Hypoglycemic Effect Of Insulin Research Articles

Synthesis and Hypoglycemic Effect of Insulin from the Venom of Sea Anemone Exaiptasia diaphana.

Sea anemone venom, abundant in protein and peptide toxins, serves primarily for predatory defense and competition. This study delves into the insulin-like peptides (ILPs) present in sea anemones, particularly focusing on their role in potentially inducing hypoglycemic shock in prey. We identified five distinct ILPs in Exaiptasia diaphana, exhibiting varied sequences. Among these, ILP-Ap04 was successfully synthesized using solid phase peptide synthesis (SPPS) to evaluate its hypoglycemic activity. When tested in zebrafish, ILP-Ap04 significantly reduced blood glucose levels in a model of diabetes induced by streptozotocin (STZ) and glucose, concurrently affecting the normal locomotor behavior of zebrafish larvae. Furthermore, molecular docking studies revealed ILP-Ap04's unique interaction with the human insulin receptor, characterized by a detailed hydrogen-bonding network, which supports a unique mechanism for its hypoglycemic effects. Our findings suggest that sea anemones have evolved sophisticated strategies to activate insulin receptors in vertebrates, providing innovative insights into the design of novel drugs for the treatment of diabetes.

2 ′ -O-Methylperlatolic Acid Enhances Insulin-Regulated Blood Glucose-Lowering Effect through Insulin Receptor Signaling Pathway

Purpose Insulin receptor (InsR) sensitizers represent a new type of therapeutic agent for the treatment of diabetes, with 2′-O-methylperlatolic acid (2-O-M) being a potential InsR targeting drug. The purpose of this study was to determine whether 2-O-M functions as an activator of the insulin signaling pathway, regulating glucose hemostasis through the InsR and exerting a glucose-lowering effect in an animal model of diabetes. Methods SPR-based analyses were used to detect the binding of different concentrations of 2-O-M to the InsR. The protein levels of IR-β, p-IR, AKT, and p-AKT in Hepa and C2C12 cell lines and liver and muscle tissues were determined by western blotting. Glucose uptake capacity was determined in C2C12 cells. Streptozotocin-induced diabetic mice were randomly divided into four groups: the control, insulin treated, 2-O-M treated, and combined insulin and 2-O-M treated. Mice were injected with 2-O-M or normal saline and the average blood glucose concentration after 120 min, and the serum levels of insulin, glucagon, and C-peptide were measured. Next, qRT-PCR was performed to detect the mRNA expression of genes involved in lipid and glucose metabolism in the liver and muscle tissues. Results 2-O-M binds to the extracellular domain of the InsR. Moreover, combination treatment with 2-O-M and insulin resulted in significant activation of the insulin signaling pathway in vitro and significant stimulation of the glucose uptake capacity of C2C12 myotubes. In mice with streptozotocin-induced diabetes, 2-O-M significantly prolonged the blood glucose-lowering effect of insulin, significantly reduced the secretion of exogenous insulin, and reduced the blood glucose concentration in vivo. In addition, treatment with 2-O-M alone significantly enhanced the phosphorylation of AKT in muscle tissue, which enhanced glucose uptake in C2C12 myotubes. Further, 2-O-M significantly increased glucagon secretion and enhanced liver gluconeogenesis to prevent hypoglycemia. Conclusion 2-O-M enhances the hypoglycemic effect of insulin through the insulin signaling pathway and can be used as a complement to insulin. This synergetic effect may lower the required dose of insulin and protect β cells.

Insulin- and cholic acid-loaded zein/casein-dextran nanoparticles enhance the oral absorption and hypoglycemic effect of insulin.

Diabetes mellitus is the most common metabolic disease in the world. Herein, insulin- and cholic acid-loaded zein nanoparticles with dextran surfaces were fabricated to enhance the oral absorptions of insulin in the intestine and in the liver which is the primary action organ of endogenous insulin. In the nanoparticles, zein acted as cement to embed insulin, cholic acid and casein by hydrophobic interactions. The hydrophilic dextran conjugated to casein by the Maillard reaction was located on the nanoparticle surface. The nanoparticles had an insulin loading efficiency of 74.6%, a cholic acid loading efficiency of 55.1% and a hydrodynamic diameter of 267 nm. The dextran significantly increased the disperse stability of the nanoparticles, protected the loaded insulin from hydrolysis in digestive juices, and increased the trans-mucus permeability of the insulin. The embedded cholic acid molecules were consecutively exposed to the surface when the nanoparticles were gradually eroded by proteases. The exposed cholic acid promoted the absorptions of the nanoparticles in the ileum and liver via bile acid transporters. The effect of pretreated lymphatic transport inhibitor cycloheximide revealed that about half of the nanoparticles were transported via the intestinal lymphatic transport pathway and the other half of the nanoparticles were transported via portal blood absorption. The oral pharmacological bioavailability of the nanoparticles in type I diabetic mice was 12.5-20.5%. This study demonstrates that nanoparticles are a promising oral delivery system for insulin.

