Lower Fasting Blood Glucose Levels Research Articles

Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity

ObjectiveThe gut microbiota is an environmental regulator of fat storage and adiposity. Whether the microbiota represents a realistic therapeutic target for improving metabolic health is unclear. This study explored two...

Naringin Ameliorates Atherogenic Dyslipidemia but not Hyperglycemia in Rats With Type 1 Diabetes

Antiatherogenic and hypoglycemic effects of naringin are hereby investigated in type 1 diabetes. Wistar rats (n = 6) were treated daily with 1.0 mL of water (group 1), naringin (50 mg/kg) (groups 2 and 3, respectively), regular insulin (4 U/kg, subcutaneously, twice daily) (group 4), and simvastatin (20 mg/kg) (group 6). Groups 3, 4, 5, and 6 exhibited polydipsia and hyperglycemia after injection with streptozotocin (60 mg/kg body weight). Insulin, but not naringin, significantly lowered fasting blood glucose levels in diabetic rats. Plasma low-density lipoprotein cholesterol concentrations were significantly higher in nontreated diabetic rats (group 5) compared with control (group 1), whereas total and high-density lipoprotein cholesterol were significantly higher in naringin- and simvastatin-treated diabetic rats, respectively. Hepatic total cholesterol and triglycerides were significantly elevated in nontreated diabetic compared with the control, naringin-, insulin-, and simvastatin-treated diabetic rats, respectively. Hepatic 3-hydroxy-3-methyl-glutaryl CoA reductase and Acyl-CoA:cholesterol acyltransferase activities were significantly elevated in nontreated diabetic compared with the control, naringin-, and simvastatin-treated diabetic rats, respectively. However, plasma low-density lipoprotein to high-density lipoprotein ratio was significantly higher in nontreated diabetic compared with the control, whereas naringin and simvastatin significantly reduced the ratio in diabetic rats. Naringin is not hypoglycemic but improves atherogenic index in type 1 diabetes.

Fasting and Post-Challenge Glucose as Quantitative Cardiovascular Risk Factors: A Meta-Analysis

The post-challenge glucose (PCG) level has been suggested to be superior to the fasting blood glucose (FG) level for predicting the risk of future cardiovascular disease (CVD); however, the extent of its superiority has not been consistently shown among previous cohort studies. Therefore, we conducted a meta-analysis to summarize the quantitative association of FG and PCG with CVD risk and compared the strengths of the two associations. Electronic literature searches using MEDLINE and EMBASE with an additional manual search were conducted for prospective observational studies of the association of FG and PCG with CVD risk. Studies were included if they were prospective studies in which the relative risk (RR) of CVD per 1 standard deviation increase in both FG and PCG could be estimated. Pooled relative risks for the incremental increase were calculated as RR(FG) and RR(PCG) using a bivariate random-effects model. Data were obtained from 14 eligible studies that included 70,889 participants and 2,927 cases. The pooled RR(FG) and RR(PCG) (95% confidence interval) were, respectively, 1.15 (1.06 to 1.26) and 1.24 (1.12 to 1.36); the difference was significant (P =0.001). The association of PCG with CVD risk was stronger in studies that targeted participants with a baseline mean FG < 100 mg/dl (P < 0.001) or mean age ≥ 55 years (P =0.004). Overall, the association of PCG with CVD risk was stronger than that of FG by approximately 50% on a log scale. Measuring PCG is especially important in populations with relatively low FG levels or in the elderly, although it is often burdensome in routine clinical practice.

Rhein Reduces Fat Weight indb/dbMouse and Prevents Diet-Induced Obesity in C57Bl/6 Mouse through the Inhibition of PPARγSignaling

Rheum palmatum has been used most frequently in the weight-reducing formulae in traditional Chinese medicine. However, the components of Rheum palmatum that play the antiobesity role are still uncertain. Here, we tested the weight-reducing effect of two major Rheum palmatum compounds on db/db mouse. We found that rhein (100 mg kg−1 day−1), but not emodin, reduced the fat weight in db/db mouse. Using diet-induced obese (DIO) C57BL/6 mice, we identified that rhein blocked high-fat diet-induced obesity, decreased fat mass and the size of white and brown adipocytes, and lowered serum cholesterol, LDL cholesterol, and fasting blood glucose levels in the mice. To elucidate the underlying mechanisms, we used reporter assay and gene expression analysis and found that rhein inhibited peroxisome proliferator-activated receptor γ (PPARγ) transactivity and the expression of its target genes, suggesting that rhein may act as a PPARγ antagonist. Our data indicate that rhein may be a promising choice for antiobesity therapy.

