Hyperglycemia In Diabetic Patients Research Articles

The effect of chloroquine induced hypoglycemia on the levels of major blood serum proteins in diabetic mice

Article History Chloroquine is a drug derived from cinchona bark has been used for long time to treat different diseases including malaria and accidently it was proved to lower hyperglycemia. Diabetes mellitus is accompanied with many disorders including blood serum proteins levels. Taking into consideration that insulin administration controls hyperglycemia of diabetic patients but it is not sufficient to restore the level of blood serum proteins. In the present work we compared the action of chloroquine and insulin on major blood serum proteins of alloxan induced diabetes. Mice were injected once with alloxan and then treated either with chloroquine or insulin. Another category of mice were fed with high glucose diet for short or long period to induce hyperglycemia independent of insulin level. Major blood serum proteins namely; transferrin, albumin, antitrypsin, acid glycoprotein and immunoglobulin G were estimated by SDS-PAGE and Image J software. Our results showed that chloroquine and insulin were independently effective in lowering fasting blood glucose level in alloxan treated animals. Also chloroquine significantly raises blood serum insulin level in diabetic animals without exogenous insulin treatment. Chloroquine restored partially or completely the level of transferrin, antitrypsin, acid glycoprotein and immunoglobulin G significantly and more efficiently than insulin. Both chloroquine and insulin had no influence on restoring the level of albumin in diabetic mice. The results indicate that chloroquine treatment may be a good adjuvant therapy with insulin to control diabetes and its complications.

Treatment of hyperglycaemia in newly diagnosed diabetic patients is associated with a reduction in oxidative stress and improvement in β‐cell function

There exist several reports demonstrating enhancement in oxidative stress in diabetic patients; however, serial and comprehensive measurement of oxidative stress parameters in newly diagnosed diabetic patients is not yet reported. We measured the oxidative stress parameters in diabetic patients serially from the time of diagnosis and after starting treatment to study their association with glycaemia, insulin resistance and β-cell function. Fifty-four newly diagnosed diabetic patients were studied at diagnosis and 4 and 8 weeks after initiating anti-hyperglycaemic treatment. Oxidative stress parameters included activity of antioxidant enzymes, concentration of antioxidant molecules and damage markers. Oxidative stress score was computed as a collective measure of oxidative stress to interpret total oxidative stress state. Association of changing glucose levels with changing oxidative stress parameters over 8 weeks and association of oxidative stress score with insulin resistance and β-cell function was analysed by homeostasis model assessment (HOMA-IR and HOMA-β, respectively). Eight weeks of treatment improved HbA1C from 9.8 ± 2.1 to 7.7 ± 1.0%. There was a significant increase in oxidative stress in diabetic patients [23.8 (95% CI 20.0, 27.6)] compared with non-diabetic subjects [-1.2 (-3.4, 0.9)] (p < 0.001). Non-diabetic subjects showed a stable status over 8 weeks. Improvement in hyperglycaemia in diabetic patients was associated with an improvement in oxidative stress parameters irrespective of the anti-diabetic treatment received. Oxidative stress score fell after 8 weeks and was significantly associated with an improvement in HOMA-β (standardized β = -0.38, p < 0.01) but not with HOMA-IR. Controlling hyperglycaemia in diabetic patients alleviates oxidative stress within 8 weeks of treatment, and improvement in oxidative stress parameters was related to an improved β-cell function.

