β-Cell response to glucose is compromised in individuals with type 2 diabetes (T2D), possibly due in part to excessive carbohydrate consumption.

This study was conducted to determine if a eucaloric carbohydrate-restricted (CR) diet (∼9% energy from carbohydrate, 65% energy from fat), compared to a eucaloric higher carbohydrate (HC) diet (∼55% energy from carbohydrate, 20% energy from fat), would improve β-cell response to glucose in participants with T2D.

Participants were 57 African American and European American adults with T2D not using insulin. Medications were discontinued 1 to 2 weeks prior to baseline testing. A hyperglycemic clamp was used to assess the acute (first-phase) and maximal (arginine-stimulated) C-peptide response to glucose at baseline and after 12 weeks of controlled diet therapy (all food provided). An oral glucose tolerance test (OGTT) was used to assess the disposition index (DI).

At 12 weeks, a statistically significant effect of diet was observed on acute C-peptide response (2-fold greater with the CR diet; P < .01). For maximal C-peptide, a significant effect of diet was observed (22% greater with the CR diet; P < .05), as was a significant diet-by-race interaction (P < .05), indicating that the diet effect was specific to European Americans (48% greater with the CR diet; P < .01). OGTT results showed a significant effect of diet on DI at 12 weeks (32% greater with the CR diet; P < .05).

These results suggest that a eucaloric CR diet has beneficial effects on β-cell function in patients with mild T2D.

The prevalence and incidence of young-onset type 2 diabetes is increasing globally, especially in low- and middle-income countries, and predominantly affects non-White ethnic and racial populations. Young-onset type 2 is heterogeneous in terms of the genetic and environmental contributions to its underlying pathophysiology, which poses challenges for glycemic management. Young at-risk individuals remain underrepresented in clinical trials, including diabetes prevention studies, and there is still an insufficient evidence base to inform practice for this age group. Improvements in diabetes care delivery have not reached young people who will progress to have disabling complications at an age when they are most productive. This review summarizes recent studies on the epidemiology of young-onset type 2 diabetes and its complications. We discuss the genetic and environmental risk factors that act in concert to promote glycemic dysregulation and early onset of type 2 diabetes. We provide perspectives on diabetes prevention and management, and propose strategies to address the unique medical and psychosocial issues associated with young-onset type 2 diabetes. The Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes Randomized Controlled Trial (PRISM-RCT) is the first large-scale clinical trial designed to evaluate the effect of a structured care model that integrates biogenetic markers with communication and information technology on attaining strict metabolic targets and improving clinical outcomes in individuals with young-onset type 2 diabetes. The results of this study will inform the scientific community about the impact of multifactorial intervention and precision care in young patients, for whom the legacy effect is particularly significant.

There is an unmet need for pharmacological therapies for children with type 2 diabetes mellitus (T2DM). We assessed the efficacy and safety of an oral dipeptidyl peptidase-4 inhibitor, alogliptin, 25 mg once daily (QD), as a potential treatment for pediatric patients with T2DM.

This phase 3, 52-week, multicenter, randomized, double-blind, placebo-controlled trial was conducted in children and adolescents (10-17 years old) with T2DM. Participants had glycosylated hemoglobin (HbA1c) ≥ 6.5% at baseline (≥ 6.5% to < 11% without treatment or on metformin alone; ≥ 7.0% to < 11% on insulin alone or in combination with metformin). Where required, participants underwent prerandomization stabilization of their background metformin and/or insulin therapy. All received diabetes education and home glucose-monitoring training (during screening, prerandomization stabilization, and specified visits through week 26). Participants were then stratified based on previous antihyperglycemic therapy for 12 weeks before screening into schedule A (antihyperglycemic treatment-naïve) or B (metformin and/or insulin). The primary efficacy endpoint was change in HbA1c levels from baseline at week 26. Safety was assessed as a secondary endpoint at week 52.

Overall, 152 participants (median age, 14 years; 68.9% female) were randomized (1:1) to receive either alogliptin (n = 75) or placebo (n = 77). The majority were white (58.3%), had a body mass index of ≥ 30 kg/m2 (60.3%), and had received previous antihyperglycemic therapy (82.1%). The difference in HbA1c levels from baseline to week 26 between the alogliptin and placebo groups (least squares mean change [95% confidence interval]) was 0.10 (- 0.63, 0.83; p = 0.78). There was no difference in efficacy endpoints between alogliptin and placebo across both subgroups. No new safety concerns were observed with alogliptin treatment.

Alogliptin 25 mg QD did not significantly improve glycemic control versus placebo in pediatric patients with T2DM. Alogliptin treatment was safe and well tolerated, and no new safety concerns were observed in this study.

