Autonomic cardiac regulation during spontaneous nocturnal hypoglycemia in patients with type 1 diabetes

OBJECTIVE

Experimental clamp studies have suggested that hypoglycemia evokes a reduction of cardiac vagal control in patients with type 1 diabetes. However, there are limited data on the influence of spontaneous nocturnal hypoglycemia on cardiac autonomic regulation.

RESEARCH DESIGN AND METHODS

Adults with type 1 diabetes (n = 37) underwent continuous glucose monitoring via a subcutaneous sensor as well as recording of R-R interval or electrocardiogram for 3 nights. Heart rate (HR) variability was analyzed during periods of hypoglycemia (glucose <3.5 mmol/L) (minimum length of 20 min) and a control nonhypoglycemic period (glucose >3.9 mmol/L) of equal duration and at the same time of night.

RESULTS

The duration of hypoglycemic and control episodes (n = 18) ranged from 20 to 190 min (mean 71 min). HR (62 ± 7 vs. 63 ± 9 beats per min; P = 0.30) or the high-frequency component of HR power spectrum (2,002 ± 1,965 vs. 1,336 ± 1,506 ms²; P = 0.26) did not change during hypoglycemia. Hypoglycemia resulted in a significant decrease in the low-frequency component of HR variability (2,134 ± 1,635 vs. 1,169 ± 1,029 ms², respectively; P = 0.006). The decline in the glucose concentration displayed a significant positive correlation with the decrease of the low-frequency component of HR variability (r = 0.48; P = 0.04). The latter was closely related to an increase in muscle sympathetic nerve activity recorded in 10 subjects during controlled sympathetic activation.

CONCLUSIONS

Spontaneous nocturnal hypoglycemia in patients with type 1 diabetes results in a reduction of the low-frequency component of HR, which is best explained by excessive sympathetic activation without a concomitant withdrawal of vagal outflow.Individuals with type 1 diabetes adhering to strict glycemic control are prone to suffer severe hypoglycemia. Other well-established risk factors for hypoglycemia include a history of severe hypoglycemia and impaired awareness of hypoglycemia (1–3). Despite advanced technology and new insulin analogs, the fear of hypoglycemia is still a major problem complicating the management of diabetes (4,5).Since 1991, when Tattersall and Gill (6) introduced the term “dead in bed syndrome,” the role of hypoglycemia as a factor predisposing young adults to sudden arrhythmic death has been hypothesized (7,8). According to earlier studies, ~2–4% of deaths of type 1 diabetic subjects have been attributed to hypoglycemia (9). However, more recent reports have indicated that as many as 6–10% of deaths in individuals with type 1 diabetes were the result of hypoglycemia (10–12).Heart rate (HR) variability has been used to detect autonomic dysfunction in various clinical settings. A dysfunction of autonomic nervous system has been associated with increased mortality after myocardial infarction (13,14) in patients with diabetes (15,16) and in the general population (17). Nonetheless, very little is known about changes in the parameters of HR variability during hypoglycemia. In our previous clamp study, controlled hypoglycemia resulted in progressive reductions of the high-frequency spectral component and beat-to-beat HR variability (SD1) in patients with type 1 diabetes and their healthy counterparts—evidence of reduced cardiac vagal outflow during hypoglycemia (18). Since symptoms at the time of hypoglycemia induced by clamp technique in the awake state may contribute to autonomic responses, it was decided to assess the effects of spontaneous hypoglycemia on HR variability during sleep in type 1 diabetic subjects.     

Real-Time Hypoglycemia Prediction Suite Using Continuous Glucose Monitoring: A safety net for the artificial pancreas

OBJECTIVE

The purpose of this study was to develop an advanced algorithm that detects pending hypoglycemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycemia, a major concern of patients with diabetes.

RESEARCH DESIGN AND METHODS

This real-time hypoglycemia prediction algorithm (HPA) combines five individual algorithms, all based on continuous glucose monitoring 1-min data. A predictive alarm is issued by a voting algorithm when a hypoglycemic event is predicted to occur in the next 35 min. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. We confirmed the function of the HPA using a separate dataset from 22 admissions of type 1 diabetic subjects. During these admissions, hypoglycemia was induced by gradual increases in the basal insulin infusion rate up to 180% from the subject''s own baseline infusion rate.

RESULTS

Using a prediction horizon of 35 min, a glucose threshold of 80 mg/dl, and a voting threshold of three of five algorithms to predict hypoglycemia (defined as a FreeStyle plasma glucose readings <60 mg/dl), the HPA predicted 91% of the hypoglycemic events. When four of five algorithms were required to be positive, then 82% of the events were predicted.

CONCLUSIONS

The HPA will enable automated insulin-pump suspension in response to a pending event that has been detected prior to severe immediate complications.The Diabetes Control and Complications Trial (DCCT) proved that glucose control in the closer-to-normal range (tight glycemic control) reduced the likelihood of eye, kidney, nerve, and cardiovascular complications of diabetes (1,2). Unfortunately, the DCCT also showed that the incidence of severe hypoglycemia was three times higher in the intensively treated group compared with the standard treatment group (1). In the DCCT, 55% of the severe lows occurred during sleep hours (1). Further, in the adolescent portion of the DCCT, the risk for severe hypoglycemia was even greater, with one episode every 1.17 years (85.7 per 100 patient-years) (2). One report in children found 75% of severe lows to occur during the nighttime hours (3). The high frequency and duration of nocturnal hypoglycemia has been confirmed in clinical research center (CRC) studies, in which frequent laboratory reference glucose values were obtained. For example, in a DirecNet study of exercise-induced nocturnal hypoglycemia, children who did not exercise had a 28% incidence of nocturnal hypoglycemia (glucose <60 mg/dl), and those who exercised had a 48% incidence of nocturnal hypoglycemia (4). In a recent study (5) of bedtime snacks and nocturnal hypoglycemia, on nights when adult subjects did not have a snack, 57% became hypoglycemic (<70 mg/dl), with an average duration of hypoglycemia of over 2.5 h. In this study, the duration of hypoglycemia was as long as 8.75 h.Real-time continuous glucose monitoring (CGM) is becoming available with the Food and Drug Administration (FDA) approval of the MiniMed Guardian, the DexCom STS, and the Abbott Navigator. One of the major perceived benefits of real-time glucose monitoring is the ability of these devices to have alarms for hypoglycemia. For a real-time alarm to be effective, it must awaken a sleeping subject. The first FDA-approved real-time glucose monitor was the GlucoWatch^TM. To determine whether the alarm function on the GlucoWatch was effective in awakening children while they were sleeping, an infrared camera was used to videotape them throughout the night in the CRCs. During this admission, reference glucose values were obtained every half hour to document hypoglycemia. In this study, 71% of youths wearing the watch did not respond to nighttime alarms (6), placing these patients at a risk for nocturnal hypoglycemia despite wearing a real-time continuous glucose sensor. One possible correction of this problem would be to have the sensor send a signal to the pump so that it will stop infusing insulin when pending or real hypoglycemia has been reached and the patient has not responded to alarms. This is the primary focus of the hypoglycemia prediction algorithm.Previous studies (7–9) have shown that when insulin infusion is stopped for 2 h or when an infusion set is disconnected for up to 30 min (7), there is essentially no risk of the patient developing significant ketones or acidosis. Three previous studies (8–10) have demonstrated that turning off an insulin pump for 2 h did not result in diabetic ketoacidosis (DKA). In all three studies, blood β-hydroxybutyrate concentrations were determined using both a meter (Precision Xtra^TM) and the hospital laboratory. In two of the studies (9,10), the continuous subcutaneous insulin infusion pumps were purposely turned off for periods of 4 and 5 h, with a gradual increase in β-hydroxybutyratek concentrations after 2 h to the upper normal range. No cases of DKA occurred in these studies.     

Hypoglycemia Unawareness in Older Compared With Middle-Aged Patients With Type 2 Diabetes

OBJECTIVE

Older patients with type 2 diabetes are at a particularly high risk for severe hypoglycemic episodes, and experimental studies in healthy subjects hint at a reduced awareness of hypoglycemia in aged humans. However, subjective responses to hypoglycemia have rarely been assessed in older type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We tested hormonal, subjective, and cognitive responses (reaction time) to 30-min steady-state hypoglycemia at a level of 2.8 mmol/l in 13 older (≥65 years) and 13 middle-aged (39–64 years) type 2 diabetic patients.

RESULTS

Hormonal counterregulatory responses to hypoglycemia did not differ between older and middle-aged patients. In contrast, middle-aged patients showed a pronounced increase in autonomic and neuroglycopenic symptom scores at the end of the hypoglycemic plateau that was not observed in older patients (both P < 0.01). Also, seven middle-aged patients, but only one older participant, correctly estimated their blood glucose concentration to be <3.3 mmol/l during hypoglycemia (P = 0.011). A profound prolongation of reaction times induced by hypoglycemia in both groups persisted even after 30 min of subsequent euglycemia.

CONCLUSIONS

Our data indicate marked subjective unawareness of hypoglycemia in older type 2 diabetic patients that does not depend on altered neuroendocrine counterregulation and may contribute to the increased probability of severe hypoglycemia frequently reported in these patients. The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.Hypoglycemia is the limiting factor in the glycemic management of diabetes (1). For a long time hypoglycemia was assumed a major problem only in patients suffering from type 1 diabetes (2); however, there is increasing evidence that hypoglycemic episodes are a critical factor also in type 2 diabetes (3,4). Older subjects aged >65 years, who represent the majority of type 2 diabetic patients, appear at a particularly high risk of experiencing severe hypoglycemia (3,4). Previous studies (5–7) have shown weakened perception of hypoglycemia-related symptoms in healthy older (i.e., nondiabetic older subjects, aged 65–80 years) as compared with younger subjects (aged 24–49 years). Of note, in aged humans, the perception of hypoglycemic symptoms was found to simultaneously occur with the impairment of cognitive functions during a stepwise reduction of blood glucose levels (7), contrasting the well-known hierarchical succession of central nervous responses to hypoglycemia in younger healthy adults who normally perceive hypoglycemic symptoms at higher glucose levels than cognitive dysfunction (4). The concurrence of glycemic thresholds for the onset of symptoms and of cognitive dysfunction may be expected to increase the risk for severe hypoglycemic episodes since it likely prevents behavioral counteractions (e.g., the intake of carbohydrates) (3).To date only one study (8) has assessed subjective responses to standardized hypoglycemia in older type 2 diabetic patients (aged 72 ± 1 years), revealing an impairment in the perception of hypoglycemic symptoms that was comparable to that of age-matched healthy control subjects. Although this finding points to a decrease in hypoglycemia awareness that develops in the course of aging also in type 2 diabetic patients, this assumption has not yet been experimentally elucidated. Moreover, in the previous studies in healthy subjects (5–7), the age gap between experimental groups was rather large, raising the question as to the perception of hypoglycemia in middle-aged subjects. On this background, we examined whether older (aged ≥65 years) as compared with middle-aged (aged 39–64 years) type 2 diabetic patients differ in their subjective response to hypoglycemia and how hypoglycemia awareness in these age-groups relates to hormonal and cognitive effects of hypoglycemia.     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes

OBJECTIVE

To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A_1c (HbA_1c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients.

RESULTS

The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA_1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference −0.27%; 95% CI −0.47 to −0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009).

CONCLUSIONS

Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA_1c in children and adults with type 1 diabetes.The benefits of intensive treatment of type 1 diabetes, established almost 20 years ago (1), are difficult to achieve, despite the increased use of insulin analogs and insulin pumps, with only a minority of patients maintaining their glycated hemoglobin A_1c (HbA_1c) within the target range (2). Intensive insulin treatment and lower HbA_1c increase exposure to hypoglycemia (3,4). The risk of hypoglycemia is even higher in children and adolescents (5,6) and increases with the duration of diabetes (7). Frequent hypoglycemia is associated with hypoglycemia unawareness (8,9), which may in turn lead to reduced adherence to therapeutic decisions (10). Finally, hypoglycemia may be associated with permanent damage to the central nervous system (11) and may permanently influence cognitive functions in children (12) but not in adults (13).Recently, devices for real-time continuous glucose monitoring have been introduced to aid self-management of glycemic control and have been shown to improve HbA_1c levels in people with type 1 diabetes (14–17). In clinical practice recommendations, it has also been suggested that continuous glucose monitoring is especially useful in patients with hypoglycemia unawareness and/or frequent episodes of hypoglycemia (18). However, the hypoglycemia preventive effect of continuous glucose monitoring has not been established. Therefore, we designed a randomized, controlled, multicenter clinical trial to evaluate the effect of continuous glucose monitoring on hypoglycemia in children and adults with type 1 diabetes.     

Insomnia With Objective Short Sleep Duration Is Associated With Type 2 Diabetes: A population-based study

OBJECTIVE

We examined the joint effects of insomnia and objective short sleep duration, the combination of which is associated with higher morbidity, on diabetes risk.

