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1. Contribution of gestational diabetes mellitus heterogeneity and prepregnancy body mass index to large‐for‐gestational‐age infants—A retrospective case‐control study

   https://doi.org/10.1111/1753-0407.13113  

   Wang, Ning ; Song, Lin ; Sun, Bo ; Peng, Yanqi ; Fei, Sijia ; Cui, Jiaqi ; Mi, Yang ; Cui, Wei ( September 2020 , Journal of Diabetes)

   To study the associations between heterogeneity of gestational diabetes mellitus (GDM) subtype/prepregnancy body mass index (pre‐BMI) and large‐for‐gestational‐age (LGA) infants of Chinese women.

   We performed a retrospective case‐control study of 299 women with GDM and 204 women with normal glucose tolerance (NGT), using oral glucose tolerance test‐based indices performed at 24‐25 weeks of gestation. Women with GDM were classified into the following three physiologic subtypes: GDM with a predominant insulin‐secretion defect (GDM‐dysfunction), GDM with a predominant insulin‐sensitivity defect (GDM‐resistance), or GDM with both defects (GDM‐mixed). We then used a binary logistic regression model to evaluate the potential associations of GDM subtypes and pre‐BMI with newborn macrosomia or LGA.

   Women with GDM‐resistance had a higher pre‐BMI (P < 0.001), whereas women in the GDM‐dysfunction and GDM‐mixed groups had pre‐BMIs comparable to the NGT group. In the logistic regression model, women in the GDM‐mixed group exhibited an increased risk of bearing newborns with macrosomia and LGA, and women in the GDM‐dysfunction group tended to have newborns with LGA after adjusting for pre‐BMI and other potential confounders. Women who were overweight or obese prepregnancy manifested an increased risk of having newborns with macrosomia and LGA relative to normal‐weight women, regardless of whether values were unadjusted or adjusted for all potential confounders. There was no significant interaction between GDM subtype and pre‐BMI for any of the studied outcomes.

   Heterogeneity of GDM (GDM‐dysfunction and GDM‐mixed) and prepregnancy overweight/obesity were independently associated with LGA in Chinese women. There was no significant interaction between GDM subtypes and pre‐BMI for LGA.

    

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2. A probabilistic computation framework to estimate the dawn phenomenon in type 2 diabetes using continuous glucose monitoring

   https://doi.org/10.1038/s41598-024-52461-1  

   Barua, Souptik ; Glantz, Namino ; Larez, Arianna ; Bevier, Wendy ; Sabharwal, Ashutosh ; Kerr, David ( February 2024 , Scientific Reports)

   In type 2 diabetes (T2D), the dawn phenomenon is an overnight glucose rise recognized to contribute to overall glycemia and is a potential target for therapeutic intervention. Existing CGM-based approaches do not account for sensor error, which can mask the true extent of the dawn phenomenon. To address this challenge, we developed a probabilistic framework that incorporates sensor error to assign a probability to the occurrence of dawn phenomenon. In contrast, the current approaches label glucose fluctuations as dawn phenomena as a binary yes/no. We compared the proposed probabilistic model with a standard binary model on CGM data from 173 participants (71% female, 87% Hispanic/Latino, 54 ± 12 years, with either a diagnosis of T2D for six months or with an elevated risk of T2D) stratified by HbA_1clevels into normal but at risk for T2D, with pre-T2D, or with non-insulin-treated T2D. The probabilistic model revealed a higher dawn phenomenon frequency in T2D [49% (95% CI 37–63%)] compared to pre-T2D [36% (95% CI 31–48%), p = 0.01] and at-risk participants [34% (95% CI 27–39%), p < 0.0001]. While these trends were also found using the binary approach, the probabilistic model identified significantly greater dawn phenomenon frequency than the traditional binary model across all three HbA_1csub-groups (p < 0.0001), indicating its potential to detect the dawn phenomenon earlier across diabetes risk categories.

