Lutz Heinemann

Smoking Is Associated With Progression of Diabetic Nephropathy

OBJECTIVE To investigate the association between cigarette smoking and the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS A prospective, follow-up study over one year was conducted in a sequential sample of 34 smokers, 35 nonsmokers, and 24 ex-smokers with type I diabetes, hypertension, and diabetic nephropathy. Progression of renal disease was defined according to the stage of nephropathy as an increase in proteinuria or serum creatinine or a decrease in the glomerular filtration rate. RESULTS Progression of nephropathy was less common in nonsmokers (11%) than in smokers (53%) and patients who had quit smoking (33%), P > 0.001. In a stepwise logistic regression analysis, cigarette pack years, 24-h sodium excretion, and GHb were independent predictive factors for the progression of diabetic nephropathy. Because blood pressure (BP) was well controlled in these patients and most values were within a normotensive range, neither standing, sitting, nor supine BP values were associated with progression of nephropathy. CONCLUSIONS Cigarette smoking represents an important factor associated with progression of nephropathy in treated hypertensive type I diabetic patients.

Variability of Insulin Absorption and Insulin Action

Subcutaneous (s.c.) injections of identical insulin doses may lead to considerable intra- and inter-individual differences in the current metabolic control of patients with diabetes mellitus. This well-known variability of the metabolic effect of insulin hampers practical insulin therapy considerably. The aim of this review is to summarize the knowledge about this topic, with a special focus on the variability of insulin action after pulmonary administration of insulin. A number of studies have been published describing the variability of insulin absorption from the s.c. depot. Only in a few published studies has the variability of insulin action after s.c. administration been quantified. Under controlled experimental conditions s.c. injections of regular insulins result in an intra-individual coefficient of variation (CV) of 15-25% of certain pharmacodynamic summary measures--which characterize the metabolic effect of the applied insulin--in healthy subjects. The inter-individual variability was approximately 10% higher than the intra-individual variability. Subcutaneously injected intermediate- and long-acting insulin preparations were described to have an even greater variability (> 50%) than subcutaneously injected regular insulin. However, in a glucose clamp study s.c. application of NPH insulin led to an intra-individual CV in the range of 12-45% in healthy subjects. The reason for this discrepancy might be that the NPH insulin suspension was sufficiently shaken prior to drawing up the dose. Compared with conventional insulin formulations, rapid- and long-acting insulin analogues appear to have a similar variability, which means that, unfortunately, no considerable advantages in terms of variability were achieved by the invention of these novel insulin preparations. There are no appropriate studies available investigating the variability of the metabolic effect after s.c. insulin administration in patients with diabetes. The inhalation of insulin is a novel form of insulin administration that is currently under clinical development. The variability of the metabolic effect induced by the inhalation of insulin has up to now only been investigated in a small number of (published) studies. In a glucose-clamp study with healthy subjects the inhalation of an identical insulin dose on three study days led to an intra-individual variability that was comparable to that after s.c. injection of regular insulin. In a dose-response study with patients with type 1 diabetes the intra-individual CV was 34% for the area under the curve of the glucose infusion rate for 0-10 h. Studies with patients with type 2 diabetes have shown that the intra-individual CVs were within the range seen after s.c. insulin administration or even lower. In summary, the intra-individual variability of the metabolic effect observed after insulin application, be it subcutaneously injected or be it inhaled, is considerable and, therefore, hampers practical diabetes therapy. To date no means have been found that could lead to a clinically relevant reduction in the variable metabolic effect.

Home Use of an Artificial Beta Cell in Type 1 Diabetes

BACKGROUND The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use. CONCLUSIONS Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).

Time‐action profile of the soluble, fatty acid acylated, long‐acting insulin analogue NN304

Aims To compare the pharmacokinetic and pharmacodynamic properties of subcutaneously injected NN304, a novel long‐acting insulin analogue, to NPH‐insulin during euglycaemic glucose clamps in 11 healthy volunteers.

Time–action Profile of Inhaled Insulin

We compared the pharmacodynamics of insulin after inhalation of 99 U microcrystalline solid insulin and subcutaneous injection of 10 U regular insulin and intravenous injection of 5 U regular insulin. The time–action profiles of the three insulin administrations were studied in 11 healthy volunteers using the euglycaemic glucose clamp technique. The insulins were administered to each volunteer on three separate occasions in random order. Onset of action, assessed as glucose infusion rate, after insulin inhalation was substantially more rapid than after subcutaneous injection and half‐maximal action was reached earlier (31 ± 17 vs 54 ± 12 min; p < 0.001). Maximal metabolic response was reached earlier after insulin inhalation in comparison to subcutaneous injection (108 ± 49 vs 147 ± 53 min; p < 0.001). The maximal glucose infusion rate after inhalation of insulin was lower than after subcutaneous insulin injection (6.2 ± 2.4 vs 9.1 ± 2.5 mg kg−1 min−1; p < 0.001). The glucose infusion rates in the first 60 min after inhalation were significantly greater than after insulin injection (area under the glucose infusion rate curve: 0.23 ± 0.12 vs 0.13 ± 0.08 g kg−1 60 min−1; p < 0.001). However, the total metabolic effect after inhalation was significantly lower than after insulin injection (1.44 ± 0.68 vs 1.90 ± 0.47 g kg−1 360 min−1; p < 0.001). Relative effectiveness of inhaled insulin calculated with regard to the data from the intravenous insulin application was 9.5 ± 4.1 % and of the subcutaneous insulin application was 7.6 ± 2.9 %. With its rapid onset of action, inhaled insulin might have potential for clinical use.

Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients : Using the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin

The time–action profile of the insulin analogue insulin lispro ([Lys(B28), Pro(B29)] human insulin) with its rapid onset and short duration of action might be more suitable to limit hyperglycaemic excursions after a meal rich in rapidly absorbable carbohydrates in comparison to regular human insulin. A randomized, double‐blind study was performed in 10 Type I diabetic patients with good metabolic control (HbA1c 7.0 ± 0.5 %). After a baseline period of 3 h (blood glucose clamped at 6.7 mmol l−1, i.v. insulin infusion of 0.2 mU kg−1 min−1 throughout the study), the patients ate a pizza, drank a cola and had a carbohydrate‐rich dessert (total carbohydrate content 140 g). Immediately before the meal 15.4 ± 3.5 U of either insulin preparation were injected subcutaneously. Blood glucose concentrations were monitored continuously thereafter. Following the injection of insulin lispro the area under the blood glucose curve after the meal was 78 % of that of regular insulin (1.76 ± 0.34 vs 2.26 ± 0.68 mol l−1 *240 min−1; p < 0.01). Maximal blood glucose excursions were higher and were reached later after regular insulin as compared to insulin lispro (11.9 ± 2.8 vs 9.9 ± 1.4 mmol l−1; p < 0.05; 66 ± 37 vs 41 ± 7 min; p < 0.05). Maximal individual differences in the blood glucose excursions (regular human insulin minus insulin lispro) were 4.8 ± 2.2 mmol l−1 (p < 0.0001 against zero) after 110 ± 37 min. In Type I diabetic patients prandial blood glucose excursions after a carbohydrate rich meal were reduced after preprandial injection of insulin lispro in comparison to human regular insulin.

Day and Night Home Closed-Loop Insulin Delivery in Adults With Type 1 Diabetes: Three-Center Randomized Crossover Study

OBJECTIVE To evaluate the feasibility of day and night closed-loop insulin delivery in adults with type 1 diabetes under free-living conditions. RESEARCH DESIGN AND METHODS Seventeen adults with type 1 diabetes on insulin pump therapy (means ± SD age 34 ± 9 years, HbA1c 7.6 ± 0.8%, and duration of diabetes 19 ± 9 years) participated in an open-label multinational three-center crossover study. In a random order, participants underwent two 8-day periods (first day at the clinical research facility followed by 7 days at home) of sensor-augmented insulin pump therapy (SAP) or automated closed-loop insulin delivery. The primary end point was the time when sensor glucose was in target range between 3.9 and 10.0 mmol/L during the 7-day home phase. RESULTS During the home phase, the percentage of time when glucose was in target range was significantly higher during closed-loop compared with SAP (median 75% [interquartile range 61–79] vs. 62% [53–70], P = 0.005). Mean glucose (8.1 vs. 8.8 mmol/L, P = 0.027) and time spent above target (P = 0.013) were lower during closed loop, while time spent below target was comparable (P = 0.339). Increased time in target was observed during both daytime (P = 0.017) and nighttime (P = 0.013). CONCLUSIONS Compared with SAP, 1 week of closed-loop insulin delivery at home reduces mean glucose and increases time in target without increasing the risk of hypoglycemia in adults with relatively well-controlled type 1 diabetes.

Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects

SummarySubcutaneous insulin absorption kinetics were assessed in 50 healthy study subjects (21 female, 29 male; age 26±3 years, BMI 22.5±1.8 kg/m2; mean±SD) during 45 min after periumbilical injection of soluble human U40- or U100-insulin (0.15 IU/kg). Subcutaneous fat thickness was measured by ultrasound, and skin temperature at the injection site was registered. Serum insulin concentrations increased within 30 min from basal values of 37±15 to 140±46 pmol/l after U40-insulin and from 36±10 to 116±37 pmol/l after U100-insulin (p<0.001). After 45 min serum insulin concentrations were 164±43 pmol/l with U40-insulin and 128±35 pmol/l with U100-insulin (p<0.001). Decline in blood glucose levels and suppression of C-peptide were comparable. The serum insulin levels reached 30 and 45 min after U40- and U100-insulin injection were positively correlated with skin temperature (p<0.0008), and negatively correlated with subcutaneous fat thickness (p<0.009). In conclusion, the lower insulin concentration of U40-insulin, higher skin temperature, and a thinner subcutaneous fat tissue at the injection site are associated with accelerated and enhanced subcutaneous insulin absorption.

Insulin Aspart in a 30/70 Premixed Formulation: Pharmacodynamic properties of a rapid-acting insulin analog in stable mixture

OBJECTIVE To study the pharmacodynamic properties of a 30/70 premixed formulation of the rapid-acting insulin analog insulin aspart (B28Asp) and its protamine-retarded preparation (30/70 IA) in comparison with a respective mixture of soluble human insulin and NPH insulin (30/70 HI). RESEARCH DESIGN AND METHODS In this single-center double-blind euglycemic glucose-clamp study, 24 healthy male volunteers (age, 26 ± 2 years; BMI, 23.7 ± 1.7 kg/m2) received single subcutaneous injections of 0.3 U/kg body wt of either 30/70 IA or 30/70 HI on 2 study days in randomized order. Glucose infusion rates (GIRs) were determined over a 24-h period after administration. RESULTS The injection of 30/70 IA resulted in an earlier onset and more pronounced peak of action (tmax, 127 ± 24 min; GIRmax 9.7 ± 2.3 mg · kg−1 · min−1) than 30/70 HI (tmax, 185 ± 52 min; GIRmax, 7.4 ± 1.7 mg · kg−1 · min−1_ (P < 0.001). The metabolic activity of 30/70 IA (measured as the sum of the glucose infused) within the first 4 h after injection was 37% > that of 30/70 HI (P < 0.0001), while the total metabolic potencies over 24 h of both preparations were comparable. CONCLUSIONS The 30/70 premixed formulation of insulin aspart shows a significantly greater metabolic effect in the first 4 h after subcutaneous injection than the 30/70 mixture of human insulin. Insulin aspart retains its pharmacodynamic properties in a premixed 30/70 formulation.

Oral Insulin and Buccal Insulin: A Critical Reappraisal

Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a “tablet” in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical-experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration.