Premature twins of a mother with Graves' disease with discordant thyroid function: a case report.

Thyroid dysfunction is recognized in the newborns of mothers affected by Graves' disease during pregnancy. We describe the development of concurrent hyperthyroidism and hypothyroidism in the twin infants of a mother with Graves' disease diagnosed during pregnancy.

Self-treatment of hypoglycemia while driving.

OBJECTIVE: While it is clear that progressive diabetic hypoglycemia leads to neuroglycopenia, which impairs driving, it is not clear what contributes to patients' detection and subsequent self-correction of hypoglycemia/driving impairments. Drivers with Type 1 Diabetes Mellitus (T1DM) who did and did not engage in self-treatment during experimental hypoglycemia driving are compared physiologically and psychologically. METHOD: 38 drivers with T1DM drove a sophisticated driving simulator during euglycemia and progressive hypoglycemia. Subjects were continually monitored for driving performance, EEG activity and whether they self-treated with a glucose drink. Every 5 min measures were taken of blood glucose (BG) and epinephrine levels, perceived neurogenic and neuroglycopenic symptoms and driving ability. For the four weeks prior to this hospital study, subjects participated in a field study. Using a hand-held computer just prior to routine self-measurements of BG, subjects rated neurogenic and neuroglycopenic symptoms and made judgements about BG level and ability to drive as they did in the hospital. RESULTS: Drivers who did and did not self-treat did not differ in terms of their pre-hospital exposure to hypoglycemia, their depth and rate of BG fall during experimental testing, or their epinephrine response to hypoglycemia. Subjects who self-treated detected more neurogenic and neuroglycopenic symptoms than those who did not self-treat. They also experienced less EEG defined neuroglycopenia during the progressive hypoglycemic drive as compared to those who did not self-treat. Perceived need to self-treat and EEG parameters correctly classified 88% of those who did treat from those who did not self-treat. Further, subjects who self-treated were more aware of hypoglycemia and when not to drive while hypoglycemic in the field study. CONCLUSION: There is a narrow window between a patient's detection of hypoglycemic symptoms and the need to self-treat, and neuroglycopenia, which impairs self-treatment. Consequently, drivers with T1DM should be vigilant for signs of hypoglycemia and driving impairment (e.g. trembling, uncoordination, visual difficulties) and encouraged to treat themselves immediately when they suspect hypoglycemia while driving.

Episodes of severe hypoglycemia in type 1 diabetes are preceded and followed within 48 hours by measurable disturbances in blood glucose.

This study quantifies blood glucose (BG) disturbances occurring before and after episodes of severe hypoglycemia (SH). For 6-8 months, 85 individuals with type 1 diabetes and a history of SH (age, 44+/-10 yr; 41 women and 44 men; duration of diabetes, 26+/-11 yr; hemoglobin A1c, 7.7+/-1.1%) used Lifescan One Touch BG meters for self-monitoring three to five times daily and recorded the date and time of SH episodes in diaries. For each subject, the timing of SH episodes was located in the temporal stream of SMBG readings recorded by the meter, and characteristics, including the Low BG index (LBGI), were computed in 24-h increments. In the 24-h period before the SH episode LBGI rose (P < 0.001), average BG was lower (P = 0.001), and BG variance increased (P = 0.001). In the 24 h after SH, LBGI and BGvariance remained elevated (P < 0.001), but average BG returned to baseline. These disturbances disappeared in 48 h. On the basis of LBGI we identified subjects at low, moderate, and high risk of SH, who reported, on the average, 1.7, 3.4, and 7.4 SH episodes (P < 0.005) during the study. In addition, we designed an algorithm that predicted 50% of all SH episodes that occurred in this subject group. We conclude that episodes of SH are preceded and followed by quantifiable BG disturbances, which could be used to devise warnings of imminent SH.

Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of beta-cell function referred to as maturity-onset diabetes of the young 4. IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN). During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol x kg(-1) x min(-1)). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the dose-response curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of beta-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of beta-cell dysfunction.

Progressive hypoglycemia's impact on driving simulation performance. Occurrence, awareness and correction.

OBJECTIVE: Progressive hypoglycemia leads to cognitive-motor and driving impairments. This study evaluated the blood glucose (BG) levels at which driving was impaired, impairment was detected, and corrective action was taken by subjects, along with the mechanisms underlying these three issues. RESEARCH DESIGN AND METHODS: There were 37 adults with type 1 diabetes who drove a simulator during continuous euglycemia and progressive hypoglycemia. During testing, driving performance, EEG, and corrective behaviors (drinking a soda or discontinuing driving) were continually monitored, and BG, symptom perception, and judgement concerning impairment were assessed every 5 min. Mean +/- SD euglycemia performance was used to quantify z scores for performance in three hypoglycemic ranges (4.0-3.4, 3.3-2.8, and <2.8 mmol/l). RESULTS: During all three hypoglycemic BG ranges, driving was significantly impaired, and subjects were aware of their impaired driving. However, corrective actions did not occur until BG was <2.8 mmol/l. Driving impairment was related to increased neurogenic symptoms and increased theta-wave activity. Awareness of impaired driving was associated with neuroglycopenic symptoms. increased beta-wave activity, and awareness of hypoglycemia. High beta and low theta activity and awareness of both hypoglycemia and the need to treat low BG influenced corrective behavior. CONCLUSIONS: Driving performance is significantly disrupted at relatively mild hypoglycemia, yet subjects demonstrated a hesitation to take corrective action. The longer treatment is delayed, the greater the neuroglycopenia (increased theta), which precludes corrective behaviors. Patients should treat themselves while driving as soon as low BG and/or impaired driving is suspected and should not begin driving when their BG is in the 5.0-4.0 mmol/l range without prophylactic treatment.

Biopsychobehavioral model of severe hypoglycemia. II. Understanding the risk of severe hypoglycemia.

OBJECTIVE: To evaluate the clinical/research utility of the biopsycho-behavioral model of severe hypoglycemia in differentiating patients with and without a history of severe hypoglycemia and in predicting occurrence of future severe hypoglycemia. RESEARCH DESIGN AND METHODS: A total of 93 adults with type 1 diabetes (mean age 35.8 years, duration of diabetes 16 +/- 10 years, HbA1 8.6 +/- 1.8%), 42 of whom had a recent history of recurrent severe hypoglycemia (SH) and 51 who did not (NoSH), used a handheld computer for 70 trials during 1 month recording cognitive-motor functioning, symptoms, blood glucose (BG) estimates, judgments concerning self-treatment of BG, actual BG readings, and actual treatment of low BG. For the next 6 months, patients recorded occurrence of severe hypoglycemia. RESULTS: SH patients demonstrated significantly more frequent and extreme low BG readings (low BG index), greater cognitive-motor impairments during hypoglycemia, fewer perceived symptoms of hypoglycemia, and poorer detection of hypoglycemia. SH patients were also less likely to treat their hypoglycemia with glucose and more likely to treat with general foods. Low BG index, magnitude of hypoglycemia-impaired ability to do mental subtraction, and awareness of neuroglycopenia, neurogenic symptoms, and hypoglycemia correlated separately with number of SH episodes in the subsequent 6 months. However, only low BG index, hypoglycemia-impaired ability to do mental subtraction, and awareness of hypoglycemia entered into a regression model predicting future severe hypoglycemia (R2 = 0.25, P < 0.001). CONCLUSIONS: Patients with a history of severe hypoglycemia differed on five of the seven steps of the biopsychobehavioral model of severe hypoglycemia. Helping patients with a recent history of severe hypoglycemia to reduce the frequency of their low-BG events, become more sensitive to early signs of neuroglycopenia and neurogenic symptoms, better recognize occurrence of low BG, and use fast-acting glucose more frequently in the treatment of low BG, may reduce occurrence of future severe hypoglycemia.

Hypoglycemia and the decision to drive a motor vehicle by persons with diabetes.

CONTEXT: Laboratory studies have shown impairments in driving performance among subjects with type 1 diabetes mellitus when their blood glucose (BG) level is between 2.6 and 3.6 mmol/L (47-65 mg/dL). However, to our knowledge, no data exist examining subjects' decisions to drive at various BG levels during their daily routine. OBJECTIVE: To examine type 1 diabetic subjects' decisions to drive during their daily routine based on perception of BG levels compared with actual measured BG levels. DESIGN AND SETTING: Two separate groups of patients were recruited 2 years apart from 4 academic medical centers. PARTICIPANTS: All subjects were adults with type 1 diabetes who were drivers and who performed at least 2 BG tests per day. Group 1 (initial) subjects (n = 65) had a mean (SD) age of 38.6 (8.9) years with a mean (SD) diabetes duration of 20.5 (10.6) years, were taking 38.8 (16.8) U/d of insulin, and had a mean (SD) glycosylated hemoglobin (HbA1) level of 10.0% (1.9%). Group 2 (replication) subjects (n = 93) were 35.8 (8.0) years old with a mean diabetes duration of 17.0 (10.6) years, were taking 40.0 (15.5) U/d of insulin, and had a mean (SD) HbA1 level of 8.5% (1.6%). Each subject used a handheld computer to record data on symptoms, cognitive function, insulin dosage, food, activity, estimated and actual BG levels, and whether he/she would drive. Data were entered 3 to 6 times per day for a total of 50 to 70 collections per subject during a 3- to 4-week period. MAIN OUTCOME MEASURES: Decisions to drive when subjects estimated their BG level to be less than 2.2 mmol/L (40 mg/dL), 2.2 to 2.8 mmol/L (40-50 mg/dL), 2.8 to 3.3 mmol/L (50-60 mg/dL), 3.3 to 3.9 mmol/L (60-70 mg/dL), 3.9 to 10 mmol/L (70-180 mg/dL), and more than 10 mmol/L (>180 mg/dL), and driving decisions when actual BG levels were in these ranges. RESULTS: Subjects stated they would drive 43% to 44% of the time when they estimated their BG level to be 3.3 to 3.9 mmol/L (60-70 mg/dL), and 38% to 47% of the time when their actual BG level was less than 2.2 mmol/L (40 mg/dL). Logistic regression analysis demonstrated that number of autonomic symptoms, degree of impairment on cognitive function tests, and BG level estimate predicted 76% to 80% of decisions to drive (P<.01 for all). Approximately 50% of subjects in each group decided to drive at least 50% of the time when their BG level was less than 3.9 mmol/L (70 mg/dL). CONCLUSIONS: Our data suggest that persons with type 1 diabetes may not judge correctly when their BG level is too low to permit safe driving and may consider driving with a low BG level even when they are aware of the low level. Health care professionals should counsel their patients about the risk of driving with hypoglycemia and the importance of measuring BG level before driving.

Biopsychobehavioral model of risk of severe hypoglycemia. Self-management behaviors.

