Different FreeSurfer versions might generate different statistical outcomes in case-control comparison studies.

PURPOSE: Neuroimaging pipelines have long been known to generate mildly differing results depending on various factors, including software version. While considered generally acceptable and within the margin of reasonable error, little is known about their effect in common research scenarios such as inter-group comparisons between healthy controls and various pathological conditions. The aim of the presented study was to explore the differences in the inferences and statistical significances in a model situation comparing volumetric parameters between healthy controls and type 1 diabetes patients using various FreeSurfer versions. METHODS: T1- and T2-weighted structural scans of healthy controls and type 1 diabetes patients were processed with FreeSurfer 5.3, FreeSurfer 5.3 HCP, FreeSurfer 6.0 and FreeSurfer 7.1, followed by inter-group statistical comparison using outputs of individual FreeSurfer versions. RESULTS: Worryingly, FreeSurfer 5.3 detected both cortical and subcortical volume differences out of the preselected regions of interest, but newer versions such as FreeSurfer 5.3 HCP and FreeSurfer 6.0 reported only subcortical differences of lower magnitude and FreeSurfer 7.1 failed to find any statistically significant inter-group differences. CONCLUSION: Since group averages of individual FreeSurfer versions closely matched, in keeping with previous literature, the main origin of this disparity seemed to lie in substantially higher within-group variability in the model pathological condition. Ergo, until validation in common research scenarios as case-control comparison studies is included into the development process of new software suites, confirmatory analyses utilising a similar software based on analogous, but not fully equivalent principles, might be considered as supplement to careful quality control.

Multiple predictively equivalent risk models for handling missing data at time of prediction: With an application in severe hypoglycemia risk prediction for type 2 diabetes.

The presence of missing data at the time of prediction limits the application of risk models in clinical and research settings. Common ways of handling missing data at the time of prediction include measuring the missing value and employing statistical methods. Measuring missing value incurs additional cost, whereas previously reported statistical methods results in reduced performance compared to when all variables are measured. To tackle these challenges, we introduce a new strategy, the MMTOP algorithm (Multiple models for Missing values at Time Of Prediction), which does not require measuring additional data elements or data imputation. Specifically, at model construction time, the MMTOP constructs multiple predictively equivalent risk models utilizing different risk factor sets. The collection of models are stored and to be queried at prediction time. To predict an individual's risk in the presence of incomplete data, the MMTOP selects the risk model based on measurement availability for that individual from the collection of predictively equivalent models and makes the risk prediction with the selected model. We illustrate the MMTOP with severe hypoglycemia (SH) risk prediction based on data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. We identified 77 predictively equivalent models for SH with cross-validated c-index of 0.77 ± 0.03. These models are based on 77 distinct risk factor sets containing 12-17 risk factors. In terms of handling missing data at the time of prediction, the MMTOP outperforms all four tested competitor methods and maintains consistent performance as the number of missing variables increase.

Prospective study evaluating the use of nasal glucagon for the treatment of moderate to severe hypoglycaemia in adults with type 1 diabetes in a real-world setting.

In the present multicentre, open-label, prospective, phase III study, we evaluated the real-world effectiveness and ease of use of nasal glucagon (NG) in the treatment of moderate/severe hypoglycaemic events (HEs) in adults with type 1 diabetes (T1D). Patients and caregivers were taught how to use NG (3 mg) to treat moderate/severe HEs, record the time taken to awaken or return to normal status, and measure blood glucose (BG) levels over time. Questionnaires were used to collect information about adverse events and ease of use of NG. In the efficacy analysis population, 69 patients experienced 157 HEs. In 95.7% patients, HEs resolved within 30 minutes of NG administration. In all the 12 severe HEs, patients awakened or returned to normal status within 15 minutes of NG administration without additional external medical help. Most caregivers reported that NG was easy to use. Most adverse events were local and of low to moderate severity. In this study, a single, 3-mg dose of NG demonstrated real-life effectiveness in treating moderate and severe HEs in adults with T1D. NG was well tolerated and easy to use.

Biomarkers related to severe hypoglycaemia and lack of good glycaemic control in ACCORD.

