Aim:To compare the efficacy and safety of an intensified insulin regimen, using insulin glargine (glargine) once daily and pre-meal insulin glulisine (glulisine) (basal-bolus), with a conventional therapy, using premixed insulin (premix) twice daily. Methods:This 52-week, open-label, randomized, multinational, multicentre trial included 310 subjects with type 2 diabetes (T2D) on premix, with or without metformin, who were randomized to a basal-bolus regimen with glargine and glulisine (n = 153; mean ± s.d. age 60.2 ± 7.5 years; HbA1c 8.6 ± 0.8%; weight 87.0 ± 15.1 kg; T2D duration 12.8 ± 5.8 years) or twice-daily premix (n = 157; age 60.9 ± 7.8 years; HbA1c 8.5 ± 0.9%; weight 84.3 ± 15.0 kg; T2D duration 12.5 ± 6.8 years). The primary endpoint was change in HbA1c from baseline to endpoint. Results:Mean decrease in baseline-to-endpoint HbA1c for basal-bolus vs. premix was −1.31 vs. −0.80% (difference: −0.476%; 95% Cl: −0.714, −0.238; p = 0.0001, ANCOVA). More subjects reached HbA1c ≤7.0% in the basal-bolus group than in the premix group [68 (46.6%) vs. 43 (27.9%); p = 0.0004], while they also experienced significantly lower mean ± s.d. daytime (−2.7 ± 2.3 vs. −2.3 ± 2.5 mmol/l; p = 0.0033) and postprandial (−3.1 ± 2.6 vs. −2.5 ± 2.8 mmol/l; p < 0.0001) blood glucose. Endpoint daily insulin doses were 98.0 ± 48.7 vs. 91.3 ± 44.3 IU (p = 0.2104); mean weight gain was +3.6 ± 4.0 vs. +2.2 ± 4.5 kg (p = 0.0073). Mean number of overall hypoglycaemic events with basal-bolus and premix was 13.99 and 18.54 events/patient year, respectively (difference: −3.90; 95% CI: −10.40, 2.60; p = 0.2385). Conclusions:An intensified basal-bolus regimen using glargine/glulisine results in a significantly superior glycaemic control vs. premix therapy in a population with long-standing insulin-treated T2D, with no increase in the rates of hypoglycaemia.

Insulin resistance in patients with type 2 diabetes is associated with an increased risk of cardiovascular events. While this can be partly explained by an impairment of direct insulin action on the endothelial cell, an independent contribution can be assigned also to the secretory dysfunction of the beta-cell. If the demand for insulin triggered by insulin resistance is arriving at a certain threshold, an insufficiency of the cleavage capacity of beta-cell carboxypeptidase H leads to an increased secretion of intact proinsulin in addition to the desired insulin molecule. Proinsulin, however, has been demonstrated to be an independent cardiovascular risk factor by stimulating plasminogen activator inhibitor-1 secretion and blocking fibrinolysis. A recently introduced intact proinsulin assay is able to distinguish between intact proinsulin and its specific and non-specific cleavage products. This assay allows for a pathophysiological staging of type 2 diabetes based on beta-cell secretion. It could be confirmed by a large epidemiological study (IRIS-2, 4,265 patients) that intact proinsulin is a highly specific marker for insulin resistance. It could also be shown in other studies that successful resistance treatment with insulin or glitazones led to a decrease in elevated proinsulin levels and, thus, to a decrease of cardiovascular risk, while the levels remained high during sulfonylurea therapy. Therefore, patients with increased fasting intact proinsulin values should be treated with a therapy focusing on insulin resistance. Assessment of beta-cell function by determination of intact proinsulin may facilitate the selection of the most promising therapy and may also serve to monitor treatment success in the further course of the disease.

Impedance spectroscopy allows for the assessment of changes in the permittivity and conductivity of erythrocyte cell membranes, induced by blood glucose variations. This study was performed to evaluate the potential influence of motion-induced microvascular blood flow variations from different forearm postures on the PENDRA (Pendragon Medical AG, Zürich, Switzerland) signal. Fifteen volunteers without diabetes were included (seven female, eight male, mean +/- SD age 33.3 +/- 9.9 years, body mass index 24.8 +/- 3.0 kg/m(2)). PENDRA devices were fixed at both upper extremities with different fixation techniques (bracelet and adhesive tape). Standardized position changes of the upper extremities were performed to induce variations in cutaneous microcirculation, which were assessed by laser-Doppler-fluxmetry with different probe temperatures on the forearm. Changes in microcirculation were seen in some of the different motion procedures: supine to hanging, 61.1 +/- 29.9 arbitrary units (AU) to 46.2 +/- 24.8 AU at 37 degrees C and 15.9 +/- 13.0 AU to 13.4 +/- 10.1 at skin temperature (P < 0.01 for both probes); supine to upright, 80.5 +/- 55.4 AU to 74.9 +/- 43.8 AU (not significant) at 37 degrees C and 18.7 +/- 16.8 AU to 20.9 +/- 16.1 AU at skin temperature (P < 0.01). An initially observed subtle influence of microcirculation variations on the impedance signal was minimized when the device was fixed by both bracelet and tape. Other influencing factors (such as temperature, local anatomy, etc.) are addressed in the complex calibration procedure. Well-educated patients might be the best candidates for first using the device for continuous glucose monitoring. They may especially benefit from the trend indication and the hypoglycemia/hyperglycemia threshold and alarm functions.

Aim:Postprandial release of intact proinsulin (IP) is an independent marker for β-cell dysfunction in patients with type 2 diabetes. This open-label, parallel-group, two-arm, pilot study compared the β-cell protective effect of adding insulin glargine (GLA) vs. NPH insulin to ongoing metformin.Material and methods:Overall, 28 insulin-naive type 2 diabetes subjects (mean ± SD age, 61.5 ± 6.7 years; diabetes duration, 9.8 ± 6.5 years; HbA1c, 7.1 ± 0.5%; BMI, 30.7 ± 4.3 kg/m2) treated with metformin and sulfonylurea were randomized to add once-daily GLA or NPH at bedtime. At baseline and after 3 months, subjects received a standardized breakfast, lunch and dinner, with pre- and postprandial blood sampling to measure plasma IP, total insulin and blood glucose (BG).Results:Insulin dose after 3 months was comparable in both groups (GLA vs. NPH: 23.6 ± 13.4 vs. 23.3 ± 12.7; p = NS ). Both treatments significantly reduced fasting BG levels (GLA: 158 ± 19 to 121 ± 23 mg/dl; NPH: 156 ± 34 to 119 ± 29 mg/dl; both p < 0.01 vs. baseline). Fasting and postprandial BG levels did not differ between groups. IP levels decreased in both groups (p < 0.05 at all timepoints). Although IP release after breakfast did not differ between treatments, GLA induced a greater reduction in IP release after lunch (p = 0.08) and dinner (p = 0.04). Total plasma insulin levels did not differ between groups.Conclusions:Adding basal insulin to metformin reduces postprandial β-cell load. While GLA and NPH had comparable effects at breakfast, GLA reduces β-cell stress more effectively at dinner, and with a trend at lunch, most probably because of its longer lasting pharmacodynamic profile.

Abbreviations: (AUC 0-300 ) area under the concentration time curve from 0 to 300 min, (DPP-4-I) dipeptidyl-peptidase-4 inhibitors, (GLA) insulin glargine, (GLP-1) glucagon-like peptide-1, (HbA1c) glycated hemoglobin, (MET) metformin, (OAD) oral antidiabetic drug, (OGTT) oral glucose tolerance test, (PAI-1) plasminogen activator inhibitor-1, (SU) sulfonylureas, (T2DM) type 2 diabetes mellitus Our objective was to investigate how postprandial processing of intact proinsulin is influenced by different pharmacological strategies in type 2 diabetes mellitus (T2DM). Materials/Methods:This exploratory, nonrandomized, cross-sectional study recruited T2DM patients and healthy subjects. Upon recruitment, eligible T2DM patients had been treated for ≥6 months with insulin glargine (GLA) plus metformin (MET), sulfonylureas (SU) plus MET, or dipeptidyl-peptidase-4 inhibitors (DPP-4-I) plus MET. Blood samples were drawn from study participants after an 8 h fast and at regular intervals for up to 5 h after consumption of a standardized meal. Study endpoints included postprandial intact proinsulin and insulin levels and the insulin/proinsulin ratio. Results:As expected, postprandial secretion of proinsulin was greater in all T2DM treatment groups than in healthy subjects (p < .01 for all comparisons). Postprandial release of proinsulin was significantly greater in T2DM patients treated with SU plus MET than in those treated with GLA plus MET (p = .003). Treatment with DPP-4-I plus MET was associated with reduced proinsulin secretion versus SU plus MET and an increased insulin/proinsulin ratio versus the other T2DM groups. Conclusions:Treatment of T2DM with GLA plus MET or DPP-4-I plus MET was associated with a more physiological postprandial secretion pattern of the β cell compared with those treated with SU plus MET.