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PURPOSE OF REVIEW: In this article, we consider advanced technologies for the management of diabetes. RECENT FINDINGS: Specifically, we pose the question of which should come first: an insulin pump (CSII) or a continuous glucose monitor (CGM)? Historical perspective on both insulin delivery and glucose measurement is provided. Recently published clinical trials are reviewed. Practical issues including quality of life, patient education, and out-of-pocket cost are discussed. Based on available evidence and clinical experience, we favor CGM as a first-line technology recommendation for the treatment of type 1 diabetes (T1D).
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Automonitorização da Glicemia , Glicemia , Diabetes Mellitus Tipo 1 , Humanos , Hipoglicemiantes , Insulina , Sistemas de Infusão de Insulina , Qualidade de VidaRESUMO
Background: To evaluate the long-term safety and effectiveness of the Omnipod® 5 Automated Insulin Delivery (AID) System in very young children with type 1 diabetes with up to 2 years of use. Methods: Following a 13-week single-arm, multicenter, pivotal trial that took place after 14 days of standard therapy data collection, participating children (2-5.9 years of age at study enrollment) were provided the option to continue use of the AID system in an extension phase. HbA1c was measured every 3 months, up to 15 months of total use, and continuous glucose monitor metrics were collected through the completion of the extension study (for up to 2 years). Results: Participants (N = 80) completed 18.2 [17.4, 23.4] (median [interquartile range]) total months of AID, inclusive of the 3-month pivotal trial. During the pivotal trial, HbA1c decreased from 7.4% ± 1.0% (57 ± 10.9 mmol/mol) to 6.9% ± 0.7% (52 ± 7.7 mmol/mol, P < 0.0001) and was maintained at 7.0% ± 0.7% (53 ± 7.7 mmol/mol) after 15 months total use (P < 0.0001 from baseline). Time in target range (70-180 mg/dL) increased from 57.2% ± 15.3% during standard therapy to 68.1% ± 9.0% during the pivotal trial (P < 0.0001) and was maintained at 67.2% ± 9.3% during the extension phase (P < 0.0001 from standard therapy). Participants spent a median 97.1% of time in Automated Mode during the extension phase, with one episode of severe hypoglycemia and one episode of diabetic ketoacidosis. Conclusion: This evaluation of the Omnipod 5 AID System indicates that long-term use can safely maintain improvements in glycemic outcomes with up to 2 years of use in very young children with type 1 diabetes. Clinical Trials Registration Number: NCT04476472.
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Glicemia , Diabetes Mellitus Tipo 1 , Hemoglobinas Glicadas , Hipoglicemiantes , Sistemas de Infusão de Insulina , Insulina , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/sangue , Pré-Escolar , Insulina/administração & dosagem , Insulina/uso terapêutico , Feminino , Masculino , Glicemia/análise , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Hemoglobinas Glicadas/análise , Hipoglicemia/prevenção & controle , Resultado do Tratamento , Controle Glicêmico/métodos , Automonitorização da GlicemiaRESUMO
Background: The Omnipod® 5 Automated Insulin Delivery (AID) System was shown to be safe and effective following 3 months of use in people with type 1 diabetes (T1D); however, data on the durability of these results are limited. This study evaluated the long-term safety and effectiveness of Omnipod 5 use in people with T1D during up to 2 years of use. Materials and Methods: After a 3-month single-arm, multicenter, pivotal trial in children (6-13.9 years) and adolescents/adults (14-70 years), participants could continue system use in an extension phase. HbA1c was measured every 3 months for up to 15 months; continuous glucose monitor metrics were collected for up to 2 years. Results: Participants (N = 224) completed median (interquartile range) 22.3 (21.7, 22.7) months of AID. HbA1c was reduced in the pivotal trial from 7.7% ± 0.9% in children and 7.2% ± 0.9% in adolescents/adults to 7.0% ± 0.6% and 6.8% ± 0.7%, respectively, (P < 0.0001), and was maintained at 7.2% ± 0.7% and 6.9% ± 0.6% after 15 months (P < 0.0001 from baseline). Time in target range (70-180 mg/dL) increased from 52.4% ± 15.6% in children and 63.6% ± 16.5% in adolescents/adults at baseline to 67.9% ± 8.0% and 73.8% ± 10.8%, respectively, during the pivotal trial (P < 0.0001) and was maintained at 65.9% ± 8.9% and 72.9% ± 11.3% during the extension (P < 0.0001 from baseline). One episode of diabetic ketoacidosis and seven episodes of severe hypoglycemia occurred during the extension. Children and adolescents/adults spent median 96.1% and 96.3% of time in Automated Mode, respectively. Conclusion: Our study supports that long-term use of the Omnipod 5 AID System can safely maintain improvements in glycemic outcomes for up to 2 years of use in people with T1D. Clinical Trials Registration Number: NCT04196140.