ClinicalTrials.gov: NCT02856113; EudraCT: 2015-000208-25.

The pig is a valuable animal model in diabetes research; however, standardized protocols are essential for evaluating in vivo metabolism. Here, we present a protocol for in vivo assessment of glucose control and insulin secretion and sensitivity in the pig. We describe steps for catheter implantation, testing of intravenous glucose tolerance, performance of hyperinsulinemic-euglycemic clamps (HECs) and hyperglycemic clamps (HGCs), and blood processing. We then detail procedures for analysis of plasma glucose, insulin, glucagon, and C-peptide concentrations as well as data analysis. For complete details on the use and execution of this protocol, please refer to Renner et al.1 and Renner et al.2.

Youth-onset type 2 diabetes (YO-T2D) is an urgent public health challenge that demands immediate and innovative action. The devastating trajectory of this disease - from rapid β-cell decline to early complications and poor responses to medications - compels us to rethink our approach. Here, we argue that by investing in targeted research to unravel the unique mechanisms of this condition, ensuring equitable access to cutting-edge clinical trials, and building clinical care models tailored specifically for youth, we can rewrite the narrative for these at-risk youth.

Insulin resistance and compensatory hyperinsulinaemia are core features leading to beta cell failure in youth-onset type 2 diabetes. Insulin clearance (IC) is also a key regulator of insulin concentrations, but few data exist on IC in youth-onset type 2 diabetes. In a secondary analysis of our Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomised clinical trial, we investigated potential sex-, race-, ethnicity- and treatment-related differences in IC in youth-onset type 2 diabetes and aimed to identify metabolic phenotypes associated with IC at baseline and in response to metformin, metformin plus a lifestyle intervention, and metformin plus rosiglitazone.

A total of 640 youth aged 10-18 years with type 2 diabetes underwent fasting blood tests, anthropometric measurements, dual-energy x-ray absorptiometry to estimate subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) mass, and OGTTs longitudinally over 5 years. IC was calculated from the fasting C-peptide:insulin ratio (fasting IC) and 2 h OGTT C-peptide incremental AUC (iAUC):insulin iAUC ratio (2 h IC). Linear mixed models were used to assess covariate effects on the mean of IC over repeated time points.

Baseline fasting IC (×10-2 nmol/pmol) was significantly lower in female participants than male participants (median [IQR] 0.72 [0.57-0.93] vs 0.79 [0.63-1.00], respectively; p=0.04) and in non-Hispanic Black participants than Hispanic and non-Hispanic White participants (median [IQR] 0.64 [0.51-0.81] vs 0.78 [0.64-1.00] vs 0.84 [0.68-1.01], respectively; p<0.0001). Similar results were observed for 2 h IC. Lower IC most strongly correlated with higher weight over time (% change [95% CI] in IC per 5 kg increase: fasting IC -1.52 [-2.05, -0.99]; 2 h IC -3.46 [-4.05, -2.86]). Lower IC also correlated with other markers of adiposity (higher BMI and SAT mass), and markers of insulin sensitivity (higher waist:height ratio, VAT mass, VAT:SAT mass ratio, triacylglycerol concentrations, triacylglycerol:HDL-cholesterol ratio, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] concentrations, and systolic and diastolic BP, and lower HDL-cholesterol and total and high molecular weight adiponectin concentrations) over time. Beta cell function as determined from OGTTs, not insulin sensitivity or IC, was predictive of persistently elevated blood glucose levels. IC was higher with metformin+rosiglitazone than metformin alone (p=0.03 for fasting IC; p=0.02 for 2 h IC) and metformin+lifestyle (2 h IC, p=0.005), but not after adjusting for adiponectin (p value not significant for all).

In youth with type 2 diabetes, low IC is correlated with female sex, non-Hispanic Black race and ethnicity, and markers of adiposity and insulin resistance, but not with beta cell function. Along with insulin sensitivity and adiponectin, IC increased in response to rosiglitazone treatment. These findings suggest that, in youth-onset type 2 diabetes, low IC is a compensatory response to changes in insulin sensitivity and/or adiponectin concentrations and is not a mediator of beta cell function.

ClinicalTrials.gov NCT00081328 DATA AVAILABILITY: Data from the TODAY study (V4; https://doi.org/10.58020/2w6w-pv88 ) reported here are available on request from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository (NIDDK-CR) Resources for Research ( https://repository.niddk.nih.gov/ ).

Metabolic bariatric surgery reduces weight in youth with severe obesity; however, its impacts on youth-onset type 2 diabetes (T2D) are unclear.

We evaluated short-term outcomes in youth with T2D 3 months after vertical sleeve gastrectomy (VSG).

Longitudinal, observational study in the Impact of Metabolic surgery on Pancreatic, Renal, and cardiOVascular hEalth in youth with T2D study (IMPROVE-T2D).

Academic medical university and children's hospital.

Fourteen youth with T2D [mean age ± SD 16.8 ± 1.4 years; 50% female, pre-VSG hemoglobin A1c (HbA1c) 6.6 ± 0.2%; diabetes duration 17.6 ± 13.8 months; age at diabetes diagnosis 15.9 ± 1.4 years; body mass index (BMI) 46.7 ± 2 kg/m2].

Participants underwent a mixed-meal tolerance test (MMTT), body composition, and indirect calorimetry before and 3 months after VSG.

Glycemic control (HbA1c, diabetes medications), insulin sensitivity (Matsuda Index, Homeostasis Model of Insulin Sensitivity, oral minimal model), and secretion (C-peptide model).

After VSG, weight and BMI decreased (25.2 ± 5.6 kg [19%], -8.7 ± 2 kg/m2 [18%], respectively, P < .001). Body fat decreased (4.5%, P = .012), with reductions of 14.1 ± 5.4 kg of fat mass (P = .005) and 4.5 kg of fat-free mass (P = .034). HbA1c decreased from 6.6 ± 0.2% to 5.7 ± 0.2% (P = .003), with 86% of participants no longer requiring diabetes medications. Glucose was lower throughout the MMTT, with insulin, C-peptide, free fatty acids, glucagon-like peptide-1, and peptide-YY significantly changing postsurgery (P < .05 for all). Insulin sensitivity and insulin secretion rate during the MMTT significantly improved.

Three months post-VSG, youth showed significant improvements in weight, body composition, insulin sensitivity and secretion, and glycemic control, with most no longer requiring diabetes medications.

Epidemiological surveys indicate an increasing incidence of type 2 diabetes mellitus (T2DM) among children and adolescents worldwide. Due to rapid disease progression, severe long-term cardiorenal complications, a lack of effective treatment strategies, and substantial socioeconomic burdens, it has become an urgent public health issue that requires management and resolution. Adolescent T2DM differs from adult T2DM. Despite a significant increase in our understanding of youth-onset T2DM over the past two decades, the related review and evidence-based content remain limited.

To visualize the hotspots and trends in pediatric and adolescent T2DM research and to forecast their future research themes.

This study utilized the terms "children", "adolescents", and "type 2 diabetes", retrieving relevant articles published between 1983 and 2023 from three citation databases within the Web of Science Core Collection (SCI, SSCI, ESCI). Utilizing CiteSpace and VoSviewer software, we analyze and visually represent the annual output of literature, countries involved, and participating institutions. This allows us to predict trends in this research field. Our analysis encompasses co-cited authors, journal overlays, citation overlays, time-zone views, keyword analysis, and reference analysis, etc.

A total of 9210 articles were included, and the annual publication volume in this field showed a steady growth trend. The United States had the highest number of publications and the highest H-index. The United States also had the most research institutions and the strongest research capacity. The global hot journals were primarily diabetes professional journals but also included journals related to nutrition, endocrinology, and metabolism. Keyword analysis showed that research related to endothelial dysfunction, exposure risk, cardiac metabolic risk, changes in gut microbiota, the impact on comorbidities and outcomes, etc., were emerging keywords. They have maintained their popularity in this field, suggesting that these areas have garnered significant research interest in recent years.

Pediatric and adolescent T2DM is increasingly drawing global attention, with genes, behaviors, environmental factors, and multisystemic interventions potentially emerging as future research hot spots.

Youth-onset type 2 diabetes (T2D) results from genetic, environmental, and metabolic causes that differ among individuals and populations. This chapter builds on the 2022 ISPAD guidelines and summarizes recent advances in the management of T2D in children and adolescents. Updates include diagnostic algorithm for youth with new onset T2D, algorithms and tables for treatment, management, and assessment of comorbidities and complications and recommendations on recently approved pharmacologic therapies for the treatment of youth-onset T2D and management strategies. Youth-onset type 2 diabetes (T2D) results from genetic, environmental, and metabolic causes that differ among individuals and populations. This chapter builds on the 2022 ISPAD guidelines and summarizes recent advances in the management of T2D in children and adolescents. Updates include diagnostic algorithm for youth with new onset T2D, algorithms and tables for treatment, management, and assessment of comorbidities and complications and recommendations on recently approved pharmacologic therapies for the treatment of youth-onset T2D and management strategies.