RESEARCH DESIGN AND METHODS

A total of 1,741 men and women randomly selected from Central Pennsylvania were studied in the sleep laboratory. Insomnia was defined by a complaint of insomnia with duration of ≥1 year, whereas poor sleep was defined as a complaint of difficulty falling asleep, staying asleep, or early final awakening. Polysomnographic sleep duration was classified into three categories: ≥6 h of sleep (top 50% of the sample); 5–6 h (approximately third quartile of the sample); and ≤5 h (approximately the bottom quartile of the sample). Diabetes was defined either based on a fasting blood glucose >126 mg/dl or use of medication. In the logistic regression model, we simultaneously adjusted for age, race, sex, BMI, smoking, alcohol use, depression, sleep-disordered breathing, and periodic limb movement.

RESULTS

Chronic insomnia but not poor sleep was associated with a higher risk for diabetes. Compared with the normal sleeping and ≥6 h sleep duration group, the highest risk of diabetes was in individuals with insomnia and ≤5 h sleep duration group (odds ratio [95% CI] 2.95 [1.2–7.0]) and in insomniacs who slept 5–6 h (2.07 [0.68–6.4]).

CONCLUSIONS

Insomnia with short sleep duration is associated with increased odds of diabetes. Objective sleep duration may predict cardiometabolic morbidity of chronic insomnia, the medical impact of which has been underestimated.Many studies have established that insomnia, the most common sleep disorder, is highly comorbid with psychiatric disorders and is a risk factor for the development of depression, anxiety, and suicide (1,2). In contrast with sleep-disordered breathing (SDB), the second most common sleep disorder, chronic insomnia has not been associated with significant medical morbidity, e.g., cardiovascular disorders (3,4).Recently, we demonstrated that insomnia with objective short sleep duration is associated with a high risk for hypertension (5). These data suggest that objective sleep measures in insomnia provide an index of the severity of the disorder and that the more severe form of insomnia is most likely associated with morbidity and possibly mortality. This hypothesis is further supported by physiological studies, which demonstrated that activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic system, including increased heart rate, 24-h metabolic rate, and impaired heart rate variability, is present in insomniacs who meet both subjective and objective polysomnographic criteria (6–11). Given the association of the HPA axis and sympathetic system activation with the pathogenesis of metabolic disorders, including diabetes (12), we hypothesized that insomnia with objective short sleep duration will be associated with type 2 diabetes.Previous studies have shown that sleep disturbances or complaints are associated with increased incidence of type 2 diabetes (13–16). However, in these studies, the presence of sleep disturbances was based only on a subjective questionnaire and did not control for obstructive sleep apnea, a sleep disorder whose association with diabetes and insulin resistance is well established (12). Thus, it is not known whether insomnia per se is associated with an increased risk for diabetes.To test this hypothesis, we examined the joint effects of the complaints of chronic insomnia and poor sleep (a milder form of insomnia) and objective sleep duration on the prevalence of diabetes in a large cross-sectional population-based sample from Central Pennsylvania (Penn State Cohort).     

Hypoglycemia in Type 1 Diabetic Pregnancy: Role of preconception insulin aspart treatment in a randomized study

OBJECTIVE

A recent randomized trial compared prandial insulin aspart (IAsp) with human insulin in type 1 diabetic pregnancy. The aim of this exploratory analysis was to investigate the incidence of severe hypoglycemia during pregnancy and compare women enrolled preconception with women enrolled during early pregnancy.

RESEARCH DESIGN AND METHODS

IAsp administered immediately before each meal was compared with human insulin administered 30 min before each meal in 99 subjects (44 to IAsp and 55 to human insulin) randomly assigned preconception and in 223 subjects (113 for IAsp and 110 for human insulin) randomly assigned in early pregnancy (<10 weeks). NPH insulin was the basal insulin. Severe hypoglycemia (requiring third-party assistance) was recorded prospectively preconception (where possible), during pregnancy, and postpartum. Relative risk (RR) of severe hypoglycemia was evaluated with a gamma frailty model.

RESULTS

Of the patients, 23% experienced severe hypoglycemia during pregnancy with the peak incidence in early pregnancy. In the first half of pregnancy, the RR of severe hypoglycemia in women randomly assigned in early pregnancy/preconception was 1.70 (95% CI 0.91–3.18, P = 0.097); the RR in the second half of pregnancy was 1.35 (0.38–4.77, P = 0.640). In women randomly assigned preconception, severe hypoglycemia rates occurring before and during the first and second halves of pregnancy and postpartum for IAsp versus human insulin were 0.9 versus 2.4, 0.9 versus 2.4, 0.3 versus 1.2, and 0.2 versus 2.2 episodes per patient per year, respectively (NS).

CONCLUSIONS

These data suggest that initiation of insulin analog treatment preconception rather than during early pregnancy may result in a lower risk of severe hypoglycemia in women with type 1 diabetes.Severe hypoglycemia is common in pregnant women with type 1 diabetes, with observed rates up to 15 times those reported by the Diabetes Control and Complications Trial (1), and severe hypoglycemia occurs in 19–44% of patients treated with intensive insulin therapy during pregnancy (2). The risk of experiencing a severe event is usually highest in early pregnancy, particularly during the first trimester (3–5).The risk factors that predict severe hypoglycemic episodes during pregnancy include duration of diabetes, a history of previous severe episodes (recurrent events), hypoglycemic unawareness, a change in insulin treatment (such as regimen or dosing) or a high insulin dose, and A1C <6.5% (4,6,7). However, because normoglycemia is universally recommended in diabetic pregnancy (8,9), with A1C levels between 4.0 and 6.0% advocated to optimize pregnancy outcome (10,11), minimizing the risk of severe hypoglycemia is a major challenge to those caring for pregnant women with type 1 diabetes.Preconception care programs are associated with both reduced malformations and fewer early fetal losses in pregnant women with type 1 diabetes (12–14), perhaps due to improved glycemic control in the first stages of pregnancy. It is possible that working with women to improve metabolic control and optimize their insulin regimen before pregnancy might also help to reduce the high rate of severe episodes of hypoglycemia postconception, but this has yet to be demonstrated.We recently completed a randomized, open-label, parallel-group, multinational, multicenter study investigating maternal and fetal outcomes in 322 women with type 1 diabetes treated with either prandial insulin aspart (IAsp) or human insulin (15–17). IAsp injected immediately before eating was as effective and well tolerated as human insulin administered 30 min before eating. Although the study was somewhat underpowered, there were strong trends toward improved postprandial glucose control and prevention of severe hypoglycemia in the IAsp group (15,16). This study supports the conclusions of trials in nonpregnant individuals with type 1 diabetes, which suggest that the advantages of rapid-acting insulin analogs are most likely to be seen in those with tight control (18–20).The aim of this exploratory analysis was to compare the incidence of severe hypoglycemia during pregnancy between women enrolled into the trial either preconception or early in the first trimester. Finally, we also compared the effects of the different insulins on rates of severe hypoglycemia according to the time of enrollment of (pregnant) women into the study.     

Real-Time Continuous Glucose Monitoring in Critically Ill Patients: A prospective randomized trial

OBJECTIVE

To evaluate the impact of real-time continuous glucose monitoring (CGM) on glycemic control and risk of hypoglycemia in critically ill patients.

RESEARCH DESIGN AND METHODS

A total 124 patients receiving mechanical ventilation were randomly assigned to the real-time CGM group (n = 63; glucose values given every 5 min) or to the control group (n = 61; selective arterial glucose measurements according to an algorithm; simultaneously blinded CGM) for 72 h. Insulin infusion rates were guided according to the same algorithm in both groups. The primary end point was percentage of time at a glucose level <110 mg/dl. Secondary end points were mean glucose levels and rate of severe hypoglycemia (<40 mg/dl).

RESULTS

Percentage of time at a glucose level <110 mg/dl (59.0 ± 20 vs. 55.0 ± 18% in the control group, P = 0.245) and the mean glucose level (106 ± 18 vs. 111 ± 10 mg/dl in the control group, P = 0.076) could not be improved using real-time CGM. The rate of severe hypoglycemia was lower in the real-time CGM group (1.6 vs. 11.5% in the control group, P = 0.031). CGM reduced the absolute risk of severe hypoglycemia by 9.9% (95% CI 1.2–18.6) with a number needed to treat of 10.1 (95% CI 5.4–83.3).

CONCLUSIONS

In critically ill patients, real-time CGM reduces hypoglycemic events but does not improve glycemic control compared with intensive insulin therapy guided by an algorithm.Hyperglycemia, a frequent finding in up to 90% of all critically ill patients, is associated with increased morbidity and mortality (1,2). In three monocentric studies, intensive insulin therapy to achieve and maintain normoglycemia resulted in decreased morbidity and mortality (3–5). However, in two subsequent multicenter studies, normoglycemia was not adequately reached, and the studies were stopped prematurely because of safety reasons with increased rates of severe hypoglycemia (6,7). However, in a recent trial, intensive insulin therapy resulted in improved short-term outcome in pediatric intensive care; another recent trial demonstrated increased mortality among adults under intensive glucose control (5,8). An updated meta-analysis of 26 randomized trials including 13,567 patients reported that intensive insulin therapy had no effect on the overall risk of death but simultaneously resulted in a sixfold increased risk of severe hypoglycemia. Currently, there is still an intense and conflicting discussion on the difficulty of obtaining near-normoglycemia and thereby avoiding the risk of severe hypoglycemia (9). In critically ill patients, accurate real-time continuous glucose monitoring (CGM) might be the best way to minimize a consistently reported increased rate of severe hypoglycemia associated with intensive insulin therapy and to increase effectiveness and safety of tight glucose control.Numerous studies in diabetic patients tested CGM devices and demonstrated high accuracy of the CGM-derived glucose values compared with blood glucose measurements (10–12). In particular, these devices were highly sensitive in detecting rapid glucose excursions (12). Recently, these CGM techniques have also been evaluated in critically ill patients and have yielded similar positive results (13–17). Mainly, subcutaneous CGM devices have been intensely investigated (13–17). Accuracy and reliability of a subcutaneous CGM device could be demonstrated both in critically ill patients with and without circulatory shock (16). Subcutaneous CGM worked equally in patients without and with norepinephrine therapy. Validity of the subcutaneous CGM under norepinephrine therapy was furthermore independent of levels of blood glucose values, severity of illness, and patients'' BMI (16). With use of this subcutaneous CGM device, ∼99% of all measured sensor glucose values were within the acceptable treatment zone according to an insulin titration grid analysis (16). Based on these underlying data, we hypothesized that subcutaneous real-time CGM improves glucose control, simultaneously reducing the risk of hypoglycemia.     

Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes

OBJECTIVE

To compare the efficacy and safety of adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a 24-week open-label, multicenter study, 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 μg) or a titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving <50 units/day basal insulin for <6 months. The basal insulin dosage was titrated from day 1, seeking fasting plasma glucose (FPG) ≥70–<100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The proportion of patients achieving A1C ≤7.0% without weight gain or severe hypoglycemia at week 24 was the primary end point.

RESULTS

More pramlintide- than RAIA-treated patients achieved the primary end point (30 vs. 11%, P = 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded similar mean ± SEM values for FPG and A1C at 24 weeks (122 ± 7 vs. 123 ± 5 mg/dl and 7.2 ± 0.2 vs. 7.0 ± 0.1%, respectively) and similar least squares mean reductions from baseline to end point (−31 ± 6 vs. −34 ± 6 mg/dl and −1.1 ± 0.2 vs. −1.3 ± 0.2%, respectively). RAIAs but not pramlintide caused weight gain (+4.7 ± 0.7 vs. +0.0 ± 0.7 kg, P < 0.0001). Fewer patients reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group.

CONCLUSIONS

In patients taking basal insulin and OADs, premeal fixed-dose pramlintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen sometimes caused nausea but no weight gain and less hypoglycemia.Adding basal insulin therapy to oral agents improves glycemic control for many patients with type 2 diabetes, but up to 50% of patients continue to have A1C values >7% (1,2,3,4,5). Persistent after-meal hyperglycemia is generally observed in such patients (6). The usual next step in treatment is addition of mealtime insulin injections, but this approach increases risks of weight gain and hypoglycemia (4,6).Previous studies have shown that defects in addition to insulin deficiency contribute to after-meal hyperglycemia. Both insulin and amylin are secreted by β-cells, and, in individuals with abnormal β-cell function, glucose- and mixed meal–stimulated secretion of both hormones is delayed and reduced (7,8,9). Insulin deficiency impairs suppression of hepatic glucose production and enhancement of glucose uptake by tissues that normally limit postmeal hyperglycemia. Amylin deficiency accelerates gastric emptying, increases glucagon secretion, and alters satiety mechanisms (10,11).Pramlintide, an injectable synthetic analog of amylin, slows gastric emptying, attenuates postprandial glucagon secretion, enhances satiety, and reduces food intake (12,13,14). Pramlintide is approved as adjunctive treatment for patients with diabetes who use mealtime insulin with or without oral antihyperglycemic drugs (OADs) and have not achieved desired glucose control. Recently, a 16-week, double-blind, placebo-controlled study of patients with type 2 diabetes showed that pramlintide reduces A1C and weight without increasing insulin-induced hypoglycemia when added to basal insulin ± OADs without mealtime insulin (15).Pramlintide may offer an additional therapeutic option for mealtime use by patients with type 2 diabetes already using basal insulin. Rapid-acting insulin analogs (RAIAs) and pramlintide have different mechanisms of action and different patterns of desired and unwanted effects. Although both can limit after-meal hyperglycemia, RAIAs often cause weight gain and hypoglycemia (6), whereas pramlintide is associated with weight loss and nausea (15,16). This study was designed to compare the efficacy and side effects of pramlintide versus RAIAs when added to basal insulin to intensify treatment of type 2 diabetes.     

