Avoiding hypoglycemia: the use of insulin pump combined with continuous glucose monitor in type 1 diabetes crossing a Rocky Gorge.

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring systems (CGMS) have been proven very effective in diabetes management. AIM: This study evaluated the usefulness of these devices during prolonged, intense physical activity in an uncontrolled natural environment away from the clinical research center. DESIGN: Non-randomized, prospective and observational study. METHODS: During the summer, 38 participants with type 1 diabetes crossed the Samaria gorge, the second largest gorge in Europe (17 km). Twenty subjects on CSII combined with real-time CGMS and 18 on multiple daily injections (MDI) combined with professional (retrospective) CGMS participated in the program. All participants were unsupervised during the event. RESULTS: All 38 participants managed to reach the destination point safely. There were no episodes of severe hypoglycemia. The duration of the exercise (mean ±SD) was 6.4 ± 1.3 h. The CSII group exhibited significantly lower hypoglycemic episodes during exercise (0.1 ± 0.3 vs. 0.4 ± 0.6; P = 0.047) as well as lower AUC below 70 mg/dl compared with the MDI, during the 24 h (0.61 ± 0.78 vs. 1.84 ± 1.55; P = 0.007). Individuals on CSII were significantly less likely to develop a hypoglycemic episode during exercise (P = 0.038). Exercise induced nocturnal hypoglycemia was not prevented effectively in neither group. CONCLUSIONS: CSII combined with CGMS is effective in controlling blood glucose levels in type 1 diabetics who perform prolonged strenuous exercise. The use of insulin pump technology in regions with hot Mediterranean climates is safe and can provide protection against exercise-induced hypoglycemia. Development of precise instructions for T1DM who occasionally get involved in exercise activities, requires further studies.

Seasonality at the clinical onset of type 1 diabetes-Lessons from the SWEET database.

BACKGROUND: Seasonality at the clinical onset of type 1 diabetes (T1D) has been suggested by different studies, however, the results are conflicting. This study aimed to evaluate the presence of seasonality at clinical onset of T1D based on the SWEET database comprising data from 32 different countries. METHODS: The study cohort included 23 603 patients (52% males) recorded in the international multicenter SWEET database (48 centers), with T1D onset ≤20 years, year of onset between 1980 and 2015, gender, year and month of birth and T1D-diagnosis documented. Data were stratified according to four age groups (<5, 5-<10, 10-<15, 15-20 years) at T1D onset, the latitude of European center (Northern ≥50°N and Southern Europe <50°N) and the year of onset ≤ or >2009. RESULTS: Analysis by month revealed significant seasonality with January being the month with the highest and June with the lowest percentage of incident cases (P < .001). Winter, early spring and late autumn months had higher percentage of incident cases compared with late spring and summer months. Stratification by age showed similar seasonality patterns in all four age groups (P ≤ .003 each), but not in children <24 months of age. There was no gender or latitude effect on seasonality pattern, however, the pattern differed by the year of onset (P < .001). Seasonality of diagnosis conformed to a sinusoidal model for all cases, females and males, age groups, northern and southern European countries. CONCLUSIONS: Seasonality at T1D clinical onset is documented by the large SWEET database with no gender or latitude (Europe only) effect except from the year of manifestation.

Comparison of office, ambulatory and home blood pressure in children and adolescents on the basis of normalcy tables.

In children and adolescents, the diagnosis of hypertension is based on office, home and ambulatory blood pressure (BP) measurements. Different normalcy tables for each method have provided 95th percentiles of BP as thresholds for hypertension diagnosis. This study assessed the differences in BP thresholds among these methods when applied in the pediatric population. The most widely used office, home and ambulatory BP normalcy tables were compared in terms of the 50th and 95th percentiles by gender and age. The range of office BP change with increasing age is wider than for home or ambulatory BP in boys and girls, apart from systolic BP in boys. Percentiles of home BP are consistently lower than that of daytime ambulatory BP. There is a trend for office BP to be lower than home or daytime ambulatory BP in the younger age subgroups. This difference is progressively eliminated with increasing age, apart from systolic BP in boys. In conclusion, in children and adolescents, the relationship between office, home and ambulatory BP thresholds provided by the widely used normalcy tables is not the same as in the adults. These findings should be taken into account when evaluating BP measurements in children and adolescents in clinical practice.

Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries.

