Effects of hypoglycaemia on working memory and regional cerebral blood flow in type 1 diabetes: a randomised, crossover trial.

AIMS/HYPOTHESIS: The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus. METHODS: In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8 ± 0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l ± 10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H215O-positron emission tomographies (PET) per session. RESULTS: Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] -0.63 [95% CI -1.13, -0.14], p = 0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p = 0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p < 0.05). Working memory activation (mDSST - cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p = 0.002). CONCLUSIONS/INTERPRETATION: During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion. TRIAL REGISTRATION: NCT01789593, clinicaltrials.gov FUNDING: This study was funded by Novo Nordisk.

Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes.

AIM: To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes. MATERIALS AND METHODS: In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period. RESULTS: Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P < .0001). The distribution of glucose-lowering effect was stable across 6-hour intervals (24%-26%) for IDeg, while IGlar-U300 had greater effects in the first (35%) and last (28%) intervals compared with 6 to 12 hours (20%) and 12 to 18 hours (17%). Within-day variability (relative fluctuation) was 37% lower with IDeg than with IGlar-U300 (estimated ratio IDeg/IGlar-U300: 0.63, 95% CI 0.54; 0.73; P < .0001). The day-to-day variability in glucose-lowering effect with IDeg was approximately 4 times lower than IGlar-U300 (variance ratio IGlar-U300/IDeg: 3.70, 95% CI 2.42; 5.67; P < .0001). The day-to-day variability in glucose-lowering effect assessed in 2-hour intervals was consistently low with IDeg over 24 hours, but steadily increased with IGlar-U300 to a maximum at 10 to 12 hours and 12 to 14 hours after dosing (variance ratios 12.4 and 11.4, respectively). CONCLUSION: IDeg has lower day-to-day and within-day variability than IGlar-U300 and a more stable glucose-lowering effect, which might facilitate titration and enable tighter glycaemic control with a reduced risk of hypoglycaemia.

Day-to-Day and Within-Day Variability in Glucose-Lowering Effect Between Insulin Degludec and Insulin Glargine (100 U/mL and 300 U/mL): A Comparison Across Studies.

BACKGROUND: Insulin degludec (IDeg) has significantly lower day-to-day and within-day variability compared to insulin glargine (IGlar) 100U/mL (U100) and 300U/mL (U300). Here, we report post hoc assessments to confirm the robustness of these observations while accounting for potential experimental confounders. METHODS: Two euglycemic clamp studies in type 1 diabetes patients, comparing IDeg to IGlar-U100 (Study A, parallel design, 54 patients; Study B, crossover, 22 patients) and one study comparing IDeg to IGlar-U300 (Study C, crossover, 57 patients), all dosed at 0.4U/kg, were evaluated. Pharmacodynamic parameters were assessed at steady state from glucose infusion rate (GIR) profiles following three 24-hour euglycemic clamps in Studies A (162 clamps) and C (342 clamps), and one 42-hour clamp in Study B (44 clamps). RESULTS: Pooled data (Studies A and B) showed that IDeg had an even distribution of glucose-lowering effect over the 24-hour dosing interval that was consistent with Study C. IGlar-U100 showed a constant decrease in glucose-lowering effect over 24 hours while IGlar-U300 had a lower effect in the middle of the dosing interval (6-18 hours). Relative within-day variability of IDeg was 40% and 37% lower than IGlar-U100 and -U300, respectively. Exclusion of profiles with low response in Study C (19/342 clamps) did not impact the difference in the distribution of glucose-lowering effect or within-day variability. Day-to-day variability was significantly lower with IDeg compared to IGlar-U100 and -U300 based on smoothed and unsmoothed GIR data. CONCLUSIONS: Significantly lower relative within-day and day-to-day variability was confirmed irrespective of experimental considerations for IDeg compared to IGlar-U100 and IGlar-U300.

Heart rate dynamics during cardio-pulmonary exercise testing are associated with glycemic control in individuals with type 1 diabetes.

INTRODUCTION: This study investigated the degree and direction (kHR) of the heart rate to performance curve (HRPC) during cardio-pulmonary exercise (CPX) testing and explored the relationship with diabetes markers, anthropometry and exercise physiological markers in type 1 diabetes (T1DM). MATERIAL AND METHODS: Sixty-four people with T1DM (13 females; age: 34 ± 8 years; HbA1c: 7.8 ± 1% (62 ± 13 mmol.mol-1) performed a CPX test until maximum exhaustion. kHR was calculated by a second-degree polynomial representation between post-warm up and maximum power output. Adjusted stepwise linear regression analysis was performed to investigate kHR and its associations. Receiver operating characteristic (ROC) curve was performed based on kHR for groups kHR < 0.20 vs. > 0.20 in relation to HbA1c. RESULTS: We found significant relationships between kHR and HbA1c (ß = -0.70, P < 0.0001), age (ß = -0.23, P = 0.03) and duration of diabetes (ß = 0.20, P = 0.04). Stepwise linear regression resulted in an overall adjusted R2 of 0.57 (R = 0.79, P < 0.0001). Our data revealed also significant associations between kHR and percentage of heart rate at heart rate turn point from maximum heart rate (ß = 0.43, P < 0.0001) and maximum power output relativized to bodyweight (ß = 0.44, P = 0.001) (overall adjusted R2 of 0.44 (R = 0.53, P < 0.0001)). ROC curve analysis based on kHR resulted in a HbA1c threshold of 7.9% (62 mmol.mol-1). CONCLUSION: Our data demonstrate atypical HRPC during CPX testing that were mainly related to glycemic control in people with T1DM.

Poor glycaemic control is associated with reduced exercise performance and oxygen economy during cardio-pulmonary exercise testing in people with type 1 diabetes.

BACKGROUND: To explore the impact of glycaemic control (HbA1c) on functional capacity during cardio-pulmonary exercise testing in people with type 1 diabetes. METHODS: Sixty-four individuals with type 1 diabetes (age: 34 ± 8 years; 13 females, HbA1c: 7.8 ± 1% (62 ± 13 mmol/mol), duration of diabetes: 17 ± 9 years) performed a cardio-pulmonary cycle ergometer exercise test until volitional exhaustion. Stepwise linear regression was used to explore relationships between HbA1c and cardio-respiratory data with p ≤ 0.05. Furthermore, participants were divided into quartiles based on HbA1c levels and cardio-respiratory data were analysed by one-way ANOVA. Multiple regression analysis was performed to explore the relationships between changes in time to exhaustion and cardio-respiratory data. Data were adjusted for confounder. RESULTS: HbA1c was related to time to exhaustion and oxygen consumption at the power output elicited at the sub-maximal threshold of the heart rate turn point (r = 0.47, R2 = 0.22, p = 0.03). Significant differences were found at time to exhaustion between QI vs. QIV and at oxygen consumption at the power output elicited at the heart rate turn point between QI vs. QII and QI vs. QIV (p < 0.05). Changes in oxygen uptake, power output and in oxygen consumption at the power output elicited at the heart rate turn point and at maximum power output explained 55% of the variance in time to exhaustion (r = 0.74, R2 = 0.55, p < 0.01). CONCLUSIONS: Poor glycaemic control is related to less economical use of oxygen at sub-maximal work rates and an earlier time to exhaustion during cardio-pulmonary exercise testing. However, exercise training could have the same potential to counteract the influence of poor glycaemic control on functional capacity. Trial registration NCT01704417. Date of registration: October 11, 2012.

Cardiovascular control during exercise: insights from spinal cord-injured humans.

BACKGROUND: We studied the role of the central nervous system, neural feedback from contracting skeletal muscles, and sympathetic activity to the heart in the control of heart rate and blood pressure during 2 levels of dynamic exercise. METHODS AND RESULTS: Spinal cord-injured individuals (SCI) with (paraplegia, n=4) or without (tetraplegia, n=6) sympathetic innervation to the heart performed electrically induced exercise. Responses were compared with those established by able-bodied individuals (control, n=6) performing voluntary exercise at a similar pulmonary oxygen uptake. In all subjects, cardiac output and leg blood flow increased, but in SCI they reached a maximal value. The increase in cardiac output was mainly elicited by an increase in stroke volume in individuals with tetraplegia, whereas in individuals with paraplegia it was by heart rate. The increase in SCI was slow compared with that in controls. During exercise, blood pressure was stable in controls, whereas it decreased over time in SCI and especially in individuals with tetraplegia. CONCLUSIONS: The autonomic nervous system provides for acceleration of the heart at the onset of exercise, but a slow increase in heart rate is established even without central command, neural feedback from working muscles, or autonomic influence on the heart. Yet an intact autonomic nervous system is a prerequisite for a large rise in cardiac output and in turn leg blood flow during exercise. Thus, when the sympathetic nervous system is injured at a level where it influences the heart, vasodilatation in working muscles challenges blood pressure.

Biphasic insulin aspart 30/70: pharmacokinetics and pharmacodynamics compared with once-daily biphasic human insulin and Basal-bolus therapy.

OBJECTIVE Pharmacological profiles of biphasic insulin aspart 30/70 (BIAsp 30) once daily (OD), twice daily (b.i.d.), and three times daily (t.i.d.) were compared with other insulin regimens in two crossover glucose clamp studies of insulin-treated type 2 diabetic patients. RESEARCH DESIGNS AND METHODS Study 1 consisted of BIAsp 30 OD, b.i.d., and t.i.d. versus biphasic human insulin 30/70 (BHI 30), OD (n = 24). Study 2 examined BIAsp 30 t.i.d. versus basal-bolus therapy (insulin glargine OD plus insulin glulisine t.i.d.) (n = 24). Pharmacokinetics/pharmacodynamics (PK/PD) were investigated over 24 h. RESULTS Study 1: PK and PD were markedly different between BIAsp 30 OD and BHI 30 OD: the maximum insulin concentration and glucose infusion rate (GIR) were higher for BIAsp 30; time to maximum metabolism was 1.7 h sooner for BIAsp 30. Study 2: both regimens showed three distinct prandial-related GIR peaks. GIR 24-h area under the curve for BIAsp t.i.d. was higher than for basal-bolus therapy: 2,585.2 vs. 2,289.2 mg/kg. CONCLUSIONS BIAsp had pharmacological advantages over BHI. BIAsp t.i.d. had a similar PD profile to basal-bolus therapy.