Precocious puberty (PP) typically refers to the initiation of puberty prior to the age of eight in females and before the age of nine in males. The objective of this systematic review and meta-analysis is to pinpoint the risk factors linked to PP, thereby facilitating early diagnosis and timely intervention for individuals at high risk.

A thorough search was carried out in the Cochrane Library, PubMed, and Embase databases up to November 10, 2024. The eligible studies comprised participants diagnosed with PP in the exposure group and participants without PP in the control group. The odds ratio (OR) and weighted mean difference (WMD) with 95 % confidence interval (CI) were computed using a random-effects model.

Out of 653 initially identified papers, 13 studies involving 15 cohorts were ultimately included. The mate-analysis findings indicated significant associations between several factors and the incidence of PP: BMI, maternal menarche age, and duration of breastfeeding. These three factors are significantly associated with the presence of pp: estrogen (E2) levels, follicle-stimulating hormone (FSH) levels, luteinizing hormone (LH) levels.

The occurrence of PP is strongly associated with several factors including BMI, maternal menarche age, and breastfeeding duration. The presence of PP is associated with three factors including E2, LH, FSH.

Management of type 1 diabetes is complex and benefits from adequate executive function (EF) (planning, organization, problem-solving). Teens with diabetes and executive dysfunction may have challenges with the acquisition of self-care skills.

Over 18 months, parents of teens with type 1 diabetes aged 13 to 17 completed the Diabetes Family Responsibility Questionnaire (DFRQ) and Readiness for Independent Self-Care Questionnaire (RISQ) every 6 months. Parents assessed teen EF, completing the Behavior Rating Inventory of Executive Function (BRIEF). T-score ≥60 defined EF challenges. EF, demographic, and diabetes treatment variables predicted RISQ score over time using longitudinal mixed modeling with false discovery rate adjustment.

There were 169 teen participants (54% male) aged 15.9 ± 1.3 years, diabetes duration 8.4 ± 3.7 years, and A1c 8.6 ± 1.2%. About a third (31.4%) of teens had parent-reported BRIEF Global Executive Composite (GEC) scores ≥60. After adjusting for age, sex, and DFRQ, those with GEC <60 had a RISQ score 4.1 points higher than those with GEC ≥60, P = .016. Metacognition index (MI; adjusted for age,sex, and DFRQ) predicted RISQ while behavioral regulation index (adjusted for age, continuous glucose monitor use, DFRQ, and A1c) did not; those with MI <60 had a RISQ score 5.3 points higher than those with MI ≥60, P < .001. In all models, older teen age (P < .05) and less parental involvement (P < .001) predicted higher RISQ score.

EF skills, especially metacognition, appear important for the acquisition of self-care behaviors in teens with type 1 diabetes. Evaluating EF during adolescence may identify teens needing extra support during the transition process.

Background/Objectives: Little is known about the relationship between obesity, the triglyceride-glucose (TyG) index, and insulin resistance (IR). This cross-sectional study of Korean children investigated whether the TyG index mediates the relationship between the waist-to-hip ratio (WHtR) and homeostatic model assessment for IR (HOMA-IR). Methods: Six-hundred-and-thirteen Korean children (320 boys and 293 girls) aged 9-12 years old participated in this study. The participants were classified as insulin-sensitive or insulin-resistant based on gender-specific cut-off values of HOMA-IR. The TyG index was calculated as follows: ln [fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Results: Children with IR were older, more likely to be girls, and had fewer favorable metabolic risk factors than children without IR. A mediation analysis revealed that while WHtR has a direct effect on HOMA-IR, it also has an indirect effect on HOMA-IR through the TyG index. The bootstrapped 95% confidence interval (CI) confirmed that the TyG index had an indirect effect on the relationship between the WHtR and HOMA-IR (effect = 0.349, SE = 0.075, 95% CI [0.210, 0.504]). The interaction effect between the WHtR and sex for the TyG index was statistically significant (β = -1.369, SE = 0.631, 95% CI [-2.608, -0.129]), but it was no longer significant when vigorous physical activity was considered as a covariate. Conclusions: Our findings suggest that girls are more vulnerable than boys to an increase in the TyG index caused by an increase in WHtR. This gender disparity observed in the study needs to be investigated causally.

The global prevalence of end-stage kidney disease (ESKD) is increasing despite optimal management of traditional risk factors such as hyperglycaemia, hypertension, and dyslipidaemia. This study examines the influence of cardiorenal risk factors, socioeconomic status, and ethnic and cardiovascular comorbidities on ESKD outcomes in the general population.

This cross-sectional study analysed data from 502,408 UK Biobank study participants recruited between 2006 and 2010. Multivariable logistic regression models were fitted to assess risk factors for ESKD, with results presented as adjusted odds ratio (aOR) and 95% confidence intervals (95% CI).

A total of 1191 (0.2%) of the study participants reported ESKD. Diabetes increased ESKD risk by 62% [1.62 (1.36-1.93)], with early-onset diabetes (before age 40) conferring higher odds compared to later-onset (after age 40) [2.26 (1.57-3.24)]. Similarly, early-onset hypertension (before age 40), compared to later onset (after age 40), increased ESKD odds by 73% [1.73 (1.21-2.44)]. Cardiovascular comorbidities, including stroke, hypertension, myocardial infarction and angina, were strongly associated with ESKD [5.97 (3.99-8.72), 5.35 (4.38-6.56), 4.94 (3.56-6.78), and 4.89 (3.47-6.81)], respectively. Males were at 22% higher risk of ESKD than females [1.22 (1.04-1.43)]. Each additional year of diabetes duration increased ESKD odds by 2% [1.02 (1.01-1.03)]. Non-white ethnicity, compared to white and socioeconomically most deprived, compared to the least deprived quintiles, were at 70% and 83% higher odds of ESKD. Each unit of HbA1c rise increased the odds of ESKD by 2%. Compared to microalbuminuria, macroalbuminuria increased the odds of ESKD by almost 10-fold [9.47 (7.95-11.27)] while normoalbuminuria reduced the odds by 73% [0.27 (0.22-0.32)].

Early onset of diabetes and hypertension, male sex, non-white ethnicity, deprivation, poor glycaemic control, and prolonged hyperglycaemia are significant risk factors for ESKD. These findings highlight the complexity of ESKD and the need for multifactorial targeted interventions in high-risk populations.