Oxadiazoles and thiadiazoles: Novel α-glucosidase inhibitors

Oxadiazoles and thiadiazoles 1–37 were synthesized and evaluated for the first time for their α-glucosidase inhibitory activities. As a result, fifteen of them 1, 4, 5, 7, 8, 13, 17, 23, 25, 30, 32, 33, 35, 36 and 37 were identified as potent inhibitors of the enzyme. Kinetic studies of the most active compounds (oxadiazoles 1, 23 and 25, and thiadiazoles 35 and 37) were carried out to determine their mode of inhibition and dissociation constants Ki. The most potent compound of the oxadiazole series (compound 23) was found to be a non-competitive inhibitor (Ki=4.36±0.017μM), while most potent thiadiazole 35 was identified as a competitive inhibitor (Ki=6.0±0.059μM). The selectivity and toxicity of these compounds were also studied by evaluating their potential against other enzymes, such as carbonic anhydrase-II and phosphodiesterase-I. Cytotoxicity was evaluated against rat fibroblast 3T3 cell line. Interestingly, these compounds were found to be inactive against other enzymes, exhibiting their selectivity towards α-glucosidase. Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. α-Glucosidase inhibitors can also be used as anti-obesity and anti-viral drugs. Our study identifies two novel series of potent α-glucosidase inhibitors for further investigation.

Inhibiting enzymatic starch digestion by hydrolyzable tannins isolated from Eugenia jambolana

Slowing down starch digestion is one method of controlling postprandial hyperglycaemia of diabetes, for which naturally occurring α-amylase inhibitors from edible botanicals have a great potential. We reported herein that Eugenia jambolana, a traditional herbal tea for the treatment of diabetes in South Asia, contains potent α-amylase inhibitors because of monomeric and polymeric hydrolyzable tannins (HT). These compounds demonstrated a dose dependent inhibitory activity against α-amylase (IC50 = 1.1 ± 0.4 μg/mL), which was significantly stronger than acarbose (IC50 = 19.0 ± 2.0 μg/mL). Kinetic studies revealed that the HT were mixed non-competitive inhibitors against α-amylase. Using an in vitro human starch digestion model, incorporation of 0.125 mg/mL HT into a real food system (wheat flour) was effective in delaying enzymatic starch digestion moderately, with a significantly stronger inhibitory effect in the absence of proteins in the food matrix. Pre-incubation of HT with α-amylase prior to substrate addition also significantly enhanced their inhibitory activity. These results provide useful knowledge on HT as potential α-amylase inhibitors, which could potentially alleviate postprandial hyperglycaemia in diabetic patients.

Reducing harm in patients using insulin.

Controlling blood sugars with insulin is an important part of managing hyperglycemia in diabetic patients. However, the literature has shown that the use of insulin has been associated with more medication errors than any other type or class of drug. This article will highlight medication errors that may arise during the use of insulin in the long-term facility and provide risk-reduction recommendations to address the potential for error and patient harm.

A linearization approach for the model‐based analysis of combined aggregate and individual patient data

The application of model-based meta-analysis in drug development has gained prominence recently, particularly for characterizing dose-response relationships and quantifying treatment effect sizes of competitor drugs. The models are typically nonlinear in nature and involve covariates to explain the heterogeneity in summary-level literature (or aggregate data (AD)). Inferring individual patient-level relationships from these nonlinear meta-analysis models leads to aggregation bias. Individual patient-level data (IPD) are indeed required to characterize patient-level relationships but too often this information is limited. Since combined analyses of AD and IPD allow advantage of the information they share to be taken, the models developed for AD must be derived from IPD models; in the case of linear models, the solution is a closed form, while for nonlinear models, closed form solutions do not exist. Here, we propose a linearization method based on a second order Taylor series approximation for fitting models to AD alone or combined AD and IPD. The application of this method is illustrated by an analysis of a continuous landmark endpoint, i.e., change from baseline in HbA1c at week 12, from 18 clinical trials evaluating the effects of DPP-4 inhibitors on hyperglycemia in diabetic patients. The performance of this method is demonstrated by a simulation study where the effects of varying the degree of nonlinearity and of heterogeneity in covariates (as assessed by the ratio of between-trial to within-trial variability) were studied. A dose-response relationship using an Emax model with linear and nonlinear effects of covariates on the emax parameter was used to simulate data. The simulation results showed that when an IPD model is simply used for modeling AD, the bias in the emax parameter estimate increased noticeably with an increasing degree of nonlinearity in the model, with respect to covariates. When using an appropriately derived AD model, the linearization method adequately corrected for bias. It was also noted that the bias in the model parameter estimates decreased as the ratio of between-trial to within-trial variability in covariate distribution increased. Taken together, the proposed linearization approach allows addressing the issue of aggregation bias in the particular case of nonlinear models of aggregate data.

