Combined intake of caffeine and low-dose glucose to reduce exercise-related hypoglycaemia in individuals with type 1 diabetes on ultra-long-acting insulin degludec: A randomized, controlled, double-blind, cross-over trial.

AIM: To evaluate whether caffeine combined with a moderate amount of glucose reduces the risk for exercise-related hypoglycaemia compared with glucose alone or control in adult people with type 1 diabetes using ultra-long-acting insulin degludec. MATERIALS AND METHODS: Sixteen participants conducted three aerobic exercise sessions (maximum 75 min) in a randomized, double-blind, cross-over design. Thirty minutes before exercise, participants ingested a drink containing either 250 mg of caffeine + 10 g of glucose + aspartame (CAF), 10 g of glucose + aspartame (GLU), or aspartame alone (ASP). The primary outcome was time to hypoglycaemia. RESULTS: There was a significant effect of the condition on time to hypoglycaemia (χ2 = 7.674, p = .0216). Pairwise comparisons revealed an 85.7% risk reduction of hypoglycaemia for CAF compared with ASP (p = .044). No difference was observed between GLU and ASP (p = .104) or between CAF and GLU (p = .77). While CAF increased glucose levels during exercise compared with GLU and ASP (8.3 ± 1.9 mmol/L vs. 7.7 ± 2.2 mmol/L vs. 5.8 ± 1.4 mmol/L; p < .001), peak plasma glucose levels during exercise did not differ between CAF and GLU (9.3 ± 1.4 mmol/L and 9.1 ± 1.6 mmol/L, p = .80), but were higher than in ASP (6.6 ± 1.1 mmol/L; p < .001). The difference in glucose levels between CAF and GLU was largest during the last 15 min of exercise (p = .002). Compared with GLU, CAF lowered perceived exertion (p = .023). CONCLUSIONS: Pre-exercise caffeine ingestion combined with a low dose of glucose reduced exercise-related hypoglycaemia compared with control while avoiding hyperglycaemia.

Glycaemic management around postprandial exercise in people with type 1 diabetes: Challenge accepted.

CONTEXT: The precise glycaemic impact and clinical relevance of postprandial exercise in type 1 diabetes has not been clarified yet. OBJECTIVE: Examine acute, subacute and late effects of postprandial exercise on blood glucose (BG). DESIGN: RCT. SETTING: Four lab visits, with 24h follow-up at home. PARTICIPANTS: Adults with type 1 diabetes (n=8), age 44±13 years; BMI: 24±2.1 kg/m2. INTERVENTION: 30 min of rest (CONTROL), walking (WALK), moderate-intensity (MOD), or intermittent high-intensity (IHE) exercise performed 60min after a standardized meal. MAIN OUTCOME MEASURES: BG change during exercise/control (acute), and secondary outcomes included the subacute (≤2h after) and late glycaemic effects (≤24h after). RESULTS: Exercise reduced postprandial glucose (PPG) excursion compared to CONTROL, with a consistent BG decline in all patients for all modalities (mean declines -45±24, -71±39, and -35±21 mg/dL, during WALK, MOD and IHE, respectively (p<0.001). For this decline, clinical superiority was demonstrated separately for each exercise modality vs. CONTROL. Non-inferiority of WALK vs. MOD was not demonstrated, non-inferiority of WALK vs. IHE was demonstrated, and equivalence of IHE vs. MOD was not demonstrated. Hypoglycaemia did not occur during exercise. BG increased in the hour after exercise (more than after CONTROL, p<0.001). More than half of participants showed hyperglycaemia after exercise necessitating insulin correction. There were more nocturnal hypoglycaemic events after exercise vs. CONTROL (p<0.05). CONCLUSIONS: Postprandial exercise of all modalities is effective, safe and feasible if necessary precautions are taken (i.e., prandial insulin reductions), as exercise lowered maximal PPG excursion and caused a consistent and clinically relevant BG decline during exercise while there was no hypoglycaemia during or shortly after exercise. However, there seem two remaining challenges, being subacute post-exercise hyperglycaemia and nocturnal hypoglycaemia.

Effects of postprandial exercise on blood glucose levels in adults with type 1 diabetes: a review.