Abstract P235: Endothelium-Specific Prokineticin Receptor 1 Inactivation in Mice Leads to Endothelial Dysfunction and Metabolic Syndrome

Reciprocal relationships between endothelial dysfunction and insulin resistance result in a vicious cycle, linking between cardiovascular and metabolic disorders. Here we provide the first evidence that endothelial specific loss of prokineticin receptor-1 (PKR1) in mice leads to endothelial dysfunction and low capillary formation, ultimately contributing cardiovascular, kidney disorders and development of insulin resistance. Endothelial cells derived from these mutant hearts displayed an impaired proliferation rate and vessel-like formation. Low capillary formation in mutant heart, kidney, pancreas and adipose tissues was evident. The mutant aortas displayed increased collagen deposition, fenestrated endothelium with junctional defects, and impaired relaxation due to nitric oxide synthesize-deficits without altering blood pressure. Mutant hearts have thin ventricular wall due to an increase in apoptotic cardiomyocytes. Mutant kidneys have abnormal glomerulus structure with an increase in apoptotic cell numbers and phosphate excretion. Mutant mice exhibited low fasting blood glucose and high serum insulin levels. They cleared the blood glucose at a considerably slower rate than control mice accompanied with impaired insulin tolerance. The insulin resistance induces compensatory β cell hypertrophy but not expansion due to impaired survival signaling. Induction of cell death and fibrosis is induced by hypoxia in mutant adipocytes leads to increase in HIF1a and collagen expression. Moreover, an increase in serum FFA and inhibition of insulin-signaling pathway in adipocytes may represent an early event in systemic insulin resistance. This mutation provides a genetic model for metabolic syndrome and should facilitate studies of both the pathogenesis and therapy of cardiovascular, renal and metabolic disorders in humans.

Berberine Improves Glucose Homeostasis in Streptozotocin-Induced Diabetic Rats in Association with Multiple Factors of Insulin Resistance

The present study was carried out to determine the effect of berberine on glucose homeostasis and several biomarkers associated with insulin sensitivity in male Wistar rats with intraperitoneal injection of streptozotocin (STZ)-induced diabetes. Rats with fasting blood glucose 16.7 mmol/L after 2 weeks of STZ injection were divided into two groups. One group was used as the diabetic control and another treated by gavage feeding with 100 mg/kg/d of berberine in water containing 0.5% carboxymethyl cellulose. A group of rats without receiving STZ was used as the normal control. After 7 weeks, berberine supplementation moderately but significantly lowered fasting blood glucose levels and improved oral glucose tolerance. Berberine lowered plasma free fatty acids and C-reactive protein levels without affecting plasma insulin levels. Diabetic rats treated with berberine showed significantly lower plasma triacylglycerol and cholesterol levels. Furthermore, berberine inhibited dipeptidyl peptidase-4 and protein tyrosine phosphatase-1B activities. In conclusion, berberine showed a dramatic effect of lowering blood cholesterol and triacylglycerols and improved moderately glucose homeostasis in STZ-induced diabetic rats in association with multiple factors related to insulin resistance.

Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents

Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat–fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate–1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate–activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status.

Disrupting the CH1 Domain Structure in the Acetyltransferases CBP and p300 Results in Lean Mice with Increased Metabolic Control

Opposing activities of acetyltransferases and deacetylases help regulate energy balance. Mice heterozygous for the acetyltransferase CREB binding protein (CBP) are lean and insulin sensitized, but how CBP regulates energy homeostasis is unclear. In one model, the main CBP interaction with the glucagon-responsive factor CREB is not limiting for liver gluconeogenesis, whereas a second model posits that Ser436 in the CH1 (TAZ1) domain of CBP is required for insulin and the antidiabetic drug metformin to inhibit CREB-mediated liver gluconeogenesis. Here we show that conditional knockout of CBP in liver does not decrease fasting blood glucose or gluconeogenic gene expression, consistent with the first model. However, mice in which the CBP CH1 domain structure is disrupted by deleting residues 342-393(ΔCH1) are lean and insulin sensitized, as are p300ΔCH1 mutants. CBP(ΔCH1/ΔCH1) mice remain metformin responsive. An intact CH1 domain is thus necessary for normal energy storage, but not for the blood glucose-lowering actions of insulin and metformin.