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Diabetes Mellitus Tipo 1 , Adulto , Criança , Humanos , Adolescente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Hemoglobinas Glicadas , Sistemas de Infusão de Insulina , Glicemia , Automonitorização da GlicemiaRESUMO
Background: Connected insulin pens capture data on insulin dosing/timing and can integrate with continuous glucose monitoring (CGM) devices with essential insulin and glucose metrics combined into a single platform. Standardization of connected insulin pen reports is desirable to enhance clinical utility with a single report. Methods: An international expert panel was convened to develop a standardized connected insulin pen report incorporating insulin and glucose metrics into a single report containing clinically useful information. An extensive literature review and identification of examples of current connected insulin pen reports were performed serving as the basis for creation of a draft of a standardized connected insulin pen report. The expert panel participated in three virtual standardization meetings and online surveys. Results: The Ambulatory Glucose Profile (AGP) Report: Connected Insulin Pen brings all clinically relevant CGM-derived glucose and connected insulin pen metrics into a single simplified two-page report. The first page contains the time in ranges bar, summary of key insulin and glucose metrics, the AGP curve, and detailed basal (long-acting) insulin assessment. The second page contains the bolus (mealtime and correction) insulin assessment periods with information on meal timing, insulin-to-carbohydrate ratio, average bolus insulin dose, and number of days with bolus doses recorded. The report's second page contains daily glucose profiles with an overlay of the timing and amount of basal and bolus insulin administered. Conclusion: The AGP Report: Connected Insulin Pen is a standardized clinically useful report that should be considered by companies developing connected pen technology as part of their system reporting/output.
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Objective: To evaluate safety and effectiveness of MiniMed™ 670G hybrid closed loop (HCL) in comparison with continuous subcutaneous insulin infusion (CSII) therapy for 6 months in persons with type 1 diabetes (T1D). Methods: Adults (aged 18-80 years), adolescents, and children (aged 2-17 years) with T1D who were using CSII therapy were enrolled and randomized (1:1) to 6 months of HCL intervention (n = 151, mean age of 39.9 ± 19.8 years) or CSII without continuous glucose monitoring (n = 151, 35.7 ± 18.4 years). Primary effectiveness endpoints included change in A1C for Group 1 (baseline A1C >8.0%), from baseline to the end of study, and difference in the end of study percentage of time spent below 70 mg/dL (%TBR <70 mg/dL) for Group 2 (baseline A1C ≤8.0%), to show superiority of HCL intervention versus control. Secondary effectiveness endpoints were change in A1C and %TBR <70 mg/dL for Group 2 and Group 1, respectively, to show noninferiority of HCL intervention versus control. Primary safety endpoints were rates of severe hypoglycemia and diabetic ketoacidosis (DKA). Results: Change in A1C and difference in %TBR <70 mg/dL for the overall group were significantly improved, in favor of HCL intervention. In addition, a significant mean (95% confidence interval) change in A1C was observed for both Group 1 (-0.8% [-1.1% to -0.4%], P < 0.0001) and Group 2 (-0.3% [-0.5% to -0.1%], P < 0.0001), in favor of HCL intervention. The same was observed for difference in %TBR <70 mg/dL for Group 1 (-2.2% [-3.6% to -0.9%]) and Group 2 (-4.9% [-6.3% to -3.6%]) (P < 0.0001 for both). There was one DKA event during run-in and six severe hypoglycemic events: two during run-in and four during study (HCL: n = 0 and CSII: n = 4 [6.08 per 100 patient-years]). Conclusions: This RCT demonstrates that the MiniMed 670G HCL safely and significantly improved A1C and %TBR <70 mg/dL compared with CSII control in persons with T1D, irrespective of baseline A1C level.
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Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Adolescente , Adulto , Criança , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/tratamento farmacológico , Hemoglobinas Glicadas , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Sistemas de Infusão de Insulina , Pré-Escolar , Idoso , Idoso de 80 Anos ou maisRESUMO
The significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers, and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past 6 years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage.
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Diabetes Mellitus Tipo 1 , Insulina , Humanos , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Consenso , Glicemia , Automonitorização da GlicemiaRESUMO
OBJECTIVE: Very young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population. RESEARCH DESIGN AND METHODS: A total of 80 children aged 2.0-5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy. RESULTS: There were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70-180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204). CONCLUSIONS: Use of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline.