People with type 1 diabetes experience challenges in managing blood glucose around exercise. Previous studies have examined glycaemic responses to different exercise modalities but paid little attention to participants' prandial state, although this is an important consideration and will enhance our understanding of the effects of exercise in order to improve blood glucose management around activity. This review summarises available data on the glycaemic effects of postprandial exercise (i.e. exercise within 2 h after a meal) in people with type 1 diabetes. Using a search strategy on electronic databases, literature was screened until November 2022 to identify clinical trials evaluating acute (during exercise), subacute (≤2 h after exercise) and late (>2 h to ≤24 h after exercise) effects of postprandial exercise in adults with type 1 diabetes. Studies were systematically organised and assessed by exercise modality: (1) walking exercise (WALK); (2) continuous exercise of moderate intensity (CONT MOD); (3) continuous exercise of high intensity (CONT HIGH); and (4) interval training (intermittent high-intensity exercise [IHE] or high-intensity interval training [HIIT]). Primary outcomes were blood glucose change and hypoglycaemia occurrence during and after exercise. All study details and results per outcome were listed in an evidence table. Twenty eligible articles were included: two included WALK sessions, eight included CONT MOD, seven included CONT HIGH, three included IHE and two included HIIT. All exercise modalities caused consistent acute glycaemic declines, with the largest effect size for CONT HIGH and the smallest for HIIT, depending on the duration and intensity of the exercise bout. Pre-exercise mealtime insulin reductions created higher starting blood glucose levels, thereby protecting against hypoglycaemia, in spite of similar declines in blood glucose during activity between the different insulin reduction strategies. Nocturnal hypoglycaemia occurred after higher intensity postprandial exercise, a risk that could be diminished by a post-exercise snack with concomitant bolus insulin reduction. Research on the optimal timing of postprandial exercise is inconclusive. In summary, individuals with type 1 diabetes exercising postprandially should substantially reduce insulin with the pre-exercise meal to avoid exercise-induced hypoglycaemia, with the magnitude of the reduction depending on the exercise duration and intensity. Importantly, pre-exercise blood glucose and timing of exercise should be considered to avoid hyperglycaemia around exercise. To protect against late-onset hypoglycaemia, a post-exercise meal with insulin adjustments might be advisable, especially for exercise in the evening or with a high-intensity component.

Central blood pressure estimation in type 1 diabetes: impact and implications of peripheral calibration method.

OBJECTIVE: Peripheral blood pressure (BP) waveforms are used for noninvasive central BP estimation. Central BP could assist in cardiovascular risk assessment in patients with type 1 diabetes mellitus (T1DM). However, correct calibration of peripheral BP waveforms is important to accurately estimate central BP. We examined differences in central BP estimated by radial artery tonometry depending on which brachial BP (SBP/DBP vs. MAP/DBP) is used for calibration of the radial waveforms, for the first time in T1DM. METHODS: A cross-sectional study in T1DM patients without known cardiovascular disease. Radial artery BP waveforms were acquired using applanation tonometry ( SphygmoCor ) for the estimation of central SBP, central pulse pressure (PP) and central augmentation pressure, using either brachial SBP/DBP or MAP/DBP for the calibration of the radial pressure waveforms. RESULTS: Fifty-four patients (age: 46 ±â€Š9.5 years; T1DM duration: 27 ±â€Š8.8 years) were evaluated. Central BP parameters were significantly higher when brachial MAP/DBP-calibration was used compared with brachial SBP/DBP-calibration (7.5 ±â€Š5.04, 7.5 ±â€Š5.04 and 1.5 ±â€Š1.36 mmHg higher central SBP, central PP and central augmentation pressure, respectively, P  < 0.001). CONCLUSION: In patients with T1DM, there are significant differences in central BP values estimated with radial artery tonometry, depending on the method used for calibration of the radial waveforms. Brachial MAP/DBP-calibration resulted in consistently higher central BP as compared to using brachial SBP/DBP, leading to patient re-stratification. Hence, the accuracy of noninvasive estimation of central BP by radial tonometry is dependent on calibration approach, and this problem must be resolved in validation studies using an invasive reference standard to determine which method best estimates true central BP.

Glycemic indices at night measured by CGM are predictive for a lower pulmonary function in adults but not in children with cystic fibrosis.