Insulin-loaded hydroxypropyl methyl cellulose-co-polyacrylamide-co-methacrylic acid hydrogels used as rectal suppositories to regulate the blood glucose of diabetic rats

The purpose of this study was developing a novel hydroxypropyl methyl cellulose-co-polyacrylamide-co-methacrylic acid (HPMC-co-PAM-co-PMAA) hydrogel, which was used as rectal suppository to regulate the blood glucose of diabetes. HPMC-co-PAM-co-PMAA hydrogel was fabricated via free-radical polymerization. Fourier transform infrared spectroscopy (FTIR) and Raman spectra were used to confirm the fabrication of HPMC-co-PAM-co-PMAA hydrogel. Their inner morphology was observed with scanning electron microscope (SEM). The extracts of hydrogel were applied to study their cell viability. The hypoglycemic effects of insulin (INS)-loaded HPMC-co-PAM-co-PMAA hydrogels were investigated by rectal administration. FTIR and Raman spectra confirmed the obtaining of HPMC-co-PAM-co-PMAA hydrogels. Many micro-pores were found in the SEM photograph of HPMC-co-PAM-co-PMAA hydrogels. Cell experiments indicated that HPMC-co-PAM-co-PMAA hydrogel was out of cytotoxicity. In vitro release profiles showed that INS-loaded hydrogel could release INS at a continuous manner in pH 7.4 buffer (rectal conditions). Animal experiments suggested that INS-loaded hydrogel had an obvious hypoglycemic effect. Therefore, as a convenient and economic method of administration, INS-loaded HPMC-co-PAM-co-PMAA hydrogels could be used as rectal suppositories to regulate blood glucose.

Concomitant administration of resveratrol and insulin protects against diabetes mellitus type-1-induced renal damage and impaired function via an antioxidant-mediated mechanism and up-regulation of Na+/K+-ATPase

This study investigated if a combination of resveratrol (RES) and insulin could reverse type 1 diabetic mellitus-induced (T1DM) nephropathy and illustrates mechanism of action. Rats were divided into six groups (n = 10/group) as follows: control, control + RES (20 mg/kg), T1DM, T1DM + RES, T1DM + insulin (1 U/g), and T1DM + RES + insulin and treated for eight weeks. While individual administrations of both drugs significantly but partially restored renal function and cortex architectures, combination therapy of both RES and insulin produced the maximum improvements. Mechanism of actions revealed a synergist effect of both drugs due to hypoglycaemic effect of insulin and the ability of both drugs to increase renal cortex antioxidant enzymes activities, inhibit lipid peroxidation, and up-regulate Na+/K+-ATPase, independent of each others. In conclusion, these data suggest the combined therapy with insulin and RES could provide an excellent combined drug therapy against T1DM-induced nephropathy.

Release profile of insulin from pH-sensitive hydrogel and its hypoglycemic effect by oral administration

The purpose of this study was to investigate the release profile and in vivo hypoglycemic effect of insulin (INS)-loaded pH-sensitive hydrogel (INS-TPM950) administrated by oral route. TPM950 was fabricated via a free polymerization method and its inner morphology was observed with a scanning electron microscope (SEM). INS was encapsulated into TPM950 by an adsorption method, and the in vitro release profiles of INS from INS-TPM950 were revealed in pH 1.2 and 6.8. To investigate the hypoglycemic effect of INS-TPM950, Male Wistar rats were used in modeling of diabetes mellitus by multiple intraperitoneal injection of alloxan. The in vivo hypoglycemic effect of oral INS-TPM950 was studied, and the optimal dosage was also determined. SEM photograph showed that abundant 3D meshes were distributed in the inner of TPM950 hydrogel. INS release profile suggested that only 18.2 ± 11.3% INS was released in pH 1.2, but over 88.8 ± 4.9% was delivered into phosphate buffer solution in pH 6.8. After injection to the diabetic rats, the released INS solution from INS-TPM950 exhibited an obvious hypoglycemic effect. Oral administration of 50.0 I.U./kg of INS-TPM950 showed a slow but effective hypoglycemic effect, and the lowest blood glucose level was reached to 47.5 ± 5.5% of the original level. Therefore, this formulation had a potential application in diabetes treatment via oral ingestion.

