Zinc Insulin Research Articles

Protamine zinc insulin combined with sodium selenite improves glycometabolism in the diabetic KKAy mice.

Long-term, high dosage protamine zinc insulin (PZI) treatments produce adverse reactions. The trace element selenium (Se) is a candidate for the prevention of diabetes due to anti-oxidative stress activity and the regulation of glycometabolism. In this study, we aimed to investigate the anti-diabetic effects of a combination of PZI and Se on type 2 diabetes. Diabetic KKAy mice were randomized into the following groups: model group and groups that were subcutaneously injected with PZI, Se, high or low dose PZI + Se for 6 weeks. PZI combined with Se decreased the body weight and fasting blood glucose levels. Moreover, this treatment also improved insulin tolerance, as determined by the reduced values from the oral glucose tolerance test and insulin tolerance test, and increased insulin levels and insulin sensitivity index. PZI combined with Se ameliorated skeletal muscle and β-cell damage and the impaired mitochondrial morphology. Oxidative stress was also reduced. Furthermore, PZI combined with Se upregulated phosphatidylinositol 3-kinase (PI3K) and downregulated protein tyrosine phosphatase 1B (PTP1B). Importantly, the low dosage combination produced effects similar to PZI alone. In conclusion, PZI combined with Se improved glycometabolism and ameliorated the tissue and mitochondrial damage, which might be associated with the PI3K and PTP1B pathways.

Conformational energetics of insulin in interpolyelectrolyte complexes insulin-poly(methylaminophosphazene) under near-physiological conditions

Interaction of a synthetic biodegradable polymer, poly(methylaminophosphazene), (PMAP) with human recombinant zinc insulin at pH 7.4 and different ionic strengths was studied by means of turbidimetry, phase analysis and high-sensitivity differential scanning calorimetry. The formation of stoichiometric (insoluble) and non-stoichiometric (soluble) interpolyelectrolyte Insulin-PMAP complexes was detected. It was shown that binding of zinc insulin to PMAP is accompanied by conversion of the protein to its zinc-free form as a result of the Zn+2 release from the insulin native structure. The conformational stability of the bound zinc-free insulin is defined by composition of the complexes. It increases in case of the non-stoichiometric complexes and decreases in the stoichiometric ones. We found that soluble Insulin-PMAP complexes revealed thermoresponsive properties within physiological range of temperature and ionic strength.

Effect of Gestational Diabetes on Gross Morphology, Histology and Histochemistry of Human Placenta

Gestational diabetes is the glucose intolerance of varying severity and complicates about 2-4% of pregnancies. While there is a surfeit of associative data that demonstrate the placental adaptive responses to gestational diabetes, the mechanisms at placental level remain elusive. One objective of this study was to investigate various anatomical, histological and some histochemical changes in placenta of gestational diabetes patients with re-evaluation of some mechanisms of placental adaptive responses to gestational diabetes. A second objective was to find whether the placenta adapts to diabetes and ultimately protects the fetus or whether it contributes to the adverse fetal outcome with diabetic pregnancies despite good care of these gestations. Two groups each of 30 placentas were collected at term and post Caesarian Section (CS) deliveries as one group was the control group (control) and the other group was collected from patients with gestational diabetes and were treated with zinc insulin. After morphological data assay, central and peripheral biopsies were processed for histological and histochemical assay. The diabetic placentas showed mild increase in diameter, central thickness and weight. This study confirmed that the villous portion with its corresponding intervillous space is the structural and functional unit of the placenta. Syncytial clumps among peripheral placenta were bigger than those of central placenta of the diabetic group and best examined by Hematoxylin and Eosin stain and to a lower extent by Van Gieson stain for light microscopy. The diabetic placentas showed marked increase of the chorionic villi which appeared more crowded centrally while the villous vasculature was higher peripherally. The increased young, immature and unspecialized villi among the diabetic placentas explained the enhanced fetal hypoxia with subsequent increased neonatal morbidity and mortality. These anatomical, histological and histochemical findings put diabetes in the moderate-high risk factors of vascular placental pathology. Also, placenta was not the primary cause to markedly affect the perinatal morbidity as the placenta showed a good degree of potentiality to adapt with derangements of gestational diabetes. So, the elevated rates of perinatal morbidity and mortality among diabetic deliveries were most probably due to metabolic abnormalities occurred in mother and fetus because of whatever kind of diabetes. Conclusion: Placenta itself is always perfect, innocent and helpful in managing and preventing complications via its endogenous mechanisms. It was necessary histologically to examine several preparations with different and specific measures to obtain detailed picture of the totality of the placenta structure. Lastly, the premium key in gestational diabetes is to apply scientific exogenous measures in harmony and accordance with early diagnosed and strictly controlled endogenous placental measures.

Characterization of Zinc Influx Transporters (ZIPs) in Pancreatic β Cells: ROLES IN REGULATING CYTOSOLIC ZINC HOMEOSTASIS AND INSULIN SECRETION

Zinc plays an essential role in the regulation of pancreatic β cell function, affecting important processes including insulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in the zinc efflux transport protein ZnT8 have been linked with both type 1 and type 2 diabetes, further supporting an important role for zinc in glucose homeostasis. However, very little is known about how cytosolic zinc is controlled by zinc influx transporters (ZIPs). In this study, we examined the β cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human and mouse islets and MIN6 β cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic β cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this dysregulated cytosolic zinc homeostasis led to impaired insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast two-hybrid assay. Knock-down of ZIP6 but not ZIP7 in MIN6 β cells impaired the protective effects of GLP-1 on fatty acid-induced cell apoptosis, possibly via reduced activation of the p-ERK pathway. Therefore, our data suggest that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in β cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on β cell survival.

Magnesium, zinc, and chromium levels in children, adolescents, and young adults with type 1 diabetes

Several trace elements are involved in insulin signal transduction and glucose metabolism. Our aim for this present study was to determine the levels of three important elements-magnesium, chromium, and zinc-as well as one oxidative stress marker-malondialdehyde (MDA)-in young type 1 diabetic patients at different periods of their growth, and to realize the relationships between trace elements, oxidative stress, and growth stages. A total of 88 patients with type 1 diabetes mellitus in different growth stages and 76 gender- and age-matched healthy subjects were included in this study. The levels of MDA were measured through HPLC using a C-18 column. Zinc, magnesium, and chromium concentrations in serum were assessed using atomic absorption spectrophotometry. We found higher levels of blood malondialdehyde (MDA; p<0.001), significantly lower levels of magnesium (p<0.001), and no differences in zinc and chromium levels (p=0.153 and 0.515, respectively) in younger type 1 diabetic subjects relative to those of control subjects. Only 3.4% (3/88) of younger diabetic subjects exhibited hypomagnesemia; similar results were obtained when comparing different subgroups: children, adolescents, and adults. We also observed no differences in the levels of the three elements between the genders and among the growth stages (p>0.05) of the diabetic subjects. There were no correlations between the three trace elements and HbA1C, diabetes duration, and insulin dose/BMI (all p>0.05), but there was a significant difference between zinc levels and insulin dose/BMI (p=0.043) in the diabetic patients. We found elevated blood MDA, decreased magnesium, and no changes in zinc and chromium levels in younger type 1 diabetic subjects relative to those of control subjects. Only 3.4% of younger diabetic subjects exhibited hypomagnesemia. Whether magnesium supplementation is suitable for improving insulin sensitivity and decreasing oxidative stress and inflammation will require confirmation through additional studies.

1,25(OH)2D3 downregulates the Toll-like receptor 4-mediated inflammatory pathway and ameliorates liver injury in diabetic rats.

