Assessing awareness of hypoglycemia in children and adolescents with type 1 diabetes: Evaluation of established questionnaires.

OBJECTIVE: To evaluate the use of two questionnaires assessing awareness of hypoglycemia, in a pediatric type 1 diabetes (T1D) population. METHODS: Prospective observational study with children (aged 9-18 years) and parents (for children aged 2-11 years) answering the Gold and Clarke questionnaires assessing awareness of hypoglycemia. Psychometric properties of the questionnaires were evaluated, and the most appropriate cut-off score to classify participants as having normal vs impaired awareness of hypoglycemia (IAH) was determined by ability to recognize subsequent hypoglycemia and hypoglycemia severity, documented in a 4-week blood glucose diary. Questionnaires were readministered at follow-up assessment approximately 1.5 years later. RESULTS: In total, 112 participants (51% male) with median (IQR) age 13.7 (11.1-15.8) years, T1D duration 4.7 (2.2-7.8) years, and HbA1c 62 (57-73) mmol/mol (7.8%) were included. Both questionnaires demonstrated acceptable psychometric properties. Using score ≥3 to classify IAH gave a prevalence of IAH of 41% (Gold) and 22% (Clarke). When classified using the Gold questionnaire, IAH participants had higher incidences of mild asymptomatic hypoglycemia, whereas with the Clarke questionnaire, they had higher incidences of clinically significant and severe hypoglycemia. Subgroup analyses confirmed these associations only in participants aged ≥9 years. Follow-up was completed in 90% of the participants, and a change of awareness status was observed in 22% to 36%. CONCLUSIONS: The Gold and Clarke questionnaires may be used to assess awareness of hypoglycemia in pediatric T1D in those ≥9 years of age, but the more detailed Clarke questionnaire has higher specificity and is superior in predicting risk of clinically significant hypoglycemia.

Cognitive deficits associated with impaired awareness of hypoglycaemia in type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to compare cognitive function in adults with type 1 diabetes who have impaired awareness of hypoglycaemia with those who have normal awareness of hypoglycaemia. A putative association was sought between cognitive test scores and a history of severe hypoglycaemia. METHODS: A total of 68 adults with type 1 diabetes were included: 33 had impaired and 35 had normal awareness of hypoglycaemia, as confirmed by formal testing. The groups were matched for age, sex and diabetes duration. Cognitive tests of verbal memory, object-location memory, pattern separation, executive function, working memory and processing speed were administered. RESULTS: Participants with impaired awareness of hypoglycaemia scored significantly lower on the verbal and object-location memory tests and on the pattern separation test (Cohen's d -0.86 to -0.55 [95% CI -1.39, -0.05]). Participants with impaired awareness of hypoglycaemia had reduced planning ability task scores, although the difference was not statistically significant (Cohen's d 0.57 [95% CI 0, 1.14]). Frequency of exposure to severe hypoglycaemia correlated with the number of cognitive tests that had not been performed according to instructions. CONCLUSIONS/INTERPRETATION: Impaired awareness of hypoglycaemia was associated with diminished learning, memory and pattern separation. These cognitive tasks all depend on the hippocampus, which is vulnerable to neuroglycopenia. The findings suggest that hypoglycaemia contributes to the observed correlation between impaired awareness of hypoglycaemia and impaired cognition.

Fear of hypoglycemia in women and men with type 1 diabetes.

BACKGROUND: Severe hypoglycemia is a serious complication of type1 diabetes feared by many who have the disease. OBJECTIVES: The aim of this study was to investigate specific fears related to hypoglycemia in adults with type 1 diabetes and to investigate how aspects of fear of hypoglycemia may differ between genders. METHODS: A cross-sectional study with questionnaires sent to 636 patients with type 1 diabetes, aged 18-75 years, who attended the outpatient clinic at St. Olavs Hospital, Trondheim, Norway. Fears related to hypoglycemia were assessed using the Hypoglycemia Fear Survey II Worry subscale (HFS-II-Worry). RESULTS: The response rate was 70% (N = 445, 216 women and 229 men). The mean HFS-II-Worry score was higher in women than in men (2.46 [SD = 0.80] vs. 2.22 [SD = 0.74], respectively; p < .001). Women scored higher than men in all items in the HFS-II-Worry, and women's average scores were statistically significantly higher in 5 of the 18 items after correction for multiple comparisons. The largest gender differences in mean scores occurred in the items "low blood glucose interfering with important things," "becoming upset and difficult," "difficulty thinking clearly," and "feeling lightheaded or dizzy." In both women and men, the highest mean scores appeared in the worry items "become hypoglycemic while sleeping" and "not having food available." DISCUSSION: In this sample of Norwegian adults with type 1 diabetes, women expressed more concerns about hypoglycemia than men. The highest HFS-II-Worry scores occurred in the same items in women and men, but the largest gender differences in mean scores appeared across a variety of other items, some of which were related to social esteem.

Prevalence and associations of impaired awareness of hypoglycemia in a pediatric type 1 diabetes population - The Norwegian Childhood Diabetes Registry.

AIMS: To determine the prevalence and associations of impaired awareness of hypoglycemia (IAH) in pediatric type 1 diabetes. METHODS: Nationwide, population-based cross-sectional study with 51 % participation. Participants (n = 1329; 53 % males) aged 2-19 years (median 13.3) with type 1 diabetes ≥ 6 months (median 4.6 years) self-assessed hypoglycemia awareness with a validated questionnaire ('Clarke'). Parents responded for children aged < 9 years (n = 235). We estimated associations between IAH and clinical data in the Norwegian Childhood Diabetes Registry. RESULTS: The overall prevalence of IAH was 22 %, but gradually decreased from 53 % in preschoolers to 12 % in adolescents aged ≥ 16 years. IAH was associated (adjusted OR; 95 %CI) with episodes of severe hypoglycemia (6.0; 3.04, 11.8) and diabetic ketoacidosis (3.45; 1.37, 8.68) the preceding year, increased fear of hypoglycemia (highest quartile vs. lowest: 2.27; 1.51, 3.40), female sex (1.41; 1.05, 1.90), and HbA1c ≥ 8.5 % (69 mmol/mol) vs. 7.5-8.4 % (58-68 mmol/mol) (1.48; 1.01, 2.18), but not with disease duration, use of insulin pump or continuous glucose monitoring, or HbA1c < 7.5 % (58 mmol/mol). CONCLUSIONS: IAH is prevalent in pediatric diabetes and more likely reported in young children. IAH is associated with severe hypoglycemia and fear of hypoglycemia, but good metabolic control seems achievable without increased risk of IAH.

Author Correction: Evaluation of Hypoglycaemia with Non-Invasive Sensors in People with Type 1 Diabetes and Impaired Awareness of Hypoglycaemia.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

A multiparameter model for non-invasive detection of hypoglycemia.

OBJECTIVE: Severe hypoglycemia is the most serious acute complication for people with type 1 diabetes (T1D). Approximately 25% of people with T1D have impaired ability to recognize impending hypoglycemia, and nocturnal episodes are feared. APPROACH: We have investigated the use of non-invasive sensors for detection of hypoglycemia based on a mathematical model which combines several sensor measurements to identify physiological responses to hypoglycemia. Data from randomized single-blinded euglycemic and hypoglycemic glucose clamps in 20 participants with T1D and impaired awareness of hypoglycemia was used in the analyses. MAIN RESULTS: Using a sensor combination of sudomotor activity at three skin sites, ECG-derived heart rate and heart rate corrected QT interval, near-infrared and bioimpedance spectroscopy; physiological responses associated with hypoglycemia could be identified with an F1 score accuracy up to 88%. SIGNIFICANCE: We present a novel model for identification of non-invasively measurable physiological responses related to hypoglycemia, showing potential for detection of moderate hypoglycemia using a wearable sensor system.

Regular use of pedometer does not enhance beneficial outcomes in a physical activity intervention study in type 2 diabetes mellitus.

The aim of the present study was to investigate whether the use of pedometer increases walking and/or enhances beneficial outcomes in a physical intervention study in type 2 diabetes mellitus. Seventy persons with type 2 diabetes mellitus were randomized to a pedometer and a nonpedometer group (P and non-P groups). All participants were seen by a nurse at a baseline visit (V1), after 1 month, after 3 months, and after 6 months and were then encouraged to increase walking. Subjects in the P group additionally registered pedometer steps 3 days twice per month for 6 months. After V1 and the visit at 6 months, aerobic capacity (VO2peak) was measured; and subjects reported perceived physical fitness and activity. Twenty-two subjects did not complete the study (dropouts). The VO2peak at V1 was lower in dropouts than in subjects who completed the study (completers) (P=.003). In the P group, the number of steps per day did not increase from month 1 to month 6 (P=.65). In completers, taken together, there was a decrease in body weight (P=.005), hemoglobin A1c (P=.034), fasting blood glucose (P=.033), triglycerides (P=.002), and diastolic blood pressure (P=.048) and an increase in high-density lipoprotein cholesterol (P<.001), with no difference between the P group and non-P group for these variables (all P values>.38). Perceived improvement in physical and mental state correlated with improvement in VO2peak (r=0.45, P=.008 and r=0.38, P=.03, respectively; n=34). We conclude that the use of pedometer did not increase walking or enhance beneficial metabolic outcomes. The low aerobic capacity in dropouts indicates that persons most needy of physical exercise are the least compliant in exercise programs.

