Progression to hypertension in youth and young adults with type 1 or type 2 diabetes: The SEARCH for Diabetes in Youth Study

Central obesity may contribute to the development of hypertension in youths with diabetes. The SEARCH for Diabetes in Youth Study followed 1518 youths with type 1 diabetes (T1D) and 177 with type 2 diabetes (T2D) diagnosed when <20 years of age for incident hypertension. Incident hypertension was defined as blood pressure ≥95th percentile (or ≥130/80 mm Hg) or reporting antihypertensive therapy among those without hypertension at baseline. Poisson regression models were stratified by diabetes type and included demographic and clinical factors, clinical site, and waist‐to‐height ratio (WHtR). Youths with T2D were more likely to develop hypertension than those with T1D (35.6% vs 14.8%, P < .0001). For each 0.01 unit of annual increase in WHtR, adjusted relative risk for hypertension was 1.53 (95% CI 1.36‐1.73) and 1.20 (95% CI 1.00‐1.43) for youths with T1D and T2D, respectively. Effective strategies targeted toward reducing central obesity may reduce hypertension among youths with diabetes.     

Glycaemic control and sepsis risk in adults with type 1 diabetes

Aims

To study the association between glycated haemoglobin (HbA1c) and sepsis in adults with type 1 diabetes, and to explore the relationship between HbA1c and mortality among individuals who developed sepsis.

Materials and Methods

We included 33 549 adult individuals with type 1 diabetes recorded in the Swedish National Diabetes Register between January 2005 and December 2015. We used multivariable Cox regression and restricted cubic spline analyses to study the relationship between HbA1c values and sepsis occurrence and association between HbA1c and mortality among those with sepsis.

Results

In total, 713 (2.1%) individuals developed sepsis during the study period. Compared with the HbA1c reference interval of 48-52 mmol/mol (6.5-6.9%), the adjusted hazard ratio for sepsis was: 2.50 [95% confidence interval (CI) 1.18-5.29] for HbA1c <43 mmol/mol; 1.88 (95% CI 0.96-3.67) for HbA1c 43-47 mmol/mol; 1.78 (95% CI 1.09-2.89) for HbA1c 53-62 mmol/mol; 1.86 (95% CI 1.14-3.03) for HbA1c 63-72 mmol/mol; 3.15 (95% CI 1.91-5.19) for HbA1c 73-82 mmol/mol; and 4.26 (95% CI 2.53-7.16) for HbA1c >82 mmol/mol. On multivariable restricted cubic spline analysis, we found a J-shaped association between HbA1c and sepsis risk, with the lowest risk observed at HbA1c of approximately 53 mmol/mol. We found no association between HbA1c and mortality among those individuals who developed sepsis.

Conclusions

In our nationwide observational study of adult individuals with type 1 diabetes we found a J-shaped relationship between HbA1c and risk of sepsis, with the lowest risk at HbA1c levels about 53 mmol/mol (7.0%). HbA1c was not associated with mortality in individuals affected by sepsis.     

Vitamin D deficiency in children and adolescents with type 1 diabetes

Objective: To investigate the frequency and effects of vitamin D deficiency in children with type 1 diabetes (T1D) in a region which is known to have a high rate of vitamin D deficiency among adolescents. Methods: In this prospective cross-sectional study, 120 children and adolescents with T1D (55 girls and 65 boys) aged 3-20 years were evaluated. Serum 25-hydroxyvitamin D [25(OH)D], parathormone (PTH), and alkaline phosphatase (ALP) levels were measured. Hemoglobin A1c levels and daily insulin requirement were also evaluated. Classification of vitamin D status was made according to the American Academy of Pediatrics (AAP)/LWEPS’s recommendations. The patients were divided into 2 groups according to their vitamin D status and also according to the season of the year in which 25(OH)D sampling was done. Results: Serum 25(OH)D levels revealed vitamin D deficiency or insufficiency in 38% of the patients. Higher PTH levels were found in the patient group whose mean 25(OH)D level was <20 ng/mL as compared to the group whose mean 25(OH)D level was >20 ng/mL (p<0.05). Only 11% of patients had secondary hyperparathyroidism. The 25(OH)D levels of patients whose serum samples were taken in summer and spring months were significantly different (p<0.05). There were no significant correlationsbetween 25(OH)D level and daily insulin dose. Conclusion: Although we could not show a significant association between vitamin D deficiency and metabolic parameters, the frequency of vitamin D deficiency in T1D children is substantial. Vitamin D status should be assessed also in patients who do not have signs of rickets.Conflict of interest:None declared.     