    

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3. Disparities in Hemoglobin A 1c Levels in the First Year After Diagnosis Among Youths With Type 1 Diabetes Offered Continuous Glucose Monitoring

   https://doi.org/10.1001/jamanetworkopen.2023.8881  

   Addala, Ananta ; Ding, Victoria ; Zaharieva, Dessi P. ; Bishop, Franziska K. ; Adams, Alyce S. ; King, Abby C. ; Johari, Ramesh ; Scheinker, David ; Hood, Korey K. ; Desai, Manisha ; et al ( April 2023 , JAMA Network Open)

   Importance Continuous glucose monitoring (CGM) is associated with improvements in hemoglobin A 1c (HbA 1c ) in youths with type 1 diabetes (T1D); however, youths from minoritized racial and ethnic groups and those with public insurance face greater barriers to CGM access. Early initiation of and access to CGM may reduce disparities in CGM uptake and improve diabetes outcomes. Objective To determine whether HbA 1c decreases differed by ethnicity and insurance status among a cohort of youths newly diagnosed with T1D and provided CGM. Design, Setting, and Participants This cohort study used data from the Teamwork, Targets, Technology, and Tight Control (4T) study, a clinical research program that aims to initiate CGM within 1 month of T1D diagnosis. All youths with new-onset T1D diagnosed between July 25, 2018, and June 15, 2020, at Stanford Children’s Hospital, a single-site, freestanding children’s hospital in California, were approached to enroll in the Pilot-4T study and were followed for 12 months. Data analysis was performed and completed on June 3, 2022. Exposures All eligible participants were offered CGM within 1 month of diabetes diagnosis. Main Outcomes and Measures To assess HbA 1c change over the study period, analyses were stratified by ethnicity (Hispanic vs non-Hispanic) or insurance status (public vs private) to compare the Pilot-4T cohort with a historical cohort of 272 youths diagnosed with T1D between June 1, 2014, and December 28, 2016. Results The Pilot-4T cohort comprised 135 youths, with a median age of 9.7 years (IQR, 6.8-12.7 years) at diagnosis. There were 71 boys (52.6%) and 64 girls (47.4%). Based on self-report, participants’ race was categorized as Asian or Pacific Islander (19 [14.1%]), White (62 [45.9%]), or other race (39 [28.9%]); race was missing or not reported for 15 participants (11.1%). Participants also self-reported their ethnicity as Hispanic (29 [21.5%]) or non-Hispanic (92 [68.1%]). A total of 104 participants (77.0%) had private insurance and 31 (23.0%) had public insurance. Compared with the historical cohort, similar reductions in HbA 1c at 6, 9, and 12 months postdiagnosis were observed for Hispanic individuals (estimated difference, −0.26% [95% CI, −1.05% to 0.43%], −0.60% [−1.46% to 0.21%], and −0.15% [−1.48% to 0.80%]) and non-Hispanic individuals (estimated difference, −0.27% [95% CI, −0.62% to 0.10%], −0.50% [−0.81% to −0.11%], and −0.47% [−0.91% to 0.06%]) in the Pilot-4T cohort. Similar reductions in HbA 1c at 6, 9, and 12 months postdiagnosis were also observed for publicly insured individuals (estimated difference, −0.52% [95% CI, −1.22% to 0.15%], −0.38% [−1.26% to 0.33%], and −0.57% [−2.08% to 0.74%]) and privately insured individuals (estimated difference, −0.34% [95% CI, −0.67% to 0.03%], −0.57% [−0.85% to −0.26%], and −0.43% [−0.85% to 0.01%]) in the Pilot-4T cohort. Hispanic youths in the Pilot-4T cohort had higher HbA 1c at 6, 9, and 12 months postdiagnosis than non-Hispanic youths (estimated difference, 0.28% [95% CI, −0.46% to 0.86%], 0.63% [0.02% to 1.20%], and 1.39% [0.37% to 1.96%]), as did publicly insured youths compared with privately insured youths (estimated difference, 0.39% [95% CI, −0.23% to 0.99%], 0.95% [0.28% to 1.45%], and 1.16% [−0.09% to 2.13%]). Conclusions and Relevance The findings of this cohort study suggest that CGM initiation soon after diagnosis is associated with similar improvements in HbA 1c for Hispanic and non-Hispanic youths as well as for publicly and privately insured youths. These results further suggest that equitable access to CGM soon after T1D diagnosis may be a first step to improve HbA 1c for all youths but is unlikely to eliminate disparities entirely. Trial Registration ClinicalTrials.gov Identifier: NCT04336969 

