Saleh Adi

Real-time continuous glucose monitoring among participants in the T1D Exchange clinic registry.

OBJECTIVE To assess the frequency of continuous glucose monitoring (CGM) device use, factors associated with its use, and the relationship of CGM with diabetes outcomes (HbA1c, severe hypoglycemia [SH], and diabetic ketoacidosis [DKA]). RESEARCH DESIGN AND METHODS Survey questions related to CGM device use 1 year after enrollment in the T1D Exchange clinic registry were completed by 17,317 participants. Participants were defined as CGM users if they indicated using real-time CGM during the prior 30 days. RESULTS Nine percent of participants used CGM (6% of children <13 years old, 4% of adolescents 13 to <18 years, 6% of young adults 18 to <26 years, and 21% of adults ≥26 years). CGM use was more likely with higher education, higher household income, private health insurance, longer duration of diabetes, and use of insulin pump (P < 0.01 all factors). CGM use was associated with lower HbA1c in children (8.3% vs. 8.6%, P < 0.001) and adults (7.7% vs. 7.9%, P < 0.001). In adults, more frequent use of CGM (≥6 days/week) was associated with lower mean HbA1c. Only 27% of users downloaded data from their device at least once per month, and ≤15% of users reported downloading their device at least weekly. Among participants who used CGM at baseline, 41% had discontinued within 1 year. CONCLUSIONS CGM use is uncommon but associated with lower HbA1c in some age-groups, especially when used more frequently. Factors associated with discontinuation and infrequent use of retrospective analysis of CGM data should be considered in developing next-generation devices and education on CGM use.

Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.

Infection and inflammation are associated with hypertriglyceridemia, which is thought to be mediated by cytokines. Previous studies at our laboratory and others have shown that tumor necrosis factor acutely increases serum triglyceride levels primarily by stimulating hepatic lipid synthesis and secretion. The role of interleukin-1 (IL-1), a cytokine that is also secreted by stimulated macrophages and that has many actions that overlap those of tumor necrosis factor, has not been studied in depth. The present study demonstrates that IL-1, at doses similar to those that cause fever and anorexia and that stimulate adrenocorticotropic hormone secretion, rapidly increases serum triglyceride levels; this elevation persists for at least 17 hours. Serum cholesterol levels are not altered by IL-1. Neither is the clearance of triglyceride-rich lipoproteins affected by IL-1. However, hepatic triglyceride secretion, measured by the Triton WR-1339 technique, is increased in IL-1-treated animals. Accompanying this stimulation in hepatic lipid secretion is an increase in de novo fatty acid synthesis in the liver. IL-1 does not increase serum free fatty acid and glycerol levels, suggesting that IL-1 does not stimulate lipolysis in vivo. Additionally, inhibition of lipolysis does not prevent the increase in serum triglyceride levels, providing further evidence that lipolysis does not play a crucial role in the increased hepatic lipid synthesis and secretion induced by IL-1. In contrast, tumor necrosis factor increases lipolysis, which contributes to the increase in serum triglycerides. That multiple cytokines rapidly elevate plasma triglyceride levels suggest that these changes in lipid metabolism may play an important role in the organisms response to infection and inflammation.

Insulin pump use in young children in the T1D Exchange clinic registry is associated with lower hemoglobin A1c levels than injection therapy

Insulin delivery via injection and continuous subcutaneous insulin infusion (CSII) via insulin pump were compared in a cross‐sectional study (n = 669) and retrospective longitudinal study (n = 1904) of young children (<6 yr) with type 1 diabetes (T1D) participating in the T1D Exchange clinic registry. Use of CSII correlated with longer T1D duration (p < 0.001), higher parental education (p < 0.001), and annual household income (p < 0.006) but not with race/ethnicity. Wide variation in pump use was observed among T1D Exchange centers even after adjusting for these factors, suggesting that prescriber preference is a substantial determinant of CSII use. Hemoglobin A1c (HbA1c) was lower in pump vs. injection users (7.9 vs. 8.5%, adjusted p < 0.001) in the cross‐sectional study. In the longitudinal study, HbA1c decreased after initiation of CSII by 0.2%, on average (p < 0.001). Frequency of a severe hypoglycemia (SH) event did not differ in pump vs. injection users (p = 0.2). Frequency of ≥1 parent‐reported diabetic ketoacidosis (DKA) event in the prior year was greater in pump users than injection users (10 vs. 8%, p = 0.04). No differences between pump and injection users were observed for clinic‐reported DKA events. Children below 6 yr have many unique metabolic characteristics, feeding behaviors, and care needs compared with older children and adolescents. These data support the use of insulin pumps in this youngest age group, and suggest that metabolic control may be improved without increasing the frequency of SH, but care should be taken as to the possibly increased risk of DKA.