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Diabetes Mellitus Tipo 1 , Hipoglicemia , Glicemia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Sistemas de Infusão de Insulina , Insulina Regular Humana/uso terapêuticoRESUMO
Use of telemedicine and remote monitoring technologies can significantly improve glycemic control in patients with type 1 diabetes and type 2 diabetes. Patients' ability to interact remotely with their health care providers via smartphones and other communication devices can increase their access to clinical care and online coaching and support programs. The establishment of metrics for clinical use of continuous glucose monitoring data and standardization of data reporting has enabled clinicians to maintain high-quality diabetes care through remote monitoring and telemedicine visits during the COVID-19 pandemic. This article discusses our experiences using remote monitoring and telemedicine visits during this time.
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Automonitorização da Glicemia , Diabetes Mellitus Tipo 2 , Telemedicina , Glicemia , COVID-19 , Diabetes Mellitus Tipo 2/terapia , Humanos , PandemiasRESUMO
OBJECTIVE: Advances in diabetes technology have transformed the treatment paradigm for type 1 diabetes, yet the burden of disease is significant. We report on a pivotal safety study of the first tubeless, on-body automated insulin delivery system with customizable glycemic targets. RESEARCH DESIGN AND METHODS: This single-arm, multicenter, prospective study enrolled 112 children (age 6-13.9 years) and 129 adults (age 14-70 years). A 2-week standard therapy phase (usual insulin regimen) was followed by 3 months of automated insulin delivery. Primary safety outcomes were incidence of severe hypoglycemia and diabetic ketoacidosis. Primary effectiveness outcomes were change in HbA1c and percent time in sensor glucose range 70-180 mg/dL ("time in range"). RESULTS: A total of 235 participants (98% of enrolled, including 111 children and 124 adults) completed the study. HbA1c was significantly reduced in children by 0.71% (7.8 mmol/mol) (mean ± SD: 7.67 ± 0.95% to 6.99 ± 0.63% [60 ± 10.4 mmol/mol to 53 ± 6.9 mmol/mol], P < 0.0001) and in adults by 0.38% (4.2 mmol/mol) (7.16 ± 0.86% to 6.78 ± 0.68% [55 ± 9.4 mmol/mol to 51 ± 7.4 mmol/mol], P < 0.0001). Time in range was improved from standard therapy by 15.6 ± 11.5% or 3.7 h/day in children and 9.3 ± 11.8% or 2.2 h/day in adults (both P < 0.0001). This was accomplished with a reduction in time in hypoglycemia <70 mg/dL among adults (median [interquartile range]: 2.00% [0.63, 4.06] to 1.09% [0.46, 1.75], P < 0.0001), while this parameter remained the same in children. There were three severe hypoglycemia events not attributable to automated insulin delivery malfunction and one diabetic ketoacidosis event from an infusion site failure. CONCLUSIONS: This tubeless automated insulin delivery system was safe and allowed participants to significantly improve HbA1c levels and time in target glucose range with a very low occurrence of hypoglycemia.
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Diabetes Mellitus Tipo 1 , Insulina , Adolescente , Adulto , Idoso , Glicemia , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes , Sistemas de Infusão de Insulina , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Background: The objective of this study was to assess the safety and effectiveness of the first commercial configuration of a tubeless automated insulin delivery system, Omnipod® 5, in children (6-13.9 years) and adults (14-70 years) with type 1 diabetes (T1D) in an outpatient setting. Materials and Methods: This was a single-arm, multicenter, prospective clinical study. Data were collected over a 14-day standard therapy (ST) phase followed by a 14-day hybrid closed-loop (HCL) phase, where participants (n = 36) spent 72 h at each of three prespecified glucose targets (130, 140, and 150 mg/dL, 9 days total) then 5 days with free choice of glucose targets (110-150 mg/dL) using the Omnipod 5. Remote safety monitoring alerts were enabled during the HCL phase. Primary endpoints were difference in time in range (TIR) (70-180 mg/dL) between ST and HCL phases and proportion of participants reporting serious device-related adverse events. Results: Mean TIR was significantly higher among children in the free-choice period overall (64.9% ± 12.2%, P < 0.01) and when using a 110 mg/dL target (71.2% ± 10.2%, P < 0.01), a 130 mg/dL target (61.5% ± 7.7%, P < 0.01), and a 140 mg/dL target (64.8% ± 11.6%, P < 0.01), and among adults using a 130 mg/dL target (75.1% ± 11.6%, P < 0.05), compared to the ST phase (children: 51.0% ± 13.3% and adults: 65.6% ± 15.7%). There were no serious device-related adverse events reported during the HCL phase, nor were there episodes of severe hypoglycemia or diabetic ketoacidosis. Conclusion: The Omnipod 5 System was safe and effective when used at glucose targets from 110 to 150 mg/dL for 14 days at home in children and adults with T1D.