BackgroundFatty acid deposition in the liver can activate a number of pro-inflammatory signaling pathways such as the Toll-like receptor 4 (TLR4) pathway, which may be important in the pathogenesis of nonalcoholic steatohepatitis. 1,25(OH)2D3 downregulates the expression of TLR4 and may represent a novel treatment strategy for reducing hepatocyte injury. Therefore, in this study, we investigated the protective effects of 1,25(OH)2D3 on diabetic liver injury in vivo.MethodsStreptozotocin (STZ)-induced diabetic rats were randomly divided into five groups and treated with low-dose 1,25(OH)2D3 (0.025 μg/kg/day), medium-dose 1,25(OH)2D3 (0.15 μg/kg/day), high-dose 1,25(OH)2D3 (0.3 μg/kg/day), insulin (protamine zinc insulin 16 U/kg/day, subcutaneous injection), or no intervention (the control group). Sixteen weeks later, the rats were killed, and blood samples were obtained to test lipid profiles and hepatic function. The infiltration of inflammatory cells, the level of fibrosis, and the expression levels of TLR4, nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α) in the liver were analyzed. The hepatocytes were treated with vehicle control, LPS (100 ng), high fat [DMEM + FFA (0.1 mM: palmitic acid, oleic acid, 1:2)], LPS + high fat, vehicle + 1,25(OH)2D3 (10−7 M), LPS + 1,25(OH)2D3, high fat + 1,25(OH)2D3, or LPS + high fat + 1,25(OH)2D3. RNA and protein were extracted to detect the expression of TLR4 and downstream inflammatory factors such as NF-ΚB, TNF-α, and IL-6. Groups of data were compared by single factor variance analysis.ResultsHigh-dose 1,25(OH)2D3 administration for 16 weeks downregulated the expression of TLR4, NF-κB, and TNF-α in the liver tissue of diabetic rats and attenuated hepatic inflammation and fibrosis, as shown by immunohistochemical staining, hematoxylin and eosin staining, Masson’s trichrome staining, reverse transcription polymerase chain reaction (RT-PCR), and western blotting. In vitro, hepatocytes treated with high fat or LPS exhibited significantly increased expression of TLR4, NF-κB, and downstream inflammatory factors (P < 0.05). Intervention with 1,25(OH)2D3 decreased the expression of TLR4, NF-κB, and inflammatory factors (P < 0.05).Conclusions1,25(OH)2D3 exhibited protective effects against diabetes-related liver injury, possibly through downregulation of components of the TLR4 signaling pathway.

A research report on the prescription rights of Chinese nurses

Abstract Objective To explore the feasibility of the nurse's prescription right in China, to develop the requirements for the qualification of the applicant for the prescription right of nurse, and to determine the content of certain prescriptions in the specific circumstances. Methods Literature review on the relevant articles/material with the contents of the nurse's right of prescription home and abroad. Semi-structured depth interview method was used to interview 18 experts on whether the nurses can participate in the graded nursing decision and whether nurses with certain ability can make the decision. Using the self-made questionnaire “Nurses involved in graded nursing decision-recognition questionnaire”, 553 nurses completed questionnaires on willingness to nurse decision-making grading. Using the analytic hierarchy process, the 23 experts' judgment on the main body of the graded nursing was rated. Using semi-structured depth interview method, 17 experts were interviewed on the graded nursing quality assessment and training outline. The form of expert personal judgment and the “grading nursing qualification experts predict questionnaire” were used as a preliminary designing tool, 32 experts were asked to predict the graded nursing quality. The relatively important factors that might promote implementation of right of Chinese nurse prescribing weights setting were obtained by analytic hierarchy process. Using Delphi method, 2 rounds of consultation to 291 experts/times were performed, and determined its content on the fields of graded nursing decision, nurses' job description, decision making nurse in graded nursing work process and related management system, decision-making main body of clinical nursing, nurse authority of prescription application qualification, clinical nurses, diabetes specialist nurses, tumor specialist nurses, nurses in emergency department, community nurses in certain circumstances writing prescription, and nursing undergraduate added with nurse authority of prescription related courses. Results The physician is not considered to be the best decision-making main body of clinical nursing work and graded nursing, nurses can participate in the work of decision-making. The qualification of hierarchical decision-making nurse and nurse prescribing applicants have been determined. The hierarchical nursing decision-making nurses' position description and training outline have been compiled. Experts suggest that clinical nurses with certain qualifications should be given the rights of some prescription form (independent prescription, prescription, prescription protocol extension) to prescribe specific drugs in high fever, hypoglycemia, hypertension, anaphylactic shock and other 11 specific circumstances. The nurses of the diabetes should be given the right of prescribing sulfonylureas, biguanides, glucosidase inhibitor, and protamine zinc insulin, and the right to write the prescription and consultation for part of medical equipment, health education, and four routine tests, which contains blood sugar monitoring, urine glucose monitoring, glycosylated hemoglobin assay, and oral glucose tolerance test. Tumor specialist nurses should be given the right to write the prescription of 7 specific circumstances including blood routine tests, electrocardiogram, blood biochemistry and other 9 laboratory tests, constipation, phlebitis, and cancer pain, and the right of 5 tumor emergency prescription including chemotherapy drug allergy, hemorrhagic shock, acute upper gastrointestinal bleeding. Nurses in emergency department with certain qualification should be given the right to prescribe specific drugs in 15 circumstances which include cardiac arrest, ventricular fibrillation, and acute cardiogenic chest pain. Community nurses with certain qualification should be given the right to write the prescriptions on 14 contents including disinfection and cleaning, sterile infusion type, and wound care products. Experts suggest that nursing undergraduate education in China should be added with 2 courses which are prescription rights related laws and regulations and nursing intervention, and that pharmacology course should be supplemented with related course in order to adapt to the implementation of nurse prescribing rights. Conclusions China's nurses with certain qualification or after special training have the ability to accept and should be given the right of prescriptions in certain circumstance within the scope of their work.

