Robin Chisholm

Impaired Cardiometabolic Responses to Glucagon-Like Peptide 1 in Obesity and Type 2 Diabetes Mellitus

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7–36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Contributions of dysglycaemia, obesity, and insulin resistance to impaired endothelium‐dependent vasodilation in humans

Individual effects of hyperglycaemia and obesity to impair vascular health are recognized. However, the relative contributions of dysglycaemia versus other obesity‐related traits to vascular dysfunction have not been systematically evaluated.

Effects of losartan on whole body, skeletal muscle and vascular insulin responses in obesity/insulin resistance without hypertension

Aims: Renin‐angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin‐mediated vasodilation, and thereby improve insulin‐stimulated glucose uptake in skeletal muscle of insulin‐resistant subjects.

[13C]Glucose Breath Testing Provides a Noninvasive Measure of Insulin Resistance: Calibration Analyses Against Clamp Studies

BACKGROUND Exhaled (13)CO2 following ingestion of [(13)C]glucose with a standard oral glucose tolerance load correlates with blood glucose values but is determined by tissue glucose uptake. Therefore exhaled (13)CO2 may also be a surrogate measure of the whole-body glucose disposal rate (GDR) measured by the gold standard hyperinsulinemic euglycemic clamp. SUBJECTS AND METHODS Subjects from across the glycemia range were studied on 2 consecutive days under fasting conditions. On Day 1, a 75-g oral glucose load spiked with [(13)C]glucose was administered. On Day 2, a hyperinsulinemic euglycemic clamp was performed. Correlations between breath parameters and clamp-derived GDR were evaluated, and calibration analyses were performed to evaluate the precision of breath parameter predictions of clamp measures. RESULTS Correlations of breath parameters with GDR and GDR per kilogram of fat-free mass (GDRffm) ranged from 0.54 to 0.61 and 0.54 to 0.66, respectively (all P<0.001). In calibration analyses the root mean square error for breath parameters predicting GDR and GDRffm ranged from 2.32 to 2.46 and from 3.23 to 3.51, respectively. Cross-validation prediction error (CVPE) estimates were 2.35-2.51 (GDR) and 3.29-3.57 (GDRffm). Prediction precision of breath enrichment at 180 min predicting GDR (CVPE=2.35) was superior to that for inverse insulin (2.68) and the Matsuda Index (2.51) but inferior to that for the log of homeostasis model assessment (2.21) and Quantitative Insulin Sensitivity Check Index (2.29) (all P<10(-5)). Similar patterns were seen for predictions of GDRffm. CONCLUSIONS (13)CO2 appearance in exhaled breath following a standard oral glucose load with added [(13)C]glucose provides a valid surrogate index of clamp-derived measures of whole-body insulin resistance, with good accuracy and precision. This noninvasive breath test-based approach can provide a useful measure of whole-body insulin resistance in physiologic and epidemiologic studies.

Intra-individual variability of CO2 breath isotope enrichment compared to blood glucose in the oral glucose tolerance test

BACKGROUND Glucose tolerance can be assessed noninvasively using (13)C-labeled glucose added to a standard oral glucose load, by measuring isotope-enriched CO(2) in exhaled air. In addition to the clear advantage of the noninvasive measurements, this approach may be of value in overcoming the high variability in blood glucose determination. METHODS We compared within-individual variability of breath CO(2) isotope enrichment with that for blood glucose in a 75-g oral glucose tolerance test (OGTT) by adding 150 mg of d-[(13)C]glucose ((13)C 99%) to a standard 75-g glucose load. Measurements of whole blood glucose (by glucose oxidase) and breath isotope enrichment (by isotope ratio mass spectrometry) were made every 30  min for 3 h. Subjects underwent three repeat tests over a 3-week period. Values for variability of breath isotope enrichment at 3 h (∂‰180) and of area under the curve for enrichment to 180  min (AUC180) were compared with variability of the 2-h OGTT blood glucose. RESULTS Breath test-derived measures exhibited lower within-subject variability than the 2-h OGTT glucose. The coefficient of variation for ∂‰180 was 7.4 ± 3.9% (mean ± SD), for AUC180 was 9.4 ± 6.3%, and for 2-h OGTT blood glucose was 13 ± 7.1% (P = 0.005 comparing ∂‰180 versus 2-h blood glucose; P = 0.061 comparing AUC180 versus 2-h blood glucose; P = 0.03 comparing ∂‰180 versus AUC180). CONCLUSIONS Breath test-derived measurements of glucose handling had lower within-subject variability versus the standard 2-h blood glucose reading used in clinical practice. These findings support further development of this noninvasive method for evaluating glucose tolerance.

