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COVID-2019 Alert

The latest information about the 2019 Novel Coronavirus, including vaccine clinics for children ages 5 years old and older.

La información más reciente sobre el nuevo Coronavirus de 2019, incluidas las clínicas de vacunación para niños de 5 años en adelante.

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Rayhan Lal, MD

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Specialties

Endocrinology, Diabetes & Metabolism

Work and Education

Professional Education

University of California Davis School of Medicine, Sacramento, CA, 05/31/2011

Residency

LAC+USC Internal Medicine and Pediatric Residency, Los Angeles, CA, 06/30/2015

Fellowship

Stanford University Endocrinology Fellowship, Stanford, CA, 06/30/2019

Stanford University Pediatric Endocrinology Fellowship, Stanford, CA, 06/30/2019

Board Certifications

Endocrinology, Diabetes & Metabolism, American Board of Internal Medicine

Internal Medicine, American Board of Internal Medicine

Pediatric Endocrinology, American Board of Pediatrics

Pediatrics, American Board of Pediatrics

Services

Endocrinology

All Publications

Current Status and Emerging Options for Automated Insulin Delivery Systems. Diabetes technology & therapeutics Forlenza, G. P., Lal, R. A. 1800

Abstract

Combining technologies including rapid insulin analogs, insulin pumps, continuous glucose monitors (CGMs), and control algorithms has allowed for the creation of automated insulin delivery (AID) systems. These systems have proven to be the most effective technology for optimizing metabolic control and could hold the key to broadly achieving goal-level glycemic control for people with type 1 diabetes (T1D). The use of AID has exploded in the past several years with several options available in the United States and even more in Europe. In this article, we review the largest studies involving these AID systems, and then examine future directions for AID with an emphasis on usability.

View details for DOI 10.1089/dia.2021.0514

View details for PubMedID 35099302

Qualitative Study of User Experiences with Loop, an Open-Source Automated Insulin Delivery (AID) System. Diabetes technology & therapeutics Suttiratana, S., Wong, J., Lanning, M. S., Dunlap, A. R., Hanes, S., Hood, K., Lal, R. A., Naranjo, D. 1800

Abstract

BACKGROUND: Loop is an open-source automated insulin delivery (AID) system, used by more than 9,000 people with Type 1 diabetes. Understanding the pros and cons of Loop use may help improve disease management and support population level innovation.METHODS: Focus groups revealed 72 new and existing users' perspectives on Loop uptake, use and persistence. A subsample of participants from a mixed methods observational cohort study shared first-hand accounts of their experiences using Loop. Participants were predominately white (95%), male (50%), privately insured (94%), reported annual household income $100K (73%) and education exceeding a bachelor's degree (87%) with a mean HbA1c of 6.60.8%. Data were analyzed and synthesized by a multidisciplinary team.RESULTS: Participants detailed their experiences with a) Loop technical support and troubleshooting, b) decreased mental/behavioral burden, c) technical issues with parts of the system, d) glycemic control, e) personalizing settings, and f) providers while using Loop. Decreased burden was the most endorsed benefit defined by less worry, stress, and cognitive effort and less time spent on diabetes management tasks. Participants highlighted the benefits of Loop overnight and their introduction to "Loop communities" during use. The most discussed challenges involved technical issues. A range of provider attitudes and knowledge about Loop complicated users' clinical experiences and disclosure.CONCLUSIONS: This sample of new and experienced Loop users reported benefits to quality of life and glycemic control that outweighed challenges of setting up system components, customizing the system to suit one's lifestyle and habits, and adjusting system settings. Challenges related to system set up and calibrating settings are remediable and, if addressed, may better serve Loop users. Users reported feeling empowered by the customizability of and the educational effects facilitated by the open source AID system. Loop helped users learn more about their chronic illness and physiology in an acceptable format.

View details for DOI 10.1089/dia.2021.0485

View details for PubMedID 35099278

Novel Pathogenic de novo INS p.T97P Variant Presenting with Severe Neonatal DKA. Endocrinology Lal, R. A., Moeller, H. P., Thomson, E. A., Horton, T. M., Lee, S., Freeman, R., Prahalad, P., Poon, A. S., Annes, J. P. 2021

Abstract

Pathogenic INS gene mutations are causative for Mutant INS-gene-induced Diabetes of Youth (MIDY). We characterize a novel de novo heterozygous INS gene mutation (c.289A>C, p.T97P) that presented in an autoantibody-negative 5-month-old male infant with severe diabetic ketoacidosis. In silico pathogenicity prediction tools provided contradictory interpretations, while structural modeling indicated a deleterious effect on proinsulin folding. Transfection of wildtype and INS p.T97P expression and luciferase reporter constructs demonstrated elevated intracellular mutant proinsulin levels and dramatically impaired proinsulin/insulin and luciferase secretion. Notably, proteasome inhibition partially and selectively rescued INS p.T97P-derived luciferase secretion. Additionally, expression of INS p.T97P caused increased intracellular proinsulin aggregate formation and XBP-1s protein levels, consistent with induction of endoplasmic reticulum stress. We conclude that INS p.T97P is a newly identified pathogenic A-chain variant that is causative for MIDY via disruption of proinsulin folding and processing with induction of the endoplasmic reticulum stress response.

View details for DOI 10.1210/endocr/bqab246

View details for PubMedID 34888628

Open-source automated insulin delivery: international consensus statement and practical guidance for health-care professionals. The lancet. Diabetes & endocrinology Braune, K., Lal, R. A., Petruzelkova, L., Scheiner, G., Winterdijk, P., Schmidt, S., Raimond, L., Hood, K. K., Riddell, M. C., Skinner, T. C., Raile, K., Hussain, S., OPEN International Healthcare Professional Network and OPEN Legal Advisory Group 2021

Abstract

Open-source automated insulin delivery systems, commonly referred to as do-it-yourself automated insulin delivery systems, are examples of user-driven innovation that was co-created and supported by an online community who were directly affected by diabetes. Their uptake continues to increase globally, with current estimates suggesting several thousand active users worldwide. Real-world user-driven evidence is growing and provides insights into safety and effectiveness of these systems. The aim of this consensus statement is two-fold. Firstly, it provides a review of the current evidence, description of the technologies, and discusses the ethics and legal considerations for these systems from an international perspective. Secondly, it provides a much-needed international health-care consensus supporting the implementation of open-source systems in clinical settings, with detailed clinical guidance. This consensus also provides important recommendations for key stakeholders that are involved in diabetes technologies, including developers, regulators, and industry, and provides medico-legal and ethical support for patient-driven, open-source innovations.