Pharmacological Efficacy of Insulin-Loaded Granules Made Up of Various Grades of Hydroxypropyl Methylcellulose in Normal Rats

The aim was to study the potential of various hydroxypropyl methylcellulose (HPMC) grades (K100LV, E50LV, E5LV, E4M, K4M and K100M) in enhancing oral bioavailability of insulin. Enteric coated insulin-loaded-HPMC granules were compared with peroral solution of zinc insulin in glycerine IP (0.788 mg/0.2 ml). Since lowering of blood glucose levels (BGLs) was used as pharmacological response, the area above curve 24 0 AAC was measured as a pharmacokinetic parameter instead of area under curve (AUC) for calculating bioavailability or pharmacological efficacy. In vitro studies showed that insulin release from granules was barred in acidic medium while almost complete release took place in basic medium upto 8h. In vivo studies in normal rats showed a maximum blood glucose reduction by K100LV based insulin-loaded granules, which corresponded to a relative pharmacological efficacy of ~1.4% and absolute pharmacological efficacy of ~0.5%. In contrast, neither control granules nor control (peroral) solution showed a comparable effect. The multiple comparison post-hoc test, least square difference (LSD; at p = 0.05), showed a significant difference of K100LV-, E50LV-, E5LV-, E4M- based insulin-loaded granules from placebo and of K100LV-, E50LV- based insulin-loaded granules from peroral solution. The potential of insulin-loaded HPMC granules followed a general order of K100LV > E50LV > E5LV > E4M > K4M > K100M in lowering of % BGLs. Therefore, low viscosity grades of HPMC are efficient in enhancing oral insulin absorption as compared to high viscosity grades.

New drugs for small animals in 2014

In 2014, six active pharmaceutical ingredients were released on the German market for small animals. Those are the ektoparasiticide of the isoxazoline group afoxolaner (NexGard®) and fluralaner (Bravecto®) and the neonicotinoid dinotefuran (Vectra 3D, Vectra Felis), the antidiabetic protamine zinc insulin of human origin (ProZinc®), the antifungal agent ketoconazole (Fugazid®) as well as the cytostatic drug oclacitinib (Apoquel®). Two substances were authorized for an additional species. The antiparasiticide eprinomectin and the antibiotic clindamycin were also authorized for use in cats. In addition, two active pharmaceutical ingredients, which were approved 2014 for use in human medicine and are of potential interest to veterinary medicine, are discussed. These are the antihypertensive drug riociguat and the urological substance mirabegron.

Owner experiences in treating dogs and cats diagnosed with diabetes mellitus in the United States.

