Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study.

BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for both insulin-dependent and non-insulin-dependent diabetes. We sought to clarify the pathophysiology of diabetes after abdRT by performing dynamic studies of insulin and glucose and testing for type 1 diabetes-associated autoantibodies. PROCEDURE: Cross-sectional analysis of 2-year childhood cancer survivors treated with abdRT at age ≤21 years who underwent oral glucose tolerance testing and assessment of diabetes-related autoantibodies from December 2014 to September 2016. Prevalence of insulin/glucose derangements, indices of insulin sensitivity/secretion (homeostatic model assessment of insulin resistance [HOMA-IR], whole-body insulin sensitivity, insulinogenic index), autoantibody positivity, and treatment/demographic factors associated with adverse metabolic outcomes were assessed. RESULTS: Among 40 participants previously exposed to abdRT (57.5% male; median age at cancer diagnosis, 3.3 years [range, 0.5-20.1]; median age at study 14.3 years [range, 8.3-49.8]; none with obesity), 9 (22.5%) had glucose derangements (n = 4 with impaired fasting glucose [≥100 mg/dL]; n = 4 with impaired glucose tolerance [2-hour glucose 140-199 mg/dL]; n = 1 with previously unrecognized diabetes [2-hour glucose ≥200 mg/dL]). Three of the four individuals with impaired fasting glucose also had insulin resistance, as measured by HOMA-IR; an additional four subjects with normal glucose tolerance were insulin resistant. The subject with diabetes had normal HOMA-IR. No participant had absolute insulinopenia or >1 positive diabetes-related autoantibody. CONCLUSIONS: This study suggests that radiation-induced damage to the insulin-producing ß-cells is an unlikely explanation for the early derangements in glucose metabolism observed after abdRT. Research into alternative pathways leading to diabetes after abdRT is needed.

A metabolomic study on the effect of intravascular laser blood irradiation on type 2 diabetic patients.

Intravenous laser blood irradiation (ILBI) is widely applied in the treatment of different pathologies including diabetes mellitus. The aim of this study is to evaluate the effects of ILBI on the metabolites of blood in diabetic type 2 patients using metabolomics. We compared blood samples of nine diabetic type 2 patients, using metabolomics, before and after ILBI with blue light laser. The results showed significant decrease in glucose, glucose 6 phosphate, dehydroascorbic acid, R-3-hydroxybutyric acid, L-histidine, and L-alanine and significant increase in L-arginine level in blood and blood sugar in the patients have reduced significantly (p < 0.05). This study clearly demonstrated a significant positive effect of ILBI on metabolites of blood in diabetic type 2 patients. These findings support the therapeutic potential of ILBI in diabetic patients.

[The development of method of intravenous laser irradiation of blood with green laser in patients with hyperlipidemia].

The impact of intravenous laser irradiation of blood with green laser in patients with hyperlipidemia was investigated. The blood of patients was chosen as sample for analysis. The patients were divided in two groups: patients with atherosclerosis of various localization and patients with atherosclerosis associated with diabetes mellitus. The effectiveness of laser impact was evaluated according the blood biochemical indicators. The levels of crude cholesterol, triglycerides, low and very low density lipoproteins, apoproteins A and B, highly sensitive C-reactive protein, atherogenity indicator, glucose content, uric acid content were determined befor and after 1, 3 and 6 months after impact. The study results indicate the occurrence of hypolipedemic and hypoglycemic effects.

Can photobiomodulation therapy (PBMT) control blood glucose levels and alter muscle glycogen synthesis?

