0.05) but was similar with ultralente (20 ± 6 h). NPH and ultralente exhibited a peak concentration and action (at 4.5 ± 0.5 and 10.1 ± 1 h, respectively) followed by waning, whereas glargine had no peak but had a flat concentration/action profile mimicking CSII. Interindividual variability (calculated as differences in SD of plasma insulin concentrations and glucose infusion rates in different treatments) was lower with glargine than with NPH and ultralente (P < 0.05) but was similar with glargine and CSII (NS). In conclusion, NPH and ultralente are both peak insulins. Duration of action of ultralente is greater, but intersubject variability is also greater than that of NPH. Glargine is a peakless insulin, it lasts nearly 24 h, it has lower intersubject variability than NPH and ultralente, and it closely mimics CSII, the gold standard of basal insulin replacement. Diabetes 49:2142-2148, 2000 T he goal of treatment of type 1 diabetes is maintenance of long-term near-normoglycemia to prevent the onset and/or progression of long-term complications (1,2). At present, this goal is feasible with physiological models of insulin replacement (3), provided that patients are appropriately educated about the strategy of intensive insulin therapy (4,5). However, several obstacles, such as day-to-day variability in insulin requirements and slow (6) and variable absorption (7) of insulin from the subcutaneous (SC) site of injection, make it difficult for type 1 diabetic patients to maintain long-term near-normoglycemia.The DNA-recombinant technique has led to synthesis of the short-acting human insulin analogs lispro and aspart, which are absorbed faster than human regular insulin and improve 1-and 2-h postprandial blood glucose levels (8). However, better postprandial blood glucose control with short-acting insulin analogs results in improvement in glycemic control in the long term only by the extent to which replacement of basal insulin is optimized at the same time, either by continuous subcutaneous insulin infusion (CSII) or multiple daily administrations of NPH (8). The latter regimen results in lower HbA 1c (9), with no increase (9) or a decrease in the frequency of hypoglycemia compared with the regimen based on mealtime administration of human regular insulin and bedtime NPH (8). In turn, less frequent hypoglycemia results in better awareness of and counterregulation to hypoglycemia in the long term (10). However, the approach of multiple daily injections of NPH or CSII may be too demanding for the majority of patients worldwide who use mealtime administration of short-acting insulin analogs.An ideal basal insulin candidate is a peakless long-lasting preparation that mimics the flat interprandial insulin secretion of nondiabetic subjects, with reproducible SC absorption. The presently available intermediate-acting (NPH) or long-acting (ultralente) insulin preparations are poor surrogates for the ideal basal insulin, primarily because of their peak-action profile (11,12) and day-to-day variability in SC absorption (7)....

on behalf of the EGIR-RISC Study Group* OBJECTIVE-Physical activity is a modifiable risk factor for type 2 diabetes, partly through its action on insulin sensitivity. We report the relation between insulin sensitivity and physical activity measured by accelerometry.RESEARCH DESIGN AND METHODS-This is a cross-sectional study of 346 men and 455 women, aged 30 -60 years, without cardiovascular disease and not treated by drugs for diabetes, hypertension, dyslipidemia, or obesity. Participants were recruited in 18 clinical centers from 13 European countries. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Physical activity was recorded by accelerometry for a median of 6 days. We studied the relationship of insulin sensitivity with total activity (in counts per minute), percent of time spent sedentary, percent of time in light activity, and activity intensity (whether the participant recorded some vigorous or some moderate activity).RESULTS-In both men and women, total activity was associated with insulin sensitivity (P Ͻ 0.0001). Time spent sedentary, in light activity, and activity intensity was also associated with insulin sensitivity (P Ͻ 0.0004/0.01, 0.002/0.03, and 0.02/0.004, respectively, for men/women) but lost significance once adjusted for total activity. Adjustment for confounders such as adiposity attenuated the relationship with total activity; there were no interactions with confounders. Even in the 25% most sedentary individuals, total activity was significantly associated with better insulin sensitivity (P Ͻ 0.0001).CONCLUSIONS-Accumulated daily physical activity is a major determinant of insulin sensitivity. Time spent sedentary, time spent in light-activity, and bouts of moderate or vigorous activity did not impact insulin sensitivity independently of total activity.

OBJECTIVE -To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 Ϯ 10 years, BMI 22.4 Ϯ 1.6 kg/m 2 , and A1C 7.2 Ϯ 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study).RESEARCH DESIGN AND METHODS -Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was Ͼ150 mg/dl).RESULTS -With glargine, plasma glucose remained at 103 Ϯ 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose Ͻ180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P Ͻ 0.001). Estimated total insulin activity (GIR area under the curve [AUC] 0 -end of GIR ) was 1,412 Ϯ 662 and 915 Ϯ 225 mg/kg (glargine vs. detemir, P Ͻ 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P Ͻ 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids 0 -24 h 11 Ϯ 1.7 vs. 8 Ϯ 2.8 mmol/l, respectively, P Ͻ 0.001).CONCLUSIONS -Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12-24 h.

To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 +/- 0.05 to 0.045 +/- 0.03 episodes/patient-day) and an increase in HbA1c (5.8 +/- 0.3 to 6.9 +/- 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.

OBJECTIVETo compare the pharmacokinetics and pharmacodynamics of NPH, glargine, and detemir insulins in type 2 diabetic subjects.RESEARCH DESIGN AND METHODSThis study used a single-blind, three-way, cross-over design. A total of 18 type 2 diabetic subjects underwent a euglycemic clamp for 32 h after a subcutaneous injection of 0.4 units/kg at 2200 h of either NPH, glargine, or detemir after 1 week of bedtime treatment with each insulin.RESULTSThe glucose infusion rate area under the curve0–32 h was greater for glargine than for detemir and NPH (1,538 ± 688; 1,081 ± 785; and 1,170 ± 703 mg/kg, respectively; P < 0.05). Glargine suppressed endogenous glucose production more than detemir (P < 0.05) and similarly to NPH (P = 0.16). Glucagon, C-peptide, free fatty acids, and β-hydroxy-butyrate were more suppressed with glargine than detemir. All 18 subjects completed the glargine study, but two subjects on NPH and three on detemir interrupted the study because of plasma glucose >150 mg/dL.CONCLUSIONSCompared with NPH and detemir, glargine provided greater metabolic activity and superior glucose control for up to 32 h.