The objective of this study was to report owner experiences and satisfaction in treating a pet with diabetes mellitus using a descriptive report from an Internet-based survey. Descriptive analysis of results was performed, χ(2) tests were used to detect differences in responses between dog and cat owners, and correlations were assessed using the nonparametric Spearman rank correlation. A total of 834 owners participated in the survey. More diabetic dogs (97%) than cats (82%) were treated with insulin injections. Insulin was administered twice daily in 87% of dogs and 73% of cats. Porcine lente and neutral protamine Hagedorn were the most commonly administered insulins in dogs. In cats, glargine and protamine zinc insulin were the most commonly used insulins. Most pets were not fed a prescribed diabetes diet. More cat (66%) than dog (50%) owners were satisfied with the diabetic control achieved. Cat owners were more likely to use home blood glucose monitoring. Treatment was considered expensive by the majority of owners. Few published reports follow diabetic pets after diagnosis or report owner satisfaction. The results of this study provide useful information that may help veterinarians better educate owners and set expectations regarding diabetes treatment and quality of life for diabetic pets.

Expression of insulin-like growth factor-1 mRNA in rat bladder of diabetic cystopathy

Objective To observe the insulin-like growth factor-1 (IGF-1) mRNA expression in diabetic rat bladder.Methods Thirty Sprague-Dawley (SD) male rats were randomly divided into 3 groups:normal control group,diabetic group,and treatment group,n =10 each.The rats in diabetic group and treatment group were injected intraperitoneally with 60 mg/kg Stretopzin (STZ).After 72 h,fasting blood glucose was measure,and BG ＞ 16.7 mmol/L indicated the successful establishment of diabetic model.SD rats in treatment group were given subcutaneous injection of protamine zinc insulin,so BG remained at 3.9-10.0 mmol/L.Bladders of three groups were obtained after 8 weeks,The mRNA from bladders was extracted for detection of △Ct of IGF-1 mRNA by real-time quantitative polymerase chain reaction (Real-time PCR).Results IGF-1 mRNA △Ct in the diabetic group,normal control group and treatment group was 6.141 ±0.916,4.018 ±0.491 and 4.922 ±0.788.the lower the Delta Ct value was lower,the greater the actual copy number was and the higher the amount of gene expression.Conclusion IGF-1 mRNA expression in diabetic rat bladder was significantly reduced.The insulin treatment may up-regulate the IGF-1 mRNA expression in the bladders of diabetic rats. Key words: Diabetes mellitus; Insulin-like growth factor-1 ; Bladder

Antidiabetic Activity of Zinc Oxide and Silver Nanoparticles on Streptozotocin-Induced Diabetic Rats

The use of nanoparticles in medicine is an attractive proposition. In the present study, zinc oxide and silver nanoparticles were evaluated for their antidiabetic activity. Fifty male albino rats with weight 120 ± 20 and age 6 months were used. Animals were grouped as follows: control; did not receive any type of treatment, diabetic; received a single intraperitoneal dose of streptozotocin (100 mg/kg), diabetic + zinc oxide nanoparticles (ZnONPs), received single daily oral dose of 10 mg/kg ZnONPs in suspension, diabetic + silver nanoparticles (SNPs); received a single daily oral dose of SNP of 10 mg/kg in suspension and diabetic + insulin; received a single subcutaneous dose of 0.6 units/50 g body weight. Zinc oxide and silver nanoparticles induce a significant reduced blood glucose, higher serum insulin, higher glucokinase activity higher expression level of insulin, insulin receptor, GLUT-2 and glucokinase genes in diabetic rats treated with zinc oxide, silver nanoparticles and insulin. In conclusion, zinc oxide and sliver nanoparticles act as potent antidiabetic agents.

A pilot trial using topical regular crystalline insulin vs. aqueous zinc solution for uncomplicated cutaneous wound healing: Impact on quality of life

When wounds are treated with regular insulin, they are also being treated with zinc; used in the formula to crystallize insulin molecules. It is not clear if regular insulin-accelerated wound healing is due to insulin, the zinc it contains, or both. Thus, we aimed to compare topical regular crystalline insulin (containing zinc) vs. aqueous zinc chloride solution to controls, on healing of open uncomplicated cutaneous wounds. In this randomized controlled pilot study, 90 nondiabetic patients were randomly assigned to one of three groups depending on the twice daily applications received; group I: regular insulin; group II: aqueous zinc chloride solution, and group III: 0.9% saline (control). A questionnaire was used to determine the effect of wounds on the quality of life. Both topical regular crystalline insulin (containing zinc) and aqueous zinc chloride solution enhanced healing of uncomplicated cutaneous wounds of nondiabetic patients, than control (p < 0.001), and hence improved patients' quality of life. However, regular insulin showed better results than aqueous zinc solution (p = 0.015), probably due to synergistic effect between insulin and zinc of its formulation. Healing rate was significantly higher in acute than chronic wounds (p < 0.001), in those ≤40 years than those >40 (p = 0.004), and in upper body wounds than lower body (p = 0.015).