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, the precipitous decline of β-cell function, and the role of other hormonal abnormalities in the pathogenesis of the disease. We discuss the critical importance of social determinants of health in the predisposition and progression of these conditions and present current management strategies and the advances in therapeutic approaches. These must adapt to meet the unique needs of the individual patient and family. Significant knowledge gaps remain that need to be addressed in future research.

To identify determinants of the course of Type 2 diabetes in Indian adolescents.

Records of 37 adolescents (24 boys; 29 post pubertal and eight pubertal) with Type 2 diabetes (initial HbA1C 10.1 ± 1.9% and BMI SDS 2.0 ± 0.8; family history of diabetes in 33, 89.2%) diagnosed at 15.2 ± 2.5 y and followed up for 3.8 ± 2.2 y till 19.1 ± 3.3 y of age, were reviewed.

Initial treatment included insulin in 11 (29.7%), metformin alone in 22 (59.5%), and a combination of anti-diabetic medication in four (10.8%). Eleven subjects (29.7%) achieved remission at a median period of 5.3 mo (IQR- 17.13) after diagnosis; six of these relapsed within 0.9 ± 0.3 (range 0.4-1.3) y. The proportion of subjects requiring multiple anti-diabetic agents increased over follow-up (19% at six months, 32.5% at one year, 50% at two years, 59.1% at three, and 64.8% at four years), with the need for combination therapy after 0.9 ± 1.4 y. At the last follow-up, five were off treatment (13.5%), 10 (27%) were on metformin alone, and 22 (59.5%) were on multiple medications. The need for combination therapy at the last follow-up was lower in subjects with remission (27% against 73.1%, p = 0.02).

The findings of this study suggest delayed presentation and rapid progression of Type 2 diabetes in Indian adolescents. Diagnosis on screening and achievement of remission were predictors of good outcome.

Human studies linking metabolism with organism-wide physiologic function have been challenged by confounding, adherence, and precisionHere, we united physiologic and molecular phenotypes of metabolism during controlled dietary intervention to understand integrated metabolic-physiologic responses to nutrition. In an inpatient study of individuals who underwent serial 24-hour metabolic chamber experiments (indirect calorimetry) and metabolite profiling, we mapped a human metabolome onto substrate oxidation rates and energy expenditure across up to 7 dietary conditions (energy balance, fasting, multiple 200% caloric excess overfeeding of varying fat, protein, and carbohydrate composition). Diets exhibiting greater fat oxidation (e.g., fasting, high-fat) were associated with changes in metabolites within pathways of mitochondrial β-oxidation, ketogenesis, adipose tissue fatty acid liberation, and/or multiple anapleurotic substrates for tricarboxylic acid cycle flux, with inverse associations for diets with greater carbohydrate availability. Changes in each of these metabolite classes were strongly related to 24-hour respiratory quotient (RQ) and substrate oxidation rates (e.g., acylcarnitines related to lower 24-hour RQ and higher 24-hour lipid oxidation), underscoring links between substrate availability, physiology, and metabolism in humans. Physiologic responses to diet determined by gold-standard human metabolic chambers are strongly coordinated with biologically consistent, interconnected metabolic pathways encoded in the metabolome.

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.

Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.

Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.

Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.

Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.

This review explores the emerging evidence regarding pathogenesis, future trajectories, treatment options, and phenotypes of youth-onset type 2 diabetes (T2D).

Youth-onset T2D is increasing in incidence and prevalence worldwide, disproportionately affecting First Nations communities, socioeconomically disadvantaged youth, and people of colour. Youth-onset T2D differs in pathogenesis to later-onset T2D and progresses more rapidly. It is associated with more complications, and these occur earlier. While there are limited licensed treatment options available, the available medications also appear to have a poorer response in youth with T2D. Multiple interacting factors likely contribute to this rising prevalence, as well as the increased severity of the condition, including structural inequities, increasing obesity and sedentary lifestyles, and intergenerational transmission from in-utero exposure to maternal hyperglycemia and obesity. Youth-onset T2D is also associated with stigma and poorer mental health, and these impact clinical management. There is an urgent need to develop effective interventions to prevent youth-onset T2D and enhance engagement of affected youth. It is also critical to better understand the differing phenotypes of youth-onset T2D, to effectively target treatments, and to address intergenerational transmission in high-risk populations.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) are increasing. The rise in frequency and severity of childhood obesity, inclination to sedentary lifestyle, and epigenetic risks related to prenatal hyperglycemia exposure are important drivers of the youth-onset T2DM epidemic and might as well be responsible for the early onset of diabetes complications. Indeed, youth-onset T2DM has a more extreme metabolic phenotype than adult-onset T2DM, with greater insulin resistance and more rapid deterioration of beta cell function. Therefore, intermediate complications such as microalbuminuria develop in late childhood or early adulthood, while end-stage complications develop in mid-life. Due to the lack of efficacy and safety data, several drugs available for the treatment of adults with T2DM have not been approved in youth, reducing the pharmacological treatment options. In this mini review, we will try to address the present challenges and pitfalls related to youth-onset T2DM and summarize the available interventions to mitigate the risk of microvascular and macrovascular complications.

Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D.

In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test.

At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI.

Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

The emerging field of precision nutrition is based on the notion that inter-individual responses across diets of different calorie-macronutrient content may contribute to inter-individual differences in metabolism, adiposity, and weight gain. Free-living diet studies have been traditionally challenged by difficulties in controlling adherence to prescribed calories and macronutrient content and rarely allow a period of metabolic stability prior to metabolic measures (to minimize influences of weight changes). In this context, key physiologic measures central to precision nutrition responses may be most precisely quantified via whole room indirect calorimetry over 24-h, in which precise control of activity and nutrition can be achieved. In addition, these studies represent unique "N of 1" human crossover metabolic-physiologic experiments during which specific molecular pathways central to nutrient metabolism may be discerned. Here, we quantified 263 circulating metabolites during a ≈40-day inpatient admission in which up to 94 participants underwent seven monitored 24-h nutritional interventions of differing macronutrient composition in a whole-room indirect calorimeter to capture precision metabolic responses. Broadly, we observed heterogenous responses in metabolites across dietary chambers, with the exception of carnitines which tracked with 24-h respiratory quotient. We identified excursions in shared metabolic species (e.g., carnitines, glycerophospholipids, amino acids) that mapped onto gold-standard calorimetric measures of substrate oxidation preference and lipid availability. These findings support a coordinated metabolic-physiologic response to nutrition, highlighting the relevance of these controlled settings to uncover biological pathways of energy utilization during precision nutrition studies.

Efficient and accurate methods to estimate insulin sensitivity (SI) and β-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and β-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

Branched-chain amino acids (BCAAs) and aromatic AAs (AAAs) are associated with increased risk for type 2 diabetes in adults. Studies in youth show conflicting results. We hypothesized that an AA metabolomic signature can be defined to identify youth at risk for β-cell failure and the development of type 2 diabetes. We performed targeted AA metabolomics analysis on 127 adolescents (65 girls; 15.5 [SD ±1.9] years old, Tanner stage II-V) with normal weight or obesity across the spectrum of glycemia, with assessment of AA concentrations by mass spectrometry, at fasting, and steady state of a hyperinsulinemic-euglycemic clamp, with determination of insulin sensitivity (IS) per fat-free mass (FFM). We measured insulin secretion during a 2-h hyperglycemic clamp and calculated the disposition index per FFM (DIFFM), a measure of β-cell function. Our results showed that concentration of glycine (Gly) and the glutamine (Gln)-to-glutamate (Glu) ratio were lower, whereas BCAA, tyrosine, and lysine (Lys) concentrations were higher in the groups with obesity and dysglycemia compared with those with normal weight. Gly and Gln-to-Glu ratio were positively related to IS and DIFFM, with opposite relationships observed for BCAAs, AAAs, and Lys. We conclude that a metabolic signature of low Gly concentration and low Gln-to-Glu ratio, and elevated BCAAs, AAAs, and Lys concentrations may constitute a biomarker to identify youth at risk for β-cell failure.

β-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored.

Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition.

Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia.

Youth with type 2 diabetes demonstrated severe β-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.

Overconsumption of energy-rich foods that disrupt caloric balance is a fundamental cause of overweight, obesity and diabetes. Dysglycemia and the resulting cardiovascular disease cause substantial morbidity and mortality worldwide, as well as high societal cost. The prevalence of obesity in childhood and adolescence is increasing, leading to younger diabetes diagnosis, and higher severity of microvascular and macrovascular complications. An important goal is to identify early life conditions that increase future metabolic risk, toward the goal of preventing diabetes and cardiovascular disease. An ample body of evidence implicates prenatal and postnatal childhood growth trajectories in the programming of adult metabolic disease. Human epidemiological data show that accelerated childhood growth increases risk of type 2 diabetes in adulthood. Type 2 diabetes results from the combination of insulin resistance and pancreatic β-cell failure, but specific mechanisms by which accelerated postnatal growth impact one or both of these processes remain uncertain. This review explores the metabolic impact of overnutrition during postnatal life in humans and in rodent models, with specific attention to the connection between accelerated childhood growth and future adiposity, insulin resistance, β-cell mass and β-cell dysfunction. With improved knowledge in this area, we might one day be able to modulate nutrition and growth in the critical postnatal window to maximize lifelong metabolic health.

