30 ng/mL. Continue vitamin D supplementation for at least one year to ensure optimal benefit from vitamin D supplementation during the partial clinical remission phase of type 1 diabetes.

Partial Clinical Remission of Type 1 Diabetes: The Need for an Integrated Functional Definition Based on Insulin-Dose Adjusted A1c and Insulin Sensitivity Score.

Despite advances in the characterization of partial clinical remission (PR) of type 1 diabetes, an accurate definition of PR remains problematic. Two recent studies in children with new-onset T1D demonstrated serious limitations of the present gold standard definition of PR, a stimulated C-peptide (SCP) concentration of >300 pmol/L. The first study employed the concept of insulin sensitivity score (ISS) to show that 55% of subjects with new-onset T1D and a detectable SCP level of >300 pmol/L had low insulin sensitivity (IS) and thus might not be in remission when assessed by insulin-dose adjusted A1c (IDAA1c), an acceptable clinical marker of PR. The second study, a randomized controlled trial of vitamin D (ergocalciferol) administration in children and adolescents with new-onset T1D, demonstrated no significant difference in SCP between the ergocalciferol and placebo groups, but showed a significant blunting of the temporal trend in both A1c and IDAA1c in the ergocalciferol group. These two recent studies indicate the poor specificity and sensitivity of SCP to adequately characterize PR and thus call for a re-examination of current approaches to the definition of PR. They demonstrate the limited sensitivity of SCP, a static biochemical test, to detect the complex physiological changes that occur during PR such as changes in insulin sensitivity, insulin requirements, body weight, and physical activity. These shortcomings call for a broader definition of PR using a combination of functional markers such as IDAA1c and ISS to provide a valid assessment of PR that reaches beyond the static changes in SCP alone.

The Theory of Hyperlipidemic Memory of Type 1 Diabetes.

A literature search was conducted to identify publications addressing the early phases of lipid phenotypes in children and adults with either type 1 diabetes or type 2 diabetes. Medline, EMBASE, and Ovid were searched using the following search terms: clinical remission, partial remission, partial clinical remission, honeymoon phase, C-peptide, type 1 or 2 diabetes, children, pediatric type 1 or 2 diabetes, and paediatrics type 1 or 2 diabetes, adults, adult type 1 or type 2 diabetes. Partial clinical remission (PR) of type 1 diabetes (T1D) is characterized by continued endogenous production of insulin and C-peptide following the diagnosis and the introduction of exogenous insulin therapy. PR is associated with improved glycemic control and reduced prevalence of diabetes complications. The theory of hyperglycemic memory was proposed to explain this concept of improved glycemic outcomes in remitters (those who experienced PR) versus non-remitters (those who did not experience PR). However, this theory is incomplete as it does not explain the dichotomy in early lipid phenotypes in T1D based on PR status, which is an understudied area in diabetology and lipidology. To fill this knowledge gap, we propose the Theory of Hyperlipidemic Memory of T1D. This theory is premised on our 5-year research on early post-diagnostic dichotomy in lipid phenotypes between remitters and non-remitters across the lifespan. It provides a more rigorous explanation for the differences in lifelong atherosclerotic cardiovascular disease (ASCVD) risk between remitters and non-remitters. We conducted 4 clinical studies in pediatric and adult subjects with diabetes mellitus to characterize the particulars of the hyperlipidemic memory. In the first investigation, we explored the impact of the presence or absence of PR on lipid parameters in children and adolescents with T1D. In the second, we investigated whether pubertal maturation influenced our findings in T1D; and whether these findings could be replicated in healthy, non-diabetic children and adolescents. In the third, we leveraged our findings from T1D and controls to investigate the mechanisms of early lipid changes in T2D by comparing the earliest lipid phenotype of subjects with type 2 diabetes (T2D) to those of remitters, non-remitters, and controls. In the fourth, we investigated the impact of PR on the earliest lipid phenotypes in adults with T1D and compared these early lipid data to those of T2D subjects and controls. This body of work across the lifespan in children, adolescents, and adults supports the Theory of Hyperlipidemic Memory. This new theory clarifies why PR largely determines the risks for early-phase dyslipidemia, mid-term microvascular disease risk, and long-term ASCVD risk in subjects with T1D.

Ergocalciferol in New-onset Type 1 Diabetes: A Randomized Controlled Trial.