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Diabetes Mellitus Tipo 1 , Adulto , Glicemia , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Sistemas de Infusão de Insulina , Pacientes Ambulatoriais , Estudos ProspectivosRESUMO
Continuous glucose monitoring (CGM) use is growing rapidly among people with diabetes and beginning to be standard of care for managing glucose levels in insulin therapy. With this increased use, there is a need to standardize CGM data. CGM standardization has been set forth by expert panels. The Glucose Management Indicator is a concept using the CGM-derived mean glucose to provide a value that can be understood similarly to hemoglobin A1c. The times an individual spends in various glucose ranges is emerging as an important set of metrics. Metrics derived from patient CGM data are changing the way diabetes is managed.
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Diabetes Mellitus/sangue , Hemoglobinas Glicadas/fisiologia , Controle Glicêmico , Padrões de Prática Médica/normas , Biomarcadores/análise , Biomarcadores/sangue , Glicemia/análise , Glicemia/metabolismo , Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/normas , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/terapia , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Controle Glicêmico/instrumentação , Controle Glicêmico/métodos , Controle Glicêmico/normas , Indicadores Básicos de Saúde , Humanos , Insulina/administração & dosagem , Sistemas de Infusão de Insulina/normas , Padrões de Referência , Fatores de TempoRESUMO
Use of continuous glucose monitoring (CGM) is recognized as a valuable component of diabetes self-management and is increasingly considered a standard of care for individuals with diabetes who are treated with intensive insulin therapy. As the clinical use of CGM technology expands, consistent and standardized glycemic metrics and glucose profile visualization have become increasingly important. A common set of CGM metrics has been proposed by an international expert panel in 2017, including standard definitions of time in ranges, glucose variability, and adequacy of data collection. We describe the core CGM metrics, as well as the standardized glucose profile format consolidating 2 weeks of CGM measurements, referred to as the ambulatory glucose profile (AGP), which was also recommended by the CGM expert panel. We present an updated AGP report featuring the core CGM metrics and a visualization of glucose patterns that need clinical attention. New tools for use by clinicians and patients to interpret AGP data are reviewed. Strategies based on the authors' experience in implementing CGM technology across the clinical care spectrum are highlighted.
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Automonitorização da Glicemia/normas , Glicemia/análise , Diabetes Mellitus/sangue , Monitorização Ambulatorial/normas , Humanos , Guias de Prática Clínica como Assunto , Padrões de Referência , SoftwareAssuntos
Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Diabetes Mellitus/terapia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Telemedicina/tendências , Automonitorização da Glicemia , COVID-19 , Educação Médica Continuada , Humanos , Insulina/administração & dosagem , Educação de Pacientes como Assunto/métodos , SARS-CoV-2 , AutoadministraçãoRESUMO
The aim of the present study was to use (13)C nuclear magnetic resonance (NMR) to measure the cerebral oxidative metabolic rate of glucose (CMRglc[ox]) in patients with diabetes and to compare these measurements with those collected from matched controls. We elected to study a group with type 1 diabetes mellitus and hypoglycemia unawareness because we had previously found such patients to have higher brain glucose concentrations than healthy volunteers under steady-state conditions. We sought to determine if this difference in steady-state brain concentrations could be explained by a difference in CMRglc(ox). Time courses of (13)C label incorporation in brain amino acids were measured in occipital cortex during infusion of [1-(13)C]glucose. These time courses were fitted using a 1-compartment metabolic model to determine CMRglc(ox). Our results show that the tricarboxylic acid cycle (TCA) cycle rate (V(TCA), which is twice CMRglc[ox]) in subjects with type 1 diabetes mellitus was not significantly different from that of healthy controls (0.84 +/- 0.03 vs 0.79 +/- 0.03 micromol/[g min], n = 5 in each group, mean +/- SEM). We conclude that the changes in steady-state brain glucose concentrations that we observed in patients with type 1 diabetes mellitus in a previous study (J Neurosci Res. 2005;79:42-47) cannot be explained by changes in oxidative glucose consumption.
