Efficacy of Vanadyl Sulfate and Selenium Tetrachloride as Anti-Diabetic Agents against Hyperglycemia and Oxidative Stress Induced by Diabetes Mellitus in Male Rats

The use of metals in medicine has grown in popularity in clinical and commercial settings. In this study, the immune-protecting effects and the hypoglycemic and antioxidant activity of vanadyl sulfate (VOSO₄) and/or selenium tetrachloride (Se) on oxidative injury, DNA damage, insulin resistance, and hyperglycemia were assessed. Fifty male albino rats were divided into five groups, and all treatments were administrated at 9:00 a.m. daily for 60 successive days: control, STZ (Streptozotocin; 50 mg/kg of STZ was given to 6 h fasted animals in a single dose, followed by confirmation of diabetic state occurrence after 72 h by blood glucose estimation at >280 mg/dl), STZ (Diabetic) plus administration of VOSO₄ (15 mg/kg) for 60 days, STZ (Diabetic) plus administration of selenium tetrachloride (0.87 mg/Kg), and STZ plus VOSO₄ and, after 1/2 h, administration of selenium tetrachloride at the above doses. The test subjects’ blood glucose, insulin hormone, HbA1C, C-peptide, antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, myeloperoxidase, and xanthine oxidase), markers of lipid peroxidation (MDA), and histological sections of pancreatic tissues were evaluated, and a comet assay was performed. Histological sections in pancreas tissues were treated as indicators of both VOSO₄ and selenium tetrachloride efficacy, either alone or combined, for the alleviation of STZ toxicity. The genotoxicity of diabetes mellitus was assessed, and the possible therapeutic roles of VOSO₄ or selenium tetrachloride, or both, on antioxidant enzymes were studied. The findings show that the administration of VOSO₄ with selenium tetrachloride reduced oxidative stress to normal levels, lowered blood glucose levels, and elevated insulin hormone. Additionally, VOSO₄ with selenium tetrachloride had a synergistic effect and significantly decreased pancreatic genotoxicity. The data clearly show that both VOSO₄ and selenium tetrachloride inhibit pancreatic and DNA injury and improve the oxidative state in male rats, suggesting that the use of VOSO₄ with selenium tetrachloride is a promising synergistic potential ameliorative agent in the diabetic animal model.     

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.     

Impaired duodenal bicarbonate secretion in diabetic rats. Salutary effect of nitric oxide synthase inhibitor

We previously reported the impaired HCO₃⁻ secretion and the increased mucosal susceptibility to acid in the duodenum of streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the salutary effect of the NO synthase inhibitor L-NAME (N^G-nitro-L-arginine methyl ester) on these changes and compared it with those of insulin. Animals were injected streptozotocin (STZ: 70 mg/kg, ip) and used after 1, 3–4, and 5–6 weeks of diabetes with blood glucose levels of > 300 mg/dL. Under urethane anesthesia the HCO₃⁻ secretion was measured in the proximal duodenal loop using a pH-stat method and by adding 10 mM HCl. L-NAME (20 mg/kg × 2) or insulin (4 units/rat) was administered sc for 4–5 weeks, starting 1 week after STZ treatment. The duodenal HCO₃⁻ secretory responses to various stimuli such as mucosal acidification (10 mM HCl for 10 min), 16,16-dimethyl prostaglandin E₂ (dmPGE₂: 10 μg/kg, iv), and vagal stimulation (0.5 mA, 2 ms, 3 Hz) were significantly decreased in STZ-treated rats, depending on the duration of diabetes. Repeated administration of L-NAME, starting from 1 week after STZ treatment, significantly reduced blood glucose levels toward normal values and restored the HCO₃⁻ responses to various stimuli in STZ rats, the effects being similar to those observed after supplementation of insulin. Diabetic rats developed duodenal lesions after perfusion of the duodenum with 150 mM HCl for 4 h, but this ulcerogenic response was significantly inhibited by the repeated treatment with L-NAME as well as insulin. We conclude that L-NAME is effective in ameliorating hyperglycemic conditions in STZ-diabetic rats, similar to insulin, and restores the impaired HCO₃⁻ secretion and the increased mucosal susceptibility to acid in diabetic rat duodenums.     