AIMS/HYPOTHESIS: To assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90 days and relating them to outcome. METHODS: Pump programming data from patients aged 0-18 years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA(1c) was measured centrally. RESULTS: A total of 1,041 patients (age: 11.8 +/- 4.2 years; diabetes duration: 6.0 +/- 3.6 years; average CSII duration: 2.0 +/- 1.3 years; HbA(1c): 8.0 +/- 1.3% [means +/- SD]) participated. Glycaemic control was better in preschool (n = 142; 7.5 +/- 0.9%) and pre-adolescent (6-11 years, n = 321; 7.7 +/- 1.0%) children than in adolescent patients (12-18 years, n = 578; 8.3 +/- 1.4%). There was a significant negative correlation between HbA(1c) and daily bolus number, but not between HbA(1c) and total daily insulin dose. The use of <6.7 daily boluses was a significant predictor of an HbA(1c) level >7.5%. The incidence of severe hypoglycaemia and ketoacidosis was 6.63 and 6.26 events per 100 patient-years, respectively. CONCLUSIONS/INTERPRETATION: This large paediatric survey of CSII shows that glycaemic targets can be frequently achieved, particularly in young children, and the incidence of acute complications is low. Adequate substitution of basal and prandial insulin is associated with a better HbA(1c).

Cardiovascular impairment in children, adolescents, and young adults with type 1 diabetes mellitus (T1DM).

Left ventricular (LV) function was assessed in 42 patients (mean age +/- SD, 18.45 +/- 3.76 years; 17 males) with type I diabetes mellitus (T1DM; mean duration 9.89 years) and in 43 healthy controls (mean age +/- SD, 18.27 +/- 3.36 years; 18 males). Systolic, diastolic cardiac function and LV dimensions were assessed using M-mode and Doppler echocardiography. Neural autonomic function was assessed by measuring RR variation during deep breathing, Valsava maneuver, 30/15 ratio, and blood pressure response to standing. Fractional shortening, peak velocity of early ventricular filling (E wave), peak velocity of LV filling (A wave), E/A ratio, deceleration time, isovolumic relaxation time, LV dimensions (interventricular septum, posterior wall thickness, end diastolic diameter [EDD] and systolic diameter [ESD]) were all comparable between patients with T1DM and controls. However, in 11 T1DM patients with microalbuminuria and/or retinopathy, EDD, ESD, E/A ratio, and E wave were all lower (p = 0.0011, p = 0.019, p = 0.0011, and p = 0.030, respectively) while, A wave, heart rate, and diastolic blood pressure were all higher (p = 0.008, p = 0.0024 and p = 0.004, respectively) compared to matched for age and sex controls. Furthermore, in six of the 11 T1DM patients with microangiopathy who had E/A <1.12 (<2 SD of the control mean), significant and marginally significant correlations were found between E/A ratio and the duration of the disease as well as the mean HbA1c of the last year (r = -0.38, p = 0.011 and r = -0.287, p = 0.064, respectively). In conclusion, it has been found that impairment of diastolic, but not systolic, LV function can be detected early in young patients with T1DM and microangiopathy.

Genetic screening for individuals at high risk for type 1 diabetes in the general population using HLA Class II alleles as disease markers. A comparison between three European populations with variable rates of disease incidence.

BACKGROUND: To develop screening strategies for identification of individuals at increased genetic risk for type 1 diabetes in three populations with variable disease incidence rates and distinct ethnic origin. METHODS: A stepwise HLA DQB1-DQA1-DRB1-based screening approach was evaluated. Patients with childhood-onset type 1 diabetes were recruited from Finland (n = 1739), Hungary (n = 149), and Greece (n = 119). Consecutive newborns (2568 from Finland and 1047 from Greece) or healthy schoolchildren (n = 177 from Hungary) served as controls. RESULTS: The DQB1*02/0302 genotype conferred the highest disease risk in all populations. The DQB1*02/y (y not equal DQB1*0301,*0302,*0602,*0603, *0604) genotypes were more common and conferred a higher disease risk in the Greek population (OR 4.9) compared to the Finns (OR 1.2). DQB1*0302/x (x not equal DQB1*02, *0301, *0602, *0603, *0604) genotypes were, in contrast, more prevalent among Finnish cases (32.7%) as compared to Hungarians (18.1%) or Greeks (13.5%). The protective DQB1*0602 or *0603 positive genotypes were most common in the Finns, while DQB1*0301 was more common in Hungarians and Greeks. In all groups, DQA1 and DRB1*04 typing considerably increased the sensitivity of the DQB1-based screening. The different high-risk genotype combinations present in about 10% of the background population had a diagnostic sensitivity of 60% in Finland and 80% in Hungary and Greece. CONCLUSIONS: HLA DR-DQ-based screening is a feasible tool for the identification of individuals at increased genetic risk for type 1 diabetes in populations with diverse genetic background. The risk markers should, however, be individually selected for the target population since the screening efficiency of various markers is highly dependent on the ethnic group studied.