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4. Hypoglycemia in children and young adults with cystic fibrosis during oral glucose tolerance testing vs. continuous glucose monitoring

   https://doi.org/10.1002/ppul.26533  

   Finn, Erin ; Severn, Cameron ; Pyle, Laura ; Garrish, Justin ; Vigers, Timothy ; Behn, Cecilia G. Diniz ; Zeitler, Philip S. ; Sagel, Scott D. ; Nadeau, Kristen J. ; Chan, Christine L. ( June 2023 , Pediatric Pulmonology)

   Hypoglycemia is common in people with cystic fibrosis (pwCF) during oral glucose tolerance tests (OGTTs) and in the free‐living setting, yet its pathophysiology remains unclear.

   To evaluate hypoglycemia in children and young adults with CF by OGTT and continuous glucose monitoring (CGM).

   A 3‐h OGTT was performed in children and young adults with CF and healthy controls (HC). Individuals were classified as experiencing hypoglycemia on OGTT (glucose <70 mg/dL) or not. Insulin, C‐peptide, glucose, glucagon, and incretins were measured. CGM was performed for 7 days in the free‐living setting. Measures of insulin sensitivity, beta cell function accounting for insulin sensitivity, and insulin clearance were calculated.

   A total of 57 participants (40 CF and 17 HC) underwent assessment. Rates of hypoglycemia by OGTT were similar in pwCF (53%, 21/40) compared to HC (35%, 6/17),p = 0.23. PwCF compared to HC had higher A1c; on OGTT higher and later glucose peaks, later insulin peaks; and on CGM more glucose variability. CF Hypo+ versus CF Hypo− had higher lung function, higher insulin sensitivity, higher beta cell function accounting for insulin sensitivity, and decreased CGM variability. When comparing CF Hypo+ to HC Hypo+, although rates of hypoglycemia are similar, pwCF had blunted glucagon responses to hypoglycemia. OGTT hypoglycemia was not associated with CGM hypoglycemia in any group.

   Youth with CF have increased insulin sensitivity and impaired glucagon response to hypoglycemia on OGTT. Hypoglycemia on OGTT did not associate with free‐living hypoglycemia.

    

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5. Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

   https://doi.org/10.1113/JP278726  

   Yates, Dustin T. ; Camacho, Leticia E. ; Kelly, Amy C. ; Steyn, Leah V. ; Davis, Melissa A. ; Antolic, Andrew T. ; Anderson, Miranda J. ; Goyal, Ravi ; Allen, Ronald E. ; Papas, Klearchos K. ; et al ( November 2019 , The Journal of Physiology)

   Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity.

   Although whole‐body glucose clearance is normal, 1‐month‐old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation.

   Impaired glucose‐stimulated insulin secretion in IUGR lambs is due to lower intra‐islet insulin availability and not from glucose sensing.

   We investigated adrenergic receptor (ADR) β2 desensitization by administering oral ADRβ modifiers for the first month after birth to activate ADRβ2 and antagonize ADRβ1/3. In IUGR lambs ADRβ2 activation increased whole‐body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies.

   IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose‐stimulated insulin secretion and insulin‐stimulated glucose oxidation, providing new insights into potential mechanisms for this risk.

   Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin‐sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose‐stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR‐AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole‐body GUR were not different from controls. Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole‐body glucose utilization in IUGR lambs. In IUGR and IUGR‐AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates andex vivoskeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR‐AR skeletal muscle than in controls but GLUT1 was greater in IUGR‐AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR‐AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole‐body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch‐up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.

    

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