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Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine–hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.

OBJECTIVE--We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the [...]

OBJECTIVE--To examine insulin's effect on the tissue glucose concentration at the site of subcutaneous insulin administration. RESEARCH DESIGN AND METHODS--A CMA-60 microdialysis (MD) catheter and a 24-gauge microperfusion (MP) catheter [...]

OBJECTIVE--To simplify and improve the treatment of patients with type 1 diabetes, we ascertained whether the site of subcutaneous insulin infusion can be used for the measurement of glucose. RESEARCH [...]

OBJECTIVE--This study investigated the effect of moderate exercise on the absorption of inhaled insulin via the AERx insulin diabetes management system (iDMS). RESEARCH DESIGN AND METHODS--In this randomized, open-label, four-period, [...]

OBJECTIVE--Physiologically elevated insulin concentrations promote access of macromolecules to skeletal muscle in dogs. We investigated whether insulin has a stimulating effect on the access of macromolecules to insulin-sensitive tissues in [...]

OBJECTIVE--To evaluate a fully automated algorithm for the establishment of tight glycemic control in critically ill patients and to compare the results with different routine glucose management protocols of three [...]

OBJECTIVE--To investigate the pharmacodynamic profile and duration of action for five subcutaneous doses of insulin detemir (0.1, 0.2, 0.4, 0.8, and 1.6 units/kg; 1 unit = 24 nmol) and one [...]

OBJECTIVE -- To evaluate the influence of regular chiropodist care on the recurrence rate of diabetic foot ulcers within 1 year. RESEARCH DESIGN AND METHODS -- Ninety-one diabetic outpatients with [...]

OBJECTIVE -- Both rapid-acting insulin analogs, insulin aspart and lispro, attenuate prandial glucose excursion compared with human soluble insulin. This trial was performed to study the pharmacokinetic and pharmacodynamic profiles [...]

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Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation.

Patient education in diabetes has become an integral part of diabetes management (1-3). Systematic reviews report the best results in terms of improved metabolic control, weight loss, and diabetes-related knowledge [...]

AbstractObjectivesThe present cost–consequence analysis compared estimated hospitalization costs in a Canadian setting with insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk.MethodsMedical terms were mapped across the different vocabularies, in order to assign unit costs from eligible hospital abstracts in Canadian Institute for Health Information data (International Statistical Classification of Diseases and Related Health Problems, 10thRevision, Canada) to serious adverse events (SAEs; Medical Dictionary for Regulatory Activities) from the randomized DEVOTE trial comparing the two insulins degludec and glargine. Mean annual costs of SAE-related hospitalizations were estimated by treatment, the cost difference (degludec − glargine U100) was bootstrapped to compute confidence intervals (CIs) and p-values, and the cost ratio (degludec/glargine U100) was estimated using a Tweedie distribution.ResultsThe mean annual cost per patient for SAE-related hospitalizations was 4,074 CAD with degludec and 4,569 CAD with glargine U100 (cost difference: −495, 95% confidence interval [CI]: −966; −24, p = .039), for a cost ratio of 0.89 (95% CI: 0.81; 0.98, p = .016). Overall, cost ratios from sensitivity analyses varying individual methodological assumptions were consistent with the main analysis. Of the system organ classes from DEVOTE SAEs, cardiac disorderswere the largest contributor to the costs savings with degludec versus glargine U100.ConclusionsIn patients with T2D at high CV risk, our findings suggest that there are likely to be lower hospitalization costs with degludec versus glargine U100 based on the SAEs observed in DEVOTE and in a Canadian setting.

Introduction:The main differential diagnoses of secondary hyperthyroidism include thyrotropin-secreting neuroendocrine pituitary tumors (TSH-PitNETs) and resistance to thyroid hormone. As a rare cause of secondary hyperthyroidism, ectopic thyrotropin-producing neuroendocrine pituitary tumors must also be considered. Case Presentation:A 48-year-old female patient with overt hyperthyroidism and elevated thyrotropin was admitted to the endocrine outpatient clinic of a secondary care hospital in March 2018. The patient had an inconspicuous pituitary MRI and F18-F-DOPA PET-CT, but showed a tumor mass located at the pharyngeal roof. Most biochemical tests and an increased tracer uptake of the pharyngeal mass in a Ga68-DOTANOC PET-CT argued for the presence of an ectopic TSH-PitNET. After treatment with octreotide over 5 days and a consecutive normalization of free thyroxine and free triiodothyronine, the tumor was endoscopically resected. Histologically, the mass consisted of small partially spindle, partially polygonal monomorphic to mildly pleomorphic cells with immunoreactivity for thyrotropin and luteinizing hormone. Postoperatively, the patient required intermittent levothyroxine therapy. Discussion and Conclusions:Ectopic TSH-PitNETs represent an extremely rare cause for secondary hyperthyroidism. While the diagnostic process may be complicated by negative imaging studies of the pituitary gland, family history, biochemical tests, and functional imaging using gallium-labelled somatostatin analogues may be helpful in establishing the diagnosis.

Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell–mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r−/−mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r−/−mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r−/−mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1mRNA expression. Together, Glp1r agonism protects mice from a T-cell–dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy.

Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg.

The AERx[TM] Diabetes Management System (AERx[TM]-DMS) provides aerosols of bolus insulin of a precisely controlled particle size that lead to efficient and reproducible delivery to the deep lung. Aim of [...]

THE EUROPEAN STUDY GROUP OP HOE 901 IN TYPE 1 DIABETES OBJECTIVE -- HOE 901 (Hoechst Marion Roussel, Frankfurt, Germany) is a biosynthetic insulin with a prolonged action. The aim [...]

Evaluation of the Single-Compartment Glucose Distribution Assumption in the Minimal Models Recent experimental evidence suggests that estimates of glucose effectiveness ([S.sub.G]) from the minimal model of unlabeled glucose disappearance (Cold-MM) [...]

Albumin is an important carrier protein for several metabolic products (e.g. free fatty acids). The 'true' albumin concentration in interstitial fluid of human peripheral tissue compartments is still a controversial [...]

NN304 is a long-acting insulin analog that is acylated with a 14-C-fatty acid chain. In contrast to NPH insulin protraction of action of NN304 is due not to slow absorption [...]

Insulin analogs with a rapid onset of action may provide satisfying pram dial glycemia even when injected after the meal. Quality of life for type 1 diabetic patients could thus [...]

Use of HC was associated with higher total 25(OH)D, whereas free 25(OH)D was not different between users and nonusers of HC.

Complete loss of β-cell function in patients with type 1 diabetes mellitus (T1DM) may lead to an increased risk of severe hypoglycemia.

Tight control of blood glucose concentration in people with type 1 diabetes predisposes to hypoglycaemia. We aimed to investigate whether day-and-night hybrid closed-loop insulin delivery can improve glucose control while alleviating the risk of hypoglycaemia in adults with HbA1cbelow 7·5% (58 mmol/mol).

Establishing accurate and precise analytical methods for vitamin D species is of rising importance as awareness of the vitamin D deficiency problem grows. Here, we report an analytical method for quantifying vitamin D and relevant vitamin D metabolites by high-resolution mass spectrometry (HRMS). We combine a straightforward time saving sample preparation and chromatographic separation, employing gradients and a column-switching technique, with high-resolution MS detection, extending its applicability to a broader range of relevant vitamin D metabolites. We calibrated the method to NIST standards and validated it for 25(OH)D2and 25(OH)D3. We also present short- and long-term sample-stability data and proof-of-concept by applying the method to serum samples from a healthy patient library that were previously measured by immunoassay. Compared to the immunoassay data, our method showed a good correlation of 25(OH)D3concentrations. Thus, we show that quantitative HRMS is now within reach of clinical diagnostics for vitamin D and its metabolites.

ABSTRACTLoss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the development of cardiovascular disease. Dietary spermidine elicits cardioprotective effects in aged mice through enhancing cardiac autophagy and mitophagy. In salt-sensitive rats, spermidine supplementation also delays the development of hypertensive heart disease, coinciding with reduced arterial blood pressure. The high blood pressure-lowering effect likely results from improved global arginine bioavailability and protection from hypertension-associated renal damage. The polyamine spermidine is naturally present in human diets, though to a varying amount depending on food type and preparation. In humans, high dietary spermidine intake correlates with reduced blood pressure and decreased risk of cardiovascular disease and related death. Altogether, spermidine represents a cardio- and vascular-protective autophagy inducer that can be readily integrated in common diets.

Spermidine is a naturally occurring polyamine involved in multiple biological processes, including DNA metabolism, autophagy and aging. Like other polyamines, spermidine is also indispensable for successful reproduction at several stages. However, a direct influence on the actual fertilization process, i.e., the fusion of an oocyte with a spermatocyte, remains uncertain. To explore this possibility, we established the mating process in the yeast Saccharomyces cerevisiaeas a model for fertilization in higher eukaryotes. During human fertilization, the sperm capacitates and the acrosome reaction is necessary for penetration of the oocyte. Similarly, sexually active yeasts form a protrusion called “shmoo” as a prerequisite for mating. In this study, we demonstrate that pheromone-induced shmoo formation requires spermidine. In addition, we show that spermidine is essential for mating in yeast as well as for egg fertilization in the nematode Caenorhabditis elegans. In both cases, this occurs independently from autophagy. In synthesis, we identify spermidine as an important mating component in unicellular and multicellular model organisms, supporting an unprecedented evolutionary conservation of the mechanisms governing fertilization-related cellular fusion.

