Diabetogenic Side Effects Research Articles

Oncodiabetology III. The relationship of antineoplastic therapies and carbohydrate metabolism

The epidemiological indicators of malignant diseases and diabetes are changing similarly, as lately both have been dynamically increasing worldwide. They occur usually in the same patient synchronously or metachronously, because of their common metabolic and molecular background. Consequently, in more and more cases they require common treatment. That has led to a new science, called oncodiabetology, the main purpose of which is to optimize the combination of antineoplastic and antidiabetic therapies. Regarding the antineoplastic agents, their complex influence on metabolism has to be considered, especially diabetogenic side effects inducing insulin-resistance and decreasing insulin production. According to antidiabetic agents’ role in preventing tumors, diminishing toxicity of cytostatic drugs, and promoting the breakthrough of chemoresistance should be considered. In this study, we investigate the contexts of antineoplastic agents’ efficiency and the glucometabolism of the organization, the characteristics of oncotherapy in patients suffering from malignant disease and diabetes, and review those cytostatic agents, having massive diabetogenic adverse effects. We describe the properties and subtypes of secondary diabetes, thoroughly discuss the specific characteristics of hyperglycaemia and diabetes caused by malignant diseases and antineoplastic treatments, especially pancreatic diabetes. In the end, we attempt to determine the proper place and role of oncodiabetology in the treatment of patients suffering from malignancies. During our investigation, we assessed the effects on glucometabolism of the recently used classic cytostatics, molecularly targeted therapies and different endocrine manipulations treating malignancies. We reviewed the schedules and scientific background of almost 300 medicines for this aim. We established that every third antineoplastic agent influenced glucometabolism adversely. We report our further observations in our next reviews.

Antipsychotics inhibit the mitochondrial bioenergetics of pancreatic beta cells isolated from CD1 mice

Antipsychotics (APs) are widely used medications with reported diabetogenic side effects. This study investigated the effect of commonly used APs, namely chlorpromazine (CPZ), haloperidol (HAL) and clozapine, on the bioenergetics of male CD1 mice isolated pancreatic beta cells as an underlying mechanism of their diabetogenic effects. The effect of APs on Alamar blue reduction, adenosine triphosphate (ATP) production and glucose-stimulated insulin secretion (GSIS) of isolated beta cells was evaluated. Then, the effects of APs on the activities of mitochondrial complexes and their common coding genes expression, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and lactate production were investigated. The effects of APs on the mitochondrial membrane fluidity (MMF) and mitochondrial membrane fatty acid composition were also examined. Results showed that the tested APs significantly decreased cellular ATP production and GSIS of the beta cells. The APs significantly inhibited the activities of mitochondrial complexes and their coding gene expression, MMP and OCR of the treated cells, with a parallel increase in lactate production to different extents with the different APs. CPZ and HAL showed increased MMF and mitochondrial membrane polyunsaturated fatty acid content. In conclusion, the tested APs-induced mitochondrial disruption can play a role in their diabetogenic side effect.

Daucane esters from laserwort (Laserpitium latifolium L.) inhibit cytokine and chemokine production in human lung epithelial cells

BackgroundLaserwort, Laserpitium latifolium L. (Apiaceae), is a European medicinal plant. Its roots and rhizomes were traditionally used as a general tonic and to treat inflammatory and infective diseases. PurposeThe anti-inflammatory potential of daucane esters, isolated from underground parts extract of L. latifolium and specific structural features that contribute to their activity were investigated. In addition, we studied their interference with the transactivation capacity of the Glucocorticoid Receptor when added together with a classic glucocorticoid (GC), dexamethasone (DEX). This particular property may be relevant in combination strategies, attempting to circumvent diabetogenic side effects of glucocorticoids upon long-term anti-inflammatory treatments. Materials and methodsNine L. latifolium daucane esters were isolated and elucidated as derivatives of desoxodehydrolaserpitin, laserpitin and a novel 2β-esterified laserpitinol analogue. Of all compounds effects on NF-κB- and AP-1-driven pro-inflammatory pathways were assessed using TNF- or PMA-induced reporter gene analysis in A549 cells. Daucanes with a strong and concentration-dependent inhibition of both NF-κB and AP-1, were tested for a potential effect on DEX-stimulated GR-driven Glucocorticoid Response Element (GRE) reporter gene activity. In addition, GRE-driven anti-inflammatory mRNA expression was determined (GILZ and DUSP1). Also anti-inflammatory properties were validated by monitoring effects on CCL-2, IL-6, IL-1β mRNA expression levels (qPCR) and on CCL-2 chemokine production (ELISA). ResultsDaucanes featuring an ester moiety and/or a hydroxy group at positions 2β, 6α and 10α and especially the novel 2β-esterified laserpitinol derivative that, in comparison to other isolated compounds, features an additional 9α-hydroxy group, demonstrated suppression of both NF-κB- and AP-1-dependent pro-inflammatory pathways. Remarkably, those entities competitively and concentration-dependently repressed GR-driven GRE-dependent reporter gene activities. The most active compounds inhibited CCL-2 protein excretion and compound 4 downregulated genes coding for IL-1β and IL-6 induced upon TNF treatment in A549. In absence of TNF, compound 4 upregulated the GRE-mediated anti-inflammatory gene GILZ, but not DUSP1. ConclusionsDaucane esters are novel anti-inflammatory agents that may, in combination with GCs, potentially improve therapeutic benefit. These results contribute to the ongoing search for novel anti-inflammatory agents as safer alternatives to, or with, GCs.