Chronic hyperglycemia in critically ill: Another piece in the glycemic control puzzle

Chronic hyperglycemia in critically ill: Another piece in the glycemic control puzzle

The use of peritoneal dialysis in the management of patients with renal failure at institute of kidney diseases, Peshawar

Peritoneal dialysis (PD) using an ordinary stylet cannula was studied in 253 patients (67% male and 33% female with age ranging from 3-67 years) suffering from renal failure. The study was conducted between January 2007 and December 2012. The procedure was well tolerated by the patients. The desired aims of dialysis including improvement in chemistry were achieved in all surviving (94.5%) cases. Mortality during PD was 5.5% and was related to the underlying causes of renal failure. Peritonitis seen in 30% cases was the commonest complication. Other complications in order of frequency were, hypokalemia (8%), severe hyperglycemia in diabetic patients (6%), and sever hypovolemia (5%), pericatheter leak (5%) and catheter blockage (2%). Perforation of the bowel, a serious complication occurring during insertion of the PD cannula was not seen in any of the cases. It is concluded from the study that PD is a simple and cost effective alternative to hemodialysis and have special advantages in the current set-up of the institute. The objective of our work was to study the results and complications of peritoneal dialysis in light of its efficacy as an alternative form of renal replacement therapy (RRT) to hemodialysis.

Inhibition of salivary and pancreatic α-amylases by a pinhão coat (Araucaria angustifolia) extract rich in condensed tannin

The purpose of the present work was to investigate the possible inhibitory effect of a pinhão coat extract rich in condensed tannin on the activity of α-amylases (human salivary and porcine pancreatic). Experiments with the classic α-amylase inhibitor acarbose and a condensed tannin from Acacia mearnsii were done for comparative purposes. Fourier transform-infrared spectroscopy analysis of the pinhão coat tannin revealed a higher proportion of procyanidins to prodelphinidins when compared to the A. mearnsii tannin. The pinhão coat extract rich in condensed tannin was an effective inhibitor of both human salivary and porcine pancreatic α-amylase. Inhibition was of the mixed S-parabolic I-parabolic type. For the human salivary α-amylase the inhibition constants were 56.88±5.74 and 103.27±11.85μg/L; for the porcine pancreatic α-amylase the inhibition constants were smaller, namely, 20.25±1.97 and 46.79±4.57μg/L. The decreasing potency sequence was: acarbose>pinhão coat extract rich in tannin>A. mearnsii tannin. Similarly to acarbose and the A. mearnsii tannin, the pinhão coat extract was also effective in diminishing the post-prandial glycemic levels in rats after starch administration. The inhibitory properties of the pinhão coat extract indicate that it can be used to suppress postprandial hyperglycemia in diabetic patients.

