Glucose Metabolism In Diabetic Animals Research Articles

Deuterium-depleted water stimulates GLUT4 translocation in the presence of insulin, which leads to decreased blood glucose concentration

Deuterium (D) is a stable isotope of hydrogen (H) with a mass number of 2. It is present in natural waters in the form of HDO, at a concentration of 16.8 mmol/L, equivalent to 150 ppm. In a phase II clinical study, deuterium depletion reduced fasting glucose concentration and insulin resistance. In this study, we tested the effect of subnormal D-concentration on glucose metabolism in a streptozotocin (STZ)-induced diabetic rat model. Animals were randomly distributed into nine groups to test the effect of D2O (in a range of 25–150 ppm) on glucose metabolism in diabetic animals with or without insulin treatment. Serum glucose, fructose amine-, HbA1c, insulin and urine glucose levels were monitored, respectively. After the 8-week treatment, membrane-associated GLUT4 fractions from the soleus muscle were estimated by Western blot technique. Our results indicate that, in the presence of insulin, deuterium depletion markedly reduced serum levels of glucose, -fructose amine, and –HbA1c, in a dose-dependent manner. The optimal concentration of deuterium was between 125 and 140 ppm. After a 4-week period of deuterium depletion, the highest membrane-associated GLUT4 content was detected at 125 ppm. These data suggest that deuterium depletion dose-dependently enhances the effect of insulin on GLUT4 translocation and potentiates glucose uptake in diabetic rats, which explains the lower serum glucose, -fructose amine, and –HbA1c concentrations. Based on our experimental data, deuterium-depleted water could be used to treat patients with metabolic syndrome (MS) by increasing insulin sensitivity. These experiments indicate that naturally occurring deuterium has an impact on metabolic regulations.

Glucose consumption assay discovers coptisine with beneficial effect on diabetic mice

Many drugs with anti-diabetic effects regulate glucose consumption in peripheral tissues. Via cellular glucose consumption assays, we identified that coptisine, a main effective constituent from the plant Coptis chinensis, enhanced hepatic and skeletal muscle glucose consumption. We further explored its effects on glucose metabolism in diabetic animals to elucidate its mechanism of action. Our results showed that coptisine did not show cytotoxicity. Intragastric administration of coptisine for ten days in normal ICR mice markedly decreased fasting blood-glucose levels without significant effects on body weight. In alloxan-induced type 1 diabetic mice, intragastric administration of coptisine for 28 days decreased fasting and non-fasting blood-glucose levels as well. In type 2 diabetic KKAy mice, intragastric administration of coptisine for nine weeks improved glucose tolerance. It decreased fasting/non-fasting blood-glucose and fructosamine levels. Coptisine decreased low-density lipoprotein and total cholesterol levels, however, had no significant effect on triglyceride levels. Coptisine increased AMPK phosphorylation while decreasing Akt phosphorylation in HepG2 hepatic cells and C2C12 myotubes. Coptisine also reduced mitochondrial respiration in isolated and cellular mitochondria, suggesting that coptisine lowered cellular energy levels. In particularly, coptisine administration (10−6 M) decreased the mitochondrial oxygen consumption rate (OCR) with a greater extracellular acidification rate (ECAR), resulting in an oxidative-to-glycolysis phosphorylation shifted for cellular energy generation. Our results demonstrate that coptisine acts as an enhancer of peripheral glucose consumption could improve glucose metabolism in diabetic animals. Coptisine may serve as a novel anti-diabetic agent and warrant further evaluation.

Low dose doxycycline decreases systemic inflammation and improves glycemic control, lipid profiles, and islet morphology and function in db/db mice

The aim of this study was to determine whether low dose doxycycline as an anti-inflammatory agent could improve glucose metabolism in diabetic animals. Therefore, doxycycline was supplemented in drinking water to 6-week-old male db/db mice for 10 weeks. Doxycycline reduced perirenal/epididymal fat, Lee’s index, and liver cholesterol. Blood HDL-cholesterol increased, but total cholesterol and aspartate transaminase decreased. Glucose and insulin tolerances were improved, accompanying with reduced fasting blood glucose, insulin, HOMA-IR and advanced glycation end products. Islet number, β-cell percentage and mass increased, while islet size decreased. Consistently, less apoptosis but more β-cell proliferation were found in islets of treated mice. Freshly isolated islets from treated mice showed higher insulin content and enhanced glucose stimulated insulin secretion (GSIS). In addition, purified islets of Balb/c mice showed increased GSIS after cultivation in vitro with doxycycline, but not with chloramphenicol and levofloxacin. Inflammation markers, including lipopolysaccharides (LPS) and C-reactive protein (CRP) in serum as well as CD68-positive cells in treated islets, decreased significantly. Finally, LPS stimulated the production of inflammatory factors but inhibited GSIS of MIN6 cells; however, the effects were completely reversed by doxycycline. The results support further study of possible long-term usage of sub-antimicrobial doxycycline in diabetic patients.

L-Cysteine supplementation as an adjuvant therapy for type-2 diabetes

Diabetes remains a major public health issue. According to the American Diabetes Association, 23.5 million, or 10.7% of people in the USA aged 20 years and older, have diabetes. Type-2 diabetes is treated both by controlling the diet and with oral hypoglycemic drugs. However, for many patients, achieving a tight control of glucose is difficult with current regimens. This chapter discusses a relatively low-cost dietary supplement that could be used as an adjuvant therapy for type-2 diabetes. A review of the literature indicates that cysteine-rich whey protein improves glucose metabolism in diabetic animals and type-2 diabetic patients. Similarly, in animal studies, improvement in glucose metabolism is observed after supplementation with L-cysteine, or molecules containing a cysteine moiety. This chapter discusses the biochemical mechanisms by which L-cysteine can upregulate the insulin-dependent signaling cascades of glucose metabolism. Further studies are needed to examine whether clinical interventions using L-cysteine as an adjuvant therapy indeed help to control glycemia and vascular inflammation in the diabetic patient population.

Endocrinological function of brain‐derived neurotrophic factor in diabetic mice

We previously found that chronic administration of Brain‐derived neurotrophic factor (BDNF) ameliorates glucose metabolism in diabetic animals. This demonstrated a new concept that a neurotrophic factor plays endocrinological function as well as neurological one. However, the mechanism underlying this new function is still poorly understood. In this study, we investigated the acute effects of BDNF on glucose metabolism and energy expenditure in diabetic mice. First, a single subcutaneous (s.c.) (70 mg/kg) or intracerebroventricular (i.c.v.)(0.3 mg/kg) injection of BDNF immediately enhanced insulin‐dependent hypoglycemic action in streptozotocin‐induced diabetic mice. In liver of this model, s.c. BDNF injection rapidly increased insulin‐stimulated tyrosine phosphorylation of insulin receptors (3.8 fold) and PI 3‐kinase activity (1.8 fold). Since i.c.v. injection reproduced the similar actions, BDNF may act on the central nervous system and rapidly modulate insulin signal transduction in peripheral tissues. Next, we examined the acute effects of BDNF on energy expenditure. The body temperatures of hyperphagic and obese diabetic C57BL/KsJ‐db/db mice dropped remarkably in 24 h after food removal. A single s.c. (20 mg/kg) or i.c.v. (0.125 mg/kg) injection of BDNF to db/db mice prevented the reduction of body temperature. BDNF increased the norepinephrine turnover and uncoupling protein‐1 mRNA levels in brown adipose tissue of db/db mice. Taken together, these suggest that BDNF has the direct action on the central nervous system and then regulates glucose and energy metabolisms possibly through modulating the autonomic nervous system in diabetic animals.

Oral Glucose Tolerance Test After High-Dose i.v. Biotin Administration in Normoglucemic Hemodialysis Patients

Abnormal glucose metabolism in uremia may result from a complex interplay between decreased insulin secretion and insulin resistance. Recent studies report beneficial effect of biotin administration in glucose metabolism in diabetic animals and in a small number of patients with diabetes mellitus. The aim of the present study was to evaluate the response of oral glucose tolerance test (OGTT) to the i.v. administration of large doses of biotin in hemodialysis patients. Eleven hemodialysis patients aged 56.90 +/- 11.20 (32-76) years on regular hemodialysis thrice a week for 2.72 +/- 1.79 (1-7) years were studied. Fasting venous plasma glucose, glucosylated hemoglobin (%GH), and plasma glucose concentration 2 h after the administration of a 75-g glucose load were measured before, and 2 weeks and 2 months after administration of 50 mg of biotin i.v. postdialysis, and after a 2-month washout period. During the study, dialysis schedule and patients' medication, diet, and dry weight were kept unchanged. OGTT was abnormal in 4 patients before biotin administration and became normal in 3 patients (75%). Our results offer support to the findings of other studies about the beneficial effect of biotin in experimental or clinical diabetes mellitus, and argue for the involvement of biotin in glucose metabolism.

Effects of U46619 and of inhibitors of the synthesis of TXA 2 on insulin action on the metabolism of labelled glucose in uteri isolated from ovariectomized-diabetic rats

The production of 14CO 2 from labelled glucose by isolated uterine strips from ovariectomized-diabetic rats has been studied. U46619, an analogue of TXA 2 did not affect basal glucose metabolism; however, insulin-induced increment in CO 2 production was completely blocked, both in ovariectomized (OVD) or ovariectomized-estrogenized (OVED) diabetic uterus. OKY064 as well as UK38485, both inhibitors of TXA 2 synthesis, stimulated glucose metabolism (p<0.05) similar to that of insulin in uterine tissue from OVD and OVED rats. Inhibition in the synthesis and release of TXB 2 was detected (p<0.01) by uterine radioconversion of 14C-arachidonic acid when adding OKY38485 to the incubation medium, and the production of other prostanoids such as 6-keto-PGF 1α, PGF 2α and PGE 2 was enhanced. In summary, TXA 2 inhibited insulin-induced glucose metabolism in diabetic animals.

Effects of prostaglandins and of leukotriene C 4 on the metabolism of labelled glucose in uteri isolated from ovariectomized-diabetic rats. Influences of 17-beta-estradiol and of insulin

The influences of exogenous PGE 1, PGE 2, PGF 2α, LTC 4 and insulin (INS) on glucose oxidation in uterine strips isolated from ovariectomized-diabetic (OVD) and ovariectomized-estrogenized-diabetic (OVED) rats, were studied. The spayed animals were made diabetic by a single injection of streptozotocin (65 mg.kg −1 body weight). The effects of prostaglandins were studied in the presence of indomethacin (INDO) in the incubation medium and the effects of LTC 4 in the presence of INDO and nordihydroguaretic acid (NDGA). These procedures were followed in order to avoid the possible influences of endogenous derivatives of arachidonic acid formed by the activity of cyclooxygenase and of lipoxygenases. INDO and NDGA did not modify significantly the formation of 14CO 2 from U- 14C-glucose in uteri from OVD and from OVED rats. INS (0.5 U.ml −1) augmented significantly labelled glucose metabolism, both in OVD as well as in OVED rats. On the other hand, added PGE 1, PGE 2, PGF 2α or LTC 4 failed to alter glucose metabolism in uteri from OVD rats. Only PGE 1 was able to increase significantly (p < 0.05) 14CO 2 production from labelled glucose in uterine strips from OVED rats. In OVD rats the stimulatory action of INS on uterine glucose metabolism was significantly enhanced by exogenous PGE 1, but not modified by PGE 2, by PGF 2α or by LTC 4. PGE 1, PGE 2 and LTC 4 sensitized uterine strips obtained from OVED rats to the effects of INS. The possible importance of PGE 1 in improving uterine glucose metabolism in diabetic animals is discussed.

Metabolic effects of acute and prolonged growth hormone deficiency in streptozotocin-diabetic rats.

To determine whether endogenous GH contributes to impairments of glucose metabolism in diabetes mellitus, we examined the metabolic consequences of GH deficiency in streptozotocin (SZ)-diabetic rats. Diabetic rats were treated with a highly specific antirat GH serum (ArGH) to neutralize the activity of circulating GH, and glucose metabolism was measured in adipose tissue in vitro in the absence or presence of insulin. Short term (6-h) GH deficiency led to a 10% decrease in hyperglycemia (P = 0.002) in SZ-diabetic rats. Basal glucose oxidation and insulin responses in adipose tissue were unchanged by acute ArGH treatment. Since hyperglycemia was improved when adipose tissue metabolism was unaltered, GH-dependent changes occurring in other tissues, such as liver or muscle, most likely contribute to derangements of glucose metabolism in diabetes, even when GH is not elevated. Prolonged GH deficiency was produced by infusing ArGH into SZ-diabetic rats for 5 days. In these animals, the relative fat content (percentage of wet weight) of adipose tissue was significantly increased. In addition, the conversion of [14C]glucose to lipid and CO2 in adipose tissue was significantly increased with chronic GH deficiency in SZ-diabetic rats, but the ability of insulin to stimulate glucose metabolism in the tissue was unaffected. These results indicate that endogenous GH suppresses basal glucose utilization in adipose tissue of diabetic animals; this is reversed by prolonged (5-day), but not acute (6-h), ArGH treatment. Taken together, these findings suggest that the role of endogenous GH in the regulation of glucose metabolism in diabetic animals involves several mechanisms and multiple tissues.