The in vivo performance of bioartificial pancreas in bone marrow cavity: A case report of a spontaneous diabetic feline

Recent studies reported that bone marrow cavity offers a widely distributed and well-vascularized microenvironment which is a considerable implantation site for bioartificial pancreas (BAP). In this study, the in vivo performance of BAPs in bone marrow was further demonstrated in a spontaneous diabetes animal. Mouse insulinoma cells encapsulating in agarose gel were enclosed in a calcium phosphate cement chamber to create a BAP. Ten BAPs were implanted into the femur bone marrow cavity of a diabetic feline. The preprandial blood glucose level, 2 h glucose curve, serum C-peptide level and physiological conditions of the recipient were recorded perioperatively. Results showed that the cat still suffered from hyperglycemia postoperatively. However, the physiological conditions of feline were improved with an increase of serum C-peptide level. The peak point of 2 h glucose curve decreased from 400 to 165-290 mg/dl. The efficiency of exogenous insulin extended from 2 to 10-14 h postoperatively which reveals that the implanted BAPs had partial function. This case report revealed that BAPs implanted in the bone marrow cavity for the spontaneous diabetic is effective. The implanted BAPs provided therapeutic benefit despite sustained hyperglycemia. Further study shall be considered to improve the outcomes of BAPs transplantation.     

Reversal of new-onset type 1 diabetes in mice by syngeneic bone marrow transplantation

Autologous hematopoietic stem cell transplantation (HSCT) has recently been performed as a novel strategy to treat patients with new-onset type 1 diabetes (T1D). However, the mechanism of autologous HSCT-induced remission of diabetes remains unknown. In order to help clarify the mechanism of remission-induction following autologous HSCT in patients with T1D, mice treated with multiple low doses of streptozotocin to induce diabetes were used as both donors (n = 20) and recipients (n = 20). Compared to streptozocin-treated mice not receiving transplantation, syngeneic bone marrow transplantation (syn-BMT) from a streptozocin-treated diabetic donor, if applied during new-onset T1D (day 10 after diabetes onset), can reverse hyperglycemia without relapse (P < 0.001), maintain normal blood insulin levels (P < 0.001), and preserve islet cell mass. Compared to diabetic mice not undergoing HSCT, syn-BMT, results in restoration of Tregs in spleens (P < 0.01), increased Foxp3 mRNA expression (P < 0.01) and increased Foxp3 protein expression (P < 0.05). This diabetic-remission-inducing effect occurred in mice receiving bone marrow from either streptozocin-treated diabetic or non-diabetic normal donors. We conclude that autologous HSCT remission of diabetes is more than transient immune suppression, and is capable of prolonged remission-induction via regeneration of CD4+CD25+FoxP3+ Tregs.     

Anti-diabetic effects of sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate in streptozotocin-induced diabetic rats

The evaluation of the anti-diabetic effects of an organic vanadium(V) complex in streptozotocin (STZ)-induced diabetic rats was investigated. The STZ-induced diabetic rats were orally administrated with sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate (V5dipic-NH₂), a vanadium(V) coordination compound. The compound was administered through drinking water at a concentration of 0.1 mg/mL for 20 days, and then the concentration was increased to 0.3 mg/mL for the following 20 days. At the end of the experiment, V5dipic-NH₂ statistically significantly reduced the levels of blood glucose (P < 0.01), serum total cholesterol (P < 0.01), triglycerides (P < 0.01) and the activities of serum aspartate amino transferase (P < 0.05) and alkaline phosphatase (P < 0.01) compared to untreated diabetic animals. After treatment with 0.3 mg/mL V5dipic-NH₂, the oral glucose tolerance was improved in diabetic animals (P < 0.01). In addition, the daily intake of elemental vanadium was markedly decreased in V5dipic-NH₂-treated diabetic rats compared to vanadyl sulfate (VOSO₄)-treated diabetic rats, which suggested that the anti-diabetic activity of the element vanadium was elevated after being modified with an organic ligand. These results suggested that V5dipic-NH₂, as an organic vanadium compound, is more effective than inorganic vanadium salt at alleviating the symptoms of diabetes.     

Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal

Objective

Metformin, a leading drug used to treat diabetic patients, is reported to benefit bone homeostasis under hyperglycemia in animal models. However, both the molecular targets and the biological pathways affected by metformin in bone are not well identified or characterized. The objective of this study is to investigate the bioengergeric pathways affected by metformin in bone marrow cells of mice.

Materials and Methods

Metabolite levels were examined in bone marrow samples extracted from metformin or PBS -treated healthy (Wild type) and hyperglycemic (diabetic) mice using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. We applied an untargeted high performance LC-MS approach which combined multimode chromatography (ion exchange, reversed phase and hydrophilic interaction (HILIC)) and Orbitrap-based ultra-high accuracy mass spectrometry to achieve a wide coverage. A multivariate clustering was applied to reveal the global trends and major metabolite players.

Results

A total of 346 unique metabolites were identified, and they are grouped into distinctive clusters that reflected general and diabetes-specific responses to metformin. As evidenced by changes in the TCA and urea cycles, increased catabolism and nitrogen waste that are commonly associated with diabetes were rebalanced upon treatment with metformin. In particular, we found glutamate and succinate whose levels were drastically elevated in diabetic animals were brought back to normal levels by metformin. These two metabolites were further validated as the major targets of metformin in bone marrow stromal cells.

Conclusion

Overall using limited sample size, our study revealed the metabolic pathways modulated by metformin in bones which have broad implication in our understanding of bone remodeling under hyperglycemia and in finding therapeutic interventions in mammals.     

Intensive exercise training does not improve intravenous glucose tolerance in severely diabetic rats

Several studies have recently demonstrated that exercise training improves glucose tolerance in mildly diabetic rats. To test whether some minimal levels of circulating insulin are required to observe the beneficial effects of exercise training, severe diabetes was induced by injecting female Wistar rats with streptozotocin. Half of diabetic and control rats were submitted to a strenuous program of swimming exercise. After 4 wks of training, intravenous glucose tolerance tests (IVGTT) were performed in precannulated, unrestrained and unanesthetized animals. In non-diabetic rats, exercise training significantly reduced both basal and glucose-stimulated levels of insulin (P less than 0.01) without altering glucose tolerance. On the other hand, the same training program applied to severely diabetic animals (basal plasma insulin levels less than 8 microU/ml) failed to reduce the marked hyperglycemia in the resting state (400 mg% range) as well as during the entire IVGTT (400-500 mg%). The results indicate that exercise training effectively increased the sensitivity of peripheral tissues to insulin in non-diabetic but not in diabetic animals. The data also suggest that a minimal amount of circulating insulin is required in order to observe the beneficial effects of exercise training.     

Glibenclamide or metformin combined with honey improves glycemic control in streptozotocin-induced diabetic rats

Diabetes mellitus is associated with deterioration of glycemic control and progressive metabolic derangements. This study investigated the effect of honey as an adjunct to glibenclamide or metformin on glycemic control in streptozotocin-induced diabetic rats. Diabetes was induced in rats by streptozotocin. The diabetic rats were randomized into six groups and administered distilled water, honey, glibenclamide, glibenclamide and honey, metformin or metformin and honey. The animals were treated orally once daily for four weeks. The diabetic control rats showed hypoinsulinemia (0.27 ± 0.01 ng/ml), hyperglycemia (22.4 ± 1.0 mmol/L) and increased fructosamine (360.0 ± 15.6 μmol/L). Honey significantly increased insulin (0.41 ± 0.06 ng/ml), decreased hyperglycemia (12.3 ± 3.1 mmol/L) and fructosamine (304.5 ± 10.1 μmol/L). Although glibenclamide or metformin alone significantly (p < 0.05) reduced hyperglycemia, glibenclamide or metformin combined with honey produced significantly much lower blood glucose (8.8 ± 2.9 or 9.9 ± 3.3 mmol/L, respectively) compared to glibenclamide or metformin alone (13.9 ± 3.4 or 13.2 ± 2.9 mmol/L, respectively). Similarly, glibenclamide or metformin combined with honey produced significantly (p < 0.05) lower fructosamine levels (301.3 ± 19.5 or 285.8 ± 22.6 μmol/L, respectively) whereas glibenclamide or metformin alone did not decrease fructosamine (330.0 ± 29.9 or 314.6 ± 17.9 μmol/L, respectively). Besides, these drugs or their combination with honey increased insulin levels. Glibenclamide or metformin combined with honey also significantly reduced the elevated levels of creatinine, bilirubin, triglycerides, and VLDL cholesterol. These results indicate that combination of glibenclamide or metformin with honey improves glycemic control, and provides additional metabolic benefits, not achieved with either glibenclamide or metformin alone.     

