Profil Institute for Metabolic Research

Neuß, Germany

Profil Institute for Metabolic Research

Neuß, Germany

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Martin S.,Heinrich Heine University Düsseldorf | Herder C.,Heinrich Heine University Düsseldorf | Schloot N.C.,Heinrich Heine University Düsseldorf | Schloot N.C.,University Hospital | And 4 more authors.
PLoS ONE | Year: 2011

Background: Recent evidence suggests that the lipid-lowering agent atorvastatin is also a potent immunomodulator. The aim of this study was to investigate the possible effect of atorvastatin on the decline of residual beta cell function in recent-onset type 1 diabetes. Methods and Findings: The randomised placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and islet autoantibodies (mean age 30 years, 40% females), in 12 centres in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. An intent-to-treat analysis was performed. Fasting and stimulated C-peptide levels were not significantly different between groups at 18 months. However, median fasting serum C-peptide levels dropped from baseline to 12 and 18 months in the placebo group (from 0.34 to 0.23 and 0.20 nmol/l, p<0.001) versus a nonsignificant decline in the atorvastatin group (from 0.34 to 0.27 and 0.30 nmol/l, ns). Median stimulated C-peptide concentrations declined between baseline and 12 months (placebo from 0.89 to 0.71 nmol/l, atorvastatin from 0.88 to 0.73 nmol/l, p<0.01 each) followed by a major loss by month 18 in the placebo group (to 0.48 nmol/l, p = 0.047) but not in the atorvastatin group (to 0.71 nmol/l, ns). Median levels of total cholesterol and C-reactive protein decreased in the atorvastatin group only (p<0.001 and p = 0.04). Metabolic control was similar between groups. Conclusions: Atorvastatin treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study. Trial Registration: ClinicalTrials.gov NCT00974740. © 2011 Martin et al.


Morgan J.L.L.,NASA | Zwart S.R.,NASA | Heer M.,University of Bonn | Heer M.,NASA | And 4 more authors.
Journal of Applied Physiology | Year: 2012

Bone metabolism and nutritional status during 30-day headdown- tilt bed rest. J Appl Physiol 113: 1519-1529, 2012. First published September 20, 2012; doi:10.1152/japplphysiol.01064.2012.-Bed rest studies provide an important tool for modeling physiological changes that occur during spaceflight. Markers of bone metabolism and nutritional status were evaluated in 12 subjects (8 men, 4 women; ages 25-49 yr) who participated in a 30-day -6° head-down-tilt dietcontrolled bed rest study. Blood and urine samples were collected twice before, once a week during, and twice after bed rest. Data were analyzed using a mixed-effects linear regression with a priori contrasts comparing all days to the second week of the pre-bed rest acclimation period. During bed rest, all urinary markers of bone resorption increased ̃20% (P < 0.001), and serum parathyroid hormone decreased ̃25% (P < 0.001). Unlike longer (̃60 days) bed rest studies, neither markers of oxidative damage nor iron status indexes changed over the 30 days of bed rest. Urinary oxalate excretion decreased ̃20% during bed rest (P < 0.001) and correlated inversely with urinary calcium (R = -0.18, P < 0.02). These data provide a broad overview of the biochemistry associated with shortduration bed rest studies and provide an impetus for using shorter studies to save time and costs wherever possible. For some effects related to bone biochemistry, short-duration bed rest will fulfill the scientific requirements to simulate spaceflight, but other effects (antioxidants/ oxidative damage, iron status) do not manifest until subjects are in bed longer, in which case longer studies or other analogs may be needed. Regardless, maximizing research funding and opportunities will be critical to enable the next steps in space exploration. Copyright © 2012 the American Physiological Society.


Heise T.,Profil Institute for Metabolic Research | Nosek L.,Profil Institute for Metabolic Research | Bottcher S.G.,Novo Nordisk AS | Hastrup H.,Novo Nordisk AS | Haahr H.,Novo Nordisk AS
Diabetes, Obesity and Metabolism | Year: 2012

Aims: Insulin degludec (IDeg) is a new-generation, ultra-long-acting basal insulin that forms soluble multihexamers upon subcutaneous injection, resulting in a depot from which IDeg is absorbed slowly and continuously into circulation. This double-blind, two-period, incomplete block cross-over trial investigated the pharmacodynamic and pharmacokinetic properties of IDeg at steady state (SS) in people with type 2 diabetes. Methods: Forty-nine subjects treated with insulin without concomitant oral anti-diabetic drugs were given IDeg (0.4, 0.6 and/or 0.8 U/kg) once daily for two 6-day periods, separated by an interval of 13-21 days. Following dosing on Day 6, subjects underwent a 26-h euglycaemic glucose clamp (Biostator®; clamp blood glucose level: 90 mg/dl; 5.0 mmol/l). Pharmacokinetic samples were taken until 120 h after last dosing. Results: For all dose levels, the mean glucose infusion rate (GIR) profiles were flat and stable. The glucose-lowering effect of IDeg was evenly distributed over the dosing interval τ, with area under the curve (AUC) for each of the four 6-h intervals being approximately 25% of the total AUC (AUCGIR,τ,SS). Total glucose-lowering effect increased linearly with increasing dose. The blood glucose levels of all subjects stayed very close to the clamp target until end of clamp. The terminal half-life of IDeg was approximately 25 h at steady state. IDeg was well tolerated and no safety concerns were identified. No injection site reactions were reported. Conclusions: IDeg has a flat and consistent glucose-lowering effect in people with type 2 diabetes. © 2012 Blackwell Publishing Ltd.


Stirban A.,Ruhr University Bochum | Stirban A.,Profil Institute for Metabolic Research | Kotsi P.,Ruhr University Bochum | Franke K.,German Institute of Food Technologies | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-Recent evidence indicates that heat-enhanced food advanced glycation end products (AGEs) adversely affect vascular function. The aim of this study was to examine the acute effects of an oral load of heat-treated, AGE-modified β-lactoglobulins (AGE-BLG) compared with heat-treated, nonglycated BLG (C-BLG) on vascular function in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS-In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG. We measured macrovascular [brachial ultrasound of flowmediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T0), 90 (T90), and 180 (T 180) min. RESULTS-Following the AGE-BLG, FMD decreased at T 90 by 80% from baseline and remained decreased by 42% at T 180 (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T 90). By comparison, following C-BLG, FMD decreased by 27% at T 90 and 51% at T180 (P < 0.05 vs. baseline at T 180). A significant decrease in nitrite (T180) and nitrate (T90 and T180), as well as a significant increase in N-carboxymethyllisine, accompanied intake of AGE-BLG. There was no change in microvascular function caused by either beverage. CONCLUSIONS-In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability. These AGE-related changes were independent of heat treatment. © 2013 by the American Diabetes Association.


Plum L.,Columbia University | Plum L.,Profil Institute for Metabolic Research | Ahmed L.,Columbia University | Febres G.,Columbia University | And 5 more authors.
Obesity | Year: 2011

Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin-supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8±0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2±86.6 vs. 55.9±19.9; P<0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point. © 2011 The Obesity Society.


Nosek L.,Profil Institute for Metabolic Research | Roggen K.,Profil Institute for Metabolic Research | Heinemann L.,Profil Institute for Metabolic Research | Gottschalk C.,Profil Institute for Metabolic Research | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2013

Aims: Regular human insulin (RHI) at high doses shows prolongation of its duration of action potentially leading to late postprandial hypoglycaemia. This study compared late metabolic activity (4-12 and 6-12h post-dosing) and duration of action (time to reach late half-maximal activity) over a range of doses between insulin aspart (IAsp) and RHI. Methods: Pharmacokinetic and pharmacodynamic properties of subcutaneous IAsp and RHI (6, 12 and 24 (I)U) were compared in 16 healthy subjects in this double-blind, randomized, six-way crossover glucose clamp study. Results: With increasing doses of both insulins, metabolic activity, insulin exposure, maximum metabolic effect and maximum serum insulin concentration increased linearly. Late metabolic activity was lower for IAsp than RHI at all doses, reaching statistical significance (p<0.05) for 12 and 24 (I)U. Likewise, IAsp had a shorter duration of action at all doses (p<0.01) and reached time to 80% of total metabolic activity earlier at doses of 12 and 24 (I)U (p<0.05). IAsp, compared with RHI, showed a higher maximum metabolic effect at 12 and 24 (I)U (p<0.0001) and a stronger early metabolic activity for all three doses (p<0.05). Conclusions: IAsp showed a shorter duration of action and, particularly with doses of 12 and 24 (I)U, less late metabolic activity than RHI. These properties might contribute to the lower incidence of hypoglycaemia observed with IAsp versus RHI in clinical trials as lower late metabolic activity should decrease the risk of late postprandial hypoglycaemia. © 2012 Blackwell Publishing Ltd.