The association of pre-diabetes and type 2 diabetes (T2D) with incident lung cancer is uncertain, and the incident risk across the glycemic spectrum is unclear. We aimed to explore the associations of glycosylated hemoglobin (HbA1c), pre-diabetes, and T2D with incident lung cancer in a large prospective cohort.

Leveraging a total of 210,779 cancer-free adults recruited in the UK Biobank between 2006 and 2010. We performed multivariable Cox proportional hazards models and restricted cubic spline methods to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the associations of HbA1c, pre-diabetes, and T2D with incident lung cancer.

During a median follow-up of 11.06 years, 1738 incident lung cancer cases were ascertained. The incidence of lung cancer was 20% higher among people with diabetes (HR: 1.20, 95% CI: 1.02 to 1.42) and 38% higher among people with pre-diabetes (HR: 1.38, 95% CI: 1.15 to 1.65). After dividing people with diabetes by whether taking antidiabetic medications, the incidence was 28% higher among people with diabetes without medications (HR: 1.28, 95% CI: 1.02 to 1.61) and 15% higher among people with diabetes with medications (HR: 1.15, 95% CI: 0.93 to 1.41). The increased risk of incident lung cancer for each standard deviation (6.45 mmol/mol) increase in HbA1c was more pronounced across HbA1c values of 32-42 mmol/mol (HR: 1.37, 95% CI: 1.18 to 1.59). The risk was more pronounced among participants <60 years.

Pre-diabetes and T2D are associated with an increased incidence of lung cancer. The increased risk of incident lung cancer is more pronounced across HbA1c values of 32-42 mmol/mol, which are currently considered normal values.

The prevalence of youth-onset type 2 diabetes is growing worldwide and current first-line treatment with metformin and intensive behavior and lifestyle changes are suboptimal in over 50% of youth within 2 years of diagnosis. This perspective article is a call to action for reevaluation of existing strategies and critical appraisal of metformin as first-line therapy in youth-onset type 2 diabetes. Increased attention should be given to novel therapeutics approved in youth, including glucagon-like 1 receptor agonists, sodium glucose cotransporter-2, and sociocultural interventions that will promote diabetes self-management.

Youth-onset type 2 diabetes is a growing epidemic with a rising incidence worldwide. Although the pathogenesis and diagnosis of youth-onset type 2 diabetes are similar to adult-onset type 2 diabetes, youth-onset type 2 diabetes is unique, with greater insulin resistance, insulin hypersecretion, and faster progression of pancreatic beta cell function decline. Individuals with youth-onset type 2 diabetes also develop complications at higher rates within short periods of time compared to adults with type 2 diabetes or youth with type 1 diabetes. The highest prevalence and incidence of youth-onset type 2 diabetes in the United States is among youth from minoritized racial and ethnic groups. Risk factors include obesity, family history of type 2 diabetes, comorbid conditions and use of medications associated with insulin resistance and rapid weight gain, socioeconomic and environmental stressors, and birth history of small-for-gestational-age or pregnancy associated with gestational or pregestational diabetes. Patients with youth-onset type 2 diabetes should be treated using a multidisciplinary model with frequent clinic visits and emphasis on addressing of social and psychological barriers to care and glycemic control, as well as close monitoring for comorbidities and complications. Intensive health behavior therapy is an important component of treatment, in addition to medical management, both of which should be initiated at the diagnosis of type 2 diabetes. There are limited but growing pharmacologic treatment options, including metformin, insulin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Although long-term outcomes are not fully known, metabolic/bariatric surgery in youth with type 2 diabetes has led to improved cardiometabolic outcomes.

Testing 1-h glucose (1HG) concentration during oral glucose tolerance test is cost-effective to identify individuals at risk of incident type 2 diabetes. Aim of the study was to define 1HG cutoffs diagnostic of incident impaired glucose tolerance (IGT) in youths with obesity, and to evaluate prevalence and association of cutoffs identified in the cohort and from the literature (133 and 155 mg/dl) to cardiovascular disease (CVD) in a population of youths with obesity.

This is a longitudinal study of 154 youths to identify 1HG cutoffs, and cross-sectional study of 2295 youths to estimate prevalence of high 1HG and association to CVD. Receiver-operating characteristic curves (ROC) were used to establish 1HG cutoffs, and univariate regression analyses to test association of 1HG to blood pressure, lipids and aminotransferases.