Beneficial Effect of Metformin on Nerve Regeneration and Functional Recovery After Sciatic Nerve Crush Injury in Diabetic Rats

Neuroprotective effects of metformin have been increasingly recognized in both diabetic and non-diabetic conditions. Thus far, no information has been available on the potential beneficial effects of metformin on peripheral nerve regeneration in diabetes mellitus. The present study was designed to investigate such a possibility. Diabetes was established by a single injection of streptozotocin at 50 mg/kg in rats. After sciatic nerve crush injury, the diabetic rats were intraperitoneally administrated daily for 4 weeks with metformin (30, 200 and 500 mg/kg), or normal saline, respectively. The axonal regeneration was investigated by morphometric analysis and retrograde labeling. The functional recovery was evaluated by electrophysiological studies and behavioral analysis. It was found that metformin significantly enhanced axonal regeneration and functional recovery compared to saline after sciatic nerve injury in diabetic rats. In addition, metformin at 200 and 500 mg/kg showed better performance than that at 30 mg/kg. Taken together, metformin is capable of promoting nerve regeneration after sciatic nerve injuries in diabetes mellitus, highlighting its therapeutic values for peripheral nerve injury repair in diabetes mellitus.     

Insulin down-regulates TRAIL expression in vascular smooth muscle cells both in vivo and in vitro

To dissect the effect of hyperinsulinemia versus hyperglycemia on TNF-related apoptosis inducing ligand (TRAIL) expression in the macrovascular district, we measured TRAIL mRNA and protein in four groups of animals: streptozotocin (SZT)-induced diabetic rats, vehicle-treated control animals, diabetic rats treated with insulin and non-diabetic rats treated with insulin. While the aortas of diabetic rats did not show significant differences in TRAIL expression with respect to vehicle-treated control animals, the aortas of both diabetic and non-diabetic rats treated in vivo for 16 days with insulin showed a significant decrease in TRAIL expression with respect to either diabetic and control rats. Moreover, in vitro treatment of both rat and human vascular smooth muscle cells (VSMC) with insulin induced the down-regulation of TRAIL protein. While the addition of recombinant TRAIL to rat VSMC promoted the dose-dependent release of bioactive nitric oxide (NO), this effect was significantly counteracted by pre-exposure of VSMC to insulin. These findings suggest that TRAIL might act as an endogenous regulator of the vascular tone and that chronic elevation of insulin might contribute to the vascular abnormalities characterizing type-2 diabetes mellitus by down-regulating TRAIL expression and activity.     