Pathomechanism of Renal Damage in Type 2 Diabetes Mellitus Patients

BACKGROUND: Hyperglycemia in diabetic patients cause both chronic inflammation and extracellular matrix accumulation that can lead to progressive renal damage. Albumin, Gammaglutamytransferase (GGT) and clusterin in urine are markers to detect damage in glomerulus, cell of the tubules and proximal tubules, respectively.METHODS: This study aimed to evaluate the pathomechanism of haemoglobin A1c (HbA1c), albumin, GGT, clusterin, type IV collagen in urine, and high sensitivity C-reactive protein (hsCRP) in type 2 diabetes mellitus (DM) patients. The study was a cross sectional study involving 82 subjects consisting of 36 males and 46 females, 35-65 years old, divided into 3 groups: uncontrolled DM, controlled DM and non DM. Data were obtained from interviews, physical examinations (weight, height, blood pressure) and laboratory examinations (HbA1c, serum glutamic oxaloacetic (SGOT), serum glutamic pyruvic (SGPT), creatinine, hsCRP, urinary albumin, urinary GGT, urinary clusterin, and urinary type IV collagen). Statistical analysis was performed for correlation, difference and cross tabulation tests.RESULTS: The study results showed there were significant differences (p&lt;0.05) between uncontrolled DM group compared with controlled DM and non DM groups in HbA1c, ratio of urinary type IV collagen and ratio of urinary albumin. However, there were no significant differences between controlled DM and non DM groups. There were positive significant correlations between HbA1c with hsCRP (r=0.223, p&lt;0.05), HbA1c with ratio of urinary type IV collagen/creatinine (r=0.563, p&lt;0.001), HbA1c with ratio of urinary albumin/creatinine (r=0.263, p&lt;0.05), and ratio of urinary type IV collagen/creatinine with ratio urinary albumin/creatinine (r=0.613, p&lt;0.001).CONCLUSION: Results of this study indicated that albumin and type IV collagen in urine play a role in renal damage caused by uncontrolled glucose level in subjects with type 2 DM. The increased concentration of both HbA1c and urinary type IV collagen indicates increased risk factor of glomerulus damage. Urinary type IV collagen is likely to be future potential marker for early detection of renal damage.KEYWORDS: renal damage, HbA1c, hsCRP, type IV collagen, GGT, clusterin, diabetes mellitus

Reactive oxygen species-mediated mitochondrial dysfunction plays a critical role in high glucose-induced nucleus pulposus cell injury.

Dear Editor, We read with interest and appreciation the article by Park et al. [1] attempting to illustrate the role of reactive oxygen species (ROS) in notochordal cells under high glucose concentrations. The study indicated that high glucose-induced oxidative stress promotes autophagy through mitochondrial damage of rat notochordal cells in a dose- and time-dependent manner. In humans, most notochordal cells are larger than nucleus pulposus (NP) cells, containing vacuoles, and disappear within the first decade of life [2]. A previous study showed that notochordal cells will be first replaced by smaller chondrocyte-like NP cells and then replaced by cells with a fibrocartilagenous phenotype with age [3]. The chondrocyte-like NP cells are the major cells in the adult nucleus pulposus and excessive apoptosis of NP cells plays an important role in the development of intervertebral disc degeneration[4]. As we know, there are two main types of diabetes: type1 diabetes and type 2 diabetes. Type 2 diabetes accounts for 90–95 % percent of all diabetes cases, and it usually occurs in people aged over 40. Moreover, intervertebral disk disease occurs primarily in middle aged and older persons. Therefore, NP cells may be the main cells which are affected by hyperglycaemia in diabetic patients with degenerative disc diseases. However, it is still unknown whether ROS-mediated mitochondrial dysfunction also play a critical role in high glucose-induced NP cell injury. Therefore, we performed a study to investigate the question. In our study, rat NP cells showed chondrocyte-like morphology under phase-contrast microscope (Fig. 1A1). By immunohistochemical staining (Fig. 1A2) and immunofluorescence staining (Fig. 1A3), cells were demonstrated to exhibit collagen II protein expression. To determine the effects of high glucose concentrations on cell viability, cells were treated with two concentrations (0.1M and 0.2M) of high glucose for 24 hours. Hoechst 33258 nuclear staining showed that the majority of NP cells exhibited significant morphological features of apoptosis such as bright nuclear condensation or fragments after treatment with high glucose concentrations (Fig. 1B2 and 1B3). To further explore whether ROS-mediated mitochondrial dysfunction plays a causal role in high glucose-induced NP cell injury, the level of ROS and mitochondrial membrane potential in cells was detected by DCFH-DA assay and JC-1 assay, respectively. As anticipated, the intracellular ROS levels which exhibit a green fluorescence signal were obviously increased in both high glucose groups compared with the control group (Fig. 1c). Mitochondrial membrane potential (Δψm) is an important indicator of mitochondrial function. We observed that in both high glucose groups (Fig. 1D2 and 1D3), there was an obvious decrease in the Δψm with a decrease in red fluorescence (JC-1 polymers) which indicates the intact Δψm, and an increase in green fluorescence (JC-1 monomers), which indicates the disruption of Δψm. Fig. 1 The effect of high glucose concentrations on NP intracellular ROS production and mitochondrial membrane potential (ΔΨm). (a1) Morphology of NP cells observed by phase-contrast microscopy. (a2) NP cells identified by collagen II immunohistochemical ... Combined with the previous research by Park et al. [1], we can draw a conclusion that ROS-mediated mitochondrial dysfunction not only plays a critical role in notochordal cells but also in NP cells under high glucose concentration. Further, it confirmed our previous hypothesis that antioxidants may be a novel treatment option for diabetic patients with degenerative disc diseases [5].