ROC analysis identified the 1HG cutoff of 159 mg/dl as having diagnostic accuracy of IGT with area under the ROC 0.82 (95% CI 0.66-0.98), sensitivity 0.86% and specificity 0.79%. In the cross-sectional population, prevalence of high 1HG was 36% and 15% for 133 and 155 mg/dl cutoffs, respectively, and 17% for the 159 mg/dl value. All the examined cutoffs were significantly associated with worse lipid profile, liver function test, reduced insulin sensitivity, secretion and disposition index.

High 1HG is marker of persistent IGT and increased risk of metabolic abnormalities in youths. The 155 mg/dl cutoff is a convenient estimate in young people but longitudinal studies with retinopathy and overt diabetes as end points are advised to verify the 1HG cutoff with the best diagnostic accuracy.

We compared beta-cell function in Chinese with type 2 diabetes diagnosed at age < 40 years (young-onset diabetes, YOD) and ≥ 40 years (late-onset diabetes, LOD).

In this cross-sectional study, we selected participants from two cohorts of people with type 2 diabetes recruited in 1996-2012 (n = 4,376) and 2020-2021 (n = 794). Multivariable linear regression models were applied to compare homeostasis model assessment of beta-cell function (HOMA2-%B) and fasting plasma C-peptide across diabetes duration at enrolment between YOD and LOD.

The YOD group (n = 1,876, mean [SD] age: 39.9 [7.5] years, median [IQR] diabetes duration: 6 [2-12] years) was more likely to have family history of diabetes (61.6 % vs 43.6 %), obesity (41.9 % vs 26.8 %), dyslipidaemia (61.7 % vs 54.4 %), and worse glycaemic control (mean HbA1c 7.7 % vs 7.4 %) than those with LOD (n = 3,294, age: 60.8 [10.6] years, diabetes duration: 5 [1-10] years). When compared to people with LOD, HOMA2-%B and fasting plasma C-peptide were lower in the YOD group, consistently among those with BMI < 27.5 kg/m2 and HOMA2-IR ≤ 1.6 (median value), adjusted for year at enrolment, sex, diabetes duration, family history of diabetes, HbA1c, weight and lipid indices (p < 0.01). Cross-sectionally, the slopes of decline in HOMA2-%B by diabetes duration were greater in YOD than LOD among individuals with BMI < 27.5 kg/m2 (p-interaction = 0.015).

Chinese with YOD had accelerated loss of beta-cell function than those with LOD especially in non-obese individuals.

Previous work found poor reproducibility for measures of glycemia in individuals at risk for dysglycemia. Differences between youth and adults have not been assessed. Using youth and adults in the Restoring Insulin Secretion Study, we tested variability and classification concordance for hemoglobin A1C (HbA1c), fasting and 2-hour glucose from oral glucose tolerance tests (OGTTs).

HbA1c and glucose on repeated samples obtained ∼6 weeks apart were compared in 66 youth (mean age 14.2 years) and 354 adults (52.7 years). Changes, coefficient of variation (CV), and concordance of diagnostic categories between the 2 visits were compared.

Mean difference between the 2 visits in HbA1c was higher in youth than adults (P < .001), while fasting glucose was similar and 2-hour glucose was lower in youth (P = .051). CV was smallest for HbA1c compared to fasting and 2-hour glucose. For HbA1c, youth had higher CV (P < .001); whereas CV for 2-hour glucose was lower for youth (P = .041). Classification concordance by HbA1c was lower in youth (P = .004). Using OGTT or HbA1c for classification, intervisit variability produced discordant classification in 20% of youth and 28% of adults. Using both fasting glucose and HbA1c, intervisit variability reduced discordant classification to 16% of adults while not improving classification in youth.

Poor reproducibility and lack of classification concordance highlight the limitations of one-time testing, with important implications for assessing eligibility in clinical trials. Consideration should be given to using more than a single parameter for screening and diagnosis, especially when classification category is important.

Little is known about the impact of early attainment of tight glycemic control on long-term β-cell function and glycemic control in youth-onset type 2 diabetes. We examined the effect of the initial 6 months of glycemic control on β-cell function and glycemic control longitudinally over 9 years and the impact of sex, race/ethnicity, and BMI on these relationships in adolescents with youth-onset type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

Oral glucose tolerance tests were performed longitudinally through year 9 to derive estimates of insulin sensitivity and secretion. Early glycemia was defined by mean HbA1c during the first 6 months postrandomization, categorized into five HbA1c groups (<5.7%, 5.7 to <6.4%, 6.4 to <7.0%, 7.0 to <8.0%, and ≥8.0%). The long-term period was defined as the period between years 2 and 9.