Expression of basic fibroblast growth factor,protein kinase C and members of the apoptotic pathway in skeletal muscle of streptozotocin-induced diabetic rats

This study investigated the potential mechanisms that may underlie diabetes induced amyoatrophy. Sprague-Dawley rats were either injected intraperiotneally with STZ (test group; N = 8) to induce diabetic-like symptoms (blood glucose level ≥16.65 mmol/L) or with buffer (control group; N = 8). Differences in muscle structure between the STZ-induced diabetic and control groups were evaluated by histochemistry. Protein and mRNA levels of basic FGF (bFGF), bax, bcl-2, and caspase 3 in skeletal muscle were compared between the 2 groups using immunohistochemistry and quantitative PCR, respectively. Serum level of insulin and protein kinase C (PKC) were measured by competitive RIA and ELISA, respectively. Unlike control animals, the skeletal muscle fibers from STZ-induced diabetic animals were broken and pyknotic, the sarcomeric structure disrupted, and mild hyperplasia of interstitial adipose tissues was detected. The serum level of PKC was higher (P = 0.003) and the protein and mRNA levels of bFGF in skeletal muscle were lower (P = 0.001) in STZ-induced diabetic versus control animals. Protein and mRNA levels of the apoptosis promoting genes caspase-3 and bax were higher in skeletal muscle from STZ-induced diabetic rats as compared to control animals (P < 0.001 and P = 0.037, respectively), while mRNA and protein levels of bcl-2, an inhibitor of apoptosis, was lower in STZ-induced diabetic rats versus control animals (P = 0.026). Increasing apoptosis in skeletal muscle from STZ-induced diabetic rats was further demonstrated by TNNEL assay. Our findings suggest that enhanced PKC levels, reduction of bFGF expression, and increased in apoptosis might be associated with the development of diabetes-induced myoatrophy.     

Differential impact of structurally different anti-diabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells

Hyperglycemia during hyper-CVAD chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL) (Cancer 2004; 100:1179–85). The optimal clinical strategy to manage hyperglycemia during hyper-CVAD is unclear. To examine whether anti-diabetic pharmacotherapy can influence chemosensitivity of ALL cells, we examined the impacts of different anti-diabetic agents on ALL cell lines and patient samples. Pharmacologically achievable concentrations of insulin, aspart and glargine significantly increased the number of ALL cells, and aspart and glargine did so at lower concentrations than human insulin. In contrast, metformin and rosiglitazone significantly decreased the cell number. Human insulin and analogs activated AKT/mTOR signaling and stimulated ALL cell proliferation (as measured by flow cytometric methods), but metformin and rosiglitazone blocked AKT/mTOR signaling and inhibited proliferation. Metformin 500 μM and rosiglitazone 10 μM were found to sensitize Reh cells to daunorubicin, while aspart, glargine and human insulin (all at 1.25 mIU/L) enhanced chemoresistance. Metformin and rosiglitazone enhanced daunorubicin-induced apoptosis, while insulin, aspart and glargine antagonized daunorubicin-induced apoptosis. In addition, metformin increased etoposide-induced and L-asparaginase-induced apoptosis; rosiglitazone increased etoposide-induced and vincristine-induced apoptosis. In conclusion, our results suggest that use of insulins to control hyperglycemia in ALL patients may contribute to anthracycline chemoresistance, while metformin and thiazolidinediones may improve chemosensitivity to anthracycline as well as other chemotherapy drugs through their different impacts on AKT/mTOR signaling in leukemic cells. Our data suggest that the choice of anti-diabetic pharmacotherapy during chemotherapy may influence clinical outcomes in ALL.     

Metformin reverses hexokinase and 6-phosphofructo-1-kinase inhibition in skeletal muscle, liver and adipose tissues from streptozotocin-induced diabetic mouse

The present work describes the effects of metformin on hexokinase (HK) and phosphofructokinase (PFK) activities and localization in different tissues from streptozotocin-induced diabetic mice. Diabetic mice present lower HK and PFK activities (50%) in skeletal muscle, liver and adipose tissue, as compared with control (P < 0.05). Treatment with 250 mg/kg metformin reverses this pattern of enzyme inhibition with concomitant reversal of hyperglycemia and hypolactacidemia. Furthermore, the treatment increases the cytoskeleton-associated PFK activity in skeletal muscle; this activity has been described as an important mechanism for the enzyme activation. This effect might be due to the increased phosphorylation of serine residues in the enzyme, a modification which has been described to increase the interaction of PFK with f-actin. The current work supports the hypothesis that metformin hypoglycemic effects involve the activation of glycolysis through its regulatory enzymes, which may be potential targets for the development of new hypoglycemic drugs.     

Protective role of D-saccharic acid-1,4-lactone in alloxan induced oxidative stress in the spleen tissue of diabetic rats is mediated by suppressing mitochondria dependent apoptotic pathway

The present study investigated the role of D-saccharic acid 1,4-lactone (DSL) in the spleen tissue of alloxan (ALX) induced diabetic rats. Diabetes was induced in rats by injecting ALX (at a dose of 120 mg/kg body weight) intraperitoneally in sterile normal saline. Elevated levels of blood glucose, glycosylated Hb and TNFα decreased levels of plasma insulin and disturbed intra-cellular antioxidant machineries were detected in ALX exposed animals. Oral administration of DSL at a dose of 80 mg/kg body weight, however, restored these alterations in diabetic rats. Studies on the mechanism of ALX-induced diabetes showed that hyperglycemia caused disruption of mitochondrial membrane potential in the spleen, released cytochrome C in the cytosol, activated caspase 3 and ultimately led to apoptotic cell death. Results suggest that DSL possesses the ability of protecting the spleen tissue from ALX-induced hyperglycemia and thus could act as an anti-diabetic agent in lessening diabetes associated spleen dysfunction.     

Protective role of D-saccharic acid-1,4-lactone in alloxan induced oxidative stress in the spleen tissue of diabetic rats is mediated by suppressing mitochondria dependent apoptotic pathway

The present study investigated the role of D-saccharic acid 1,4-lactone (DSL) in the spleen tissue of alloxan (ALX) induced diabetic rats. Diabetes was induced in rats by injecting ALX (at a dose of 120 mg/kg body weight) intraperitoneally in sterile normal saline. Elevated levels of blood glucose, glycosylated Hb and TNFα decreased levels of plasma insulin and disturbed intra-cellular antioxidant machineries were detected in ALX exposed animals. Oral administration of DSL at a dose of 80 mg/kg body weight, however, restored these alterations in diabetic rats. Studies on the mechanism of ALX-induced diabetes showed that hyperglycemia caused disruption of mitochondrial membrane potential in the spleen, released cytochrome C in the cytosol, activated caspase 3 and ultimately led to apoptotic cell death. Results suggest that DSL possesses the ability of protecting the spleen tissue from ALX-induced hyperglycemia and thus could act as an anti-diabetic agent in lessening diabetes associated spleen dysfunction.     

Phosphorylation of JNK Increases in the Cortex of Rat Subjected to Diabetic Cerebral Ischemia

Previous studies have demonstrated that the c-Jun N-terminal kinase (JNK) pathway plays an important role in inducing neuronal apoptosis following cerebral ischemic injury. JNK signaling pathway in activated during cerebral ischemic injury. It participates in ischemia-induced neuronal apoptosis. However, whether JNK signaling is involved in the process of neuronal apoptosis of diabetes-induced cerebral ischemia is largely unknown. This study was undertaken to evaluate the influence of cerebral ischemia–reperfusion injury on phosphorylation of JNK in diabetic rats. Twenty-four adult streptozotocin induced diabetic and 24 adult non-diabetic rats were randomly subjected to 15 min of forebrain ischemia followed by reperfusion for 0, 1, 3, and 6 h. Sixteen sham-operated diabetic and non-diabetic rats were used as controls. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL). Protein expression of phospho-JNK was examined by immunohistochemistry and Western blot. The numbers of TUNEL-positive cells and phospho-JNK protein expression in the cerebral cortices after 1, 3 and 6 h reperfusion was significantly higher in diabetic rats compared to non-diabetic animals subjected to ischemia and reperfusion (p < 0.05). Western blot analysis showed significantly higher phospho-JNK protein expression in the cerebral cortices of the diabetic rats after 1 and 3 h reperfusion than that was presented in non-diabetic animals subjected to ischemia and reperfusion (p < 0.05). These findings suggest that increased phosphorylation of JNK may be associated with diabetes-enhanced ischemic brain damage.     

Hyperglycemia induces elevated expression of thyroid hormone binding protein in vivo in kidney and heart and in vitro in mesangial cells

During a search for glucose-regulated abundant mRNAs in the diabetic rat kidney, we cloned thyroid hormone binding protein (THBP), also known as μ-crystallin or CRYM. The aim of this study was to investigate the effect of hyperglycemia/high glucose on the expression of THBP. THBP mRNA copy numbers were determined in kidneys and hearts of diabetic GK rats vs normoglycemic Wistar rats, and in human mesangial cells (HMCs) exposed to high glucose using real-time qPCR, and THBP protein levels were measured by Western blotting and immunofluorescence. Intracellular ROS was measured in THBP transfected cells using DCF fluorescence. Hyperglycemia significantly increased THBP mRNA in GK rat kidneys (326 ± 50 vs 147 ± 54, p < 0.05), and hearts (1583 ± 277 vs 191 ± 63, p < 0.05). Moreover, the levels of THBP mRNA increased with age and hyperglycemia in GK rat kidneys, whereas in normoglycemic Wistar rat kidneys there was a decline with age. High glucose significantly increased THBP mRNA (92 ± 37 vs 18 ± 4, p < 0.005), and protein in HMCs. The expression of THBP as a fusion protein in transfected HMCs resulted in reduction of glucose-induced intracellular ROS. We have shown that THBP mRNA is increased in diabetic kidney and heart, is regulated by high glucose in renal cells, and appears to attenuate glucose-induced intracellular ROS. These data suggest that THBP may be involved in the cellular pathways activated in response to glucose. This is the first report linking hyperglycemia with THBP and suggests that the role of THBP in diabetic complications should be further investigated.     

PPAR’s and Diosgenin a chemico biological insight in NIDDM

Diosgenin a steroidal saponin found widely in nature is reported to contain several biological activities in recent years. The present work elaborates the modulation of the lipid and antioxidant profile by Diosgenin in diabetic condition. Type 2 diabetes was induced in experimental animals by feeding high fat diet (HFD) for 8 weeks followed by streptozotocin (STZ) injection (sub-diabetogenic dose; 35 mg/kg body weight). Diosgenin administered orally at two doses (40 and 80 mg/kg body weight) for 14 days reduced hyperglycemia, hypercholesterolemia and hypertriglyceridemia (p < 0.001). Oxidative stress a crucial marker of diabetes and obesity associated complications was analyzed and noteworthy changes were observed. Improved levels of the antioxidant enzymes SOD and GPx and a minimized level of lipid peroxidation were also observed in Diosgenin treated rats. Further, analyzing the lipid accumulation by Oil Red O staining in 3T3-L1 preadipocytes confirmed its adipogenic activity which was influenced by PPAR γ and PPAR α. This was also substantiated through docking studies of Diosgenin with the PPARs. Altogether, Diosgenin a phytochemical of natural origin is found to mitigate diabetes induced oxidative stress and dyslipidemia which is crucial in cardio-metabolic risks by modulating the PPARs.     

Lack of micronuclei formation in bone marrow of rats after oral exposure to thiocyclam insecticide

In this study, a nereistoxin analogue insecticide, thiocyclam, was administered to adult male albino rats by gavage dose of 135, 270 and 540 mg/kg b.w. repeated for 5 days at 24 h intervals. Control animals received only water. Thiocyclam was tested for its potential to cause genotoxic effects in rat bone marrow cells using an in vivo micronucleus assay. After 24 h of the last treatment, rats from all dose levels were sacrificed. Bone marrow cells were collected and assayed for the presence of micronuclei. Thiocyclam did not cause any increase in the incidence of micronucleated polychromatic erythrocytes in rats bone marrow at any of the dose levels. The polychromatic erythrocytes/normochromatic erythrocytes (PCE:NCE) ratio was found to be in the range from 0.50 ± 0.11 to 0.55 ± 0.02. The results of this study demonstrate that the effect of thiocyclam is not significant in the rat in vivo micronucleus assay.     

Non-insulin dependent anti-diabetic activity of (2S, 3R, 4S) 4-hydroxyisoleucine of fenugreek (Trigonella foenum graecum) in streptozotocin-induced type I diabetic rats

The seeds of fenugreek, Trigonella foenum graecum, commonly used as a spice in Middle Eastern countries and widely used in south Asia and Europe, are known to have anti-diabetic properties. They contain an unusual amino acid (2S, 3R, 4S) 4-hydroxyisoleucine (4HO-Ile), so far found only in fenugreek, which has anti-diabetic properties of enhancing insulin secretion under hyperglycaemic conditions, and increasing insulin sensitivity. Here we describe for the first time the anti-diabetic activity of 4HO-Ile in a model of type I diabetes, streptozotocin-treated rats, where levels of insulin are much reduced, by 65%, compared to normal animals. Treatment of diabetic rats with daily doses of 4HO-Ile at 50 mg/kg/day for four weeks could reduce plasma glucose in the diabetic group. Moreover the high levels of lipids (cholesterol, HDL, LDL and triglycerides) and uric acid in the diabetic rats, could be restored to levels found in non-diabetic controls by the treatment with 4HO-Ile. These results demonstrate that 4HO-Ile has significant anti-diabetic activities that are independent of insulin and suggest the potential of 4HO-Ile as an adjunct to diabetes treatment and for type 1 as well as type 2 diabetes.     

Similar incretin secretion in obese and non-obese Japanese subjects with type 2 diabetes

Incretin secretion and effect on insulin secretion are not fully understood in patients with type 2 diabetes. We investigated incretin and insulin secretion after meal intake in obese and non-obese Japanese patients with type 2 diabetes compared to non-diabetic subjects. Nine patients with type 2 diabetes and 5 non-diabetic subjects were recruited for this study. Five diabetic patients were obese (BMI ? 25) and 4 patients were non-obese (BMI < 25). In response to a mixed meal test, the levels of immunoreactive insulin during 15-90 min and C-peptide during 0-180 min in non-obese patients were significantly lower than those in obese patients. Total GLP-1 and active GIP levels showed no significant difference between obese and non-obese patients throughout the meal tolerance test. In addition, there were no significant differences between diabetic patients and non-diabetic subjects. In conclusion, incretin secretion does not differ between Japanese obese and non-obese patients with type 2 diabetes and non-diabetic subjects.     

Therapeutic effects of stem cell on hyperglycemia,hyperlipidemia, and oxidative stress in alloxan-treated rats

Diabetes mellitus is the most common endocrine disorder that affects more than 285 million people worldwide. The purpose of this study was to investigate the effect of mesenchymal stem cells (MSCs) from the bone marrow of albino rats, on hyperglycemia, hyperlipidemia, and oxidative stress induced by intraperitoneal injection (i.p.) of alloxan at a dose of 150 mg/kg in rats. Injection of alloxan into rats resulted in a significant increase in serum glucose, total cholesterol, triglyceride, low density lipoprotein cholesterol, and sialic acid level and a significant decrease in serum insulin, high density lipoprotein-cholesterol, vitamin E, and liver glycogen as compared to their corresponding controls. Also, oxidative stress was noticed in pancreatic tissue as evidenced by a significant decrease in glutathione level, superoxide dismutase, glutathione-S-transferase activities, also a significant increase in malondialdehyde and nitric oxide levels when compared to control group. Treatment of diabetic rats with MSCs stem cells significantly prevented these alterations and attenuated alloxan-induced oxidative stress. In conclusion, rat bone marrow harbors cells that have the capacity to differentiate into functional insulin-producing cells capable of controlling hyperglycemia, hyperlipidemia, and oxidative stress in diabetic rats. This may be helpful in the prevention of diabetic complications associated with oxidative stress.