RESUMO
BACKGROUND: The incidence of type 2 diabetes mellitus is increasing among youths. Once-weekly treatment with dulaglutide, a glucagon-like peptide-1 receptor agonist, may have efficacy with regard to glycemic control in youths with type 2 diabetes. METHODS: In a double-blind, placebo-controlled, 26-week trial, we randomly assigned participants (10 to <18 years of age; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75 mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75 mg. The primary end point was the change from baseline in the glycated hemoglobin level at 26 weeks. Secondary end points included a glycated hemoglobin level of less than 7.0% and changes from baseline in the fasting glucose concentration and BMI. Safety was also assessed. RESULTS: A total of 154 participants underwent randomization. At 26 weeks, the mean glycated hemoglobin level had increased in the placebo group (0.6 percentage points) and had decreased in the dulaglutide groups (-0.6 percentage points in the 0.75-mg group and -0.9 percentage points in the 1.5-mg group, P<0.001 for both comparisons vs. placebo). At 26 weeks, a higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated hemoglobin level of less than 7.0% (51% vs. 14%, P<0.001). The fasting glucose concentration increased in the placebo group (17.1 mg per deciliter) and decreased in the pooled dulaglutide groups (-18.9 mg per deciliter, P<0.001), and there were no between-group differences in the change in BMI. The incidence of gastrointestinal adverse events was higher with dulaglutide therapy than with placebo. The safety profile of dulaglutide was consistent with that reported in adults. CONCLUSIONS: Treatment with dulaglutide at a once-weekly dose of 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control through 26 weeks among youths with type 2 diabetes who were being treated with or without metformin or basal insulin, without an effect on BMI. (Funded by Eli Lilly; AWARD-PEDS ClinicalTrials.gov number, NCT02963766.).
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Adolescente , Glicemia/efeitos dos fármacos , Criança , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Injeções Subcutâneas , Insulinas/uso terapêutico , Metformina/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood. METHODS: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated. RESULTS: At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up. CONCLUSIONS: Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.).
Assuntos
Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Adolescente , Criança , Complicações do Diabetes/etnologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/complicações , Dislipidemias/epidemiologia , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Fatores de RiscoRESUMO
Metformin is the first-line treatment for type 2 diabetes (T2D) in youth but with limited sustained glycemic response. To identify common variants associated with metformin response, we used a genome-wide approach in 506 youth from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and examined the relationship between T2D partitioned polygenic scores (pPS), glycemic traits, and metformin response in these youth. Several variants met a suggestive threshold (P < 1 × 10-6), though none including published adult variants reached genome-wide significance. We pursued replication of top nine variants in three cohorts, and rs76195229 in ATRNL1 was associated with worse metformin response in the Metformin Genetics Consortium (n = 7,812), though statistically not being significant after Bonferroni correction (P = 0.06). A higher ß-cell pPS was associated with a lower insulinogenic index (P = 0.02) and C-peptide (P = 0.047) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline (P = 0.04,0.02). Although pPS were not associated with changes in glycemic traits or metformin response, our results indicate a trend in the association of the ß-cell pPS with reduced ß-cell function over time. Our data show initial evidence for genetic variation associated with metformin response in youth with T2D.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Adulto , Humanos , Adolescente , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Peptídeo C , Falha de Tratamento , Variação Genética , Glicemia , Hipoglicemiantes/uso terapêuticoRESUMO
BACKGROUND AND AIMS: The lack of easily measurable biomarkers remains a challenge in executing clinical trials for diabetic neuropathy (DN). Plasma Neurofilament light chain (NFL) concentration is a promising biomarker in immune-mediated neuropathies. Longitudinal studies evaluating NFL in DN have not been performed. METHODS: A nested case-control study was performed on participants with youth-onset type 2 diabetes enrolled in the prospective Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Plasma NFL concentrations were measured at 4-year intervals from 2008 to 2020 in 50 participants who developed DN and 50 participants with type 2 diabetes who did not develop DN. RESULTS: NFL concentrations were similar in the DN and no DN groups at the first assessment. Concentrations were higher in DN participants at all subsequent assessment periods (all p < .01). NFL concentrations increased over time in both groups, with higher degrees of change in DN participants (interaction p = .045). A doubling of the NFL value at Assessment 2 in those without DN increased the odds of ultimate DN outcome by an estimated ratio of 2.86 (95% CI: [1.30, 6.33], p = .0046). At the final study visit, positive Spearman correlations (controlled for age, sex, diabetes duration, and BMI) were observed between NFL and HbA1c (0.48, p < .0001), total cholesterol (0.25, p = .018), and low-density lipoprotein (LDL (0.30, p = .0037)). Negative correlations were observed with measures of heart rate variability (-0.42 to -0.46, p = <.0001). INTERPRETATION: The findings that NFL concentrations are elevated in individuals with youth-onset type 2 diabetes, and increase more rapidly in those who develop DN, suggest that NFL could be a valuable biomarker for DN.
