Glucose Homeostasis In Diabetic Mice Research Articles

Host Factors Alter Effects of Angiopoietin-Like Protein 8 on Glucose Homeostasis in Diabetic Mice.

Recovery of functional beta cell mass offers a biological cure for type 1 diabetes. However, beta cell mass is difficult to regain once lost since the proliferation rate of beta cells after youth is very low. Angiopoietin like-protein 8 (ANGPTL8), a peptide that has a role in the regulation of lipoprotein lipase activity, was reported to increase beta cell proliferation in mice in 2013. Subsequent studies of human ANGPTL8 for short term (3 to 8 days) in non-diabetic mice showed little or no increase in beta cell proliferation. Here, we examined the effect of ANGPTL8 on glucose homeostasis in models that have not been examined previously. We expressed mouse ANGPTL8 using adenovirus in 2 mouse models of diabetes (streptozotocin and Non-Obese Diabetic (NOD) mice) over 2 weeks. Also, we tested ANGPTL8 in NOD mice deficient in leukocyte 12-lipoxygenase (12LO), an enzyme that contributes to insulitis and loss of beta cell function in NOD, in an effort to determine whether 12LO deficiency alters the response to ANGPTL8. Adenovirus-mediated expression of ANGPTL8 lowered blood glucose levels in streptozotocin treated mice without an increase in beta cell proliferation or serum insulin concentration. While ANGPTL8 did not reverse hyperglycemia in overtly hyperglycemic NOD mice or alter glucose homeostasis of non-diabetic NOD mice, ANGPTL8 reduced blood glucose levels in 12LOKO NOD mice. However, the lower glucose levels in 12LOKO NOD were not associated with higher serum insulin levels or beta cell proliferation. In summary, while mouse ANGPTL8 does not increase beta cell proliferation in NOD mice or streptozotocin treated mice in agreement with studies in non-diabetic mice, it lowers blood glucose levels in multiple low-dose streptozotocin induced diabetes and 12LO deficiency indicating that host factors influence the impact of ANGPTL8 on glucose homeostasis.

Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling.

Recent reports have highlighted the roles of free fatty acid receptor 2 (FFAR2) in the regulation of metabolic and inflammatory processes. However, the potential function of FFAR2 in type 1 diabetes (T1D) remains unexplored. Our results indicated that the mRNA level of FFAR2 was upregulated in peripheral blood mononuclear cells of T1D patients. The human FFAR2 promoter regions were cloned, and luciferase reporter assays revealed that NFκB activation induced FFAR2 expression. Furthermore, we showed that FFAR2 activation by overexpression induced cell apoptosis through ERK signaling. Finally, treatment with the FFAR2 agonists acetate or phenylacetamide 1 attenuated the inflammatory response in multiple-low-dose streptozocin-induced diabetic mice, and improved the impaired glucose tolerance. These results indicate that FFAR2 may play a protective role by inducing apoptosis of infiltrated macrophage in the pancreas through its feedback upregulation and activation, thus, in turn, improving glucose homeostasis in diabetic mice. These findings highlight FFAR2 as a potential therapeutic target of T1D, representing a link between immune response and glucose homeostasis.

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.

Optogenetic Therapeutic Cell Implants

Optogenetic Therapeutic Cell Implants

Insulinotrophic and hypolipidemic effects of Ecklonia cava in streptozotocin–induced diabetic mice

ObjectiveTo explore the anti-diabetic activity of Ecklonia cava (EC) in streptozotocin (STZ)-induced diabetic mice. MethodsDiabetes was induced by a single intraperitoneal injection of STZ (90 mg/kg). Normal and diabetic mice were treated with 0%, 3%, and 5% EC diet for 4 weeks. Serum glucose and insulin concentrations, serum lipid profile, oral glucose tolerance test, and liver and pancreatic β-cell histopathological observations were performed. In addition, in vitro glucose-induced insulin secretion was determined using pancreatic β-islet cells. ResultsEC supplementation significantly and dose-dependently decreased serum glucose concentration, and improved glucose homeostasis in diabetic mice by preventing loss of β-cell mass resulting in increase of insulin secretion. The triglyceride and total cholesterol concentrations in the serum and liver were markedly reduced by EC treatment in STZ-diabetic mice. Moreover, LDL-, and HDL-cholesterol levels were ameliorated in EC supplemented diabetic mice. Liver steatosis induced by STZ was ameliorated by EC supplementation. Furthermore, in vitro insulinotrophic effect of EC extract was observed in pancreatic β-islets. ConclusionsThis study demonstrated that EC is a potent and efficacious hypoglycemic and hypolipidemic agent, and prevents the loss of β-cell mass resulting in increase of insulin secretary capacity.