Association Between Excessive Daytime Sleepiness and Severe Hypoglycemia in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

Sleep-disordered breathing and sleepiness cause metabolic, cognitive, and behavioral disturbance. Sleep-disordered breathing is common in type 2 diabetes, a condition that requires adherence to complex dietary, behavioral, and drug treatment regimens. Hypoglycemia is an important side effect of treatment, causing physical and psychological harm and limiting ability to achieve optimal glycemic control. We hypothesized that sleep disorder might increase the risk of hypoglycemia through effects on self-management and glucose regulation.

RESEARCH DESIGN AND METHODS

People with type 2 diabetes (n = 898) completed questionnaires to assess sleep-disordered breathing, daytime sleepiness, and occurrence of severe hypoglycemia.

RESULTS

Subjects who scored highly on the Epworth Sleepiness Scale were significantly more likely to have suffered from severe hypoglycemia. This was a significant predictor of severe hypoglycemia in regression analysis including the variables age, sex, duration of diabetes, HbA_1c, BMI, and treatment type.

CONCLUSIONS

Daytime sleepiness may be a novel risk factor for hypoglycemia.Hypoglycemia is an adverse side effect of insulin and sulfonylurea treatment for type 2 diabetes. Factors influencing risk of severe hypoglycemia (requiring external assistance) include duration of diabetes (1), duration of insulin treatment (2), renal impairment (2), age (1), comorbidities (3), and impaired awareness of hypoglycemia (4). Sleep-disordered breathing with associated daytime somnolence is reported in up to 75% of people with type 2 diabetes (5) and is linked to a range of cardiovascular and metabolic morbidities (6). We hypothesized that sleep disorder and increased daytime sleepiness would be associated with increased frequency of severe hypoglycemia in people with diabetes.     

Effectiveness of a Computerized Insulin Order Template in General Medical Inpatients With Type 2 Diabetes: A cluster randomized trial

OBJECTIVE

To determine whether an electronic order template for basal-bolus insulin ordering improves mean blood glucose in hospitalized general medical patients with hyperglycemia and type 2 diabetes.

RESEARCH DESIGN AND METHODS

We randomly assigned internal medicine resident teams on acute general medical floors to the use of an electronic insulin order template or usual insulin ordering. We measured diabetes care parameters for 1 month on all patients with type 2 diabetes and blood glucose <60 mg/dl or >180 mg/dl treated by these physicians.

RESULTS

Intervention group patients (n = 65) had mean glucose of 195 ± 66 mg/dl. Control group patients (n = 63) had mean glucose of 224 ± 57 mg/dl (P = 0.004). In the intervention group, there was no increase in hypoglycemia.

CONCLUSIONS

Access to a computer insulin order template was associated with improved mean glucose levels without increasing hypoglycemia in patients with type 2 diabetes.Physiological, basal-bolus insulin prescribing is safe, effective (1), and the standard of care in hospitalized patients with type 2 diabetes and hyperglycemia (2). Yet only about half of such patients are prescribed basal insulin in the hospital (3). Order templates to support basal-bolus insulin prescribing (usually as part of a comprehensive inpatient diabetes quality improvement program) have been effective in improving glycemia in observational trials (4–8). Randomized trials have shown more modest effects (9,10). Knowledge of appropriate insulin ordering is a barrier to ordering basal-bolus insulin among inpatient providers (11–13).We tested the hypothesis that giving internal medicine residents access to an electronic insulin order template would be more effective than usual insulin ordering in lowering mean blood glucose in medical inpatients with type 2 diabetes.     

Effects of Acute Insulin-Induced Hypoglycemia on Indices of Inflammation: Putative mechanism for aggravating vascular disease in diabetes

OBJECTIVE

To examine the effects of acute insulin-induced hypoglycemia on inflammation, endothelial dysfunction, and platelet activation in adults with and without type 1 diabetes.

RESEARCH DESIGN AND METHODS

We studied 16 nondiabetic adults and 16 subjects with type 1 diabetes during euglycemia (blood glucose 4.5 mmol/l) and hypoglycemia (blood glucose 2.5 mmol/l). Markers of inflammation, thrombosis, and endothelial dysfunction (soluble P-selectin, interleukin-6, von Willebrand factor [vWF], tissue plasminogen activator [tPA], high-sensitivity C-reactive protein [hsCRP], and soluble CD40 ligand [sCD40L]) were measured; platelet-monocyte aggregation and CD40 expression on monocytes were determined using flow cytometry.

RESULTS

In nondiabetic participants, platelet activation occurred after hypoglycemia, with increments in platelet-monocyte aggregation and P-selectin (P ≤ 0.02). Inflammation was triggered with CD40 expression increasing maximally at 24 h (3.13 ± 2.3% vs. 2.06 ± 1.0%) after hypoglycemia (P = 0.009). Both sCD40L and hsCRP (P = 0.02) increased with a nonsignificant rise in vWF and tPA, indicating a possible endothelial effect. A reduction in sCD40L, tPA, and P-selectin occurred during euglycemia (P = 0.03, P ≤ 0.006, and P = 0.006, respectively). In type 1 diabetes, both CD40 expression (5.54 ± 4.4% vs. 3.65 ± 1.8%; P = 0.006) and plasma sCD40L concentrations increased during hypoglycemia (peak 3.41 ± 3.2 vs. 2.85 ± 2.8 ng/ml; P = 0.03). Platelet-monocyte aggregation also increased significantly at 24 h after hypoglycemia (P = 0.03). A decline in vWF and P-selectin occurred during euglycemia (P ≤ 0.04).