Assuntos
Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Humanos , Adolescente , Estudos de Casos e Controles , Filamentos Intermediários , Proteínas de Neurofilamentos , BiomarcadoresRESUMO
Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.
Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Adolescente , Criança , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Incidência , Pandemias , Fatores de Risco , Adulto JovemRESUMO
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).
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Segurança do Paciente/normas , Fosfato de Sitagliptina/farmacologia , Administração Oral , Adolescente , Glicemia/análise , Criança , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada/métodos , Quimioterapia Combinada/estatística & dados numéricos , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Segurança do Paciente/estatística & dados numéricos , Fosfato de Sitagliptina/uso terapêutico , Resultado do TratamentoRESUMO
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).
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Segurança do Paciente/normas , Fosfato de Sitagliptina/farmacologia , Administração Oral , Adolescente , Glicemia/análise , Criança , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada/métodos , Quimioterapia Combinada/estatística & dados numéricos , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Segurança do Paciente/estatística & dados numéricos , Fosfato de Sitagliptina/uso terapêutico , Resultado do TratamentoRESUMO
Our objective was to explore the longitudinal trajectory of hemoglobin A1c (HbA1c) in well-characterized youth (n = 84) with normal weight and obesity during puberty. HbA1c rose from early puberty to Tanner stage 5, even in healthy, normal weight youth, revealing important implications for defining normal glycemia and prediabetes in adolescents.
Assuntos
Peso Corporal , Hemoglobinas Glicadas/análise , Obesidade Infantil/epidemiologia , Puberdade/sangue , Adolescente , Criança , Feminino , Humanos , Masculino , Valores de ReferênciaRESUMO
OBJECTIVE: Adult women with polycystic ovary syndrome (PCOS) and obesity have an 8-fold increased risk of developing type 2 diabetes (T2D). Our goal was to determine the incidence and risk factors for T2D in adolescents with PCOS and obesity. RESEARCH DESIGN AND METHODS: Retrospective chart review of girls aged 11-21 years with confirmed PCOS (oligomenorrhea and hyperandrogenism) diagnosis between July 2013 and Aug 2018 and at least one follow-up visit and BMI >85%ile. T2D incidence, defined with an HbA1c ≥6.5%, was calculated. A nested case-control study with 1:3 matching by race, ethnicity, and BMI was performed to determine predictors of T2D diagnosis. RESULTS: Four hundred ninety-three patients with PCOS (age 15.6 ± 1.9 years, BMI 36.2 ± 6.3 kg/m2 ) were identified with a follow-up of 1018 person-years. Twenty-three developed T2D (incidence 22.6/1000 person-years) with diagnosis a median of 1.8 years (2 months-5.5 years) after PCOS diagnosis. T2D risk was higher in girls with a prediabetes HbA1c (5.7%-6.4%) (HR 14.6 [4.8-44.5]) and among Hispanic girls with an elevated HbA1c and alanine aminotransferase (HR 19.0 [3.7-97.2]) at the time of PCOS diagnosis. In the 1:3 matched cohort, T2D risk was 18.7 times higher (OR 18.66 [2.27-153.24]) for every 0.1% increase in HbA1c at the time of PCOS diagnoses. CONCLUSIONS: Girls with PCOS and obesity have an 18-fold increase in T2D incidence compared to published rates in non-PCOS youth. Hispanic girls with elevated HbA1c and ALT are at particular risk. Due to the morbidity associated with youth onset T2D, these findings argue for better screening and prevention approaches in this population.
