Insulin glulisine has a faster onset of action compared with insulin aspart in healthy volunteers.

AIM: Because of its zinc-free formulation insulin glulisine (GLU) might have a faster onset of action than other short-acting analogues. We compared the pharmacokinetics and pharmacodynamics of GLU with those of insulin aspart (ASP). METHODS: Twelve healthy subjects, aged 18-65 years, participated in this randomized, double-blind, crossover trial. Subjects received 0.2 U/kg GLU or ASP under euglycaemic glucose-clamp conditions. RESULTS: GLU showed a significantly higher early metabolic effect (area under the glucose infusion rate (GIR) curve in the first 30 min AUC-GIR (0-)30↓ min 30.3 ± 26.4 vs. 16.2 ± 18.4 mg/kg, P = 0.0421) than ASP, an earlier onset of action (time to 10% of GIR (max) (GIR (max)-t (10%)) 9 vs. 17 min, P = 0.0146) and a faster absorption (shorter times to 10% and 20% of INS (max,) P = 0.0005 each). CONCLUSIONS: As demonstrated previously versus lispro, GLU, the only analogue formulated without zinc, also has an earlier onset of action than ASP.

Pharmacokinetics and linear exposure of AFRESA compared with the subcutaneous injection of regular human insulin.

AIM: AFRESA [Technosphere Insulin (TI); MannKind Corporation, Valencia, CA], a dry powder preparation of regular human insulin (RHI), utilizes a novel and versatile drug carrier platform that enables pulmonary administration of medications typically administered by injection. The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of three different inhaled doses of TI with those of subcutaneous (s.c.) RHI. METHODS: This randomized, open-label, four-way crossover study of 11 healthy, non-smoking volunteers evaluated PK and PD profiles following single inhalations of 25, 50 or 100 U TI and 10 IU RHI administered subcutaneously using a euglycaemic clamp technique. RESULTS: Following inhalation of TI, peak insulin concentrations (C(max)) were achieved approximately 2 h earlier than with RHI (12-17 min for TI vs. 134 min for RHI). Area under the insulin concentration-time curve (AUC) and insulin C(max) values increased with increasing TI dose. Insulin exposure, as measured by AUC, was found to be linear over the dose range studied. Compared with s.c. RHI, TI at doses of 25, 50 and 100 U showed a relative bioavailability of 25, 23 and 21%, respectively. The maximum bioeffect, as measured by the glucose infusion rate, occurred approximately 2 h earlier for all three TI doses (42, 50 and 58 min, respectively) than for s.c. RHI (171 min). No treatment-related adverse events were reported with TI. CONCLUSION: TI is an inhaled insulin with a more rapid absorption and a more rapid elimination than subcutaneously administered RHI, resulting in a quick onset and short duration of action. Insulin exposure following TI administration was found to be linear over the dose range of 25-100 U.

Renal glucose excretion and tubular reabsorption rate related to blood glucose in subjects with type 2 diabetes with a critical reappraisal of the "renal glucose threshold" model.

Until today a "renal threshold for glucose" is described in most medical textbooks. Notwithstanding, low glucose levels are detectable in urine even under euglycaemic conditions - a phenomenon which was observed already in 1904 and labelled as "basal glucosuria". We aimed to characterise renal glucose transport during various steady-state blood glucose levels. Twenty-two subjects with type 2 diabetes and normal renal function underwent two 5-period hyperglycaemic glucose-clamps with blood glucose target levels between 7.8 and 13.3 mmol x l(-1). A virtual renal threshold for glucose excretion (VRT (G)) was calculated for every subject as the highest blood glucose concentration during the glucose-clamps associated with a concomitant urinary glucose level of <2.8 mmol x l(-1). VRT (G) of subjects was classified as low, medium, and high. Each urine sample contained a detectable amount of glucose with a minimal urinary glucose concentration of 0.73 mmol x l(-1). Median VRT (G) was 11.0 mmol x l(-1), ranging from 7.8 and 12.1 mmol x l(-1). With increasing blood glucose renal glucose excretion increased in each subject - but varied considerably between subjects. For example, at a blood glucose concentration of 11 mmol x l(-1) renal glucose excretion ranged from 163 micromol x min(-1) to 25 micromol x min(-1) in subjects exhibiting a low to high VRT (G), thus showing a variability >factor 6. This study reinforces the rejection of the concept of a renal threshold for glucose. Instead, this study shows a substantial variability of renal glucose excretion between subjects with type 2 diabetes.

PROMAXX inhaled insulin: safe and efficacious administration with a commercially available dry powder inhaler.

OBJECTIVES: We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) properties of recombinant human insulin inhalation powder (RHIIP), manufactured with PROMAXX technology, which allows formation of uniform protein microspheres. METHODS: Thirty healthy male subjects [age 30 +/- 1 years (mean +/- s.e.), body mass index 24.2 +/- 0.3 kg/m(2)] in a randomized crossover study received 10 IU subcutaneous regular human insulin (SCIns) and 6.5 mg of RHIIP [187 IU, Cyclohaler dry powder inhaler (DPI)] under euglycaemic glucose clamp conditions. Subjects were trained to inhale RHIIP with a flow rate of 90 +/- 30 l/min prior to dosing. RESULTS: Inhalation of RHIIP was well tolerated with no episode of cough or shortness of breath. RHIIP showed a faster onset of action than SCIns [time to reach 10% of total area under the glucose infusion rate (GIR) curves 73 +/- 2 vs. 95 +/- 3 min, time to maximal metabolic effect (T(max)GIR) 173 +/- 13 vs. 218 +/- 9 min, both p < 0.0001]. Duration of action (371 +/- 11 vs. 366 +/- 7 min) and total metabolic effect (AUCGIR0-10 h 2734 +/- 274 vs. 2482 +/- 155 mg/kg) were comparable. PK results were in accordance with the PD findings. Relative bioavailability (BA) of RHIIP was 12 +/- 2%, and relative biopotency (BP) was 6 +/- 1%. CONCLUSIONS: PROMAXX technology allowed for safe and efficacious administration of RHIIP to the deep lung with an off-the-shelf DPI. RHIIP showed a fast onset of action and BA/BP comparable to that reported for other inhaled insulin formulations using specifically designed inhalers. Improvements in the insulin delivery technique might allow to optimize drug application in all cases with even higher BA/BP with RHIIP.

Fluctuation and reproducibility of exposure and effect of insulin glargine in healthy subjects.

AIM: Low diurnal fluctuation and high day-to-day reproducibility in exposure and effect characterize beneficial basal insulin products. Two insulin glargine (LANTUS) formulations [without (R) or with polysorbate-20 (T)], added to minimize unfolding of proteins and subsequent formation of fibril structures, were assessed for equivalence in exposure and effect, and aspects of fluctuation and reproducibility in time-concentration and time-action profiles. METHODS: A dose of 0.4 U/kg was subcutaneously administered to 24 healthy subjects in a two-sequence (R-T-R-T or T-R-T-R), randomized, four-way crossover trial utilizing 30-h Biostator-based euglycaemic glucose clamps. RESULTS: Identical serum insulin glargine concentration and time-action profiles established average, individual and population equivalence in insulin exposure and effect. Point estimates for 24-h area under the curve for insulin (INS-AUC(0-24) (h)) and glucose infusion rates (GIR-AUC(0-24) (h)) were 97% [90% confidence interval (CI): 91-103%] and 100% (88-114%), respectively. Within-subject variability (coefficient of variation) for INS-AUC(0-24) (h) and GIR-AUC(0-24) (h) were 19% (95% CI: 14-25%) and 34% (24-43%), respectively. The diurnal relative fluctuation of the serum insulin glargine concentration was 20% (95% CI: 19-21%). CONCLUSION: Insulin glargine in either formulation presents with a high day-to-day reproducibility of a uniform release after injection enabling an effective basal insulin supplementation.

Inhaled micronized crystalline human insulin using a dry powder inhaler: dose-response and time-action profiles.

AIM: The aim of this euglycaemic glucose clamp study was to investigate the pharmacokinetics, glucodynamics, safety and tolerability of micronized crystalline human insulin inhalation powder delivered by a Spiros dry powder inhaler system in healthy volunteers. METHODS: Thirteen healthy, non-smoking, male and female volunteers [age 30 +/- 7 years; BMI 23.5 +/- 2.7 kg/m(2); (mean +/- sd)] with normal pulmonary function participated in an open-label, randomised, 6-period crossover trial. Each volunteer received four single doses of inhaled insulin (60, 90, 120, 150 U) on separate occasions. For comparison, each volunteer also received two of three possible doses of subcutaneous (s.c.) injected regular human insulin (8, 14, or 20 U). RESULTS: Serum immunoreactive insulin following inhalation of insulin peaked an average of 60 min earlier compared with s.c. injected insulin (P < 0.0001). Following inhalation, the time to maximum glucose infusion rate occurred an average of 70 min earlier than with s.c. insulin: 187, 129, 161 and 162 min vs. 227, 241 and 241 min (P < 0.0001). The dose-response relationships for serum insulin pharmacokinetics and glucodynamics were linear for both inhaled and s.c. insulin. Relative bioavailability (based on serum insulin levels) ranged from 11.5 to 12.2% for the four doses of inhaled insulin and relative biopotency (based on glucose infusion rates) was 10.0 to 16.5%, respectively. Dosing was well tolerated by all volunteers. CONCLUSION: This study demonstrates that inhalation of human insulin via a dry powder inhaler system provides a promising alternative route for administration of insulin.

Dependency of the metabolic effect of sc-injected human regular insulin on intra-abdominal fat in patients with type 2 diabetes.

Ten patients with type 2 diabetes were enrolled in an isoglycemic glucose clamp study to determine the impact of intra-abdominal fat, subcutaneous abdominal fat and total abdominal fat on the metabolic effect of a single bolus (0.2 IU/kg) of sc-injected human regular insulin. The maximum metabolic effect associated highly and negatively with intra-abdominal fat (r = - 0.72, p < 0.02) and with the homeostasis model assessment insulin resistance score (HOMA, r = - 0.71, p < 0.03). Likewise, the total metabolic effect of sc-injected insulin correlated strongly and negatively with intra-abdominal fat (r = - 0.77, p < 0.01), HOMA (r = - 0.74, p < 0.02) and HbA (1c) (r = - 0.70, p < 0.03). Stepwise multiple regression analyses showed that the highest metabolic effect was only significantly predicted by intra-abdominal fat, indicating a high negative correlation with the maximum effect (beta = - 0.72) whereas time to maximum metabolic effect showed a strong (beta = 0.72) and positive correlation with HOMA. In combination with the HOMA, it is intra-abdominal fat, and not subcutaneous abdominal fat, which explains 50 - 75 % of the variability of the effect of sc human regular insulin in patients with type 2 diabetes.

No evidence for accumulation of insulin glargine (LANTUS): a multiple injection study in patients with Type 1 diabetes.

AIMS: Insulin glargine is a long-acting insulin analogue that is metabolically active for at least 24 h. We investigated the multiple-dose pharmacokinetic properties of insulin glargine to determine whether daily injections lead to the accumulation of circulating insulin levels and a corresponding decrease in blood glucose levels in patients with Type 1 diabetes. METHODS: Fifteen patients using preprandial insulin lispro (mean age 36 +/- 9 years, body mass index 24.6 +/- 2.2 kg/m(2)) completed the study. Each patient's optimal insulin glargine dose was determined during a dose-finding phase. After a washout period, patients were treated over 12 days with a constant daily dose of insulin glargine injected in the abdominal subcutaneous adipose tissue at 22:00 h, and with preprandial insulin lispro. Free serum insulin (FSI) and blood glucose concentrations were assessed hourly after the first, fourth, and eleventh injection, after which patients fasted for 24 h and did not use any other insulin preparation. RESULTS: There were no changes in daily insulin doses during the dose-finding phase (insulin glargine: initial dose 24 +/- 6 IU, mean change 0 +/- 3 IU; insulin lispro: 18 +/- 9 IU, 0 +/- 7 IU). The time course of FSI was comparable on the three pharmacokinetic study days. Notably, the trough FSI at the end of the sampling periods was almost identical (day 1, 79 +/- 56 pmol/l, day 4, 77 +/- 56 pmol/l, day 11, 86 +/- 60 pmol/l). No changes occurred in any of the pharmacokinetic parameters studied. CONCLUSIONS: There is no evidence that insulin glargine accumulates after multiple injections over 12 days. These results indicate that the predetermined dose of insulin glargine will not need to be reduced after commencing treatment because of a risk of accumulation.

Technosphere/Insulin--proof of concept study with a new insulin formulation for pulmonary delivery.

Summary.Technosphere/Insulin (TI) is a formulation of regular human insulin and Technosphere, a new drug delivery system for pulmonary administration. The formulation is designed for efficient transport of insulin across the intact respiratory epithelium into the systemic circulation. We have investigated the pharmacodynamic and pharmacokinetic properties of Technosphere/Insulin in five healthy, non-smoking volunteers. In an open, randomized, three-way crossover study, subjects received 5 IU regular human insulin (HI) intravenously, 10 IU HI subcutaneously; and 100 IU TI via inhalation using a small commercially available asthma inhaler. The time action profiles of all three insulin formulations were assessed by the euglycemic glucose clamp technique on three different study days. Glucose infusion rates were monitored from 2 h before until 6 h after insulin administration. Other study measures were serum insulin, serum C-peptide concentrations, and safety parameters. The inhalation of TI was well tolerated. The time to peak action was significantly shorter with both i.v. injection and inhalation, as compared to s.c. (14 +/- 6 min and 39 +/- 36 min vs. 163 +/- 25 min; p < 0.0002 and p < 0.007 (mean +/- SD)). The metabolic effect during the first 3 h after insulin administration was higher with inhaled TI than with HI s.c. (AUC0-180 for glucose infusion rate: 1.94 +/- 0.77 mg/kg * min vs. 1.15 +/- 0.50 mg/kg * min; p < 0.04). Relative and absolute bioavailability for the first 3 h were 26 +/- 12% and 15 +/- 5% respectively (6 h: 16 +/- 8 and 16 +/- 6%). We conclude that inhalation of TI leads to a rapid onset of metabolic action resembling the effect observed with i.v. administration of regular HI. Despite the use of a common asthma inhaler, bioavailability over the three hour prandial period was substantially greater than with other reported pulmonary systems. Therefore, inhalation of Technosphere/Insulin may become a suitable and attractive alternative for prandial insulin delivery, especially for patients with type 2 diabetes mellitus.

Impact of diabetic nephropathy on pharmacodynamic and Pharmacokinetic properties of insulin in type 1 diabetic patients.

OBJECTIVE: To quantify pharmacokinetic and pharmacodynamic properties of regular insulin and insulin lispro in type 1 diabetic patients with and without overt diabetic nephropathy. RESEARCH DESIGN AND METHODS: In this double-blind, two-way cross-over, euglycemic (5 mmol/l) glucose clamp study, we investigated the metabolic response to subcutaneous injections of regular insulin and insulin lispro (0.2 U/kg) in 12 type 1 diabetic patients with overt diabetic nephropathy (proteinuria >500 mg/24 h and/or serum creatinine >1.5 mg/dl; NP group) and in a control group of 12 type 1 diabetic patients with normal renal function (DC group). RESULTS: Peak plasma free insulin levels with insulin lispro (359 [NP] vs. 254 pmol/l [DC]) were higher and time to maximal insulin concentrations (85 [NP] vs. 99 min [DC]) shorter than with regular insulin (213 [NP] vs. 144 pmol/l [DC]; 118 [NP] vs. 153 min [DC]) in both patient groups. Overall insulin levels for regular insulin and for insulin lispro were higher in patients with overt diabetic nephropathy compared with control patients. Time to maximal metabolic effect was shorter with insulin lispro than with regular insulin in both patient groups (102 vs. 191 min [NP]; 105 vs. 172 min [DC]). The overall metabolic effect of regular insulin but not of insulin lispro was lower in patients with diabetic nephropathy than in diabetic control patients (967 vs. 1,510 mg/kg, respectively). CONCLUSIONS: Although insulin levels are higher in patients with overt diabetic nephropathy, the metabolic response to regular insulin is reduced. Insulin lispro maintains its characteristic pharmacokinetic and pharmacodynamic properties in patients with overt diabetic nephropathy.

Intra-individual variability of the metabolic effect of inhaled insulin together with an absorption enhancer.

OBJECTIVE: To study the metabolic effect and the variability of the effect elicited by inhalation of 87.2 U insulin powder combined with an absorption enhancer. The metabolic effect was compared with that of 10.2 U regular insulin injected subcutaneously and of 5.5 U regular insulin given intravenously RESEARCH DESIGN AND METHODS: In this single-center open euglycemic glucose clamp study 13 healthy male volunteers received 5 insulin administrations on separate study days: once as an intravenous dose, once as a subcutaneous injection, and 3 times by inhalation, in randomized order. Glucose infusion rates (GIRs) necessary to keep blood glucose concentrations constant at 5.0 mmol/l were determined over an 8-h period after administration. RESULTS: After inhalation of the insulin powder aerosol, the onset of action was substantially more rapid than after subcutaneous insulin injection, and maximal action was reached earlier (86+/-47 vs. 182+/-53 min, P<0.0001). The maximal glucose infusion rate after inhalation of insulin was comparable to that after subcutaneous insulin injection (9.2+/-2.6 vs. 8.8+/-2.8 mg x kg(-1) x min(-1), NS). The metabolic effect in the first 2 h after inhalation was significantly greater than that after subcutaneous insulin injection (amount of glucose infused: 0.88+/-0.25 vs. 0.59+/-0.20 g x kg(-1) x 120 min(-1), P<0.0001). However, the total metabolic effect after inhalation and subcutaneous injection was comparable (2.50+/-0.76 vs. 2.56+/-0.69 g x kg(-1) x 480 min(-1), NS). The relative bioefficacy of inhaled insulin calculated in relation to the data from the subcutaneous insulin application was 12.0+/-3.5% (absolute bioefficacy 10.1+/-3.1%) but was highest in the first 2 h after application (18.5+/-3.7%; absolute bioefficacy 8.2+/-4.1%). The intraindividual variability of the metabolic response induced by insulin inhalation was 14+/-9% for the maximal glucose infusion rate, 15+/-10% for the time-to-maximal effect, and 16+/-12% for the total amount of glucose infused. CONCLUSIONS: This feasibility study shows that inhaled insulin with an absorption enhancer has a pronounced metabolic effect compared with the results of a previous study of inhaled insulin without an enhancer. The intraindividual variability of the metabolic effect was comparable with that of inhaled and subcutaneously injected insulin.

A cross-over evaluation of different methods and devices to measure blood pressure in type 1 diabetic patients with nephropathy.

BACKGROUND: In type 1 diabetic patients with nephropathy, tight blood pressure control has been shown to prevent the progression of the disease. Up until now, self-monitoring, ambulatory and office blood pressure values have not been compared in these patients. Thus, we have evaluated blood pressure values obtained in the office by a physician and at home by self-monitoring with those measured under ambulatory conditions in these patients. Additionally, for blood pressure self-monitoring, three different devices (the sphygmomanometer, upper-arm oscillometer and wrist oscillometer) were compared. METHODS: Twenty-one treated hypertensive type 1 diabetic patients [age 45+/-9 years, duration of diabetes 33+/-12 years (mean+/-SD)] with overt diabetic nephropathy participated in this study. At both baseline and the end of the study, daytime ambulatory blood pressure measurement was performed. Office blood pressure was measured at baseline. Additionally, all the patients measured their blood pressure over a 3-week period using each of the three different devices, in random order, for 1 week. RESULTS: The mean office blood pressure values (135+/-21/85+/-12mmHg) were higher than both the ambulatory (131+/-23/80+/-12, P<0.05) and self-monitoring values (130+/-14/78+/-10; P<0.05 for systolic and P<0.02 for diastolic values). The difference between the ambulatory and self-monitoring values were not statistically significant. Diastolic blood pressure values measured with the oscillometric wrist device showed a trend towards higher values when compared to those measured with the sphygmomanometer and with the oscillometric upper-arm device (P=0.065 for diastolic values). CONCLUSION: Office blood pressure measurements may over-estimate blood pressure in patients with type 1 diabetes and diabetic nephropathy. Because the oscillometric wrist device tends to over-estimate diastolic values, upper-arm devices should be preferred for blood pressure self-monitoring in these patients.

Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo.

OBJECTIVE: To study the pharmacodynamic properties of the subcutaneously injected long-acting insulin analog HOE901 (30 microg/ml zinc) in comparison with those of NPH insulin and placebo. RESEARCH DESIGN AND METHODS: In this single-center double-blind euglycemic glucose clamp study, 15 healthy male volunteers (aged 27 +/- 4 years, BMI 22.2 +/- 1.8 kg/m2) received single subcutaneous injections of 0.4 U/kg body wt of HOE901, NPH insulin, or placebo on 3 study days in a randomized order. The necessary glucose infusion rates (GIRs) to keep blood glucose concentrations constant at 5.0 mmol/l were determined over a 30-h period after administration. RESULTS: The injection of HOE901 did not induce the pronounced peak in metabolic activity observed with NPH insulin (GIRmax 5.3 +/- 1.1 vs. 7.7 +/- 1.3 mg x kg(-1) x min(-1)) (P < 0.05); after an initial rise, metabolic activity was rather constant over the study period. This lack of peak was confirmed by a lower glucose consumption in the first 4 h after injection (area under the curve from 0 to 4 h [AUC(0-4 h)] 1.02 +/- 0.34 vs. 1.48 +/- 0.34 g/kg) (P < 0.001) with HOE901, as compared with NPH insulin. In this single-dose study, the metabolic effect measured over a period of 30 h was lower with HOE901 than with NPH insulin (AUC(0-30 h) 7.93 +/- 1.82 vs. 9.24 +/- 1.29 g/kg) (P < 0.05). CONCLUSIONS: This study shows that the soluble long-acting insulin analog HOE901 induces a smoother metabolic effect than NPH insulin, from which a better substitution of basal insulin requirements may follow.

Noninvasive glucose measurement by monitoring of scattering coefficient during oral glucose tolerance tests. Non-Invasive Task Force.

BACKGROUND: Continuous glucose monitoring by means of optical glucose sensors would allow patients with diabetes to check their metabolic control to their convenience. In an earlier study, we showed that noninvasive glucose monitoring is feasible for rapid changes in blood glucose by means of measuring the scattering coefficient of human skin. In this study, we investigated whether also slower changes in blood glucose, this time induced by an oral glucose load, can also be monitored by this approach. METHODS: Five healthy subjects and 13 patients with type 2 diabetes have been given a 75-g oral glucose load. Portable noninvasive systems were used to measure the skin tissue scattering coefficient. For this purpose, two optical sensor heads were attached directly to the skin of each volunteer. Light was applied to the skin and the reflected light intensity was registered. RESULTS: In 8 of 10 measurements, correlation of changes in scattering coefficient with changes in glycemia was acceptable. In 19 of 26 measurements (73%) of patients with type 2 diabetes the observed changes in the scattering coefficient also correlated in acceptable manner. The accordance between the simultaneous measurements of the two sensor heads was acceptable in 13 of 18 volunteers and patients studied. There were virtually no differences in the quality of the measurements between healthy volunteers and patients with diabetes. CONCLUSIONS: This study shows that also slow changes in blood glucose induced by an oral glucose load can be monitored by registration of scattering coefficient changes. It remains to be elucidated why this has not been possible in all experiments.

Lack of effects of the beta3-adrenoreceptor agonist UL-TG 307 on insulin sensitivity and insulin secretion in Type 2 diabetic patients.

The effects of a novel beta3-adrenoreceptor agonist, UL-TG 307, on insulin sensitivity and insulin secretion, lipid metabolism, and body weight were investigated. Thirteen diet treated male Type 2 diabetic patients participated in a randomized, double-blind, placebo controlled cross-over trial with two 14 day administration periods with placebo and UL-TG 307 (24 mg daily). After each administration period insulin secretion was assessed by means of an OGTT and insulin sensitivity was measured by an hyperinsulinaemic euglycaemic glucose clamp. Lipid metabolism was evaluated by measuring non-esterified fatty acid, glycerol, and triglyceride serum concentrations at the end of each administration period. Treatment with UL-TG 307 did not improve insulin sensitivity (insulin sensitivity index (S(I)): UL-TG 307 2.5 -/+ 0.6 (mean +/- SD) vs. placebo 2.2 +/- 0.8 ml/min*m2 per microU/ml) nor increased insulin secretion (area under the serum insulin profile AUC0-240/plasma glucose AUC0-240: UL-TG 307 8.8 +/- 7.4 vs. placebo 8.3 +/- 6.4 microU/ ml/mmol/l). No differences in lipid metabolism, metabolic control, and body weight were observed. We conclude that two weeks' administration of the beta3-adrenoreceptor agonist UL-TG 307 in a daily dose of 24 mg did not lead to any significant effect in diet treated type 2 diabetic patients.

Measurement of insulin sensitivity: influence of potassium supply during euglycaemic glucose clamps in healthy volunteers.

Insulin sensitivity can be quantitatively measured by the hyperinsulinaemic euglycaemic glucose clamp technique. Infusion of insulin during the clamp procedure leads to a decline of kalaemia unless potassium is supplied. We investigated whether supplementation of potassium during euglycaemic glucose clamps influences insulin sensitivity. In a randomised study the insulin sensitivity index (S(I)) was determined with two-step hyperinsulinaemic (insulin infusion rates 0.25 (step 1) and 1.0 mU kg(-1) min(-1) (step 2)) euglycaemic (5.0 mmol L(-1)) glucose clamps in 20 healthy male volunteers on two different study days. On one day blood potassium was kept constant by means of a variable i.v. potassium chloride infusion ("eukalaemic potassium clamp"), whereas on the other day the decline in blood potassium was monitored only. Without potassium supply kalaemia decreased from basal levels of 4.35 +/- 0.18 mval L(-1) to 4.25 +/- 0.17 (step 1) and further to 3.88 +/-0.14 mval L(-1) (step 2 (mean +/- SD)). Without and with potassium supply the insulin sensitivity index measured was comparable (S1 10.6 +/- 3.6 vs. 9.5 +/- 3.5 ml min(-1) m2 per microU ml(-1), n.s.; glucose infusion rates 3.6+/-1.6/12.6 +/- 2.6 (step 1/step 2) vs. 3.7 +/- 1.5/12.2 +/- 2.7 mg kg(-1) min(-1), n.s.). In conclusion, this study shows that potassium supply during hyperinsulinaemic euglycaemic glucose clamps in healthy subjects does not influence the insulin sensitivity index.

Value of blood pressure self-monitoring as a predictor of progression of diabetic nephropathy.

OBJECTIVE: To determine the impact of self-monitoring of blood pressure values (BP(S)) as compared with office blood pressure measurements (BP(O)) on the progression of diabetic nephropathy. DESIGN: Long-term, follow-up cohort study. SUBJECTS AND METHODS: Hypertensive, type 1 diabetic patients with overt diabetic nephropathy were investigated. Patients initially participated in a hypertension treatment and teaching programme including extensive advice on blood pressure self-monitoring. Self-monitoring and office blood pressure values were continuously assessed during the entire follow-up period. Progression of diabetic nephropathy over the study period was individually assessed as the mean decline of glomerular filtration rate (GFR) per patient per year. Baseline and follow-up parameters were included in stepwise multiple regression analyses with the decline of GFR per year as the dependent variable. RESULTS: Seventy-seven type 1 diabetic patients (37 women, 40 men) were followed for a mean period of 6.2 +/- 2.8 years (mean +/- SD; range 2-12) resulting in a total of 481 patient-years. During the follow-up period, mean BP(O) decreased from 166/95 at baseline to 154/89 mmHg during follow-up, and mean BP(S) fell from 159/93 to 138/83 mmHg. The mean decline of GFR was 4.1 +/- 5.6 ml/min per year. Loss of kidney function was significantly correlated with proteinuria, blood pressure and glycosylated haemoglobin values. In the multiple regression analyses, BP(S) predicted the loss of renal function better than BP(O) (R2 = 0.52 versus 0.42). The simple correlation between BP(S) and GFR decline was higher compared to BP(O) and GFR (r = -0.42; P < 0.0001 versus -0.33; P < 0.004). CONCLUSION: Blood pressure self-monitoring values are a better predictor of progression of diabetic nephropathy when compared with office blood pressure measurements.