CONTEXT: The effect of the anti-inflammatory and immunomodulatory actions of vitamin D on the duration of partial clinical remission (PR) in youth with type 1 diabetes (T1D) is unclear. OBJECTIVE: This work aimed to determine the effect of adjunctive ergocalciferol on residual ß-cell function (RBCF) and PR in youth with newly diagnosed T1D who were maintained on a standardized insulin treatment protocol. The hypothesis was that ergocalciferol supplementation increases RBCF and prolongs PR. METHODS: A 12-month, randomized, double-blind, placebo-controlled trial was conducted of 50 000 IU of ergocalciferol per week for 2 months, and then once every 2 weeks for 10 months, vs placebo in 36 individuals aged 10 to 21 years, with T1D of less than 3 months and a stimulated C-peptide (SCP) level greater than or equal to 0.2 nmol/L (≥ 0.6 ng/mL). The ergocalciferol group had 18 randomly assigned participants (10 male/8 female), mean age 13.3 ±â€…2.8 years, while the control group had 18 participants (14 male/4 female), aged 14.3 ±â€…2.9 years. RESULTS: The ergocalciferol treatment group had statistically significantly higher serum 25-hydroxyvitamin D at 6 months (P = .01) and 9 months (P = .02) than the placebo group. At 12 months, the ergocalciferol group had a statistically significantly lower serum tumor necrosis factor α (TNF-α) concentration (P = .03). There were no statistically significant differences between the groups at each time point from baseline to 12 months for SCP concentration (P = .08), glycated hemoglobin A1c (HbA1c) (P = .09), insulin dose-adjusted A1c (IDAA1c), or total daily dose of insulin. Temporal trends for rising HbA1c (P = .04) and IDAA1c (P = .02) were statistically significantly blunted in the ergocalciferol group. CONCLUSION: Ergocalciferol statistically significantly reduced serum TNF-α concentration and the rates of increase both in A1c and IDAA1c, suggesting a protection of RBCF and PR in youth with newly diagnosed T1D.

Association between physical activity before diagnosis and the presence of clinical remission in type 1 diabetes - InlipoDiab1 study.

AIM: To investigate whether physical activity is associated with the occurrence of remission in adults with type 1 diabetes. METHODS: Ninety nine adult participants with newly diagnosed type 1 diabetes were enroled into a prospective, observational study. The participants were advised to exercise 2-3 times a week with moderate intensity for a one-year period. Physical activity was assessed by a self-administrated questionnaire on every fourth visit. We counted the months in which participants fulfiled a partial-remission criteria: HbA1c < 6.5%, C-peptide > 0.5 ng/ml, and daily dose of insulin <0.3 U/kg/day. We assigned the participants to two groups: MORE EFFORT and LESS EFFORT, depending on the median value of physical activity in the studied population. RESULTS: The occurrence of the remission achieved statistical significance at 6th month with a greater prevalence in MORE EFFORT group (55% vs. 35% p = 0.047). In multivariate logistic regression analysis for the occurrence of remission at 12th month, physical activity before the diagnosis was the only variable that influences the occurrence of the remission (adjusted odds ratios = 3.32 [95% confidence intervals 1.25-8.80]; p = 0.02). CONCLUSION: In adults with newly diagnosed type 1 diabetes physical activity before the diagnosis is associated with higher occurrence of remission.

Partial Clinical Remission Reduces Lipid-Based Cardiovascular Risk in Adult Patients With Type 1 Diabetes.

Importance: Risk factors for atherosclerotic cardiovascular disease (ASCVD) are well established in type 2 diabetes (T2D), but not in type 1 diabetes (T1D). The impact of partial clinical remission (PR) on short-term ASCVD risk in T1D is unclear. Aim: To investigate the impact of PR on the earliest ASCVD risk phenotype in adult T1D using factor analysis to compare the lipid phenotypes of T1D, T2D and controls after stratifying the T1D cohort into remitters and non-remitters. Subjects and Methods: A study of 203 adults subjects consisting of 86 T2D subjects, and 77 T1D subjects stratified into remitters (n=49), and non-remitters (n=28). PR was defined as insulin-dose adjusted HbA1c of ≤9, and obesity as a BMI ≥30 kg/m2. Factor analysis was used to stratify the groups by ASCVD risk by factorizing seven lipid parameters (TC, LDL, HDL, non-HDL, TC/HDL, TG, TG/HDL) into 2 orthogonal factors (factor 1: TC*LDL; factor 2: HDL*TG) that explained 90% of the variance in the original seven parameters. Results: The analysis of individual lipid parameters showed that TC/HDL was similar between the controls and remitters (p=NS) but was significantly higher in the non-remitters compared to the remitters (p=0.026). TG/HDL was equally similar between the controls and remitters (p=NS) but was lower in the remitters compared to the non-remitters (p=0.007). TG was significantly lower in the remitters compared to T2D subjects (p<0.0001) but was similar between T2D subjects and non-remitters (p=NS). Non-HDL was significantly lower in the controls versus non-remitters (p=0.0003) but was similar between the controls and remitters (p=NS). Factor analysis showed that the means of factor 1 and factor 2 composite scores for dyslipidemia increased linearly from the controls, remitters, non-remitters to T2D, p value 0.0042 for factor 1, and <0.0001 for factor 2, with remitters having similar lipid phenotype as controls, while non-remitters were similar to T2D. Conclusions: Partial clinical remission of T1D is associated with a favorable early lipid phenotype which could translate to reduced long-term CVD risk in adults.