Effect of Transdermal Nitroglycerin on Insulin Resistance in Healthy Young Men

Objective: There are evidences indicating transdermal nitroglycerin changes the sensitivity of peripheral tissues to the hypoglycemic effect of insulin. In this study we determined effect of continuous application of transdermal nitroglycerin patches in healthy volunteers on development of tolerance to the hypotensive effect of nitroglycerin and hypoglycemic effect of insulin. Materials and methods: The effect of transdermal application of nitroglycerin, as NO donor was studied during 24 hours on blood insulin and glucose level and on blood pressure in healthy, young volunteers. Patches of 0.2 mg/ hour nitroglycerine were administered to young healthy volunteers along 24 hours and Venous blood samples were taken early before and 24 hours after the nitroglycerin. Serum was separated and free zed (-80°C) for insulin and glucose determination. Blood pressure also was determined in 6 hours intervals. Results: Before nitroglycerin patches application mean serum insulin level determined level 9.53 ± 4.37 and after nitroglycerin were 9.18 ± μU/ml which is statistically significant (P>0.05). Fasting blood glucose levels were increased by 6.63 ± 1.9 mg/dl determined 24 hours after nitroglycerine application in comparison with before treatment. The changes observed in blood glucose levels also were statistically significant (P<0.001). Insulin resistance calculated by Homa formula was 1.445 before treatment and 1.540 after nitroglycerin treatment. Conclusion: Transdermal nitroglycerin by doses of 0.2 mg/h causing blood glucose level changes more than change of insulin level indicating change in tissue sensitivity to insulin. The present work was therefore concerned with the possibility that nitrate tolerance impairs the sensitivity of tissues to the hypoglycemic effect of insulin.

IRAP deficiency attenuates diet-induced obesity in mice through increased energy expenditure

Activation of the adipose renin–angiotensin system contributes to the development of obesity and metabolic syndrome. Insulin-regulated aminopeptidase (IRAP) has been identified a key regulator of GLUT4 transporter as well as angiotensin IV (AngIV) receptor (AT4R). Although AngII-AT1R axis appears as anorexigenic and as an effector of energy expenditure, the impact of AngIV-IRAP/AT4R axis on energy metabolism remains unknown. The aim was to determine the role of IRAP in energy metabolism in mice. Methods and resultsIn adipocyte culture, plasminogen activator inhibitor type 1 (PAI-1) expression levels were diminished in IRAP knockout (IRAP−/−) if compared with those of wild-type (C57Bl/6J, WT) mice. Mice were fed high-fat diet (32% fat) at age of 8weeks. At the entry, body weight, body fat content, and parameters of saccharometabolism were similar between groups. However, IRAP−/− mice exhibited blunted body weight gain compared to that of WT mice, despite comparable food intake and physical activity. At 20weeks of age, IRAP−/− mice had 25% lower body weight than WT mice. Glucose and insulin tolerance tests revealed that the glucose disposal and the hypoglycemic effect of insulin were pronounced in IRAP−/− mice after a high fat diet. Indirect calorimetry demonstrated that whole-body oxygen consumption rates were significantly higher in IRAP−/− mice by 18% with mild hyperthermia. Analysis of brown adipose tissue (BAT) in IRAP−/− showed increased levels of uncoupling protein-1 (UCP-1) at basal level and adaptive thermogenesis was not impaired. ConclusionsIRAP deficiency may lead to suppression of PAI-1 expression in adipocytes and upregulation of UCP-1-mediated thermogenesis in BAT and increased energy expenditure to prevent the development of obesity, and these facts suggest a therapeutic potential of IRAP/AT4R blockade in diet-induced obesity.