Characterization of the in vitro kinase activity of a partially purified soluble GST/JAK2 fusion protein

In vivo effects of insulin and vanadium treatment on glycogen synthase (GS), glycogen synthase kinase-3 (GSK-3) and protein phosphatase-1 (PP1) activity were determined in Wistar rats with streptozotocin (STZ)-induced diabetes. The skeletal muscle was freeze-clamped before or following an insulin injection (5 U/kg i.v.). Diabetes, vanadium, and insulin in vivo treatment did not affect muscle GSK-3 activity as compared to controls. Following insulin stimulation in 4-week STZ-diabetic rats muscle GS fractional activity (GSFA) was increased 3 fold (p < 0.05), while in 7-week diabetic rats it remained unchanged, suggesting development of insulin resistance in longer term diabetes. Muscle PP1 activity was increased in diabetic rats and returned to normal after vanadium treatment, while muscle GSFA remained unchanged. Therefore, it is possible that PP1 is involved in the regulation of some other cellular events of vanadium (other than regulation of glycogen synthesis). The lack of effect of vanadium treatment in stimulating glycogen synthesis in skeletal muscle suggests the involvement of other metabolic pathways in the observed glucoregulatory effect of vanadium.     

Is the Hypoglycemic Action of Vanadium Compounds Related to the Suppression of Feeding?

Vanadium compounds exhibit effective hypoglycemic activity in both type I and type II diabetes mellitus. However, there was one argument that the hypoglycemic action of vanadium compounds could be attributable to the suppression of feeding—one common toxic aspect of vanadium compounds. To clarify this question, we investigated in this work the effect of a vanadyl complex, BSOV (bis((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl-2-hydroxy-benzoatato) oxovanadium (IV)), on diabetic obese (db/db) mice at a low dose (0.05 mmol/kg/day) when BSOV did not inhibit feeding. The experimental results showed that this dose of BSOV effectively normalized the blood glucose level in diabetic mice without affecting the body weight growth. Western blotting assays on the white adipose tissue of db/db mice further indicated that BSOV treatment significantly improved expression of peroxisome proliferator-activated receptor γ (PPARγ) and activated AMP-activated protein kinase (AMPK). In addition, vanadium treatment caused a significant suppression of phosphorylation of c-Jun N-terminal protein kinase (JNK), which plays a key role in insulin-resistance in type II diabetes. This is the first evidence that the mechanism of insulin enhancement action involves interaction of vanadium compounds with JNK. Overall, the present work indicated that vanadium compounds exhibit antidiabetic effects irrelevant to food intake suppression but by modulating the signal transductions of diabetes and other metabolic disorders.     

Reduction of oxidative stress induced vanadium toxicity by complexing with a flavonoid, quercetin: A pragmatic therapeutic approach for diabetes

Vanadium compounds are known to lower blood glucose level in diabetes but are associated with toxicity. In vitro cytotoxicity of VOSO₄ and bis(quercetinato) oxovanadium(IV) (BQOV) was examined in CHO cells. Both the agents showed time and dose dependent increase in ROS generation however it was relatively less in BQOV. Moreover, VOSO₄ also caused higher necrosis. Hypoglycemic potential of VOSO₄ and BQOV was tested in streptozotocin-induced diabetic Balb/c mice. A marked difference was observed in the hypoglycemic action of VOSO₄ and BQOV treated mice that lasted only for about 6 h in VOSO₄ as against 24 h in BQOV. Comparison of acute toxicity of the compounds in normal Balb/c mice revealed negligible nephrotoxicity of BQOV. Kidney analyses of VOSO₄ treated animals’ revealed high ROS generation and tubular necrosis. Similarly serum levels of urea and creatinine were elevated in these animals indicating kidney dysfunction. No such abnormality was observed in BQOV treated animals. Reduced nephrotoxicity of BQOV could be due to increased catalase activity found in the kidney of BQOV treated animals and BQOV’s radical scavenging activity. The data clearly demonstrates immense hypoglycemic activity and reduced toxicity of BQOV thus making the conjugate a suitable candidate for therapeutic utility.     

Sustained normoglycemia and remission phase in newly diagnosed type I diabetic subjects. Comparison between continuous subcutaneous insulin infusion and conventional therapy during a one year follow-up

After onset of type I diabetes 7 diabetics were randomized to subcutaneous insulin pump treatment (CSII) (age 12 to 29 years, mean: 21 years) and 7 diabetics to conventional insulin treatment (CI) (age 14 to 28 years, mean: 21 years). HbA1, glycosylated serum proteins and mean blood glucose (MBG) as parameters of metabolic control were determined monthly. After 2 months both groups showed HbA1 values in the normal range. Mean MBG values were (mean +/- SD) 116 +/- 7 mg/dl for CSII and 118 +/- 14 mg/dl for CI. Residual insulin secretion was determined monthly by fasting C-peptide. After 14 days, 5, 7, 8 months fasting C-peptide values were significantly (P less than 0.05) higher in CI. After one year fasting C-peptide was comparable in both groups (CSII and CI mean: 0.06 nmol/l). The administered insulin dose was comparable in both groups with a 55% reduction of insulin dose after 5 months in CSII (0.35 +/- 0.15 U/kg/24 h) and in CI after 7 months (0.31 +/- 0.28 U/kg/24 h). After 12 months of insulin therapy about 60% of the initial insulin dose was injected in both groups. 1 patient on CSII (12 years) and 2 patients on CI (15, 28 years) showed a complete remission (for 3-9 months) with no exogenous insulin and normal HbA1 values. 50% of the patients had episodes where they did need less than 0.2 U/kg/24 h insulin to maintain optimal diabetic control (3 CSII, 4 CI). During the first year of insulin treatment in type I diabetes with CSII as well as with CI a comparable near normalisation of diabetic control could be achieved.     

Differences in plasma homocysteine levels between Zucker fatty and Zucker diabetic fatty rats following 3 weeks oral administration of organic vanadium compounds

PURPOSE: Recently, our laboratory group has reported that rats with Type 1 diabetes have decreased plasma homocysteine and cysteine levels compared to non-diabetic controls and that organic vanadium treatment increased plasma homocysteine concentrations to non-diabetic concentrations. However, to date, no studies have been done investigating the effects of organic vanadium compounds on plasma homocysteine and its metabolites in Type 2 diabetic animal model. These studies examined the effect of organic vanadium compounds [bis(maltolato)oxovanadium(IV) and bis(ethylmaltolato)oxovanadium(IV); BMOV and BEOV] administered orally on plasma concentrations of homocysteine and its metabolites (cysteine and cysteinylglycine) in lean, Zucker fatty (ZF) and Zucker diabetic fatty (ZDF) rats. ZF rats are a model of pre-diabetic Type 2 diabetes characterized by hyperinsulinemia and normoglycemia. The ZDF rat is a model of Type 2 diabetes characterized by relative hypoinsulinemia and hyperglycemia. METHODS: Zucker lean and ZF rats received BMOV in the drinking water at a dose of 0.19 +/- 0.02 mmol/kg/day. Lean and ZDF rats received BEOV by oral gavage daily at dose of 0.1 mmol/kg. The treatment period for both studies was 21 days. At termination, animals were fasted overnight (approximately 16 h) and blood samples were collected by cardiac puncture for determination of plasma glucose, insulin and homocysteine levels. Plasma homocysteine and its metabolites levels were determined using high-pressure liquid chromatography. Plasma glucose was determined using a Glucose Analyzer 2. Plasma insulin levels were determined by radioimmunoassay. Plasma triglycerides were determined by an enzymatic assay methodology. RESULTS: ZF (n = 4) and ZDF (n = 10) rats had significantly lower plasma homocysteine as compared to their respective lean groups (ZF 0.78 +/- 0.1 micromol/L vs. Zucker lean 2.19 +/- 0.7 micromol/L; ZDF 1.71 +/- 0.2 micromol/L vs. Zucker lean 3.02 +/- 0.3 micromol/L; p < 0.05). BMOV treatment in ZF rats restored plasma homocysteine levels to those observed in lean untreated rats (ZF treated: 2.04 +/- 0.2 micromol/L; lean 2.19 +/- 0.7 micromol/L). There was a modest effect of BMOV treatment on plasma glucose levels in ZF rats. BEOV treatment significantly decreased the elevated plasma glucose levels in the ZDF rats (lean 7.9 +/- 0.1 mmol/L; lean + vanadium 7.7 +/- 0.2 mmol/L; ZDF 29.9 +/- 0.4 mmol/L; ZDF + vanadium 17.4 +/- 0.3 mmol/L, p < 0.05). Organic vanadium treatment reduced cysteine levels in both ZF and ZDF rats. No differences in total plasma cysteinylglycine concentrations were observed. CONCLUSION: Plasma homocysteine levels are significantly reduced in a pre-diabetic model of Type 2 diabetes, which was restored to lean levels upon vanadium treatment; however, this restoration of plasma homocysteine levels was not seen in ZDF Type 2 diabetic rats following vanadium treatment. In the latter case vanadium treatment may not have totally overcome the insulin resistance seen in these animals.     