View details for DOI 10.1016/S2213-8587(21)00267-9

View details for PubMedID 34785000

Automated Insulin Dosing Systems: Advances After a Century of Insulin. Diabetic medicine : a journal of the British Diabetic Association Thabit, H., Lal, R., Leelarathna, L. 2021: e14695

Abstract

The daily complexities of insulin therapy and glucose variability in type 1 diabetes still pose significant challenges, despite advancements in modern insulin analogues. Minimising hypoglycaemia and optimising time spent within target glucose range are recommended to reduce the risk of diabetes-related complications and distress. Access to structured education and adjuvant diabetes technologies such as insulin pumps and glucose sensors, are recommended by National Institute for Health and Care Excellence (NICE) to enable people with type 1 diabetes achieve their glycaemic goals. One hundred years after the discovery of insulin, automated insulin dosing (AID, a.k.a. closed-loop or artificial pancreas) systems are a reality with a number of systems available and being used in usual clinical practice. Evidence from randomised clinical trials and real-world prospective studies support efficacy, effectiveness and safety of AID systems. Qualitative evaluations reveal treatment satisfaction and positive effects on quality-of-life. Current insulin-only AID systems still require carbohydrate and activity announcement (hybrid closed-loop) due to the inherent pharmacokinetic limitations of rapid-acting insulin analogies. Ultra-rapid acting insulin, and adjunctive use of other therapies (e.g. glucagon, pramlitide) are being evaluated to achieve full closed-loop. Open-source AID (OS-AID) systems have been developed by the diabetes community, driven by a desire for safety and to accelerate technological advancement. In addition to effectiveness and safety, real-world prospective studies suggest that OS-AID systems fulfill unmet needs of commercially approved systems. The development, ongoing challenges and expectations of AID are outlined in this review.

View details for DOI 10.1111/dme.14695

View details for PubMedID 34547133

Ultra-Fast Insulin-Pramlintide Co-Formulation for Improved Glucose Management in Diabetic Rats. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Maikawa, C. L., Chen, P. C., Vuong, E. T., Nguyen, L. T., Mann, J. L., d'Aquino, A. I., Lal, R. A., Maahs, D. M., Buckingham, B. A., Appel, E. A. 2021: e2101575

Abstract

Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co-formulation result in increased insulin-pramlintide overlap of 75 6% compared to only 47 7% for separate injections. The co-formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co-formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.

View details for DOI 10.1002/advs.202101575

View details for PubMedID 34499434

Democratizing type 1 diabetes specialty care in the primary care setting to reduce health disparities: project extension for community healthcare outcomes (ECHO) T1D. BMJ open diabetes research & care Walker, A. F., Cuttriss, N., Haller, M. J., Hood, K. K., Gurka, M. J., Filipp, S. L., Anez-Zabala, C., Yabut, K., Roque, X., Wong, J. J., Baer, L., Figg, L., Bernier, A., Westen, S., Lewit, E., Sheehan, E., Basina, M., Lal, R., Maizel, J., Maahs, D. M. 2021; 9 (1)

Abstract

INTRODUCTION: Project ECHO (Extension for Community Healthcare Outcomes) is a tele-education outreach model that seeks to democratize specialty knowledge to reduce disparities and improve health outcomes. Limited utilization of endocrinologists forces many primary care providers (PCPs) to care for patients with type 1 diabetes (T1D) without specialty support. Accordingly, an ECHO T1D program was developed and piloted in Florida and California. Our goal was to demonstrate the feasibility of an ECHO program focused on T1D and improve PCPs' abilities to manage patients with T1D.RESEARCH DESIGN AND METHODS: Health centers (ie, spokes) were recruited into the ECHO T1D pilot through an innovative approach, focusing on Federally Qualified Health Centers and through identification of high-need catchment areas using the Neighborhood Deprivation Index and provider geocoding. Participating spokes received weekly tele-education provided by the University of Florida and Stanford University hub specialty team through virtual ECHO clinics, real-time support with complex T1D medical decision-making, access to a diabetes support coach, and access to an online repository of diabetes care resources. Participating PCPs completed pre/post-tests assessing diabetes knowledge and confidence and an exit survey gleaning feedback about overall ECHO T1D program experiences.RESULTS: In Florida, 12 spoke sites enrolled with 67 clinics serving >1000 patients with T1D. In California, 11 spoke sites enrolled with 37 clinics serving >900 patients with T1D. During the 6-month intervention, 27 tele-education clinics were offered and n=70 PCPs (22 from Florida, 48 from California) from participating spoke sites completed pre/post-test surveys assessing diabetes care knowledge and confidence in diabetes care. There was statistically significant improvement in diabetes knowledge (p0.01) as well as in diabetes confidence (p0.01).CONCLUSIONS: The ECHO T1D pilot demonstrated proof of concept for a T1D-specific ECHO program and represents a viable model to reach medically underserved communities which do not use specialists.

View details for DOI 10.1136/bmjdrc-2021-002262

View details for PubMedID 34244218

Insulin Delivery Hardware: Pumps and Pens. Diabetes technology & therapeutics Lal, R. A., Leelarathna, L. 2021; 23 (S2): S32-S45

View details for DOI 10.1089/dia.2021.2503

View details for PubMedID 34061635

Longevity of the Novel ConvaTec Infusion Set with Lantern Technology. Diabetes, obesity & metabolism Lal, R. A., Hsu, L., Zhang, J., Schondorff, P. K., Heschel, M., Buckingham, B. 2021

Abstract

Current insulin infusion sets are approved for only 2-3days. The novel ConvaTec infusion set with Lantern Technology is designed to extend infusion set wear time. The goal of this pilot study was to evaluate duration of wear for this set. This was a pilot safety study in adults with type 1 diabetes using tethered insulin pumps. Participants inserted the set and wore it for 10days or until failure. Among 24 participants, 2 were excluded. 45% of the sets lasted 10days. Median wear time was 9.1 (7.1,10.0) days. Among 12 premature failures: 6 (50%) involved adhesive failures, 4 (33%) hyperglycemia unresponsive to correction, 1 (8%) hyperglycemia with ketones and 1 (8%) infection. Average CGM glucose per day of infusion set wear demonstrated a statistically significant increase over time, while total daily insulin over the same period did not change. In this pilot study the duration of wear for the novel infusion set exceeded previously reported commercial sets (p<0.001). This extended wear technology may eventually allow for a combined glucose sensor and infusion set. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/dom.14395

View details for PubMedID 33822472

Full closed loop open-source algorithm performance comparison in pigs with diabetes. Clinical and translational medicine Lal, R. A., Maikawa, C. L., Lewis, D., Baker, S. W., Smith, A. A., Roth, G. A., Gale, E. C., Stapleton, L. M., Mann, J. L., Yu, A. C., Correa, S., Grosskopf, A. K., Liong, C. S., Meis, C. M., Chan, D., Garner, J. P., Maahs, D. M., Buckingham, B. A., Appel, E. A. 2021; 11 (4): e387

Abstract

Understanding how automated insulin delivery (AID) algorithm features impact glucose control under full closed loop delivery represents a critical step toward reducing patient burden by eliminating the need for carbohydrate entries at mealtimes. Here, we use a pig model of diabetes to compare AndroidAPS and Loop open-source AID systems without meal announcements. Overall time-in-range (70-180mg/dl) for AndroidAPS was 58% 5%, while time-in-range for Loop was 35% 5%. The effect of the algorithms on time-in-range differed between meals and overnight. During the overnight monitoring period, pigs had an average time-in-range of 90% 7% when on AndroidAPS compared to 22% 8% on Loop. Time-in-hypoglycemia also differed significantly during the lunch meal, whereby pigs running AndroidAPS spent an average of 1.4% (+0.4/-0.8)% in hypoglycemia compared to 10% (+3/-6)% for those using Loop. As algorithm design for closed loop systems continues to develop, the strategies employed in the OpenAPS algorithm (known as oref1) as implemented in AndroidAPS for unannounced meals may result in a better overall control for full closed loop systems.

View details for DOI 10.1002/ctm2.387

View details for PubMedID 33931977

Feasibility of Spotlight Consultations Tool in Routine Care: Real-World Evidence. Journal of diabetes science and technology Barnard-Kelly, K., Kelly, R. C., Chernavvsky, D., Lal, R., Cohen, L., Ali, A. 2021: 1932296821994088

Abstract

BACKGROUND: Burnout in people with diabetes and healthcare professionals (HCPs) is at an all-time high. Spotlight AQ, a novel "smart" adaptive patient questionnaire, is designed to improve consultations by rapidly identifying patient priorities and presenting these in the context of best-practice care pathways to aid consultations. We aimed to determine Spotlight AQ's feasibility in routine care.MATERIALS AND METHODS: The Spotlight prototype tool was trialed at three centers: two UK primary care centers and one US specialist center (June-September 2020). Participants with type 1 (T1D) or type 2 diabetes (T2D) completed the questionnaire prior to their routine consultations. Results were immediately available and formed the basis of the clinical discussion and decision-making within the clinic visit.RESULTS: A convenience sample of 49 adults took part, n=31 T1D, (n=18 female); and n=18 T2D (n=10 male, n=4 female, n=4 gender unreported). Each identified two priority concerns. "Psychological burden of diabetes" was the most common priority concern (T1D n = 27, 87.1%) followed by "gaining more skills about particular aspects of diabetes" (T1D n=19, 61.3%), "improving support around me" (n=8, 25.8%) and "diabetes-related treatment issues" (n=8, 25.8%). Burden of diabetes was widespread as was lack of confidence around self-management. Similarly, psychological burden of diabetes was the primary concern for participants with T2D (n=18,100%) followed by "gaining more skills about aspects of diabetes" (n=7, 38.9%), "improving support around me" (n=7, 38.9%) and "diabetes-related treatment issues" (n=4; 22.2%).CONCLUSIONS: Spotlight AQ is acceptable and feasible for use in routine care. Gaining more skills and addressing the psychological burden of diabetes are high-priority areas that must be addressed to reduce high levels of distress.

View details for DOI 10.1177/1932296821994088

View details for PubMedID 33709795

Health-Related Quality of Life and Treatment Satisfaction in Parents and Children with Type 1 Diabetes Using Closed-Loop Control. Diabetes technology & therapeutics Cobry, E., Kanapka, L., Cengiz, E., Carria, L., Ekhlaspour, L., Buckingham, B. A., Hood, K., Hsu, L. J., Messer, L., Schoelwer, M., Emory, E., Ruedy, K. J., Beck, R. W., Wadwa, R. P. 2021

Abstract

INTRODUCTION: Hybrid closed-loop systems increase time-in-range and reduce glycemic variability. Person-reported outcomes (PROs) are essential to assess the utility of new devices and their impact on quality of life. This manuscript focuses on the PROs for pediatric participants (ages 6-13 yrs) with type 1 diabetes (T1D) and their parents during a trial using the Tandem Control-IQ system, which was shown to increase time-in-range and improve other glycemic metrics.METHODS: One-hundred-one children 6 to 13 years old with T1D were randomly assigned to closed-loop control (CLC) or sensor augmented pump (SAP) in a 16-week randomized clinical trial with extension to 28 weeks during which the SAP group crossed over to CLC. Health-related quality of life and treatment satisfaction measures were obtained from children and their parents at baseline, 16 weeks, and 28 weeks.RESULTS: Neither the children in the CLC group nor their parents had statistically significant changes in PRO outcomes compared with the SAP group at the end of the 16-week RCT and the 28-week extension. Parents in the CLC group reported non-significant improvements in some PRO scores when compared with the SAP group at 16 weeks, which were sustained at 28 weeks. Sleep scores for parents improved from "poor sleep quality" to "adequate sleep quality" between baseline and 16 weeks, however, the change in scores was not statistically different between groups.CONCLUSIONS: Children with T1D who used the Control-IQ system did not experience increased burden compared with those using SAP based on person-reported outcomes from the children and their parents.

View details for DOI 10.1089/dia.2020.0532

View details for PubMedID 33404325

Predictors of Time-in-Range (70-180mg/dL) Achieved Using a Closed-Loop Control System. Diabetes technology & therapeutics Schoelwer, M. J., Kanapka, L. G., Wadwa, R. P., Breton, M. D., Ruedy, K. J., Ekhlaspour, L. n., Forlenza, G. P., Cobry, E. C., Messer, L. H., Cengiz, E. n., Jost, E. n., Carria, L. n., Emory, E. n., Hsu, L. J., Weinzimer, S. A., Buckingham, B. A., Lal, R. A., Oliveri, M. C., Kollman, C. C., Dokken, B. B., Cheravvsky, D. R., Beck, R. W., DeBoer, M. D. 2021