Effect of Ethanolic Olive leaf and its Callus Ethanol Extracts in Alloxan- induced Diabetic mice (Blood glucose and lipid profiles)

This study was designed to test the lipid-lowering and antidiabetic activities of olive leaf and its callus extract. Diabetes in mice was induced by intraperitoneal injections of alloxan. The serum glucose and serum lipid were examined. Diabetic mice showed hypeglycemia, hypelipidemia. The administration, for 2 weeks of olive leaf and its callus extracts significantly decreased the Total cholesterol (TC). Triglycerides (TG). Low density lipoprotein (LDL), very low density lipoprotein (VLDL). Both types of olive extracts had significant hypoglycemic effects on blood glucose levels in diabetic mice. This hypoglycemic effect was as potent as the hypoglycemic effect of insulin. However, the callus extract was more potent than the leaves extracts and most potent than insulin in causing a significant decrease in LDL, VLDL, TC, TG and in antidiabetic effects.

The Implantable and Biodegradable PHBHHx 3D Scaffolds Loaded with Protein-Phospholipid Complex for Sustained Delivery of Proteins

PHBHHx (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)) is an excellent biomaterial for tissue repair. Here, we aim to develop a PHBHHx-based three-dimensional (3D) scaffold system for sustained delivery of proteins (insulin serves as a model protein). The insulin-phospholipid complex (INS-PLC) was prepared to enhance the insulin lipophilicity. INS-PLC loaded PHBHHx 3D scaffolds (INS-PLC-SCAs) containing PEG-2000 were fabricated by lyophilization. In vitro release was performed in the medium with or without lipase. The bioactivity of INS-PLC-SCAs was measured in diabetic rats. In vitro release shows that the release rate of INS-PLC-SCAs was very slow (~6% of total insulin was released within 120days), and PEG-2000 or lipase had no effect on its release pattern. The bioactivity test shows that the hypoglycaemic effect of insulin was maintained after formulated into scaffolds. After subcutaneous (s.c.) implantation, its therapeutic effect lasted for over 130h, and its bioavailability was enhanced by 4-fold. PHBHHx based 3D scaffold has a great potential for sustained delivery of proteins, especially growth factors. When growth factors are incorporated, it can serve as a bifunctional system that provides a porous skeleton for cells attachment and proliferation, as well as a matrix for long term release of the loaded growth factors.

Application of Model‐based Methods to Characterize Exenatide‐loaded Double‐walled Microspheres: In vivo Release, Pharmacokinetic/Pharmacodynamic Model, and In Vitro and In Vivo Correlation

The objective of this study was to characterize exenatide double-walled microspheres (DWMS) using model-based methods. Exenatide DWMS were prepared using oil-in-oil-in-water method, and physicochemical characterization and in vitro release and degradation of DWMS were evaluated. The pharmacokinetics (PK) and pharmacodynamics (PD) were investigated after subcutaneous injection to diabetic rats. Transit compartment model was used to describe the in vivo release of exenatide from DWMS successfully. On the basis of the insulinotropic effects of exenatide and hypoglycemic effects of insulin, PK/PD model was developed and nicely described the concentration-effect relationship of exenatide. Moreover, on the basis of the transit compartment model, a simulation method was applied to predict in vivo release, and in vitro and in vivo correlation was established. In conclusion, DWMS was a promising vehicle for delivery of exenatide, and the proposed PK/PD model allowed a better understanding of the pharmacological properties of exenatide DWMS. Transit compartment model-based modeling and simulation methods provided more options for the description and prediction of the in vivo exenatide release from DWMS.

Increased action of pulsatile compared to non-pulsatile insulin delivery during a meal-like glucose exposure simulated by computerized infusion in healthy humans

It has previously been demonstrated that pulsatile insulin has a greater hypoglycemic effect than non-pulsatile insulin during euglycemic conditions. The aim of the present study was to examine the effect of pulsatile versus non-pulsatile insulin delivery during a meal-like iv-glucose challenge. Ten healthy young subjects were examined on two occasions. A pancreatic–pituitary clamp was maintained with somatostatin infusion and replacement of glucagon and growth hormone at baseline levels. During the first three hours on both study days, insulin was infused in a pulsatile manner. Hereafter glucose and insulin were infused by computer-controlled pumps for four hours in a pattern mimicking the postprandial glucose and insulin profiles. At one study day, insulin infusion was done in a continuous manner, while at the other study day this profile was done in a pulsatile pattern. The hypoglycemic effect of insulin was measured as the integrated area under the curve of glucose during the four-hour infusion period. The mean insulin concentration measured as the integrated area under the curve was identical (P > .9). The hypoglycemic effect of insulin was significantly augmented by 13% during pulsatile delivery as compared to continuous delivery (P = .015). Likewise was the maximal glucose concentration significantly lower at the day of the pulsatile profile (9.9 ± 1.0 vs. 11.4 ± 2.3mmol/l, P = .036). Pulsatile insulin release plays an important role in the postprandial glucose homeostasis. The disturbed insulin pulsatility in type 2 diabetes mellitus may contribute to the postprandial hyperglycemia.

β-Arrestin-1 Protein Represses Diet-induced Obesity

Diet-related obesity is a major metabolic disorder. Excessive fat mass is associated with type 2 diabetes, hepatic steatosis, and arteriosclerosis. Dysregulation of lipid metabolism and adipose tissue function contributes to diet-induced obesity. Here, we report that β-arrestin-1 knock-out mice are susceptible to diet-induced obesity. Knock-out of the gene encoding β-arrestin-1 caused increased fat mass accumulation and decreased whole-body insulin sensitivity in mice fed a high-fat diet. In β-arrestin-1 knock-out mice, we observed disrupted food intake and energy expenditure and increased macrophage infiltration in white adipose tissue. At the molecular level, β-arrestin-1 deficiency affected the expression of many lipid metabolic genes and inflammatory genes in adipose tissue. Consistently, transgenic overexpression of β-arrestin-1 repressed diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Thus, our findings reveal that β-arrestin-1 plays a role in metabolism regulation.

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.

Glucose intolerance in thiamine-deficient rats.

Abstract The mechanism of glucose intolerance in thiamine-deficient rats has been examined. Deficient rats showed marked glucose intolerance. However, the hypoglycaemic effect of insulin (1 i.u. kg−1, i.p.) was similar in the deficient, pair-fed and normal groups, though somewhat weaker in the normal group than in the other two groups. After injection of tolbutamide (40 mg kg−1, i.p.), the hypoglycaemic effects in the three groups were the same. Tyramine (10 mg kg−1, s.c.) restored the impaired glucose tolerance of deficient rats to normal, but not that of alloxan diabetic rats. Furthermore, tyramine did not restore the intolerance of deficient rats pretreated with alloxan. These results suggest that the main factor causing glucose intolerance in the deficient rats may be suppressed insulin secretion.

Counterpoint: Appreciating Homeostasis Model Assessment

The insulin-deficient mechanism for diabetes, discovered around a century ago, was questioned by observations on the human response to intravenous insulin (1). Later, it was more severely challenged by the raised plasma insulin values usually found by radioimmunoassay in type 2 diabetic subjects (2), then and since rapidly increasing in number, and often with accompanying adiposity (3). At this time, the pathogenesis of type 2 diabetes was unknown, and it seemed crucial to determine whether it was essentially based on increased resistance to the hypoglycemic action of insulin or on failing β-cells with secondary gluco- and lipotoxicities. Could this be determined from the glucose and insulin levels of single or duplicate basal blood samples? If so, epidemiological logistics might be transformed, without the need for stimulated tests or tests as sophisticated as measurement of the basal endogenous glucose production rate with tritiated glucose, and the calculation of postabsorptive hepatic insulin resistance to the hypoglycemic effect of insulin as the product of this and the overnight fasting insulin concentration (4). Basal and stimulated tests measure two different phenomena, rather than two different aspects of the same thing. In theory, the two islet cell states do not need to be closer than are muscular activity in movement and in posture. There will always be common features (e.g., muscle bulk), and, indeed, there are consistent positive relationships between basal and poststimulation insulin. However, there are also many different properties with altered membrane potentials (e.g., in the basal state, there is no influence on β-cell activity from recent glucose variation [5], which presumably leaves β-cells aware of changes in glucose). Additionally, the various clamp tests do not measure basal function, for while they involve steady states, clamp tests follow considerable interference. In these tests, insulin action in muscle is the major …

The inhibitory effect of proglumide on meal-induced insulin sensitization in rats

We studied the role of cholecystokinin in meal-induced insulin sensitization in rats. Experiments were done with fed or fasted male Wistar rats. Whole-body insulin sensitivity was determined by the rapid insulin sensitivity test in either group. The fed animals were more sensitive to the hypoglycemic effect of insulin than those in the fasted group. Single intravenous doses of proglumide, a cholecystokinin-1 receptor antagonist, decreased insulin sensitivity in fed animals in a dose-dependent manner, whereas it was without effect in the fasted state. We conclude that prandial insulin sensitization strongly depends on pathways regulated by cholecystokinin.

Development of insulin resistance by nitrate tolerance in conscious rabbits.

Clinical evidence has been raised to suggest that transdermal nitroglycerin increases the sensitivity of peripheral tissues to the hypoglycemic effect of insulin. In this study we determined whether development of tolerance to the hypotensive effect of nitroglycerin also resulted in tolerance to the insulin-sensitizing effect in rabbits. Intravenous glucose disposal and hyperinsulinemic euglycemic glucose clamp studies were performed on naive and hemodynamic nitrate tolerant conscious New Zealand white rabbits. These rabbits were exposed to continuous "patch on" with nitroglycerin (0.07 mg/kg/h) or placebo patches over 7 days. Nitroglycerin treatment of 7 days produced a lack of hypotensive response to a single intravenous bolus of 30 microg/kg nitroglycerin, which caused a significant decrease in mean arterial blood pressure in control rabbits. A six-hour exposure to transdermal nitroglycerin significantly increased insulin sensitivity determined by hyperinsulinemic (100 microU/ml) euglycemic (5.5 mmol/l) glucose clamping as compared with that seen in rabbits treated with placebo patches. A significant decrease in insulin sensitivity was observed in the nitroglycerin patch-treated animals both in the presence and after the removal of the last patch when the patches were applied over 7 days. We conclude that acutely nitrate patches improve insulin sensitivity whereas a 7-day chronic treatment schedule that results in hemodynamic nitrate tolerance also produces insulin resistance.

Lysosomal proteolysis: effects of aging and insulin.

Age-related characteristics of the effect of insulin on the activity of lysosomal proteolytic enzymes were studied. The relationship between the insulin effect on protein degradation and insulin degradation was analyzed. The effect of insulin on the activities of lysosomal enzymes was opposite in young and old rats (inhibitory in 3-month-old and stimulatory in 24-month-old animals). The activities of proteolytic enzymes were regulated by insulin in a glucose-independent manner: similar hypoglycemic effects of insulin in animals of different ages were accompanied by opposite changes in the activities of lysosomal enzymes. The inhibition of lysosomal enzymes by insulin in 3-month-old rats is consistent with a notion on the inhibitory effect of insulin on protein degradation. An opposite insulin effect in 24-month-old rats (i.e., stimulation of proteolytic activity by insulin) may be partly associated with attenuation of the degradation of insulin, resulting in disturbances in signaling that mediates the regulatory effects of insulin on protein degradation.

Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice.

Glucose homeostasis was examined in male transgenic (Tg) mice that overexpressed the human insulin-like growth factor (IGF)-binding protein (IGFBP)-3 cDNA, driven by either the cytomegalovirus (CMV) or the phosphoglycerate kinase (PGK) promoter. The Tg mice of both lineages demonstrated increased serum levels of human (h) IGFBP-3 and total IGF-I compared with wild-type (Wt) mice. Fasting blood glucose levels were significantly elevated in 8-wk-old CMV-binding protein (CMVBP)-3- and PGK binding protein (PGKBP)-3-Tg mice compared with Wt mice: 6.35 +/- 0.22 and 5.22 +/- 0.39 vs. 3.99 +/- 0.26 mmol/l, respectively. Plasma insulin was significantly elevated only in CMVBP-3-Tg mice. The responses to a glucose challenge were significantly increased in both Tg strains: area under the glucose curve = 1,824 +/- 65 and 1,910 +/- 115 vs. 1,590 +/- 67 mmol. l(-1). min for CMVBP-3, PGKBP-3, and Wt mice, respectively. The hypoglycemic effects of insulin and IGF-I were significantly attenuated in Tg mice compared with Wt mice. There were no differences in adipose tissue resistin, retinoid X receptor-alpha, or peroxisome proliferator-activated receptor-gamma mRNA levels between Tg and Wt mice. Uptake of 2-deoxyglucose was reduced in muscle and adipose tissue from Tg mice compared with Wt mice. These data demonstrate that overexpression of hIGFBP-3 results in fasting hyperglycemia, impaired glucose tolerance, and insulin resistance.