Glyceollin-containing fermented soybeans improve glucose homeostasis in diabetic mice

ObjectiveOur previous in vitro study demonstrated that glyceollins help normalize glucose homeostasis by potentiating β-cell function and survival in insulinoma cells as well as improving glucose utilization in adipocytes. Here, we investigated whether fermented soybeans containing glyceollins had an antidiabetic action in type 2 diabetic animals. MethodsThe diabetic mice, their diabetes induced by intraperitoneal injections of streptozotocin (20 mg/kg bw), were administered a high fat diet with no soybeans (control), 10% unfermented soybeans and 10% fermented soybeans containing glyceollins, respectively, (FSG) for 8 weeks. As positive controls, rosiglitazone (20 mg/kg/bw) was given to diabetic mice fed a no soybean diet and non-diabetic mice were also placed on the same diet. ResultsAmong the diabetic mice, FSG-treated mice exhibited the lowest peak for blood glucose levels with an elevation of serum insulin levels during the first part of oral glucose tolerance testing. FSG also made blood glucose levels drop quickly after the peak and it decreased blood glucose levels more than the control during insulin tolerance testing. This improvement was associated with increased hepatic glycogen accumulation and decreased triglyceride storage. The phosphorylation of Akt, AMP-kinase, and acetyl-CoA carboxylase in the liver was potentiated by FSG, whereas phosphoenolpyruvate carboxykinase expression decreased. The enhancement of glucose homeostasis was comparable to the effect induced by rosiglitazone, a commercial peroxisome proliferator-activated receptor-γ agonist, but it did not match the level of glucose homeostasis in the non-diabetic mice. ConclusionGlyceollin-containing FSG improves glucose homeostasis, partly by enhancing hepatic insulin sensitivity in type 2 diabetic mice.

Modulation of Bone Morphogenetic Protein-9 Expression and Processing by Insulin, Glucose, and Glucocorticoids: Possible Candidate for Hepatic Insulin-Sensitizing Substance

Bone morphogenetic protein 9 (BMP-9), a member of the TGF-beta superfamily predominantly expressed in nonparenchymal liver cells, has been demonstrated to improve glucose homeostasis in diabetic mice. Along with this therapeutic effect, BMP-9 was proposed as a candidate for the hepatic insulin-sensitizing substance (HISS). Whether BMP-9 plays a physiological role in glucose homeostasis is still unknown. In the present study, we show that BMP-9 expression and processing is severely reduced in the liver of insulin-resistant rats. BMP-9 expression and processing was directly stimulated by in situ exposition of the liver to the combination of glucose and insulin and oral glucose in overnight fasted rats. Additionally, prolonged fasting (72 h) abrogated refeeding-induced BMP-9 expression and processing. Previous exposition to dexamethasone, a known inductor of insulin resistance, reduced BMP-9 processing stimulated by the combination of insulin and glucose. Finally, we show that neutralization of BMP-9 with an anti-BMP-9 antibody induces glucose intolerance and insulin resistance in 12-h fasted rats. Collectively, the present results demonstrate that BMP-9 plays an important role in the control of glucose homeostasis of the normal rat. Additionally, BMP-9 is expressed and processed in an HISS-like fashion, which is impaired in the presence of insulin resistance. BMP-9 regulation according to the feeding status and the presence of diabetogenic factors reinforces the hypothesis that BMP-9 might exert the role of HISS in glucose homeostasis physiology.

Exendin-4 Treatment Expands Graft β-Cell Mass in Diabetic Mice Transplanted with a Marginal Number of Fresh Islets