Body composition in adolescent girls with type 1 diabetes.

AIMS: To compare body composition in adolescent girls with Type 1 diabetes with healthy controls. RESEARCH DESIGN AND METHODS: In this population-based study, body composition was examined, using dual-energy X-ray absorptiometry (DXA) and skinfold measurements, in 18 adolescent post-menarcheal females, 16-19 years of age, with Type 1 diabetes since childhood in comparison to age-matched healthy control subjects. RESULTS: Body mass index was 2.7 kg/m2 higher in diabetic patients (26.3 +/- 2.6 vs. 23.6 +/- 3.8; P < 0.05). The overweight consisted almost entirely of increased fat mass, as evaluated by both skinfold measurements and DXA. Bone mineral density did not differ between the two groups. In diabetic females, the distribution of the fat mass was increased in the upper part of the body. The fat distribution, expressed as the abdominal-to-leg ratio, was significantly correlated to glycated haemoglobin (HbA1c) (r = 0.69; P < 0.005), daily dosage of insulin expressed per kilogram body weight (r = 0.78; P < 0.0005) and total cholesterol (r = 0.60; P < 0.001). CONCLUSIONS: The observed overweight in adolescent females with Type 1 diabetes is explained by an increased fat mass. Abdominal fat accumulation was associated with poor glycaemic control, increased need for insulin and elevated blood lipids.     

Glycaemic control and diabetes care utilization in young adults with Type 1 diabetes1

Objectives To explore how glycaemic control in young adults is related to diabetes care utilization during the transition to adult diabetes care and if these variables differ between males and females. Methods This is a retrospective, longitudinal design following patients’ records from age 18–24 years. Adolescents (n = 104) connected to one paediatric outpatient clinic and referred to six different adult clinics were included. Data were collected regarding gender, age at diagnosis and transfer, yearly glycated haemoglobin (HbA_1c) and body mass index, severe hypoglycaemia and diabetic ketoacidosis, retinopathy and diabetes care utilization. Results HbA_1c decreased over time in females (P = 0.004) but not in males. Less than 10% had HbA_1c in the recommended range during the study period. The decrease in severe hypoglycaemia and diabetic ketoacidosis was not significant. The prevalence of background retinopathy increased from 5 to 29% during the study period (P < 0.001). Mean transfer age was 19.8 years. The youths visited the paediatric clinic more often than the adult clinic (P < 0.001) and females visited adult care more often than males (P = 0.04). There was a steady decrease in the number of visits/year over time (P < 0. 001). Poor glycaemic control was associated with more visits for both males and females (P = 0.005) in adult care. Conclusions As there was no gender difference in the relation between HbA_1c and the number of visits in adult diabetes care, the higher frequency of visits in adult care for females cannot be solely explained by their glycaemic control. Gender differences regarding diabetes care utilization should be further explored.     

Glycaemic risk assessment in children and young people with Type 1 diabetes mellitus

Aim To ascertain if those with diabetes (and their carers) ascribe a similar level of risk to blood glucose control as healthcare professionals. Methods We used a structured questionnaire to ask fifty healthcare professionals how ‘dangerous’ a given blood glucose value was. Their answers were modelled to produce an algorithm of assessed risk. To examine if patients (and their carers) would apportion a similar level of risk to that of healthcare professionals, the same questionnaire was issued to fifty children and adolescents with Type 1 diabetes. For patients under 8 years old the carers completed the questionnaires (n = 23). Both patient and carers together completed the questionnaire for those aged 8–11 years (n = 15) and patients over the age of 11 years completed the questionnaire themselves (n = 12). The median results and interquartile range of the assessed level of risk, as determined by the two groups, were compared using a generalized linear model. Results A significant difference (P < 0.0001) was identified between the median risk assessments of the two groups. The zero level of assessed risk was upward shifted in the patient group by 0.8 mmol/l and indicated the patients’ view of risk increased. Conclusions Patients with Type 1 diabetes (and their carers) evaluate the risk from blood glucose values differently from healthcare professionals. The euglycaemic state (zero ascribed risk) that patients chose was 0.8 mmol/l greater than that of healthcare professionals, indicating, perhaps, hypoglycaemia avoidance, a more pragmatic approach or less exposure to current trends in glycaemic control.     