Flavonoids as drugs at the small intestinal level

Flavonoids represent a biologically active class of secondary plant compounds. For selected members there is convincing evidence regarding their beneficial effects on human health. Accordingly these compounds are tested as supporting or alternative therapies for a number of diseases such as cancer or type-II diabetes. Subsequent to their ingestion a first site of interference are digestive enzymes and transporters in the small intestine. Through interactions with glucose transporters in the apical membranes of enterocytes flavonoid glycosides and also some aglycones appear to reduce postprandial hyperglycaemia in diabetic patients. Moreover, many flavonoids have been shown to interfere with ATP-dependent drug-efflux transporters which are relevant for the resistance of cancer cells versus various cytostatic drugs and makes them candidates to overcome multidrug-resistance.

Binding study of novel anti-diabetic pyrimidine fused heterocycles to β-lactoglobulin as a carrier protein

Bovine milk β-lactoglobulin (β-LG) demonstrates significant resistance against both gastric- and simulated duodenal digestions. Therefore, it seems a realistic protein candidate for safe delivery and protection of particularly pH sensitive drugs in stomach. Recently, pyrimidine fused heterocycles (PFHs) revealed inhibitory properties against α-glucosidase (α-Gls) which is an important target enzyme for those drugs playing significant role in treatment of type-II diabetes and HIV/AIDS infection. The delivery of these compounds to small intestine where the enzyme plays its biological function is of great importance. Therefore, in this work the interaction of PFH compounds with β-LG, as a carrier protein has been investigated. Fluorescence, circular dichroism (CD) and UV–vis spectroscopic studies were used to examine the binding parameters and binding modes of the interaction. Moreover, the effects of PFH complexation on the secondary structures of β-LG were studied. All of these compounds significantly quenched the fluorescence intensity of β-LG due to a ground state complex formation. The binding and thermodynamic parameters were calculated. While hydrophobic interactions were proved to play significant role in the interaction of L1, L2 and L3, hydrogen bonding was shown to be important in the complexation of L4. The secondary structures of β-LG were preserved upon interaction of these synthetic compounds. Based on the achieved results, these potentially therapeutic agents can significantly bind to β-LG. Consequently, this protein might be useful for delivery of PFH compounds to small intestine where representing their potential ability to inhibit α-Gls and to reduce the postprandial hyperglycemia in diabetic patients.

Production, fractionation, characterization of extracellular polysaccharide from a newly isolated Trametes gibbosa and its hypoglycemic activity

The submerged fermentation for extracellular polysaccharide (EPS) production from Trametes gibbosa was optimized. An optimal medium for EPS production was obtained through central composite design (CCD) as follows: 53.12g/L maltose and 4.21g/L polypeptone in distilled water. Furthermore, four groups of EPSs (designated as Fr-I, Fr-II, Fr-III and Fr-IV) were obtained from the culture filtrates by size exclusion chromatography (SEC), and their molecular characteristics were examined by a multiangle laser-light scattering (MALLS) and refractive index (RI) detector system. The weight-average molar mass of Fr-I was determined to be 3.872x105g/mol and its molecular shape was revealed to be a rigid rod in an aqueous solution. Finally, the hypoglycemic effect of the EPS, investigated in streptozotocin induced diabetic mice, decreased plasma glucose, total cholesterol and triacylglycerol concentrations by 17.4%, 14.0% and 12.6%, respectively. The results indicate the potential of this EPS to prevent hyperglycemia in diabetic patients.

Management of Hyperglycemia in Diabetic Patients with Hematologic Malignancies During Dexamethasone Therapy

To compare the response to different insulin regimens for management of hyperglycemia in diabetic patients with hematologic malignancies who are receiving dexamethasone. A retrospective analysis was conducted to determine whether a basal bolus insulin (BBI) regimen with detemir and aspart is superior to a sliding scale regular insulin (SSI) regimen for management of hyperglycemia in hospitalized diabetic patients receiving dexamethasone. Forty patients with hematologic malignancies were treated with intravenous (8 to 12 mg/day) or oral (40 mg/day) dexamethasone for 3 days. The average blood glucose (BG) level was 301 ± 57 mg/dL in the SSI group (n = 28) and 219 ± 51 mg/dL in the BBI group (n = 12) (P <.001). The BBI regimen resulted in an average BG reduction of 52 ± 82 mg/dL throughout the course of dexamethasone therapy, while the SSI regimen produced an increase in the mean daily BG level of 128 ± 77 mg/dL (P <.001). On the last day of dexamethasone administration, the insulin requirement was 49 ± 29 units/day in the SSI group and 122 ± 39 units/day in the BBI group (P <.001). Three patients in the SSI group developed diabetic ketoacidosis or hyperosmolar hyperglycemia during steroid therapy. No hypoglycemia was observed in either group. The length of stay and infection rates were similar between groups. Basal and bolus insulin regimen is an effective and safe approach for managing dexamethasone-induced hyperglycemia in hospitalized patients with hematologic malignancies.

Pathogenic Role of TGF- β in Diabetic Nephropathy

About one-third of diabetic patients develop diabetic kidney disease. In renal cells, transforming growth factor- β (TGF-β) is a key regulator of extracellular matrix protein synthesis and is secreted as latent complexes. Chronic hyperglycemia in diabetic patients seems to stimulate the glomerular mesangial cells to secrete TGF- β, which is stored in the mesangial matrix and then localized to the podocyte surface. Glomerular hypertension in the diabetic kidney may upregulate angiotensin II (Ang II) in podocytes, which may activate the latent TGF- β. Activated TGF- β /Smad signaling may stimulate the podocytes to overproduce α3(IV) collagen, leading to glomerular basement membrane (GBM) thickening. Furthermore, TGF-β-induced connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) may stimulate mesangial cells to overproduce matrix, culminating in diabetic glomerulo sclerosis. TGF-β- induced podocyte loss may also contribute to the development of glomerulosclerosis. Together, this review provides new mechanistic insights into the renal activation of TGF-s signaling and TGF-s-induced glomerular pathology in diabetic nephropathy.

Fermentation characteristics and hypoglycemic activity of an exopolysaccharide produced by submerged culture of Stropharia rugosoannulata #2

We have investigated the mycelial growth and extracellular polysaccharide (EPS) production of Stropharia rugosoannulata #2 under optimal culture conditions in a 5-L stirred-tank fermenter. Maximum biomass growth (16.35 g/L) was achieved after 5 days of cultivation, whereas EPS reached its maximum level (10.83 g/L) after 8 days. The morphological parameters (i.e., mean diameter, circularity, roughness, compactness) of the fungal pellets and broth viscosity were also characterized. The compactness of the pellets was determined to be significantly and positively correlated with EPS content. The hypoglycemic effect of the polysaccharide, investigated in streptozotocin-induced diabetic rats, included decreases in the plasma concentrations of glucose (37 %), total cholesterol (26 %), and triacylglycerol (24 %) and decreased aspartate aminotransferase activity (20 %). The results indicate the potential of this polysaccharide to prevent hyperglycemia in diabetic patients.