INTRODUCTION: In patients with cystic fibrosis (CF), it is still unclear to which extent glucose abnormalities - preceding the diagnosis of cystic fibrosis related diabetes (CFRD) - are associated with pulmonary and nutritional outcome parameters. This study related circadian glycemic patterns to clinical outcomes in a group of CF patients not previously diagnosed with diabetes. METHODS: Continuous glucose monitoring (CGM) readings (7 days) of 47 CF patients (26 children, 21 adults) with an impaired oral glucose tolerance test (OGTT) (n = 25) and/or increased Hb1Ac (> 5.5%) were analyzed. Biometric, pulmonary function and clinical parameters were retrospectively collected over a period of 1 year before (T-1) and 1 year after (T + 1) CGM (T0). RESULTS: 96% (45/47) of CGM readings showed glucose values > 140 mg/dL ≥ 4.5% of the time and at least one ≥ 200 mg/dL. In the pediatric cohort, no significant associations were found between CGM parameters and pulmonary and nutritional outcome parameters. In the adult cohort, an area under the curve (AUC) > 140 mg/dL and%-time > 140 mg/dL during the night were associated with a lower forced expiratory volume in 1 s (FEV1)% predicted (pp) at time of evaluation but not with change in FEV1pp. CONCLUSION: This is the first study reporting the circadian glycemic pattern in children and adults at risk for CFRD. In the adult cohort an association between detection of abnormal glucose exposure and a lower FEV1pp was found. Our results support continued screening for glucose intolerance in patients with CF.

Time-varying parameters of glycemic control and glycation in relation to arterial stiffness in patients with type 1 diabetes.

BACKGROUND: A substantial proportion of type 1 diabetes (T1D) patients free from known cardiovascular disease (CVD) show premature arterial stiffening, with age, blood pressure, and HbA1c-as gold standard of glycemic control-as main predictors. However, the relationship of arterial stiffness with other time-varying parameters of glycemic control and glycation has been far less explored. This study investigated the relationship of arterial stiffness with several short- and long-term parameters of glycemic control and glycation in patients with T1D, such as advanced glycation end-products (AGEs) and continuous glucose monitoring (CGM)-derived parameters. METHODS: Cross-sectional study at a tertiary care centre including 54 patients with T1D free from known CVD. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (cf-PWV). Current level and 10-year history of HbA1c were evaluated, and skin AGEs, urinary AGEs, and serum soluble AGE-receptor (sRAGE) concentrations. CGM for 7 days was used to determine time in range, time in hyper- and hypoglycemia, and glycemic variability. RESULTS: Cf-PWV was associated with current HbA1c (rs = + 0.28), mean 10-years HbA1c (rs = + 0.36), skin AGEs (rs = + 0.40) and the skin AGEs-to-sRAGE ratio (rs = + 0.40), but not with urinary AGE or serum sRAGE concentrations; and not with any of the CGM-parameters. Multiple linear regression for cf-PWV showed that the model with the best fit included age, T1D duration, 24-h mean arterial pressure and mean 10-years HbA1c (adjusted R2 = 0.645, p < 0.001). CONCLUSIONS: Longer-term glycemic exposure as reflected by current and mean 10-years HbA1c is a key predictor of arterial stiffness in patients with T1D, while no relationship was found with any of the short-term CGM parameters. Our findings stress the importance of early and sustained good glycemic control to prevent premature CVD in patients with T1D and suggest that HbA1c should continue to be used in the risk assessment for diabetic complications. The role of skin glycation, as a biomarker for vascular aging, in the risk assessment for CVD is an interesting avenue for further research.

Arterial stiffness in patients with type 1 diabetes and its comparison to cardiovascular risk evaluation tools.