Design and development of a scale measuring fear of complications in type 1 diabetes

BACKGROUND: There are many determinants of glycaemic control in patients with type 1 diabetes. Patients with type 1 diabetes and poor glycaemic control have been reported as being more likely to have a greater fear of hypoglycaemia. The relationship between fear of diabetes-related complications and glycaemic control is unclear, and therefore a brief measure of fear of diabetes complications was developed. METHODS: A questionnaire was designed, comprising items relating to general fears, specific fears (e.g. blindness, kidney problems, heart disease), lifestyle fears, fear of hypoglycaemia and weight gain. The questionnaire was piloted on 147 outpatients with type 1 diabetes, along with other measures such as the Hypoglycaemia Fear Survey, the Hospital Anxiety and Depression Scales, the Coping with Health, Injuries and Problems Scale and the Eysenck Personality Questionnaire. RESULTS: Factor analysis was carried out on the 30 items and, after rotation, 15 emerged as loading heavily on the first factor. Factor analysis was rerun on these 15 items and the first factor accounted for 56% of the total variance. This factor remained invariant when the scale was split randomly and by age and gender. The reliability of the scale (alpha) was 0.94. The scale did not correlate with any demographic variables but did with measures of negative affectivity (HADS anxiety = 0.34, p < 0.001; Depression = 0.24, p < 0.004), the Hypoglycaemia fear survey worry Scale (0.44, p < 0.001), presence of complications (0.17, p < 0.04) and number of complications (0.28, p < 0.001). CONCLUSIONS: These results indicate that the scale identifies a fear that is moderately related to the presence of complications and general negative affectivity but which is a uniquely diabetes-related emotion.     

Integrated safety and efficacy analysis of dasiglucagon for the treatment of severe hypoglycaemia in individuals with type 1 diabetes

Aims

To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready-to-use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D).

Materials and Methods

An integrated analysis of dasiglucagon safety was conducted on data from two placebo-controlled trials (placebo-controlled pool) and two placebo-controlled and four non-placebo-controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo-controlled and two non-placebo-controlled trials in adults with T1D.

Results

Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo-controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin-induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo-controlled trial subgroups.

Conclusions

Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin-induced SH in people with T1D.     

Impact of obesity on the increasing incidence of type 1 diabetes

Published estimates of the incidence of type 1 diabetes (T1D) in children in the last decade varies between 2% and 4% per annum. If this trend continued, the disease incidence would double in the next 20 years. The risk of developing T1D is determined by a complex interaction between multiple genes (mainly human leukocyte antigens) and environmental factors. Notwithstanding that genetic susceptibility represents a relevant element in T1D risk, genetics alone cannot explain the increase in incidence. Various environmental factors have been suggested as potential triggers for T1D, including several viruses and the hygiene hypothesis; however, none of these seems to explain the large increase in T1D incidence observed over the last decades. Several studies have demonstrated that the prevalence of childhood/adolescence overweight and obesity has risen during the past 30 years in T1D. Currently, at diagnosis, the majority of patients with T1D have normal or elevated body weight and ~50% of patients with longstanding T1D are either overweight or obese. The growing prevalence of obesity in childhood and adolescence offers a plausible explanation for the increase in T1D incidence observed in recent decades. Possible mechanisms of the enhancement of β-cell autoimmunity by obesity include: a) insulin resistance-induced β-cell secretory demand triggering autoimmunity through cytokine release, neo-epitope antigen formation and increase in β-cell apoptosis, and b) obesity-induced low-grade inflammation with pro-inflammatory cytokines secreted by locally infiltrating macrophages, which contribute to the presentation by islet cells of autoantigens generally not accessible to T cells. Further studies are needed to clarify whether the control of body weight can prevent or delay the current and continuing rise in T1D incidence.     