Coagulanolide modulates hepatic glucose metabolism in C57BL/KsJ-db/dbmice

Increased hepatic glucose output is one of the major causes of fasting hyperglycemia in diabetic patients. In this study, we investigated the mechanism of action of coagulanolide on hepatic glucose, regulating enzymes in type 2 diabetic C57BL/KsJ-db/db (db/db) mice. Coagulanolide is an active component of Withania coagulans fruit. Oral administration of coagulanolide for 3 weeks decreases fasting blood glucose and plasma insulin significantly, and it improves glucose tolerance in the db/db mice group. The enzyme activity and protein expression of glucokinase and pyruvate kinase was significantly enhanced in coagulanolide-treated db/db group when compared with untreated one. On the other hand, activities and protein expression of fructose-1,6-bisphosphatase, glucose 6-phosphatase, phosphoenolpyruvate carboxykinase, and glycogen phosphorylase enzymes were significantly lowered in treated group. The treatment with coagulanolide also normalizes the concentrations of plasma cholesterol, triglyceride, free fatty acid, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in the db/db mice. These findings suggested that the coagulanolide is useful in the control of fasting hyperglycemia in type 2 diabetes by regulating the production of hepatic glucose.

Identification of Key Residues for the Binding of Glucagon to the N-Terminal Domain of its Receptor: An Alanine Scan and Modeling Study

Glucagon plays an essential role in the glycemia maintenance during fasting, but also aggravates hyperglycemia in diabetic patients. A series of analogues of glucagon were synthesized replacing each amino acid of the C-terminal region (residues 15-29) with alanine. The residues affecting the binding to the glucagon receptor are found to be located on one face of the glucagon helix. Several 3-dimensional models of the N-terminal domain of the glucagon receptor in complex with its ligand peptide were built and used to analyze the peptide-receptor interface in terms of the nature of the peptide residues and the interactions they form with the receptor. The models suggest that glucagon keeps its native helical structure upon binding, and that a large part of the interface formed with the receptor is hydrophobic. We find that in the C-terminal region, F22, V23, M27, and D15 are the most important residues for peptide binding. They bury a large portion of their solvent accessible surface area and make numerous interactions with the receptor mainly of the hydrophobic type.

O-GlcNAc Transferase/Host Cell Factor C1 Complex Regulates Gluconeogenesis by Modulating PGC-1α Stability

A major cause of hyperglycemia in diabetic patients is inappropriate hepatic gluconeogenesis. PGC-1α is a master regulator of gluconeogenesis, and its activity is controlled by various posttranslational modifications. A small portion of glucose metabolizes through the hexosamine biosynthetic pathway, which leads to O-linked β-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins. Using a proteomic approach, we identified a broad variety of proteins associated with O-GlcNAc transferase (OGT), among which host cell factor C1 (HCF-1) is highly abundant. HCF-1 recruits OGT to O-GlcNAcylate PGC-1α, and O-GlcNAcylation facilitates the binding of the deubiquitinase BAP1, thus protecting PGC-1α from degradation and promoting gluconeogenesis. Glucose availability modulates gluconeogenesis through the regulation of PGC-1α O-GlcNAcylation and stability by the OGT/HCF-1 complex. Hepatic knockdown of OGT and HCF-1 improves glucose homeostasis in diabetic mice. These findings define the OGT/HCF-1 complex as a glucose sensor and key regulator of gluconeogenesis, shedding light on new strategies for treating diabetes.