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

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This study was undertaken to examine whether insulin resistance in adolescents with poorly controlled type 1 diabetes mellitus (T1DM) is associated with the failure of insulin to suppress lipolysis in adipose and muscle tissues. Using microdialysis techniques, extracellular fluid concentrations of glycerol was measured in adipose and muscle tissue 3 h before and 3 h during a 0.8 mU · kg Ϫ1 · min Ϫ1 · euglycemic clamp. Ten adolescents with poorly controlled T1DM (HbA 1c 10.2 Ϯ 0.2%) were compared with six healthy lean adolescent control subjects. Despite similar increases in plasma insulin in both groups, diabetic subjects exhibited a 39% reduction in peripheral glucose uptake compared with controls (p Ͻ 0.05). In contrast, hepatic glucose production was fully suppressed by insulin in diabetic subjects. At the end of the clamp, extracellular glycerol concentrations were significantly elevated in subjects with diabetes (muscle: 85 Ϯ 7 M for diabetics and 51 Ϯ 8 M for controls, p Ͻ 0.01; adipose: 149 Ϯ 23 M for T1DM and 82 Ϯ 11 M for controls, p Ͻ 0.05), indicating impaired in situ suppression of lipolysis in patients with diabetes. With all subjects considered, the rate of insulin-stimulated metabolism was inversely correlated to glycerol concentration in both adipose (r ϭ Ϫ0.63, p Ͻ 0.01) and muscle (r ϭ Ϫ0.63, p Ͻ 0.01). Our data suggest that failure of insulin to inhibit lipolysis in muscle and adipose tissue contributes to the severe peripheral insulin resistance that characterizes poorly controlled T1DM during adolescence. Type 1 diabetes mellitus (T1DM) in adolescents is a disease in which end organ resistance to insulin and deficiency of the hormone coexist (1). During normal puberty, responsiveness to insulin declines and this physiologic insulin resistance is exaggerated by poorly controlled diabetes (1-3). Compared with healthy lean preadolescents, healthy lean adolescents show a selective defect in insulin's ability to stimulate nonoxidative glucose disposal in peripheral (muscle and adipose) tissues; insulin-mediated increases in peripheral glucose oxidation are unaffected by normal puberty (4, 5). In contrast, the exaggerated insulin resistance in adolescents with poorly controlled T1DM involves defects in insulin's ability to stimulate both oxidative and nonoxidative glucose metabolism (5).An implication of the much debated glucose fatty-acid cycle (Randle cycle) is that increased FFA availability interferes with muscle glucose metabolism and contributes to the cause of many insulin-resistant states, including adolescence and T1DM (6 -8). Using the insulin clamp technique and indirect calorimetry, we have shown that severely insulin-resistant adolescents with poorly controlled T1DM fail to suppress circulating FFA levels or rates of fat oxidation in comparison with healthy adolescent controls in response to insulin levels similar to those achieved postprandially by healthy adolescents (5). The wholebody methods used in that study, however, did not allow us to distinguish the relative contributions of...

It has been suggested that the counterregulatory hormone (CRH) response to acute hypoglycemia is triggered via glucose sensors situated in either the hypothalamus or the portohepatic area. If the latter were critical during hypoglycemia, one would anticipate that ingestion of glucose, by raising glucose levels in the portal circulation, should attenuate CRH responses previously described in animal studies. To evaluate the effect of raising portal, but not peripheral, glucose levels during insulin-induced hypoglycemia, we performed hypoglycemic clamp studies in five healthy adult males on two occasions. On one occasion, subjects received oral glucose (OG) (25 g) during hypoglycemia; and on one occasion, noncarbohydrate-containing drink of equal volume, while maintaining plasma glucose at 55 +/- 2 mg/dL (3.08 mmol/L). As a result, there were no significant differences in systemic plasma glucose levels between the two hypoglycemic clamp studies, and basal CRH concentrations were also similar. As expected, there was a brisk rise in all CRH during the control (hypoglycemia+noncarbohydrate drink) study. In the experimental study, administration of OG (hypoglycemia+OG), to raise intraportal glucose levels during systemic hypoglycemia, did not attenuate CRH responses. Indeed, OG enhanced the rise in epinephrine, glucagon, and GH. Increases in cortisol and norepinephrine did not differ between the two studies. Therefore, our data suggest that increasing the level of glucose in the portal vein above that in the systemic circulation, during hypoglycemia, enhances (rather than suppresses) CRH responses. Thus, ingestion of glucose may reverse hypoglycemia directly by provision of substrate, as well as indirectly by stimulating counteregulatory mechanisms.