RESUMO
AIMS: Increased adiposity is a risk factor for suboptimal diabetes control and cardiovascular disease (CVD) complications. Our goal was to identify modifiable behavioral characteristics of overweight and obese pediatric patients with type 1 diabetes mellitus (T1DM) who achieve optimal glycemic control and to evaluate their CVD risk compared to lean patients. Our hypothesis was that optimally controlled obese and overweight participants require more total daily insulin and are at higher CVD risk compared to optimally controlled lean participants. METHODS: We analyzed a cohort of 9263 participants with T1DM aged <21â¯years in the T1D Exchange Registry. Optimal diabetes control was defined as HbA1câ¯≤â¯7.5% (58â¯mmol/mol). We compared factors that influence glycemic control in lean, overweight and obese participants with optimal vs. suboptimal control, using logistic regression. RESULTS: Age, race, overweight status, continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) use were important variables influencing glycemic control. In the optimally controlled cohort, 27% of participants were overweight or obese versus 30% in the suboptimally controlled cohort (Pâ¯<â¯0.001). Overweight and obese participants with optimal control were not significantly different from lean participants in terms of CSII use, total daily insulin dosage per kg of bodyweight, glucose checks per day, boluses with bedtime snack, use of CGM, but had higher LDL cholesterol and triglycerides, and lower HDL cholesterol (Pâ¯<â¯0.05). CONCLUSIONS: There were no differences in modifiable behavioral characteristics between the obese, overweight and lean optimally controlled participants. However, predictors of cardiovascular disease were higher in the overweight and obese group.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Controle Glicêmico/estatística & dados numéricos , Sobrepeso/epidemiologia , Obesidade Infantil/epidemiologia , Adolescente , Glicemia/metabolismo , Automonitorização da Glicemia , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Feminino , Hemoglobinas Glicadas/metabolismo , Controle Glicêmico/normas , Humanos , Lactente , Recém-Nascido , Insulina/administração & dosagem , Sistemas de Infusão de Insulina , Masculino , Sobrepeso/sangue , Sobrepeso/complicações , Obesidade Infantil/sangue , Obesidade Infantil/complicações , Sistema de Registros/estatística & dados numéricos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: To identify and define clinically meaningful type 1 diabetes outcomes beyond hemoglobin A1c (HbA1c) based upon a review of the evidence, consensus from clinical experts, and input from researchers, people with type 1 diabetes, and industry. Priority outcomes include hypoglycemia, hyperglycemia, time in range, diabetic ketoacidosis (DKA), and patient-reported outcomes (PROs). While priority outcomes for type 1 and type 2 diabetes may overlap, type 1 diabetes was the focus of this work. RESEARCH AND METHODS: A Steering Committee-comprising representatives from the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange-was the decision-making body for the Type 1 Diabetes Outcomes Program. Their work was informed by input from researchers, industry, and people with diabetes through Advisory Committees representing each stakeholder group. Stakeholder surveys were used to identify priority outcomes. The outcomes prioritized in the surveys were hypoglycemia, hyperglycemia, time in range, DKA, and PROs. To develop consensus on the definitions of these outcomes, the Steering Committee relied on published evidence, their clinical expertise, and feedback from the Advisory Committees. RESULTS: The Steering Committee developed definitions for hypoglycemia, hyperglycemia, time in range, and DKA in type 1 diabetes. The definitions reflect their assessment of the outcome's short- and long-term clinical impact on people with type 1 diabetes. Knowledge gaps to be addressed by future research were identified. The Steering Committee discussed PROs and concluded that further type 1 diabetes-specific development is needed. CONCLUSIONS: The Steering Committee recommends use of the defined clinically meaningful outcomes beyond HbA1c in the research, development, and evaluation of type 1 diabetes therapies.