Use of aglepristone for the treatment of P4 induced insulin resistance in dogs.

Insulin resistance (IR) in dogs is suspected when hyperglycemia is present despite administration of insulin doses greater than 1.0 to 1.5 UI/kg. IR is caused by increases in counter regulatory hormones concentrations (glucagon, glucocorticoids, catecholamines and growth hormone). This study was conducted to investigate the use of aglepristone (RU 46534), a P4 receptor antagonist, for the treatment of IR diabetes mellitus in bitches during the luteal phase. All animals were treated with porcine insulin zinc suspension (Caninsulin) and aglepristone (Alizin) 10 mg/kg subcutaneously at day 1, 2, 9 and 17 from diagnosis. At day 5, no significant variation in glycemia was shown. At day 12 and 20, serum glucose concentrations were significant lower (p < 0.05). From day 12 the insulin dose was reduced to 0.8 IU BID. Insulin was reduced in the following weeks and glycemia was controlled.

The Future of Basal Insulin

Diabetes has been known to mankind for hundreds of years and was considered a deadly disease before the advent of insulin. It was the discovery of insulin by Frederick Banting and Charles Best that revolutionized the management of diabetes. Early insulins were made from either bovine or porcine whole pancreata. These early insulins were rather crude and impure. Because they differ by two or three amino acids from human insulin, immunologic reactions resulted such as insulin allergy, immune-mediated lipoatrophy at the injection site, antibody-mediated insulin resistance, and significant hyperglycemia and hypoglycemia due to unpredictable dissociation of insulin from antibodies. The initial insulins including bovine and porcine insulins were short-acting, and therefore it was difficult for patients to take several injections per day. Patients were often unable to optimize glucose control because of difficulty in adjusting the frequent doses of insulin needed to achieve euglycemia without hypoglycemia. Over a period of time, we understood that, physiologically, there is a continuous small amount of insulin secretion from the b-cells in the pancreas called basal insulin. Therefore, it became necessary to look for a more pure and ideal insulin that had a duration of action of at least 24 h. The early development of insulin diverged in two directions; many researchers were working on the purification of existing insulins, while others were working on longeracting insulins. It was Sanger’s discovery of insulin’s amino acid sequence in 1950 that paved the way to manufacturing of human insulin. The task of manufacturing insulin on a larger scale was made possible with the use of recombinant technology in the 1970s. Currently available insulins are recombinant DNA-derived human insulins. Bovine and porcine insulins are no longer available worldwide. During the same time frame, researchers were working on prolonging the duration of insulin action, resulting in the development of the first long-acting insulin analog (LAIA) known as protamine zinc insulin in the 1930s. Use of protamine zinc insulin was limited by the great risk of sudden hypoglycemia, slow onset of action, and high interand intraindividual variability. Soon after, in 1946, Hans Hagedorn and colleagues introduced crystalline neutral protamine Hagedorn (NPH) insulin, which was a more stable protamine zinc insulin. This modification combined insulin and protamine in ‘‘isophane’’ proportions (no excess of insulin or protamine) at neutral pH in the presence of a small amount of zinc and phenol and/or phenol derivatives to form a tetragonal oblong-shaped hexamer. During the same time in 1950, Hallas-Moller developed the lente insulins: lente, semilente, and ultralente, of which ultralente was the longer-acting insulin. These long-acting insulins (NPH and ultralente) came on the market and quickly gained widespread popularity among physicians in the 1940s and 1950s. However, these LAIAs were still not ideal. The NPH insulin exhibited a highly variable absorption profile (especially if not properly mixed before injection) and had a peak action of approximately 6 h, resulting in poor glycemic control and unpredictable hypoglycemia, especially nocturnal.