Stirban A.,Profil Institute for Metabolic Research
Current diabetes reports | Year: 2014

Microvascular dysfunction in diabetes plays a crucial role in the development of diabetic complications. The skin, as one of the most accessible organs, serves as a model for the investigation of microvascular dysfunction. Several non-invasive, mostly laser-Doppler-based methods have been developed lately to assess microvascular function in the skin. Microvascular functional changes occur even in the prediabetic state and become more complex with overt diabetes, being exacerbated by the presence of peripheral and/or autonomic diabetic neuropathy. The present article aims at shedding light on the implication of endothelial and neurovascular dysfunction in microvascular changes in diabetes, highlighting the contribution of different forms of diabetic neuropathy.


Heise T.,Profil Institute for Metabolic Research | Nosek L.,Profil Institute for Metabolic Research | Roepstorff C.,Novo Nordisk AS | Chenji S.,Novo Nordisk AS | And 2 more authors.
Diabetes Therapy | Year: 2014

Introduction/aim: Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of long-acting and short-acting insulin analogs. The primary objective of this study was to investigate the pharmacodynamic response of once-daily IDegAsp dosing in patients with type 1 diabetes. Pharmacokinetic response, as well as safety and tolerability, were assessed as secondary objectives.Methodology: This was a single-center, open-label, single-arm study. Twenty-two subjects received once-daily insulin degludec (IDeg) (0.42 U/kg) for five consecutive days [with separate bolus insulin aspart (IAsp) as needed for safety and glycemic control], to achieve clinical steady state of the basal component. On Day 6, they received a single injection of IDegAsp (0.6 U/kg, comprising 0.42 U/kg IDeg and 0.18 U/kg IAsp). Pharmacodynamic response was assessed using a 30-h euglycemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/L.Results: The glucose infusion rate profile showed a rapid onset of action and a distinct peak due to IAsp, followed by a separate, flat and stable basal glucose-lowering effect due to the IDeg component. Modeling data suggested that the pharmacodynamic profile of IDegAsp was retained with twice-daily dosing (allowing for coverage of two main meals daily). IDegAsp was well tolerated and no safety issues were identified in this trial.Conclusions: In conclusion, the IAsp component of IDegAsp has a fast onset of appearance and a peak covering the prandial phase, while the IDeg component has a flat and an evenly distributed pharmacokinetic profile over 24 h. IDegAsp is the first co-formulation of a basal insulin analog with an ultra-long duration of action and a mealtime insulin analog in a single soluble injection. These properties translate into clinically relevant benefits, including improved glycemic control and reduction in hypoglycemia. © 2014, The Author(s).


Meier J.J.,Ruhr University Bochum | Pennartz C.,Ruhr University Bochum | Schenker N.,Ruhr University Bochum | Menge B.A.,Ruhr University Bochum | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2013

Aim: Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion? Methods: Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis. Results: Insulin treatment lowered fasting glycaemia from 179.6±7.5mg/dl to 117.6±6.5mg/dl (p<0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p<0.0001). The total calculated insulin secretion rate increased with insulin treatment (p=0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r2=0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r2=0.0073 and 0.031). Conclusions: Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous β-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes. © 2012 Blackwell Publishing Ltd.


Plum L.,Columbia University | Plum L.,Profil Institute for Metabolic Research | Lin H.V.,Columbia University | Aizawa K.S.,Columbia University | And 2 more authors.
PLoS ONE | Year: 2012

Insulin receptor (InsR) signaling through transcription factor FoxO1 is important in the development of hypothalamic neuron feeding circuits, but knowledge about underlying mechanisms is limited. To investigate the role of InsR/FoxO1 signaling in the development and maintenance of these circuits, we surveyed the pool of hypothalamic neurons expressing Pomc mRNA in different mouse models of impaired hypothalamic InsR signaling. InsR ablation in the entire hypothalamus did not affect Pomc-neuron number at birth, but resulted in a 25% increase, most notably in the middle arcuate nucleus region, in young adults. Selective restoration of InsR expression in POMC neurons in these mice partly reversed the abnormality, resulting in a 10% decrease compared to age-matched controls. To establish whether FoxO1 signaling plays a role in this process, we examined POMC neuron number in mice with POMC-specific deletion of FoxO1, and detected a 23% decrease in age-matched animals, consistent with a cell-autonomous role of InsR/FoxO1 signaling in regulating POMC neuron number, distinct from its established role to activate Pomc transcription. These changes in Pomc cells occurred in the absence of marked changes in humoral factors or hypothalamic NPY neurons. © 2012 Plum et al.

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