Photobiomodulation therapy (PBMT) has many effects on the energy metabolism of musculoskeletal tissue, such as increased glycogen and adenosine triphosphate synthesis. In addition, these effects may be due to a systemic blood glucose control. Twenty-four Wistar rats were randomly and equally allocated into four groups: sham, PBMT 10 J/cm2, PBMT 30 J/cm2 and PBMT 60 J/cm2. The animals were fasting for 6 h for blood glucose evaluations during pre-irradiation period, 1 h, 3 h and 6 h after PBMT. Muscle glycogen synthesis was measured 24 h after PBMT. This PBMT used a cluster of 69 LEDs (light-emitting diodes) with 35 red (630 ± 10 nm) and 34 infrared (850 ± 20 nm); 114 mW/cm2 for 90s (10 J/cm2), 270 s (30 J/cm2), 540 s (60 J/cm2) applied on large muscle areas (back and hind legs) of the animals. The 10 J/cm2 group showed lower blood glucose levels and glucose variability over 6 h (5.92 mg/dL) compared to the sham (13.03 mg/dL), 30 J/cm2 (7.77 mg/dL) and 60 J/cm2 (9.07 mg/dL) groups. The PBMT groups had the greatest increase in muscle glycogen (10 J/cm2 > 60 J/cm2 > 30 J/cm2 > sham), characterizing a triphasic dose-response of PBMT. There was a strong negative correlation between blood glucose variability over 6 h and muscle glycogen concentration for 10 J/cm2 group (r = -0.94; p < .001) followed by 30 J/cm2 group (r = -0.84; p < .001) and 60 J/cm2 group(r = -0.73; p < .006). These results suggest that PBMT can play a very important role in the control of blood glucose levels, and its possible mechanism of action is the induction of greater muscle glycogen synthesis independently of physical exercise.

Dirty electricity elevates blood sugar among electrically sensitive diabetics and may explain brittle diabetes.

Transient electromagnetic fields (dirty electricity), in the kilohertz range on electrical wiring, may be contributing to elevated blood sugar levels among diabetics and pre-diabetics. By closely following plasma glucose levels in four Type 1 and Type 2 diabetics, we find that they responded directly to the amount of dirty electricity in their environment. In an electromagnetically clean environment, Type 1 diabetics require less insulin and Type 2 diabetics have lower levels of plasma glucose. Dirty electricity, generated by electronic equipment and wireless devices, is ubiquitous in the environment. Exercise on a treadmill, which produces dirty electricity, increases plasma glucose. These findings may explain why brittle diabetics have difficulty regulating blood sugar. Based on estimates of people who suffer from symptoms of electrical hypersensitivity (3-35%), as many as 5-60 million diabetics worldwide may be affected. Exposure to electromagnetic pollution in its various forms may account for higher plasma glucose levels and may contribute to the misdiagnosis of diabetes. Reducing exposure to electromagnetic pollution by avoidance or with specially designed GS filters may enable some diabetics to better regulate their blood sugar with less medication and borderline or pre-diabetics to remain non diabetic longer.

Effects of Daytime Exposure to Light from Blue-Enriched Light-Emitting Diodes on the Nighttime Melatonin Amplitude and Circadian Regulation of Rodent Metabolism and Physiology.

Regular cycles of exposure to light and dark control pineal melatonin production and temporally coordinate circadian rhythms of metabolism and physiology in mammals. Previously we demonstrated that the peak circadian amplitude of nocturnal blood melatonin levels of rats were more than 6-fold higher after exposure to cool white fluorescent (CWF) light through blue-tinted (compared with clear) rodent cages. Here, we evaluated the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit light rich in the blue-appearing portion of the visible spectrum (465-485 nm), compared with standard broadspectrum CWF light, on melatonin levels during the subsequent dark phase and on plasma measures of metabolism and physiology. Compared with those in male rats under a 12:12-h light:dark cycle in CWF light, peak plasma melatonin levels at the middark phase (time, 2400) in rats under daytime LED light were over 7-fold higher, whereas midlight phase levels (1200) were low in both groups. Food and water intakes, body growth rate, and total fatty acid content of major metabolic tissues were markedly lower, whereas protein content was higher, in the LED group compared with CWF group. Circadian rhythms of arterial plasma levels of total fatty acids, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were generally lower in LED-exposed rats. Therefore, daytime exposure of rats to LED light with high blue emissions has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing and thus may influence scientific outcomes.

Involvement of serotonin in the hypoglycemic response to 2 Hz electroacupuncture of zusanli acupoint (ST36) in rats.

In our previous studies, an insulin-dependent hypoglycemic effect produced by electroacupuncture (EA) was shown to be mediated by endogenous opioid peptides (EOP). In the present study, we applied 2 Hz EA to both zusanli acupoints (ST36) in the test group for 30 min, and to a nonacupoint area in the control group for 30 min to compare the acupoint specific character in the hypoglycemic effect of EA. Assays of plasma beta-endorphin and insulin levels were performed by ELISA kits. The insulin-dependent mechanism of the hypoglycemic effect was also investigated in streptozotocin (STZ)-induced diabetic rats. The mediation of EOP and the role of mu-opioid receptor were examined by naloxone and mu-opioid receptor knockout mice (MOR-KOM). The serotonin depletion was carried out by injecting (i.p.) p-chlorophenylalanine (PCPA); two low doses of serotonin were also injected (i.v.) to analyze the direct effect on plasma glucose levels. The hypoglycemic effect of EA was much greater in rats stimulated at ST36 than in rats receiving the same stimulation at the nonacupoint area. The plasma levels of insulin and beta-endorphin were also significantly elevated after stimulation of both zusanli acupoints, but remained unchanged following stimulation at the nonacupoint area. There was no sharp hypoglycemic response to 2 Hz EA at zusanli acupoint of STZ-induced diabetic rats. However, the hypoglycemic effect of this EA was not totally blocked by the sufficient dose of naloxone (1 mg/kg, i.v.). Additionally, 2 Hz EA at ST36 also showed a sharp decrease in plasma glucose levels of MOR-KOM. Pretreatment with PCPA did not reproduce hypoglycemic response to 2 Hz EA in naloxone-treated rats and MOR-KOM mice. Furthermore, injection of serotonin decreased the plasma glucose levels significantly. Therefore, we suggest that serotonin also involved in the hypoglycemic action of 2 Hz EA at both zusanli acupoints of normal rats.

Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles.

Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP-transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics.

Prevention of type I diabetes by low-dose gamma irradiation in NOD mice.

Pretreatment with nonlethal, low-dose irradiation has been shown to have a protective effect against oxidative injury in animal tissues. Since oxidative injury of tissues is known to be a major cause of many human diseases, we examined the effect of low-dose irradiation on the progression of type I diabetes in mice. Nonobese diabetic (NOD) mice were treated with gamma irradiation and the progression of the disease was monitored. An elevated level of glucose in urine was first detected at 15 weeks of age in the control NOD mice, whereas the detection was delayed as long as 7 weeks when the mice received a single dose of 0.5 Gy total-body irradiation between 12 and 14 weeks of age. The greatest effect was observed in the mice irradiated at 13 weeks of age. The increase in blood glucose and decrease in blood insulin were effectively suppressed by irradiation at 13 weeks of age. Both suppression of cell death by apoptosis and an increase in superoxide dismutase (SOD) activity were observed in the pancreas 1 week after irradiation. The results indicate that treatment with 0.5 Gy gamma rays suppresses progression of type I diabetes in NOD mice. This is the first report on the preventive effect of low-dose irradiation on disease progression.

Daily variations of blood glucose, acid-base state and PCO2 in rats: effect of light exposure.

The suprachiasmatic nuclei (SCN) of the hypothalamus are the site of the main circadian clock in mammals. Synchronization of the SCN to light is achieved by direct retinal inputs. The present study performed in rats transferred to constant darkness shows that blood glucose, pH and PCO2 display significant diurnal changes when measurements were made during the subjective day, the early subjective night or the late subjective night. The effects of a 30-min light exposure (100 lx) on these metabolic parameters at each of these circadian times were assessed. Regardless of the circadian time, light induced an increase in blood glucose, but did not affect plasma pH and PCO2. This study suggests that blood glucose, PCO2 and acid-base state are under circadian control, most likely mediated by the SCN, while the hyperglycemic response to light seems not to be gated by a circadian clock and may thus involve retinal inputs to non-SCN retino-recipient areas.

Mitochondrial dysfunction by gamma-irradiation accompanies the induction of cytochrome P450 2E1 (CYP2E1) in rat liver.

Multiple biological effects are induced by ionizing radiation through dysfunction of cellular organelles, direct interaction with nucleic acids and production of free radical species. The expression of cytochrome P450s was assessed in the livers of 60Co gamma-irradiated rats. Three gray (G) of gamma-irradiation caused CYP2E1 induction with a 3.6-fold increase in the mRNA at 24 h, whereas the expression of CYP1A2 and CYP3A was not changed. Pharmacokinetics of chlorzoxazone, a specific substrate of CYP2E1, was studied in 3 G-irradiated rats. The area under the plasma concentration-time curve from time zero to infinity of 6-hydroxychlorzoxazone and the amount of 6-hydroxychlorzoxazone excreted in 8 h urine were both significantly greater than those in control rats. Hepatic CYP2E1 was not induced in rats exposed to 0.5-1 G of gamma-rays. Rats irradiated at 6-9 G accumulated doses of gamma-rays exhibited smaller increases in the mRNA due to liver injury than those irradiated at a single dose of 3 G gamma-rays. The plasma glucose and insulin levels were not altered in rats with 3 G of gamma-irradiation. As the exposure level of gamma-irradiation increased, the activity of hepatic aconitase, a key enzyme in energy metabolism in mitochondria, was 30-90% decreased. The amount of mitochondrial DNA per gram of wet liver was 50% decreased in rats exposed to 3 G of gamma-rays. These results demonstrated that gamma-ray irradiation at the exposure level inducing organelle dysfunction induced CYP2E1 in the liver, which might be associated with mitochondrial damage, but not with alterations in glucose or insulin levels.