CONCLUSIONS

Acute hypoglycemia may provoke upregulation and release of vasoactive substances in adults with and without type 1 diabetes. This may be a putative mechanism for hypoglycemia-induced vascular injury.In people with type 1 diabetes the rapid institution of strict glycemic control aggravates microvascular complications, particularly retinopathy (1). Although attributed to reduced capillary blood flow causing localized ischemia (1), greater exposure to hypoglycemia may have worsened microangiopathy through its putative effects on local vasculature (2). In addition, cardiovascular stress associated with hypoglycemia may precipitate acute macrovascular events in a diseased circulation. While supported by anecdotal reports (3), the increase in cardiovascular mortality in people with type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (4) (and possibly in the Veterans Affairs Diabetes Trial [5]), in which intensive treatment had tripled the frequency of severe hypoglycemia, has caused concern.Possible mechanisms by which hypoglycemia may damage blood vessels include changes in regional blood flow, mobilization and activation of neutrophils, platelet activation, and enhanced coagulation and viscosity of the blood (3,6–8). Plasma concentrations of C-reactive protein, interleukin-6 (IL-6), and endothelin-1 increase during hypoglycemia (9–11) and may promote vascular disease (12).Investigation of processes operating at a cellular level to cause atherosclerosis has focused on the potential influences of vascular inflammation, endothelial dysfunction, coagulation, and platelet activation. The present study sought to determine the effects of acute insulin-induced hypoglycemia on inflammation, coagulation, and platelet and monocyte function in adults with and without type 1 diabetes.     

Glucagon-Like Peptide 1 Reduces Endothelial Dysfunction,Inflammation, and Oxidative Stress Induced by Both Hyperglycemia and Hypoglycemia in Type 1 Diabetes

OBJECTIVE

Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function.

RESEARCH DESIGN AND METHODS

The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated.

RESULTS

Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects.

CONCLUSIONS

These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.Recent evidence suggests that hypoglycemia also may play an important role in favoring diabetic vascular complications (1). Hypoglycemia causes oxidative stress (2), inflammation (3,4), and endothelial dysfunction (5). Oxidative stress is considered the key player in the pathogenesis of diabetes complications (6). It is of interest that during hyperglycemia, oxidative stress is mainly produced at the mitochondrial level (6), similar to what happens in hypoglycemia (2). Therefore, oxidative stress might be considered the common factor linking hyperglycemia, hypoglycemia, and vascular complications of diabetes. Consistent with this hypothesis is the evidence that both hyperglycemia (7) and hypoglycemia produce endothelial dysfunction and inflammation through oxidative stress generation (5,8). Both endothelial dysfunction and inflammation are well-recognized pathogenic factors for vascular disease, particularly in diabetes (9).Glucagon-like peptide 1 (GLP-1) and its analogs are now being used in clinics to enhance insulin secretion and to reduce body weight in patients with type 2 diabetes (10) in whom a defect of GLP-1 secretion or action in response to the meal often has been reported (11). GLP-1 has been shown to lower postprandial and fasting glucose and HbA_1c, to suppress the elevated glucagon level, and to stimulate glucose-dependent insulin synthesis and secretion (10). Recently, a possible beneficial effect of GLP-1 analogs in the management of type 1 diabetes has been suggested (12). GLP-1, in addition to its insulin-tropic action in alleviating hyperglycemia, has beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass, and suppression of glucagon secretion, gastric emptying, and appetite, which are all characteristics that could be beneficial for the management of type 1 diabetes (12).Apart from the well-documented incretin effect of GLP-1, its role in the cardiovascular system also arouses interest. GLP-1 effects on the cardiovascular system may include a direct action on the endothelium in which the presence of specific receptors for GLP-1 has been demonstrated (13). Consistently, GLP-1 has been demonstrated to improve endothelial function in diabetes (14,15). This protective effect should be exerted to improve the antioxidant defenses of the endothelium (16) and to decrease oxidative stress generation (15).The aim of this study is to test whether GLP-1 can protect endothelial function and reduce the generation of oxidative stress and inflammation during acute hyperglycemia and hypoglycemia in type 1 diabetes.     

Type 1 Diabetic Drivers With and Without a History of Recurrent Hypoglycemia�CRelated Driving Mishaps: Physiological and performance differences during euglycemia and the induction of hypoglycemia

OBJECTIVE

Collisions are more common among drivers with type 1 diabetes than among their nondiabetic spouses. This increased risk appears to be attributable to a subgroup of drivers with type 1 diabetes. The hypothesis tested is that this vulnerable subgroup is more at risk for hypoglycemia and its disruptive effects on driving.

RESEARCH DESIGN AND METHODS

Thirty-eight drivers with type 1 diabetes, 16 with (+history) and 22 without (−history) a recent history of recurrent hypoglycemia-related driving mishaps, drove a virtual reality driving simulator and watched a videotape of someone driving a simulator for 30-min periods. Driving and video testing occurred in a double-blind, randomized, crossover manner during euglycemia (5.5 mmol/l) and progressive hypoglycemia (3.9–2.5 mmol/l). Examiners were blind to which subjects were +/−history, whereas subjects were blind to their blood glucose levels and targets.

RESULTS

During euglycemia, +history participants reported more autonomic and neuroglycopenic symptoms (P ≤ 0.01) and tended to require more dextrose infusion to maintain euglycemia with the same insulin infusion (P < 0.09). During progressive hypoglycemia, these subjects demonstrated less epinephrine release (P = 0.02) and greater driving impairments (P = 0.03).

CONCLUSIONS

Findings support the speculation that there is a subgroup of type 1 diabetic drivers more vulnerable to experiencing hypoglycemia-related driving mishaps. This increased vulnerability may be due to more symptom “noise” (more symptoms during euglycemia), making it harder to detect hypoglycemia while driving; possibly greater carbohydrate utilization, rendering them more vulnerable to experiencing hypoglycemia; less hormonal counterregulation, leading to more profound hypoglycemia; and more neuroglycopenia, rendering them more vulnerable to impaired driving.Worldwide driving collisions account for 1.2 million fatalities and 50 million injuries annually (1). Drivers with type 1 diabetes have more driving mishaps (2). In both Europe and the U.S. type 1 diabetic drivers have been found to have more than twice as many collisions as their nondiabetic spouses (3) possibly because mild hypoglycemia significantly affects cognitive-motor functioning in general (4–6) and the cognitive-motor skills relevant to driving a car in particular (7,8). Severe hypoglycemia precludes safe driving and can contribute to vehicular fatalities (9). Further, mild hypoglycemia can impair judgment as to whether or not to drive (10,11).Just as some individuals with type 1 diabetes are more vulnerable to experiencing severe hypoglycemia (12), some individuals may be more vulnerable to hypoglycemia-related driving mishaps. This speculation is supported by the U.S.-European survey (3) in which only 27% of the type 1 diabetic drivers reported vehicular collisions in the previous 2 years (3) and a prospective study in which only 22% of the sample reported a collision during the 12-month observation (13). In a previous study of hypoglycemia and driving, we conducted post hoc analyses comparing individuals with a recent history of no driving mishaps versus individuals with a history of multiple driving mishaps (14). Those with a +history were more likely to be female (P = 0.02), tended to demonstrate greater carbohydrate utilization (P = 0.07) and less epinephrine release (P = 0.11), and drove significantly worse during hypoglycemia (P = 0.01) (14). The present study was an a priori hypothesis-testing replication comparing subjects with or without a recent history of recurrent hypoglycemia-related driving mishaps, using a similar methodology, to test whether +history type 1 diabetic drivers were 1) more vulnerable to experiencing hypoglycemia through greater carbohydrate utilization, 2) more likely to be female, 3) more vulnerable to progressive hypoglycemia because of a smaller counterregulatory epinephrine response, 4) less aware of hypoglycemia due to fewer symptoms (autonomic and neuroglycopenic) during hypoglycemia, and 5) more impaired while driving during hypoglycemia.     

