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AIMS: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome (HbA1c ≥ 8% for at least 6 months) within 4 years which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating miRNA species associated with decline in beta cell function. METHODS: Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. RESULTS: Using a backward selection approach, four baseline miRNA log2 fold changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold changes remained significant predictors of this C-peptide oDI decline ≥20% (p < 0.05). Increased levels of miRNA-155 (OR:1.2, 95%CI:1.1-1.4) and miRNA-130b (OR:1.3, 95%CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR:0.6, 95%CI: 0.4-0.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24-months (R = 0.22, p < 0.01 and R = 0.19, p < 0.01, respectively), and positively correlated with proinsulin, at baseline, 24-, and 60- months (R = 0.26, p < 0.01, R = 0.26, p < 0.01, R = 0.18, p < 0.01, respectively). CONCLUSIONS: The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.

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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.

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Youth-onset type 2 diabetes mellitus (T2DM), influenced by an increase in obesity, is a rising problem worldwide. Pathophysiological mechanisms of this early-onset T2DM include both peripheral and hepatic insulin resistance, along with increased hepatic fasting glucose production accompanied by inadequate first and second-phase insulin secretion. Moreover, the incretin effect is reduced. The initial presentation of type 2 diabetes can be dramatic and symptoms may overlap with those of type 1 diabetes mellitus. Therefore, immediate therapy should address hyperglycemia and associated metabolic derangements irrespective of ultimate diabetes type, while further therapy adjustments are prone to patients' phenotype. New agents with proven glycemic and beyond glycemia benefits, such as Glucagon-like polypeptide 1 receptor agonists and Sodium-glucose cotransporter-2 inhibitors, used in the adult population of T2DM patients, might become increasingly important in the treatment armamentarium. Moreover, metabolic surgery is an option for markedly obese (body mass index > 35 kg/m2) children and adolescents suffering from T2DM who have uncontrolled glycemia and/or serious comorbidities when lifestyle and pharmacologic interventions fail. In this mini-review, we will discuss the potential of treatment options considering new data available from randomized control trials, including individuals with adult-onset type diabetes mellitus.

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AIM: To assess the short-term, real-world use and effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) medications in the management of type 2 diabetes (T2D) in a diverse cohort of youth. METHODS: This multicentre retrospective study analysed youth prescribed a GLP-1RA for the management of T2D at two academic paediatric diabetes centres prior to June 2022. Change in HbA1c and insulin use from baseline to first (median 91 days) and second (median 190 days) follow-up were evaluated for those taking a GLP-1RA. Multivariable linear mixed effects models adjusting for baseline sex, age, race/ethnicity, insurance, insulin regimen, metformin regimen, GLP-1RA dosing frequency and the body mass index Z-score (BMI-Z) examined the change in HbA1c for participants for up to 6 months after baseline. RESULTS: A total of 136 patients with T2D (median age 16.1 [interquartile range 13.9-18.0] years, 54% female, 56% non-Hispanic Black, 24% Hispanic, 77% with public insurance) were prescribed GLP-1RAs and taking them at first or second follow-up. Median HbA1c decreased from 7.9% to 7.6% (P < .001) at a median follow-up of 91 days (n = 109) and, among those with HbA1c available at baseline and second follow-up (n = 83), from 8.4% to 7.4%. The proportion of patients prescribed insulin decreased from baseline to the first follow-up visit (basal 69% to 60% [P = .008], prandial 46% to 38% [P = .03]). In multivariable analysis, there was a mean decrease in HbA1c by 0.09 percentage points per month (P = .005, 95% confidence interval -0.15, -0.03). CONCLUSIONS: Real-world use of GLP-1RAs in youth with T2D is associated with decreased HbA1c levels, despite challenges with access and adherence. GLP-1RA treatment may reduce insulin doses for youth with T2D.

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OBJECTIVES: Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids including tryptophan for uptake into ß cells. To explore relationships between BCAAs and tryptophan metabolism, adiposity, and glucose tolerance, we compared urine metabolites in overweight/obese youth with type 2 diabetes (T2D) with those in nondiabetic overweight/obese and lean youth. METHODS: Metabolites were measured in 24-hour and first-morning urine samples of 56 nondiabetic adolescents with overweight/obesity, 42 adolescents with T2D, and 43 lean controls, aged 12 to 21 years. Group differences were assessed by Kruskal Wallis or ANOVA. RESULTS: Groups were comparable for age, pubertal status, and ethnicity. Youth with T2D were predominantly female and had highest percent body fat. BCAAs, branched-chain ketoacids (BCKAs), tryptophan, and kynurenine were higher in urine of subjects with T2D. There were no differences between lean controls and nondiabetic youth with overweight/obesity. T2D was associated with diversion of tryptophan from the serotonin to the kynurenine pathway, with higher urinary kynurenine/serotonin ratio and lower serotonin/tryptophan and 5-HIAA/kynurenine ratios. Urinary BCAAs, BCKAs, tryptophan, and ratios reflecting diversion to the kynurenine pathway correlated positively with metrics of body fat and hemoglobin A1c. Increases in these metabolites in the obese T2D group were more pronounced and statistically significant only in adolescent girls. CONCLUSION: Increases in urinary BCAAs and BCKAs in adolescent females with T2D are accompanied by diversion of tryptophan metabolism from the serotonin to the kynurenine pathway. These adaptations associate with higher risks of T2D in obese adolescent females than adolescent males.