Exendin-4 stimulates insulin secretion, suppresses glucagons secretion, increases beta-cell replication and neogenesis, and reduces beta-cell apoptosis. However, it has been shown that posttransplant exendin-4 treatment did not improve glucose homeostasis in diabetic mice transplanted with a large number of freshly isolated islets. The aim of this study was to test if exendin-4 is beneficial for hyperglycemic recipients with a marginal number of fresh islets. We transplanted 150 C57BL/6 mouse islets under the kidney capsule of inbred streptozotocin-diabetic mice, and then treated the recipients with and without exendin-4 for 6 weeks. Before and after transplantation, recipients' blood glucose, body weight, and intraperitoneal glucose tolerance test were measured. At 6 weeks, the grafts were removed to determine beta-cell mass. Blood glucose levels in both groups decreased progressively after transplantation, and the exendin-4-treated group had had lower blood glucose than controls since day 3. By 6 weeks, euglycemia was achieved more in mice treated with exendin-4 than in controls (100% vs. 62.5%, p = 0.018). The time to obtain normoglycemia was shorter in the exendin-4-treated group than in controls (12 +/- 8 vs. 29 +/- 13 days, p < 0.001). Blood glucose at 6 weeks was 123 +/- 18 and 170 +/- 62 mg/dl in the exendin-4-treated group and controls, respectively (p = 0.008). Additionally, the exendin-4-treated group had better glucose tolerance than controls at 2 and 4 weeks (p <0.02). However, both groups exhibited increased body weight over time, and weight changes did not significantly differ between the two groups throughout the study period. At 6 weeks after transplantation, grafts in the exendin-4-treated group were more prominent and contained more insulin-stained cells than those of controls. They had 2.3-fold beta-cell mass of the graft compared with controls (0.30 +/- 0.11 vs. 0.13 +/- 0.03 mg, p = 0.012). These results indicate posttransplant exendin-4 treatment in the diabetic recipient with a marginal number of fresh islets expands graft beta-cell mass and improves transplantation outcome.

ACE2 over‐expression ameliorates glycemic homeostasis in diabetic mice

ACE inhibitor therapy has been shown to prevent new onset diabetes and pancreatic â‐cell dysfunction. We hypothesized that ACE2 would ameliorate glycemia in diabetic mice. Diabetic obese mice (db/db) and control lean littermates (db/m) were infected with a hACE2 or control (GFP) adenovirus (2x10e6 pfu 100 ìL) to the pancreas. After 7d, fasting blood glucose (12 hrs) and glucose tolerance (GT, 2 g/kg IP) were measured as indices of glycemic control. ACE2 immunofluorescence (arbitrary units) revealed high expression of hACE2 in the liver of mice infected with Ad‐hACE2 vs. Ad‐GFP (120±6 vs. 14±1, n=9, P&lt;0.01), while hACE2 in the pancreas was not different between groups. Body weight (g) in db/db mice was not affected by Ad‐ACE2 (35±1, n=5) or Ad‐GFP (36±1 n=5) delivery. Baseline glycemia (mg/dL) was significantly higher in db/db vs. db/m mice (246±18 vs. 102±6, n=10, P&lt;0.01) and was dramatically reduced in Ad‐hACE2‐ vs. Ad‐GFP‐treated db/db mice (157±12 vs. 203±6, n=5, P&lt;0.05). Ad‐hACE2 infection had no effect on glycemia in db/m (92±8, n=10) compared to Ad‐GFP‐infected mice (75±10). In addition, Ad‐hACE2 infection significantly improved GT in db/db compared to GFP‐treated‐mice (573±43 vs. 749±18 mg/dL respectively, P&lt;0.01) 1 hr post glucose administration. These data confirm the role of ACE2 in diabetes and suggest that ACE2 gene therapy can ameliorate glucose homeostasis in diabetic mice. (NIH NS052479 and RR018766)

Inhibition of 11βHSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice

BackgroundA substantial body of evidence indicates that reduced plasma adiponectin levels may be key in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. Glucocorticoids decrease the levels of adiponectin in animals and humans. Cortisone is transformed to its active form cortisol, via 11β-hydroxysteroid dehydrogenase (HSD) type 1. This study sought to ascertain if inhibition of 11β HSD1 with a new selective inhibitor, BVT116429, affects the concentrations of circulating adiponectin with concomitant effects on glucose homeostasis in diabetic mice.ResultsKKAy mice were treated with BVT116429 (3, 10, 30 mg/kg), rosiglitazone (5 mg/kg) or vehicle once daily for ten days. Plasma adiponectin levels rose in mice treated with BVT116429 and this was found to be both the hexameric and the high molecular weight multimeric forms of adiponectin. Seven days of treatment with the 11β HSD1-inhibitor BVT116429 decreased basal insulin levels but no changes in glucose tolerance were seen. After ten days of treatment, fasting blood glucose level was decreased by BVT116429 comparable to the effects of rosiglitazone. Another 11β HSD1 inhibitor, BVT2733, improved HbA1c but had no effect on adiponectin.ConclusionInhibition of 11β HSD1 can be expected to be beneficial for treating the pathology of type 2 diabetes mellitus. The differences seen in adiponectin between BVT116429 and BVT2733 could be explained by different pharmacodynamics exerted by the compounds in different tissues in the body. Increases in adiponectin concentrations may be an integral component in the mechanism of action of this new11β HSD1 inhibitor and may be a useful marker of efficacy during the clinical development of 11β HSD1 inhibitor compounds.