Evaluation of Hypoglycaemia with Non-Invasive Sensors in People with Type 1 Diabetes and Impaired Awareness of Hypoglycaemia.

People with type 1 diabetes and impaired awareness of hypoglycaemia (IAH) are prone to severe hypoglycaemia. Previous attempts to develop non-invasive hypoglycaemia alarm systems have shown promising results, but it is not known if such alarms can detect severe hypoglycaemia in people with IAH. We aimed to explore whether a combination of non-invasive sensors could reliably evaluate hypoglycaemia (plasma glucose (PG) minimum 2.5 mmol/L) in people with IAH. Twenty participants with type 1 diabetes and IAH underwent randomly ordered, single blinded hyperinsulinemic euglycaemic and hyperinsulinemic hypoglycaemic clamps. Sweating, skin temperature, ECG, counterregulatory hormones and symptoms of hypoglycaemia were assessed. Overall, we were not able to detect clamp-induced hypoglycaemia with sufficient sensitivity and specificity for further clinical use. As a post-hoc analysis, we stratified participants according to their ability to identify hypoglycaemic symptoms during hypoglycaemic clamps. Five out of 20 participants could identify such symptoms. These participants had a significantly higher adrenaline response to hypoglycaemia (p < 0.001) and were reliably identified by sensors. Based on our observations, a non-invasive alarm system based on measurement of sweating responses and ECG changes during hypoglycaemia might provide an alert at a plasma glucose concentration around 2.5 mmol/L if an adequate sympatho-adrenal reaction is elicited.

Detection of sympathoadrenal discharge by parameterisation of skin conductance and ECG measurement.

Detection of sympathoadrenal discharge is valuable for stress monitoring, but measuring the circulating adrenaline level directly is inconvenient, making non-invasive physiological sensors an attractive alternative. Little is known however, about their performance in detecting different adrenaline levels. In this study, adrenaline measurements over time from 20 subjects × 2 trials were compared with skin conductance (SC) from different skin sites and ECG recordings from which the heart rate and QT interval were derived. The frequency of sudomotor responses (FSR) was derived from the SC recording, and a new composite parameter for amplification of synchronous changes in multiple sensor signals was calculated for different combinations of FSR from different skin sites, heart rate and QT interval. The single and composite parameters were evaluated for detection performance of adrenaline levels above 1000, 1500 and 2000 pmol/L. The best prediction performance was indicated for the composite parameter using the FSR from the abdomen, FSR from the forehead and the heart rate, with a ROC area under the curve of 0.93 for the 2000 pmol/L threshold. In conclusion, detection of strong sympathoadrenal discharges is feasible with good accuracy during resting conditions in comfortable room temperature.

Effects of n-3 fatty acids in subjects with type 2 diabetes: reduction of insulin sensitivity and time-dependent alteration from carbohydrate to fat oxidation.

BACKGROUND: Effects of fish oil supplements on metabolic variables are insufficiently clarified in type 2 diabetes. OBJECTIVE: We aimed to investigate short-term (1 wk) and longer-term (9 wk) effects of n-3 fatty acids. DESIGN: Twenty-six subjects with type 2 diabetes without hypertriacylglycerolemia participated in a double-blind controlled study. Median intake in the intervention group was 17.6 mL fish oil/d (1.8 g 20:5n-3, 3.0 g 22:6n-3, and 5.9 g total n-3 fatty acids). The control group received 17.8 mL corn oil/d (8.5 g 18:2n-6). RESULTS: Plasma phospholipid 20:5n-3 and 22:6n-3 increased, whereas 18:2n-6 decreased, in the fish oil group compared with the corn oil group after 1 wk. The two n-3 fatty acids also increased in adipose tissue biopsy samples taken after 9 wk in the fish oil group. Glucose concentrations (home-monitored) were approximately 1 mmol/L higher in the fish oil group than in the corn oil group at the end of the intervention (P = 0.035). Glucose utilization measured by using an isoglycemic clamp was lowered in the fish oil group compared with that in the corn oil group at the end of the intervention (P = 0.049), whereas glucagon-stimulated C-peptide tended to increase (P = 0.078). The fish oil group utilized less fat for oxidation after 1 wk, with a change to more fat and less carbohydrate oxidation after 9 wk (P = 0.040), than did the corn oil group. CONCLUSION: A high intake of fish oil moderately increases blood glucose and decreases insulin sensitivity in persons with type 2 diabetes without hypertriacylglycerolemia and alters carbohydrate and fat utilization in a time-dependent manner.

Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes Is Not Associated With Autonomic Dysfunction or Peripheral Neuropathy.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in people with insulin-treated diabetes; autonomic neuropathy has been suggested to underlie its development. The aim was to evaluate a putative association between IAH and autonomic dysfunction using novel and sensitive measures of autonomic neural function. RESEARCH DESIGN AND METHODS: Sixty-six adults with type 1 diabetes were studied, 33 with IAH and 33 with normal awareness of hypoglycemia (NAH), confirmed by formal testing. Participants were matched for age, sex, and diabetes duration. Clinical and laboratory evaluations included extensive autonomic function testing, peripheral nerve conduction studies, and quantitative sensory testing. Composite abnormality Z scores were used for group comparisons. RESULTS: The IAH and NAH group had similar median (interquartile range) age of 48 (14.5) vs. 47 (14.5) years, diabetes duration of 30 (13.5) vs. 31 (13.5) years, and mean ± SD HbA1c 7.8 ± 2.2% vs. 8.1 ± 1.9%, respectively. The autonomic composite Z score did not differ between the two groups (mean difference -0.15, 95% CI -0.46, 0.16; P = 0.33), nor did the thermal detection (mean difference 0.15, 95% CI -0.31, 0.61; P = 0.51) or nerve conduction scores (mean difference 0.03, 95% CI -0.43, 0.49; P = 0.89). CONCLUSIONS: In adults with type 1 diabetes, IAH was not associated with autonomic dysfunction or peripheral neuropathy.

Impact of thyrotropin receptor antibody levels on fetal development in two successive pregnancies in a woman with Graves' disease.

BACKGROUND: Treatment with radioiodine for Graves' disease regularly increases the level of antithyroid antibodies, and transplacental passage of stimulating thyrotropin receptor antibodies (TRAb) may cause fetal hyperthyroidism. CASE PRESENTATION: A 21-year-old woman with Graves' disease received radioiodine treatment to avoid use of antithyroid drugs in pregnancy. She became pregnant 4 months later and was euthyroid during pregnancy. In gestational week (GW) 33, she was admitted with an increased fetal heart rate of 176-180 beats/min. Fetal echocardiography indicated cardiac decompensation. The neonate had severe hyperthyroidism (free thyroxine >100 pmol/l, nv 12.0-22.0), cardiac insufficiency, insufficient weight gain, goiter and considerably accelerated skeletal age. In the mother and neonate, TRAb was >40 IU/l (nv <1.0), indicating transplacental passage of stimulating antibodies. After delivery, TRAb remained >40 IU/l in the woman, and 18 months later she underwent total thyroidectomy with subsequent decline in TRAb. In her next pregnancy, TRAb fluctuated between 38 and 17 IU/l, and repeated fetal ultrasound showed no goiter or sign of hyperthyroidism. In cord blood, TRAb was 10.9 IU/l, and the neonate had normal thyroid hormone levels. CONCLUSION: This case report illustrates the impact of maternal TRAb level for neonatal outcome in two successive pregnancies.

Association between posttest dexamethasone and cortisol concentrations in the 1 mg overnight dexamethasone suppression test.

It has been suggested that comparison of posttest dexamethasone and cortisol concentrations may improve the evaluation of the dexamethasone suppression test (DST) for Cushing's syndrome. In particular, this would be reasonable if posttest cortisol differs by dexamethasone levels within the range that is usually attained in the DST. Using fractional polynomial regression, we therefore studied the association between posttest 0800 h dexamethasone and cortisol levels in 53 subjects without Cushing's syndrome who were tested with the 1 mg overnight DST. Plasma dexamethasone was associated with plasma cortisol (P<0.001), and the regression line suggested a strong negative association related to dexamethasone levels <5 nmol/l. However, among the 94% of subjects with plasma dexamethasone >5.0 nmol/l, there was no association between dexamethasone and cortisol levels (P=0.55). In conclusion, subjects tested with the 1 mg overnight DST usually attain an 0800 h plasma dexamethasone >5 nmol/l, and plasma cortisol does not differ by plasma dexamethasone in these subjects. This suggests that routine comparison of dexamethasone and cortisol levels may not be a useful approach to improve the performance of the 1 mg DST. However, dexamethasone measurements may identify subjects with inadequately low plasma dexamethasone and may therefore be of value when retesting subjects with possibly false-positive DST results.

Cognitive function in type 1 diabetic adults with early exposure to severe hypoglycemia: a 16-year follow-up study.

OBJECTIVE: We assessed adulthood cognition in relation to early exposure to severe hypoglycemia (SH). RESEARCH DESIGN AND METHODS: Sixteen years subsequent to a study of cognitive function in 28 diabetic children and 28 matched control subjects, we reexamined the same subjects with a 96% participation rate. Diabetic subjects were classified as with (n = 9) or without (n = 18) early (