Abstract

Background: Studies of closed-loop control (CLC) in patients with type 1 diabetes (T1D) consistently demonstrate improvements in glycemic control as measured by increased time-in-range (TIR) 70-180mg/dL. However, clinical predictors of TIR in users of CLC systems are needed. Materials and Methods: We analyzed data from 100 children aged 6-13 years with T1D using the Tandem Control-IQ CLC system during a randomized trial or subsequent extension phase. Continuous glucose monitor data were collected at baseline and during 12-16 weeks of CLC use. Participants were stratified into quartiles of TIR on CLC to compare clinical characteristics. Results: TIR for those in the first, second, third, and fourth quartiles was 54%, 65%, 71%, and 78%, respectively. Lower baseline TIR was associated with lower TIR on CLC (r=0.69, P<0.001). However, lower baseline TIR was also associated with greater improvement in TIR on CLC (r=-0.81, P<0.001). During CLC, participants in the highest versus lowest TIR-quartile administered more user-initiated boluses daily (8.52.8 vs. 5.82.6, P<0.001) and received fewer automated boluses (3.51.0 vs. 6.01.6, P<0.001). Participants in the lowest (vs. the highest) TIR-quartile received more insulin per body weight (1.130.27 vs. 0.870.20U/kg/d, P=0.008). However, in a multivariate model adjusting for baseline TIR, user-initiated boluses and insulin-per-body-weight were no longer significant. Conclusions: Higher baseline TIR is the strongest predictor of TIR on CLC in children with T1D. However, lower baseline TIR is associated with the greatest improvement in TIR. As with open-loop systems, user engagement is important for optimal glycemic control.

View details for DOI 10.1089/dia.2020.0646

View details for PubMedID 33689454

Discontinued Use of the Loop Insulin Dosing System: A Mixed-Methods Investigation. Diabetes technology & therapeutics Wong, J., Suttiratana, S., Lal, R. A., Lum, J., Lanning, M. S., Dunlap, A., Arbiter, B., Hanes, S., Bailey, R., Hood, K., Naranjo, D. 2021

Abstract

Loop is an open-source automated insulin dosing system that allows users unrivaled control over system settings that effect future glucose prediction. Thousands use Loop, but little is known about those who discontinue.In a large observational study, 874 Loop participants completed surveys and provided glycemic data, 46 (5.3%) of those self-identified as discontinuing Loop during the observation window, 45 completed a discontinued use survey, 22 provided system settings data, and 19 participated in semi-structured interviews about their discontinuation. Qualitative data were transcribed, coded, and analyzed.Older age and not trusting Loop were associated with discontinued use, though no other demographic or clinical characteristics were significant correlates. The most endorsed reasons were "I decided to try something else" (27.8%) followed by "It just didn't help as much as I thought it would" (22.2%). Qualitative analyses revealed prominent themes centered upon mental and emotional burden and adjusting settings. Other reasons for discontinued use included: fear of disapproval of Loop use from diabetes provider, barriers to acquiring component devices, a desire to try new/different technologies, concerns that Loop could not accommodate specific exercise or low insulin dose regimens, and worry about Loop use during pregnancy. It was noted that burdens might be alleviated by enhanced technical assistance and expert guidance.While the majority of individuals in the Loop observational study continued use, those who discontinued reported similar challenges. Technical support and education specific to setting calculations could expand Loop benefits, alleviate burden, and support sustained use among new Loop users.

View details for DOI 10.1089/dia.2021.0362

View details for PubMedID 34780283

Predicting Success with a First-Generation Hybrid Closed Loop Artificial Pancreas System among Children, Adolescents, and Young Adults with Type 1 Diabetes: a Model Development and Validation Study. Diabetes technology & therapeutics Forlenza, G. P., Vigers, T., Berget, C., Messer, L., Lal, R. A., Basina, M., Maahs, D. M., Hood, K., Buckingham, B. A., Wilson, D. M., Wadwa, R. P., Driscoll, K. A., Pyle, L. 2021

Abstract

Hybrid Closed Loop (HCL) systems aid individuals with type 1 diabetes in improving glycemic control, however, sustained use over time has not been consistent for all users. This study developed and validated prognostic models for successful 12-month use of the first commercial HCL system based on baseline and 1-month or 3-month data.Data from participants at the Barbara Davis Center (N=85) who began use of the MiniMed 670G HCL were used to develop prognostic models using logistic regression and Lasso model selection. Candidate factors included sex, age, duration of diabetes, baseline HbA1c, race, ethnicity, insurance status, history of insulin pump and continuous glucose monitor use, 1-month or 3-month Auto Mode use, boluses per day, and time in range (70-180 mg/dL; TIR), and scores on behavioral questionnaires. Successful use of HCL was predefined as Auto Mode use 60%. The 3-month model was then externally validated against a sample from Stanford University (N=55).Factors in the final model included baseline HbA1c, sex, ethnicity, 1-month or 3-month Auto Mode use, Boluses per Day, and TIR. The 1-month and 3-month prognostic models had very good predictive ability with area under the curve values of 0.894 and 0.900, respectively. External validity was acceptable with an area under the curve of 0.717.Our prognostic models use clinically accessible baseline and early device-use factors to identify risk for failure to succeed with 670G HCL technology. These models may be useful to develop targeted interventions to promote success with new technologies.

View details for DOI 10.1089/dia.2021.0326

View details for PubMedID 34780306

Engineering biopharmaceutical formulations to improve diabetes management. Science translational medicine Maikawa, C. L., d'Aquino, A. I., Lal, R. A., Buckingham, B. A., Appel, E. A. 2021; 13 (578)

Abstract

Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic agents and complexity of maintaining multiple infusions. In this review, we highlight the advantages and limitations of recent advances in drug formulation that improve protein stability and pharmacokinetics, prolong drug delivery, or enable alternative dosage forms for the management of diabetes. With controlled delivery, these formulations could improve closed-loop glycemic control.

View details for DOI 10.1126/scitranslmed.abd6726

View details for PubMedID 33504649

A Real-World Prospective Study of the Safety and Effectiveness of the Loop Open Source Automated Insulin Delivery System. Diabetes technology & therapeutics Lum, J., Bailey, R., Barnes-Lomen, V., Naranjo, D., Hood, K., Lal, R. A., Arbiter, B., Brown, A., DeSalvo, D. J., Pettus, J., Calhoun, P., Beck, R. W. 2020

Abstract

OBJECTIVE: To evaluate the safety and effectiveness of the Loop Do-It-Yourself (DIY) automated insulin delivery system.RESEARCH DESIGN AND METHODS: A prospective real-world observational study was conducted, which included 558 adults and children (age range 1 to 71 years, mean HbA1c 6.81.0%) who initiated Loop either on their own or with community-developed resources and provided data for 6 months.RESULTS: Mean time-in-range 70-180 mg/dL (TIR) increased from 6716% at baseline (prior to starting Loop) to 7313% during the 6 months (mean change from baseline 6.6%, 95% confidence interval 5.9% to 7.4%; P<0.001). TIR increased in both adults and children, across the full range of baseline HbA1c, and in participants with both high and moderate income levels. Median time <54 mg/dL was 0.40% at baseline and changed by -0.05% (95% confidence interval -0.09% to -0.03%, P<0.001). Mean HbA1c was 6.81.0% at baseline and decreased to 6.50.8% after 6 months (mean difference= -0.33%, 95% confidence interval -0.40% to -0.26%, P<0.001). The incidence rate of reported severe hypoglycemia events was 18.7 per 100 person-years, a reduction from the incidence rate of 181 per 100 person-years during the 3 months prior to the study. Among the 481 users providing Loop data at 6 months, median CGM use was 96% (interquartile range 91% to 98%) and median time Loop was modulating basal insulin was at least 83% (interquartile range 73% to 88%).CONCLUSIONS: The Loop open source system can be initiated with community-developed resources and used safely and effectively by adults and children with T1D.

