Paolo Rossetti

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes A double-blind, randomized, crossover study

OBJECTIVE—To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 ± 10 years, BMI 22.4 ± 1.6 kg/m2, and A1C 7.2 ± 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 >150 mg/dl). RESULTS—With glargine, plasma glucose remained at 103 ± 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 <180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P < 0.001). Estimated total insulin activity (GIR area under the curve [AUC]0–end of GIR) was 1,412 ± 662 and 915 ± 225 mg/kg (glargine vs. detemir, P < 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P < 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids0–24 h 11 ± 1.7 vs. 8 ± 2.8 mmol/l, respectively, P < 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.

Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin

Background  Glargine is a long‐acting insulin analogue potentially more suitable than NPH insulin in intensive treatment of Type 1 diabetes mellitus (T1 DM), but no study has proven superiority. The aim of this study was to test superiority of glargine on long‐term blood glucose (BG) as well as on responses to hypoglycaemia vs. NPH.

Superiority of insulin analogues versus human insulin in the treatment of diabetes mellitus.

Abstract The modern goals of insulin replacement in Type 1 and Type 2 diabetes mellitus (T1, T2DM) are A1C <6.5% long-term, and prevention of hypoglycaemia (blood glucose, BG <70 mg/dl). In addition to appropriate education and motivation of diabetic subjects, the use of rapid- and long-acting insulin analogues, is critical to achieve these goals. The benefits of rapid-acting analogues (lispro, aspart and glulisine have similar pharmacodynamic effects) compared with non-modified human regular insulin, are: (a) lower 1- and 2-h post-prandial blood glucose; (b) lower risk of late post-prandial hypoglycaemia (and therefore lower BG variability); (c) better quality of life (greater flexibility in timing and dosing of insulin). In T1DM, rapid-acting analogues improve A1C only by the extent to which replacement of basal insulin is optimized at the same time, either by multiple daily NPH administrations, or continuous subcutaneous insulin infusion (CSII), or use of the long-acting insulin analogues glargine or detemir. In T2DM, rapid-acting analogues reduce post-prandial hyperglycaemia more than human regular insulin, but systematic studies are needed to examine the effects on A1C. The benefits of long-acting insulin analogues glargine and detemir vs. NPH, are: (1) lower fasting BG combined with lower risk of hypoglycaemia in the interprandial state (night); (2) lower variability of BG. Glargine and detemir differ in terms of potency and duration of action. Detemir should be given twice daily in the large majority of people with T1DM, and in a large percentage of subjects with T2DM as well, usually at doses greater vs those of the once daily glargine. However, when used appropriately for individual pharmacokinetics and pharmacodynamics, glargine and detemir result into similar effects on BG, risk of hypoglycaemia and A1C. Rapid- and long-acting insulin analogues should always be combined in the treatment of T1 and T2DM.

Administration of Neutral Protamine Hagedorn Insulin at Bedtime versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control: A Randomized, Controlled Trial

Context Clinicians often split evening insulin dosing (short-acting insulin at dinner and long-acting insulin at bedtime rather than both types with dinner) to avoid nocturnal hypoglycemia in patients with type 1 diabetes mellitus. Although split dosing makes sense theoretically, no rigorous studies have examined its effects on glycemic control. Contribution In this randomized, controlled crossover trial, episodes of nocturnal hypoglycemia were less frequent and fasting blood glucose and hemoglobin A1c levels were lower with split evening insulin than with mixed dosing at dinner. Clinical Implications This study supports splitting evening insulin dosing to improve glycemic control in patients with intensively treated type 1 diabetes. The Editors Nocturnal hypoglycemia is common in patients with type 1 diabetes mellitus (1-7). When insulin treatment is intensified to achieve near-normoglycemia, the frequency of hypoglycemia increases; approximately half of these episodes occur at night (2, 3). Unrecognized nocturnal hypoglycemia is common (1, 3-8). Overtreatment of symptomatic nocturnal hypoglycemia with snacks often results in hyperglycemia the next day (9-11). Asymptomatic nocturnal hypoglycemia can cause morning headache and malaise and may result in diminished awareness, reduced responses of adrenaline, and adaptation of cognitive function during the episode (12-15). Recurrent nocturnal hypoglycemia may contribute to the vicious cycle of hypoglycemia unawareness and impaired hormonal counterregulation in patients with type 1 diabetes, leading to increased risk for severe hypoglycemia (16). The nonphysiologic pharmacokinetics and pharmacodynamics of insoluble, intermediate-acting insulin preparations, such as neutral protamine Hagedorn (NPH) insulin, play a central role in inducing nocturnal hypoglycemia in type 1 diabetes (4). When injected at dinner, NPH insulin results in excess plasma insulin bioavailability at approximately midnight, a time at which patients with type 1 diabetes are more insulin sensitive (17, 18); thus, the risk for hypoglycemia increases between midnight and 3:00 a.m. Later, insulin deficiency develops at dawn (4, 18) and contributes to fasting hyperglycemia. When the nocturnal peak plasma level of insulin produced by an evening injection of intermediate-acting (NPH) insulin is postponed by 3 to 4 hours as a result of injecting NPH insulin at bedtime instead of at dinner, fasting and postbreakfast blood glucose levels decrease (19). Although the pharmacokinetics and pharmacodynamics of NPH insulin would suggest that splitting of the evening insulin regimen (administering short-acting insulin at dinner and NPH insulin at bedtime) should decrease the risk for nocturnal hypoglycemia, to the best of our knowledge no data indicate this in patients with type 1 diabetes mellitus. W e tested the hypothesis that in intensive treatment of type 1 diabetes, splitting the evening insulin administration rather than mixing short-acting and NPH insulin at dinner reduces the risk for nocturnal hypoglycemia and improves glycemic control, awareness of hypoglycemia, and counterregulation to hypoglycemia. Although split dosing makes sense theoretically, no rigorous studies have examined its effects on glycemic control. Methods Patients We recruited 22 patients (10 women, 12 men; mean age [SD], 29 3 years) with type 1 diabetes mellitus (mean duration of diagnosed diabetes [SD], 14 2 years) receiving long-term intensive insulin treatment (multiple insulin injections with regular human insulin before meals and NPH insulin at bedtime) from the outpatient Diabetes Clinic of the Department of Internal Medicine at the University of Perugia. At baseline, the mean (SD) body mass index of the cohort was 23 1 kg/m2, and the mean (SD) hemoglobin A1c value was 6.7% 0.4%. Patients had no detectable microangiopathic complications; autonomic neuropathy, as assessed by using a standard battery of cardiovascular tests [20]; peripheral neuropathy; or microalbuminuria. The patients had no history or clinical evidence of hypertension and were taking no medications other than insulin. We excluded 1) patients with hypoglycemia unawareness, defined as an absence of symptoms while the blood glucose level is approximately 2.5 to 2.8 mmol/L [45 to 50 mg/dL] and 2) patients with a history of severe hypoglycemia, defined as episodes of hypoglycemia requiring assistance from another person in the previous year. All patients in the study gave informed consent. The Institutional Review Board of University of Perugia in Perugia, Italy, approved this study. Study Design After a 1-month run-in period, during which patients continued their usual regimen of multiple daily insulin injections, we randomly assigned patients to receive one of the two following treatment regimens for the first 4-month treatment period: 1) a continued regimen of four daily insulin injections (evening split treatment)that is, administration of regular insulin before dinner and NPH insulin at bedtime [usually between 10:30 p.m. and 11:00 p.m.] or 2) a regimen of regular insulin at breakfast and lunch and a mixture of regular and NPH insulins at dinner (evening mixed treatment). Thereafter, the patients were switched to the other treatment for an additional 4 months. Insulin (short-acting and NPH) was administered with syringes to achieve the target values for fasting blood glucose of 5.0 to 6.7 mmol/L (90 to 120 mg/dL) before meals and at bedtime [2]. The dose of mealtime regular insulin was titrated on the basis of the blood glucose measurement obtained 1) before the meal and 2) on the previous day, 4 to 5 hours after that meal, or, in the case of the evening meal, at bedtime. The dose of NPH insulin given at dinner or at bedtime was titrated on the basis of the predinner or bedtime blood glucose level, respectively. The patients were instructed to measure capillary blood glucose levels by using Reflolux S (Boehringer Mannheim, Mannheim, Germany) before each insulin injection, at bedtime, and every other day at 3:00 a.m. The patients were also asked to skip no more than one of their daily capillary glucose measurements and to keep diaries of blood glucose values, insulin dosage, and hypoglycemic episodes (blood glucose level 4.0 mmol/L [ 72 mg/dL]) occurring any time during the day. To prevent nocturnal hypoglycemia, the patient instructions included a suggestion to consume a snack containing approximately 20 g of carbohydrates (approximately 20 g of bread and approximately 60 mL of 2% milk) when the capillary blood glucose level at bedtime was less than 7.0 mmol/L (<126 mg/dL) with the evening mixed treatment and less than 6.0 mmol/L (<108 mg/dL) with the evening split treatment. We also suggested that patients have a similar snack if the blood glucose level at 3:00 a.m. was 4.0 mmol/L or less ( 72 mg/dL) at any time during the night. If such a snack did not relieve hypoglycemic symptoms in approximately 10 minutes, patients were told to have another snack (for a total of 40 g of carbohydrates). Throughout the study, patients visited the outpatient clinic monthly to submit their diaries and had frequent telephone contacts (every 3 to 6 days) with the investigators. At the end of each treatment period, patients were admitted to the clinical research unit of the hospital, where blood glucose was monitored overnight; the next morning, counterregulatory and symptomatic responses to hypoglycemia and cognitive performance were evaluated during a hyperinsulinemic, stepped hypoglycemic clamp study. Hemoglobin A1c values were measured before randomization and at the end of both treatment periods. In-Hospital Evaluation Overnight Testing Patients were admitted for overnight evaluations after dinner (and, thus, after premeal insulin administration), at approximately 9:00 p.m. A hand vein of the nondominant arm was cannulated retrogradely, and the hand was maintained in a hot pad (approximately 60 C) for sampling of arterialized-venous blood (21). A second venous line of the ipsilateral arm was cannulated for intravenous infusion of glucose whenever an infusion was needed to prevent hypoglycemia (that is, to prevent a decrease in plasma glucose level to 4.0 mmol/L [ 72 mg/dL]). Glucose was infused whenever the plasma glucose level decreased to less than 4.4 mmol/L (<80 mg/dL). On overnight stays, patients were allowed to watch television until 11:00 p.m., at which time patients receiving the evening split regimen had their bedtime injection of NPH insulin. Overnight, patients gave blood samples for measurement of plasma glucose and insulin levels every 30 minutes. Stepped Hypoglycemic Clamp Studies At 8:30 a.m. on the following morning, a variable intravenous infusion of human regular insulin (diluted to 1 U/mL in 2 mL of the patients blood and sodium chloride [NaCl 0.9%] to a final volume of 100 mL) was begun to maintain a plasma glucose level of 5.0 mmol/L (90 mg/dL). Infusion continued until 10:00 a.m. For this procedure, which was done according to a previously described algorithm (22), we used an intravenous syringe pump (Harvard Apparatus, Ealing, South Natick, Massachusetts). At 10:00 a.m., the rate of intravenous insulin infusion was increased to 1 mU/kg 1 min 1 until 2:30 p.m. (270 minutes), followed by 2 mU/kg 1 min 1 for an additional 90 minutes, until 4:00 p.m. (time, 360 minutes). Plasma glucose was clamped by variable glucose infusion at sequential target glucose values of 4.3, 3.7, 3.0, and 2.3 mmol/L (78, 66, 54, and 42 mg/dL); at each target level, blood was drawn to measure hormone and metabolite levels, and patients were assessed for symptoms of hypoglycemia and for cognitive function (23-25). Symptoms were quantified by asking the patients to score (on a scale in which 0 = none and 5 = severe) each of the following symptoms: dizziness, tingling, blurred vision, difficulty in thinking, faintness, anxiety, palpitations, hunger, sweating, irritability, and

Metabolism of Insulin Glargine After Repeated Daily Subcutaneous Injections in Subjects With Type 2 Diabetes

OBJECTIVE To investigate concentration of plasma insulin glargine after its subcutaneous dosing compared with concentration of its metabolites 1 (M1) and 2 (M2) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Nine subjects underwent a 32-h euglycemic glucose clamp study (0.4 units/kg glargine after 1 week of daily glargine administration). Glargine, M1, and M2 were measured by a specific liquid chromatography-tandem mass spectrometry assay. RESULTS Glargine was detected in only five of the nine subjects, at few time points, and at negligible concentrations. M1 was detected in all subjects and exhibited the same pattern as traditional radioimmunoassay-measured plasma insulin. M2 was not detected at all. CONCLUSIONS After subcutaneous injection, glargine was minimally detectable in blood, whereas its metabolite M1 accounted for most (>90%) of the plasma insulin concentration and metabolic action of the injected glargine.

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

OBJECTIVE—The acylated long-acting insulin analog detemir is more lipophilic than human insulin and likely crosses the blood-to-brain barrier more easily than does human insulin. The aim of these studies was to assess the brain/hypothalamus responses to euglycemia and hypoglycemia in humans during intravenous infusion of equipotent doses of detemir and human insulin. RESEARCH DESIGN AND METHODS—Ten normal, nondiabetic subjects (six men, age 36±7 years, and BMI 22.9±2.6 kg/m2) were studied on four occasions at random during intravenous infusion of either detemir or human insulin in euglycemia (plasma glucose 90 mg/dl) or during stepped hypoglycemia (plasma glucose 90, 78, 66, 54, and 42 mg/dl steps). RESULTS—Plasma counterregulatory hormone response to hypoglycemia did not differ between detemir and human insulin. The glycemic thresholds for adrenergic symptoms were higher with detemir (51 ± 7.7 mg/dl) versus human insulin (56 ± 7.8 mg/dl) (P = 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 ± 2.5 vs. 2.4 ± 1.8) and neuroglycopenic (4 ± 3.9 vs. 2.7±2.5) symptoms (score, P < 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 ± 8.1 vs. 47 ± 3.6 mg/dl, P = 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P < 0.05). CONCLUSIONS—Compared with human insulin, responses to hypoglycemia with detemir resulted in higher glycemic thresholds for adrenergic symptoms and greater maximal responses for adrenergic and neuroglycopenic symptoms, with an earlier and greater impairment of cognitive function. Additional studies are needed to establish the effects of detemir on responses to hypoglycemia in subjects with diabetes.

Effect of Oral Amino Acids on Counterregulatory Responses and Cognitive Function During Insulin-Induced Hypoglycemia in Nondiabetic and Type 1 Diabetic People

OBJECTIVE—Amino acids stimulate glucagon responses to hypoglycemia and may be utilized by the brain. The aim of this study was to assess the responses to hypoglycemia in nondiabetic and type 1 diabetic subjects after ingestion of an amino acid mixture. RESEARCH DESIGN AND METHODS—Ten nondiabetic and 10 diabetic type 1 subjects were studied on three different occasions during intravenous insulin (2 mU · kg−1 · min−1) plus variable glucose for 160 min. In two studies, clamped hypoglycemia (47 mg/dl plasma glucose for 40 min) was induced and either oral placebo or an amino acid mixture (42 g) was given at 30 min. In the third study, amino acids were given, but euglycemia was maintained. RESULTS—Plasma glucose and insulin were no different in the hypoglycemia studies with both placebo and amino acids (P > 0.2). After the amino acid mixture, plasma amino acid concentrations increased to levels observed after a mixed meal (2.4 ± 0.13 vs. placebo study 1.7 ± 0.1 mmol/l, P = 0.02). During clamped euglycemia, ingestion of amino acids resulted in transient increases in glucagon concentrations, which returned to basal by the end of the study. During clamped hypoglycemia, glucagon response was sustained and increased more in amino acid studies versus placebo in nondiabetic and diabetic subjects (P < 0.05), but other counter-regulatory hormones and total symptom score were not different. β-OH-butyrate was less suppressed after amino acids (200 ± 15 vs. 93 ± 9 μmol/l, P = 0.01). Among the cognitive tests administered, the following indicated less deterioration after amino acids than placebo: Trail-Making part B, PASAT (Paced Auditory Serial Addition Test) (2 s), digit span forward, Stroop colored words, and verbal memory tests for nondiabetic subjects; and Trail-Making part B, digit span backward, and Stroop color tests for diabetic subjects. CONCLUSIONS—Oral amino acids improve cognitive function in response to hypoglycemia and enhance the response of glucagon in nondiabetic and diabetic subjects.

Short-Term Effects of the Long-Acting Insulin Analog Detemir and Human Insulin on Plasma Levels of Insulin-Like Growth Factor-I and Its Binding Proteins in Humans

OBJECTIVE The objective of the study was to compare responses of plasma levels of IGF-I and IGF binding proteins (IGFBP-1 and IGFBP-3) induced by human regular insulin (HI) and the long-acting insulin analog detemir (IDet) at doses equivalent with respect to the glucose-lowering effect. EXPERIMENTAL DESIGN Ten nondiabetic subjects (six males, four females; age, 36 +/- 7 yr; body mass index, 22.9 +/- 2.6 kg/m(2)) were studied on four randomized occasions with iv infusion of IDet (2 mU/kg . min for 4 h, followed by 4 mU/kg . min for 1 h) or HI (1 mU/kg . min for 4 h, followed by 2 mU/kg . min for 1 h) in euglycemia [plasma glucose (PG), 90 mg/dl] or during stepped hypoglycemia (PG, 90, 78, 66, 54, and 42 mg/dl). RESULTS PG was maintained at preselected plateaus, without any significant difference between IDet and HI (P > 0.2). Plasma insulin concentrations were on average approximately nine times greater with IDet than HI (749 +/- 52 vs. 83 +/- 19 muU/ml, respectively). Plasma IGF-I concentrations did not change from baseline during insulin infusion in euglycemia (IDet, 147 +/- 16 ng/ml; HI, 155 +/- 15 ng/ml) and hypoglycemia (IDet, 163 +/- 14 ng/ml; HI, 165 +/- 14 ng/ml) with no differences between the two insulins (P > 0.2). A similar pattern was observed for plasma IGFBP-3 levels. Insulin infusion resulted in a suppression of plasma IGFBP-1 concentrations with no differences between IDet (baseline, 16.6 +/- 3.8 ng/ml; endpoint, 2.0 +/- 0.6 ng/ml) and HI (baseline, 16.6 +/- 4.1 ng/ml; endpoint, 2.6 +/- 1.4 ng/ml) (P > 0.2) and study conditions (P > 0.2). CONCLUSIONS The greater plasma insulin concentrations obtained with IDet exert effects on plasma levels of IGF-I, IGFBP-1, and IGFBP-3 similar to those of HI. Additional studies are needed to confirm these short-term results in patients with diabetes mellitus on long-term treatment with IDet.

Counterregulatory responses in CSII

Abstract Normally, glucose is the only substrate used by the brain to meet its metabolic requirements. Therefore, a continuous supply of circulatory glucose is a necessary prerequisite for normal cerebral metabolism. Acute hypoglycemia produces several physiological responses, known as counterregulatory, symptomatic and behavioral responses, that aim at preventing further decrease in plasma glucose and thus correct hypoglycemia. Subjects with type 1 diabetes mellitus under intensive insulin treatment either with multiple daily injections (MDI) or with continuous subcutaneous insulin infusion (CSII) exhibit defects in these responses, mainly the adrenaline response, which may increase the recurrence of hypoglycemia in daily life. Unfortunately, recurrence of hypoglycemia [i.e. blood glucose