Simple modeling allows prediction of steady-state glucose disposal rate from early data in hyperinsulinemic glucose clamps

After a constant insulin infusion is initiated, determination of steady-state conditions for glucose infusion rates (GIR) typically requires >or=3 h. The glucose infusion follows a simple time-dependent rise, reaching a plateau at steady state. We hypothesized that nonlinear fitting of abbreviated data sets consisting of only the early portion of the clamp study can provide accurate estimates of steady-state GIR. Data sets from two independent laboratories were used to develop and validate this approach. Accuracy of the predicted steady-state GDR was assessed using regression analysis and Altman-Bland plots, and precision was compared by applying a calibration model. In the development data set (n = 88 glucose clamp studies), fitting the full data set with a simple monoexponential model predicted reference GDR values with good accuracy (difference between the 2 methods -0.37 mg x kg(-1) x min(-1)) and precision [root mean square error (RMSE) = 1.11], validating the modeling procedure. Fitting data from the first 180 or 120 min predicted final GDRs with comparable accuracy but with progressively reduced precision [fitGDR-180 RMSE = 1.27 (P = NS vs. fitGDR-full); fitGDR-120 RMSE = 1.56 (P < 0.001)]. Similar results were obtained with the validation data set (n = 183 glucose clamp studies), confirming the generalizability of this approach. The modeling approach also derives kinetic parameters that are not available from standard approaches to clamp data analysis. We conclude that fitting a monoexponential curve to abbreviated clamp data produces steady-state GDR values that accurately predict the GDR values obtained from the full data sets, albeit with reduced precision. This approach may help reduce the resources required for undertaking clamp studies.

Weapons Retrieved after the Implementation of Emergency Department Metal Detection

BACKGROUND Several high-profile violent incidents have occurred within emergency departments (EDs). There are no recent studies reporting the effectiveness of ED metal detection. OBJECTIVE Our aim was to assess the effect of metal detection on ED weapons retrieval. METHODS In September 2011, a metal detector was installed at the entrance of an urban, high-volume teaching hospital ED. The security company recorded retrieved firearms, knives, chemical sprays, and other weapons. We performed qualitative analysis of weapons retrieval data for a 26-month period. RESULTS A total of 5877 weapons were retrieved, an average of 218 per month: 268 firearms, 4842 knives, 512 chemical sprays, and 275 other weapons, such as brass knuckles, stun guns, and box cutters. The number of retrieved guns decreased from 2012 to 2013 (from 182 to 47), despite an increase in metal detection hours from 8 h per day to 16 h per day. The number of retrieved knives, chemical sprays, and other weapons increased. Recovered knives increased from 2062 in 2012 to 2222 in 2013, chemical sprays increased from 170 to 305, and other weapons increased from 51 to 201. CONCLUSIONS A large number of weapons were retrieved after the initiation of metal detection in the ED entrance. Increasing hours of metal detection increased the number of retrieved knives, chemical sprays, and other weapons. Retrieved firearms decreased after increasing metal detection hours. Metal detection in the ED entrance is effective in reducing entrance of weapons into the ED. Metal detectors may offer additional benefit in reducing attempts to enter with firearms.

Failure of hyperglycemia and hyperinsulinemia to compensate for impaired metabolic response to an oral glucose load

OBJECTIVE To evaluate whether the augmented insulin and glucose response to a glucose challenge is sufficient to compensate for defects in glucose utilization in obesity and type 2 diabetes, using a breath test measurement of integrated glucose metabolism. METHODS Non-obese, obese normoglycemic and obese type 2 diabetic subjects were studied on 2 consecutive days. A 75g oral glucose load spiked with ¹³C-glucose was administered, measuring exhaled breath ¹³CO₂ as an integrated measure of glucose metabolism and oxidation. A hyperinsulinemic euglycemic clamp was performed, measuring whole body glucose disposal rate. Body composition was measured by DEXA. Multivariable analyses were performed to evaluate the determinants of the breath ¹³CO₂. RESULTS Breath ¹³CO₂ was reduced in obese and type 2 diabetic subjects despite hyperglycemia and hyperinsulinemia. The primary determinants of breath response were lean mass, fat mass, fasting FFA concentrations, and OGTT glucose excursion. Multiple approaches to analysis showed that hyperglycemia and hyperinsulinemia were not sufficient to compensate for the defect in glucose metabolism in obesity and diabetes. CONCLUSIONS Augmented insulin and glucose responses during an OGTT are not sufficient to overcome the underlying defects in glucose metabolism in obesity and diabetes.