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes.

Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

Detection and in vitro metabolism of AOD9604.

AOD9604 is a peptide consisting of the C-terminal fragment of human growth hormone from amino acids 177-191 with an additional tyrosine residue at the N-terminus of the peptide. It is reported to mimic the lipolytic properties of growth hormone without the diabetogenic side effects. Therefore, AOD9604 may be used as a performance enhancing drug and is banned by the World Anti-doping Agency (WADA). The peptide is available on several Internet websites and was recently identified in confiscated vials in the USA. To detect abuse of the peptide in athletes, a solid-phase extraction method was validated in urine with a limit of detection of 50 pg/mL. The method has good linearity, precision (<20%), specificity and recovery (62%). Six potential metabolites of the peptide were identified after incubation of AOD9604 in serum and urine. Quantification of the metabolites in serum identified a single metabolite, consisting of amino acids CRSVEGSCG, which is significantly more stable than the other metabolites or the parent compound. Screening for AOD9604 and the stable metabolite may potentially allow an increased window of detection.

Reduced Insulin Sensitivity as a Marker for Acute Mountain Sickness?

Reduced insulin sensitivity might increase the susceptibility to acute mountain sickness (AMS). The diabetogenic side effects of dexamethasone should therefore be considered for AMS treatment. To examine whether reduced insulin sensitivity is predictive of AMS and how it is affected by dexamethasone at high altitude, we analyzed endocrine and metabolic parameters obtained from healthy mountaineers in Zurich (LA; 490 m), and 2 and 4 days after fast ascent to the Capanna Regina Margherita (HA2, HA4; 4559 m). 14 of 25 participants developed AMS and were treated with dexamethasone starting in the evening of HA2. Before and after ingestion of an 1800 kJ meal, plasma was analyzed for erythropoietin (EPO) and cholecystokinin (CCK). Insulin sensitivity (HOMA-S) and beta cell activity were calculated. HOMA-S (p<0.01) and EPO levels (p<0.05) were lower in Zurich in the group developing AMS and given dexamethasone, i.e., before treatment and exposure to hypoxia. CCK was lower (p<0.01) and glucose and insulin were higher on HA4 in the dexamethasone group compared to the untreated group. Individuals with low baseline insulin sensitivity and low baseline EPO levels were more susceptible to AMS. Reduced CCK may contribute to the beneficial effect of dexamethasone on high altitude anorexia. However, reduced insulin sensitivity questions the widespread use of dexamethasone to prevent/treat AMS.

Antidepressant drug use and future diabetes risk

Antidepressant drug use and future diabetes risk

Preclinical In vivo Study of New Insulin-Like Growth Factor-I Receptor–Specific Inhibitor in Ewing's Sarcoma

Small-molecule insulin-like growth factor-I receptor (IGF-IR)-specific tyrosine kinase inhibitors have been recently proposed as clinically viable approaches to impair IGF-IR functions. NVP-AEW541 seems one of the most promising agents. In this article, we point out its effects against migration, metastasis, vasculogenicity, and angiogenesis of Ewing's sarcoma cells. In vivo NVP-AEW541 effectiveness was analyzed against TC-71 Ewing's sarcoma growth and bone metastasis after cell inoculation in athymic mice. Activity of the compound against angiogenesis as well as vasculogenesis properties was also considered both in vitro and in xenografts. Serum glucose, urea, transaminase levels, as well as other signs of distress were checked in mice treated with the IGF-IR inhibitor. Significant inhibition of migration, metastasis, vasculogenicity, and angiogenesis was recorded after treatment of Ewing's sarcoma cells with NVP-AEW541. In view of its application and the similarity of insulin receptor and IGF-IR, diabetogenic side effects were considered. We observed a significant decrease of glucose blood serum due to increased glucose uptake at cellular level and an increase in urea concentration. Moreover, an initial weight loss was observed in mice bearing tumors. All these side effects were similarly detected in mice treated with vincristine. After the first days of treatment, all the animals started to grow again. Our results globally reinforce the idea that IGF-IR inhibitor NVP-AEW541 could have a role in future combined therapies and suggest to pursue a thorough molecular analysis of the metabolic activity of IGF-IR to avoid possible side effects of these inhibitors.

Achieving and Maintaining Insulin Independence in Human Islet Transplant Recipients

For islet transplants to complete the transition from clinical research to clinical care restoration of insulin independence must be achieved--as with pancreas transplants--with a single donor. To achieve this critical milestone more consistently it will be imperative to pursue the following complementary strategies simultaneously: 1) enhancing the metabolic potency, inflammatory resilience, and immune stealth of isolated islets; 2) inhibiting the thrombotic and inflammatory responses to transplanted islets; and 3) achieving immune protection with strategies lacking diabetogenic side effects. Maintaining insulin independence will be a different challenge requiring us to clarify whether failure of initially successful islet allografts in type 1 diabetes is related: to 1) failure of immunosuppressive regimens to control alloimmunity and autoimmunity; 2) failure of islet regeneration in the presence of currently applied immunosuppressive regimens; and/or 3) failure of islet neogenesis in the absence of an adequate mass and viability of co-transplanted/engrafted islet precursor cells.

Genetic dissection of corticosteroid receptor function in mice.

Functional genomic technologies, including artificial chromosome-based transgenesis and conditional gene targeting, allowed us to generate mouse models harboring genes with loss-of-function mutations, gain-of-function mutations, spatially and/or temporally restricted mutations, tissue-specific mutations, and function-selective mutations. This kind of "allelic series" for corticosteroid receptors in mouse models provides a very useful resource for the molecular understanding of corticosteroid function in vivo. These models will also support the identification of steroid receptor target genes in order to define a steroid signaling cascade in molecular terms. They provide opportunities for the identification of compounds that regulate steroid receptors in a tissue-specific and function-selective manner. For example, selective glucocorticoid receptor modulators preventing receptor dimerization and DNA binding can be expected to reduce osteoporotic and/or diabetogenic side effects, but to display partial or full anti-inflammatory potential. Thus, these mouse models will help to evaluate distinct steroid receptor functions for therapeutic intervention.

Update on the status of pancreas-kidney transplantation.

Patient and graft survival rates after combined kidney and pancreas transplantation continue to improve. Percutaneous and cystoscopic pancreas biopsies are safe and aid in the diagnosis of acute rejection. Primary enteric drainage of pancreatic exocrine secretions is being re-evaluated to avoid the morbidity associated with bladder drainage. The use of FK506 might reduce the number of acute rejection episodes with no diabetogenic side effects. More studies have been presented which demonstrate that pancreas transplantation might improve diabetic microangiopathy and polyneuropathy and protect the transplanted kidney from diabetic nephropathy.

Augmentation of postresection mucosal hyperplasia by plerocercoid growth factor (PGF). Analog of human growth hormone.

Postresection villus hyperplasia is a major compensatory mechanism in the short-bowel patient. Substances capable of augmenting postresection mucosal hyperplasia could have therapeutic implications. Human growth hormone (hGH) and human growth hormone releasing factor (hGHRF) stimulate growth of the gastrointestinal tract; however, the diabetogenic actions of growth hormone limit its usefulness in clinical practice. Plerocercoid larvae of the tapeworm Spirometra mansonoides produce an analog of hGH void of diabetogenic side effects. We assessed effects of plerocercoid growth factor (PGF) on mucosal adaptation following 70% proximal jejunoileal resection in young rats. Mucosal weight, DNA, protein, and total sucrase activity per centimeter of bowel were increased in resected PGF-treated animals compared to resected controls. We conclude PGF augments intrinsic postresection mucosal hyperplasia following extensive intestinal resection.