In type 2 diabetes patients, insulin glargine is associated with lower postprandial release of intact proinsulin compared with sulfonylurea treatment.

OBJECTIVE: 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 ß cell compared with those treated with SU plus MET.

Effect of insulin glulisine on microvascular blood flow and endothelial function in the postprandial state.

OBJECTIVE: To investigate the effect of insulin glulisine on postprandial microvascular blood flow in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 15 patients with type 2 diabetes received insulin glulisine or human insulin before a liquid meal test. Thereafter, skin microvascular blood flow was measured by laser Doppler fluxmetry and blood samples were taken for measurement of plasma levels of glucose, insulin, intact proinsulin, asymmetric dimethylarginine, nitrotyrosine, interleukin-18, matrix metalloproteinase-9, oxidized LDL, and free fatty acids. RESULTS: Insulin glulisine injections resulted in higher postprandial insulin levels (means +/- SEM area under the curve [AUC](0-120) 51.0 +/- 6.8 vs. 38.2 +/- 5.4 mU/l; P = 0.004), while plasma glucose (AUC(0-240) 158 +/- 9 vs. 180 +/- 9 mg/dl; P < 0.05) and intact proinsulin (AUC(0-240) 26.2 +/- 3.5 vs. 31.2 +/- 4.3 pmol/l; P = 0.002) were lower. Microvascular blood flow increased after insulin glulisine injection (27.9 +/- 3.1 to 51.7 +/- 9.9 arbitrary units [AU]; P < 0.05), while only a minor increase was found during human insulin (27.9 +/- 3.1 to 34.4 +/- 7.8 AU; not significant). Asymmetric dimethylarginine and nitrotyrosine levels were reduced after insulin glulisine (P < 0.05). CONCLUSIONS: Insulin glulisine is superior to human insulin in restoring postprandial metabolic and microvascular physiology.

Evaluation of CGMS during rapid blood glucose changes in patients with type 1 diabetes.

BACKGROUND: CGMS (Medtronic Minimed, Duesseldorf, Germany) allows continuous glucose monitoring. Recent studies with invasive monitoring techniques revealed discrepancies in blood glucose measurements obtained from different anatomical sites compared with those from the fingertip. The aim of this study was to investigate the CGMS and a device for alternative site testing (AST) during dynamic blood glucose changes and to compare these results with fingertip measurements. METHODS: Twelve patients with type 1 diabetes (seven women, five men; age, 33.3 +/- 8.7 years) received a 75-g oral glucose load. Insulin was applied intravenously (rapid glucose decline) or subcutaneously (moderate glucose decline) in a dosage between 3 to 18 units 2 h later in a randomized sequence on two different days. For continuous glucose measurements the CGMS standard sensor was inserted into the lower abdominal subcutis. Glucose measurements were obtained from the forearm using a minimally invasive technique (AST). CGMS and AST measurements were compared with glucose measurements obtained from the fingertip using a standard glucose oxidase method. RESULTS: No significant difference could be observed among all three methods during increasing glucose levels. Insulin-induced blood glucose decline resulted in a significant time lag in the time course of blood glucose measurements obtained by AST compared with those obtained from the fingertip (P < 0.05, respectively). No significant difference could be observed between CGMS and fingertip measurements. Error grid analysis revealed 100% during rapid glucose fall and 98.5% during modest glucose fall of CGMS measurements within the clinically acceptable zones A and B. CONCLUSIONS: Continuous glucose measurements using CGMS provide reliable glucose measurements even in the case of dynamic blood glucose changes.

Intact and total proinsulin: new aspects for diagnosis and treatment of type 2 diabetes mellitus and insulin resistance.

Proinsulin, the precursor of insulin during physiological insulin production, has been demonstrated in the past to stimulate PAI-1 secretion and consecutively block fibrinolysis. Therefore, proinsulin is contributing as an independent factor to the increased cardiovascular risk of patients with type 2 diabetes. However, development of insulin resistance in the course of type 2 diabetes leads to increased insulin demands and finally to an impairment of beta-cell function in later disease stages. Appearance of intact proinsulin in the peripheral blood has been shown to be a good laboratory marker for this phenomenon since it indicates an exhaustion of the cleavage capacity of the intracellular processing enzymes. However, the close relation of the two pathophysiological entities also makes it a very specific marker for insulin resistance per se. During the past years, new immunoassays have been developed that are able to distinguish between intact proinsulin and its specific and unspecific cleavage products. Use of these assays in recent epidemiological and intervention studies has helped to get a better understanding about beta-cell dysfunction and its relation to insulin resistance and cardiovascular risk. In a large cross-sectional study with 4270 orally treated patients, elevation of fasting intact proinsulin was very closely related to insulin resistance, as assessed by iv glucose tolerance test in a subgroup, and by HOMA analysis in the entire patient population. Effective treatment of insulin resistance (e.g. with thiazolidindiones) led to a decrease in elevated proinsulin levels and to a decrease of the cardiovascular risk profile, while the levels remained high during sulfonylurea therapy. These results suggest to reconsider intact and total proinsulin as valuable diagnostic tools in diagnosis and treatment of type 2 diabetes. Based on the published data of the new specific immunoassays, patients with elevated intact proinsulin levels (> 10 pmol/L) should be regarded and treated as being insulin-resistant, while elevation of total proinsulin (>45 pmol/l) may help to identify the high cardiovascular risk patients. Both assays can thus be used to assess beta-cell function, to facilitate the selection of the most promising therapy, and may also serve to monitor treatment success in the further course of the disease.

Impact of posture and fixation technique on impedance spectroscopy used for continuous and noninvasive glucose monitoring.

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.

Role of intact proinsulin in diagnosis and treatment of type 2 diabetes mellitus.

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.

Evaluation of SET--a new device for the measurement of pain perception in comparison to standard measures of diabetic neuropathy.

BACKGROUND: Early detection of sensory impairment and loss of protective pain sensation is of major importance for the prevention of neuropathic foot ulceration. The aim of our study was to evaluate a new handheld device (SET, a prototype developed by Dr. W. Henniges, Zülpich, Germany) for measurement of pain perception, in comparison with established methods for diagnosis of diabetic neuropathy. METHODS: Sixty-one patients with diabetes mellitus (13 type 1, 48 type 2; 42 men, 19 women; mean +/- SD age 61.6 +/- 11.6 years) received measurement of pain perception threshold using the new SET device and a measurement of light touch sensation, temperature sensation, and vibration sensation by the use of standard clinical devices. In addition, warm, cold, heat pain and vibration perception thresholds were determined by the use of a computer-based peltier thermode and a vibration stimulator (TSA 2001, Medoc, Ramat Yishai, Israel). RESULTS: Using the new SET device, patients with sensory impairment showed significantly elevated pain perception thresholds at the dorsum of the foot (P < 0.001), while only a trend towards higher measurements could be observed at the plantar aspect of the foot. A significant correlation could be observed between plantar and dorsal measuring sites (r = 0.78, P < 0.0001) and between both feet (r = 0.85, P < 0.0001). Compared with other qualities of sensory dysfunction, pain perception measurement with the SET device provided the highest sensitivity (pain = 0.82; vibration = 0.61; temperature = 0.42; light touch = 0.11). CONCLUSIONS: Measurement of pain perception threshold using the SET device is an easy and reliable method for identifying patients with impaired small nerve fiber function.

Cross-sectional investigation on the accuracy of alternate site glucose testing using the Soft-Sense glucose meter.

QUESTIONS UNDER STUDY: The aim of this study was to evaluate possible differences in the results of blood glucose testing with the Soft-Sense blood glucose monitoring system (Abbott MediSense, Wiesbaden, Germany; not yet available in Switzerland) using different sites for drawing whole blood samples. METHODS: In total, 66 patients participated in the study. Blood glucose measurements were performed with the Soft-Sense device taking capillary blood from the forearm and the fingertip. The results were compared with blood glucose measurements by means of a laboratory reference method using blood from the fingertips. RESULTS: 276 blood glucose data sets could be obtained and were used for the examination of the accuracy of blood glucose measurements at both different sites. Blood glucose results obtained from the arm with Soft-Sense correlated well and were nearly parallel with the results achieved from the fingertip with a laboratory reference method (regression analysis: slope = 0.981; intercept = 0.045 mmol/l (0.819 mg/dl); correlation coefficient r = 0.943). Error grid analysis showed 99.2% of the measurements within clinically acceptable zones A and B. In addition, finger stick measurements done with the Soft-Sense device and the reference method revealed a strong correlation (regression analysis: slope = 0.959; intercept = -0.042 mmol/l (0.748 mg/dl); correlation coefficient r = 0.972). Error grid analysis showed 98.9% of all blood glucose readings within clinically acceptable zones A and B. Mean absolute percent deviations were 9.3+/- 8.1% for the finger tests and 11.2+/- 8.7% for the arm tests. If blood glucose values exceeded 11.1 mmol/l (200 mg/dl), measurements revealed from the forearm were slightly lower than the measurements obtained from the fingertips. CONCLUSIONS: The results indicate that the automated blood glucose monitoring device Soft-Sense provides accurate results independent of the measuring site. As with other alternate site testing devices, nearly painless blood collection at the forearm might help to increase patients readiness to perform more frequent measurements by self blood glucose monitoring, which is a known prerequisite of improved blood glucose control.