Not applicable.

Insulin requirements in the human body undergo continuous changes in response to growth and development. We assessed the life course relationships between insulin demand and insulin adequacy.

Three independent Chinese cohorts (204 children, aged [mean ± SD] 7.0 ± 0.5 years; 214 adolescents, aged 15.0 ± 1.8 years; 605 adults, aged 41.5 ± 9.3 years), recruited between 1998 and 2013, underwent OGTT tests. Indices of insulin sensitivity and insulin secretion were calculated based on paired glucose/insulin values during fasting, early phase and late phase of OGTT. Insulin demand and insulin adequacy were calculated by standardised major axis (SMA) regression from the paired insulin sensitivity and secretion indices. We derived the natural logarithm of ratio between the exponential functions of insulin adequacy and insulin demand (RAD) index for further evaluating the relationship between insulin demand and adequacy. The risk of abnormal glucose tolerance (AGT) was evaluated by logistic regression analyses. Area under the receiver-operating characteristic curve (AUC-ROC) analyses, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices were used to demonstrate the discriminative value of the RAD method model.

Adolescents had the lowest insulin sensitivity and the highest insulin secretion in all phases (fasting, early and late phase) of the OGTT, as compared with children and adults in each phase (all p<0.001). Adolescents had the highest insulin demand in all phases and lowest insulin adequacy in the fasting phase (p<0.001). In general, adults had the lowest insulin adequacy in both the early phase (p>0.05) and late phase (p<0.001) of the OGTT. Adolescents had negative RAD values irrespective of overweight and obesity, while, in general, children and adults had positive RAD values (p<0.001 between age groups in each of the fasting, early and late phases of the OGTT). Participants with RAD values below the 25th percentile had a higher risk of AGT compared with those above the 25th percentile (fasting-phase OR 1.86 [95% CI 1.18, 2.91]; early-phase OR 1.99 [95% CI 1.24, 3.19]; late-phase OR 2.49 [95% CI 1.57, 3.97]). The late-phase RAD index had the best performance in evaluating the risk of AGT compared with the fasting- and early-phase RAD indices (late-phase AUC-ROC = 0.635 [95% CI 0.583, 0.687]; late-phase NRI = 0.350 [95% CI 0.190, 0.510]; late-phase IDI = 0.033 [95% CI 0.015, 0.050]).

The relationship between insulin demand and insulin adequacy changed throughout the life course. Adolescents had an imbalanced relationship between insulin demand and insulin adequacy, while, in general, children and adults had a balanced relationship. RAD is a novel index that was used to efficiently describe this relationship and evaluate the risk of AGT.

Polycystic ovary syndrome (PCOS) in adults is linked with insulin resistance (IR) and obstructive sleep apnea (OSA). However, less is known about these associations in adolescents.

We studied three groups of adolescents: 27 obese PCOS (OPCOS) (ages 13-21), 11 normal-weight PCOS (NPCOS) (ages 13-21 years), and eight healthy controls (ages 18-21 years). A hyperinsulinemic euglycemic clamp study was performed in all groups to determine IR by insulin sensitivity (M/I). Polysomnography was performed to assess for OSA in OPCOS and NPCOS groups. We compared indices of IR among all groups and OSA among OPCOS, and NPCOS.

We noted that OPCOS and NPCOS and controls differed significantly in their IR. M/I was significantly lower in OPCOS vs. controls (P=0.0061), and also lower for NPCOS vs control but this approached but did not reach statistical significance (P=0.084). In addition, none of the NPCOS subjects had OSA compared to 42% of OPCOS (P=0.03).

Our study suggests OPCOS adolescents have increased IR compared to controls and NPCOS subjects. Higher IR for NPCOS vs controls approached but did not reach statistical significance. Larger studies are needed. In addition, adolescents with OPCOS are at a high risk for OSA.

Historically perceived as a disease mainly affecting adults, the prevalence of type 2 diabetes mellitus (T2DM) among children and adolescents has been rising, mirroring the increasing rates of childhood obesity. Currently, youth-onset T2DM poses a significant public health challenge globally. Treating youth-onset T2DM poses numerous critical challenges, namely limited and inadequate therapeutic options, and difficulties with conducting therapeutic studies. As a result, current treatment guidelines are based on adult studies and expert consensus. Few prominent guidelines on the treatment of youth-onset T2DM have been published recently, i.e., by the American Diabetes Association (ADA) 2024, National Institute for Healthcare and Excellence United Kingdom (NICE UK) 2023, International Society Paediatric and Adolescents Diabetes (ISPAD) 2022, Australasian Paediatric Endocrine Group (APEG) 2020 and Diabetes Canada 2018. This review first explores the unique aspects of youth-onset T2DM. It then summarises the different treatment guidelines, discusses the different treatment modalities based on available evidence and identifies any gaps. The review also explores challenges in the treatment of youth-onset T2DM with potential solutions and discusses recent trials on the treatment of youth-onset T2DM. Continued research aims to optimise treatment, improve outcomes, and alleviate the burden of T2DM on youths.

Pubertal research has primarily focused on hypothalamic-pituitary-gonadal axis (HPG) regulation of puberty, though the hypothalamic-pituitary-adrenal axis (HPA) is increasingly considered critical. Heightened HPA function proxied by increasing cortisol levels may play a role in accelerated pubertal timing. However, the extent to which cortisol varies across ages and its relation to pubertal changes in linear growth are less well substantiated. We explored relationships between age, linear growth, adiposity, C-peptide (proxy for insulin), and cortisol across puberty, and we tested whether higher cortisol levels are associated with earlier ages at menarche and peak height velocity. We utilize longitudinal data (n = 777 urine samples) from Qom females ages 7-14 (n = 46) and test our pre-registered analysis using Bayesian longitudinal mixed effects models and joint modeling techniques. We find limited evidence supporting the overarching hypothesis that HPA upregulation is associated with pubertal maturation or timing. We find some evidence that HPA upregulation, as proxied by cortisol, may be more clearly related to differences in relative linear growth at early-mid puberty, as measured by height-for-age z-scores. Transdisciplinary perspectives on puberty, including the assumption that stressors acting via cortisol accelerate pubertal development, are discussed.

Pediatric obesity can drastically heighten the risk of cardiometabolic alterations later in life, with insulin resistance standing as the cornerstone linking adiposity to the increased cardiovascular risk. Puberty has been pointed out as a critical stage after which obesity-associated insulin resistance is more difficult to revert. Timely prediction of insulin resistance in pediatric obesity is therefore vital for mitigating the risk of its associated comorbidities. The construction of effective and robust predictive systems for a complex health outcome like insulin resistance during the early stages of life demands the adoption of longitudinal designs for more causal inferences, and the integration of factors of varying nature involved in its onset. In this work, we propose an eXplainable Artificial Intelligence-based decision support pipeline for early diagnosis of insulin resistance in a longitudinal cohort of 90 children. For that, we leverage multi-omics (genomics and epigenomics) and clinical data from the pre-pubertal stage. Different data layers combinations, pre-processing techniques (missing values, feature selection, class imbalance, etc.), algorithms, training procedures were considered following good practices for Machine Learning. SHapley Additive exPlanations were provided for specialists to understand both the decision-making mechanisms of the system and the impact of the features on each automatic decision, an essential issue in high-risk areas such as this one where system decisions may affect people's lives. The system showed a relevant predictive ability (AUC and G-mean of 0.92). A deep exploration, both at the global and the local level, revealed promising biomarkers of insulin resistance in our population, highlighting classical markers, such as Body Mass Index z-score or leptin/adiponectin ratio, and novel ones such as methylation patterns of relevant genes, such as HDAC4, PTPRN2, MATN2, RASGRF1 and EBF1. Our findings highlight the importance of integrating multi-omics data and following eXplainable Artificial Intelligence trends when building decision support systems.

Growth hormone (GH) is a central regulator of β-cell proliferation, insulin secretion and sensitivity. Aim of this study was to investigate the effect of GH insensitivity on pancreatic β-cell histomorphology and consequences for metabolism in vivo.

Pancreata from pigs with growth hormone receptor deficiency (GHR-KO, n = 12) were analyzed by unbiased quantitative stereology in comparison to wild-type controls (WT, n = 12) at 3 and 7-8.5 months of age. In vivo secretion capacity for insulin and glucose tolerance were assessed by intravenous glucose tolerance tests (ivGTTs) in GHR-KO (n = 3) and WT (n = 3) pigs of the respective age groups.

Unbiased quantitative stereological analyses revealed a significant reduction in total β-cell volume (83% and 73% reduction in young and adult GHR-KO vs. age-matched WT pigs; p < 0.0001) and volume density of β-cells in the pancreas of GHR-KO pigs (42% and 39% reduction in young and adult GHR-KO pigs; p = 0.0018). GHR-KO pigs displayed a significant, age-dependent increase in the proportion of isolated β-cells in the pancreas (28% in young and 97% in adult GHR-KO vs. age-matched WT pigs; p = 0.0009). Despite reduced insulin secretion in ivGTTs, GHR-KO pigs maintained normal glucose tolerance.

GH insensitivity in GHR-KO pigs leads to decreased β-cell volume and volume proportion of β-cells in the pancreas, causing a reduced insulin secretion capacity. The increased proportion of isolated β-cells in the pancreas of GHR-KO pigs highlights the dependency on GH stimulation for proper β-cell maturation. Preserved glucose tolerance accomplished with decreased insulin secretion indicates enhanced sensitivity for insulin in GH insensitivity.

Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic β-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent and complex multidisciplinary disorder. Data regarding the role of genes involved in vitamin D metabolism in PCOS are as-yet elusive but suggest an association of VDR (vitamin D receptor) and vitamin D levels with metabolic, endocrine and cutaneous manifestations. The aim of this study was to evaluate the association between VDR gene polymorphisms and cutaneous manifestations, to find a correlation between hormonal parameters, oxidative stress and skin manifestations in women with PCOS, and to determine the impact of VDR gene polymorphisms on these parameters. Materials and Methods: This case-control study included 39 controls and 46 women with PCOS, matched by age and BMI distribution. Acne, hirsutism, seborrhea, androgenetic alopecia, oxidative stress and androgen hormones were recorded. VDR gene polymorphisms ApaI, FokI and TaqI were examined by polymerase chain reaction restriction fragment length polymorphism, and the androgen hormone (total testosterone, DHEAS), SHBG and malondialdehyde levels were assessed. Results: The most frequent skin manifestations in PCOS cases were acne followed by seborrhea, hirsutism and androgenic alopecia. The VDR-FokI polymorphism CC genotype had a significant protective role in the odds of acne (OR = 0.11, 95% CI: [0.02, 0.70], p = 0.015, p-corrected = 0.040) and seborrhea (OR = 0.15, 95% CI: [0.03, 0.75], p = 0.019, p-corrected = 0.039). The results demonstrated a significant protective effect of the C allele on the odds of acne and seborrhea in PCOS cases. Moreover, the dominant genotype of VDR-TaqI could have a protective role against oxidative stress (lower MDA levels) compared to patients carrying the TT genotype. Conclusions: In summary, this is the first study to demonstrate that the FokI CC genotype may have a protective role against both acne and seborrhea in women with PCOS, while the VDR-TaqI dominant genotype is associated with diminished oxidative stress in PCOS patients.

The incidence of early-onset colorectal cancer (EOCRC), which exhibits differential clinical, pathological, and molecular features compared to late-onset CRC (LOCRC), is rising globally. The potential differential effects of blood glucose on EOCRC compared to LOCRC have not been investigated.

This study analyzed 374,568 participants from the UK Biobank cohort and 172,809 participants from the Kailuan cohort. The linear associations between blood glucose and EOCRC/LOCRC were estimated using Cox regression models. Restricted cubic spline (RCS) analysis and non-linear Mendelian randomization (MR) analysis using a 70-SNPs genetic instrument for fasting glucose were used to explore the potential non-linear associations.

Participants in the highest quintile of blood glucose had higher overall CRC risk compared to the lowest quintile (HR = 1.10 in the UK Biobank cohort, 95% CI: 1.01-1.21, P-trend = 0.012; HR = 1.23 in the Kailuan cohort, 95% CI: 1.01-1.51, P-trend = 0.036). Elevated glucose (>7.0 mmol/L) was more strongly associated with increased risk of EOCRC (HR = 1.61, 95% CI: 1.07-2.44) than with LOCRC (HR = 1.14, 95% CI: 1.02-1.27) in the UK Biobank cohort (P-heterogeneity = 0.014). Elevated glucose (>7.0 mmol/L) was associated with increased risk of LOCRC (HR = 1.25, 95% CI: 1.04-1.65) in the Kailuan cohort as well. There was no evidence for non-linear associations between blood glucose and risks of EOCRC/LOCRC.

This study showed a positive association between blood glucose and CRC risk in a dose-response manner, particularly for EOCRC, suggesting that tighter glucose control should be a priority for younger age groups.

Insulin resistance, an increasingly prevalent characteristic among children and adolescents with obesity, is now recognized as a significant contributor to the development of type 2 diabetes mellitus (T2DM) and other metabolic diseases in individuals with obesity. Insulin resistance refers to a decrease in the sensitivity of peripheral tissues (primarily skeletal muscle, adipose tissue, and liver) to insulin, which is mainly characterized by impaired glucose uptake and utilization. Although the mechanisms underlying insulin resistance in children with obesity remain incompletely elucidated, several risk factors including lipid metabolism disorders, oxidative stress (OS), mitochondrial dysfunction, inflammation, and genetic factors have been identified as pivotal contributors to the pathogenesis of obesity-related insulin resistance. In this review, we comprehensively analyze relevant literature and studies to elucidate the underlying mechanisms of insulin resistance in childhood obesity. Additionally, we discuss treatment strategies for pediatric obesity from a perspective centered on improving insulin sensitivity, aiming to provide valuable insights for the prevention and management of pediatric obesity.

To analyse the relationships between muscular fitness (MF), fat mass (FM), fat-free mass (FFM) and its combined ratio with cardiometabolic risk (CMR) and whether the relationship between MF and CMR is mediated by body composition in schoolchildren.

A cross-sectional study was conducted on schoolchildren from Cuenca, Spain, between September and November 2017. FM and FFM were estimated using bioimpedance analysis. The CMR index was calculated from triglycerides-HDL-c ratio, arterial pressure and fasting insulin. The MF index was assessed using handgrip and standing long jump tests. Analysis of covariance models assessed CMR index differences across the MF index and the FM/FFM ratio categories. Mediation analysis examined whether the MF index and the CMR index association were mediated by FM, FFM or FM/FFM ratio.

The analyses involved 485 schoolchildren aged 9-11 years (55.4% girls). Children with a higher MF index had a lower CMR index (p < 0.05). This association did not persist after controlling for FM/FFM. FM, FFM and FM/FFM ratio mediated the relationship between the MF index and the CMR index.

Better levels of MF are associated with better cardiometabolic profile, but a healthy body composition is determinant to improve future health.

Emerging adulthood is challenging for young people with type 1 diabetes (T1D). This study evaluated transition to diabetes self-management and perceptions of care transfer using mixed methods.

An online survey queried demographics, management characteristics, diabetes knowledge, self-care readiness, adherence, and diabetes distress. T-tests compared survey scores between those with self-reported target A1c <7.0% versus ≥7.0%. Pearson correlations assessed associations between A1c and diabetes distress, stratified by A1c <7.0% versus ≥7.0%. Qualitative semi-structured interviews elicited perceptions of young adults; transcripts were analyzed using directed qualitative content analysis.

Of 141 participants (30% male, 84% non-Hispanic white) completing the survey, 41% self-reported target A1c <7.0%. Diabetes knowledge and self-care readiness scores did not differ between those with A1c <7.0% versus ≥7.0%, while diabetes distress was lower (45 ± 20 vs 52 ± 20, p=0.01) and adherence higher (77 ± 12 vs 71 ± 14, p=0.02) in those with A1c <7.0% versus ≥7.0%. Diabetes distress was significantly associated with glycemic outcomes in those reporting A1c ≥7.0% (R=0.36, p<0.01). Qualitative analysis (24 participants) revealed five themes and two sub-themes, notable for need for more mental health support, support from others with T1D, benefits of technology for care autonomy, and challenges of obtaining diabetes supplies.

Emerging adults with self-reported target A1c endorsed lower diabetes distress and higher adherence than those with elevated A1c. Mental health access, support from others with T1D, technology use, and guidance for supply acquisition may improve transition to self-management and care transfer for emerging adults with T1D.

Since its discovery, much attention has been drawn to irisin's potential role in metabolic and reproductive diseases. This narrative review summarizes and updates the possible role played by this fascinating molecule in different physiological (puberty and menopause) and pathological (polycystic ovary syndrome (PCOS), functional hypothalamic amenorrhea (FHA), endometriosis, and gestational diabetes) conditions that can affect women throughout their entire lives. Irisin appears to be an important factor for the hypothalamic-pituitary-gonadal axis activation, and appears to play a role in the timing of puberty onset. Serum irisin levels have been proposed as a biomarker for predicting the future development of gestational diabetes (GDM). Its role in PCOS is still controversial, although an "irisin resistance" mechanism has been hypothesized. In addition to its impact on metabolism, irisin also appears to influence bone health. Irisin levels are inversely correlated with the prevalence of fractures in postmenopausal women. Similar mechanisms have also been postulated in young women with FHA. In clinical settings, further controlled, prospective and randomized clinical trials are needed to investigate the casual relationship between irisin levels and the conditions described and, in turn, to establish the role of irisin as a prognostic/diagnostic biomarker or a therapeutic target.

Lipids and micronutrients play a major role in the pathophysiology of diabetes, and several studies have established the association between lipids and diabetes. The aim of this study was to determine the interaction between lipid profile and micronutrient status with different prediabetes and diabetes diagnosis criteria among school-aged children in India.

The data used in this study was from Comprehensive National Nutritional Survey conducted in India from 2016 to 2018. Glycosylated hemoglobin values and fasting blood glucose were used to classify normal, prediabetes, and diabetes. The interaction analysis between the lipid profile and eight micronutrients was conducted using multiple logistic regression analyses, and the predicted probabilities were determined.