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 (≤10 years of age) SH, which was defined as convulsions or loss of consciousness.

RESULTS

Overall, cognitive scores were 0.9 SDs lower in subjects with early SH compared with subjects without early SH (P = 0.003). The two diabetic groups particularly differed with respect to problem solving, verbal function, and psychomotor efficiency. Earlier age at first incident of SH was associated with poorer cognition (P for trend = 0.001).

CONCLUSIONS

The findings suggest that early exposure to SH may have lasting and clinically relevant effects on cognition.Early-onset diabetes is associated with reduced cognition (1), possibly due to the effects of severe hypoglycemia (SH) on the developing brain (2–5). Although moderate (1), this cognitive deficit seems to be enduring (5–7). We hypothesized that earlier age at SH occurrence would entail more pronounced effects on cognition. In this 16-year follow-up study of diabetic subjects, we investigated cognitive function in relation to early exposure to SH.     

Sleep disturbances and their relationship to glucose tolerance in pregnancy

OBJECTIVE

To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes.

RESEARCH DESIGN AND METHODS

Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT).

RESULTS

Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] >8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = −0.21, P < 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2–7.4]), SS (2.4 [1.0–5.9]), SDB/SS (3.4 [1.3–8.7]), and frequent snoring (3.4 [1.3–8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P < 0.01) in mothers.

CONCLUSIONS

Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of <7 h/night have increased risk of developing GDM.Sleep-disordered breathing (SDB) is present in 24% of men and 9% of women in the U.S. population (1) and has been linked to insulin resistance and type 2 diabetes (2–5). Recent studies reveal that SDB is present in up to 86% of patients with type 2 diabetes (6,7). SDB severity has been associated with poorer glucose control (6).Decreases in both duration and quality of sleep are common in pregnant women as a result of hormonal and physical factors (8,9). Collectively, these disorders have been termed pregnancy-associated sleep disorders by the International Classification of Sleep Disorders (10).Prospective studies show that SDB symptoms increase during pregnancy (11). SDB in pregnancy has been associated with preeclampsia, intrauterine growth retardation, and preterm delivery (12,13). A few recent studies using questionnaires that variably assess snoring, SDB symptoms, and/or sleep duration report an association between short sleep (SS) and/or frequent snoring and glucose intolerance and gestational diabetes mellitus (GDM) (14–16).We used four validated sleep questionnaires to obtain a comprehensive evaluation of sleep duration and quality and assess associations with glucose tolerance and pregnancy outcomes.     

Terbutaline and the prevention of nocturnal hypoglycemia in type 1 diabetes

OBJECTIVE—Bedtime administration of 5.0 mg of the β₂-adrenergic agonist terbutaline prevents nocturnal hypoglycemia but causes morning hyperglycemia in type 1 diabetes. We tested the hypothesis that 2.5 mg terbutaline prevents nocturnal hypoglycemia without causing morning hyperglycemia.RESEARCH DESIGN AND METHODS—This was a randomized double-blind crossover pilot study (placebo, 2.5 mg terbutaline, and 5.0 mg terbutaline) in 15 patients with type 1 diabetes.RESULTS—Mean ± SE nadir nocturnal plasma glucose concentrations were 87 ± 14 mg/dl following placebo, 100 ± 14 mg/dl following 2.5 mg terbutaline, and 122 ± 13 mg/dl following 5.0 mg terbutaline (P < 0.05 vs. placebo). Nadir levels were <50 mg/dl in 5, 2, and 0 patients (P < 0.05 vs. placebo), respectively. Morning levels were 113 ± 18, 127 ± 17, and 183 ± 19 mg/dl (P < 0.02 vs. placebo), respectively.CONCLUSIONS—Terbutaline may be shown to be effective and safe in the prevention of nocturnal hypoglycemia in type 1 diabetes in a suitably powered randomized controlled trial.Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1). Most episodes of hypoglycemia occur at night, specifically during sleep, in type 1 diabetes—a finding in the Diabetes Control and Complications Trial (2) that continues to be documented (3,4). Sympathoadrenal responses to hypoglycemia are reduced further during sleep (5,6), and, probably because of their markedly reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia than nondiabetic individuals (6,7).Among the approaches to the prevention of nocturnal hypoglycemia in type 1 diabetes, we found bedtime administration of a conventional snack, uncooked cornstarch, or an α-glucosidase inhibitor to be ineffective (3). In contrast, bedtime administration of the epinephrine-simulating β₂-adrenergic agonist terbutaline in a dose of 5.0 mg prevented nocturnal hypoglycemia (3). However, it also caused hyperglycemia the following morning. Therefore, we used a randomized double-blind crossover design (placebo, 2.5 mg terbutaline, and 5.0 mg terbutaline) in a pilot study to test the hypothesis that bedtime administration of 2.5 mg terbutaline prevents nocturnal hypoglycemia without causing morning hypoglycemia in patients with aggressively treated type 1 diabetes.     

Insulin pump therapy with automated insulin suspension in response to hypoglycemia: reduction in nocturnal hypoglycemia in those at greatest risk

OBJECTIVE

To evaluate a sensor-augmented insulin pump with a low glucose suspend (LGS) feature that automatically suspends basal insulin delivery for up to 2 h in response to sensor-detected hypoglycemia.

RESEARCH DESIGN AND METHODS

The LGS feature of the Paradigm Veo insulin pump (Medtronic, Inc., Northridge, CA) was tested for 3 weeks in 31 adults with type 1 diabetes.

RESULTS

There were 166 episodes of LGS: 66% of daytime LGS episodes were terminated within 10 min, and 20 episodes lasted the maximum 2 h. LGS use was associated with reduced nocturnal duration ≤2.2 mmol/L in those in the highest quartile of nocturnal hypoglycemia at baseline (median 46.2 vs. 1.8 min/day, P = 0.02 [LGS-OFF vs. LGS-ON]). Median sensor glucose was 3.9 mmol/L after 2-h LGS and 8.2 mmol/L at 2 h after basal restart.