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Diabetes poses a significant threat to public health. In the last 30 years, the worldwide incidence of type 2 diabetes mellitus (T2DM) has increased drastically among adolescents. Since the number of young people with T2DM is rising, it is anticipated that early-onset T2DM will become a common characteristic of the diabetes population in developed and developing nations. Current evidence suggests that ß-cell function declines more rapidly in early-onset T2DM than in older-onset T2DM. In addition, early-onset T2DM appears to be associated with a greater risk of complications, comorbidities and mortality than type 1 diabetes mellitus. A stressful lifestyle, a shifted dietary habit and a lack of physical activity are cited as causes of early-onset T2DM. Early-onset T2DM is, therefore, an urgent public health concern requiring early prevention, efficient screening and prompt intervention. This article discusses the recent literature on the incidence, mortality, morbidity and risk variables of early-onset T2DM, and the current priorities and prospective directions.

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AIMS: To examine the impact of pregnancy on microvascular and cardiovascular measures in women with youth-onset T2D. METHODS: Microvascular and cardiovascular measures were compared in in a cohort of 116 women who experienced a pregnancy of ≥ 20 weeks gestation and 291 women who did not among women in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. RESULTS: Cox regression models adjusted for participant characteristics at baseline including age, race/ethnicity, household income, diabetes duration, HbA1c (>6%), and BMI, demonstrated those who experienced pregnancy had 2.76 (1.38-5.49; p = 0.004) fold increased risk of hyperfiltration (eGFR ≥ 135 ml/min/1.73 m2), compared to those without a pregnancy. No differences were observed in rates of retinopathy (48.9% vs. 41.1%) or neuropathy (23.3% vs. 16.3%) in women who experienced pregnancy vs. women who did not, respectively. In fully adjusted models, pregnancy did not impact changes in echocardiographic or arterial stiffness compared to changes in women who were never pregnant. CONCLUSIONS: These results indicate that pregnancy increases the risk of hyperfiltration in women with youth-onset T2D, but not other micro or macrovascular complications. The rates of vascular complications are very high in youth-onset T2D potentially obscuring micro- and macrovascular changes attributable to pregnancy. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov numbers,NCT01364350andNCT02310724.

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INTRODUCTION: Diabetic kidney disease (DKD) is a leading cause of mortality in people with type 2 diabetes (T2D), and over 50% of individuals with youth-onset T2D will develop DKD as a young adult. Diagnosis of early-onset DKD remains a challenge in young persons with T2D secondary to a lack of available biomarkers for early DKD, while the injuries may still be reversible. Furthermore, multiple barriers exist to initiate timely prevention and treatment strategies for DKD, including a lack of Food and Drug Administration approval of medications in pediatrics; provider comfort with medication prescription, titration, and monitoring; and medication adherence. AREAS COVERED: Therapies that have promise for slowing DKD progression in youth with T2D include metformin, renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide-1 receptor agonists, sodium glucose co-transporter 2 inhibitors, thiazolidinediones, sulfonylureas, endothelin receptor agonists, and mineralocorticoid antagonists. Novel agents are also in development to act synergistically on the kidneys with the aforementioned medications. We comprehensively review the available pharmacologic strategies for DKD in youth-onset T2D including mechanisms of action, potential adverse effects, and kidney-specific effects, with an emphasis on published pediatric and adult trials. EXPERT OPINION: Large clinical trials evaluating pharmacologic interventions targeting the treatment of DKD in youth-onset T2D are strongly needed.