A low frequency variant within the GWAS locus of MTNR1B affects fasting glucose concentrations: Genetic risk is modulated by obesity

Two common variants (rs1387153, rs10830963) in MTNR1B have been reported to have independent effects on fasting blood glucose (FBG) levels with increased risk to type 2 diabetes (T2D) in recent genome-wide association studies (GWAS). In this investigation, we report the association of these two variants, and an additional variant (rs1374645) within the GWAS locus of MTNR1B with FBG, 2h glucose, insulin resistance (HOMA IR), β-cell function (HOMA B), and T2D in our sample of Asian Sikhs from India. Our cohort comprised 2222 subjects [1201 T2D, 1021 controls]. None of these SNPs was associated with T2D in this cohort. Our data also could not confirm association of rs1387153 and rs10830963 with FBG phenotype. However, upon stratifying data according to body mass index (BMI) (low ≤ 25 kg/m2 and high > 25 kg/m2) in normoglycemic subjects (n = 1021), the rs1374645 revealed a strong association with low FBG levels in low BMI group (β = −0.073, p = 0.002, Bonferroni p = 0.01) compared to the high BMI group (β = 0.015, p = 0.50). We also detected a strong evidence of interaction between rs1374645 and BMI with respect to FBG levels (p = 0.002). Our data provide new information about the significant impact of another MTNR1B variant on FBG levels that appears to be modulated by BMI. Future confirmation on independent datasets and functional studies will be required to define the role of this variant in fasting glucose variation.

Bioactivity of American Ginseng by Knockout Extract Preparation Using Monoclonal Antibody

We produced anti-ginsenoside Re (GRe)-4G10 monoclonal antibody that specifically recognizes GRe and used this to prepare an immunoaffinity column to remove GRe from American ginseng berry extract (AGBE) (thus producing GRe knock-out AGBE (GRe-KO-AGBE)). We compared the anti-diabetic and anti-obesity effects of AGBE and GRe-KO-AGBE in adult diabetic C57BL/6J ob/ob mice. Fasting blood glucose levels and body weight were measured in mice receiving daily intraperitoneal injections of 150 mg/kg of either extract for 27 consecutive days. On Day 6, the group taking AGBE had significantly lower fasting blood glucose levels compared to GRe-KO-AGBE-treated mice (70.5 mg/dl vs. 140 mg/dl). On Day 13, the glucose levels in both groups were 201 mg/dl for AGBE-treated group and 169 mg/dl for GRe-KO-AGBE, respectively. GRe (20 mg/kg) had dose-related effects on fasting blood glucose levels (reduced to 188 and 180 mg/dl on Day 5 and Day 12, respectively, compared to 229 and 235 mg/dl, respectively, in the vehicle group). This hypoglycemic effect persisted even after treatment discontinued (blood glucose levels at 3 days post-treatment: 198 and 253 mg/dl with ginsenoside and vehicle treatment, respectively). The monoclonal antibody technique can be used to prepare botanical knockout extracts for bioactivity studies.

Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets

The objective of this work was to prepare Glimepiride (1 mg) rapidly disintegrating tablets (RDT) by direct compression, and also, to evaluate Pharmaburst™ as a newly introduced diluent for this type of tablets, either alone or in combination with other well known tablet excipients. Another goal was to study the stability, as well as, the in vivo effects of selected formulations. Orange flavor was the most preferred flavor for the prepared rapidly disintegrating tablets containing Pharmaburst™ as a single diluent. Pharmaburst™ alone is sufficient to produce rapidly (orally) disintegrating tablets of Glimepiride with good physical characteristics, better compactability and shorter in-vivo and in-vitro disintegration time. The prepared Glimepiride RDT were found to have faster onset of action than the conventional Glimepiride tablets. Also, they were effective in lowering fasting blood glucose levels (FBG) in rabbits. Glimepiride RDT containing Pharmaburst™ alone were found to be stable when subjected to accelerated stability conditions (40 °C / 75 % relative humidity) for at least 3 months. Packaging the prepared Glimepiride RDT in 40 CC high density polyethylene (HDPE) bottles with 2 grams silica gel desiccant canisters and rayon had provided sufficient protection for the tablets. The used packaging system is believed to be very practical and convenient for elderly diabetic patients. It is also assumed to be preferred by the manufacturers.

Fraxinus excelsior seed extract FraxiPure™ limits weight gains and hyperglycemia in high-fat diet-induced obese mice

The aim of this study was to determine whether a Fraxinus excelsior L. seed extract, FraxiPure™ (0.5% in the diet), limits weight gain and hyperglycemia in mice. In a previous report, we identified several secoiridoids in FraxiPure™, some of which activated peroxisome proliferator-activated receptor alpha (PPARα) in vitro and inhibited the differentiation of 3T3-L1 preadipocyte cells. In a separate study, FraxiPure™ reduced glycemia in healthy volunteers, following an oral glucose tolerance test. These findings suggest that FraxiPure™ has antiobesity and antihyperglycemia effects. FraxiPure™ was tested in mice that were fed a high-fat diet over 16 weeks and compared with low-fat and high-fat diet controls. Weight gain, omental and retroperitoneal fat, fasting blood glucose, and fasting blood insulin were measured. FraxiPure™ reduced gains in body weight by 32.30% (p < 0.05), omental fat by 17.92%, and retroperitoneal fat by 17.78%. FraxiPure™ also lowered fasting blood glucose levels by 76.52% (p < 0.001) and plasma insulin levels by 53.43% (p < 0.05) after 16 weeks. Moreover, FraxiPure™ lowered liver weight gains by 63.62% (p < 0.05) and the incidence of fatty livers by 66.67%. Our novel results demonstrate the antiobesity effects of chronic administration of an F. excelsior seed extract and confirm its ability to regulate glycemia and insulinemia. In addition, this extract, which is rich in secoiridoid glucosides, protects against obesity-related liver steatosis.

Hypoglycemic effect of Belamcanda chinensis leaf extract in normal and STZ-induced diabetic rats and its potential active faction

Belamcanda chinensis (Iridaceae) belongs to the family of iridaceae and its rhizoma has been widely used for the treatment of throat ailment. Here we report a new pharmacological activity of B. chinensis leaf extract (BCL), that is, the hypoglycemic effect in normal and STZ-induced diabetic rats. Animals either healthy or STZ-induced diabetic show significantly lowered fasting blood glucose levels after treatment with BCL. The serum insulin concentration in normal rats is also enhanced. Additionally, the increase in blood glucose levels after administration of various carbohydrates in normal rats is significantly decreased and the oral glucose tolerance (OGTT) of STZ-induced diabetic rats is largely improved by BCL treatment. However, co-administration of BCL with Nifedipine, a Ca(2+) ion channel blocker, or Nicorandil, an ATP-sensitive K(+) ion channel opener thoroughly abolishes the hypoglycemic effect of BCL. HPLC analysis and compound identification showed that several isoflavone glycosides with antidiabetic activities were contained in BCL while pharmacological experiment showed that the polysaccharide fraction of BCL had no significant hypoglycemic effect on normal rats. Therefore, the isoflavone glycosides but not polysaccharides might be the active fraction of BCL in diabetes treatment.

Association between chronic generalized periodontitis and hyperlipidemia – a case control study

Introduction: Hyperlipidemia is a major risk factor for cardiovascular disease. Periodontal disease is caused by predominantly anaerobic gram negative bacteria. Microbial substances initiate and perpetuate the inflammation resulting in the production of high levels of proinflammatory cytokines and hyperactivity of white blood cells and of blood platelets, thus promoting the development of hyperlipidemia. Objective: To evaluate the plasma lipids (Total cholesterol, Low Density Lipoproteins and Triglycerides) as well as Fasting blood glucose levels in non diabetic, non-obese periodontal disease patients and controls. Materials and methods: 18 subjects with chronic periodontal disease (aged 38 to 50 years) were matched for age, sex and BMI (Body Mass Index) with 18 healthy subjects. Total cholesterol, low density lipoprotein, triglycerides and fasting blood glucose levels were measured using routine enzymatic biochemical methods. Results: Total cholesterol, LDL cholesterol and triglycerides was significantly higher in chronic periodontitis patients by 12% ( p&lt;0.02), 14% ( p&lt;0.03) and 22% ( p&lt;0.03) respectively as compared to controls. Fasting blood glucose levels was higher by 7% (p&lt;0.04) in chronic periodontitis patients than controls. Conclusion: Hyperlipidemia and prediabetic state may be associated with chronic periodontitis. Key words: chronic periodontitis; plasma lipids; body mass index; fasting blood glucose. DOI: 10.3329/bjms.v9i2.5657Bangladesh Journal of Medical Science Vol.09 No.2 Apr 2010 pp.95-100

Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice

Metformin, the major target of which is liver, is commonly used to treat type 2 diabetes. Although metformin activates AMP-activated protein kinase (AMPK) in hepatocytes, the mechanism of activation is still not well known. To investigate AMPK activation by metformin in liver, we examined the role of reactive nitrogen species (RNS) in suppression of hepatic gluconeogenesis. To determine RNS, we performed fluorescence examination and immunocytochemical staining in mouse hepatocytes. Since metformin is a mild mitochondrial complex I inhibitor, we compared its effects on suppression of gluconeogenesis, AMPK activation and generation of the RNS peroxynitrite (ONOO(-)) with those of rotenone, a representative complex I inhibitor. To determine whether endogenous nitric oxide production is required for ONOO(-) generation and metformin action, we used mice lacking endothelial nitric oxide synthase (eNOS). Metformin and rotenone significantly decreased gluconeogenesis and increased phosphorylation of AMPK in wild-type mouse hepatocytes. However, unlike rotenone, metformin did not increase the AMP/ATP ratio. It did, however, increase ONOO(-) generation, whereas rotenone did not. Exposure of eNOS-deficient hepatocytes to metformin did not suppress gluconeogenesis, activate AMPK or increase ONOO(-) generation. Furthermore, metformin lowered fasting blood glucose levels in wild-type diabetic mice, but not in eNOS-deficient diabetic mice. Activation of AMPK by metformin is dependent on ONOO(-). For metformin action in liver, intra-hepatocellular eNOS is required.

Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome in Offspring without Diabetes Mellitus of Nonagenarian Siblings: The Leiden Longevity Study

To explore measures of metabolic syndrome and glucose metabolism in families with exceptional longevity. Case-control study. A university hospital in Leiden, the Netherlands. One hundred twenty-one offspring of nonagenarian siblings, who were enriched for familial factors promoting longevity, and 113 of their partners. No subject had diabetes mellitus. Prevalence of metabolic syndrome was determined according to the criteria of the Third Report of the National Cholesterol Education Program. Glucose tolerance was assessed according to a 2-hour oral glucose tolerance test. The offspring of nonagenarians siblings had a lower prevalence of metabolic syndrome (P=.03), similar body composition, lower mean fasting blood glucose levels (4.99 vs 5.16 mmol/L; P=.01), lower mean fasting insulin levels (5.81 vs 6.75 mU/L; P=.04), a higher mean homeostasis model assessment of insulin sensitivity (0.78 vs 0.65; P=.02), and a more-favorable glucose tolerance (mean area under the receiver operating characteristic curve for glucose (13.2 vs 14.3; P=.007) than their partners. No significant differences were observed between the offspring and their partners in beta-cell function (insulogenic index 13.6 vs 12.5; P=.38). Despite similar body composition, the offspring of nonagenarian siblings showed a lower prevalence of metabolic syndrome and better glucose tolerance than their partners, centralizing the role of favorable glucose metabolism in familial longevity.

Role of Pyruvate Dehydrogenase Kinase 4 in Regulation of Blood Glucose Levels

In the well-fed state a relatively high activity of the pyruvate dehydrogenase complex (PDC) reduces blood glucose levels by directing the carbon of pyruvate into the citric acid cycle. In the fasted state a relatively low activity of the PDC helps maintain blood glucose levels by conserving pyruvate and other three carbon compounds for gluconeogenesis. The relative activities of the pyruvate dehydrogenase kinases (PDKs) and the opposing pyruvate dehydrogenase phosphatases determine the activity of PDC in the fed and fasted states. Up regulation of PDK4 is largely responsible for inactivation of PDC in the fasted state. PDK4 knockout mice have lower fasting blood glucose levels than wild type mice, proving that up regulation of PDK4 is important for normal glucose homeostasis. In type 2 diabetes, up regulation of PDK4 also inactivates PDC, which promotes gluconeogenesis and thereby contributes to the hyperglycemia characteristic of this disease. When fed a high fat diet, wild type mice develop fasting hyperglycemia but PDK4 knockout mice remain euglycemic, proving that up regulation of PDK4 contributes to hyperglycemia in diabetes. These finding suggest PDK4 inhibitors might prove useful in the treatment of type 2 diabetes.

Prevalence of non-diabetic renal disease in patients with type 2 diabetes

It is important to differentiate proteinuria from non-diabetic renal diseases (NDRD) or diabetic nephropathy in diabetic patients. The purpose of our study was to evaluate the prevalence of NDRD. A retrospective analysis was performed on diabetic patients who had undergone renal biopsy during a 6-year period. Our study revealed a high prevalence of NDRD in the diabetic population. Sixty-nine patients were investigated, 52.2% were diagnosed as NDRD and 47.8% as DN. Focal segmental glomerulosclerosis was the most common lesion found in patients with NDRD. We found a relationship between DN and fasting blood glucose level, systolic blood pressure, diastolic blood pressure, LVMI, intima-media thickening (IMT), and the presence of carotid plaques. Patients with NDRD had a lower incidence of diabetic retinopathy (DR). The absence of DR to differentiate NDRD had a sensitivity of 72.7%, a specificity 91.7%, and an ROC = 0.822. Fasting blood glucose level had a sensitivity and specificity of 93.9% and 75%, respectively. Similarly, the use of IMT had sensitivity and specificity of 90% and 75.8%, respectively. In this study, we determined that the absence of DR, a lower fasting blood glucose level, and IMT is useful in differentiating NDRD from DN in diabetic patients with overt proteinuria.

Prodrug delivery of novel PTP1B inhibitors to enhance insulin signalling

A growing percentage of the population is resistant to two key hormones - insulin and leptin - as a result of increased obesity, often leading to significant health consequences such as type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of signalling by both of these hormones, so that inhibitors of this enzyme may provide promise for correcting endocrine abnormalities in both diabetes and obesity. As with other tyrosine phosphatases, identification of viable drug candidates targeting PTP1B has been elusive because of the nature of its active site. Beginning with novel phosphotyrosine mimetics, we have designed some of the most potent PTP1B inhibitors. However, their highly acidic structures limit intrinsic permeability and pharmacokinetics. Ester prodrugs of these inhibitors improve their drug-like properties with the goal of delivering these nanomolar inhibitors to the cytoplasm of cells within target tissues. In addition to identifying prodrugs that is able to deliver active drugs into cells to inhibit PTP1B and increase insulin signalling, these compounds were further modified to gain a variety of cleavage properties for targeting activity in vivo. One such prodrug candidate improved insulin sensitivity in ob/ob mice, with lowered fasting blood glucose levels seen in the context of lowered fasting insulin levels following 4 days of intraperitoneal dosing. The results presented in this study highlight the potential for design of orally active drug candidates targeting PTP1B, while also delineating the considerable challenges remaining.

Fully Human Monoclonal Antibodies Antagonizing the Glucagon Receptor Improve Glucose Homeostasis in Mice and Monkeys

Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for reducing excess hepatic glucose production in patients with type 2 diabetes. Despite extensive efforts, there is currently no human therapeutic that directly inhibits the glucagon/glucagon receptor pathway. We undertook a novel approach by generating high-affinity human monoclonal antibodies (mAbs) to the human glucagon receptor (GCGR) that display potent antagonistic activity in vitro and in vivo. A single injection of a lead antibody, mAb B, at 3 mg/kg, normalized blood glucose levels in ob/ob mice for 8 days. In addition, a single injection of mAb B dose-dependently lowered fasting blood glucose levels without inducing hypoglycemia and improved glucose tolerance in normal C57BL/6 mice. In normal cynomolgus monkeys, a single injection improved glucose tolerance while increasing glucagon and active glucagon-like peptide-1 levels. Thus, the anti-GCGR mAb could represent an effective new therapeutic for the treatment of type 2 diabetes.