A total of 656 participants (64.8% female, baseline mean age 14 years, diabetes duration <2 years) had longitudinal data available over an average of 6.4 ± 3.2 years of follow-up. HbA1c significantly increased in all early glycemic groups during years 2-9, with a steeper increase (+0.40%/year) among participants with the tightest initial control (mean early HbA1c <5.7%), in parallel to a decline in the C-peptide-derived disposition index. Nevertheless, the lower HbA1c categories continued to have relatively lower HbA1c over time.

Early tight glycemic control in the TODAY study was related to β-cell reserve and translated to better long-term glycemic control. However, tight early glycemic control on the randomized treatment in the TODAY study did not prevent deterioration of β-cell function.

Not meeting recommended A1C targets may be associated with postoperative complications in adults, but there are no studies reporting on the relationship between preoperative A1C and postoperative complications in children with type 1 or type 2 diabetes. The objective of this study was to determine whether elevated A1C levels were associated with an increased incidence of postoperative complications in children with diabetes presenting for elective noncardiac surgery or diagnostic procedures. It found no such association, suggesting no need to delay elective surgery in children with diabetes until A1C is optimized.

Growing numbers of children and young people are diagnosed with type 2 diabetes, partly due to the obesogenic environment they grow up in. The increasing prevalence of type 2 diabetes is seen particularly in adolescent girls and in children and young people of non-white ethnic backgrounds. There are numerous challenges relating to the diagnosis, treatment and management of type 2 diabetes in children and young people, notably the fact that the condition can lead to serious complications and often triggers high levels of anxiety and stress in patients and families. This article outlines the challenges faced by children and young people with type 2 diabetes, their families and carers, and suggests ways in which nurses can support them with the aim of achieving optimal management and self-management.

Efficient and accurate methods to estimate insulin sensitivity (SI) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Many methods exist, ranging in input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic models (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts including individuals at high risk of prediabetes (adult women with a wide range of BMI and adolescents with obesity). The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and hyperinsulinemic-euglycemic clamp. The ISS model has broad clinical applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.

To determine and compare the incidence of diabetes complications in Chinese with youth-onset type 2 and type 1 diabetes.

We conducted a population-based prospective cohort study, including 1,260 people with type 2 diabetes and 1,227 with type 1 diabetes diagnosed at age <20 years who underwent metabolic and complication assessment in Hong Kong Hospital Authority between 2000 and 2018. They were followed for incident cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death until 2019. Multivariable Cox regression analysis was applied to compare the risks of these complications in type 2 versus type 1 diabetes.

People with type 1 diabetes (median age: 20 years, median diabetes duration: 9 years) and type 2 diabetes (median age: 21 years, median diabetes duration: 6 years) were followed for a mean period of 9.2 and 8.8 years respectively. The risks of CVD (HR [95% CI] 1.66 [1.01-2.72]) and ESKD (HR 1.96 [1.27-3.04]) but not death (HR 1.10 [0.72-1.67]) were higher in type 2 versus type 1 diabetes, adjusted for age at diagnosis, diabetes duration and sex. The association became nonsignificant with further adjustment for glycaemic and metabolic control. Youth-onset type 2 diabetes conferred mortality excess (standardized mortality ratio 4.15 [3.28-5.17]) to age- and sex-matched general population.

People with youth-onset type 2 diabetes had higher incidence rates of CVD and ESKD than type 1 diabetes. The excess risks in type 2 diabetes were removed after adjusted for cardio-metabolic risk factors.

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.

With the rise in prevalence of youth-onset type 2 diabetes (T2DM), it is imperative to understand the clinical burden of the disease and the socioeconomic burden this disease imposes. We review the most recent data on youth-onset T2DM, including its pathophysiology, complications, and treatment. We also review existing data to determine the socioeconomic burden of youth-onset T2DM.

The incidence of youth-onset T2DM is rising, and significantly accelerated following the COVID-19 pandemic. Youth with T2DM are more frequently from families of racial/ethnic minorities and lower socioeconomic status. Youth-onset T2DM has more rapid disease progression compared to adult-onset type 2 diabetes. It results in earlier and more severe microvascular and macrovascular complications compared to both adult-onset T2DM and youth-onset type 1 diabetes (T1DM). While there is a lack of data describing the socioeconomic cost of youth-onset T2DM, based on extrapolation from analyses of the burden of T2DM in adults and T1DM in youth, we propose that youth-onset T2DM has higher direct and indirect costs than adult-onset T2DM. Youth-onset T2DM presents a significant clinical and socioeconomic burden due to its aggressive presentation and earlier appearance of complications. Additional research is needed regarding the cost of illness in this population.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.