OBJECTIVE -Children with type 1 diabetes are usually asked to perform self-monitoring of blood glucose (SMBG) before meals and at bedtime, and it is assumed that if results are in target range, along with HbA 1c measurements, then overall glycemic control is adequate. However, the brief glimpses in the 24-h glucose profile provided by SMBG may miss marked glycemic excursions. The MiniMed Continuous Glucose Monitoring System (CGMS) has provided a new method to obtain continuous glucose profiles and opportunities to examine limitations of conventional monitoring.RESEARCH DESIGN AND METHODS -A total of 56 children with type 1 diabetes (age 2-18 years) wore the CGMS for 3 days. Patients entered four fingerstick blood samples into the monitor for calibration and kept records of food intake, exercise, and hypoglycemic symptoms. Data were downloaded, and glycemic patterns were identified.RESULTS -Despite satisfactory HbA 1c levels (7.7 Ϯ 1.4%) and premeal glucose levels near the target range, the CGMS revealed profound postprandial hyperglycemia. Almost 90% of the peak postprandial glucose levels after every meal were Ͼ180 mg/dl (above target), and almost 50% were Ͼ300 mg/dl. Additionally, the CGMS revealed frequent and prolonged asymptomatic hypoglycemia (glucose Ͻ60 mg/dl) in almost 70% of the children.CONCLUSIONS -Despite excellent HbA 1c levels and target preprandial glucose levels, children often experience nocturnal hypoglycemia and postprandial hyperglycemia that are not evident with routine monitoring. Repeated use of the CGMS may provide a means to optimize basal and bolus insulin replacement in patients with type 1 diabetes.

Ghrelin is a novel peptide that acts on the growth hormone (GH) secretagogue receptor in the pituitary and hypothalamus. It may function as a third physiological regulator of GH secretion, along with GH-releasing hormone and somatostatin. In addition to the action of ghrelin on the GH axis, it appears to have a role in the determination of energy homeostasis. Although feeding suppresses ghrelin production and fasting stimulates ghrelin release, the underlying mechanisms controlling this process remain unclear. The purpose of this study was to test the hypotheses, by use of a stepped hyperinsulinemic eu-hypo-hyperglycemic glucose clamp, that either hyperinsulinemia or hypoglycemia may influence ghrelin production. Having been stable in the period before the clamp, ghrelin levels rapidly fell in response to insulin infusion during euglycemia (baseline ghrelin 207 Ϯ 12 vs. 169 Ϯ 10 fmol/ml at t ϭ 30 min, P Ͻ 0.001). Ghrelin remained suppressed during subsequent periods of hypoglycemia (mean glucose 53 Ϯ 2 mg/dl) and hyperglycemia (mean glucose 163 Ϯ 6 mg/dl). Despite suppression of ghrelin, GH showed a significant rise during hypoglycemia (baseline 4.1 Ϯ 1.3 vs. 28.2 Ϯ 3.9 g/l at t ϭ 120 min, P Ͻ 0.001). Our data suggest that insulin may suppress circulating ghrelin independently of glucose, although glucose may have an additional effect. We conclude that the GH response seen during hypoglycemia is not regulated by circulating ghrelin. growth hormone; somatostatin; hypothalamus; hypoglycemia; glucose clamp GHRELIN IS A NOVEL PEPTIDE that acts on the growth hormone (GH) secretagogue receptor in the pituitary and hypothalamus, possibly functioning as a third physiological regulator of GH secretion along with GHreleasing hormone (GHRH) and somatostatin. In addition to the action of ghrelin on the GH axis, it appears to have a role in the determination of energy homeostasis (3, 12, 13). Ghrelin acts as an orexigenic hormone, stimulating both neuropeptide Y (NPY) and agoutirelated peptide, and thus feeding (14, 21). Although feeding suppresses ghrelin production and fasting stimulates ghrelin release, the underlying mechanisms controlling these processes remain unclear (4,19). This relationship is the opposite of that seen with leptin (14), which has been shown to be increased by insulin (18). Specifically, the roles that alterations in plasma glucose and insulin have in regulating ghrelin secretion have not been established. To address this issue, we employed a stepped hyperinsulinemic eu-hypo-hyperglycemic glucose clamp. This procedure allowed us to examine the ghrelin response to marked variations in circulating concentrations of insulin and glucose in human subjects. METHODSEleven young adult volunteers (9 women, 2 men) participated in the study. The age of the subjects was 24 Ϯ 4 yr (range 18-31 yr), and the body mass index was 22.1 Ϯ 2.8 kg/m 2 (18.4-26.6 kg/m 2 ). All subjects were healthy and taking no medication. They were instructed to maintain their normal physical activity and to consume a normal diet contai...

OBJECTIVE -The MiniMed Continuous Glucose Monitoring System (CGMS) measures subcutaneous interstitial glucose levels that are calibrated against three or more fingerstick glucose levels daily. The objective of the present study was to examine whether the relationship between plasma and interstitial fluid glucose is altered by changes in plasma glucose and insulin levels and how such alterations might influence CGMS performance.RESEARCH DESIGN AND METHODS -Arterialized plasma glucose, sensor glucose, and interstitial fluid glucose were measured by microdialysis in 11 healthy subjects during a 1.0 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 stepped euglycemic-hypoglycemic-hyperglycemic (plasma glucose ϳ5, 3.1, and 8.6 mmol/l, respectively) insulin clamp that raised plasma insulin to ϳ360 -390 pmol/l. RESULTS -When the CGMS was calibrated versus plasma glucose levels before insulin infusion, basal sensor and plasma glucose were similar (5.0 Ϯ 0.3 vs. 5.2 Ϯ 0.3 mmol/l, respectively); dialysate glucose was 3.3 Ϯ 0.9 mmol/l. During the hyperinsulinemic-euglycemia study (plasma glucose 4.9 Ϯ 0.3 mmol/l), dialysate glucose fell by 30 -35%, accompanied by a significant reduction in sensor glucose (to 3.7 Ϯ 0.6 mmol/l; P Ͻ 0.001 vs. plasma). Subsequently, sensor levels remained lower than plasma values during mild hypoglycemia (2.5 Ϯ 0.6 vs. 3.1 Ϯ 0.3 mmol/l; P Ͻ 0.01) and during recovery from hypoglycemia (7.3 Ϯ 1.2 vs. 8.6 Ϯ 0.6; P Ͻ 0.01). However, when the CGMS was calibrated against plasma glucose levels before and during each step of the clamp, sensor glucose levels increased throughout the study and did not differ from plasma glucose values during hypoglycemia.CONCLUSIONS -Although hyperinsulinemia may contribute to modest discrepancies between plasma and sensor glucose levels, the CGMS is able to accurately track acute changes in plasma glucose when calibrated across a range of plasma glucose and insulin levels. Diabetes Care 25:889 -893, 2002

OBJECTIVE -Fear of a severe hypoglycemic reaction is a major obstacle to achieving nearnormal plasma glucose levels. Although parenteral glucagon is effective in treating these reactions, it is cumbersome to use, causes severe nausea, and is impractical in the school setting. Epinephrine is available as a premixed injection (Epipen) that may be used by all care providers. Using Epipen to treat hypoglycemia may be an effective, safe, and easy-to-use alternative to glucagon.RESEARCH DESIGN AND METHODS -Ten children (age 11.7 Ϯ 2.4 years) with type 1 diabetes were studied on two occasions. After an overnight equilibration period, hypoglycemia was induced via an insulin pump (1 mU ⅐ kg -1 ⅐ min -1 ). At a blood glucose level of 2.8 mmol/l, either glucagon (1 mg) or epinephrine (0.3 mg), in random order, was administered intramuscularly and responses were monitored.RESULTS -Plasma free insulin concentrations were similar in both studies. Plasma glucose levels increased by 1.7 Ϯ 0.2 mmol/l (mean Ϯ SEM) in 10 min and by 2.6 Ϯ 0.2 mmol/l in 15 min with administration of glucagon and were not consistently increased with administration of epinephrine (P Ͻ 0.01). Peak glucagon concentrations after administration of glucagon were Ͼ60-fold higher than basal concentrations. After administration of epinephrine, peak epinephrine levels were 20-fold higher than basal concentrations.CONCLUSIONS -Epinephrine does not seem to be an adequate substitute for glucagon in the treatment of severe hypoglycemia. The effectiveness of glucagon in reversing hypoglycemia and its side effects of nausea and vomiting are likely related to the markedly supraphysiologic plasma levels achieved with the standard intramuscular dose. Diabetes Care 24:701-704, 2001S evere hypoglycemia is the most frequent and feared acute complication of treatment of type 1 diabetes during childhood. In fact, fear of a severe hypoglycemic reaction has become a major obstacle in achieving lower glycosylated hemoglobin levels with intensive treatment. Parenteral injection of 1.0 mg glucagon is the standard treatment for a severe insulin reaction (1,2), but the need to reconstitute the hormone with diluent makes it difficult to use in an emergent situation. In addition, the standard dose of glucagon is often associated with severe nausea and occasionally with vomiting, which can complicate recovery from hypoglycemia by limiting the patient's intake of oral carbohydrate. Because glucagon can only be administered by a licensed health professional in many school systems, diabetic children may be precluded from field trips and other extracurricular activities for reasons of safety.Even though stimulation of epinephrine secretion is one of the main endogenous hormonal defenses against insulininduced hypoglycemia in type 1 diabetes, use of epinephrine for treatment of severe hypoglycemia in children has not been tested. This is surprising because a premixed and prefilled injection system for parenteral epinephrine administration is available for treatment of severe allergic reac...