Partial Clinical Remission of Type 1 Diabetes Mellitus in Children: Clinical Applications and Challenges with its Definitions.

The honeymoon phase, or partial clinical remission (PCR) phase, of Type 1 diabetes mellitus (T1DM) is a transitory period that is marked by endogenous insulin production by surviving 3 cells following a diabetes diagnosis and the introduction of insulin therapy. It is a critical window in the course of the disease that has short and long-term implications for the patient, such as a significant reduction in the risk of long-term complications of T1DM. To promote long-term cardiovascular health in children with newly diagnosed T1DM, three key steps are necessary: the generation of a predictive model for non-remission, the adoption of a user-friendly monitoring tool for remission and non-remission, and the establishment of the magnitude of the early-phase cardiovascular disease risk in these children in objective terms through changes in lipid profile. However, only about 50% of children diagnosed with T1DM experience the honeymoon phase. Accurate and prompt detection of the honeymoon phase has been hampered by the lack of an objective and easily applicable predictive model for its detection at the time of T1DM diagnosis, the complex formulas needed to confirm and monitor PCR, and the absence of a straightforward, user-friendly tool for monitoring PCR. This literature review discusses the most up-to-date information in this field by describing an objective predictive model for non-remission, an easy tool for monitoring remission or non-remission, and objective evidence for the cardiovascular protective effect of PCR in the early phase of the disease. The goal is to present non-remission as an independent clinical entity with significantly poorer long-term prognosis than partial remission.

Pubertal Lipid Levels Are Significantly Lower in Youth With Type 1 Diabetes Who Experienced Partial Clinical Remission.

IMPORTANCE: The physiologic changes in lipids during puberty in type 1 diabetes (T1D) are unclear because subjects in previous studies were not stratified by partial clinical remission status. AIM: To determine the effect of partial clinical remission on lipid changes during puberty in youth with T1D. SUBJECTS AND METHODS: A retrospective cross-sectional study of 194 subjects consisting of 71 control subjects of age 12.9 ± 1.3 years and 123 subjects with T1D stratified into remitters (n = 44; age, 13.0 ± 0.8 years) and nonremitters (n = 79; age, 11.2 ± 0.6 years). Partial clinical remission was defined as insulin-dose adjusted HbA1c of ≤9. Pubertal status was determined by Tanner staging. RESULTS: Among the pubertal cohort, low-density lipoprotein cholesterol concentration was significantly higher in the nonremitters compared with remitters (91.1 ± 25.6 vs 77.2 ± 25.8 mg/dL, P = 0.018) and with normal-weight control subjects (91.1 ± 25.6 vs 70.4 ± 22.9 mg/dL, P = 0.009) but was similar between overweight/obese control subjects and nonremitters (89.7 ± 28.9 vs 91.1± 25.6 mg/dL, P = 0.81) and between normal-weight control subjects and remitters (70.4 ± 22.9 vs 77.2 ± 25.8 mg/dL, P = 0.39). Total cholesterol was also significantly higher in nonremitters compared with remitters (167.8 ± 30.5 vs 149.8 ± 32.1 mg/dL, P = 0.012) and with normal-weight control subjects (167.8 ± 30.5 vs 143.2 ± 30.1 mg/dL, P = 0.011) but was similar between nonremitters and overweight/obese control subjects (P = 0.098) and between remitters and normal-weight control subjects (P = 0.51). Non-high-density lipoprotein cholesterol was equally significantly higher in nonremitters compared with remitters (111.3 ± 30.1 vs 95.9 ± 29.1 mg/dL, P = 0.028) and normal-weight control subjects (111.3 ± 30.1 vs 86.2 ± 32.2 mg/dL, P = 0.028) but was similar between nonremitters and overweight/obese control subjects (P = 0.48) and between remitters vs normal-weight control subjects (P = 0.39). CONCLUSIONS: Puberty-related reductions in low-density lipoprotein, total cholesterol, and non-high-density lipoprotein occur in remitters and normal-weight control subjects but not in nonremitters and overweight/obese control subjects.