Glycaemic control in individuals with type 1 diabetes using an open source artificial pancreas system (OpenAPS)

Open source artificial pancreas systems (OpenAPS) have gained considerable interest in the diabetes community. We analyzed continuous glucose monitoring (CGM) records of 80 OpenAPS users with type 1 diabetes (T1D). A total of 19 495 days (53.4 years) of CGM records were available. Mean glucose was 7.6 ± 1.1 mmol/L, time in range 3.9–10 mmol/L was 77.5 ± 10.5%, <3.9 mmol/L was 4.3 ± 3.6%, <3.0 mmol/L was 1.3 ± 1.9%, >10 mmol/L was 18.2 ± 11.0% and > 13.9 mmol/L was 4.1 ± 4.0%, respectively. In 34 OpenAPS users, additional CGM records were obtained while using sensor-augmented pump therapy (SAP). After changing from SAP to OpenAPS, lower mean glucose (−0.6 ± 0.7; P < 0.0001), lower estimated HbA1c (−0.4 ± 0.5%; P < 0.0001), higher time in range 3.9–10 mmol/L (+9.3 ± 9.5%; P < 0.0001), less time < 3.0 mmol/L (−0.7 ± 2.2%; P = 0.0171), lower coefficient of variation (−2.4 ± 5.8; P = 0.0198) and lower mean of daily differences (−0.6 ± 0.9 mmol/L; P = 0.0005) was observed. Glycaemic control using OpenAPS was comparable with results of more rigorously developed and tested AP systems. However, OpenAPS was used by a highly selective, motivated and technology-adept cohort, despite not being approved for the treatment of individuals with T1D.     

Evaluation of subcutaneous glucose monitoring systems under routine environmental conditions in patients with type 1 diabetes

Continuous and flash glucose monitoring (GM) systems have been established in diabetes care. We compared the sensor performance of 3 commercially available GM systems. A total of 12 patients with type 1 diabetes were included in a single‐centre, open‐label study in which the sensor performance of the Abbott FreeStyle libre (Abbott), Dexcom G4 Platinum (Dexcom) and Medtronic MiniMed 640G (Medtronic) systems over 12 hours was compared during mimicked real‐life conditions (meals, exercise, hypo‐ and hyperglycaemia). Sensor performance was determined by fulfilment of ISO 15197:2013 criteria, calculating mean absolute relative difference (MARD), and was also illustrated using Parkes error grid and Bland–Altman plots. Sensor performance during changes in metabolic variables (lactate, betahydroxybutyrate, glucagon, non‐esterified‐fatty‐acids) was determined by Spearman's rank correlation coefficient testing. The systems fulfilled ISO 15197:2013 criteria by 73.2% (Abbott), 56.1% (Dexcom) and 52.0% (Medtronic). The MARDs ± standard deviation in the entire glycaemic range were 13.2% ± 10.9% (Abbott), 16.8% ± 12.3% (Dexcom) and 21.4% ± 17.6% (Medtronic), respectively. All sensors performed less accurately during hypoglycaemia and best during hyperglycaemia. We did not observe an influence of metabolic variables on sensor performance.     

Change in DASH diet score and cardiovascular risk factors in youth with type 1 and type 2 diabetes mellitus: The SEARCH for Diabetes in Youth Study

Youth with diabetes are at an increased risk of cardiovascular disease (CVD). Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet has been shown to improve CVD risk. In this study, we evaluated whether changes in diet quality as characterized by DASH are associated with changes in CVD risk factors in youth with diabetes over time. Longitudinal mixed models were applied to data from 797 participants in the SEARCH for Diabetes in Youth Study representing three time points: baseline, 12- and 60-month follow-up. Data were restricted to youth whose diabetes was first diagnosed in 2002–2005. DASH-related adherence was poor and changed very little over time. However, an increase in DASH diet score was significantly associated with a decrease in HbA_1c levels in youth with type 1 diabetes (β=−0.20, P-value=0.0063) and a decrease in systolic blood pressure among youth with type 2 diabetes (β=−2.02, P-value=0.0406). Improvements in dietary quality may be beneficial in youth with type 1 or type 2 diabetes. However, further work in larger groups of youth with type 1 and 2 diabetes is desirable.     