View details for DOI 10.1089/dia.2020.0535

View details for PubMedID 33226840

A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes. The New England journal of medicine Breton, M. D., Kanapka, L. G., Beck, R. W., Ekhlaspour, L., Forlenza, G. P., Cengiz, E., Schoelwer, M., Ruedy, K. J., Jost, E., Carria, L., Emory, E., Hsu, L. J., Oliveri, M., Kollman, C. C., Dokken, B. B., Weinzimer, S. A., DeBoer, M. D., Buckingham, B. A., Chernavvsky, D., Wadwa, R. P., iDCL Trial Research Group, Schoelwer, M., Breton, M., DeBoer, M., Gonder-Frederick, L., Chernavvsky, D., Robic, J., Emory, E., Voelmle, M., Conschafter, K., Morris, K., Barnett, C., Carr, K., Hellmann, J., Kime, M., Oliveri, M., Wadwa, R. P., Forlenza, G., Alonso, G. T., Slover, R., Messer, L., Cobry, E., Jost, E., Berget, C., Towers, L., Lange, S., Buckingham, B., Maahs, D., Lal, R., Ekhlaspour, L., Norlander, L., Hood, K., Town, M., Weir, C., Smith, K., Hsu, L., Shinksy, D., Viana, J., Cengiz, E., Weinzimer, S., Weyman, K., Carria, L., Zgorski, M., Ruedy, K., Beck, R., Borgman, S., Rusnak, J., Kanapka, L., Kollman, C., Murphy, C., Arreza-Rubin, G., Green, N., Kovatchev, B., Brown, S., Anderson, S., Laffel, L., Pinsker, J., Levy, C., Kudva, Y. C., Doyle, F. 3., Renard, E., Cobelli, C., Reznik, Y., Lum, J., Janicek, R., Gabrielson, D. 2020; 383 (9): 83645

Abstract

BACKGROUND: A closed-loop system of insulin delivery (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes.METHODS: In a 16-week, multicenter, randomized, open-label, parallel-group trial, we assigned, in a 3:1 ratio, children 6 to 13 years of age who had type 1 diabetes to receive treatment with the use of either a closed-loop system of insulin delivery (closed-loop group) or a sensor-augmented insulin pump (control group). The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring.RESULTS: A total of 101 children underwent randomization (78 to the closed-loop group and 23 to the control group); the glycated hemoglobin levels at baseline ranged from 5.7 to 10.1%. The mean (SD) percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter increased from 5317% at baseline to 6710% (the mean over 16 weeks of treatment) in the closed-loop group and from 5116% to 5513% in the control group (mean adjusted difference, 11 percentage points [equivalent to 2.6 hours per day]; 95% confidence interval, 7 to 14; P<0.001). In both groups, the median percentage of time that the glucose level was below 70 mg per deciliter was low (1.6% in the closed-loop group and 1.8% in the control group). In the closed-loop group, the median percentage of time that the system was in the closed-loop mode was 93% (interquartile range, 91 to 95). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group.CONCLUSIONS: In this 16-week trial involving children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with the use of a closed-loop system than with the use of a sensor-augmented insulin pump. (Funded by Tandem Diabetes Care and the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT03844789.).

View details for DOI 10.1056/NEJMoa2004736

View details for PubMedID 32846062

An Intolerable Burden: Suicide, Intended Self-Injury and Diabetes. Canadian journal of diabetes Barnard-Kelly, K. D., Naranjo, D., Majidi, S., Akturk, H. K., Breton, M., Courtet, P., Olie, E., Lal, R. A., Johnson, N., Atkinson, M., Renard, E. 2020

View details for DOI 10.1016/j.jcjd.2020.01.008

View details for PubMedID 32305294

Insulin Pumps. Diabetes technology & therapeutics Lal, R. n., Leelarathna, L. n. 2020; 22 (S1): S17S31

View details for DOI 10.1089/dia.2020.2502

View details for PubMedID 32069156

Primary Care Providers in California and Florida Report Low Confidence in Providing Type 1 Diabetes Care. Clinical diabetes : a publication of the American Diabetes Association Lal, R. A., Cuttriss, N. n., Haller, M. J., Yabut, K. n., Anez-Zabala, C. n., Hood, K. K., Sheehan, E. n., Basina, M. n., Bernier, A. n., Baer, L. G., Filipp, S. L., Wang, C. J., Town, M. A., Gurka, M. J., Maahs, D. M., Walker, A. F. 2020; 38 (2): 15965

Abstract

People with type 1 diabetes may receive a significant portion of their care from primary care providers (PCPs). To understand the involvement of PCPs in delivering type 1 diabetes care, we performed surveys in California and Florida, two of the most populous and diverse states in the United States. PCPs fill insulin prescriptions but report low confidence in providing type 1 diabetes care and difficulty accessing specialty referrals to endocrinologists.

View details for DOI 10.2337/cd19-0060

View details for PubMedID 32327888

View details for PubMedCentralID PMC7164993

THE GUIDED TRANSFER OF CARE IMPROVES ADULT CLINIC SHOW RATE. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Lal, R. A., Maahs, D. M., Dosiou, C. n., Aye, T. n., Basina, M. n. 2020

Abstract

Objective Every year 500,000 youths in the U.S. with chronic disease turn 18 and eventually require transfer to adult subspecialty care. Evidence-based interventions on the organization of transfer of care are limited, although engagement and retention in adult clinic are considered appropriate outcomes. Sustained continuity of care improves patient satisfaction and reduces hospitalization. Methods We conducted a prospective non-randomized cohort study of patients with pediatric endocrine conditions, age 16-26 years, enrolled upon referral to the adult endocrine clinic of a physician trained in both adult and pediatric endocrinology (Med+Peds Endocrinologist). Patients differed based on whether their referral originated from another pediatric endocrinologist (traditional transfer) or if the Med+Peds Endocrinologist previously saw the patient in his pediatric endocrine clinic (guided transfer). Rather than relying on arbitrary age criteria, guided transfer to adult clinic occurred when physician and patient considered it appropriate. The primary outcome was show rate at the first and second adult visits. Results Of 36 patients, 21 were referred by another pediatric endocrinologist and 15 underwent guided transfer. For traditional transfer, show rate to the first and second visit was 38% compared to 100% in the guided transfer group (p = 0.0001). Subgroup analysis of 27 patients with diabetes revealed that both groups had similar initial HbA1c (p = 0.38) and the guided transfer group maintained HbA1c. Conclusions Most traditional transfers were unsuccessful. Guided transfer was significantly more effective, with every patient successfully transferring, and could be implemented with adult endocrinologists willing to see patients in the pediatric clinic.

View details for DOI 10.4158/EP-2019-0470

View details for PubMedID 32045296

Fast-Acting Insulin Aspart Use with the MiniMed 670G System. Diabetes technology & therapeutics Hsu, L. J., Buckingham, B. A., Basina, M. n., Ekhlaspour, L. n., von Eyben, R. n., Wang, J. n., Lal, R. A. 2020

Abstract

BACKGROUND This study assessed the efficacy and safety of ultra-rapid insulin Fiasp in the hybrid closed-loop MiniMed 670G system. METHODS This was a pilot randomized, double-blinded, cross-over study among established MiniMed 670G users comparing percent time in range (TIR) and hypoglycemia for Novolog and Fiasp. Following two weeks optimization with their home insulin, participants were randomized to receive Novolog or Fiasp for two weeks, followed by the other insulin for the next two weeks. Data from the second week of blinded insulin use was analyzed to allow one week for 670G adaptation. During the second week, individuals were asked to eat the same breakfast for three days to assess differences in meal pharmacodynamics. RESULTS Nineteen adults were recruited with mean age of 4018 years, diabetes duration of 2712 years and median HbA1c of 7.1 (6.9,7.5)%, using 0.72 (0.4,1.2) units/kg/day. For Novolog and Fiasp respectively the %TIR (70-180mg/dL) was 75.39.5 and 78.4 9.3; %time <70mg/dL was 3.12.1 and 2.32.0; %time >180mg/dL was 21.69.0 and 19.38.9; mean glucose was 14712 and 14612mg/dL; coefficient of variation was 28.64.5% and 26.84.4%; %time in Auto Mode 86.49.2 and 84.49.2. All comparisons were non-significant for insulin type. Total daily dose (Novolog 48.828.4 vs. Fiasp 52.431.7 units; p=0.01) and daily basal (Novolog 17.6 (15.5,33.8) vs. Fiasp 19.1 (15.3,38.5) units; p=0.07) correlated with TIR and %time >180mg/dL. For insulin delivery in Auto Mode there was no statistical difference in total daily dose or daily basal between arms. Paired analysis for matched breakfast meals revealed no significant differences in time to maximum glucose, peak glucose or glucose excursion. CONCLUSIONS In this pilot study the use of either Novolog or Fiasp in a commercially available MiniMed 670G system operating in Auto Mode resulted in clinically similar glycemic outcomes, with a slight increase in daily insulin requirements using Fiasp.

View details for DOI 10.1089/dia.2020.0083

View details for PubMedID 32520594

Suicide and Self-inflicted Injury in Diabetes: A Balancing Act. Journal of diabetes science and technology Barnard-Kelly, K. D., Naranjo, D., Majidi, S., Akturk, H. K., Breton, M., Courtet, P., Olie, E., Lal, R. A., Johnson, N., Renard, E. 2019: 1932296819891136

Abstract

Glycemic control in type 1 diabetes mellitus (T1DM) remains a challenge for many, despite the availability of modern diabetes technology. While technologies have proven glycemic benefits and may reduce excess mortality in some populations, both mortality and complication rates remain significantly higher in T1DM than the general population. Diabetes technology can reduce some burdens of diabetes self-management, however, it may also increase anxiety, stress, and diabetes-related distress. Additional workload associated with diabetes technologies and the dominant focus on metabolic control may be at the expense of quality-of-life. Diabetes is associated with significantly increased risk of suicidal ideation, self-harm, and suicide. The risk increases for those with diabetes and comorbid mood disorder. For example, the prevalence of depression is significantly higher in people with diabetes than the general population, and thus, people with diabetes are at even higher risk of suicide. The Center for Disease Control and Prevention reported a 24% rise in US national suicide rates between 1999 and 2014, the highest in 30 years. In the United Kingdom, 6000 suicides occur annually. Rates of preventable self-injury mortality stand at 29.1 per 100 000 population. Individuals with diabetes have an increased risk of suicide, being three to four times more likely to attempt suicide than the general population. Furthermore, adolescents aged 15 to 19 are most likely to present at emergency departments for self-inflicted injuries (9.6 per 1000 visits), with accidents, alcohol-related injuries, and self-harm being the strongest risk factors for suicide, the second leading cause of death among 10 to 24 year olds. While we have developed tools to improve glycemic control, we must be cognizant that the psychological burden of chronic disease is a significant problem for this vulnerable population. It is crucial to determine the psychosocial and behavioral predictors to uptake and continued use of technology in order to aid the identification of those individuals most likely to realize benefits of any intervention as well as those individuals who may require more support to succeed with technology.

View details for DOI 10.1177/1932296819891136

View details for PubMedID 31801353

Perspectives on long-acting growth hormone therapy in children and adults. Archives of endocrinology and metabolism Lal, R. A., Hoffman, A. R. 2019; 63 (6): 6017

Abstract

Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world. Arch Endocrinol Metab. 2019;63(6):601-7.

View details for DOI 10.20945/2359-3997000000190

View details for PubMedID 31939485

Fluoroscopic-assisted laparoscopic retrieval of retained glucose sensor wire from the omentum CLINICAL CASE REPORTS Sang, A. X., Lal, R., August, A., Danzer, E., Buckingham, B., Mueller, C. M. 2019

View details for DOI 10.1002/ccr3.2348

View details for Web of Science ID 000478842500001

Optimizing Basal Insulin Dosing. The Journal of pediatrics Lal, R. A., Maahs, D. M. 2019

View details for DOI 10.1016/j.jpeds.2019.07.030

View details for PubMedID 31383469

Realizing a Closed-Loop (Artificial Pancreas) System for the Treatment of Type 1 Diabetes. Endocrine reviews Lal, R. A., Ekhlaspour, L., Hood, K., Buckingham, B. 2019

Abstract

Recent, rapid changes in the treatment of type 1 diabetes have allowed for commercialization of an "artificial pancreas" which is better described as a closed-loop controller of insulin delivery. This review presents the current state of closed-loop control systems and expected future developments with a discussion of the human factor issues in allowing automation of glucose control. The goal of these systems is to minimize or prevent both short and long-term complications from diabetes and to decrease the daily burden of managing diabetes. The closed-loop systems are generally very effective and safe at night, have allowed for improved sleep and have decreased the burden of diabetes management overnight. However, there are still significant barriers to achieving excellent daytime glucose control while simultaneously decreasing the burden of daytime diabetes management. These systems utilize a subcutaneous continuous glucose sensor, an algorithm that accounts for the current glucose and rate of change of the glucose, and the amount of insulin which has already been delivered in order to safely deliver insulin to control hyperglycemia, while minimizing the risk of hypoglycemia. The future challenge will be to allow for full closed-loop control with minimal burden on the patient during the day alleviating meal announcements, carbohydrate counting, alerts and maintenance. The human factors involved with interfacing with a closed-loop system and allowing the system to take control of diabetes management are significant. It is important to find a balance between enthusiasm and realistic expectations and experiences with closed loop.

View details for DOI 10.1210/er.2018-00174

View details for PubMedID 31276160

Diabetes Technology and Therapy in the Pediatric Age Group. Diabetes technology & therapeutics Maahs, D. M., Lal, R., Shalitin, S. 2019; 21 (S1): S123S137

View details for DOI 10.1089/dia.2019.2510

View details for PubMedID 30785328

Fluoroscopic-assisted laparoscopic retrieval of retained glucose sensor wire from the omentum. Clinical case reports Sang, A. X., Lal, R. n., August, A. n., Danzer, E. n., Buckingham, B. n., Mueller, C. M. 2019; 7 (9): 171720

Abstract

We describe a case in which retained wires from a continuous glucose monitor were removed from the abdominal wall and peritoneum of a 6-year-old boy. We highlight a concern for continuous glucose monitor use in children and discuss surgical techniques used to retrieve tiny, mobile objects from complex body cavities.

View details for DOI 10.1002/ccr3.2348

View details for PubMedID 31534734

View details for PubMedCentralID PMC6745354

One Year Clinical Experience of the First Commercial Hybrid Closed-Loop. Diabetes care Lal, R. A., Basina, M. n., Maahs, D. M., Hood, K. n., Buckingham, B. n., Wilson, D. M. 2019

Abstract

In September 2016, the U.S. Food and Drug Administration approved the Medtronic 670G "hybrid" closed-loop system. In Auto Mode, this system automatically controls basal insulin delivery based on continuous glucose monitoring data, but requires users enter carbohydrates and blood glucose for boluses. To track real-world experience with this first commercial closed-loop device, we prospectively followed pediatric and adult patients starting the 670G system.This was a 1-year prospective observational study of patients with type 1 diabetes starting the 670G system between May 2017 and May 2018 in clinic.A total of 84 patients received 670G and consented, 5 never returned for follow-up, with 79 (aged 9-61 years) providing data at 1 week and 3, 6, 9, and/or 12 months after Auto Mode initiation. For the 86% (68 out of 79) with 1-week data, 99% (67 out of 68) successfully started. By 3 months, at least 28% (22 out of 79) stopped using Auto Mode; at 6 months, 34% (27 out of 79); at 9 months, 35% (28 out of 79); and by 12 months, 33% (26 out of 79). The primary reason for continuing Auto Mode was desire for increased time in range. Reasons for discontinuation included sensor issues in 62% (16 out of 26), problems obtaining supplies in 12% (3 out of 26), hypoglycemia fear in 12% (3 out of 26), multiple daily injection preference in 8% (2 out of 26), and sports in 8% (2 out of 26). At all visits, there was a significant correlation between hemoglobin A1c (HbA1c) and Auto Mode utilization.While Auto Mode utilization correlates with improved glycemic control, a focus on usability and human factors is necessary to ensure use of Auto Mode. Alarms and sensor calibration are a major patient concern, which future technology should alleviate.

View details for DOI 10.2337/dc19-0855

View details for PubMedID 31548247

Long-Acting Growth Hormone Preparations in the Treatment of Children. Pediatric endocrinology reviews : PER Lal, R. A., Hoffman, A. R. 2018; 16 (Suppl 1): 16267

Abstract

Human growth hormone (hGH), which had been in use since 1958, was supplanted by recombinant human growth hormone (rhGH) in 1985 for those with growth hormone deficiency (GHD). Adherence to daily subcutaneous growth hormone is challenging for patients. Thus, several companies have pursued the creation of long acting rhGH. These agents can be divided broadly into depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding GH and GH fusion proteins. Nutropin Depot is the only long acting rhGH ever approved by the U.S. Food and Drug Administration, and it was removed from the market in 2004. Of the approximately seventeen candidate drugs, only a handful remain under active clinical investigation or are commercially available.

View details for PubMedID 30378794

Advances in Care for Insulin-Requiring Patients Without Closed Loop. Diabetes technology & therapeutics Lal, R. A., Buckingham, B., Maahs, D. M. 2018; 20 (S2): S285S291

View details for PubMedID 29916743

Postmenopausal Hyperandrogenism. Journal of women's health care Lal, R. A., Basina, M. 2018; 7 (1)

View details for DOI 10.4172/2167-0420.1000e132

View details for PubMedID 32284912

A Case Report of Hypoglycemia and Hypogammaglobulinemia: DAVID syndrome in a patient with a novel NFKB2 mutation. journal of clinical endocrinology and metabolism Lal, R. A., Bachrach, L. K., Hoffman, A. R., Inlora, J., Rego, S., Snyder, M. P., Lewis, D. B. 2017

Abstract

DAVID syndrome (Deficient Anterior pituitary with Variable Immune Deficiency) is a rare disorder in which children present with symptomatic ACTH deficiency preceded by hypogammaglobulinemia from B-cell dysfunction with recurrent infections, termed common variable immunodeficiency (CVID). Subsequent whole exome sequencing studies have revealed germline heterozygous C-terminal mutations of NFKB2 as either a cause of DAVID syndrome or of CVID without clinical hypopituitarism. However, to the best of our knowledge there have been no cases in which the endocrinopathy has presented in the absence of a prior clinical history of CVID.A previously healthy 7 year-old boy with no history of clinical immunodeficiency, presented with profound hypoglycemia and seizures. He was found to have secondary adrenal insufficiency and was started on glucocorticoid replacement. An evaluation for autoimmune disease, including for anti-pituitary antibodies, was negative. Evaluation unexpectedly revealed hypogammaglobulinemia (decreased IgG, IgM, and IgA). He had moderately reduced serotype-specific IgG responses following pneumococcal polysaccharide vaccine. Subsequently, he was found to have growth hormone (GH) deficiency. Six years after initial presentation, whole exome sequencing revealed a novel de novo heterozygous NFKB2 missense mutation c.2596A>C (p.Ser866Arg) in the C-terminal region predicted to abrogate the processing of the p100 NFKB2 protein to its active p52 form.Isolated early-onset ACTH deficiency is rare and C-terminal region NFKB2 mutations should be considered as an etiology even in the absence of a clinical history of CVID. Early immunologic evaluation is indicated in the diagnosis and management of isolated ACTH deficiency.

View details for DOI 10.1210/jc.2017-00341

View details for PubMedID 28472507

Clinical Use of Continuous Glucose Monitoring in Pediatrics. Diabetes technology & therapeutics Lal, R. A., Maahs, D. M. 2017; 19 (S2): S37-S43

View details for DOI 10.1089/dia.2017.0013

View details for PubMedID 28541138

An unusual cause of hyperglycemia JOURNAL OF POSTGRADUATE MEDICINE Lal, R., Loomba-Albrecht, L. A., Bremer, A. A. 2011; 57 (4): 34346

View details for DOI 10.4103/0022-3859.90092

View details for Web of Science ID 000298626200018

View details for PubMedID 22120869

Amyloid-beta and Glucose Metabolism in Alzheimer's Disease JOURNAL OF ALZHEIMERS DISEASE Furst, A. J., Lal, R. A. 2011; 26: 105-116

Abstract

This study used PET with the amyloid- (A) imaging agent 11 C Pittsburgh Compound-B (PIB) and the glucose metabolic tracer 18F-fluorodeoxyglucose (FDG) to map the relationship of A deposition to regional glucose metabolism in Alzheimer's disease (AD). Comparison of 13 AD patients' FDG scans with 11 healthy controls confirmed a typical temporo-parietal hypometabolic pattern in AD. In contrast, PIB distribution-volume-ratios showed a distinct pattern of specific tracer retention in fronto-temporo-parietal regions and striatum in AD with peaks in left frontal cortex, precuneus, temporal cortex, striatum and right posterior cingulate. There were no region-to-region or within region correlations between FDG and PIB uptake in PIB positive AD patients but when the impact of A load on glucose metabolism was assessed via probabilistic maps, increased amyloid burden was coupled with decreased metabolism in temporo-parietal regions and the posterior cingulate. However, importantly, severe A burden was not associated with comparable metabolic decreases in large parts of the frontal lobes, the striatum and the thalamus.

View details for DOI 10.3233/JAD-2011-0066

View details for Web of Science ID 000297842800008

View details for PubMedID 21971455

Amyloid-beta and Glucose Metabolism in Alzheimer's Disease HANDBOOK OF IMAGING THE ALZHEIMER BRAIN Furst, A. J., Lal, R. A., Ashford, J. W., Rosen, A., Adamson, M., Bayley, P., Sabri, O., Furst, A., Black, S. E., Weiner, M. 2011; 2: 23546
Striatal Dopamine and Working Memory CEREBRAL CORTEX Landau, S. M., Lal, R., O'Neil, J. P., Baker, S., Jagust, W. J. 2009; 19 (2): 445-454

Abstract

Recent studies have emphasized the importance of dopamine projections to the prefrontal cortex (PFC) for working memory (WM) function, although this system has rarely been studied in humans in vivo. However, dopamine and PFC activity can be directly measured with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), respectively. In this study, we examined WM capacity, dopamine, and PFC function in healthy older participants in order to test the hypothesis that there is a relationship between these 3 factors. We used the PET tracer 6-[18F]fluoro-L-m-tyrosine to measure dopamine synthesis capacity in the striatum (caudate, putamen), and event-related fMRI to measure brain activation during different epochs (cue, delay, probe) of a WM task. Caudate (but not putamen) dopamine correlated positively with WM capacity, whereas putamen (but not caudate) dopamine correlated positively with motor speed. In addition, delay-related fMRI activation in a left inferior prefrontal region was related to both caudate dopamine and task accuracy, suggesting that this may be a critical site for the integration of WM maintenance processes. These results provide new evidence that striatal dopaminergic function is related to PFC-dependent functions, particularly brain activation and behavioral performance during WM tasks.

View details for DOI 10.1093/cercor/bhn095

View details for Web of Science ID 000262518800019

View details for PubMedID 18550595

View details for PubMedCentralID PMC2733326

A beta Amyloid and Glucose Metabolism in Three Variants of Primary Progressive Aphasia ANNALS OF NEUROLOGY Rabinovici, G. D., Jagust, W. J., Furst, A. J., Ogar, J. M., Racine, C. A., Mormino, E. C., O'Neil, J. P., Lal, R. A., Dronkers, N. F., Miller, B. L., Gorno-Tempini, M. L. 2008; 64 (4): 388-401

Abstract

Alzheimer's disease (AD) is found at autopsy in up to one third of patients with primary progressive aphasia (PPA), but clinical features that predict AD pathology in PPA are not well defined. We studied the relationships between language presentation, Abeta amyloidosis, and glucose metabolism in three PPA variants using [11C]-Pittsburgh compound B ([11C]PIB) and [18F]-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG-PET).Patients meeting PPA criteria (N = 15) were classified as logopenic aphasia (LPA), progressive nonfluent aphasia (PNFA), or semantic dementia (SD) based on language testing. [11C]PIB distribution volume ratios were calculated using Logan graphical analysis (cerebellar reference). [18F]FDG images were normalized to pons. Partial volume correction was applied.Elevated cortical PIB (by visual inspection) was more common in LPA (4/4 patients) than in PNFA (1/6) and SD (1/5) (p < 0.02). In PIB-positive PPA, PIB uptake was diffuse and indistinguishable from the pattern in matched AD patients (n = 10). FDG patterns were focal and varied by PPA subtype, with left temporoparietal hypometabolism in LPA, left frontal hypometabolism in PNFA, and left anterior temporal hypometabolism in SD. FDG uptake was significant asymmetric (favoring left hypometabolism) in PPA (p < 0.005) but not in AD.LPA is associated with Abeta amyloidosis, suggesting that subclassification of PPA based on language features can help predict the likelihood of AD pathology. Language phenotype in PPA is closely related to metabolic changes that are focal and anatomically distinct between subtypes, but not to amyloid deposition patterns that are diffuse and similar to AD.

View details for DOI 10.1002/ana.21451

View details for Web of Science ID 000260845000007

View details for PubMedID 18991338

View details for PubMedCentralID PMC2648510