Optimal Designs for Model-Based Assessment of Insulin Sensitivity and Glucose Effectiveness.

The integrated minimal model allows assessment of clinical diagnosis indices, for example, insulin sensitivity (SI ) and glucose effectiveness (SG ), from data of the insulin-modified intravenous glucose tolerance test (IVGTT), which is laborious with an intense sampling schedule, up to 32 samples. The aim of this study was to propose a more informative, although less laborious, IVGTT design to be used for model-based assessment of SI and SG . The IVGTT design was optimized simultaneously for all design variables: glucose and insulin infusion doses, time of glucose dose and start of insulin infusion, insulin infusion duration, sampling times, and number of samples. Design efficiency was used to compare among different designs. The simultaneously optimized designs showed a profound higher efficiency than both standard rich (32 samples) and sparse (10 samples) designs. The optimized designs, after removing replicate sample times, were 1.9 and 7.1 times more efficient than the standard rich and sparse designs, respectively. After including practical aspects of the designs, for example, sufficient duration between samples and avoidance of prolonged hypoglycemia, we propose 2 practical designs with fewer sampling times and lower input of glucose and insulin than standard designs, constrained to prevent hypoglycemia. The optimized practical rich design is equally efficient in assessing SI and SG as the rich standard design, but with half the number of the samples, while the optimized practical sparse design has 1 less sample and requires 4.6 times fewer individuals for equal certainty when assessing SI and SG than the sparse standard design.

Clinical and Public Health Implications of 2019 Endocrine Society Guidelines for Diagnosis of Diabetes in Older Adults.

OBJECTIVE: Screening for diabetes is typically done using hemoglobin A1c (HbA1c) or fasting plasma glucose (FPG). The 2019 Endocrine Society guidelines recommend further testing using an oral glucose tolerance test (OGTT) in older adults with prediabetic HbA1c or FPG. We evaluated the impact of this recommendation on diabetes prevalence, eligibility for glucose-lowering treatment, and estimated cost of implementation in a nationally representative sample. RESEARCH DESIGN AND METHODS: We included 2,236 adults aged ≥65 years without known diabetes from the 2005-2016 National Health and Nutrition Examination Survey. Diabetes was defined using: 1) the Endocrine Society approach (HbA1c ≥6.5%, FPG ≥126 mg/dL, or 2-h plasma glucose ≥200 mg/dL among those with HbA1c 5.7-6.4% or FPG 100-125 mg/dL); and 2) a standard approach (HbA1c ≥6.5% or FPG ≥126 mg/dL). Treatment eligibility was defined using HbA1c cut points (≥7% to ≥9%). OGTT screening costs were estimated using Medicare fee schedules. RESULTS: Diabetes prevalence was 15.7% (∼5.0 million) using the Endocrine Society's approach and 7.3% (∼2.3 million) using the standard approach. Treatment eligibility ranged from 5.4% to 0.06% and 11.8% to 1.3% for diabetes cases identified through the Endocrine Society or standard approach, respectively. By definition, diabetes identified exclusively through the Endocrine Society approach had HbA11c <6.5% and would not be recommended for glucose-lowering treatment. Screening all older adults with prediabetic HbA1c/FPG (∼18.3 million) with OGTT could cost between $737 million and $1.7 billion. CONCLUSIONS: Adopting the 2019 Endocrine Society guidelines would substantially increase the number of older adults classified as having diabetes, require significant financial resources, but likely offer limited benefits.

Optimal Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Cut-Offs: A Cross-Sectional Study in the Czech Population.

Background and Objectives: The key pathogenetic mechanism of glucose metabolism disorders, insulin resistance (IR), can be assessed using the Homeostasis Model Assessment of IR (HOMA-IR). However, its application in clinical practice is limited due to the absence of cut-offs. In this study, we aimed to define the cut-offs for the Czech population. Methods: After undergoing anthropometric and biochemical studies, the sample of 3539 individuals was divided into either nondiabetics, including both subjects with normal glucose tolerance (NGT, n = 1947) and prediabetics (n = 1459), or diabetics (n = 133). The optimal HOMA-IR cut-offs between subgroups were determined to maximize the sum of the sensitivity and specificity for diagnosing type 2 diabetes mellitus (T2DM) or prediabetes. The predictive accuracy was illustrated using receiver operating characteristic (ROC) curves. Logistic regression was performed to assess the association between a target variable (presence/absence of T2DM) depending on the HOMA-IR score as well as on the age and sex. Results: The HOMA-IR cut-off between nondiabetics and diabetics for both sexes together was 3.63, with a sensitivity of 0.56 and a specificity of 0.86. The area under the ROC curve was 0.73 for T2DM diagnosing in both sexes. The HOMA-IR cut-off between the NGT subjects and prediabetics was 1.82, with a sensitivity of 0.60 and a specificity of 0.66. Logistic regression showed that increased HOMA-IR is a risk factor for the presence of T2DM (odds ratio (OR) 1.2, 95% confidence interval (CI) 1.14-1.28, p < 0.0001). The predictive ability of HOMA-IR in diagnosing T2DM is statistically significantly lower in females (OR 0.66, 95% CI 0.44-0.98). The results are valid for middle-aged European adults. Conclusions: The results suggest the existence of HOMA-IR cut-offs signaling established IR. Introduction of the instrument into common clinical practice, together with the known cut-offs, may contribute to preventing T2DM.

The impact of cystic fibrosis-related diabetes on health-related quality of life.

Cystic fibrosis-related diabetes (CFRD) is a well-known comorbidity among the CF population. To investigate whether CFRD impacts health-related quality of life (HRQoL), domain scores from the Cystic Fibrosis Questionnaire-Revised for adolescents and adults over 14 years old (CFQ-R 14+) were compared between CF individuals with CFRD on insulin, CFRD not on insulin, impaired glucose tolerance, and normal blood glucose tolerance. The median score for the Treatment Burden domain was significantly worse for individuals with CFRD on insulin (p < 0.001) compared to the other diagnostic groups, and this association remained significant following adjustment for confounding variables. In conclusion, the additional requirement for insulin significantly contributes to treatment burden in adults with CFRD and therefore novel strategies to reduce treatment burden for this group are urgently needed.

Assessment of glucose variability in subjects with prediabetes.

The aim of the study was to assess glucose variability in subjects with prediabetes by means of CGM. MATERIAL AND METHODS: 32 subjects with prediabetes - mean age 56.6 ±â€¯9.6 years, mean BMI 30.3 ±â€¯5.3 kg/m2 and 18 subjects with normal glucose tolerance (NGT) - mean age 54.4 ±â€¯9.9 years, mean BMI 24.8 ±â€¯6.9 kg/m2, were enrolled. Glucose tolerance was studied during OGTT. HbA1c was measured by NGSP certified method. CGM was performed with FreeStyle Libre Pro sensor. RESULTS: The following indices of glucose variability were significantly higher in the prediabetes group - CV (p < 0.041), J-index (p < 0.014), CONGA (p < 0.047) and GRADE (p < 0.036). A significant increase in HbA1c (p < 0.036), mean interstitial glucose (p < 0.025), time above range (p < 0.018) and a significant decrease in time in range (p < 0.014) was found in prediabetes compared to NGT. Significant correlations between HbA1c and LBGI (r = -0.33, p = 0.02), HBGI (r = 0.31, p = 0.03), CONGA (r = 0.36, p = 0.01), J-index (r = 0.37, p = 0.01) and M-value (r = -0.34, p = 0.02) were established. CONCLUSION: Glucose variability is significantly increased in prediabetes and is an additional parameter in the assessment of glucose homeostasis even at these early stages of glucose dysregulation.

Assessing the predictive accuracy of oral glucose effectiveness index using a calibration model.

PURPOSE: Current reference methods for measuring glucose effectiveness (GE) are the somatostatin pancreatic glucose clamp and minimal model analysis of frequently sampled intravenous glucose tolerance test (FSIVGTT), both of which are laborious and not feasible in large epidemiological studies. Consequently, surrogate indices derived from an oral glucose tolerance test (OGTT) to measure GE (oGE) have been proposed and used in many studies. However, the predictive accuracy of these surrogates has not been formally validated. In this study, we used a calibration model analysis to evaluate the accuracy of surrogate indices to predict GE from the reference FSIVGTT (SgMM). METHODS: Subjects (n = 123, mean age 48 ± 11 years; BMI 35.9 ± 7.3 kg/m2) with varying glucose tolerance (NGT, n = 37; IFG/IGT, n = 78; and T2DM, n = 8) underwent FSIVGTT and OGTT on two separate days. Predictive accuracy was assessed by both root mean squared error (RMSE) of prediction and leave-one-out cross-validation-type RMSE of prediction (CVPE). RESULTS: As expected, insulin sensitivity, SgMM, and oGE were reduced in subjects with T2DM and IFG/IGT when compared with NGT. Simple linear regression analyses revealed a modest but significant relationship between oGE and SgMM (r = 0.25, p < 0.001). However, using calibration model, measured SgMM and predicted SgMM derived from oGE were modestly correlated (r = 0.21, p < 0.05) with the best fit line suggesting poor predictive accuracy. There were no significant differences in CVPE and RMSE among the surrogates, suggesting similar predictive ability. CONCLUSIONS: Although OGTT-derived surrogate indices of GE are convenient and feasible, they have limited ability to robustly predict GE.

Continuous glucose monitoring guided insulin therapy is associated with improved clinical outcomes in cystic fibrosis-related diabetes.

INTRODUCTION: Continuous glucose monitoring (CGM) allows assessment of day to day glycaemic excursions and detects early glucose handling abnormalities that may not be apparent on oral glucose tolerance testing (OGTT). However, there is little published evidence as to whether these early dysglycaemic changes are amenable to treatment. We present outcomes following CGM guided insulin initiation at our centre. METHODS: Adults without a prior diagnosis of cystic fibrosis related diabetes (CFRD) whom underwent >72 h CGM at our adult CF centre were included in the study. Clinical outcomes including weight and pulmonary function changes over the next 12 months were compared between groups based on CGM results and subsequent management. RESULTS: CGM profiles for 59 patients were analysed. Insulin was commenced in 37 patients who had evidence of hyperglycaemia on CGM. Significant improvements in mean [95% confidence intervals] forced expiratory volume in 1 s (FEV1) (+4.3% predicted [1.06-7.48], p = 0.01) and weight (+1.2 kg [0.32-2.15], p = 0.01) were observed at 3 months in the insulin group. Annual rate of pulmonary function decline was also improved following insulin initiation. CONCLUSION: Insulin treatment targeted towards glycaemic excursions seen on CGM is associated with improvements in lung function and weight with subsequent reduced pulmonary function decline.

Glucose challenge test screening for prediabetes and early diabetes.

AIMS: To test the hypothesis that a 50-g oral glucose challenge test with 1-h glucose measurement would have superior performance compared with other opportunistic screening methods. METHODS: In this prospective study in a Veterans Health Administration primary care clinic, the following test performances, measured by area under receiver-operating characteristic curves, were compared: 50-g oral glucose challenge test; random glucose; and HbA1c level, using a 75-g oral glucose tolerance test as the 'gold standard'. RESULTS: The study population was comprised of 1535 people (mean age 56 years, BMI 30.3 kg/m2 , 94% men, 74% black). By oral glucose tolerance test criteria, diabetes was present in 10% and high-risk prediabetes was present in 22% of participants. The plasma glucose challenge test provided area under receiver-operating characteristic curves of 0.85 (95% CI 0.78-0.91) to detect diabetes and 0.76 (95% CI 0.72-0.80) to detect high-risk dysglycaemia (diabetes or high-risk prediabetes), while area under receiver-operating characteristic curves for the capillary glucose challenge test were 0.82 (95% CI 0.75-0.89) and 0.73 (95% CI 0.69-0.77) for diabetes and high-risk dysglycaemia, respectively. Random glucose performed less well [plasma: 0.76 (95% CI 0.69-0.82) and 0.66 (95% CI 0.62-0.71), respectively; capillary: 0.72 (95% CI 0.65-0.80) and 0.64 (95% CI 0.59-0.68), respectively], and HbA1c performed even less well [0.67 (95% CI 0.57-0.76) and 0.63 (95% CI 0.58-0.68), respectively]. The cost of identifying one case of high-risk dysglycaemia with a plasma glucose challenge test would be $42 from a Veterans Health Administration perspective, and $55 from a US Medicare perspective. CONCLUSIONS: Glucose challenge test screening, followed, if abnormal, by an oral glucose tolerance test, would be convenient and more accurate than other opportunistic tests. Use of glucose challenge test screening could improve management by permitting earlier therapy.

A stable isotope method for in vivo assessment of human insulin synthesis and secretion.

AIMS: In vitro, beta cells immediately secrete stored but readily releasable insulin in response to a rise of glucose. During a prolonged insulin response, this is followed by newly synthesized insulin. Our aim was to develop an in vivo test to determine the ratio between readily available and newly synthesized insulin after a stimulus in humans by labelling newly synthesized insulin. METHODS: A stable isotope tracer of 1.0 g 13C leucine with C-peptide as target peptide was administered 45 min prior to 75 g glucose load of a frequently blood sampled 210-min oral glucose tolerance test (OGTT). Our OGTT also encompassed collection of urine, which has a high content of C-peptide. Prior, the optimal conditions under which the tracer 13C leucine was administered for enrichment of (pre) proinsulin were established. Also, techniques to obtain urinary C-peptide under highly purified circumstances were set up. Our main outcome measure was the stable isotope enrichment of de novo C-peptide, which we related to early plasma insulin and glucose AUC. Twelve healthy Caucasian individuals (M4F8, age 41.8 ± 2.3, BMI 28.3 ± 1.7) with normal glucose tolerance underwent our OGTT. RESULTS: We found that during a 75-g OGTT, newly synthesized insulin contributed approximately 20 % of total insulin secretion. The pattern of isotope enrichment obtained by collecting multiple urine voids was suggestive that the newly synthesized insulin contributes to the late phase of insulin secretion. De novo C-peptide correlated negatively with both early plasma insulin AUC (r = -0.629, P = 0.028) and early plasma glucose AUC (r = -0.605, P = 0.037). CONCLUSIONS: With stable isotope technique added to OGTT, we were able to measure newly synthesized insulin in healthy individuals. This new technique holds the promise that it is feasible to develop a direct in vivo beta cell function test.

The 13C-Glucose Breath Test for Insulin Resistance Assessment in Adolescents: Comparison with Fasting and Post-Glucose Stimulus Surrogate Markers of Insulin Resistance.

OBJECTIVE: To evaluate the use of the 13C-glucose breath test (13C-GBT) for insulin resistance (IR) detection in adolescents through comparison with fasting and post-glucose stimulus surrogates. METHODS: One hundred thirty-three adolescents aged between 10 and 16 years received an oral glucose load of 1.75 g per kg of body weight dissolved in 150 mL of water followed by an oral dose of 1.5 mg/kg of U-13C-Glucose, without a specific maximum dose. Blood samples were drawn at baseline and 120 minutes, while breath samples were obtained at baseline and at 30, 60, 90, 120, 150, and 180 minutes. The 13C-GBT was compared to homeostasis model assessment (HOMA) IR (≥p95 adjusted by gender and age), fasting plasma insulin (≥p90 adjusted by gender and Tanner stage), results of 2-h oral glucose tolerance test (OGTT), insulin levels (≥65 µU/mL) in order to determine the optimal cut-off point for IR diagnosis. RESULTS: 13C-GBT data, expressed as adjusted cumulative percentage of oxidized dose (A% OD), correlated inversely with fasting and post-load IR surrogates. Sexual development alters A% OD results, therefore individuals were stratified into pubescent and post-pubescent. The optimal cut-off point for the 13C-GBT in pubescent individuals was 16.3% (sensitivity=82.8% & specificity=60.6%) and 13.0% in post-pubescents (sensitivity=87.5% & specificity=63.6%), when compared to fasting plasma insulin. Similar results were observed against HOMA and 2-h OGTT insulin. CONCLUSION: The 13C-GBT is a practical and non-invasive method to screen for IR in adolescents with reasonable sensitivity and specificity.

Random non-fasting C-peptide: bringing robust assessment of endogenous insulin secretion to the clinic.