AIMS/HYPOTHESIS: In patients with diabetes, intensive glycaemic control reduces microvascular complications. However, severe hypoglycaemia frequently complicates intensive glycaemic control. Blood biomarkers that predict successful intensification of glycaemic control in patients with type 2 diabetes without the development of severe hypoglycaemia would advance patient care. In patients who received intensive treatment for type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesised that insulin deficiency and islet autoantibodies would be associated with severe hypoglycaemia and failure to achieve near-normal glycaemia (HbA1c <6.0% [42 mmol/mol]). METHODS: A nested case-control design was used. Cases (n = 326) were defined as participants having severe hypoglycaemia and failure to achieve an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death. Controls (n = 1,075) were those who achieved an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death without severe hypoglycaemia. Each case was matched (for race, age and BMI) by up to four controls. Baseline insulin deficiency (fasting C-peptide ≤0.15 nmol/l) and islet autoantibodies (glutamic acid decarboxylase [GAD], tyrosine phosphatase-related islet antigen 2 [IA2], insulin [IAA] and zinc transporter 8 [ZnT8]) were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used on the full cohort and after removal of patients who died and their respective controls. RESULTS: Severe hypoglycaemia accompanied by an inability to achieve an HbA1c level of <6.0% (42 mmol/mol) was associated with insulin deficiency (adjusted OR 23.2 [95% CI 9.0, 59.5], p < 0.0001), the presence of IAA autoantibodies or baseline insulin use (adjusted OR 3.8 [95% CI 2.7, 5.3], p < 0.0001), GAD autoantibodies (OR 3.9 [95% CI 2.5, 6.0], p < 0.0001), IA2 autoantibodies (OR 16.7 [95% CI 3.9, 71.6], p = 0.0001) and ZnT8 autoantibodies (adjusted OR 3.9 [95% CI 1.2, 12.4], p = 0.02). CONCLUSIONS: C-peptide and islet autoantibodies may serve as biomarkers to predict the risk of severe hypoglycaemia during intensification of type 2 diabetes treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000620 (original ACCORD study).

The Impact of Diabetes on Cerebral Structure and Function.

Diabetes alters cerebral metabolism, structure, and function. Both hyperglycemia and therapy-associated hypoglycemia are believed to have an impact on the brain, and this impact may depend on the age of the individual, their stage of neurological development, and whether they have Type 1 or Type 2 diabetes. Hypoglycemia in children with Type 1 has consistently been associated with a reduction in neurocognitive function, but such a finding has not been seen in adults with Type 1 diabetes. Both hypoglycemia and hyperglycemia have been linked with dementia in adults with Type 2 diabetes. In both Type 1 and Type 2 diabetes, recurrent episodes of treatment-associated hypoglycemia impair how well the brain can sense and respond to subsequent episodes of hypoglycemia. In this brief review, we will review how diabetes affects the brain with a focus on investigations done in our own laboratory. We have focused on using high magnetic field imaging and spectroscopy to identify subtle changes in brain structure and metabolism that may contribute to the long-term cerebral complications of diabetes. We have found evidence of microstructural changes in white matter regions, reduced gray matter density, and reduced activation of the thalamus in response to recurrent hypoglycemia in patients with Type 1 diabetes.

Feasibility and reproducibility of neurochemical profile quantification in the human hippocampus at 3 T.

Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric disorders such as Alzheimer's disease, epilepsy, schizophrenia and depression; therefore, there has been significant clinical interest in studying hippocampal neurochemistry. However, the hippocampus is a challenging region to study using (1) H MRS, hence the use of MRS for clinical research in this region has been limited. Our goal was therefore to investigate the feasibility of obtaining high-quality hippocampal spectra that allow reliable quantification of a neurochemical profile and to establish inter-session reproducibility of hippocampal MRS, including reproducibility of voxel placement, spectral quality and neurochemical concentrations. Ten healthy volunteers were scanned in two consecutive sessions using a standard clinical 3 T MR scanner. Neurochemical profiles were obtained with a short-echo (T(E) = 28 ms) semi-LASER localization sequence from a relatively small (~4 mL) voxel that covered about 62% of the hippocampal volume as calculated from segmentation of T1 -weighted images. Voxel composition was highly reproducible between sessions, with test-retest coefficients of variation (CVs) of 3.5% and 7.5% for gray and white matter volume fraction, respectively. Excellent signal-to-noise ratio (~54 based on the N-acetylaspartate (NAA) methyl peak in non-apodized spectra) and linewidths (~9 Hz for water) were achieved reproducibly in all subjects. The spectral quality allowed quantification of NAA, total choline, total creatine, myo-inositol and glutamate with high scan-rescan reproducibility (CV ≤ 6%) and quantification precision (Cramér-Rao lower bound, CRLB < 9%). Four other metabolites, including glutathione and glucose, were quantified with scan-rescan CV below 20%. Therefore, the highly optimized, short-echo semi-LASER sequence together with FASTMAP shimming substantially improved the reproducibility and number of quantifiable metabolites relative to prior reports. In addition, the between-session variation in metabolite concentrations, as well as CRLB, was lower than the between-subject variation of the concentrations for most metabolites, indicating that the method has the sensitivity to detect inter-individual differences in the healthy brain.

Revisiting Glycogen Content in the Human Brain.

Glycogen provides an important glucose reservoir in the brain since the concentration of glucosyl units stored in glycogen is several fold higher than free glucose available in brain tissue. We have previously reported 3-4 µmol/g brain glycogen content using in vivo (13)C magnetic resonance spectroscopy (MRS) in conjunction with [1-(13)C]glucose administration in healthy humans, while higher levels were reported in the rodent brain. Due to the slow turnover of bulk brain glycogen in humans, complete turnover of the glycogen pool, estimated to take 3-5 days, was not observed in these prior studies. In an attempt to reach complete turnover and thereby steady state (13)C labeling in glycogen, here we administered [1-(13)C]glucose to healthy volunteers for 80 h. To eliminate any net glycogen synthesis during this period and thereby achieve an accurate estimate of glycogen concentration, volunteers were maintained at euglycemic blood glucose levels during [1-(13)C]glucose administration and (13)C-glycogen levels in the occipital lobe were measured by (13)C MRS approximately every 12 h. Finally, we fitted the data with a biophysical model that was recently developed to take into account the tiered structure of the glycogen molecule and additionally incorporated blood glucose levels and isotopic enrichments as input function in the model. We obtained excellent fits of the model to the (13)C-glycogen data, and glycogen content in the healthy human brain tissue was found to be 7.8 ± 0.3 µmol/g, a value substantially higher than previous estimates of glycogen content in the human brain.

In vivo Magnetic Resonance Spectroscopy of cerebral glycogen metabolism in animals and humans.

Glycogen serves as an important energy reservoir in the human body. Despite the abundance of glycogen in the liver and skeletal muscles, its concentration in the brain is relatively low, hence its significance has been questioned. A major challenge in studying brain glycogen metabolism has been the lack of availability of non-invasive techniques for quantification of brain glycogen in vivo. Invasive methods for brain glycogen quantification such as post mortem extraction following high energy microwave irradiation are not applicable in the human brain. With the advent of (13)C Magnetic Resonance Spectroscopy (MRS), it has been possible to measure brain glycogen concentrations and turnover in physiological conditions, as well as under the influence of stressors such as hypoglycemia and visual stimulation. This review presents an overview of the principles of the (13)C MRS methodology and its applications in both animals and humans to further our understanding of glycogen metabolism under normal physiological and pathophysiological conditions such as hypoglycemia unawareness.

Training status diverges muscle diacylglycerol accumulation during free fatty acid elevation.

How endurance training alters muscle lipid metabolism while preserving insulin sensitivity remains unclear. Because acute free fatty acid (FFA) elevation by lipid infusion reduces insulin sensitivity, we hypothesized that training status would alter accumulation of muscle triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and acylcarnitine during acute FFA elevation. Trained (n = 15) and sedentary (n = 13) participants matched for age, sex, and BMI received either a 6-h infusion of lipid (20% Intralipid at 90 ml/h) or glycerol (2.25 g/100 ml at 90 ml/h) during a hyperinsulinemic euglycemic clamp. Muscle biopsies were taken at 0, 120, and 360 min after infusion initiation to measure intramyocellular concentrations of TAG, DAG, ceramides, and acylcarnitines by liquid chromatography-tandem mass spectrometry. Trained participants had a higher Vo2 max and insulin sensitivity than sedentary participants. The lipid infusion produced a comparable elevation of FFA (594 ± 90 µmol/l in trained, 721 ± 30 µmol/l in sedentary, P = 0.4) and a decline in insulin sensitivity (-44.7% trained vs. -47.2% sedentary, P = 0.89). In both groups, lipid infusion increased the linoleic and linolenic acid content of TAG without changing total TAG. In the sedentary group, lipid infusion increased total, oleic, and linoleic acid and linolenic acid content of DAG. Regardless of training status, lipid infusion did not alter total ceramide, saturated ceramide, palmitoyl-carnitine, or oleoyl-carnitine. We conclude that during acute FFA elevation, trained adults have a similar decline in insulin sensitivity with less accumulation of muscle DAG than sedentary adults, suggesting that lipid-induced insulin resistance can occur without elevation of total muscle DAG.

Hypoglycemia as a driver of cardiovascular risk in diabetes.

Severe hypoglycemia in patients with diabetes is associated with increased risk of adverse cardiovascular events and death. Recent large randomized clinical trials in individuals with type 2 diabetes have shown that intensive glycemic control may result in increased mortality, and hypoglycemia has been investigated as a possible cause. Acute hypoglycemia is a proarrhythmic, proinflammatory, and prothrombotic state, and several mechanisms have been proposed to explain how hypoglycemia might increase cardiovascular morbidity and mortality. However, data from large clinical trials do not provide strong evidence to establish hypoglycemia as a cause of increased mortality. Severe hypoglycemia is also a marker of frailty and a predictor of adverse outcomes in patients with diabetes. Individualized therapy should be the goal in patients with diabetes to avoid severe hypoglycemia and any related adverse outcomes.

The effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons with type 2 diabetes and chronic periodontitis: a randomized clinical trial.

IMPORTANCE: Chronic periodontitis, a destructive inflammatory disorder of the supporting structures of the teeth, is prevalent in patients with diabetes. Limited evidence suggests that periodontal therapy may improve glycemic control. OBJECTIVE: To determine if nonsurgical periodontal treatment reduces levels of glycated hemoglobin (HbA1c) in persons with type 2 diabetes and moderate to advanced chronic periodontitis. DESIGN, SETTING, AND PARTICIPANTS: The Diabetes and Periodontal Therapy Trial (DPTT), a 6-month, single-masked, multicenter, randomized clinical trial. Participants had type 2 diabetes, were taking stable doses of medications, had HbA1c levels between 7% and less than 9%, and untreated chronic periodontitis. Five hundred fourteen participants were enrolled between November 2009 and March 2012 from diabetes and dental clinics and communities affiliated with 5 academic medical centers. INTERVENTIONS: The treatment group (n = 257) received scaling and root planing plus chlorhexidine oral rinse at baseline and supportive periodontal therapy at 3 and 6 months. The control group (n = 257) received no treatment for 6 months. MAIN OUTCOMES AND MEASURES: Difference in change in HbA1c level from baseline between groups at 6 months. Secondary outcomes included changes in probing pocket depths, clinical attachment loss, bleeding on probing, gingival index, fasting glucose level, and Homeostasis Model Assessment (HOMA2) score. RESULTS: Enrollment was stopped early because of futility. At 6 months, mean HbA1c levels in the periodontal therapy group increased 0.17% (SD, 1.0), compared with 0.11% (SD, 1.0) in the control group, with no significant difference between groups based on a linear regression model adjusting for clinical site (mean difference, -0.05% [95% CI, -0.23% to 0.12%]; P = .55). Periodontal measures improved in the treatment group compared with the control group at 6 months, with adjusted between-group differences of 0.28 mm (95% CI, 0.18 to 0.37) for probing depth, 0.25 mm (95% CI, 0.14 to 0.36) for clinical attachment loss, 13.1% (95% CI, 8.1% to 18.1%) for bleeding on probing, and 0.27 (95% CI, 0.17 to 0.37) for gingival index (P < .001 for all). CONCLUSIONS AND RELEVANCE: Nonsurgical periodontal therapy did not improve glycemic control in patients with type 2 diabetes and moderate to advanced chronic periodontitis. These findings do not support the use of nonsurgical periodontal treatment in patients with diabetes for the purpose of lowering levels of HbA1c. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00997178.

Translational aspects of glucagon: current use and future prospects.

Glucagon is secreted by the pancreatic alpha cell and has long been known to oppose insulin action. A lyophilized form of the hormone has been available to treat episodes of insulin-induced hypoglycemia in insulin-treated people with diabetes for decades, but the difficulty of use was a barrier to widespread utilization. Newer formulations of glucagon are stable at room temperature in single-use devices that many caregivers find are easier to use than the original glucagon emergency kit. In this review , we will review what is known about the role of glucagon in normal physiology and diabetes and then discuss how the research in this area has been translated into treatment for metabolic conditions.

Hypoglycaemia in type 1 diabetes mellitus: risks and practical prevention strategies.

Hypoglycaemia, which occurs when blood levels of glucose fall below what is considered a normal range, is a well-known complication of insulin therapy in individuals with type 1 diabetes mellitus. Despite advances in diabetes mellitus management, hypoglycaemia has continued to affect the majority of these individuals, leading to suboptimal care and decreased quality of life. Multiple epidemiological studies have demonstrated the risks associated with hypoglycaemic events. With this understanding, various advances have been made in therapeutics for diabetes mellitus management. Diabetes mellitus education continues to form the foundation for management and prevention of hypoglycaemia. The advent of newer diabetes mellitus technologies and newer insulins herald improvements in management strategies and hypoglycaemia prevention. Improved understanding of these newer approaches is needed to ensure delivery of safe and effective care to individuals with type 1 diabetes mellitus, leading to reductions in both the short-term and long-term morbidity and mortality associated with hypoglycaemic events.

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.

Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.

Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.

BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study.

OBJECTIVE: This study explored the association of BMI and insulin sensitivity with cognitive performance in type 2 diabetes. METHODS: A cross-sectional analysis of data from the baseline assessment of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE) was conducted. BMI was used as a surrogate of adiposity and the Matsuda index as the measure of insulin sensitivity. Cognitive tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and the letter and animal fluency tests. RESULTS: Cognitive assessments were completed by 5018 (99.4%) of 5047 participants aged 56.7 ± 10.0 years, of whom 36.4% were female. Higher BMI and lower insulin sensitivity were related to better performance on memory and verbal fluency tests. In models including BMI and insulin sensitivity simultaneously, only higher BMI was related to better cognitive performance. CONCLUSIONS: In this study, higher BMI and lower insulin sensitivity in type 2 diabetes were cross-sectionally associated with better cognitive performance. However, only higher BMI was related to cognitive performance when both BMI and insulin sensitivity were considered simultaneously. The causality and mechanisms for this association need to be determined in future studies.

Cognitive dysfunction and diabetes mellitus.

The deleterious effects of diabetes mellitus on the retinal, renal, cardiovascular, and peripheral nervous systems are widely acknowledged. Less attention has been given to the effect of diabetes on cognitive function. Both type 1 and type 2 diabetes mellitus have been associated with reduced performance on numerous domains of cognitive function. The exact pathophysiology of cognitive dysfunction in diabetes is not completely understood, but it is likely that hyperglycemia, vascular disease, hypoglycemia, and insulin resistance play significant roles. Modalities to study the effect of diabetes on the brain have evolved over the years, including neurocognitive testing, evoked response potentials, and magnetic resonance imaging. Although much insightful research has examined cognitive dysfunction in patients with diabetes, more needs to be understood about the mechanisms and natural history of this complication in order to develop strategies for prevention and treatment.

Impaired Awareness of Hypoglycemia in Type 1 Diabetes: A Report of An NIDDK Workshop in October 2021.

Hypoglycemia remains a limiting factor in the optimal treatment of type 1 diabetes. Repeated episodes of hypoglycemia result in impaired awareness of subsequent hypoglycemic events, inducing a vicious feed-forward cycle and increasing the risk of morbidity and mortality. Why this occurs and how to manage the problem in clinical practice remain uncertain. To address the obstacles and barriers that have hindered progress in this clinically important area, the National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on 14-15 October 2021. This perspective offers a summary of this outstanding meeting, which brought clinical and basic scientists from the fields of diabetes, neuroscience, psychology, psychiatry, and imaging together, on how to best advance the field of impaired awareness of hypoglycemia and hypoglycemia in general in patients with diabetes.

Relationship Between Hypoglycemia Awareness Status on Clarke/Gold Methods and Counterregulatory Response to Hypoglycemia.

Context: Impaired awareness of hypoglycemia (IAH) is characterized by the diminished ability to perceive symptoms of hypoglycemia. Gold and Clark questionnaires are commonly used to identify patients with IAH. The relationship between IAH status on questionnaires and a person's symptom and epinephrine responses to hypoglycemia are not well understood. Objective: We aimed to examine the relationship between hypoglycemia awareness status on Clarke and Gold questionnaires with both hormonal and symptomatic responses to experimental hypoglycemia. Methods: In this university medical center study, we examined data from 78 subjects with type 1 diabetes (T1D) who completed both questionnaires and underwent a hyperinsulinemic hypoglycemic clamp (target glucose 50 mg/dL). Results: Clarke and Gold scores were highly correlated with one another (r = 0.82) and each had a moderate negative relationship with epinephrine (Clarke: r = -0.51, Gold: r = -0.50) and total symptom response (Clarke: r = -0.59, Gold: r = -0.57). However, 32% of the subjects were classified inconsistently by Clark vs Gold. A clustering analysis was done to examine how disagreement between the 2 questionnaires on IAH classification relates to epinephrine and symptoms responses during hypoglycemia. Subjects who had partial loss of symptoms or of epinephrine response were more likely to be classified inconsistently. Conclusion: Our results show that IAH classification may be discordant between Clark and Gold questionnaires and that hypoglycemia awareness status on Clarke and Gold questionnaires poorly predicts hormonal and symptomatic responses to hypoglycemia in subjects with T1D and moderate blunting of symptoms or epinephrine.