Although hypertension is the most prevalent risk factor for cardiovascular and cerebrovascular morbidity and mortality, the level of blood pressure control remains poor. To amplify quality of care in hypertensive patients, a multifaceted program consisting of structured educational programs for both patients and staff, structured documentation and feedback reports with peer comparison, was implemented on a multicentre basis. Main targets were improvement of blood pressure control and reduction of cardiovascular risk. A provisional reimbursement was provided.

Raised levels of aldosterone, but also concentrations within the normal range are associated with elevated blood pressure. The authors of this Review assess evidence for the role of aldosterone in the development and maintenance of hypertension, including experimental and clinical studies, and discuss the genetic and environmental mechanisms that underlie its effects.

In this extensive Review, Stefan Pilz and colleagues discuss the potential mechanisms by which vitamin D might affect blood pressure and explore the clinical evidence for an association between vitamin D and arterial hypertension. The authors also make recommendations for vitamin D supplementation in patients with hypertension and 25-hydroxyvitamin D levels below target values.

This review summarizes the genetic advances of hereditary sensory neuropathies and hereditary sensory and autonomic neuropathies, and provides information on phenotype–genotype correlation and on possible underlying pathomechanisms.

We investigated the dynamic relationship between interstitial glucose (IG) in the subcutaneous adipose tissue and plasma glucose (PG) during physiologic conditions in type 1 diabetes mellitus (T1DM). Nine subjects with T1DM (5/4 M/F; age, 33 ± 13 years; body mass index, 26.6 ± 4.3 kg/m2; glycosylated hemoglobin [HbA1c], 8.6% ± 0.9%; mean ± SD) treated by continuous subcutaneous insulin infusion (CSII) with insulin lispro were studied over 12 hours after a standard meal (40 g carbohydrate [CHO]) and prandial insulin. IG was measured by open flow microperfusion. Nine compartment models were postulated to account for temporal variations in the IG/PG ratio. The models differed in the inclusion of physiologically motivated alterations of pathways entering/leaving the IG compartment in the adipose tissue. The best model included zero order (constant) glucose disposal from the interstitial fluid (ISF) and insulin-stimulated glucose transfer from plasma to the ISF. The former effect is expressed by a positive association between the IG/PG ratio and PG, eg, a decrease in PG from 9 to 3.3 mmol/L lowers the IG/PG ratio by 0.1. The latter effect results in the IG/PG ratio to be increased by 0.03 per 10 mU/L of plasma insulin. We were not able to detect the stimulatory effect of insulin on glucose disappearance from the ISF. In conclusion, we developed and quantified a model of IG kinetics in the adipose tissue applicable to physiologic conditions in subjects with T1DM.

The objective of the project Advanced Insulin Infusion using a Control Loop (ADICOL) was to develop a treatment system that continuously measures and controls the glucose concentration in subjects with type 1 diabetes. The modular concept of the ADICOL's extracorporeal artificial pancreas consisted of a minimally invasive subcutaneous glucose system, a handheld PocketPC computer, and an insulin pump (D-Tron, Disetronic, Burgdorf, Switzerland) delivering subcutaneously insulin lispro. The present paper describes a subset of ADICOL activities focusing on the development of a glucose controller for semi-closed-loop control, an in silico testing environment, clinical testing, and system integration. An incremental approach was adopted to evaluate experimentally a model predictive glucose controller. A feasibility study was followed by efficacy studies of increasing complexity. The ADICOL project demonstrated feasibility of a semi-closed-loop glucose control during fasting and fed conditions with a wearable, modular extracorporeal artificial pancreas.

Men with noninsulin-dependent diabetes mellitus (type 2 DM) provide a different subcutaneous body fat distribution and a concentration of fatness on the upper trunk compared with healthy subjects. However, subcutaneous fat distribution is always measured in an inaccurate and/or very simplified way (e.g., by caliper), and to date, there exists no study reporting on the exact and complete subcutaneous adipose tissue distribution of type 2 DM men. A new optical device, the LIPOMETER, enables the nonivasive, quick, and safe determination of the thickness of subcutaneous adipose tissue layers at any given site of the human body. The specification of 15 evenly distributed body sites allows the precise measurement of subcutaneous body fat distribution, so-called subcutaneous adipose tissue topography (SAT-Top). SAT-Tops of 21 men with clinically proven type 2 DM (mean age of 57.5 ± 6.7 years) and 111 healthy controls of similar age (mean age 59.0 ± 5.4 years) were measured. In this paper, we describe the precise SAT-Top differences of these two groups and we present the multidimensional SAT-Top information condensed in a two-dimensional factor value plot. In type 2 DM men, especially in the upper trunk, SAT-Top is significantly increased (up to +50.7% at the neck) compared with their healthy controls. One hundred eleven of the 132 individuals (84.1%) are correctly classified (healthy or type 2 DM) by their subcutaneous fat pattern by stepwise discriminant analysis.

The quantification of obesity in respect to subcutaneous adipose tissue and fat distribution is a matter of interest. We recently reported on a new optical device, LIPOMETER, and its ability to measure the thickness of subcutaneous adipose tissue and its advantages compared with other methods. To describe the subcutaneous adipose tissue distribution of the human body in a precise, reproducible, and comparable manner, 15 well-defined body sites distributed from neck to calf on the right body side were used. This set of sites defines subcutaneous adipose tissue topography (SAT-Top). To visualize SAT-Top for subjects or groups, special SAT-Top plots were used. Subcutaneous adipose tissue distribution can be recognized easily with these techniques. SAT-Top of 590 healthy men and women was measured. Factor analysis was used to extract the essential information from these 590*15 intercorrelated single measurements and to provide standard factor coefficients for later applications. As an example of how to use the results of factor analysis, the strong SAT-Top deviation of women with clinically proven type-2 diabetes mellitus (NIDDM) from healthy controls is described. Am. J. Hum. Biol. 12:231–239, 2000. © 2000 Wiley-Liss, Inc.

A newly developed optical device was applied to measure the subcutaneous adipose tissue (SAT) thickness of 20 healthy women and 18 healthy men at specified body sites. These measurements were used to derive equations to estimate percentage total body fat (TBF%). Total body electrical conductivity (TOBEC) was employed as a reference method; caliper techniques and measurements of absorbances of infrared light in fat versus lean tissue were also compared. The LIPOMETER results show good agreement with TOBEC data (r = 0.96). The technique allows the precise determination of the distribution of SAT thickness at specified body sites. The method also permits the construction of profiles of SAT thicknesses, e.g., the profiles are significantly different between women and men. Based on the normal profiles of healthy subjects, patients with proven type-2 diabetes mellitus were also evaluated. The patients showed significantly different profiles. By linear discriminant analysis, classification functions were extracted with good predictive accuracy classification of subjects according to the presence or absence of type-2 diabetes mellitus. The data suggest that measurement of SAT thickness might aid in the diagnosis and/or classification of metabolic disorders. Am. J. Hum. Biol. 12:221–230, 2000. © 2000 Wiley-Liss, Inc.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophilaaging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.

As the major lysosomal degradation pathway, autophagy represents the guardian of cellular homeostasis, removing damaged and potentially harmful material and replenishing energy reserves in conditions of starvation. Given its vast physiological importance, autophagy is crucially involved in the process of aging and associated pathologies. Although the regulation of autophagy strongly depends on nutrient availability, specific metabolites that modulate autophagic responses are poorly described. Recently, we revealed nucleo-cytosolic acetyl-coenzyme A (AcCoA) as a phylogenetically conserved inhibitor of starvation-induced and age-associated autophagy. AcCoA is the sole acetyl-group donor for protein acetylation, explaining why pharmacological or genetic manipulations that modify the concentrations of nucleo-cytosolic AcCoA directly affect the levels of protein acetylation. The acetylation of histones and cytosolic proteins inversely correlates with the rate of autophagy in yeast and mammalian cells, respectively, despite the fact that the routes of de novo AcCoA synthesis differ across phyla. Thus, we propose nucleo-cytosolic AcCoA to act as a conserved metabolic rheostat, linking the cellular metabolic state to the regulation of autophagy via effects on protein acetylation.

The multifaceted process of aging inevitably leads to disturbances in cellular metabolism and protein homeostasis. To meet this challenge, cells make use of autophagy, which is probably one of the most important pathways preserving cellular protection under stressful conditions. Thus, efficient autophagic flux is required for healthy aging in many if not all eukaryotic organisms. The regulation of autophagy itself is affected by changing metabolic conditions, but the precise metabolic circuitries are poorly understood. Recently, we found that the nucleocytosolic pool of acetyl-coenzyme A (AcCoA) functions as a major and dominant suppressor of cytoprotective autophagy during aging. Here, we propose an epigenetic mechanism for AcCoA-mediated autophagy suppression that causally involves the regulation of histone acetylation and changes in the autophagy-relevant transcriptome.

Diabetes management can be especially complex for older adults who receive health care at home. Thus, international guidelines recommend basal-insulin regimens due to simpler handling and low hypoglycaemia risk. A basal-insulin algorithm (including basal-plus) was developed to also include participant's health status and subsequently implemented into a tablet-based workflow and decision support system, GlucoTab@MobileCare. This study protocol describes a proof-of-concept study to investigate user acceptance, safety and efficacy of the GlucoTab@MobileCare system in participants receiving home health care.