BACKGROUND: Measuring endogenous insulin secretion using C-peptide can assist diabetes management, but standard stimulation tests are impractical for clinical use. Random non-fasting C-peptide assessment would allow testing when a patient is seen in clinic. METHODS: We compared C-peptide at 90 min in the mixed meal tolerance test (sCP) with random non-fasting blood C-peptide (rCP) and random non-fasting urine C-peptide creatinine ratio (rUCPCR) in 41 participants with insulin-treated diabetes [median age 72 (interquartile range 68-78); diabetes duration 21 (14-31) years]. We assessed sensitivity and specificity for previously reported optimal mixed meal test thresholds for severe insulin deficiency (sCP < 200 pmol//l) and Type 1 diabetes/inability to withdraw insulin (< 600 pmol//l), and assessed the impact of concurrent glucose. RESULTS: rCP and sCP levels were similar (median 546 and 487 pmol//l, P = 0.92). rCP was highly correlated with sCP, r = 0.91, P < 0.0001, improving to r = 0.96 when excluding samples with concurrent glucose < 8 mmol//l. An rCP cut-off of 200 pmol//l gave 100% sensitivity and 93% specificity for detecting severe insulin deficiency, with area under the receiver operating characteristic curve of 0.99. rCP < 600 pmol//l gave 87% sensitivity and 83% specificity to detect sCP < 600 pmol//l. Specificity improved to 100% when excluding samples with concurrent glucose < 8 mmol//l. rUCPCR (0.52 nmol/mmol) was also well-correlated with sCP, r = 0.82, P < 0.0001. A rUCPCR cut-off of < 0.2 nmol/ mmol gave sensitivity and specificity of 83% and 93% to detect severe insulin deficiency, with area under the receiver operating characteristic curve of 0.98. CONCLUSIONS: Random non-fasting C-peptide measures are strongly correlated with mixed meal C-peptide, and have high sensitivity and specificity for identifying clinically relevant thresholds. These tests allow assessment of C-peptide at the point patients are seen for clinical care.

Establishment of a Refined Oral Glucose Tolerance Test in Pigs, and Assessment of Insulin, Glucagon and Glucagon-Like Peptide-1 Responses.

Diabetes mellitus is increasing worldwide and reliable animal models are important for progression of the research field. The pig is a commonly used large animal model in diabetes research and the present study aimed to refine a model for oral glucose tolerance test (OGTT) in young growing pigs, as well as describing intravenous glucose tolerance test (IVGTT) in the same age group. The refined porcine OGTT will reflect that used in children and adolescents. Eighteen pigs were obtained one week after weaning and trained for two weeks to bottle-feed glucose solution, mimicking the human OGTT. The pigs subsequently underwent OGTT (1.75 g/kg BW) and IVGTT (0.5 g/kg BW). Blood samples were collected from indwelling vein catheters for measurements of glucose and the diabetes related hormones insulin, glucagon and active glucagon-like peptide-1. The study confirmed that pigs can be trained to bottle-feed glucose dissolved in water and thereby undergo an OGTT more similar to the human standard OGTT than previously described methods in pigs. With the refined method for OGTT, oral intake only consists of glucose and water, which is an advantage over previously described methods in pigs where glucose is given together with feed which will affect glucose absorption. Patterns of hormonal secretion in response to oral and intravenous glucose were similar to those in humans; however, the pigs were more glucose tolerant with lower insulin levels than humans. In translational medicine, this refined OGTT and IVGTT methods provide important tools in diabetes research when pigs are used as models for children and adolescents in diabetes research.

Use of capillary blood glucose for screening for gestational diabetes mellitus in resource-constrained settings.

AIMS: The aim of the study was to evaluate usefulness of capillary blood glucose (CBG) for diagnosis of gestational diabetes mellitus (GDM) in resource-constrained settings where venous plasma glucose (VPG) estimations may be impossible. METHODS: Consecutive pregnant women (n = 1031) attending antenatal clinics in southern India underwent 75-g oral glucose tolerance test (OGTT). Fasting, 1- and 2-h VPG (AU2700 Beckman, Fullerton, CA) and CBG (One Touch Ultra-II, LifeScan) were simultaneously measured. Sensitivity and specificity were estimated for different CBG cut points using the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for the diagnosis of GDM as gold standard. Bland-Altman plots were drawn to look at the agreement between CBG and VPG. Correlation and regression equation analysis were also derived for CBG values. RESULTS: Pearson's correlation between VPG and CBG for fasting was r = 0.433 [intraclass correlation coefficient (ICC) = 0.596, p < 0.001], for 1H, it was r = 0.653 (ICC = 0.776, p < 0.001), and for 2H, r = 0.784 (ICC = 0.834, p < 0.001). Comparing a single CBG 2-h cut point of 140 mg/dl (7.8 mmol/l) with the IADPSG criteria, the sensitivity and specificity were 62.3 and 80.7 %, respectively. If CBG cut points of 120 mg/dl (6.6 mmol/l) or 110 mg/dl (6.1 mmol/l) were used, the sensitivity improves to 78.3 and 92.5 %, respectively. CONCLUSIONS: In settings where VPG estimations are not possible, CBG can be used as an initial screening test for GDM, using lower 2H CBG cut points to maximize the sensitivity. Those who screen positive can be referred to higher centers for definitive testing, using VPG.

Comparative Evaluation of Two Venous Sampling Techniques for the Assessment of Pancreatic Insulin and Zinc Release upon Glucose Challenge.

Advances in noninvasive imaging modalities have provided opportunities to study ß cell function through imaging zinc release from insulin secreting ß cells. Understanding the temporal secretory pattern of insulin and zinc corelease after a glucose challenge is essential for proper timing of administration of zinc sensing probes. Portal venous sampling is an essential part of pharmacological and nutritional studies in animal models. The purpose of this study was to compare two different percutaneous image-guided techniques: transhepatic ultrasound guided portal vein access and transsplenic fluoroscopy guided splenic vein access for ease of access, safety, and evaluation of temporal kinetics of insulin and zinc release into the venous effluent from the pancreas. Both techniques were safe, reproducible, and easy to perform. The mean time required to obtain desired catheter position for venous sampling was 15 minutes shorter using the transsplenic technique. A clear biphasic insulin release profile was observed in both techniques. Statistically higher insulin concentration but similar zinc release after a glucose challenge was observed from splenic vein samples, as compared to the ones from the portal vein. To our knowledge, this is the first report of percutaneous methods to assess zinc release kinetics from the porcine pancreas.

Post-natal assessment of gestational diabetes: fasting glucose or full glucose tolerance test?

AIMS: To determine the performance of a fasting glucose sample compared with a full oral glucose tolerance test for the detection of glucose abnormalities in a diverse ethnic population after gestational diabetes. METHODS: Oral glucose tolerance test results for women attending post-natal testing over a 10-year (2003-2013) period at St Mary's Hospital, Manchester, UK were reviewed. Demographic data were also extracted from the hospital maternity database. RESULTS: The average attendance for a post-natal oral glucose tolerance test was approximately 45% over the study period. The prevalence of diabetes was 4.8% (30/629), with a higher rate in women of Asian ethnicity compared with other groups (6.6% vs. 3.5%). The sensitivity for a fasting plasma glucose of ≥ 6.1 mmol/l was 90% (95% CI 74.4-96.5%) for the detection of diabetes and 61% (49.1-71.5%) for the detection of diabetes and/or impaired glucose tolerance, with specificities of 91% (88.8-93.3%) and 93% (91.0-95.2%), respectively. The positive and negative likelihood ratios for diabetes and impaired glucose tolerance were 10.4 (7.8-13.8), 0.11 (0.03-0.32) and 9.2 (6.4-13.3), 0.42 (0.31-0.56), respectively. A fasting plasma glucose threshold of 5.6 mmol/l improved the sensitivity for impaired glucose tolerance (from 61% to 77%), but made no difference to the sensitivity for diabetes. CONCLUSIONS: The current study has demonstrated that detection of diabetes after gestational diabetes, in an ethnically diverse population using a fasting plasma glucose only, was approximately 90%. Compliance with post-natal screening might improve if women attended for a fasting plasma glucose only; this strategy would identify approximately 90% of cases of diabetes and 40% of cases of impaired glucose tolerance.