The influence of clinical and genetic factors on the development of obesity in children with type 1 diabetes

The exact cause of the obesity epidemic remains unknown; however, both environmental and genetic factors are involved. People at risk of developing obesity include children with type 1 diabetes mellitus (T1DM), which in turn increases their cardiovascular disease risk. Here, we discuss the clinical and genetic factors influencing weight in patients with T1DM. In children with T1DM, the presence of obesity depends mainly on sex, metabolic control, and disease duration. However, genetic factors, including the fat mass and obesity‐associated (FTO) gene, are also associated with body weight. Indeed, children with the FTO gene rs9939609 obesity‐risk allele (homozygous = AA or heterozygous = AT) are predisposed to a higher body mass index and have a greater risk of being overweight or obese. However, in this review, we show that FTO gene polymorphisms only have a small effect on body weight in children, much weaker than the effect of clinical factors. The association between FTO gene polymorphisms and body weight is only statistically significant in children without severe obesity. Moreover, other genetic factors had no effect on weight in patients with T1DM, and further research involving larger populations is required to confirm the genetic basis of diabetes and obesity. Therefore, identifying the clinical features of children with T1DM, such as their initial body mass index, sex, metabolic control, and disease duration, will still have the strongest effect on reducing risk factors for cardiovascular diseases. Physicians should pay close attention to modifiable elements of these relationships, for example, metabolic control and energy and insulin intake, when caring for patients with T1DM. Copyright © 2016 John Wiley & Sons, Ltd.     

Similar risk of exercise‐related hypoglycaemia for insulin degludec to that for insulin glargine in patients with type 1 diabetes: a randomized cross‐over trial

We compared changes in blood glucose (BG) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) or insulin glargine (IGlar) in a randomized, open‐label, two‐period, crossover trial. After individual titration and a steady‐state period, patients performed 30 min of moderate‐intensity cycle ergometer exercise (65% peak rate of oxygen uptake). BG, counter‐regulatory hormones and hypoglycaemic episodes were measured frequently during and for 24 h after exercise. BG changes during exercise were similar with IDeg and IGlar [estimated treatment difference (ETD) for maximum BG decrease: 0.14 mmol/l; 95% confidence interval (CI) ?0.15, 0.42; p = 0.34], as was mean BG (ETD ?0.16 mmol/l; 95% CI ?0.36, 0.05; p = 0.13). No hypoglycaemic episodes occurred during exercise. Post‐exercise mean BG, counter‐regulatory hormone response and number of hypoglycaemic episodes in 24 h after starting exercise were similar with IDeg (18 events in 13 patients) and IGlar (23 events in 15 patients). This clinical trial showed that, in patients with T1D treated with a basal‐bolus regimen, the risk of hypoglycaemia induced by moderate‐intensity exercise was low with IDeg and similar to that with IGlar.     

Relationship between body weight change and glycaemic control with tirzepatide treatment in people with type 2 diabetes: A post hoc assessment of the SURPASS clinical trial programme

Aim

To assess the relationship between HbA1c and body weight reductions with tirzepatide treatment (5, 10 or 15 mg).

Materials and Methods

HbA1c and body weight data at 40 weeks (SURPASS-1, -2 and -5) and 52 weeks (SURPASS-3 and -4) were analysed by trial.

Results

Across the SURPASS clinical trials, HbA1c reductions from baseline were observed in 96%-99%, 98%-99% and 94%-99% of participants treated with tirzepatide 5, 10 and 15 mg, respectively. Moreover, 87%-94%, 88%-95% and 88%-97% of participants, respectively, experienced weight loss associated with HbA1c reductions. Statistically significant associations (correlation coefficients ranging from 0.1438 to 0.3130 across studies; P ≤ .038) between HbA1c and body weight changes were observed with tirzepatide in SURPASS-2, -3, -4 (all doses) and -5 (tirzepatide 5 mg only).

Conclusions

In this post hoc analysis, consistent reductions in both HbA1c and body weight were observed in most participants treated with tirzepatide at doses of 5, 10 or 15 mg. A statistically significant but modest association between HbA1c and body weight change was observed in SURPASS-2, SURPASS-3 and SURPASS-4, suggesting that both weight-independent and weight-dependent mechanisms are responsible for the tirzepatide-induced improvement in glycaemic control.