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Diabetes Mellitus Tipo 1/sangue , Endocrinologistas/normas , Endocrinologia/normas , Hemoglobinas Glicadas/normas , Avaliação de Resultados em Cuidados de Saúde/normas , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Cetoacidose Diabética/sangue , Cetoacidose Diabética/diagnóstico , Endocrinologistas/educação , Endocrinologia/educação , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hipoglicemia/sangue , Hipoglicemia/diagnóstico , Sociedades Médicas , Estados UnidosRESUMO
The asymptomatic phase of type 1 diabetes is recognised by the presence of beta cell autoantibodies in the absence of hyperglycaemia. We propose that an accurate description of this stage is provided by the name 'Autoimmune Beta Cell Disorder' (ABCD). Specifically, we suggest that this nomenclature and diagnosis will, in a proactive manner, shift the paradigm towards type 1 diabetes being first and foremost an immune-mediated disease and only later a metabolic disease, presaging more active therapeutic intervention in the asymptomatic stage of disease, before end-stage beta cell failure. Furthermore, we argue that accepting ABCD as a diagnosis will be critical in order to accelerate pharmaceutical, academic and public activities leading to clinical trials that could reverse beta cell autoimmunity and halt progression to symptomatic insulin-requiring type 1 diabetes. We recognize that there are both opportunities and challenges in the implementation of the ABCD concept but hope that the notion of 'asymptomatic autoimmune disease' as a disorder will be widely discussed and eventually accepted.
Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/complicações , Células Secretoras de Insulina/patologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , Células Secretoras de Insulina/imunologiaRESUMO
OBJECTIVE: This study aims to compare the effectiveness of insulin glargine 300 U/mL (Gla-300) with its accompanying patient support program with that of other basal insulin and available patient support programs in patients with type 2 diabetes (T2D) in a real-world setting in terms of achieving HEDIS (Healthcare Effectiveness Data and Information Set) individualized glycemic targets without documented symptomatic hypoglycemia. METHODS: Achieve Control is a US-based, multicenter, randomized, open-label, active-controlled, parallel group pragmatic Phase IV trial in insulin-naïve patients with T2D uncontrolled on ≥2 oral antidiabetes drugs (OAD) and/or glucagon-like peptide-1 receptor antagonists (GLP-1 RA). Inclusion criteria include a diagnosis of T2D, age ≥18 years, and glycated hemoglobin (HbA1c) between 8.0% and 11.0%. Patients will be assigned to either the Gla-300 or other basal insulin group. The primary end point is the proportion of patients achieving HEDIS HbA1c targets (<8.0% [64 mmol/mol] in patients with comorbidities or aged ≥65 years; <7.0% [58 mmol/mol] in all other patients) without occurrence of symptomatic hypoglycemia (blood glucose ≤70 mg/dL) from baseline to 6 months. Secondary end points include rates of documented symptomatic nocturnal hypoglycemia and severe hypoglycemia; change from baseline in HbA1c, fasting glucose, and body weight; treatment persistence; patient-reported outcomes; and healthcare resource utilization. Planned enrollment is 3270 patients across approximately 400 clinical sites. CONCLUSION: Pragmatic clinical trials offer the potential to assess comparative effectiveness in broadly based patient populations receiving care (with or without a corresponding educational support program) in real-world clinical settings. The results of Achieve Control should elucidate the benefits of management of T2D with Gla-300 versus other basal insulins in terms of patient outcomes, experiences, and perceptions, and its impact on healthcare resource utilization and cost. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT02451137.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Detemir/uso terapêutico , Insulina Glargina/uso terapêutico , Idoso , Glicemia , Peso Corporal , Comorbidade , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Hemoglobinas Glicadas , Serviços de Saúde/economia , Serviços de Saúde/estatística & dados numéricos , Humanos , Hipoglicemia , Hipoglicemiantes/administração & dosagem , Insulina Detemir/administração & dosagem , Insulina Glargina/administração & dosagem , Masculino , Medidas de Resultados Relatados pelo Paciente , Estados UnidosRESUMO
OBJECTIVE/METHODS: Barriers to continuous glucose monitoring (CGM) use continue to hamper adoption of this valuable technology for the management of diabetes. The American Association of Clinical Endocrinologists and the American College of Endocrinology convened a public consensus conference February 20, 2016, to review available CGM data and propose strategies for expanding CGM access. RESULTS: Conference participants agreed that evidence supports the benefits of CGM in type 1 diabetes and that these benefits are likely to apply whenever intensive insulin therapy is used, regardless of diabetes type. CGM is likely to reduce healthcare resource utilization for acute and chronic complications, although real-world analyses are needed to confirm potential cost savings and quality of life improvements. Ongoing technological advances have improved CGM accuracy and usability, but more innovations in human factors, data delivery, reporting, and interpretation are needed to foster expanded use. The development of a standardized data report using similar metrics across all devices would facilitate clinician and patient understanding and utilization of CGM. Expanded CGM coverage by government and private payers is an urgent need. CONCLUSION: CGM improves glycemic control, reduces hypoglycemia, and may reduce overall costs of diabetes management. Expanding CGM coverage and utilization is likely to improve the health outcomes of people with diabetes. ABBREVIATIONS: A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology ASPIRE = Automation to Simulate Pancreatic Insulin Response CGM = continuous glucose monitoring HRQOL = health-related quality of life ICER = incremental cost-effectiveness ratio JDRF = Juvenile Diabetes Research Foundation MARD = mean absolute relative difference MDI = multiple daily injections QALY = quality-adjusted life years RCT = randomized, controlled trial SAP = sensor-augmented pump SMBG = self-monitoring of blood glucose STAR = Sensor-Augmented Pump Therapy for A1C Reduction T1D = type 1 diabetes T2D = type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Endocrinologia/normas , Automonitorização da Glicemia/normas , Consenso , Endocrinologia/organização & administração , Humanos , Qualidade de VidaRESUMO
Much progress has been made in diabetes treatments since the first dose of insulin was administered in 1921. However, a truly transformational moment in diabetes care occurred when urine testing gave way to capillary blood home glucose monitoring. As improvements were made to these devices, continuous glucose monitoring (CGM) was introduced. The advantages of experiential learnings gleaned from seeing continuous real-time data have been borne out in numerous peer-reviewed journals. Limitations to use of CGM include patient's level of numeracy and literacy, development of alarm fatigue, interfering substances leading to erroneous readings, high rates of discontinuation, and poor reimbursement.
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Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Hiperglicemia/diagnóstico , Hipoglicemia/diagnóstico , Monitorização Ambulatorial , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/economia , Erros de Diagnóstico/prevenção & controle , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/efeitos adversos , Insulina/uso terapêutico , Reembolso de Seguro de Saúde , Alfabetização , Matemática/educação , Fadiga Mental/etiologia , Fadiga Mental/prevenção & controle , Monitorização Ambulatorial/economia , Cooperação do Paciente , Educação de Pacientes como Assunto , Satisfação do PacienteRESUMO
BACKGROUND: Oxidative stress is a detrimental feature of diabetes implicated in the progression of the disease and its complications. The relationship between insulin therapy and oxidative stress is complex. This study tested the hypothesis that improved glucose control, rather than insulin dose, is central to reduced oxidative stress in patients with type 2 diabetes following continuous subcutaneous insulin infusion (CSII). METHODS: In this 16-week, multicenter study, 54 CSII-naïve patients with type 2 diabetes (age 57 ± 10 years, HbA1c 69 ± 15 mmol/mol [8.5 ± 1.4%], diabetes duration 13 ± 6 years) treated with either oral antidiabetic agents (OAD) alone (n = 17), basal insulin ± OAD (n = 17), or multiple daily injections (MDI) ± OAD (n = 20) were the evaluable group. Diabetes medications except metformin were discontinued, and 16 weeks of CSII was initiated. Insulin dose was titrated to achieve optimal glycemic control. A plasma marker of oxidative stress relevant to cardiovascular disease (oxidized low density lipoprotein [ox-LDL]) was assessed at baseline and week 16. RESULTS: CSII improved glycemic control (HbA1c -13 ± 2 mmol/mol [-1.2 ± 0.2%]; fasting glucose -36.6 ± 8.4 mg/dL; mean glucose excursion -23.2 ± 6.5 mg/dL, mean ± SE; all P < .001) and reduced ox-LDL (-10.5%; P < .05). The antioxidant effect was cohort-independent (P > .05), but was significantly more pronounced in patients on statins (P = .019). The effect of CSII was more closely correlated to improvements in glucose excursion (P = .013) than to insulin dose (P > .05) or reduction in HbA1c (P > .05). CONCLUSIONS: CSII induces depression of plasma ox-LDL associated with change in glucose control, rather than with change in insulin dose. The effect is augmented in patients receiving statins.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Insulina/uso terapêutico , Lipoproteínas LDL/sangue , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Hemoglobinas Glicadas/análise , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Fatores de Risco , Adulto JovemRESUMO
The Hypoglycemia-Hyperglycemia Minimizer (HHM) System aims to mitigate glucose excursions by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The "aggressiveness factor" is a key parameter in the HHM System algorithm, affecting how readily the system adjusts insulin infusion in response to changing CGM levels. Twenty adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 26 hours. This analysis focused on the effect of the aggressiveness factor on the insulin dosing characteristics of the algorithm and, to a lesser extent, on the glucose control results observed. As the aggressiveness factor increased from conservative to medium to aggressive: the maximum observed insulin dose delivered by the algorithmwhich is designed to give doses that are corrective in nature every 5 minutesincreased (1.00 vs 1.15 vs 2.20 U, respectively); tendency to adhere to the subject's nominal basal dose decreased (61.9% vs 56.6% vs 53.4%); and readiness to decrease insulin below basal also increased (18.4% vs 19.4% vs 25.2%). Glucose analyses by both CGM and Yellow Springs Instruments (YSI) indicated that the aggressive setting of the algorithm resulted in the least time spent at levels >180 mg/dL, and the most time spent between 70-180 mg/dL. There was no severe hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia for any of the aggressiveness values investigated. These analyses underscore the importance of investigating the sensitivity of the HHM System to its key parameters, such as the aggressiveness factor, to guide future development decisions.
Assuntos
Algoritmos , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Hiperglicemia/sangue , Hipoglicemia/sangue , Sistemas de Infusão de Insulina/estatística & dados numéricos , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/terapia , Estudos de Viabilidade , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/terapia , Hipoglicemia/terapia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Insulina/administração & dosagem , Insulina/sangue , Sistemas de Infusão de Insulina/efeitos adversos , Masculino , Segurança do PacienteRESUMO
BACKGROUND: This feasibility study investigated the insulin-delivery characteristics of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System-an automated insulin delivery device-in participants with type 1 diabetes. METHODS: Thirteen adults with type 1 diabetes were enrolled in this nonrandomized, uncontrolled, clinical-research-center-based feasibility study. The HHM System comprised a continuous subcutaneous insulin infusion pump, a continuous glucose monitor (CGM), and a model predictive control algorithm with a safety module, run on a laptop platform. Closed-loop control lasted approximately 20 hours, including an overnight period and two meals. RESULTS: When attempting to minimize glucose excursions outside of a prespecified target zone, the predictive HHM System decreased insulin infusion rates below the participants' preset basal rates in advance of below-zone excursions (CGM < 90 mg/dl), and delivered 80.4% less insulin than basal during those excursions. Similarly, the HHM System increased infusion rates above basal during above-zone excursions (CGM > 140 mg/dl), delivering 39.9% more insulin than basal during those excursions. Based on YSI, participants spent a mean ± standard deviation (SD) of 0.2 ± 0.5% of the closed-loop control time at glucose levels < 70 mg/dl, including 0.3 ± 0.9% for the overnight period. The mean ± SD glucose based on YSI for all participants was 164.5 ± 23.5 mg/dl. There were nine instances of algorithm-recommended supplemental carbohydrate administrations, and there was no severe hypoglycemia or diabetic ketoacidosis. CONCLUSIONS: Results of this study indicate that the current HHM System is a feasible foundation for development of a closed-loop insulin delivery device.
RESUMO
Safe and widespread use of diabetes technology is constrained by alarm fatigue: when someone receives so many alarms that he or she becomes less likely to respond appropriately. Alarm fatigue and related usability issues deserve consideration at every stage of alarm system design, especially as new technologies expand the potential number and complexity of alarms. The guiding principle should be patient wellbeing, while taking into consideration the regulatory and liability issues that sometimes contribute to building excessive alarms. With examples from diabetes devices, we illustrate two complementary frameworks for alarm design: a "patient safety first" perspective and a focus on human factors. We also describe opportunities and challenges that will come with new technologies such as remote monitoring, adaptive alarms, and ever-closer integration of glucose sensing with insulin delivery.
Assuntos
Alarmes Clínicos/efeitos adversos , Diabetes Mellitus/sangue , Sistemas de Infusão de Insulina , Automonitorização da Glicemia , Fadiga , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controleRESUMO
BACKGROUND AND AIM: In the context of present epidemic of childhood obesity, we aimed to find the prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in a cohort of obese children. METHODOLOGY: Retrospective chart analysis of 700 obese children was done for their anthropometric and biochemical investigations. RESULTS: Some 15.4% (9.8% girls, 22% boys) subjects had NAFLD (ALT > 40 IU/L) after excluding other identifiable causes of liver dysfunction. Age, weight, TG, fasting serum insulin and HOMA-IR levels were higher in children with NAFLD. Twenty-eight percent children had MS. Children with NAFLD had an odds ratio of 2.65 for having MS (boys 4.6, girls 1.7). The prevalence of MS increased with age 5-9 years (21%), 10-16 years (30%), 17-20 years (35%). CONCLUSION: Given high prevalence of NAFLD and MS in obese children, childhood obesity should be seriously considered as a disease and not just a cosmetic issue.
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Fígado Gorduroso/epidemiologia , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Adolescente , Distribuição por Idade , Alanina Transaminase/sangue , Criança , Estudos de Coortes , Fígado Gorduroso/metabolismo , Feminino , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica , Prevalência , Estudos Retrospectivos , Distribuição por SexoRESUMO
INTRODUCTION: While the endogenous first-phase insulin response has disappeared by the time of diagnosis of type 1 diabetes mellitus (T1DM), anecdotal evidence suggests that these patients can continue to have a second-phase insulin response during the first 12 months after diagnosis. We hypothesized that patients who are started on continuous subcutaneous insulin infusion (CSII) at the time of diagnosis of T1DM would have a lower basal insulin requirement than the 40-60% usually expected. METHODS: We analyzed 38 patients with T1DM, age 9.9 +/- 6.4 years, 71% male, who were started on CSII within the first month of diagnosis. RESULTS: Average basal insulin requirements were 47-49% of total daily dose during the first 12 months after diagnosis and decreased from 0.30 U/kg/day at diagnosis to 0.20 U/kg/day by 12 months. Baseline percentage of basal insulin was significantly correlated with hemoglobin A1c at baseline and at six months. The percentage of basal insulin requirement at 12 months after diagnosis was significantly correlated with baseline body mass index (BMI) and current BMI. No other correlations between percentage of basal insulin requirements and any other factors were seen. CONCLUSION: Our data suggest that, even though some endogenous insulin production remains during the first year after diagnosis of T1DM, the distribution of basal versus total daily insulin requirements remains the same as in the general population of people with diabetes. There may be benefits to starting patients on a higher basal rate at time of diagnosis for overall glycemic control during the first six months. Further research is needed to optimize starting insulin doses to maximize their potential in preserving beta-cell function.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/análogos & derivados , Adolescente , Adulto , Área Sob a Curva , Glicemia/análise , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Feminino , Hemoglobinas Glicadas/análise , Humanos , Lactente , Infusões Subcutâneas , Insulina/administração & dosagem , Insulina de Ação Prolongada , Masculino , Adulto JovemRESUMO
Steady progress is being made toward the development of a so-called "artificial pancreas," which may ultimately be a fully automated, closed-loop, glucose control system comprising a continuous glucose monitor, an insulin pump, and a controller. The controller will use individualized algorithms to direct delivery of insulin without user input. A major factor propelling artificial pancreas development is the substantial incidence of-and attendant patient, parental, and physician concerns about-hypoglycemia and extreme hyperglycemia associated with current means of insulin delivery for type 1 diabetes mellitus (T1DM). A successful fully automated artificial pancreas would likely reduce the frequency of and anxiety about hypoglycemia and marked hyperglycemia. Patch-pump systems ("patch pumps") are likely to be used increasingly in the control of T1DM and may be incorporated into the artificial pancreas systems of tomorrow. Patch pumps are free of tubing, small, lightweight, and unobtrusive. This article describes features of patch pumps that have been approved for U.S. marketing or are under development. Included in the review is an introduction to control algorithms driving insulin delivery, particularly the two major types: proportional integrative derivative and model predictive control. The use of advanced algorithms in the clinical development of closed-loop systems is reviewed along with projected next steps in artificial pancreas development.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Sistemas de Infusão de Insulina/tendências , Algoritmos , Órgãos Artificiais , Desenho de Equipamento/normas , Previsões , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Marketing/métodos , Miniaturização/métodos , Modelos Teóricos , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: McCune-Albright syndrome (MAS) typically comprises the constellation of polyostotic fibrous dysplasia, café-au-lait spots, and associated endocrinopathies including gonadotropin-independent precocious puberty, excessive growth hormone production and gigantism, hyperthyroidism, and hyperparathyroidism. OBJECTIVE: We report the unique case of a boy with the diagnostic criteria of MAS accompanied by atypical short stature and macroorchidism without precocious puberty. PATIENT: An 8.4-year-old prepubertal boy presented with a history of recurrent bone fractures, multiple café-au-lait spots, bilateral macroorchidism, and short stature. X-ray of the extremities was consistent with polyostotic fibrous dysplasia. Serum inhibin B (IB) and anti-müllerian hormone (AMH) were elevated; testosterone, LH, and FSH were normal for age. RESULTS: PCR-based DNA analysis of bone tissue revealed a substitution of arginine for cysteine at position 201 in the G(s)alpha protein resulting in activation of the G(s)alpha subunit. CONCLUSIONS: We report a second case of MAS associated with macroorchidism. In this case, isolated Sertoli cell hyperfunction was also associated with microlithiasis and was not associated with peripheral precocious puberty. Short stature not associated with GH-IGF-1 axis abnormality was a second anomalous finding in this case. Our experience suggests that the phenotypic variation in MAS is wider than previously described.
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Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Sequência de Bases , Criança , Difosfonatos/uso terapêutico , Displasia Fibrosa Poliostótica/diagnóstico , Displasia Fibrosa Poliostótica/tratamento farmacológico , Fraturas Ósseas/complicações , Fraturas Ósseas/genética , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Litíase/genética , Masculino , Dados de Sequência Molecular , Pamidronato , Fenótipo , Células de Sertoli/patologia , Testículo/anormalidades , Resultado do TratamentoAssuntos
Deleção Cromossômica , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Aberrações dos Cromossomos Sexuais , Pré-Escolar , Análise Citogenética , DNA/genética , DNA/isolamento & purificação , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Mães , Hibridização de Ácido Nucleico/métodos , Linhagem , IrmãosRESUMO
CONTEXT: Although GH has been used to treat short stature in GH deficiency (GHD) and other conditions for more than 40 yr, criteria for satisfactorily defining targets for GH responsiveness have never been developed. OBJECTIVE: The objective of this study was to present the first-year growth expressed as height velocity (HV) for prepubertal boys and girls with idiopathic GHD, organic GHD, idiopathic short stature, or Turner syndrome from Genentech's National Cooperative Growth Study to derive age-specific targets for GH responsiveness for each etiology and gender. DESIGN AND POPULATION: Using data from the National Cooperative Growth Study, we constructed curves of response to GH during the first year of treatment with standard daily doses in naive-to-treatment prepubertal children with idiopathic GHD (2323 males, 842 females), organic GHD (582 males, 387 females), idiopathic short stature (1392 males, 465 females), or Turner syndrome (1367 females). MAIN OUTCOME MEASURE: For each category, mean pretreatment and mean +/-1 and +/-2 sd for the first-year HV on GH were assessed. Mean and mean +/- 1 sd for HV were plotted vs. age at baseline (initiation of GH treatment) and compared with mean pretreatment HV. RESULTS: HV plots for each category as a factor of age at baseline are presented. Mean - 2 sd HV plots approximated the pretreatment HV. CONCLUSION: Using baseline age- and gender-specific targets will assist clinicians in assessing a patient's first-year growth response. We propose that HV below the mean - 1 sd on these plots be considered a "poor" response. These curves may be used to identify patients who may benefit from GH dose adjustment, to assess compliance issues, or to challenge the original diagnosis.
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Estatura/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Relação Dose-Resposta a Droga , Feminino , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Proteínas Recombinantes/uso terapêutico , Valores de ReferênciaRESUMO
UNLABELLED: Alström syndrome (AS) is an autosomal recessive disorder characterized by progressive pigmentary retinopathy, sensorineural hearing loss, fatty liver infiltration, obesity, insulin resistance and early-onset type 2 diabetes mellitus (DM2). Early onset of insulin resistance and DM2 are key components of this syndrome. AIM: To study the effect of early initiation of the insulin sensitizer metformin combined with rosiglitazone in a patient with AS with impaired glucose tolerance. PATIENT: An 8 year-old boy with AS presented with acanthosis nigricans and insulin resistance at the age of 6 years. He had progressive excessive weight gain from 9 months of age. By the age of 1 year he developed photosensitivity, blindness and nystagmus. At the age of 5.5 years, his body mass index (BMI) was above the 95th percentile. He developed impaired glucose tolerance at 6 years of age and treatment with metformin was initiated. After 8 months of treatment with metformin he developed DM2. The dose of metformin was increased, and rosiglitazone added. METHODS: A 2-hour oral glucose tolerance test (OGTT) and a rapid intravenous glucose tolerance test (IVGTT) were performed before treatment was initiated, after treatment with metformin and at the end of 1 year of combination therapy with metformin and rosiglitazone to calculate quantitative insulin sensitivity check index (QUICKI) and acute insulin response (AIR). For mutation analysis, all exons and splice site sequences of the ALMS1 gene were amplified and sequenced. RESULTS: Metformin treatment alone at the stage of impaired glucose tolerance did not prevent progression to DM2. However, metformin at a higher dose and in combination with rosiglitazone resulted in improvement of pancreatic beta-cell function, shown by markedly improved first-phase insulin response to glucose measured by AIR. The patient was found to have two heterozygous nonsense mutations in ALMS1, 8008 C-->T Ter, R2670X, and 11449 C-->T Ter, Q3817X. These alterations cause premature stops and result in a truncated ALMS1 protein. CONCLUSION: We suggest that early initiation of combined therapy comprising a high dose of metformin plus rosiglitazone may be valuable in managing insulin resistance and DM2 in children with AS.
Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Tiazolidinedionas/uso terapêutico , Anormalidades Múltiplas/genética , Criança , Quimioterapia Combinada , Fígado Gorduroso , Humanos , Hipoglicemiantes/administração & dosagem , Resistência à Insulina , Masculino , Metformina/administração & dosagem , Obesidade , Rosiglitazona , Síndrome , Tiazolidinedionas/administração & dosagemRESUMO
OBJECTIVE: Recent studies have shown a broad prevalence of vitamin D deficiency in adults. Serum 25-hydroxyvitamin D (25-OHD) levels were reported to be inversely related to body mass index (BMI) and body fat content and correlated directly with hypertension, degree of insulin resistance and progression to diabetes mellitus. We sought to determine the prevalence of vitamin D insufficiency and markers of metabolic syndrome in an obese pediatric population. METHODS: Charts of 217 obese (weight >95th percentile for age and sex) children (118 females, 99 males; mean BMI 32.2 +/- 6.4 kg/m2; mean age 12.9 2 5.5; age range 7-18 years) who had received a standard physical examination at the pediatric endocrine clinic of the Infants and Children's Hospital of Brooklyn at Maimonides, Brooklyn, NY, were retrospectively analyzed. Data obtained included age, sex, weight, BMI, height and systolic and diastolic blood pressure. The routine bloodwork panel for obesity at our pediatric endocrine facility includes fasting 25-OHD, total cholesterol, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides, ALT, AST, thyroid stimulating hormone (TSH), total T4, and insulin and glucose. Insulin sensitivity as calculated by quantitative insulin-sensitivity check index (QUICKI = 1/[log(I0) + log(G0)], where I0 is fasting insulin and G0 is fasting glucose) was computed following the visit. RESULTS: Overall, 55.2% of patients were vitamin D insufficient (25-OHD <20 ng/ml). Severely low vitamin D levels (25-OHD < or =10 ng/ml) were seen in 21.6% of 217 patients, which represents almost half of the insufficient group. In the 25-OHD <20 ng/ml group age, BMI, and SBP were significantly higher than in the 25-OHD 220 ng/ml group, while QUICKI (<0.35 is consistent with insulin resistance) was borderline low in the <20 ng/ml group. HDL-C was significantly lower in the 25-OHD < or =10 ng/ml group. The 25-OHD levels correlated negatively with BMI and positively with HDL-C. No other findings were significant. CONCLUSION: More than half of the obese children had vitamin D levels <20 ng/ml with equal gender distribution. Vitamin D insufficiency was associated with increased age, BMI, and SBP, and decreased HDL-C.