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Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glucose/metabolismo , Hipoglicemia/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Adulto , Conscientização , Isótopos de Carbono , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Modelos TeóricosRESUMO
The adult brain relies on glucose for its energy needs and stores it in the form of glycogen, primarily in astrocytes. Animal and culture studies indicate that brain glycogen may support neuronal function when the glucose supply from the blood is inadequate and/or during neuronal activation. However, the concentration of glycogen and rates of its metabolism in the human brain are unknown. We used in vivo localized 13C-NMR spectroscopy to measure glycogen content and turnover in the human brain. Nine healthy volunteers received intravenous infusions of [1-(13)C]glucose for durations ranging from 6 to 50 h, and brain glycogen labeling and washout were measured in the occipital lobe for up to 84 h. The labeling kinetics suggest that turnover is the main mechanism of label incorporation into brain glycogen. Upon fitting a model of glycogen metabolism to the time courses of newly synthesized glycogen, human brain glycogen content was estimated at approximately 3.5 micromol/g, i.e., three- to fourfold higher than free glucose at euglycemia. Turnover of bulk brain glycogen occurred at a rate of 0.16 micromol.g-1.h-1, implying that complete turnover requires 3-5 days. Twenty minutes of visual stimulation (n=5) did not result in detectable glycogen utilization in the visual cortex, as judged from similar [13C]glycogen levels before and after stimulation. We conclude that the brain stores a substantial amount of glycogen relative to free glucose and metabolizes this store very slowly under normal physiology.
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Química Encefálica , Metabolismo Energético , Glicogênio/metabolismo , Glicogênio/fisiologia , Adulto , Encéfalo/metabolismo , Feminino , Glucose/administração & dosagem , Glucose/farmacocinética , Glicogênio/análise , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Estimulação LuminosaRESUMO
Although it is well established that recurrent hypoglycemia leads to hypoglycemia unawareness, the mechanisms responsible for this are unknown. One hypothesis is that recurrent hypoglycemia alters brain glucose transport or metabolism. We measured steady-state brain glucose concentrations during a glucose clamp to determine whether subjects with type 1 diabetes and hypoglycemia unawareness may have altered cerebral glucose transport or metabolism after exposure to recurrent hypoglycemia. We compared 14 subjects with diabetes and hypoglycemia unawareness to 27 healthy control subjects. Brain glucose concentrations were measured under similar metabolic conditions using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 4 Tesla during a hyperglycemic clamp (plasma glucose = 16.7 mmol/l) with somatostatin and insulin. Subjects with type 1 diabetes and hypoglycemia unawareness had significantly higher brain glucose concentrations compared to that in controls under the same conditions (5.5 +/- 0.3 vs. 4.7 +/- 0.1 micromol/g wet weight, P = 0.016). These data suggest that changes in brain glucose transport or metabolism may occur as a result of recurrent hypoglycemia.
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Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glucose/metabolismo , Hipoglicemia/metabolismo , Adulto , Idoso , Glicemia/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Diabetes Mellitus Tipo 1/complicações , Epinefrina/metabolismo , Feminino , Glucagon/metabolismo , Técnica Clamp de Glucose/métodos , Humanos , Hipoglicemia/etiologia , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Norepinefrina/metabolismo , Radioimunoensaio/métodos , Recidiva , Trítio/metabolismoRESUMO
Mechanisms responsible for hypoglycemia unawareness remain unknown. Previously, we found that patients with type 1 diabetes and hypoglycemia unawareness had increased brain glucose concentrations as measured by (1)H-magnetic resonance spectroscopy (MRS) compared with controls measured under the same metabolic condition, suggesting that an alteration in brain glucose transport and/or metabolism may play a role in the pathogenesis of hypoglycemia unawareness. To determine whether the brain glucose concentration is altered in normal subjects subjected to recurrent hypoglycemia, we compared the brain glucose concentrations measured in healthy subjects after three episodes of hypoglycemia to blunt the counterregulatory response over 24 hr and compared this value with that measured at a time remote from the antecedent hypoglycemia protocol. Sixteen subjects (9 M/7 F, age 36 +/- 10 years, mean +/- SD) underwent three hypoglycemic clamps for 30 min at 8 AM (0 hr), 5 PM (9 hr), and 7 AM (24 hr). After the third hypoglycemic clamp, subjects underwent a hyperglycemic clamp during which brain glucose concentration was measured by MRS at 4 T. Brain glucose concentration after repeated hypoglycemia was not different from the brain glucose concentration measured in the same subjects during a control study (5.1 +/- 0.8 vs. 4.5 +/- 0.5 mumol/g wet weight, respectively, P = 0.05). These observations suggest that brain glucose transport or metabolism is not altered following short episodes of recurrent hypoglycemia in healthy human volunteers.