Autonomic neuropathy and gastrointestinal motility disorders in children and adolescents with type 1 diabetes mellitus.

INTRODUCTION: There is little information on the gastrointestinal motility abnormalities and autonomic neuropathy of children with gastrointestinal symptoms and type 1 diabetes mellitus (T1DM). METHODS: The authors studied 33 consecutive patients (mean age, 15.3 years; 13 males) with T1DM (median duration, 7.7 years) attending the outpatient clinic because of chronic dyspepsia (CD; n = 14), or chronic constipation (CC; n = 19), and 48 consecutive non-T1DM patients (mean age, 13.7 years; 18 males), who presented with similar symptoms (18 with CD; 30 with CC). Fasting serum motilin concentrations and cardiovascular autonomic function tests (CAFT) were assessed and compared with those of age- and gender-matched healthy control subjects. Gastric emptying half time (GE t1/2) of a solid meal and mouth-to-anus transit time (MATT) were measured in patients with CD and CC, respectively. RESULTS: CAFT was comparable between patients with T1DM and healthy control subjects. GE t1/2 and MATT were not different between T1DM patients and non-T1DM patients with CD and CC, respectively. However, a marginally significant positive correlation was found in the patients with T1DM between GE t1/2 and blood glucose concentrations (R = 0.54; P = 0.08). In addition, serum motilin concentrations were significantly lower in patients with T1DM compared with healthy control subjects (P < 0.0005), and in patients with T1DM and higher serum glucose concentrations compared with those with lower serum glucose concentrations (P = 0.03). CONCLUSION: Autonomic neuropathy is not an etiological factor of gastrointestinal symptoms in children and adolescents with diabetes. Mild or moderate hyperglycemia does not affect gastrointestinal motility.

Nutritional implications of chronic dyspepsia in childhood.

Chronic dyspepsia is common in children. However, the association of individual predominant symptoms with gastric emptying and their impact on nutritional status are poorly defined. We therefore studied 31 children (mean age 11 years, 14 boys) with chronic dyspepsia and classified their predominant symptoms (PS) by their character and severity. Gastric emptying (GE) T(1/2) of a solid meal was carried out in all patients, while upper gastrointestinal endoscopy was done in the treatment failures. All patients received two months treatment with cisapride. Weight for age z scores were recorded before and three months after treatment. There were 12 patients with epigastric pain (EP) as the PS (7 moderate/severe). Postprandial fullness (PF) was the PS in 19 patients (12 moderate/severe). GE T(1/2) was prolonged and weight for age z scores were lower in children who had moderate/severe (but not mild) PF comparing to those who had EP (P < 0.0001 and P = 0.003, respectively). A significant improvement in weight was observed in the same group alone following treatment with cisapride (P = 0.0003). In conclusion, impaired GE is common in dyspeptic children with PF and have adverse effects on nutritional status.

Cryogenic storage of isolated, purified porcine pancreatic islets.

Highly purified islets of Langerhans were prepared in the present study from adult pigs by collagenase digestion and density gradient purification. After overnight culture, the tissue was equilibrated with DMSO at 25 degrees C, supercooled to -7.5 degrees C, nucleated, slowly cooled at 0.25 degrees C/min to -40 degrees C, and stored at -130 degrees C. Then, after variable periods of storage, the islets were rapidly thawed at 37 degrees C. Postthaw actual islet and islet equivalent (150-microns sized islets) recovery were 75 +/- 7% and 66 +/- 4%, respectively. The frozen-thawed porcine islets maintained good morphology on histological staining by hematoxylin-eosin and aldehyde-fuchsin. Upon perifusion, basal insulin secretion was 43 +/- 10 and 67 +/- 18 pmol/L from noncryopreserved, control islets, and cryopreserved islets, respectively (P = 0.2). Peak insulin release at 16.7 mmol/L glucose was 85 +/- 28 pmol/L from noncryopreserved islets and 157 +/- 48 pmol/L from the frozen-thawed islets (P = 0.1). When 10 mmol/L theophylline was added to 16.7 mmol/L glucose, the secretion of the hormone peaked to 221 +/- 83 (control islets) and 479 +/- 140 pmol/L (cryopreserved islets, P = 0.1). Total insulin secretion differed significantly for the noncryopreserved and the cryopreserved islets at both 16.7 mmol/L (1412 +/- 306 vs. 3756 +/- 764 pmol/L, respectively, P = 0.007) and 16.7 mmol/L glucose plus 10 mmol/L theophylline (2161 +/- 371 vs. 7505 +/- 2075 pmol/L, respectively, P = 0.011). Normoglycemia was restored within 7 days from implantation in temporarily immunosuppressed (aL3T4 antibody) mice with streptozotocin-induced diabetes by transplanting 1500-2000 cryopreserved porcine islets under the kidney capsule. Mean survival time of frozen-thawed islet xenografts (39 +/- 3 days) was similar to that of noncryopreserved islet xenografts (43 +/- 6 days). This study demonstrates that cryogenic storage is feasible of isolated porcine islets, with the frozen-thawed pancreatic endocrine tissue maintaining morphological integrity and both in vitro and in vivo viability. Further studies are needed to define the effect of cryopreservation on the immunogenic properties of porcine islets.

Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets.

The goal of islet transplantation in human diabetes is to maintain the islet grafts in the recipients without the use of immunosuppression. One approach is to encapsulate the donor islets in permselective membranes. Hollow fibers fabricated from an acrylic copolymer were used to encapsulate small numbers of rat islets that were immobilized in an alginate hydrogel for transplantation in diabetic mice. The fibers were biocompatible, prevented rejection, and maintained normoglycemia when transplanted intraperitoneally; hyperglycemia returned when the fibers were removed at 60 days. Normoglycemia was also maintained by subcutaneous implants that had an appropriately constructed outer surface on the fibers.

Automated large-scale isolation, in vitro function and xenotransplantation of porcine islets of Langerhans.

To evaluate the potential of utilizing porcine islet tissue as an alternative to human islet tissue for transplantation, we developed a method for the isolation of large amounts of highly purified porcine islets, and assessed the in vitro and in vivo function of the isolated islets after 1, 4, and 7 days of culture. The pancreatic duct of the splenic lobe was cannulated and distended by injection of Hanks' balanced salt solution containing 1.5 mg/ml collagenase. The pancreas was then processed by a modification of the automated digestion-filtration method developed in this laboratory, and with purification accomplished by Euro-Ficoll gradients (dialyzed Ficoll in Eurocollins solution), consisting of two layers of 1.108 and 1.091 g/cm3 density, topped with a layer of HBSS. The postpurification yield was 5203 +/- 645 (mean +/- SEM) islets per gram of pancreas with a number of islet equivalents (IE) per gram pancreas (islet equivalence: 150-microns-sized islets) of 3551 +/- 305, and a volume of 6.27 +/- 1.7 mm3 islet tissue per gram of pancreas. The islet purity exceeded 90%. Overnight-cultured, perifused porcine islets released 53.1 +/- 8.2 pM insulin/200 IE at 3.3 mM glucose, and 114.9 +/- 25.4 pM insulin/200 IE at 16.7 mM glucose (P less than 0.001 vs. basal output). When theophylline was added, insulin secretion increased to 264.2 +/- 63.2 pM/200 IE (P less than 0.001 vs. basal secretion and P less than 0.005 vs. secretion at 16.7 mM glucose). After 4 days of culture, the islets still responded to secretagogues. The functional integrity of the isolated islets was confirmed by reversal of diabetes in aL3T4 antibody-treated C57B/B6 diabetic mice: normoglycemia was promptly restored by transplanting 1000 overnight- or 7-day-cultured (24 degrees C) islets under the kidney capsule. These results suggest that continued improvements of porcine islet isolation and culture could permit the use of porcine islets in immunoalteration and immunoisolation studies that may lead to eventual human transplantation.

Production of marked prolongation of islet xenograft survival (rat to mouse) by local release of mouse and rat antilymphocyte sera at transplant site.

Polymer rods impregnated with lyophilized particles of mouse (M) or rat (R) antilymphocyte serum (ALS) were placed adjacent to rat islet xenografts transplanted beneath the kidney capsule of diabetic mice. Insertion of rods containing only MALS or RALS had no effect on the survival time of the rat islet xenografts. In contrast, the insertion of both MALS and RALS rods with the graft produced a marked prolongation of islet xenograft survival (mean survival time greater than 55.5 +/- 10.9 days) compared with controls (14.7 +/- 2.5 days). One recipient was still normoglycemic at 100 days, and removal of the graft returned the animal to a diabetic state. The islet graft had a normal degree of beta-granulation, and a slight fibrotic reaction was present around the rods. The effect of the rods in prolonging survival of the xenografts resulted from a local slow release of MALS and RALS, because implantation of the MALS and RALS rods in the right kidney and the islets in the left kidney had no effect on prolonging islet xenograft survival. These findings indicate that local immunosuppression produced marked prolongation of rat islet xenograft survival in mice. This raises the possibility of using polymer rods for the local slow release of monoclonal antibodies to lymphokines and other agents for prevention of rejection of islet allografts and xenografts and to determine the effect of lymphokines in vivo on islet function.