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OBJECTIVES: In Australia, Aboriginal children experience disproportionate rates of type 2 diabetes (T2D) compared with non-Aboriginal children. The aim of this qualitative study was to explore the experiences of Aboriginal adolescents with T2D and their family members to better understand the influences of T2D on self-management, with findings used to inform an enhanced service model of care. METHODS: Semistructured interviews were conducted with purposively selected Western Australian Aboriginal adolescents with T2D and their parents and guardians. Interviews were transcribed verbatim and analyzed with NVivo software using interpretative thematic analysis; overarching themes were generated. RESULTS: Interviews with 24 participants, including 8 adolescents aged 11 to 16 years, were conducted across 4 regions of Western Australia. A high proportion of these adolescents were diagnosed with T2D during an unrelated hospitalization or medical appointment. Most did not fully understand or were unaware of the long-term impact of T2D. Discussions about diabetes within families did not typically occur, and shame and concealment of the diagnosis was a common finding. The parents of the adolescents described the diagnosis of T2D as compounding an already challenging set of circumstances for the family; this impacted their capacity to promote self-management activities and attend hospital and outpatient appointments. CONCLUSIONS: This study privileges the voices of Aboriginal adolescents and family members and offers insight into their personal narrative of living with T2D. Building family and community capacity to normalize preventive activities and manage T2D postdiagnosis is recommended to improve health outcomes.

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PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

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BACKGROUND: Prevalence of youth-onset type 2 diabetes (T2D) has increased worldwide, paralleling the rise in pediatric obesity. Occurrence and clinical manifestations vary regionally and demographically. OBJECTIVES: We assessed the incidence, and clinical and demographic manifestations of youth-onset T2D in Israel. METHODS: In a national observational study, demographic, clinical, and laboratory data were collected from the medical records of children and adolescents, aged 10-18 years, diagnosed with T2D between the years 2008 and 2019. RESULTS: The incidence of youth-onset T2D in Israel increased significantly from 0.63/100,000 in 2008 to 3.41/100,000 in 2019. The study cohort comprised 379 individuals (228 girls [59.7%], 221 Jews [58.3%], mean age 14.7 ± 1.9 years); 73.1% had a positive family history of T2D. Mean body mass index (BMI) z-score was 1.96 ± 0.7, higher in Jews than Arabs. High systolic (≥ 130 mmHg) and diastolic blood pressure (≥ 85 mmHg) were observed in 33.7% and 7.8% of patients, respectively; mean glycosylated hemoglobin (A1c) level at diagnosis was 8.8 ± 2.5%. Dyslipidemia, with high triglyceride (>150 mg/dl) and low HDL-c (<40 mg/dl) levels, was found in 45.6% and 56.5%, respectively. Microalbuminuria and retinopathy were documented at diagnosis, 15.2% and 1.9%, respectively) and increased (36.7% and 4.6%, respectively) at follow-up of 2.9 ± 2.1 years. Criteria of metabolic syndrome were met by 224 (62.2%) patients, and fatty liver documented in 65%, mainly Jews. Psychosocial comorbidity was found in 31%. Treatment with metformin (45.6%), insulin (20.6%), and lifestyle modification (18%) improved glycemic control. CONCLUSION: Youth-onset T2D in Israel has increased significantly and presents a unique profile.

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OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

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OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

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Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.

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Globally, the proportion of new diagnoses of youth-onset diabetes represented by type 2 diabetes is increasing, and youth with type 2 diabetes commonly have complications and comorbidities, as well as a higher rate of mortality. In this review, we summarise what is known about the natural progression of youth-onset type 2 diabetes from published clinical trials and large-scale prospective epidemiological studies. It is important to note that the robust pathophysiological and treatment data specifically related to individuals with a diabetes onset at ≤20 years of age largely hails from the USA. Youth-onset type 2 diabetes is characterised by pathophysiological heterogeneity and inadequate glycaemic control, highlighting the need for new treatment approaches and innovative study designs in populations of varied genetic and cultural backgrounds.

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OBJECTIVE: To compare treatment regimens and glycosylated hemoglobin (A1c) levels in Type 1 (T1D) and Type 2 diabetes (T2D) using diabetes registries from two countries-U.S. SEARCH for Diabetes in Youth (SEARCH) and Indian Registry of youth onset diabetes in India (YDR). METHODS: The SEARCH and YDR data were harmonized to the structure and terminology in the Observational Medical Outcomes Partnership Common Data Model. Data used were from T1D and T2D youth diagnosed <20 years between 2006-2012 for YDR, and 2006, 2008, and 2012 for SEARCH. We compared treatment regimens and A1c levels across the two registries. RESULTS: There were 4003 T1D (SEARCH = 1899; YDR = 2104) and 611 T2D (SEARCH = 384; YDR = 227) youth. The mean A1c was higher in YDR compared to SEARCH (T1D:11.0% ± 2.9% vs 7.8% ± 1.7%, P < .001; T2D:9.9% ± 2.8% vs 7.2% ± 2.1%, P < .001). Among T1D youth in SEARCH, 65.1% were on a basal/bolus regimen, whereas in YDR, 52.8% were on once/twice daily insulin regimen. Pumps were used by 16.2% of SEARCH and 1.5% of YDR youth with T1D. Among T2D youth, in SEARCH and YDR, a majority were on metformin only (43.0% vs 30.0%), followed by insulin + any oral hypoglycemic agents (26.3% vs 13.7%) and insulin only (12.8% vs 18.9%), respectively. CONCLUSION: We found significant differences between SEARCH and YDR in treatment patterns in T1D and T2D. A1c levels were higher in YDR than SEARCH youth, for both T1D and T2D, irrespective of the regimens used. Efforts to achieve better glycemic control for youth are urgently needed to reduce the risk of long-term complications.

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BACKGROUND: Youth-onset type 2 diabetes (T2D) is increasing in many countries, creating large personal and societal burdens. While many primary health-care professionals (HCPs) are aware of the classic symptoms of T2D, there are several other manifestations that could indicate its presence. SUMMARY: This narrative review summarizes information on these symptoms and indicators, focusing on those less well known. The classic symptoms and comorbidities include frequent urination, excessive thirst, metabolic syndrome, and obesity. In addition to these, the presence of dermatological (e.g., acanthosis nigricans, granuloma annulare, necrobiosis lipoidica diabeticorum, and scleredema), gynecological (e.g., polycystic ovary syndrome, oligomenorrhea, and vulvovaginitis), hepatological (e.g., nonalcoholic fatty liver disease), and psychiatric diseases (e.g., psychosis, depression, and autism) could indicate that a patient has T2D or is at increased risk of T2D. Other less well-known indicators include abnormal blood tests (e.g., oxidized lipids, inflammation markers, hepatokines, and adipokines), prescriptions for antipsychotic medications or statins, and disrupted sleep patterns. Key Message: Due to the diversity of T2D manifestations in young people, primary HCPs need to remain alert to its possible presence.

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PURPOSE OF REVIEW: Continuous glucose monitoring (CGM) technology has long been accepted as a tool for managing glycemia in type 1 diabetes (T1D) and is receiving increased attention as a tool for monitoring glucose patterns in patients with other forms of diabetes, in particular type 2 diabetes (T2D). Recent studies in adults with T2D have shown benefits of CGM in the investigation of glycemic variability, as well as utility as a tool for improving glycemic control. The literature on CGM use in youth-onset T2D, however, is sparse. This paper reviews the various roles for CGM in T2D, with a focus on published reports of CGM use in youth-onset T2D. The gaps in knowledge are highlighted, along with a discussion regarding need for future studies of potential applications for CGM in this younger population. RECENT FINDINGS: CGM systems provide insight into glycemic abnormalities in obese youth with and at risk for T2D. This technology has enabled examination of the relationship between free-living glycemic profiles and traditional diabetes screening tests, as well as markers of cardiometabolic risk in this high-risk population. Investigators are incorporating CGM technology into the study of T2D in youth, but interventional studies of CGM as a tool for glycemic control in youth-onset T2D are limited. Youth with T2D face a more aggressive disease than adults with T2D, and further studies utilizing advances in glucose monitoring technology to improve outcomes in this population are needed.

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The prevalence of youth-onset type 2 diabetes (T2D) is rapidly increasing worldwide, disproportionately affecting Indigenous youth with Oji-Cree heritage from central Canada. Candidate gene screening has uncovered a novel and private polymorphism in the Oji-Cree population in the hepatocyte nuclear factor-1 alpha (HNF-1α) gene, where a highly conserved glycine residue at position 319 is changed to a serine (termed HNF-1αG319S or simply G319S). Oji-Cree youth who carry one or two copies of the "S-allele" present at diagnosis with less obesity, reduced indicators of insulin resistance, and lower plasma insulin levels at diagnosis, suggestive of a primary defect in the insulin-secreting ß cells. Few studies on the impact of the HNF-1αG319S variant on ß cell function have been performed to date; however, much can be learned from other clinical phenotypes of HNF-1α-deficiency, including HNF-1α mutations that cause maturity-onset diabetes of the young 3 (MODY3). In addition, evaluation of Hnf-1α-deficient murine models reveals that HNF-1α plays a central role in the regulation of insulin secretion by regulating the expression of key genes involved in ß cell glucose-sensing, mitochondrial function, and the maintenance of the ß cell phenotype in differentiated ß cells. The overall goal of this minireview is to explore the impact of HNF-1α-deficiency on the ß cell to better inform future research into the mechanisms of ß cell dysfunction in Oji-Cree youth with T2D.

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