Development and Validation of an Electronic Health Record-Based Risk Assessment Tool for Hypoglycemia in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: The recent availability of high-quality data from clinical trials, together with machine learning (ML) techniques, presents exciting opportunities for developing prediction models for clinical outcomes. METHODS: As a proof-of-concept, we translated a hypoglycemia risk model derived from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study into the HypoHazardScore, a risk assessment tool applicable to electronic health record (EHR) data. To assess its performance, we conducted a 16-week clinical study at the University of Minnesota where participants (N = 40) with type 2 diabetes mellitus (T2DM) had hypoglycemia assessed prospectively by continuous glucose monitoring (CGM). RESULTS: The HypoHazardScore combines 16 risk factors commonly found within the EHR. The HypoHazardScore successfully predicted (area under the curve [AUC] = 0.723) whether participants experienced least one CGM-assessed hypoglycemic event (glucose <54 mg/dL for ≥15 minutes from two CGMs) while significantly correlating with frequency of CGM-assessed hypoglycemic events (r = 0.38) and percent time experiencing CGM-assessed hypoglycemia (r = 0.39). Compared to participants with a low HypoHazardScore (N = 19, score <4, median score of 4), participants with a high HypoHazardScore (N = 21, score ≥4) had more frequent CGM-assessed hypoglycemic events (high: 1.6 ± 2.2 events/week; low: 0.3 ± 0.5 events/week) and experienced more CGM-assessed hypoglycemia (high: 1.4% ± 2.0%; low: 0.2% ± 0.4% time) during the 16-week follow-up. CONCLUSIONS: We demonstrated that a hypoglycemia risk model can be successfully adapted from the ACCORD data to the EHR, with validation by a prospective study using CGM-assessed hypoglycemia. The HypoHazardScore represents a significant advancement toward implementing an EHR-based decision support system that can help reduce hypoglycemia in patients with T2DM.

Heterogeneity in Epinephrine Response to Experimental Hypoglycemia in Type 1 Diabetes and Controls.

Context: The epinephrine response (Epi) to a first episode of hypoglycemia (HG) has been proposed to be predictive of Epi in subsequent HG and to provide insight into the risk for developing HG-associated autonomic failure (HAAF) in healthy controls (HCs). Objective: To determine if Epi and symptom response (SR) to the first episode of HG predicts who will develop HAAF after exposure to recurrent HG in volunteers with type 1 diabetes (T1D) and in HCs. Design: Review of data collected between 2013 and 2019. Setting: Academic clinical research unit. Patients or Participants: Volunteers with T1D and HCs. Interventions: Subjects participated in a preinduction protocol where they were exposed to three 2-hour episodes of clamped HG over 2 days. Data collected during clamp 1 were compared with data collected during clamp 3. Main outcome measure: Difference in Epi and SR. Results: Using the standard definition of HAAF in which HG-induced Epi during clamp 3 is at least 20% lower than during clamp 1, 21/28 HCs and 13/19 volunteers with T1D developed HAAF. Epi during clamp 1 was significantly higher in those subjects who developed HAAF than in those who did not in both groups (P = 0.02). If HAAF is defined as achieving a 20% reduction in HG-induced SR measured during clamp 3 compared with clamp 1, 10/27 HCs and 10/19 volunteers with T1D developed SR-based HAAF. Conclusion: There was heterogeneity in the response to the preinduction protocol. Epi during clamp 1 was higher than in clamp 3 in HCs and in those with T1D who developed HAAF.

Monitoring the Neurotransmitter Response to Glycemic Changes Using an Advanced Magnetic Resonance Spectroscopy Protocol at 7T.

The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) are thought to be involved in the response of the brain to changes in glycemia. Therefore, their reliable measurement is critical for understanding the dynamics of these responses. The concentrations of Glu and GABA, as well as glucose (Glc) in brain tissue, can be measured in vivo using proton (1H) magnetic resonance spectroscopy (MRS). Advanced MRS methodology at ultrahigh field allows reliable monitoring of these metabolites under changing metabolic states. However, the long acquisition times needed for these experiments while maintaining blood Glc levels at predetermined targets present many challenges. We present an advanced MRS acquisition protocol that combines commercial 7T hardware (Siemens Scanner and Nova Medical head coil), BaTiO3 dielectric padding, optical motion tracking, and dynamic frequency and B0 shim updates to ensure the acquisition of reproducibly high-quality data. Data were acquired with a semi-LASER sequence [repetition time/echo time (TR/TE) = 5,000/26 ms] from volumes of interest (VOIs) in the prefrontal cortex (PFC) and hypothalamus (HTL). Five healthy volunteers were scanned to evaluate the effect of the BaTiO3 pads on B 1 + distribution. Use of BaTiO3 padding resulted in a 60% gain in signal-to-noise ratio in the PFC VOI over the acquisition without the pad. The protocol was tested in six patients with type 1 diabetes during a clamp study where euglycemic (~100 mg/dL) and hypoglycemic (~50 mg/dL) blood Glc levels were maintained in the scanner. The new protocol allowed retention of all HTL data compared with our prior experience of having to exclude approximately half of the HTL data in similar clamp experiments in the 7T scanner due to subject motion. The advanced MRS protocol showed excellent data quality (reliable quantification of 11-12 metabolites) and stability (p > 0.05 for both signal-to-noise ratio and water linewidths) between euglycemia and hypoglycemia. Decreased brain Glc levels under hypoglycemia were reliably detected in both VOIs. In addition, mean Glu level trended lower at hypoglycemia than euglycemia for both VOIs, consistent with prior observations in the occipital cortex. This protocol will allow robust mechanistic investigations of the primary neurotransmitters, Glu and GABA, under changing glycemic conditions.

Time-Restricted Eating Improves Quality of Life Measures in Overweight Humans.

Time-restricted eating (TRE) reduces weight in humans, but its effects on quality of life have not been well characterized. By performing a secondary analysis of a randomized clinical trial, we examined the effects of TRE (12-week intervention, 8 h eating window) vs. non-TRE (unrestricted eating) on quality of life (QoL) measures. Twenty subjects with overweight and prolonged eating window (mean (SD): 15.4 h (0.9)) were randomized to either 12 weeks of TRE (8 h eating window: (n = 11)) or non-TRE (n = 9). QoL data were collected with the 36-item Short Form Survey (SF-36) pre- and post-intervention. Given a two-way ANOVA model and post-hoc t-test analysis, the TRE group improved limitations due to emotional health post-intervention: +97.0 (10.0)) vs. baseline: +66.7 (42.2) (p = 0.02) and perceived change in health over the last year end intervention: +68.2 (16.2) vs. baseline: +52.3 (23.6) (p = 0.001) relative to baseline. The TRE group improved limitations due to emotional health TRE: +97.0 (10.0) vs. non-TRE: +55.6 (44.1) (p = 0.05) and perceived change in health (TRE: +68.2 (16.2) vs. non-TRE: +44.4 (31.6) (p = 0.04) relative to the non-TRE group at post-intervention (p < 0.025). In conclusion, 12 weeks of TRE does not adversely affect QoL and may be associated with modest improvements in QoL relative to baseline and unrestricted eating; these findings support future studies examining TRE compliance and durability.

Time-Restricted Eating Effects on Body Composition and Metabolic Measures in Humans who are Overweight: A Feasibility Study.

OBJECTIVE: In contrast to intentionally restricting energy intake, restricting the eating window may be an option for treating obesity. By comparing time-restricted eating (TRE) with an unrestricted (non-TRE) control, it was hypothesized that TRE facilitates weight loss, alters body composition, and improves metabolic measures. METHODS: Participants (17 women and 3 men; mean [SD]: 45.5 [12.1] years; BMI 34.1 [7.5] kg/m2 ) with a prolonged eating window (15.4 [0.9] hours) were randomized to TRE (n = 11: 8-hour window, unrestricted eating within window) versus non-TRE (n = 9: unrestricted eating) for 12 weeks. Weight, body composition (dual x-ray absorptiometry), lipids, blood pressure, 2-hour oral glucose tolerance, 2-week continuous glucose monitoring, and 2-week physical activity (actigraphy assessed) were measured during the pre- and end-intervention periods. RESULTS: The TRE group significantly reduced the eating window (end-intervention window: 9.9 [2.0] hours) compared with the non-TRE group (end-intervention window: 15.1 [1.1] hours) (P < 0.01). Compared with non-TRE, TRE decreased the number of eating occasions, weight, lean mass, and visceral fat (all P ≤ 0.05). Compared with preintervention measures, the TRE group reduced the number of eating occasions (-21.9% [30.1%]) and reduced weight (-3.7% [1.8%]), fat mass (-4% [2.9%]), lean mass (-3.0% [2.7%]), and visceral fat (-11.1% [13.4%]) (all P ≤ 0.05). Physical activity and metabolic measures remained unchanged. CONCLUSIONS: In the setting of a randomized trial, TRE presents a simplified view of food intake that reduces weight.

High Body Mass Index Masks Body Composition Differences in Physically Active Versus Sedentary Participants.

BACKGROUND: Despite the benefits of aerobic exercise on body composition, runners with high body mass index (BMI) remain understudied. We examined body composition differences between sedentary insulin-resistant [obese insulin-resistant sedentary (OS-IR)], sedentary insulin-sensitive [obese insulin-sensitive sedentary (OS-IS)], and trained [obese trained (OT)] individuals with high BMI (≥25 kg/m2). We hypothesized that after matching for high BMI, OT individuals would have less fat mass (absolute and relative) and greater lean mass than OS-IR or OS-IS individuals. METHODS: This is a retrospective analysis of OS-IR, OS-IS, and OT participants selected for similar age, sex, and BMI. Activity was self-reported. OT participants exercised at least 30 min/day (predominantly running) for 3-5 days/week. OS-IS and OS-IR participants actively exercised <0.5 hr/week. Body composition was measured by dual X-ray absorptiometry. RESULTS: Thirty-three participants were recruited [n = 11/group, mean age 31.7 years (standard error): (0.9)], 7 females/group, overall BMI [31.6 kg/m2 (0.7)]. Insulin resistance, quantified by the homeostatic model assessment for insulin resistance, was higher in the OS-IR [3.3 (0.2)] than the OS-IS [0.9 (0.2): P < 0.0001] or OT [1.6 (0.2): P < 0.0001] groups. We found the following: (i) Compared to the OS-IR group, the OT group had lower region-specific fat mass as measured by percent fat (trunk) or absolute fat mass (trunk, android region, and abdominal visceral region). (ii) OT and OS-IS groups had similar body composition. (iii) Total fat mass and percent body fat correlated with BMI, (iv) Visceral fat correlated with BMI (r = 0.80, P = 0.003) only in the OS-IR (P = 0.03 for BMI × group interaction). CONCLUSIONS: Using BMI to classify obesity masks body composition differences in high BMI individuals discrepant for insulin resistance and physical activity status.

X-linked high myopia associated with cone dysfunction.

OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. METHODS: X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38 and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease-affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS: Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.