CONCLUSIONS

Use of an insulin pump with LGS was associated with reduced nocturnal hypoglycemia in those at greatest risk and was well accepted by patients.Continuous glucose monitoring (CGM) can reduce HbA_1c in type 1 diabetes (1–3). Despite the use of hypoglycemia alarms, most studies have not demonstrated a significant reduction in hypoglycemia, and prolonged nocturnal hypoglycemia occurs frequently (4). This may be because patients sleep through many of the alarms (5) and insulin delivery continues during hypoglycemia.We report a user evaluation of the Paradigm Veo insulin pump (Medtronic, Inc., Northridge, CA), which can automatically suspend basal insulin delivery for up to 2 h in the event of CGM-detected hypoglycemia, thus reducing the duration of hypoglycemia.     

Medical Expenditures Associated With Diabetes Acute Complications in Privately Insured U.S. Youth

OBJECTIVE

To estimate medical expenditures attributable to diabetes ketoacidosis (DKA) and severe hypoglycemia among privately insured insulin-treated U.S. youth with diabetes.

RESEARCH DESIGN AND METHODS

We analyzed the insurance claims of 7,556 youth, age ≤19 years, with insulin-treated diabetes. The youth were continuously enrolled in fee-for-service health plans, and claims were obtained from the 2007 U.S. MarketScan Commercial Claims and Encounter database. We used regression models to estimate total medical expenditures and their subcomponents: outpatient, inpatient, and drug expenditures. The excess expenditures associated with DKA and severe hypoglycemia were estimated as the difference between predicted medical expenditures for youth who did/did not experience either DKA or severe hypoglycemia.

RESULTS

For youth with and without DKA, respectively, predicted mean annual total medical expenditures were $14,236 and $8,398 (an excess of $5,837 for those with DKA). The excess was statistically greater for those with one or more episodes of DKA ($8,455) than among those with only one episode ($3,554). Predicted mean annual total medical expenditures were $12,850 and $8,970 for youth with and without severe hypoglycemia, respectively (an excess of $3,880 for those with severe hypoglycemia). The excess was greater among those with one or more episodes ($5,929) than among those with only one ($2,888).

CONCLUSIONS

Medical expenditures for potentially preventable DKA and severe hypoglycemia in U.S. youth with insulin-treated diabetes are substantial. Improving the quality of care for these youth to prevent the development of these two complications could avert substantial U.S. health care expenditures.Diabetes ketoacidosis (DKA) and severe hypoglycemia are two common acute diabetes complications in youth. DKA, which results from absolute or relative insulin deficiency, can be the initial clinical presentation of both type 1 and type 2 diabetes or can occur in those with an established diabetes diagnosis. Severe hypoglycemia is a serious side effect of insulin treatment, especially for children and adolescents with type 1 diabetes. Despite substantial progress in diabetes management and care over the last 20 years (1), incidence and prevalence of these potentially preventable complications remain high (2,5). In 2006, among people in the U.S. with diabetes aged 0–17 years, 64% of the first-listed hospital discharge diagnoses included DKA (http://www.cdc.gov/diabetes/statistics/hosp/kidtable1.htm, accessed on 26 April 2010). An estimated 15–29% of youth with diabetes had DKA at the onset of diabetes (4–7). Among those aged <19 years with established type 1 diabetes, the overall incidence of DKA and severe hypoglycemia was estimated to be 8 and 19 per 100 patient-years, respectively (2).In addition to the risk for premature death and lower quality of life associated with these conditions, both DKA and severe hypoglycemia impose large economic burdens on the health care system (2,3,8,9). Medical expenses attributed to DKA and severe hypoglycemia have been estimated in diabetic adults (9–13), but similar estimates are not available for U.S. youth (age <20 years). We are aware of no studies that examine excess medical expenditures in youth experiencing recurrent DKA or severe hypoglycemia episodes.To evaluate the economic efficiency of programs aimed at improving quality of care and to establish health care policies for youth with diabetes, estimates of excess medical expenditures associated with these acute complications are needed. Thus, our study''s objectives were to 1) estimate the excess medical expenditures associated with DKA and severe hypoglycemia among youth with insulin-treated diabetes (ITDM) and 2) to examine the extent to which the excess expenditures are associated with the number of episodes of these complications.     

Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE

To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders.

RESULTS

Unadjusted mean HbA_1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA_1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA_1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA_1c >9%; P = 0.005) but not with average HbA_1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time.

CONCLUSIONS

This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.The Diabetes Control and Complications Trial (DCCT) showed that improved metabolic control reduces the risk of long-term complications in both adult and adolescent patients with type 1 diabetes (1,2). The observational follow-up study of the DCCT (the Epidemiology of Diabetes Interventions and Complications [EDIC] study) further proved that good glycemic control had persistent beneficial effects on long-term complications (3). Based on the results of the DCCT/EDIC study, it was recommended to optimize glycemic control as early and close to normal as possible in all patients with type 1 diabetes in order to prevent development and progression of microvascular complications.Diabetes treatment has been intensified in pediatric and adolescent patients during the past 15 years. Insulin therapy has changed from twice-daily injection regimen to intensified therapy with multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII). This has been reported from single-center and multicenter studies (4–10). In the 1990s, mainly an increased use of MDI was observed, whereas since 2000, pump therapy increased considerably, paralleled by a decrease in MDI therapy (11). With the intensification of insulin regimen, the frequency of daily self-monitoring of blood glucose (SMBG) increased continuously (5,10–12), as close glucose monitoring is a precondition for intensified insulin therapy with an appropriate dose adjustment. Likewise, the use of short-acting insulin analogs has continuously increased since the mid-1990s and the use of long-acting analogs since 2000 (4,5,10).Despite these far-ranging changes in diabetes therapy, the anticipated improvement in metabolic control in children and adolescents with type 1 diabetes has not been achieved in all settings. The multicenter Hvidoere studies did not observe any improvement in glycemic control during 1995–2005 (6–8). Other studies, however, reported a significant decrease in average HbA_1c level over the past two decades (4,5,10,11,13). Concordantly, several studies indicated a notable increase in the proportion of children and adolescents with good metabolic control (HbA_1c <7.5 or <8%) over the past years (11,13).In the DCCT study, the tradeoff with intensified insulin therapy was a marked increase in episodes of severe hypoglycemia (2). Several studies reported a higher hypoglycemia risk with lower HbA_1c level (4,6,7,10,14), but others did not (15,16). Results on the trend of severe hypoglycemic events over the past 15 years are also inconsistent (4,5,8,9,11).The aim of this study was to give a current update on the temporal trend of metabolic control in German and Austrian children and adolescents over the past 15 years (1995–2009), to identify potential determinants of metabolic control, and to analyze the simultaneous trend of severe hypoglycemic and diabetic ketoacidotic events.