Among micronutrients, the highest deficiency was observed for hemoglobin (27%), and in the lipid profile, triacylglycerol was high in 34% of children. The interaction between high total cholesterol and vitamin B12 deficiency showed the highest average probability for prediabetes (66%). The highest average probability for diabetes was observed from the interaction between normal high-density lipoprotein and vitamin A deficiency (3%).

The interaction between micronutrients and lipids suggests complex multidimensional pathways involving folate, vitamin B12, ferritin, zinc, hemoglobin, and iodine deficiencies. These interactions should be considered when planning diabetes management strategies.

Smoking is harmful, and its cessation is recommended to prevent chronic kidney disease, which often begins with abnormal leakage of albumin in the urine, called albuminuria. Smoking cessation's effect on albuminuria depends on the pack-years smoked, length of abstinence, body mass index (BMI) and glycosylated haemoglobin (HbA1c). Using the UK Biobank data, we examined the relationship between these cardiorenal variables and albuminuria.

For this study, we selected a UK Biobank cohort with urinary albumin concentration (UAC) in the first and second visits. Participants were divided into progressor and regressor groups, where progressors were defined as those with increased UAC value, and regressors were those with decreased UAC value. Three different logistic regression models were fitted. In model 1, with a cohort design, we explored the impact of a change in age, HbA1c and BMI between the first and second visits and the UAC. In model 2 and 3, in a cross-sectional design, we explored which cardiorenal risk factors were associated with a rise or fall of UAC at the time point of the second visit. Results are expressed in OR and 95% CI.

The prevalence of albuminuria was highest in ex-smokers who started smoking between the ages of 13 and 18. With a mean duration of 51 months, there was no statistically significant relationship between smoking status and BMI with albuminuria. Each year of ageing and each unit of increase in HbA1c (mmol/mol) increased the odds of progression of albuminuria by 20% and 3%, respectively. In ex-smokers, at the time point of the second visit, each year of smoking increased, and each year of abstinence decreased the odds by 4% and 6%, respectively.

Smokers should be supported to stop smoking and remain abstinent despite short-term weight gain. Childhood smoking should be actively discouraged.

Hyperglycaemia in Type 1 diabetes (T1D) results from an absolute insulin deficiency. However, insulin resistance (IR) may exacerbate glycaemic instability in T1D and contribute to long-term cardiovascular complications. We previously showed that IR in teenagers with obesity is associated with sex-dependent derangements in the catabolism of branched-chain amino acids (BCAA) and fatty acids. Here we hypothesized that byproducts of BCAA and fatty acid metabolism may serve as biomarkers or determinants of glycaemic control and IR in prepubertal or early pubertal children with T1D.

Metabolites, hormones and cytokines from fasting blood samples were analysed in 28 children (15 females, 13 males; age 6-11 years) with T1D. Principal components analysis (PCA) and multiple linear regression models were used to correlate metabolites of interest with glycaemic control, total daily insulin dose (TDD, units/kg/d), adiponectin and the triglyceride (TG) to high-density lipoprotein (HDL) ratio.

Males and females were comparable in age, BMI-z, insulin sensitivity, glycaemic control, inflammatory markers, BCAAs and C2/C3/C5-acylcarnitines. The majority of components retained in PCA were related to fatty acid oxidation (FAO) and BCAA catabolism. HbA1c correlated positively with Factor 2 (acylcarnitines, incomplete FAO) and Factor 9 (fasting glucose). TDD correlated negatively with C3 and C5 and Factor 10 (BCAA catabolism) and positively with the ratio of C2 to C3 + C5 and Factor 9 (fasting glucose).

These findings suggest that glucose intolerance in prepubertal or early pubertal children with T1D is accompanied by incomplete FAO while TDD is associated with preferential catabolism of fats relative to amino acids.

No data are available on insulin clearance (ClI) trends during the pubertal transition. The aim of this study was to investigate in 973 youths with obesity whether ClI in fasting and post-oral glucose challenge (OGTT) conditions varies at the pubertal transition in relation to the severity of obesity and the presence of steatosis liver disease (SLD). The severity of obesity was graded according to the Centers for Disease Control. SLD was graded as absent, mild and severe based on alanine amino transferase levels. ClI was defined as the molar ratio of fasting C-peptide to insulin and of the areas under the insulin to glucose curves during an OGTT. In total, 35% of participants were prepubertal, 72.6% had obesity class II, and 52.6% had mild SLD. Fasting ClI (nmol/pmol × 10-2) was significantly lower in pubertal [0.11 (0.08-0.14)] than in prepubertal individuals [0.12 (0.09-0.16)] and higher in class III [0.15 (0.11-0.16)] than in class I obesity [0.11 (0.09-0.14)]. OGTT ClI was higher in boys [0.08 (0.06-0.10)] than in girls [0.07 (0.06-0.09)]; in prepubertal [0.08 (0.06-0.11)] than in pubertal individuals [0.07 (0.05-0.09)]; in class III [0.14 (0.08-0.17)] than in class I obesity [0.07 (0.05-0.10)]; and in severe SLD [0.09 (0.04-0.14)] than in no steatosis [0.06 (0.04-0.17)]. It was lower in participants with prediabetes [0.06 (0.04-0.07)]. OGTT ClI was lower in youths with obesity at puberty along with insulin sensitivity and greater secretion. The findings suggest that the initial increase in ClI in youth with severe obesity and SLD is likely to compensate for hyperinsulinemia and its subsequent decrease at the onset of prediabetes and other metabolic abnormalities.

The authors aimed to use a large two-sample Mendelian randomization (MR) study to reveal the causality between age at menarche (AAM) and polycystic ovary syndrome (PCOS) incidence.

The authors collected summary statistics from the hitherto largest genome-wide association studies conducted in AAM and PCOS in the same ancestry. MR with inverse variance weighting was conducted as the main analysis method, while weighted median and MR-Egger regression were used for comprehensive analysis. As for pleiotropy detection, inverse variance weighting, MR-Egger regression, Mendelian Randomization Pleiotropy Residual Sum and Outlier, as well as leave-one-out analysis were used to detect pleiotropy. Risk factor analysis was conducted to investigate the underlying mechanisms linking AAM to PCOS.