Growth Factor-Stimulated Phosphorylation of Akt and p70S6K Is Differentially Inhibited by LY294002 and Wortmannin*

The phosphoinositide 3-kinase (PI3K) inhibitors, LY294002 (LY) and wortmannin (WM), are widely used to examine the role of PI3K in growth factor signaling. These compounds inhibit the kinase action of PI3K, thus preventing the accumulation of PI(3,4,5)P3 and PI(3,4)P2 (PIs) and subsequent phosphorylation and activation of the downstream effectors of PI3K, Akt and p70S6K. The efficacy of these inhibitors has been demonstrated by measuring cellular levels of PIs or the kinase activity of immunoprecipitated PI3K. However, their effects on activation of Akt and p70S6K, more widely used markers of PI3K activation, has not been formally tested. We have examined the effects of LY and WM on phosphorylation of Akt and p70S6K by insulin-like growth factor-I, insulin, and platelet-derived growth factor in skeletal muscle cells. LY is much less effective in blocking the phosphorylation of Akt than p70S6K; at concentrations which completely inhibit phosphorylation of p70S6K, phosphorylation of Akt is only partially in...

Tumor Necrosis Factor–Increased Hepatic Very-Low-Density Lipoprotein Production and Increased Serum Triglyceride Levels in Diabetic Rats

Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (∼2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 μg TNF/200 g body wt, and the halfmaximal effect is observed with 5 μg TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride t½: diabetic vs. TNFadministered diabetic, 3.5 ± 0.7 vs. 4.0 ± 0.6 min, respectively; NS). The production of triglyceride, measured by the Triton WR-1339 technique, is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl-CoA carboxylase, a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA, an allosteric inhibitor of acetyl-CoA carboxylase. However, there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase, and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis. These results suggest that the TNF-induced stimulation of hepatic lipogenesis is mediated by citrate activation of acetyl-CoA carboxylase. At 2 h after TNF administration, neither serum glucose nor p-hydroxybutyrate levels were adversely altered in the TNF group, indicating that the disturbances in lipid metabolism are not dependent on alterations in glycemic control. The increases in serum triglyceride levels that occur during infections or stress in diabetes may be secondary to TNF.

Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines.

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. The major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care.

Opposing early inhibitory and late stimulatory effects of insulin‐like growth factor‐I on myogenin gene transcription

Insulinlike growth factors (IGFs) stimulate skeletal muscle cell differentiation in association with an increase in the mRNA of myogenin, a member of the MyoD family of skeletal muscle–specific transcription factors that plays an essential role in the differentiation process. However, this is a relatively late effect, requiring treatment periods of >24 h. In contrast, IGFs initially inhibit skeletal muscle cell differentiation, associated with a marked reduction in myogenin mRNA. The mechanisms by which IGF‐I initially inhibits and subsequently stimulates myogenin expression are unknown. In the first 24 h, we find that IGF‐I inhibits myogenin gene transcription by >80% but has no effect on myogenin mRNA stability. Similarly, in the first 24 h, IGF‐I markedly inhibits myogenin promoter activity; the sequence −145 to −9 of the myogenin gene is sufficient to confer this inhibitory effect of IGF‐I. In contrast, 48 h of treatment with IGF‐I results in an increase in myogenin promoter activity that parallels the increase in myogenin steady‐state mRNA. This increase in promoter activity is completely prevented in constructs lacking the sequence −1,565 to −375 of the myogenin gene. These data indicate that the early inhibitory and late stimulatory effects of IGF‐I on myogenin expression are mediated at the level of transcription, and that these time‐dependent, opposing effects of IGF‐I on myogenin transcription are mediated by distinct regions of the myogenin gene. To our knowledge, this is the first demonstration of a gene whose promoter activity is initially inhibited and subsequently stimulated by IGF‐I. J. Cell. Biochem. 78:617–626, 2000.