OBJECTIVE: To identify self-management antecedents of low blood glucose (BG) (< 3.9 mmol/l) that might be easily recognized, treated, or avoided altogether. RESEARCH DESIGN AND METHODS: Ninety-three adults with type 1 diabetes (age, 35.8 +/- 8 years [mean +/- SD]; duration of diabetes, 17.0 +/- 11 years; daily insulin dose, 0.58 +/- 0.18 U/kg; and HbAlc, 8.6 +/- 1.8%) were recruited to participate in the study. Of the 93 subjects, 42 had a history of severe hypoglycemia (SH), defined as two or more hypoglycemic episodes in the preceding 12 months, and 51 subjects had no history of SH (No-SH) in the same time period. Before each of 70 BG measurements obtained over a 3-week period, subjects used a handheld computer to record whether their most recent insulin, food, and exercise was more than, less than, or the same as usual. Associations among self-management behaviors preceding BG readings < 3.9 mmol/l versus those preceding BG readings of 5.6-7.8 mmol/l were determined using chi 2 tests, analyses of variance, and logistic regression analyses. RESULTS: Analysis of 6,425 self-management/self-monitoring of BG events revealed that the usual amounts of insulin, food, and exercise preceded the events 58.3% of the time. No significant differences were observed for changes in insulin before readings of BG < 3.9 mmol/l versus 7.8 < BG > 5.6 mmol/l, but significantly less food (P < 0.01) was eaten and more exercise (P < 0.001) was performed before the low BG measurement. No interactions between SH and No-SH groups and management behaviors were observed. However, each of the three management variables entered significantly in a logistic model that predicted 61% of all readings of BG < 3.9 mmol/l. CONCLUSIONS: Subjects with a history of SH did not report managing their diabetes differently from those with no such history. Specifically, when low BG occurred, the preceding management behaviors, although predictive of low BG, were not different in SH and No-SH subjects. Overall, self-management behaviors did not distinguish SH from No-SH subjects. Thus, even though it might be beneficial for all patients to review their food and exercise management decisions to reduce their frequency of low BG, an educational intervention whose content stresses insulin, food, and exercise would be unlikely by itself to be sufficient to reduce the frequency of SH.

Maternal fear of hypoglycemia in their children with insulin dependent diabetes mellitus.

A modified version of the Hypoglycemia Fear Survey (HFS) was used to measure fear of hypoglycemia among mothers of 46 pre-adolescent children with IDDM. Glycosylated hemoglobin (HbA1) levels were measured, and episodes of severe hypoglycemia over the previous year were recorded. The relationships between the child's age, disease duration, HbA1, history of hypoglycemia, and maternal distress concerning hypoglycemia and HFS-P scores were explored. Maternal HFS-P scores were also compared to those of 78 IDDM adults. There was no relationship between children's age, disease duration, number of severe hypoglycemic episodes and maternal HFS-P scores. However, mothers whose children had passed out with hypoglycemia had higher HFS-P scores. Correlations between mothers' responses concerning their children's history of hypoglycemia and HFS-P scores suggested that their degree of distress associated with events which occurred when their child was asleep, or in a social situation was related to their total HFS-P, and Behavior and Worry subscores. Mothers demonstrated significantly greater fear than did adult patients themselves. The HFS-P may be an appropriate instrument for examining the psychological impact of differing treatment regimens on families of children with IDDM.

The effects of pubertal status and glycemic control on the growth hormone-IGF-I axis in boys with insulin-dependent diabetes mellitus.

Dysregulation of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis in children and adolescents with insulin-dependent diabetes mellitus (IDDM) is well documented. Elevated levels of circulating GH, increased GH secretory amplitude, and decreased concentrations of IGF-I, IGFBP-3, and GHBP have been related to poor glycemic control. We proposed that pubertal maturation may be a more significant factor, potentially overriding the effects of metabolic control, especially during mid-puberty when the GH-IGF-I axis is maximally stimulated. We studied 24 male children and adolescents with IDDM over a 5 year period. Subjects were grouped both by pubertal stage (prepubertal vs mid-pubertal) and by level of glycemic control (hemoglobin A1 (<9%, 9-11.5%, and >11.5%). Twenty-four hour every 20 minute blood sampling for GH determination was analyzed using the Cluster algorithm, and static measures of IGF-I, IGFBP-3, and GHBP were obtained. When analyzed by pubertal status, we found no difference in the number of GH secretory peaks or the interval between concentration peaks. The sum of the peak heights and area under the curve were significantly greater in the mid-pubertal boys, as was the average GH nadir. Serum levels of IGF-I and IGFBP-3 were greater in the mid-pubertal boys, but levels of GHBP were higher in the prepubertal boys. When analyzed by level of glycemic control, we found no differences in the number of GH secretory peaks or interval between peaks among the 3 groups. However, the sum of the peak heights, area under the curve, and average GH nadir were all lower in the group with the intermediate level of glycemic control (HgbA1 9-11.5%); no differences were observed between the other 2 groups. This relationship persisted when the mid-pubertal subjects were analyzed separately. No differences were found among the 3 groups for levels of IGF-I, IGFBP-3, or GHBP. We conclude that normal increases in GH secretion and levels of IGF-I and IGFBP-3 occur during mid-puberty in boys with IDDM. A concomitant increase in average GH nadir may reflect an underlying effect of metabolic control. Greater GH secretion was observed in the groups with the lowest and highest levels of glycemic control. We speculate that this may be related to an increased incidence of severe hypoglycemic episodes in the group with the lowest levels of glycosylated hemoglobin, resulting in metabolic derangements similar to those with elevated glycosylated hemoglobin levels.

The relationship between nonroutine use of insulin, food, and exercise and the occurrence of hypoglycemia in adults with IDDM and varying degrees of hypoglycemic awareness and metabolic control.

The purpose of this study was to determine objectively the relationships between changes in the usual amount of insulin injected, food eaten, and exercise performed, and the subsequent occurrence of low blood glucose (< 3.9 mM) in adults with IDDM and varying degrees of hypoglycemic awareness and metabolic control. Subjects used a handheld computer to record whether their most recent insulin, food, and exercise had been omitted or were greater than, less than, or about the same as usual following every measured blood glucose level of < 3.9 mM and > 5.6 mM. Responses for each self-management behavior were compared for the two blood glucose ranges. Food was omitted more frequently prior to a low glucose reading and exercise was omitted more frequently prior to a high glucose reading. More insulin, less food, and more exercise each were associated with low glucose levels. These findings underscore the importance of traditional diabetes education.

Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.

The homeodomain protein IPF1 (also known as IDX1, STF1 and PDX1; see Methods) is critical for development of the pancreas in mice and is a key factor for the regulation of the insulin gene in the beta-cells of the endocrine pancreas. Targeted disruption of the Ipf1 gene encoding IPF1 in transgenic mice results in a failure of the pancreas to develop (pancreatic agenesis). Here, we report the identification of a single nucleotide deletion within codon 63 of the human IPF1 gene (13q12.1) in a patient with pancreatic agenesis. The patient is homozygous for the point deletion, whereas both parents are heterozygotes for the same mutation. The deletion was not found in 184 chromosomes from normal individuals, indicating that the mutation is unlikely to be a rare polymorphism. The point deletion causes a frame shift at the C-terminal border of the transactivation domain of IPF1 resulting in the translation of 59 novel codons before termination, aminoproximal to the homeodomain essential for DNA binding. Expression of mutant IPF1 in Cos-1 cells confirms the expression of a prematurely terminated truncated protein of 16 kD. Thus, the affected patient should have no functional IPF1 protein. Given the essential role of IPF1 in pancreas development, it is likely that this autosomal recessive mutation is the cause of the pancreatic agenesis phenotype in this patient. Thus, IPF1 appears to be a critical regulator of pancreas development in humans as well as mice.

Psychometric properties and normative data for the parent version of the diabetes independence survey.

The parent version of the Diabetes Independence Survey measures parents' perceptions of their children's mastery of 38 diabetes self-care skills. The instrument was administered to 648 parents of 622 children with insulin-dependent diabetes mellitus, ages 3 and 18 years, at seven different pediatric medical centers. Data confirming the internal consistency, interrater reliability, construct validity, and concurrent validity of the instrument are presented in this paper. Age-adjusted normative data for total scores on the instrument as well as item-by-item data on the ages at which mastery of each skill was reported by 25%, 50%, and 75% of parents also are discussed. The Diabetes Independence Survey can be used as a reliable, valid, and efficient research tool for assessing the growth and development of diabetes knowledge and skills among children and adolescents, and as a screening instrument and program evaluation tool for clinical purposes.

The frequency of severe hypoglycaemia in children with insulin-dependent diabetes mellitus.

The literature contains numerous reports of the frequency of severe hypoglycaemia in childhood insulin-dependent diabetes mellitus. Unfortunately, most of these data have been collected in such a manner as to make comparisons between them difficult. Most reports have used small, well-defined populations of children who were participants in larger, complex, clinical studies. Additional difficulties are encountered in the standardization of the definition of severe hypoglycaemia. Some studies have required that the child lose consciousness while others also included children who required assistance with treatment. Even when studies clearly define the representative nature of their patient population and include universally acceptable criteria for identifying a severe hypoglycaemic episode, the frequency of severe hypoglycaemia must be qualified. Severe hypoglycaemia is generated by a series of complex biological, psychological, and behavioural processes. Its frequency must be viewed not as a fixed value, but rather as a dynamic dependent variable.

Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms.

OBJECTIVE: To prospectively evaluate the frequency and severity of hypoglycemic episodes in IDDM subjects who declare themselves to have reduced awareness of hypoglycemia, to validate their self-designations in their natural environment, and to determine objectively the presence or absence of autonomic and neuroglycopenic symptoms associated with their low blood glucose (BG) levels. RESEARCH DESIGN AND METHODS: A total of 78 insulin-dependent diabetes mellitus (IDDM) subjects (mean age 38.3 +/- 9.2 years; duration of diabetes 19.3 +/- 10.4 years) completed two sets of assessments separated by 6 months. The assessments included reports of frequency and severity of low BG, symptoms associated with low BG, and a BG symptom/estimation trial using a hand-held computer (HHC). Diaries of hypoglycemic episodes were kept for the intervening 6 months. HbA1 levels were determined at each assessment. RESULTS: Of the subjects, 39 declared themselves as having reduced awareness of hypoglycemia (reduced-awareness subjects). There were no differences between these reduced-awareness subjects and aware subjects with regard to age, sex, disease duration, insulin dose, or HbA1. During the HHC trials, reduced-awareness subjects were significantly less accurate in detecting BG < 3.9 mmol/l (33.2 +/- 47 vs. 47.6 +/- 50% detection, P = 0.001) and had significantly fewer autonomic (0.41 +/- 0.82 vs. 1.08 +/- 1.22, P = 0.006, reduced-awareness vs. aware) and neuroglycopenic (0.44 +/- 0.85 vs. 1.18 +/- 1.32, P = 0.004, reduced-awareness vs. aware) symptoms per subject. Prospective diary records revealed that reduced-awareness subjects experienced more moderate (351 vs. 238, P = 0.026) and severe (50 vs. 17, P = 0.0062) hypoglycemic events. The second assessment results were similar to the first and verified the reliability of the data. CONCLUSIONS: IDDM subjects who believe they have reduced awareness of hypoglycemia are generally correct. They have a history of more moderate and severe hypoglycemia, are less accurate at detecting BG < 3.9 mmol/l, and prospectively experience more moderate and severe hypoglycemia than do aware subjects. Neither disease duration nor level of glucose control explains their reduced awareness of hypoglycemia. Reduced-awareness individuals may benefit from interventions designed to teach them to recognize all of their potential early warning symptoms.

The Diabetes Control and Complications Trial: new challenges for the school nurse.

Results from the recently concluded Diabetes Control and Complications Trial confirm previously held beliefs regarding the relationships between hyperglycemia and the development of retinopathy, nephropathy, and neuropathy in insulin-dependent diabetes mellitus. Intensive therapy, now recommended for all patients 13 years and over, requires diabetes management throughout the school day and the active participation of the school nurse as a member of the child's health care team.