Each standard deviation increment in AAM was associated with a significantly lower incidence of PCOS (odds ratio, 0.86 [95% confidence interval, 0.75-0.98]). After adjustment in horizontal pleiotropy by eliminating four outliers, this pathogenic association was still statistically detected. All pleiotropy indexes were without statistical differences, which suggested the conclusions were robust. It showed the causal association between later AAM and lower body mass index, lower fasting insulin level and insulin resistance.

Our MR analysis verified that a slightly later onset age (15 to 18 years) at menarche could reduce the risk of PCOS. A more comprehensive investigation in a prospective setting is strongly advised.

An increase in obesity prevalence may lead to an increase in the HOMA-IR value. This study aimed to investigate changes in age- and sex-specific homeostasis model assessment of insulin resistance (HOMA-IR) values among South Korean adolescents, using data from the Korean National Health and Nutrition Examination Survey (KNHANES) IV, V, and VIII conducted between 2007-2010 and 2019-2020.

Overall, 4621 adolescents aged 10-18 years were evaluated, including 3473 from the 2007-2010 dataset and 1148 from the 2019-2020 dataset. The mean HOMA-IR values and percentile curves were evaluated by age, sex, and weight status.

The mean HOMA-IR values peaked at puberty in both sexes and further increased during puberty in the 2019-2020 dataset (boys 5.21, 95% confidence interval [CI] 4.16-6.26; girls 5.21, 95% CI 3.09-7.33) compared with the 2007-2010 dataset (boys 3.25, 95% CI 3.04-3.47; girls 3.58, 95% CI 3.31-3.85). Both groups (with normal-weight and overweight/obesity) exhibited a peak HOMA-IR value during puberty in both sexes and both datasets, although the group with overweight/obesity had a higher and wider peak age range. While the mean HOMA-IR values did not change in adolescents with normal-weight, they increased during puberty and post-puberty in boys with overweight/obesity.

HOMA-IR values should be interpreted considering sex, weight status, and pubertal stages. In particular, during the pubertal period, insulin resistance (IR) can coexist not only due to weight-related factors but also as a result of the distinct hormonal changes characteristic of puberty. Over the 10-year period, the mean HOMA-IR values increased in the group with overweight/obesity during puberty and post-puberty, highlighting the need for active intervention to prevent metabolic complications in adolescents with overweight/obesity.

To evaluate whether there is an association between the serum levels of the novel insulin-like adipokine isthmin-1 (ISM1) and obesity-related phenotypes in a population of Spanish children and to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity.

The study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls), and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity, and insulin resistance (IR) status. They were counted anthropometry, glucose and lipid metabolism, inflammation and cardiovascular biomarkers as well as isthmin-1 (ISM1) serum levels. This population was intended as a discovery population to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation examined, allowing deepening into the obesity-ISM1 molecular relationship.

Higher serum ISM1 levels were observed in boys with obesity than in normal weight (P = 0.004) and overweight (P = 0.007) boys. ISM1 serum levels were positively associated with body mass index (BMI) Z-score (P = 0.005) and fat mass (P = 0.058) and negatively associated with myeloperoxidase (MPO) (P = 0.043) in boys. Although we did not find associations between ISM1 serum levels and metabolic outcomes in girls, which may indicate a putative sexual dimorphism, fat mass was positively associated in all children, including boys and girls (P = 0.011). DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children.

ISM1 is associated with obesity in boys at the pubertal stage, elucidating how this protein might be of special relevance as a new biomarker of obesity in children. Further studies including a longitudinal design during puberty are needed.

Fasting indices of glucose-insulin-metabolism are an easy and affordable tool to assess insulin resistance. We aimed to establish reference ranges for fasting insulin indices that reflect age-dependent variation over the entire life span and subsequently test their clinical application regarding the prediction of glycemic deterioration in children.

We calculated age- and puberty-dependent reference values for HOMA-IR, HOMA2-IR, HOMA-β, McAuley index, fasting insulin, and fasting glucose from 6994 observations of 5512 non-obese healthy subjects aged 5-80 years. Applying those references, we determined the prevalence of insulin resistance among 2538 subjects with obesity. Furthermore, we investigated the intraindividual stability and the predictive values for future dysglycemia of these fasting indices in 516 children and adolescents with obesity up to 19 years of follow-up. We validated the results in three independent cohorts.

There was a strong age-dependent variation of all indices throughout the life span, including prolonged recovery of pubertal insulin resistance and a subsequent continuous increase throughout adulthood. Already from age 5 years onwards, >40% of children with obesity presented with elevated parameters of insulin resistance. Applying newly developed reference ranges, insulin resistance among children with obesity doubled the risk for future glycemic deterioration (HOMA-IR HR 1.88 (95% CI 1.1-3.21)), fasting insulin HR 1.89 (95% CI 1.11-3.23). In contrast, fasting glucose alone was not predictive for emerging dysglycemia in children with obesity (HR 1.03 (95% CI 0.62-1.71)). The new insulin-based thresholds were superior to fasting glucose and HbA1c in detecting children eventually manifesting with dysglycemia in prospective analyses.

The variation of fasting glucose-insulin-metabolism across the life span necessitates age-specific reference ranges. The improved prediction of future glycemic deterioration by indices based on fasting insulin beyond simple glucose measures alone could help to stratify risk characteristics of children with obesity in order to guide patient-tailored prevention and intervention approaches.

German Research Foundation (DFG)-through SFB 1052, project number 209933838, subproject C5; Federal Ministry of Education and Research, Germany; European Union-European Regional Development Fund; Free State of Saxony. The German Diabetes Association, the CarbHealth consortium (01EA1908B). EU-IMI2-Consortium SOPHIA (grant agreement No 875534), German Center for Diabetes Research (DZD), grant number 82DZD14E03.

The prevalence study of pre-diabetes and diabetes among children and adolescents is crucial for early detection and intervention, public health resource allocation and monitoring the trend. The national prevalence of pre-diabetes and diabetes among school-age children was 15.35% and 0.94%, whereas, among adolescents, the prevalence was 16.18% and 0.56%, respectively.

Traditionally a disease of adults, type 2 diabetes (T2D) has been increasingly diagnosed in youth, particularly among adolescents and young adults of minority ethnic groups. Especially, during the recent COVID-19 pandemic, obesity and prediabetes have surged not only in minority ethnic groups but also in the general population, further raising T2D risk. Regarding its pathogenesis, a gradually increasing insulin resistance due to central adiposity combined with a progressively defective β-cell function are the main culprits. Especially in youth-onset T2D, a rapid β-cell activity decline has been observed, leading to higher treatment failure rates, and early complications. In addition, it is well established that both the quantity and quality of food ingested by individuals play a key role in T2D pathogenesis. A chronic imbalance between caloric intake and expenditure together with impaired micronutrient intake can lead to obesity and insulin resistance on one hand, and β-cell failure and defective insulin production on the other. This review summarizes our evolving understanding of the pathophysiological mechanisms involved in defective insulin secretion by the pancreatic islets in youth- and adult-onset T2D and, further, of the role various micronutrients play in these pathomechanisms. This knowledge is essential if we are to curtail the serious long-term complications of T2D both in pediatric and adult populations.

Insulin secretion by pancreatic β cells is a dynamic and highly regulated process due to the central importance of insulin in enabling efficient utilization and storage of glucose. Multiple regulatory layers enable β cells to adapt to acute changes in nutrient availability as well as chronic changes in metabolic demand. While epigenetic factors have been well established as regulators of chronic β cell adaptations to insulin resistance, their role in acute adaptations in response to nutrient stimulation has been relatively unexplored. In this issue of the JCI, Wortham et al. report that short-term dynamic changes in histone modifications regulated insulin secretion and acute β cell adaptations in response to fasting and feeding cycles. These findings highlight the importance of investigating whether other epigenetic mechanisms may contribute to acute physiologic adaptations in β cells.

In this narrative review, we describe the epidemiology (prevalence, incidence, temporal trends, and projections) of type 2 diabetes among children and adolescents (<20 years), focusing on data from the U.S. and reporting global estimates where available. Secondarily, we discuss the clinical course of youth-onset type 2 diabetes, from prediabetes to complications and comorbidities, drawing comparisons with youth type 1 diabetes to highlight the aggressive course of this condition, which, only recently, has become recognized as a pediatric disease by health care providers. Finally, we end with an overview of emerging topics in type 2 diabetes research that have potential to inform strategies for effective preventive action at the community and individual levels.

The increasing prevalence of childhood obesity and accompanying comorbidities all over the world constitutes one of the most important public health problems of the changing world. The frequency and causes of the metabolically healthy obesity (MHO) phenotype in children is not clear.

The objective is to determine the prevalence of the MHO phenotype in obese Turkish children and adolescents and to identify clinical and biochemical indicators for this phenotype.

Eight hundred forty-seven obese children and adolescents, aged 3-18 years with BMI-SDS >+2 SD from the obesity outpatient clinic were included. Demographic, anthropometric, and physical examination information was collected from patient medical files. In addition, obesity-related comorbidities and results of laboratory tests were obtained. For study purposes, obese patients with no cardiometabolic risk factors were accepted as MHO, and those with ≥1 cardiometabolic risk factor were considered metabolically unhealthy obese (MUO). MHO was defined according to Damanhoury's criteria.

Out of 847 children (mean age 10.6±3.4 years) who met the study criteria, 289 (34.1%) were diagnosed with MHO. Being younger, prepubertal, having relatively low BMI, low waist/hip ratio, low insulin resistance (HOMA-IR) index, high high-density lipoprotein, low triglyceride, low fasting insulin and glucose levels, low uric acid and low alanine transaminase (ALT) levels were associated with MHO.

The MHO phenotype was present in just over a third of this obese pediatric cohort. The most important factors associated with MHO; age, waist-hip ratio, and BMI were determined.

A healthy lifestyle during adolescence is associated with insulin sensitivity or liver enzyme levels and thus might contribute to the prevention of non-alcoholic fatty liver disease (NAFLD). Therefore, we examined the association between adherence to a hypothesis-based lifestyle score including dietary intake, physical activity, sedentary behaviour, sleep duration and BMI in adolescence and fatty liver indices in early adulthood. Overall, 240 participants of the DOrtmund Nutritional and Anthropometric Longitudinally Designed study completed repeated measurements of lifestyle score factors during adolescence (females: 8·5-15·5 years, males: 9·5-16·5 years). Multivariable linear regression models were used to investigate the association between adolescent lifestyle scores and NAFLD risk (hepatic steatosis index (HSI) and fatty liver index (FLI)) in early adulthood (18-30 years). Participants visited the study centre 4·9 times during adolescence and achieved on average 2·8 (min: 0·6, max: 5) out of five lifestyle score points. Inverse associations were observed between the lifestyle score and fatty liver indices (HSI: ß=-5·8 % (95 % CI -8·3, -3·1), P < 0·0001, FLI: ß=-32·4 % (95 % CI -42·9, -20·0), P < 0·0001) in the overall study population. Sex-stratified analysis confirmed these results in men, while inverse but non-significant associations were observed in women (P > 0·05). A higher lifestyle score was associated with lower HSI and FLI values, suggesting that a healthy lifestyle during adolescence might contribute to NAFLD prevention, predominantly in men. Our findings on repeatedly measured lifestyle scores in adolescents and their association with NAFLD risk in early adulthood warrant confirmation in larger study populations.

Insulin action is impaired in type 2 diabetes. The functions of the hormone are an integrated product of insulin secretion from pancreatic β-cells and insulin clearance by receptor-mediated endocytosis and degradation, mostly in liver (hepatocytes) and, to a lower extent, in extrahepatic peripheral tissues. Substantial evidence indicates that genetic or acquired abnormalities of insulin secretion or action predispose to type 2 diabetes. In recent years, along with the discovery of the molecular foundation of receptor-mediated insulin clearance, such as through the membrane glycoprotein CEACAM1, a consensus has begun to emerge that reduction of insulin clearance contributes to the disease process. In this review, we consider the evidence suggesting a pathogenic role for reduced insulin clearance in insulin resistance, obesity, hepatic steatosis, and type 2 diabetes.

Macrophage activation and cytokine release play a pivotal role in inflammation-mediated metabolic disturbances in obesity. The proinflammatory macrophage secretes human chitotriosidase (CHIT1). The expression of the CHIT1 in visceral adipose tissue is associated with cytokine production. Our study aimed to assess whether the CHIT1 circulating activity, as a macrophage activation indicator, reflects the change of the adiposity level and the insulin resistance (IR) in children with obesity. We longitudinally (median follow-up period of 7 months; IQR [5 to 8.5] and {2 to 13} months) evaluated the CHIT1 circulating activity, the adiposity level (waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WtHR), and body mass index (BMI)-for-age z score), and two surrogate markers of IR (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR and the triglycerides-to-high density lipoprotein cholesterol ratio, TG/HDLc) in 29 pediatric patients (16 girls and 13 boys) with obesity. We found a significant reduction in CHIT1 circulating activity (Wilcoxon test, p = 0.015) and a decrease in TG/HDLc at the follow-up evaluation (Wilcoxon test, p < 0.001). Indicators of adiposity were positively correlated with HOMA-IR at baseline, among which WC was the sole indicator associated with HOMA-IR (Spearman’s rank correlation coefficients, p < 0.05) at follow-up. Human chitotriosidase has the potential to be a valuable measure of the progression of subclinical inflammation in children with obesity. Subclinical inflammation, as expressed by the circulating CHIT1 activity, progresses independently of the abdominal adiposity, as measured by the clinical indicators, and is associated with a change in insulin resistance.

Transient insulin resistance seen during puberty is expected to favour body growth, but our results show that increment in insulin resistance even in physiological ranges during puberty might compromise lumbar spine bone mineral density accrual independently of body composition parameters, and therefore adult bone quality might be challenged.

Insulin resistance (IR) might have a compromising effect on growing bone, and therefore adult bone quality might be challenged. The aim of the present study was to identify whether increases in IR during puberty contribute to bone mineral characteristics in males independently of body composition parameters.

This is a retrospective cohort-based longitudinal observational study. Data from 85 subjects were included. Boys were studied annually during their pubertal years (12 years at baseline) and at follow-up at the age of 18 years. Anthropometry, bone age, fasting blood samples, body composition, total body, and lumbar spine bone mineral characteristics were measured. Insulin resistance was determined by homeostatic model assessment of IR (HOMA-IR). Multiple regression analysis was performed to determine the effect of changes in HOMA-IR during pubertal years as a longitudinal predictor to fixed bone mineral outcome variables at the age of 18 years. All models were adjusted to potential clinically justified confounding variables.

After adjustment to baseline bone indices and body composition-related predictors, the pubertal increment in the HOMA-IR was a negative independent predictor of lumbar spine bone mineral areal density (β =  - 0.202, p = 0.005) and lumbar spine bone mineral apparent density (β =  - 0.235, p = 0.005) in 18-year-old males.

Pubertal increment in IR has a potential diminishing effect on lumbar spine bone mineral density accrual independently of body composition parameters. Further studies are needed to clarify whether monitoring HOMA-IR during puberty may identify subjects at increased risk of low peak bone mass and possible osteoporosis in the future.

We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk.

Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5-7.5), as well as in TNPTP Ab- children (n = 94).

Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide-to-AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab- relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001).

Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab- relatives, suggesting persistent β-cell responsiveness in nonprogressors.

Fluid and insulin treatments are the cornerstones of DKA management and indications on dosages are available. However, according to possible confounding factors, relevant data are still required to explain the different insulin dosages adopted at diabetes onset, particularly based upon insulin sensitivity.

We aimed to explore whether DKA severity is related to different insulin sensitivity states, thus resulting in different insulin requirement at diabetes onset.

Retrospective data from hospital records of 62 newly diagnosed children with type 1 diabetes with DKA were analyzed. The population was divided into three groups: severe, moderate, and mild DKA. Anthropometric, laboratory test, insulin, and glucose administration data were analyzed. The Glucose Infusion Rate (GIR), Insulin Infusion Rate (IIR), and GIR/IIR were calculated and used as indexes of insulin sensitivity. The area under the curve (AUC) for insulin and glucose infusion was calculated.

Moving among the three groups, IIR decreased while GIR and GIR/IIR increased from severe to mild DKA group (all p < 0.01). A similar trend was documented for AUC-insulin and AUC-glucose as well as AUC-glucose/AUC-insulin ratio. The Spearman correlation showed a negative correlation between pH and both IIR and AUC-Insulin as well as a positive correlation between pH and both GIR/IIR and AUC-glucose/AUC-insulin ratio.

Subjects with severe DKA have a higher insulin requirement compared to those with less severe DKA. Significant differences in terms of insulin sensitivity might be documented according to the severity of DKA, which might result in tailored insulin pH requirement in children with new onset type 1 diabetes.

Type 2 diabetes mellitus is a complex and under-treated disorder closely intertwined with obesity. Adolescents with severe obesity and type 2 diabetes have a more aggressive disease compared to adults, with a rapid decline in pancreatic β cell function and increased incidence of comorbidities. Given the relative paucity of pharmacotherapies, bariatric surgery has become increasingly used as a therapeutic option. However, subsets of this population have sub-optimal outcomes with either inadequate weight loss or little improvement in disease. Predicting which patients will benefit from surgery is a difficult task and detailed physiological characteristics of patients who do not respond to treatment are generally unknown. Identifying physiological predictors of surgical response therefore has the potential to reveal both novel phenotypes of disease as well as therapeutic targets. We leverage data assimilation paired with mechanistic models of glucose metabolism to estimate pre-operative physiological states of bariatric surgery patients, thereby identifying latent phenotypes of impaired glucose metabolism. Specifically, maximal insulin secretion capacity, σ, and insulin sensitivity, SI, differentiate aberrations in glucose metabolism underlying an individual's disease. Using multivariable logistic regression, we combine clinical data with data assimilation to predict post-operative glycemic outcomes at 12 months. Models using data assimilation sans insulin had comparable performance to models using oral glucose tolerance test glucose and insulin. Our best performing models used data assimilation and had an area under the receiver operating characteristic curve of 0.77 (95% confidence interval 0.7665, 0.7734) and mean average precision of 0.6258 (0.6206, 0.6311). We show that data assimilation extracts knowledge from mechanistic models of glucose metabolism to infer future glycemic states from limited clinical data. This method can provide a pathway to predict long-term, post-surgical glycemic states by estimating the contributions of insulin resistance and limitations of insulin secretion to pre-operative glucose metabolism.