A Minority of Patients with Type 1 Diabetes Routinely Downloads and Retrospectively Reviews Device Data

Abstract Background: In type 1 diabetes (T1D), periodic review of blood glucose and insulin dosing should be performed, but it is not known how often patients review these data on their own. We describe the proportion of patients with T1D who routinely downloaded and reviewed their data at home. Materials and Methods: A cross-sectional survey of 155 adults and 185 caregivers of children with T1D at a single academic institution was performed. “Routine Downloaders” (downloaded four or more times in the past year) were also considered “Routine Reviewers” if they reviewed their data most of the time they downloaded from devices. Logistic regression was used to identify factors associated with being a Routine Reviewer. Results: Only 31% of adults and 56% of caregivers reported ever downloading data from one or more devices, whereas 20% and 40%, respectively, were considered Routine Downloaders. Only 12% of adults and 27% of caregivers were Routine Reviewers. Mean hemoglobin A1c was lower in Routine Reviewers compared with non-Routine Reviewers (7.2±1.0% vs. 8.1±1.6% [P=0.03] in adults and 7.8±1.4% vs. 8.6±1.7% [P=0.001] in children). In adjusted analysis of adults, the odds ratio of being a Routine Reviewer of one or more devices for every 10-year increase in age was 1.5 (95% confidence interval, 1.1, 2.1 [P=0.02]). For every 10 years since diabetes diagnosis, the odds ratio of being a Routine Reviewer was 1.7 (95% confidence interval, 1.2, 2.4 [P=0.01]). For caregivers, there were no statistically significant factors associated with being a Routine Reviewer. Conclusions: A minority of T1D patients routinely downloads and reviews data from their devices on their own. Further research is needed to understand obstacles, provide better education and tools for self-review, and determine if patient self-review is associated with improved glycemic control.

A case study in open source innovation: developing the Tidepool Platform for interoperability in type 1 diabetes management

Objective Develop a device-agnostic cloud platform to host diabetes device data and catalyze an ecosystem of software innovation for type 1 diabetes (T1D) management. Materials and Methods An interdisciplinary team decided to establish a nonprofit company, Tidepool, and build open-source software. Results Through a user-centered design process, the authors created a software platform, the Tidepool Platform, to upload and host T1D device data in an integrated, device-agnostic fashion, as well as an application (“app”), Blip, to visualize the data. Tidepool’s software utilizes the principles of modular components, modern web design including REST APIs and JavaScript, cloud computing, agile development methodology, and robust privacy and security. Discussion By consolidating the currently scattered and siloed T1D device data ecosystem into one open platform, Tidepool can improve access to the data and enable new possibilities and efficiencies in T1D clinical care and research. The Tidepool Platform decouples diabetes apps from diabetes devices, allowing software developers to build innovative apps without requiring them to design a unique back-end (e.g., database and security) or unique ways of ingesting device data. It allows people with T1D to choose to use any preferred app regardless of which device(s) they use. Conclusion The authors believe that the Tidepool Platform can solve two current problems in the T1D device landscape: 1) limited access to T1D device data and 2) poor interoperability of data from different devices. If proven effective, Tidepool’s open source, cloud model for health data interoperability is applicable to other healthcare use cases.

Evaluation of Pump Discontinuation and Associated Factors in the T1D Exchange Clinic Registry

Background: The objectives of this study were to examine factors associated with insulin pump discontinuation among children and adults followed longitudinally for 1 year in the multicenter T1D Exchange clinic registry, and to provide participant-reported reasons for stopping pump therapy. Methods: We longitudinally followed 8935 participants of all ages using an insulin pump at the time of registry enrollment. Logistic regressions were used to identify demographic and clinical factors associated with pump discontinuation. Pump discontinuation was self-reported by participants on a first annual follow-up survey. Results: The overall frequency of pump discontinuation was 3%. Discontinuation was higher in adolescents (4%) and young adults (4%) than in younger children (3%) or older adults (1%). In multivariate analysis of children between 6 and <13 and 13 and <18 years, participants who discontinued pump use were more likely to have higher HbA1c levels at baseline (adjusted P < .001 for both). The top participant-reported reasons for discontinuing the pump included problems with wearability (57%), disliking the pump or feeling anxious (44%), and problems with glycemic control (30%). Conclusions: In T1D Exchange registry participants, insulin pump discontinuation is uncommon, but more prevalent among adolescents and young adults, and youth with poor glycemic control. Given the known benefits of pump therapy, these populations should be targeted for support and education on troubleshooting pump use. Common reasons for discontinuation should also be considered in future device design and technological improvement.