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Obesidade/complicações , Síndrome do Ovário Policístico/complicações , Adolescente , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Incidência , Obesidade/epidemiologia , Obesidade/patologia , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/patologia , Estado Pré-Diabético/complicações , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/patologia , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10-17 years) were well-matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1-5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Síndrome de Klinefelter/epidemiologia , Obesidade/epidemiologia , Adolescente , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Feminino , Humanos , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/patologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/patologia , Obesidade/sangue , Obesidade/patologia , Testosterona/sangue , Triglicerídeos/sangue , Circunferência da CinturaRESUMO
American Diabetes Association adult criteria are used to screen youth for diabetes, but little is known about normal glycemia in youth. In the HEALTHY Study (total n = 8814), hemoglobin A1c was ≥5.7% in 2% of normal weight youth. This suggests need for cautious interpretation of prediabetes hemoglobin A1s in youth.
Assuntos
Hemoglobinas Glicadas/análise , Estado Pré-Diabético/sangue , Estado Pré-Diabético/diagnóstico , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Valores de ReferênciaRESUMO
BACKGROUND: Individual health behaviors (ie, eating habits and sedentary lifestyle) are associated with type 2 diabetes (T2D). Health behavior profiles specific to adolescents with T2D have not been described. OBJECTIVE: To identify health behavior profiles in adolescents with T2D and examine how these profiles change over time. METHODS: Diet (via food frequency questionnaire) and activity behaviors (via 3-day physical activity recall) examined at baseline, 6 months, and 24 months from participants in the the Treatment Options for T2D in Adolescents and Youth (TODAY) study were used for this analysis. Latent profile analysis identified profiles of health behaviors within three time points, and latent transition probabilities were estimated to examine the change from baseline to 6 months (n = 450) and baseline to 24 months (n = 415). Multinomial logistic regressions were used to examine if the assigned TODAY treatment group (Metformin [Met], Met + Rosiglitazone [Rosi], or Met + Lifestyle) predicted change in health behavior profiles. RESULTS: Three profiles emerged: "most sedentary," "healthy eaters," and "active and eat most." At 6 months, 50% of males and 29% of females in the Met + Lifestyle treatment group improved in their health behavior profile. Among males only, the Met + Lifestyle treatment group were more likely to improve their profiles from baseline to 6 months (P = .01). CONCLUSIONS: Three health behavior profiles emerged and shifted over time. A high quality, lifestyle intervention had little effect on improving health behavior profiles. Optimizing outcomes in youth with T2D might require more robust and multifaceted interventions beyond family-level lifestyle, including more extensive psychosocial intervention, novel medication regimen, or bariatric surgery.
Assuntos
Comportamento do Adolescente , Diabetes Mellitus Tipo 2/psicologia , Comportamentos Relacionados com a Saúde , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Masculino , Comportamento de Redução do RiscoRESUMO
BACKGROUND: The RISE Pediatric Medication Study compared strategies for preserving ß-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability. OBJECTIVE: Evaluate OGTT measures of glucose and ß-cell response through 12 months of intervention and 9 months of medication washout. PARTICIPANTS: Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D). METHODS: A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (GâMet) or metformin alone (Met) for 12 months. We report within-group changes from baseline to end of medication intervention (M12), baseline to 9 months post-medication withdrawal (M21), and end of medication (M12) to M21. OGTT C-peptide index [CPI] paired with 1/fasting insulin evaluated ß-cell response. RESULTS: At M12, both treatments were associated with stable fasting glucose (GâMet baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2-hour glucose (GâMet baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (GâMet M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2-hour glucose (GâMet M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in ß-cell response. CONCLUSIONS: GâMet and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and ß-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Intolerância à Glucose/complicações , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Adolescente , Criança , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Jejum , Feminino , Seguimentos , Intolerância à Glucose/sangue , Intolerância à Glucose/tratamento farmacológico , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Adulto JovemRESUMO
By 2017 estimates, diabetes mellitus affects 425 million people globally; approximately 90-95% of these have type 2 diabetes. This narrative review highlights two domains of sex differences related to the burden of type 2 diabetes across the life span: sex differences in the prevalence and incidence of type 2 diabetes, and sex differences in the cardiovascular burden conferred by type 2 diabetes. In the presence of type 2 diabetes, the difference in the absolute rates of cardiovascular disease (CVD) between men and women lessens, albeit remaining higher in men. Large-scale observational studies suggest that type 2 diabetes confers 25-50% greater excess risk of incident CVD in women compared with men. Physiological and behavioural mechanisms that may underpin both the observed sex differences in the prevalence of type 2 diabetes and the associated cardiovascular burden are discussed in this review. Gender differences in social behavioural norms and disparities in provider-level treatment patterns are also highlighted, but not described in detail. We conclude by discussing research gaps in this area that are worthy of further investigation.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Doenças Cardiovasculares/etiologia , Sistema Cardiovascular/patologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Incidência , Prevalência , Fatores de Risco , Fatores SexuaisRESUMO
OBJECTIVE: To examine the associations of in utero exposure to maternal diabetes with surrogate measures of offspring pubertal timing (age at peak height velocity [APHV]) and speed of pubertal growth (peak height velocity [PHV]). STUDY DESIGN: Data from 77 exposed and 340 unexposed youth followed from age 2 to 19 years (51% non-Hispanic white, 50% female) were analyzed using the Exploring Perinatal Outcomes among Children study, a historical prospective cohort. Maternal diabetes status was collected from obstetric records, and child heights from 2 years to current age from pediatric records. Other covariates were collected during research visits. The superimposition by translation and rotation method, using height measurements (4-52 per participant), modeled APHV and PHV. Accelerated failure time analyses were used to test whether exposure to maternal diabetes was associated with younger APHV and faster PHV. RESULTS: Adjusting for child's sex, race/ethnicity, and socioeconomic status, median APHV was reached ~3 months earlier in youth exposed to maternal diabetes compared with unexposed youth (P < .03). Youth exposed to maternal diabetes had a faster PHV than unexposed youth: exposed girls had 10.5% greater median PHV compared with unexposed girls and exposed boys had a 4.0% greater median PHV compared with unexposed boys (P < .001 for exposure by sex interaction). CONCLUSIONS: Our findings provide evidence that exposure to maternal diabetes in utero is associated with earlier pubertal timing and faster pubertal growth. Whether earlier puberty or faster speed of pubertal growth mediates the association between maternal diabetes exposure and later chronic disease risk remains to be studied.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Gestacional/fisiopatologia , Gravidez em Diabéticas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Puberdade Precoce/etiologia , Adolescente , Antropometria , Estatura , Índice de Massa Corporal , Criança , Pré-Escolar , Colorado/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Feminino , Humanos , Masculino , Menarca , Gravidez , Estudos Prospectivos , Puberdade , Maturidade Sexual , Classe Social , Adulto JovemRESUMO
OBJECTIVE: Dysglycemia is prevalent in cystic fibrosis (CF) but screening with annual oral glucose tolerance tests (OGTT) can be burdensome. We investigated alternate glycemic markers-hemoglobin A1c (HbA1c), 1,5-anhydroglucitol (1,5AG), fructosamine (FA), and glycated albumin (GA)-as screening tests for CF-related diabetes (CFRD) and pre-diabetes (CFPD) in youth with CF as defined by the gold-standard OGTT 2-hour glucose (2hG). METHODS: Youth 10 to 18 years with CF had a 1,5AG, FA, GA, HbA1c, and 2-hour OGTT collected. Correlations between all glycemic markers and 2hG were evaluated. Area under the receiver operative characteristic (ROC-AUC) curves were generated. Optimal cut points for predicting CFPD (2hG ≥ 140 mg/dL) and CFRD (2hG ≥ 200 mg/dL) were determined. RESULTS: Fifty-eight youth with CF were included (2hG < 140, n = 16; CFPD, n = 33; CFRD, n = 9; 41% male, mean ± SD age 14.2 ± 3.6 years, BMI z-score 0.0 ± 0.8, % predicted forced expiratory volume in 1 second [FEV1] 89.9 ± 15.1, % predicted forced vital capacity [FVC] 103.2 ± 14.6). ROC-AUC's for all alternate markers were low for CFPD (0.52-0.67) and CFRD (0.56-0.61). At a cut point of 5.5%, HbA1c had 78% sensitivity (95% CI: 0.45-0.94) and 41% specificity (95% CI: 0.28-0.55) for identifying CFRD, correlating to a ROC-AUC of 0.61 (95% CI: 0.42-0.8). CONCLUSIONS: All alternate markers tested demonstrate poor diagnostic accuracy for identifying CFRD by 2hG.
Assuntos
Fibrose Cística/complicações , Desoxiglucose/sangue , Frutosamina/sangue , Hemoglobinas Glicadas/metabolismo , Estado Pré-Diabético/diagnóstico , Albumina Sérica/metabolismo , Adolescente , Criança , Fibrose Cística/sangue , Feminino , Produtos Finais de Glicação Avançada , Humanos , Masculino , Programas de Rastreamento , Estado Pré-Diabético/sangue , Estado Pré-Diabético/etiologia , Albumina Sérica GlicadaRESUMO
OBJECTIVE: To understand the factors associated with glycemic control after starting insulin in youth with type 2 diabetes following glycemic failure (persistent HbA1c ≥8%) with metformin alone, metformin + rosiglitazone or metformin + lifestyle in the TODAY study. METHODS: Change in HbA1c after add-on insulin therapy and the factors predictive of glycemic response were evaluated. At 1-year postinsulin initiation, 253 youth had a mean of 3.9 ± 1.0 visits since the time of insulin initiation. Participants were divided into three groups according to glycemic control: consistent decrease in HbA1c by ≥0.5%, change <0.5%, or consistent increase in HbA1c ≥0.5%, at 75% or more of the visits. RESULTS: Within 1-year postinsulin initiation, 33.2% of participants had a consistent HbA1c decrease of ≥0.5%, 46.2% changed HbA1c <0.5%, and 20.6% had an increase ≥0.5%. At randomization into TODAY and at time of insulin initiation, the three glycemia groups were similar in age, sex, race-ethnicity, pubertal stage, BMI z-score, diabetes duration, and insulin secretion indices. Consistent HbA1c improvement was associated with higher insulin sensitivity (1/fasting insulin) at randomization and at time of failure, higher adiponectin at randomization, and was not associated with indices of ß-cell function. CONCLUSIONS: Response to add-on insulin was highly variable among youth in TODAY. Greater insulin sensitivity and higher adiponectin concentrations at randomization were associated with improved glycemic control after initiation of insulin. Due to limited information on adherence to insulin injections, the roles of adherence to the prescribed insulin regimen or psychosocial factors are unknown.
Assuntos
Biomarcadores Farmacológicos/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Adiponectina/análise , Adiponectina/sangue , Adolescente , Biomarcadores Farmacológicos/análise , Glicemia/efeitos dos fármacos , Criança , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Resistência à Insulina/fisiologia , Masculino , Prognóstico , Falha de Tratamento , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported. RESULTS: Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0-∞ , Cmax , and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. CONCLUSIONS: Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes , Fosfato de Sitagliptina , Adolescente , Fatores Etários , Idade de Início , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Criança , Diabetes Mellitus Tipo 2/epidemiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Masculino , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversos , Fosfato de Sitagliptina/farmacocinéticaRESUMO
The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of ß-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of ß-cell function and changes in ß-cell function in response to interventions. In the present paper, we review approaches for measurement of ß-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of ß-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure ß-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in ß-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine.