Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus.

AIMS: To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled intravenous glucose tolerance test. RESULTS: The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. CONCLUSIONS: Fourteen weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycaemia.

Insulin detemir lowers the risk of hypoglycaemia and provides more consistent plasma glucose levels compared with NPH insulin in Type 1 diabetes.

AIMS: Hypoglycaemia remains a major barrier preventing optimal glycaemic control in Type 1 diabetes due to the limitations of conventional insulin preparations. We investigated whether basal-bolus therapy with insulin detemir (detemir), a new soluble basal insulin analogue, was more effective in reducing the risk of hypoglycaemia compared with NPH insulin (NPH). METHODS: In this multinational, open-label, cross-over trial, 130 individuals with Type 1 diabetes received detemir and NPH twice daily in a randomized order in combination with premeal insulin aspart (IAsp) during two 16-week treatment periods. Risk of hypoglycaemia was based on self-measured plasma glucose (SMPG) and self-reported episodes during the last 10 weeks of each period. RESULTS: Risk of nocturnal and overall hypoglycaemia was, respectively, 50% and 18% lower with detemir than with NPH (P < 0.001). A total of 19 severe hypoglycaemic episodes occurred during treatment with detemir compared with 33 with NPH (NS). HbA(1c) decreased by 0.3% point with both treatments and was comparable at 7.6% (+/- sem 0.06%, 95% confidence interval -0.106, 0.108) after 16 weeks with similar doses of basal insulin. Within-person variation in mean plasma glucose was lower with detemir than with NPH (sd 3.00 vs. 3.33, P < 0.001), as was prebreakfast SMPG (P < 0.0001). CONCLUSIONS: Detemir was associated with a significantly lower risk of hypoglycaemia compared with NPH at similar HbA1c when used in combination with mealtime IAsp. The more consistent plasma glucose levels observed with detemir may allow people to aim for tighter glycaemic control without an increased risk of hypoglycaemia.

Clinical experience with NovoPen II and insulin Protaphane HM Penfill.

The acceptance and convenience of an intermediate acting insulin Protaphane HM in Penfill were evaluated and compared with vials, and the safety of administration in Penfill was tested in 19 insulin-dependent diabetes mellitus patients. The design was a randomized, cross-over within-patient comparison with a run-in period of 4 weeks and two 12-week study periods. Safety was assessed by 7 point blood glucose profiles, HbA1c, total insulin dosage and frequency of hypoglycaemic episodes. Acceptance and convenience were evaluated by a questionnaire. None of the differences was statistically significant. Seventeen out of the 19 patients found NovoPen easier and quicker to use than conventional syringes and needles. The acceptance of a new pen device, NovoPen II, was tested in 56 insulin-dependent diabetes mellitus patients. Fifty-two out of 55 patients who completed a questionnaire preferred to continue with NovoPen II and 51 found it easy to preselect the dose. In conclusion, insulin Protaphane HM in Penfill can be safely administered with the NovoPen system.

The effect of alprenolol on serum myoglobin levels in acute myocardial infarction.

In a group of 37 patients with definite acute myocardial infarction (AMI) allocated to treatment with either alprenolol (n = 20) or placebo (n = 17) serial determinations of concentrations in serum of myoglobin (S-Mb), creatine kinase (S-CK), aspartate aminotransferase (S-ASAT) and lactate dehydrogenase (S-LDH) were performed. The median peak levels of S-Mb, S-CK and S-LDH were significantly (P less than 0.05) lower among patients treated with alprenolol. The median of the estimated infarct size based on S-CK curves was also significantly (P less than 0.01) lower in the alprenolol group. There was no significant difference between the estimated infarct size based on S-Mb values in the two groups. It is concluded that the present study provides indirect evidence for the assumption that early beta-blockade in AMI can reduce infarct size.

Subcutaneous measurements of 133Xe disappearance with portable CdTe(Cl) detectors: elimination of interference from combined convection and diffusion.

Portable, solid state, cadmium telluride [CdTe(C1)] detectors were used for measurements of 133Xe-disappearance rate constants as a measure of subcutaneous (s.c.) blood flow. To eliminate the disturbance on the measurements from combined local convection and diffusion of xenon in the s.c. tissue, two methods were demonstrated to be feasible in both control persons and anaesthetized rabbits. A small volume (50-80 microliters) was injected into the s.c. tissue at a depth of 5 mm and the CdTe(C1) detector elevated 20 mm above the skin surface. In this situation identical disappearance rate constants were recorded by the CdTe(C1) detector and the NaI(T1) reference detector at 15-20 cm from the depot. Similiar results were obtained when either a large volume (greater than or equal to 800 microliters of Xe in humans) was injected into the s.c. tissue or the labelling was performed with a smaller volume in an atraumatic uniform manner to obtain a constant Xe concentration exceeding the field of view of the CdTe(C1) detector, which in these cases was attached directly to the skin surface. The coefficients of variation (CV) of the disappearance rate constants measured by the CdTe(C1) detector were 9% and 11%, and these values did not differ significantly from each other (P greater than 0.2), or from CV-values calculated from measurements with NaI(T1) detectors.

Portable detectors for 125I-insulin absorption measurement during subcutaneous infusion with portable pumps.

Programmed subcutaneous insulin infusion is a promising method for normalisation of the blood glucose concentration in insulin-dependent diabetics. To evaluate insulin availability the absorption rate from the depot is usually measured intermittently by radioactively-labelled insulin and stationary scintillation detectors. Small portable detectors are an alternative, however, and continuous absorption measurements could be made during normal life conditions. Contrary to conventional single injection therapy, the insulin depot initially expands during infusion treatment, changing the geometry during measurements. In the present study the methodological aspects and geometrical dependences were investigated. Simulated studies were made with various plane disc 125I sources in Perspex phantoms as well as 125I-insulin absorption studies in short-term subcutaneous infusion experiments with anaesthetised rabbits. Results from portable, end-window Geiger-Müller (GM) detectors fixed above the depots and close to the surfaces of phantom or skin were compared with results obtained by a conventional stationary NaI(Tl) detector 15 cm from the phantom or skin surface. With a 125I-insulin infusion site at 5 mm depth in the subcutaneous tissue of rabbits, an overall linear proportionality was found between the results obtained with a NaI(Tl) detector and a GM detector raised 15 mm above the skin surface inside the detector housing.

Comparison of portable CdTe(Cl) detectors with stationary NaI(Tl) detectors for subcutaneous 133Xe disappearance measurements.

133Xe washout measurements from locally injected depots in the subcutaneous tissue of the thigh have been performed intermittently by a NaI(Tl) detector placed 15 cm from the depot and a cadmium telluride [CdTe(Cl)] detector fixed to the skin surface above the depot. In 19 experiments, the measurements were performed during rest, before and after bicycling and during circulatory arrest during an occlusion cuff pressure of 240-250 mmHg. The disappearance rates measured by the two detector systems showed a linear correlation (r = 0.934, P less than 0.001). However, the rate constants measured by the CdTe(Cl) detector were an average of 1.48 times the values obtained by the NaI(Tl) detector during a period of 1-4 h after the injection. The coefficient of variation of the proportionality factor is 3.3%. Only the central part of the local depot area is exposed to the CdTe(Cl) detector. Using the NaI(Tl) detector and lead shielding of the peripheral or central part of the depot area, it was demonstrated that the disappearance rates obtained reflect the measuring geometries. The correction itself is therefore due to differences in the measuring geometries of the two detector types, and possibly to diffusion and convection of xenon. For quantitative determination of the subcutaneous blood flow, the disappearance rate constants determined by the CdTe(Cl) detector thus have to be corrected by division with the factor 1.48.

Clinical factors influencing the absorption of 125I-NPH insulin in diabetic patients.

Clinical factors which might influence the absorption of subcutaneously injected 125I-NPH insulin were studied in 101 diabetics. The disappearance curve was monoexponential after a delay period of 1.5 +/- 0.8 h (mean +/- SD). Lipohypertrophy significantly prolonged insulin absorption (half life (T1/2) = 11.2 +/- 3.1 h, p = 0.0001). Low bicarbonate levels increased the absorption (T1/2 3.9 +/- 2.3 h, p less than 0.05). Lean diabetics had a faster absorption (6.2 +/- 1.9 h) than normal weight diabetics (7.5 +/- 2.0 h, p less than 0.02). Sex, age, diabetes duration and injection depth did not influence T1/2. The half life was significantly inversely correlated to the resting subcutaneous blood flow (r = 0.882, p less than 0.01). The overall interindividual coefficient of variation for insulin absorption in nonketotic diabetics was 27.4%. Also considerable intra-patient day-to-day variation was found (24.5%), and between different injection sites (30.2%). These variations emphasize the drawbacks of conventional insulin therapy in the management of insulin-requiring diabetics.

Simultaneous turnover studies of thyroxine, 3,5,3' and 3,3',5'-triiodothyronine, 3,5-, 3,3'-, and 3',5'- diiodothyronine, and 3'-monoiodothyronine in chronic renal failure.

The present study evaluates the sequential extra-thyroidal monodeiodination of thyroid hormones through tri-, di-, and monoiodothyronines in chronic renal failure (CRF) in man. Simultaneous turnover studies of T4, T3, rT3, 3,5-diiodothyronine (3,5-T2), 3,3'-T2, 3',5'-T2, 3'5'-T2, and 3'-monoiodothyronine (3--T1) were conducted in six patients with CRF (creatinine clearance, 9-18 ml/min) using the single-injection, noncompartmental approach. Serum levels of T4, T3, and 3,5-T2 were reduced to two thirds of control levels (P less than 0.05), whereas serum rT3 and 3,3'-T2 levels were reduced to a minor degree. Serum 3'-5'-T1 was doubled (p less than 0.05). The MCRs of T4, rT3, and 3',5'-T2 were enhanced to 168%, 127%, and 187% of normal (P less than 0.05), respectively, whereas those of T3, 3,5-T2, 3,3'-T2, and 3'-T1 were unaffected. The mean production rates (PRs) of the iodothyronines in CRF were as follows (CRF vs. control values, expressed as nanomoles per day/70 kg): T4, 119 vs. 125; T3, 26 vs. 44 (P less than 0.01); rT3, 49 vs, 48; 3,5-T2, 3.5 vs. 7.2 (P less than 0.001); 3,3'-T2, 25 vs. 35 (P less than 0.01); 3',5'-T2, 25 vs. 14 (P less than 0.01); and 3'-T1, 39 vs. 30. Previous studies have demonstrated reduced phenolic ring (5'-) deiodination of T4 in CRF, which is supported by the present finding of unaltered PR of T4 and reduced PR of T3. In contrast the 5'-deiodination of T3 leading to the formation of 3,5-T2 was found unaffected by CRF, since the conversion rate (CR) of T3 to 3,5-T2 (PR 3,5-T2/PR T3) was unaltered (16% vs. 15% in controls). The tyrosylic ring (5-) deiodination of T4 to rT3 was unaffected in patients with CRF, the CR being 42% vs. 40% in controls, in contrast to an enhanced CR of rT3 to 3',5'-T2 (53% vs. 29%, P less than 0.01), which also is a 5-deiodination step. In conclusion, our data show that CRF profoundly changes the kinetics of all iodothyronines studied. Furthermore, our data are compatible with the existence of more than one 5'-deiodinase as well as more than one 5-deiodinase in man.

Absorption and miscibility of regular porcine insulin after subcutaneous injection of insulin-treated diabetic patients.

The absorption and miscibility of subcutaneously injected 125I-regular porcine insulin was examined in 20 insulin-treated diabetic patients. The disappearance half-life (t1/2) was 2.1 +/- 0.8 h (SD) after injection of regular insulin (40 U/ml) and 2.3 +/- 0.7 h when mixed with porcine NPH insulin (NS). A significant inverse relation was demonstrated between insulin concentration and absorption, as t1/2 was 1.8 +/- 0.7 h (P less than 0.05) when using 20 U/ml. The interindividual coefficients of variation for absorption of regular insulin were 30.9-41.6% and independent of the presence of NPH insulin. The intrapatient variability, however, was much smaller, 14.5-23.6%.

Absorption of NPH-insulin from subcutaneous tissue: a methodological study in pigs.

To elucidate the validity of the indirect method of following insulin absorption from the subcutaneous tissue, i.e. external counting of injected 125-I insulin, the disappearance of 125-I NPH insulin from subcutaneous tissue was measured by a biotelemetric method (external measurement of radioactivity) and by direct determination of radioactivity and insulin in subcutaneous tissue extracted one to 300 min. after injection of 8 units 125-I NPH porcine insulin, 5 mm beneath the surface of the skin in 6 anaesthesized pigs. Furthermore, the appearance of insulin in arterial plasma was measured after inhibiting the endogenous insulin secretion of the pigs by epinephrine and propanolol. The disappearance of radioactivity measured continuously for 5 hours was of first order kinetics with t1/2=462+/-36 min. (mean+/-S.E.M.). The half-life of the injected depot of radioactivity (t1/2) demonstrated a large intra- as well as interindividual variation as seen in diabetics. In tissue extracts a highly significant (2P less than 0.001) correlation was found between radioactivity and insulin (r=0.93), indicating the radioactivity to be representative of insulin. During gel chromatography on Sephadex G 50 M only one peak of radioactivity was seen in all tissue extracts. 300 min. after NPH-insulin injection, however, the specific radioactivity of insulin was significantly higher (2P less than 0.05) than in tissue extracts sampled one min. after NPH insulin injection, indicating a slight accumulation of non-immunoreactive insulin degradation products. A fair correlation (r=0.75, 2 P less than 0.05) was seen between the disappearance of externally measured radioactivity or insulin from tissue extracts and the appearance of insulin in plasma. It is concluded that the insulin absorption coefficient is a relevant and biologically sensible expression of insulin absorption.

The relationship between plasma concentration and plasma disappearance rate of immunoreactive insulin in normal subjects.

To investigate the mechanism of insulin degradation in normal subjects, a kinetic model of insulin disappearance was constructed: insulin was assumed to be extracted from plasma by two independent processes, one saturable and one non-saturable. On the basis of these assumptions, a linear (non-proportional) relationship between steady-state plasma insulin concentration and steady-state plasma disappearance rate was predicted over the concentration range studied. Constant infusion experiments were performed on eight healthy normal subjects, normoglycaemia and fasting plasma C-peptide concentrations being maintained during the experiments. Agreement was found between the predictions of the model and the experimental results, and it is concluded that insulin degradation in normal subjects may be described in terms of two processes: one that is saturated at physiological plasma insulin concentrations and one that is apparently non-saturable over a wide concentration range.

A trial of metoprolol in hypertensive insulin-dependent diabetic patients.

Twenty-four insulin-dependent, hypertensive diabetic patients were treated with a beta 1-selective blocking agent (metoprolol) to evaluate its influence on diabetic state and arterial blood pressure (BP). Two groups were delineated after exclusion of one patient. Twelve patients (group A) obtained normotension with metoprolol alone, whilst 11 (group B) required concomitant treatment with thiazides, 7 of them both with thiazides and hydralazine. BP fell significantly in group B, by 15% (p less than 0.01), compared with pretreatment levels. Postprandial blood glucose levels, glucose excretion and insulin requirements were unchanged during treatment in all patients. Neither quantitative nor qualitative changes in the recognition of the effects of insulin were observed by 15 diabetics familiar with this sensation. Side-effects were few. One episode of severe hypoglycaemia, probably unrelated to the beta-blockade, was encountered. We suggest that antihypertensive treatment with metoprolol is a reasonable alternative in the treatment of hypertensive insulin-dependent diabetic patients.

Kinetics of subcutaneous NPH insulin in diabetics.

Kinetics of subcutaneous NPH insulin were studied in newly diagnosed insulin-dependent diabetics. Using a biotelemetric technique with small Geiger-Müller detectors applied to the skin surface, the disappearance of 125I-NPH insulin fron subcutis was monoexponential with a mean half-life of 6.6 +/- 3.3 (SD) hr. A model is presented to compare the disappearance rates of subcutaneous 125I-NPH insulin and the calculated plasma appearance insulin curve derived from the actual plasma insulin concentration measurements, assuming a one-compartment model and first-order kinetics. Areas under the absorption- and appearance-time curves calculated from external measurements and from plasma insulin concentrations were identical. There was a strong correlation between plasma concentrations and absorbed amounts of labeled insulin (r = 0.8782, P less than 0.001), as there was between the blood glucose-lowering effects and percent absorbed insulin per hour (r = 0.7659, P less than 0.001). Our results indicate that the disappearance rate of iodine-labeled insulin was a relevant biological expression of insulin absorption from subcutis and a reliable noninvasive method of quantitative determination of insulin concentration in blood.

Biotelemetric detection of the disappearance of subcutaneously injected 125I-NPH insulin.

A biotelemetric method with Geiger-Müller (GM) detectors fixed to the skin surface was used for continuous registration of the disappearance rate of subcutaneously injected 125I-NPH insulin. Methodological problems concerning counting geometry were investigated by comparing the disappearance of radioactivity, measured the GM- and NaI-detectors, respectively, and by scanning of the radioactive source. The size and position of the subcutaneous depot was unchanged throughout the study. Movement artifacts could be avoided. The coefficient of variation for distribution of ratios between count rates for GM- and NaI-detectors was 3.0% +/- 1.1 (SD) (range 0.9-4.0%) over periods of 24 h. It is concluded that the biotelemetry technique proved to be a clinically useful procedure for insulin absorption studies.