Changes in mineral status are associated with improvements in insulin sensitivity in obese patients following l-arginine supplementation

PurposeThe aim of this study is to evaluate the long-term influence of l-arginine intake on mineral concentration in patients with obesity and to assess the changes in lipid serum levels, fat content, and insulin resistance that result.MethodsA randomized double-blind placebo-controlled study was conducted. 88 obese patients were randomly assigned to receive either 9 g of l-arginine or placebo daily, for 6 months. At baseline and after 6 months, selected anthropometrical measurements and blood biochemical analyses were performed and mineral levels were assessed. To assess insulin sensitivity, the gold-standard euglycemic clamp methodology was used.ResultsWe found that 6 months of l-arginine supplementation resulted in significant increases in insulin sensitivity (Δ1.1 mg/kg/min, P < 0.01) and zinc levels (Δ1.5 μmol/L, P < 0.001). Moreover, a positive correlation between the change in zinc concentration in serum and the change in insulin sensitivity was observed (R = 0.80, P < 0.01). In the group of patients treated with l-arginine, a negative correlation between the change in zinc concentration in serum and the change in body fat content was noted (R = −0.38, P < 0.05).Conclusions l-Arginine supplementation affects zinc status in obese patients. One beneficial influence is related to the improvements in insulin sensitivity.

Biosynthetic engineered B28K–B29P human insulin monomer structure in water and in water/acetonitrile solutions

Insulin engineering is a process intended to obtain desired therapeutic properties by rationally designed sequence mutations of a wild type insulin (HI) which originally consists of two chains, having 21 and 30 amino acids (AA) in chain A and B, respectively, held together by two disulfide bridges, namely A7–B7 and A20–B19 and intra strand bridge in chain A; A6–A11. It is known that human insulin (HI) circulates in the bloodstream as a monomer and in such a form passes effectively through the capillary membrane and binds to the insulin receptor (DeFelippis et al. 2001). An increase in insulin concentration causes formation of noncovalent dimers and higher oligomers. These entities are present in pharmaceutical preparations. Natural propensity of insulin to self-association has meaningful implication on pharmacokinetic behaviour upon hormone administration. Insulin diffusion into tissues entails progressive dissociation of hexamers into dimers and monomers. This is revealed as an increase in a serum insulin concentration reaching a maximum at approximately 2–3 h after subcutaneous injection and followed by slow regression within 9 h. Such pharmacokinetic behaviour causes inconvenience to patients forcing them to adapt their schedules to a medicine, what adversely affects their quality of life. Therefore, two therapeutic strategies have emerged with the potential to mimic physiological insulin secretion. First, rapid-acting insulin analogues were designed to have a more rapid onset of action than HI preparations. These analogues are suitable for mealtime blood glucose control as they simulate pulsatile insulin secretion during meals. Secondly, long acting insulin analogues characterized by delayed absorption and peakless activity profile were developed to mimic basal insulin secretion between meals and through the night. An example is provided by Lantus, a medicinal product containing ArgB31–ArgB32, A21 ? Gly or recently published recombinant insulin LysB31–ArgB32. The pharmaceutical motivation for the addition of a dibasic tag at the end of the B-chain is to shift the isoelectric point from 5 to 7, thus leading an acidic formulation (at pH 4.0) to undergo isoelectric precipitation at physiological pH in the subcutaneous tissue. Such precipitation is accompanied by zinc insulin hexamer and provides a ‘long-acting depot’, which is redissolved slowly and absorbed into the bloodstream lasting for about 24 h (Lepore et al. 2000). Another way of protraction hypoglycaemic activity of insulin is to attach fatty acids to insulin, which forms a reversible complex with serum albumin. The binding occurs through the fatty acid moiety. As an example, insulin detemir has been developed by the removal of threonine from the position B30 and acylation of the C14 fatty acid chain (myristic acid) at position 29 on the B Electronic supplementary material The online version of this article (doi:10.1007/s10858-013-9713-2) contains supplementary material, which is available to authorized users.

Successful Treatment of Anaphylactic Shock after Protamine Administration-Report of a Case

Protamine sulfate is administered intravenously to reverse heparin induced anticoagulation during open heart surgery. Allergic reactions to protamine occur sporadically, but arguably with increased incidence in diabetic patients, especially those who receive protamine zinc insulin preparations, patients with true fish allergy or a history of previous protamine exposure, and those who have undergone vasectomy. Adverse effects of protamine administration vary from urticaria and rash to systemic hypotension, bronchospasm, pulmonary hypertension, cardiovascular collapse, and death. The most common reaction in adults is a transient decrease in systemic arterial blood pressure, which is usually associated with the rate of administration. Despite adverse effects, it remains widely used for this purpose. Life-threatening reactions to protamine, although extremely rare, entail substantial risk. We are herein report a case of coronary artery disease received the coronary artery bypass grafting and then life-threatening reactions to cardiovascular collapse after protamine administration without risk factor.

Zinc and glycemic control: A meta-analysis of randomised placebo controlled supplementation trials in humans

BackgroundImpaired zinc metabolism is prominent in chronic disorders including cardiovascular disease and diabetes. Zinc has the potential to affect glucose homeostasis in animals and humans and hence impact the risk of type 2 diabetes mellitus. MethodsA systematic review and meta-analysis of randomised placebo controlled trials was conducted to determine the effect of zinc supplementation on fasting blood glucose, HbA1c, serum insulin and serum zinc concentrations. Relevant studies for inclusion were identified from a literature search of electronic databases up to July 2011. ResultsFourteen reports (n=3978 subjects) were included in the meta-analysis. In the overall analysis, a small but statistically significant reduction in fasting glucose concentrations was observed (−0.19±0.08mmol/L, P=0.013) after zinc supplementation. HbA1c tended to decrease in zinc-supplemented individuals (−0.64±0.36%, P=0.072). No significant effect was observed for serum insulin concentrations. Plasma zinc concentrations increased significantly following supplementation (+4.03±0.81μmol/L, P=0.001). In secondary analyses of participants with chronic metabolic disease (types 1 and 2 diabetes mellitus, metabolic syndrome and obesity), zinc supplementation produced a greater reduction in glucose concentrations (−0.49±0.11mmol/L, P=0.001) compared to the effect that was observed in healthy participants. ConclusionThe significant albeit modest reduction in glucose concentrations and tendency for a decrease in HbA1c following zinc supplementation suggest that zinc may contribute to the management of hyperglycemia in individuals with chronic metabolic disease.

Design of non-standard insulin analogs for the treatment of diabetes mellitus.

Structure-based protein design has enabled the engineering of insulin analogs with improved pharmacokinetic and pharmacodynamic properties. Exploiting classical structures of zinc insulin hexamers, the first insulin analog products focused on destabilization of subunit interfaces to obtain rapid-acting (prandial) formulations. Complementary efforts sought to stabilize the insulin hexamer or promote higher-order self-assembly within the subcutaneous depot toward the goal of enhanced basal glycemic control with reduced risk of hypoglycemia. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus; Sanofi-Aventis, Paris, France) or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir; Novo-Nordisk, Basværd, Denmark). In the past year second-generation basal insulin analogs have entered clinical trials in an effort to obtain ideal flat 24-hour pharmacodynamic profiles. The strategies employ non-standard protein modifications. One candidate (insulin degludec; Novo-Nordisk a/s) undergoes extensive subcutaneous supramolecular assembly coupled to a large-scale allosteric reorganization of the insulin hexamer (the TR transition). Another candidate (LY2605541; Eli Lilly and Co., Indianapolis, IN, USA) utilizes coupling to polyethylene glycol to delay absorption and clearance. On the other end of the spectrum, advances in delivery technologies (such as microneedles and micropatches) and excipients (such as the citrate/zinc-ion chelator combination employed by Biodel, Inc., Danbury, CT, USA) suggest strategies to accelerate PK/PD toward ultra-rapid-acting insulin formulations. Next-generation insulin analogs may also address the feasibility of hepatoselective signaling. Although not in clinical trials, early-stage technologies provide a long-range vision of "smart insulins" and glucose-responsive polymers for regulated hormone release.