Effects of irradiation on red cells stored in CPDA-1 and CPD-ADSOL (AS-1).

Red blood cells (pRBC) collected in citrate, phosphate, dextrose, adenine-formula 1 (CPDA-1) and citrate, phosphate, dextrose-adenine, manitol saline solution (CPD-ADSOL [AS-1]) anticoagulants are increasingly being stored for variable periods in transfusion service inventories following irradiation. While anecdotal reports of increased K+ following irradiation and storage have recently appeared in the literature, concomitant in vitro biochemical changes resulting from differences in anticoagulants have not been reported. Utilizing two venipunctures, two units each of 225 mL of blood from five volunteers were collected in anticoagulant-adjusted CPDA-1 and AS-1 bags. Within two hours of collection, each unit was equally divided. One of each pair was irradiated (2000 rads). Samples were analyzed on Days 0, 1, 3, 7, and every seven days to expiration. Irradiation resulted in a 2.3 fold increase in K+ during the first seven days of storage for both anticoagulants, although significantly greater K+ levels were observed in the CPDA-1 pairs compared to the AS-1 pairs. Comparison of glucose utilization, plasma free hemoglobin, 2,3-diphosphoglycerate (2,3-DPG) and lactate dehydrogenase between control and irradiated CPDA-1 and AS-1 pairs and between anticoagulants were documented.

Tissue glycogen and blood glucose in irradiated rats. I. Effects of a single lethal x-irradiation.

Fed and starved (overnight) male rats of the Wistar strains were exposed to wholebody irradiation with 14.35 Gy (1 500 R) of X-rays. After irradiation and sham-irradiation all animals were starved up to the examination performed 1, 6, 24, 48 and 72 h after the treatment. Concentration of glucose in the blood and concentration of glycogen in the liver, heart, skeletal muscle, brown and white adipose tissue were determined. Concentration of blood glucose and liver glucogen was found to increase between 1 and 6 h after irradiation of the starved animals. The most pronounced increase of glycogen concentration in the liver and heart muscle was observed 24 and 48 h after irradiation. The fed and starved irradiated rats reacted differently particularly between 48 and 72 h, when the liver glycogen concentration decreased in the fed animals and remained elevated in the starved ones. Very high values of terminal glycemia were observed in both groups. Accumulation of glycogen in the heart muscle indicates that this organ is sensitive to ionizing radiation.

Tissue glucogen and blood glucose in irradiated rats. II. Effect of non-lethal doses of continuous gamma-radiation.

Male rats of the Wistar strain were continuously irradiated with an exposure of 0.57 Gy (60 R) of gamma-rays from a 60Co source. Irradiation lasted from 1 to 50 days in an experimental field, in which control animals shielded from radiation were also placed. After a 16-h starvation, concentration of glucose in the blood and of glycogen in the liver and heart was determined 1, 3, 7, 14, 21, 25, 32, 39 and 50 days after the beginning of irradiation. Concentration of blood glucose in irradiated rats did not practically differ from that of control animals during the whole period of investigation. Concentration of liver glycogen in irradiated animals was higher than that of the controls during all time intervals, except for day 1. Values of glycogen in the heart muscle were approximately identical in irradiated and control rats, except for day 21, on which they sharply increased in the irradiated animals. In addition to the investigation of blood glucose and tissue glycogen during continuous irradiation, we followed these parameters immediately, and 1, 6 and 12 months after continuous irradiation with a daily exposure of 0.57 Gy (60 R) up to a total exposure of 14.35 Gy (1 500 R) of gamma-rays. Considerably higher values of liver glycogen were detected in irradiated rats immediately and 1 and 6 months after the end of irradiation.

Metabolic changes after non-lethal x-irradiation of rats. I. Carbohydrates, hormones.

Male rats of the Wistar strain were fasted overnight prior to exposure to single total-body X-ray dose of 2.39 Gy (250 R). Irradiated and sham-irradiated rats were pair-fed for 5 days, in the next period they were fed ad libitum. The levels of corticosterone and immunoreactive insulin in serum, glucose in blood, glycogen in liver, heart and skeletal muscle were determined 1 and 6 h, 1, 2, 3, 7, 14, 28, and 38 days after irradiation and sham-irradiation. Irradiation of rats resulted, at one hour, in a decrease and, at two days, in an icrease in level of blood glucose. A marked increase in liver glycogen persisted from 6 h to 21 days after irradiation. The level of glycogen in the skeletal muscle was reduced at 6 h and increased on days 3 and 14. Heart muscle glycogen declined within the first 24 h and rose at 14 days after exposure. The kinetics of changes in the heart and skeletal muscle glycogen following non-lethal irradiation was similar and indicated an overlap of changes produced by fasting with those brought about by irradiation, particularly during the first week. Corticosterone in serum was markedly increased in rats at 24 and 72 h after irradiation compared to pair-fed controls. The serum insulin concentration did not change after irradiation, except for a single increase on day 21. Irradiation with non-lethal doses produced changes in the parameters of the carbohydrate metabolism studied, except for serum insulin, which reflected the changes in the nutrition regimen upon pair-feeding rather than the effect of ionizing irradiation.

Changes in whole-body metabolic parameters associated with radiation.

Continuous irradiation of experimental animals is an appropriate model for the research in space radiobiology. The onset and recovery of radiation injury can be estimated on the basis of the concentration/content of glycogen in liver, the phospholipid content in thymus and other radiosensitive organs and the triacylglycerol concentration in bone marrow. Further, the picture of the metabolism in irradiated organism may be completed by the analysis of serum glucocorticoid and thyroid hormone levels.

Influence of skin illumination on blood glucose level of the rabbit.

The effects of skin illumination with light beam on blood glucose level are tested on the rabbit. Significant difference in glucose values was observed only between continuous and discontinuous lighted animals 90 minutes after skin illumination (P less than 0.02).

[Elevation of serum glucose concentration after administration of 5'-AMP to rats and modulation of this process dynamics following single gamma-irradiation at 1 Gy dose]. / Povyshenie kontsentratsii gliukozy v krovi krys posle vvedeniia 5'-AMP i izmeneniie dinamiki étogo protsessa pod deistviem odnokratnogo gamma-oblucheniia v doze 1 Gr.

Injection of exogenic 5'-AMP to rats was accompanied by pronounced and transient adenosinemediated elevation of serum glucose concentration. Both efficiency and duration of the observed hyperglycemic effect were increased within the first week after single whole-body gamma-irradiation (137Cs) of the animals at 1 Gy dose. These data suggest modification of purinergic regulation of some processes of carbohydrate metabolism and disturbance of the organism tolerance towards the glucose following 1 Gy gamma-irradiation.

[The early reaction of the neuroendocrine system to irradiation at high doses]. / Ranniaia reaktsiia neiroéndokrinnoi sistemy pri obluchenii v vysokikh dozakh.

It has been found that in 2 hours after the total gamma irradiation of rats at doses of 20 and 100 Gy the ACTH and glucagon levels in plasma increased by 5-6 and 10-12 times correspondingly. No significant changes in levels of plasma insulin and glucose have been revealed.

[Energy metabolism during stressful exposures (ionizing radiation), its self-regulation and correction]. / Energeticheskii obmen pri stressovykh vozdeistviiakh (na primere ioniziruiushchei radiatsii), ego samoreguliatsiia i korrektsiia.

Normal hormonal regulation of energy metabolism is mainly realized by glucocorticoids and insulin, their physiological antagonist. Under the effect of different extremal factors (including ionizing radiation) there arises non-specific stress, a syndrome the main component of which is the hyperfunction of glucocorticoids--the intermediate hormonal link in the stress reaction. Stimulation of hypercorticism by administering hydrocortisone to intact animals as well as its stimulation by administering this preparation to irradiated animals causes development and intensification of inhibition and uncoupling of the oxidative phosphorylation as well as disturbance in adenylic nucleotides metabolism. The administered insulin, softening the reaction of hypercorticism and changing the ratio of the hormone levels in favour of insulin, weakens essentially the stress (ray) disturbances in the energy metabolism.