BACKGROUND: Arterial stiffness is a potential biomarker for cardiovascular disease (CVD) risk in patients with type 1 diabetes (T1D). However, its relation with other CV risk evaluation tools in T1D has not been elucidated yet. This study aimed to evaluate arterial stiffness in T1D patients free from known CVD, and compare it to other CV risk evaluation tools used in T1D. METHODS: Cross-sectional study in adults with a T1D duration of at least 10 years and without established CVD. Patients were categorized in CVD risk groups based on 2019 European Society of Cardiology (ESC) guidelines, and the STENO T1D risk engine was used to estimate 10-year risk for CV events. Arterial stiffness was evaluated with carotid-femoral pulse wave velocity (cf-PWV). Coronary artery calcium (CAC) score was assessed and carotid ultrasound was performed. Ambulatory 24-h blood pressure and central hemodynamic parameters were evaluated. Data on renal function and diabetic kidney disease was retrieved. RESULTS: 54 patients (age: 46 ± 9.5 years; T1D duration: 27 ± 8.8 years) were included. One-fourth of patients showed prematurely increased aortic stiffness based on cf-PWV (24%). Cf-PWV was significantly associated with CAC score, carotid intima-media thickness, central hemodynamic parameters and diabetic kidney disease. Based on STENO, 20 patients (37%) were at low, 20 patients (37%) at moderate, and 14 patients (26%) at high 10-year risk for CV event. Cf-PWV was strongly associated with the STENO score (rs = + 0.81; R2 = 0.566, p < 0.001), increasing with each higher STENO group (p < 0.01). However, cf-PWV was not significantly different between the two CV risk groups (high versus very high) based on ESC criteria, and ESC criteria compared to STENO classified 10 patients more as having > 10% 10-year risk for CV events (n = 44/54; 81.5% versus n = 34/54; 63%). CONCLUSIONS: This study demonstrated that a substantial proportion of long-standing T1D patients free from known CVD show premature arterial stiffening. Cf-PWV strongly associates with the STENO risk score for future CV events and with cardiovascular imaging and function outcomes, thereby illustrating the clinical importance of arterial stiffness. The data, however, also show considerable heterogeneity in CV risk and differences in risk categorisation between the STENO tool and ESC criteria.There is a need for refinement of CV risk classification in T1D, and future studies should investigate if evaluation of arterial stiffness should be implemented in T1D clinical practice and which patients benefit the most from its assessment.

Use and Perception of Telemedicine in People with Type 1 Diabetes During the COVID-19 Pandemic: A 1-Year Follow-Up.

Background: In the spring of 2020, our research group circulated a worldwide survey with the aim of gathering information on the use and perception of telemedicine in people living with type 1 diabetes at the start of the COVID-19 pandemic. The data suggested that a large number of respondents had rapidly adopted to telemedicine, as in-person visits were not possible, and that this was perceived positively by many. In this study, we conducted a 1-year follow-up to investigate changes in opinions and experiences to telemedicine over the past year of the pandemic. Methods: An anonymous questionnaire was distributed through social media (Twitter, Facebook, and Instagram) between May 9 and May 15, 2021, using an open-access web-based platform (SurveyMonkey.com). The survey was identical to that used in the original study, covering questions relating to the use and perception of telemedicine, diabetes treatment and control, and medical supplies during the COVID-19 pandemic. The questionnaire was available in English, Spanish, German, French, and Italian. We compared the results from the two surveys descriptively and statistically, results were stratified according to age, gender, and HbA1c. Results: There were 531 survey responses from 40 countries (Europe 54%, North America 36%, South America 2%, and Africa and Asia 2%). A large percentage of respondents (67%) reported meeting with their health care provider remotely since the beginning of the pandemic, a significant increase compared with the 28% in the 2020 survey (P < 0.001). Eighty-three percent of respondents found remote appointments to be somewhat-to-extremely useful, similar to the 86% satisfaction rate in the previous survey (P = 0.061). Remote appointments were most frequently undertaken through telephone (50%) and video call (45%), which are significant changes compared with those in 2020 (72% and 28%, respectively, P < 0.001). Forty-five percent of respondents in 2021 were likely to consider remote appointments instead of in-person appointments in the future-being significantly lower than the 75% in the initial survey (P < 0.001)-whereas 37% indicated they would not. The majority of respondents (84%) reported no issues in their access to diabetes supplies and medication over the past year. Conclusions: This study showed that the use of telemedicine in the form of remote appointments increased during the COVID-19 pandemic in people living with type 1 diabetes, with high levels of satisfaction. However, a remarkable decline took place in the past year in the proportion of patients stating a willingness to continue with remote appointments beyond the pandemic. It seems that a personalized approach is needed since a substantial proportion of respondents in this follow-up still indicated a preference for in-person diabetes care, hence the use of telemedicine should be considered on an individual basis.

The impact of diabetic neuropathy on the distal versus proximal comparison of weakness in lower and upper limb muscles of patients with type 2 diabetes mellitus: a cross-sectional study.

OBJECTIVES: This study aimed to determine the impact of diabetic neuropathy (dNP) on the distal versus proximal comparison of weakness in lower and upper limb muscles of patients with type 2 Diabetes Mellitus (T2DM). METHODS: 19 healthy male controls without neuropathy (HC) and 35 male T2DM patients, without dNP (n=8), with sensory dNP (n=13) or with sensorimotor dNP (dNPsm; n=14), were enrolled in this study. Maximal isometric (IM) and isokinetic (IK) muscle strength and IK muscle endurance of the dominant knee, ankle and elbow, and maximal IM handgrip strength were measured by means of dynamometry. RESULTS: Ankle muscle endurance was lower compared to the knee, independently of dNP (p<0.001). Maximal IK ankle muscle strength was also lower compared to the knee, albeit only in dNPsm (p=0.003). No differences were found between maximal IM handgrip and elbow strength. CONCLUSIONS: Our results suggest an impact of T2DM -with or without dNP- on lower limb muscle strength more distally than proximally, while this was not observed in the upper limb. The gradient of dNP seemed to be a determining factor for the maximal muscle strength, and not for muscle endurance, in the lower limb.

THE ADDED AND INTERPRETATIVE VALUE OF CGM-DERIVED PARAMETERS IN TYPE 1 DIABETES DEPENDS ON THE LEVEL OF GLYCEMIC CONTROL.

OBJECTIVE: In type 1 diabetes mellitus (T1DM) management, continuous glucose monitoring (CGM)-derived parameters can provide additional insights, with time in range (TIR) and other parameters reflecting glycemic control and variability being put forward. This study aimed to examine the added and interpretative value of the CGM-derived indices TIR and coefficient of variation (CV%) in T1DM patients stratified according to their level of glycemic control by means of HbA1C. METHODS: T1DM patients with a minimum disease duration of 10 years and without known macrovascular disease were enrolled. Patients were equipped with a blinded CGM device for 7 days. TIR and time spent in hypoglycemia and hyperglycemia were determined, and CV% was used as a parameter for glycemic variability. Pearson (r) and Spearman correlations (rs) and a regression analysis were used to examine associations. RESULTS: Ninety-five patients (age: 45 ± 10 years; HbA1C level: 7.7% ± 0.8% [61 ± 7 mmol/mol]) were included (mean blood glucose [MBG]: 159 ± 31 mg/dL; TIR: 55.8% ± 14.9%; CV%: 43.5% ± 7.8%) and labeled as having good (HbA1C level ≤7% [≤53 mmol/mol]; n = 20), moderate (7%-8%; n = 44), or poor (>8% [>64 mmol/mol]; n = 31) glycemic control. HbA1C was significantly associated with MBG (rs = 0.48, P < .001) and time spent in hyperglycemia (total: rs = 0.52; level 2: r = 0.46; P < .001) but not with time spent in hypoglycemia and CV%, even after an analysis of the HbA1C subgroups. Similarly, TIR was negatively associated with HbA1C (r = -0.53; P < .001), MBG (rs = -0.81; P < .001), and time spent in hyperglycemia (total: rs = -0.90; level 2: rs = -0.84; P < .001) but not with time in hypoglycemia. The subgroup analyses, however, showed that TIR was associated with shorter time spent in level-2 hypoglycemia in patients with good (rs = -0.60; P = .007) and moderate (rs = -0.25; P = .047) glycemic control. In contrast, CV% was strongly positively associated with time in hypoglycemia (total: rs = 0.78; level 2: rs = 0.76; P < .001) but not with TIR or time in hyperglycemia in the entire cohort, although the subgroup analyses showed that TIR was negatively associated with CV% in patients with good glycemic control (r = -0.81, P < .001) and positively associated in patients with poor glycemic control (r = +0.47; P < .01). CONCLUSION: The CGM-derived metrics TIR and CV% are related to clinically important situations, TIR being strongly dependent on hyperglycemia and CV% being reflective of hypoglycemic risk. However, the interpretation and applicability of TIR and CV% and their relationship depends on the level of glycemic control of the individual patient, with CV% generally adding less clinically relevant information in those with poor control. This illustrates the need for further research and evaluation of composite measures of glycemic control in T1DM.

The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review.

Rigorous glycaemic control-reflected by low HbA1c goals-is of the utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short-term glycaemic variability (GV) is also important to consider as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk of cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM. An electronic database search of Medline (PubMed), Web of Science and Embase was performed up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated using the Newcastle Ottawa Scale for observational studies. Six studies (four cross-sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV), and both found significant negative correlations. Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not, while two other studies did find significant associations between GV parameters and CART scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in the methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated continuous glucose monitoring-derived parameters of GV, while standardized assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN.