Francesca Porcellati

Meticulous Prevention of Hypoglycemia Normalizes the Glycemic Thresholds and Magnitude of Most of Neuroendocrine Responses to, Symptoms of, and Cognitive Function During Hypoglycemia in Intensively Treated Patients With Short-Term IDDM

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.

Physical Activity and Insulin Sensitivity: The RISC Study

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 < 0.0001). Time spent sedentary, in light activity, and activity intensity was also associated with insulin sensitivity (P < 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 < 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.

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.

Insulin aspart improves meal time glycaemic control in patients with Type 2 diabetes: a randomized, stratified, double-blind and cross-over trial

Aims  This randomized, multi‐centre, double‐blind, stratified, two period, cross‐over trial was undertaken to assess the pharmacokinetics and pharmacodynamics of insulin aspart injected immediately before compared with regular human insulin injected 30 min before a Mediterranean‐style meal in 37 (23 M, 14 F) patients with Type 2 diabetes.

Insulin therapy and hypoglycaemia: the size of the problem.

Hypoglycaemia is a fact of life for people with diabetes mellitus. Mild, asymptomatic episodes occur once or twice a week in insulin‐treated diabetic subjects. Asymptomatic hypoglycaemia, including nocturnal hypoglycaemia, occurs in about 25% of diabetic subjects treated with insulin therapy. Mild hypoglycaemia, if recurrent, induces unawareness of hypoglycaemia and impairs glucose counterregulation, which in turn predisposes to severe hypoglycaemia. Even brief hypoglycaemia can cause profound dysfunction of the brain. Prolonged, severe hypoglycaemia can cause permanent neurological sequels. In addition, it is possible that hypoglycaemia may accelerate the vascular complications of diabetes by increasing platelet aggregation and/or fibrinogen formation. Finally, hypoglycaemia may be fatal.

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

Pharmacokinetics and Pharmacodynamics of Therapeutic Doses of Basal Insulins NPH, Glargine, and Detemir After 1 Week of Daily Administration at Bedtime in Type 2 Diabetic Subjects: A randomized cross-over study

OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of NPH, glargine, and detemir insulins in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS This 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. RESULTS The 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. CONCLUSIONS Compared with NPH and detemir, glargine provided greater metabolic activity and superior glucose control for up to 32 h.

Prevention of Hypoglycemia While Achieving Good Glycemic Control in Type 1 Diabetes: The role of insulin analogs

Insulin therapy in diabetes, both at onset and after several years’ duration, is primarily directed to maintain near-normoglycemia to prevent the onset and/or delay progression of long-term complications (1,2). However, it is important that regimens of insulin therapy are designed not only to aim at near-normalizing blood glucose, but also to minimize the risk of hypoglycemia. Subjects with type 1 diabetes continuously drift between hyperglycemia and hypoglycemia. If the former prevails, long-term complications are frequently expected (1). On the other hand, hypoglycemia is not only dangerous and unpleasant, but may over time lead to the syndrome of hypoglycemia unawareness (3). This is relevant in type 1 diabetes but also in type 2 diabetes, since over time, many type 2 diabetic subjects develop progressive pancreatic β-cell dysfunction requiring insulin therapy. Because in subjects with advanced type 2 diabetes the neuroendocrine responses to hypoglycemia are as abnormal as in type 1 diabetic patients (4), insulin therapy may become responsible for frequent and/or severe hypoglycemia in type 2 diabetic patients as well. The goal of minimizing the risk of hypoglycemia while achieving good glycemic control is feasible as long as 1 ) a rational plan of insulin therapy is adopted, 2 ) blood glucose is properly monitored, 3 ) blood glucose targets are individualized, and 4 ) education programs are widely implemented. In the present article, the importance of the use of insulin analogs as a key tool to achieve good glycemic control and prevent hypoglycemia is emphasized. Normal nondiabetic subjects maintain plasma glucose <100 mg/dl in the fasting and <135 mg/dl in the postprandial period. In the fasting state, this is due to the continuous release of insulin from the pancreas, which results in steady plasma insulin, thus restraining hepatic glucose production and thereby preventing fasting hyperglycemia. At mealtime, the normal pancreas releases …