Ultrastructural study of the effect of insulin dosage on the myocardium of spontaneously diabetic BB rats

Cardiac ultrastructure was studied in spontaneously diabetic BB rats maintained on two different regimens of insulin daily. For 3 months from the onset of overt diabetes, one diabetic group was well controlled with daily subcutaneous administration of sufficient insulin to prevent glycosuria (9.0-13.0 U/kg). Approximately half of this dose (4.5 U/kg) of insulin was given daily to a second group of diabetic rats. Normal Wistar rats and nondiabetic BB rats were used as controls. Blood glucose values were three- to four-fold higher with respect to these controls in the diabetic BB rats receiving the smaller dose of insulin but were significantly lower than controls in diabetic animals receiving the higher insulin dose. A 30% difference in body weight with respect to the Wistar controls, obvious hyperliposis, and some nerve degeneration were seen in the low dose insulin group of diabetics. Such changes did not occur in the well-controlled insulin-treated group. Electron microscopic examination of the left ventricular tissue revealed mild damage in both groups of diabetics consisting of small focal lesions and mild edema along the sarcoplasmic reticulum and sometimes adjacent to the sarcolemma. Thus, insulin treatment, which prevented glycosuria, resulted in normal tissue lipid levels and prevented nerve damage but had little effect on the other diabetes-induced ultrastructural alterations in the myocardium of these rats.     

Vanadium increases GLUT4 in diabetic rat skeletal muscle

The effect of vanadium in lowering blood glucose in diabetic animals is well established; however, the exact mechanism of action of vanadium still eludes us. There are several reports from in vitro studies indicating that vanadium increases enzyme activity in insulin signalling pathways, however these findings have not been duplicated in vivo. Glucose transporters (GLUT) have a major role to play in any glucoregulatory effects. Insulin dependent GLUT4 is a major glucose transporter present in skeletal muscle, adipocytes and heart. In the present study we found that the plasma glucose in streptozotocin (STZ) diabetic animals was restored to normal following treatment with a single dose of BMOV, an organic vanadium compound, given by oral gavage (0.6 mmol/kg), similar to the response with chronic BMOV treatment. The response to BMOV by oral gavage was rapid and the animals were normoglycemic within 24 h of treatment and still demonstrated a significant effect even after 72 h. Using a specific antibody against GLUT4 we found an overall reduction in the GLUT4 in the total membrane fraction in skeletal muscle of diabetic animals. However, with a single dose of BMOV the GLUT4 level was restored to normal. This is the first report that establishes a direct effect of vanadium on the regulation of GLUT4 expression in diabetic animals in vivo, and may at least partially explain the glucoregulatory effects of vanadium.     

Chronic Cobalt Treatment Decreases Hyperglycemia in Streptozotocin-Diabetic Rats

Diabetes is a metabolic disorder characterized by elevated blood glucose levels. Although conventional treatments such as insulin and other drugs reduce blood glucose, there is still a therapeutic need for effective orally administered drugs. Trace elements like vanadium and tungstate have been successfully demonstrated to reduce blood glucose in experimental diabetes with minimal chronic complications. We investigated the anti-hyperglycemic effects of cobalt in streptozotocin-diabetic rats. Normal and diabetic rats were provided with drinking water containing 3.5 mM cobalt chloride for three weeks followed by 4 mM for four weeks. Body weights and fluid consumption were monitored on a daily basis, while food intake was recorded twice every week. Prior to termination, an oral glucose tolerance test was performed on the animals. Diabetic rats lost significant body weight (357 ± 2 gm) compared to controls (482 ± 3 gm). Body weight was further reduced by cobalt treatment (290 ± 2 gm). Although it was difficult to establish a dosing regimen without weight loss, food and fluid consumption in cobalt-treated diabetic rats improved significantly compared to untreated diabetics. Plasma glucose levels were significantly reduced with reference to diabetic controls (29.3 ± 0.9 mM) by the fourth week to a lower but still hyperglycemic level (13.6 ± 3.4 mM). Cobalt-treated diabetic rats demonstrated an enhanced ability to clear a glucose load compared to untreated diabetics. Cobalt treatment neither affected the feeding and drinking patterns nor plasma glucose in normoglycemic animals although body weights decreased compared to untreated controls. We conclude that chronic cobalt treatment decreases plasma glucose levels in STZ-diabetic rats and improves tolerance to glucose.     

Hydrogen Peroxide-Induced Inhibition of Vasomotor Activity: Evaluation of Single and Combined Treatments With Vitamin A and Insulin in Streptozotocin-Diabetic Rats

A positive correlation has been established between increased oxidative stress and cardiovascular diseases in diabetes mellitus. We evaluated the effects of single or combined treatments with vitamin A (retinol acetate, 30 mg/kg/day, for 12-weeks) and insulin (8-10 IU/rat/day for the final 6-week) on vasomotor activity, oxidative stress and retinol metabolism in 12-week streptozotocin diabetic rats. The vasomotor activity was determined by measuring in vitro responsiveness of aorta rings to phenylephrine (PE) and acetylcholine (ACh) in the absence or in the presence of hydrogen peroxide (H₂O₂). Preincubation with H₂O₂ (10 μM) produced a significant decrease in PE (1 mM)-induced contraction in untreated-diabetic but not in control rats. Single treatment with insulin counteracted this effect of H₂O₂ and also reversed the increased contractile response of diabetic aorta to PE, while vitamin A was found to be ineffective. H₂O₂ (10 μM) also inhibited ACh (1 mM)-stimulated endothelium- dependent relaxation two fold more in diabetic than in control aorta. In the prevention of H₂O₂-induced inhibition of vascular relaxation to ACh, vitamin A alone was markedly effective while insulin alone was not. The combination of vitamin A plus insulin removed the inhibitory action of H₂O₂ in diabetic aorta. Diabetic animals displayed an increased level of aorta thiobarbituric acid reactive substance (TBARS) in association with decreased levels of plasma retinol and retinol-binding protein (RBP). Single treatment with insulin, in spite of allowing recovery of normal growth rate and improved glucose and retinol metabolism in diabetic rats, was unable to control TBARS production to the same extent as vitamin A alone. Our findings suggest that the maintenance of ACh-stimulated endothelium-dependent vasorelaxant tone in normal physiological levels depends largely on the prevention and/or inhibition of peroxidative stress, which is achieved by combined treatment with vitamin A plus insulin. The use of vitamin A together with insulin provides a better metabolic control and more benefits than use of insulin alone in the reduction of diabetes-induced vascular complications.     

Anti-diabetic Effects of Cesium Aqua (N,N′-ethylene(salicylideneiminato)-5-sulfonato) Oxovanadium (IV) Dihydrate in Streptozotocin-induced Diabetic Rats

The study has been designed to investigate the anti-diabetic effects of cesium aqua (N,N′-ethylene (salicylideneiminato)-5-sulfonato) oxovanadium (IV) dihydrate (VO(salen-SO₃)), an organic vanadium compound, in streptozotocin-induced diabetic rats. VO(salen-SO₃) was orally administrated to diabetic rats at the dose of 0.3 mg/ml through drinking water for 24 days. Blood glucose level was significantly declined, and oral glucose tolerance was improved after VO(salen-SO₃) treatment. Moreover, liver and muscle glycogen concentrations were markedly increased in VO(salen-SO₃)-treated diabetic rats. On the other hand, aspartate amino transferase and blood urea nitrogen in serum were significantly decreased after treatment with VO(salen-SO₃). Take together, these results suggested that VO(salen-SO₃) may be of potential value in the therapy of diabetic symptom and hyperglycemia-induced hepatic and renal dysfunction.     

Calorimetric studies of the interaction between the insulin-enhancing drug candidate bis(maltolato)oxovanadium(IV) (BMOV) and human serum apo-transferrin

Bis(maltolato)oxovanadium(IV) (BMOV), and its ethylmaltol analog, bis(ethylmaltolato)oxovanadium(IV) (BEOV), are candidate insulin-enhancing agents for the treatment of type 2 diabetes mellitus; in mid-2008, BEOV advanced to phase II clinical testing. The interactions of BMOV and its inorganic congener, vanadyl sulfate (VOSO₄), with human serum apo-transferrin (hTf) were investigated using differential scanning calorimetry (DSC). Addition of BMOV or VOSO₄ to apo-hTf resulted in an increase in thermal stability of both the C- and N-lobes of transferrin as a result of binding to either vanadyl compound. A series of DSC thermograms of hTf solutions containing different molar ratios of BMOV and VOSO₄ were used to determine binding constants; at 25 °C the binding constants of BMOV to the C- and N-lobes of apo-hTf were found to be 3 (±1) × 10⁵ and 1.8 (±0.7) × 10⁵ M⁻¹, respectively. The corresponding values for VOSO₄ were 1.7 (±0.3) × 10⁵ and 7 (±2) × 10⁴ M⁻¹. The results show that the vanadium species initially presented as either BMOV or VOSO₄ had similar affinities for human serum transferrin due to oxidation of solvated vanadyl(IV) prior to complexation to transferrin. Binding of metavanadate () was confirmed by DSC and isothermal titration calorimetry (ITC) experiments of the interaction between sodium metavanadate (NaVO₃) and hTf.     

Assessment of Insulin Infusion Requirements in COVID-19-Infected Patients With Diabetic Ketoacidosis

Background/ObjectiveCoronavirus disease 2019 (COVID-19) is thought to contribute to diabetic ketoacidosis (DKA) and worse outcomes in patients with diabetes. This study compared the cumulative insulin dose required to achieve DKA resolution in the intensive care unit among patients with type 2 diabetes and COVID-19 infection versus without COVID-19 infection.MethodsThis retrospective cohort study evaluated 100 patients—50 patients with COVID-19 in cohort 1 and 50 patients without COVID-19 in cohort 2—treated with insulin infusions for DKA at a tertiary care teaching hospital. The primary outcome was to compare the cumulative insulin dose required to achieve DKA resolution in each cohort. The secondary outcomes included time to DKA resolution, mean insulin infusion rate, and mean weight-based cumulative insulin infusion dose required to achieve DKA resolution. All endpoints were adjusted for confounders.ResultsThe mean cumulative insulin dose was 190.3 units in cohort 1 versus 116.4 units in cohort 2 (P = .0038). Patients receiving steroids had a mean time to DKA resolution of 35.9 hours in cohort 1 versus 15.6 hours in cohort 2 (P = .0014). In cohort 1 versus cohort 2, the mean insulin infusion rate was 7.1 units/hour versus 5.3 units/hour (P = .0025), whereas the mean weight-based cumulative insulin infusion dose was 2.1 units/kg versus 1.5 units/kg (P = .0437), respectively.ConclusionCOVID-19-infected patients required a significantly larger cumulative insulin dose, longer time to DKA resolution, higher insulin infusion rate, and higher weight-based insulin infusion dose to achieve DKA resolution versus non–COVID-19-infected patients with type 2 diabetes.     

Restoration of ultrastructural and biochemical changes in alloxan-induced diabetic rat sciatic nerve on treatment with Na3VO4 and Trigonella—a promising antidiabetic agent

Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo. Vanadium compound, sodium orthovanadate, Na₃VO₄, is well known for its hypoglycaemic effects. However, Na₃VO₄ exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na₃VO₄ (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic agent, to reduce its toxicity without compromising its antidiabetic potential. The efficacy of the lower doses of Na₃VO₄ has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na₃VO₄. Results suggest that lower doses of Na₃VO₄ may be used in combination with TSP as an efficient antidiabetic agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.     

Defective regulation and action of atrial natriuretic peptide in type 2 diabetes.

Increased plasma atrial natriuretic peptide (ANP) levels and impaired ANP action have been reported in patients with diabetes or insulin resistance. The aim of this study was to assess the interaction between insulin and ANP in type 2 diabetes. In 12 normotensive, normoalbuminuric type 2 diabetics, we infused insulin at a high (6.6 pmol/min/kg) or, on a different day, at a low rate (0.6 pmol/min/kg) during 4 hours of isoglycemia under isovolumic, isoosmolar conditions. The normal response was established in 12 healthy volunteers using an identical protocol. Despite higher baseline ANP levels (17.7 +/- 2.8 vs. 10.8 +/- 1.8 pg/ml, p = 0.04), urinary sodium excretion was similar in diabetics and controls (113 +/- 8.5 vs. 102 +/- 8.8 mEq/24 hours, p = ns). In both groups, hyperinsulinemia caused a decrease in blood volume (0.33 +/- 0.10 l, p < 0.01), diastolic blood pressure (6 %, p < 0.02), and natriuresis. However, plasma ANP decreased in controls (from 12.7 +/- 1.9 to 8.6 +/- 1.4 pg/ml, p = 0.01) but not in type 2 diabetics (15.1 +/- 2.7 vs. 17.2 +/- 3.8 pg/ml, p = ns). We conclude that ANP release is resistant to volume stimulation in type 2 diabetic patients, and natriuresis is resistant to ANP action. This dual disruption of ANP control may play a role in blood pressure regulation in diabetes.     

Anti-diabetic effects of vanadium(III, IV, V)–chlorodipicolinate complexes in streptozotocin-induced diabetic rats

Vanadium(III, IV, V)–chlorodipicolinate (dipic-Cl) complexes, including H[V^III(dipic-Cl)₂] · 5H₂O (V₃dipic-Cl), V^IVO(dipic-Cl)(H₂O)₂ (V₄dipic-Cl) and K[V^VO₂(dipic-Cl)] (V₅dipic-Cl), were prepared with the indicated oxidation states. Our aim was to evaluate the anti-diabetic effects of V₃dipic-Cl, V₄dipic-Cl and V₅dipic-Cl in streptozotocin-induced diabetic rats. Vanadium complexes were orally administered to diabetic rats at concentrations of 0.1–0.3 mg/ml in the drinking water. We found that vanadium–chlorodipicolinate (V–dipic-Cl) complexes at the concentration of 0.1 mg/ml did not exhibit blood glucose-lowering effects when administered to diabetic rats for 20 days. However, the levels of fasting blood glucose in diabetic rats were decreased after treatment with 0.3 mg/ml of V₄dipic-Cl and V₅dipic-Cl complexes for the following 20 days. Although administration of both V₄dipic-Cl and V₅dipic-Cl significantly lowered diabetic hyperglycemia, the vanadium intake from administration of V₄dipic-Cl is nearly 1.5-fold greater compared to that of V₅dipic-Cl. Treatment with the H₂dipic-Cl ligand and all three V–dipic-Cl complexes significantly lowered serum cholesterol, while administration of the V₅dipic-Cl complex lowered serum cholesterol significantly more than administration of the ligand alone. Treatment with ligand alone did not have an effect on serum triglyceride, while administration of the V₄dipic-Cl and V₅dipic-Cl significantly lowered the elevated serum triglyceride associated with diabetes. Oral administration of the ligand and all V–dipic-Cl complexes did significantly lower diabetes elevated serum alkaline phosphatase. Treatment with H₂dipic-Cl ligand and V₄dipic-Cl and V₅dipicCl significantly lowered diabetes elevated aspartate amino transferase. These results indicate that the health of the treated animals did not seem to be further compromised compared to that of diabetic animals. In addition, oral administration of H₂dipic-Cl, V₃dipic-Cl, V₄dipic-Cl and V₅dipic-Cl did not alter diabetic serum creatinine and blood urea nitrogen levels, suggesting no significant side effects of vanadium treatment on renal functions at the dose of 0.3 mg/ml in diabetic rats. The results presented here suggest that the anti-diabetic effects of treatment with V–dipic-Cl complexes were likely associated in part with the oxidation state of vanadium.