Bioavailability of insulin detemir and human insulin at the level of peripheral interstitial fluid in humans, assessed by open-flow microperfusion

2015 ◽  
Vol 17 (12) ◽  
pp. 1166-1172 ◽  
Author(s):  
M. Bodenlenz ◽  
M. Ellmerer ◽  
L. Schaupp ◽  
L. V. Jacobsen ◽  
J. Plank ◽  
...  
Keyword(s):  
Human Insulin ◽  
Insulin Detemir ◽  
Interstitial Fluid ◽  
Open Flow

Quantification of Basal Insulin Peglispro and Human Insulin in Adipose Tissue Interstitial Fluid by Open-Flow Microperfusion

2017 ◽  
Vol 19 (5) ◽  
pp. 305-314 ◽  
Author(s):  
Katrin Tiffner ◽  
Beate Boulgaropoulos ◽  
Christian Höfferer ◽  
Thomas Birngruber ◽  
Niels Porksen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Human Insulin ◽  
Basal Insulin ◽  
Interstitial Fluid ◽  
Open Flow ◽  
Tissue Interstitial Fluid

Effects of normal human insulin, insulin aspart, and insulin detemir on the lifespan of Caenorhabditis elegans

2008 ◽  
Vol 3 (S 1) ◽  
Author(s):  
Y Ibrahim ◽  
A Schlotterer ◽  
G Kukudov ◽  
P Humpert ◽  
G Rudofsky ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Human Insulin ◽  
Insulin Aspart ◽  
Insulin Detemir ◽  
Normal Human

Direct access to interstitial fluid in adipose tissue in humans by use of open-flow microperfusion

1999 ◽  
Vol 276 (2) ◽  
pp. E401-E408 ◽  
Author(s):  
L. Schaupp ◽  
M. Ellmerer ◽  
G. A. Brunner ◽  
A. Wutte ◽  
G. Sendlhofer ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Concentration ◽  
Interstitial Fluid ◽  
Internal Standard ◽  
Ion Concentration ◽  
Direct Access ◽  
Open Flow ◽  
Hyperglycemic Clamp ◽  
Calibration Methods ◽  
Lumen Catheter

To gain direct access to the interstitial fluid (ISF), a new technique called open-flow microperfusion has been evaluated. This method is based on a double-lumen catheter with macroscopic (0.3–0.5 mm diameter) perforations that is inserted into the subcutaneous adipose tissue and constantly perfused. Thus partial equilibration between the ISF and the perfusion fluid occurs. The glucose concentration of the ISF was determined by established (zero flow rate, no net flux, and recirculation procedures) and new (ionic reference and suction technique) calibration methods by use of open-flow microperfusion. The data show that 1) the glucose concentration in the ISF is significantly lower than the corresponding arterialized venous plasma values during basal steady-state conditions (adipose tissue 3.2 ± 0.10 mM, plasma 5.27 ± 0.12 mM) as well as during hyperglycemic clamp experiments (adipose tissue 7.3 ± 0.13 mM, plasma 9.91 ± 0.16 mM), and 2) it is possible to determine the recovery continuously by using the ion concentration of the ISF as an internal standard (ionic reference).

Evaluation of Cell Proliferation in Rat Mammary Glands Is Not Predictive of the Carcinogenic Potential of Insulin In Vivo

2020 ◽  
Vol 39 (6) ◽  
pp. 560-576
Author(s):  
Vivi Flou Hjorth Jensen ◽  
Peter R. Brinck ◽  
Jette Nowak ◽  
Inger Thorup ◽  
Ingrid Sjögren ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Human Insulin ◽  
Safety Assessment ◽  
Insulin Detemir ◽  
Mammary Glands ◽  
Positive Control ◽  
Mitogenic Effect ◽  
Carcinogenic Potential ◽  
Histopathologic Evaluation

For nonclinical safety-assessment of insulin analogues in vivo, mitogenic effects are compared to that of human insulin. Besides histopathologic evaluation, this usually includes assessment of cell proliferation (CP) in mammary glands. Insulin analogue X10 is recommended as positive control, due to its known carcinogenic effect in rat mammary glands. Here, we discuss the mitogenic effect of insulin in vivo and use of X10 as positive control. We present results from 4 nonclinical rat studies evaluating effects of repeated dosing with insulin detemir (≤26 weeks) or degludec (52 weeks) in mammary glands. Studies included human insulin-dosed groups as comparators, CP, and histopathologic evaluation. One study included an X10-dosed group (26 weeks), another ≤3 weeks of dosing with X10 or human insulin evaluating effects of these comparators. Neither human insulin, insulin detemir, degludec, nor X10 induced mammary tumors or increased CP in the studies. The CP marker proliferating cell nuclear antigen varied within/between studies and was not correlated with the remaining markers or CP fluctuations during estrous cycle, whereas the other CP markers, Ki-67 and 5-bromo-2′-deoxyuridine (BrdU), correlated with estrous cycle changes and each other. In conclusion, we propose that the mitogenic effect of insulin in rat mammary glands is weak in vivo. Cell proliferation evaluation in nonclinical safety assessment studies is not predictive of the carcinogenic potential of insulin, thus, the value of including this end point is debatable. Moreover, X10 is not recommended as positive control, due to lack of proliferative effects. Typical CP markers vary greatly in quality, BrdU seemingly most reliable.

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