Reduction In Hyperinsulinemia Research Articles

The effects of sodium-glucose cotransporter 2 inhibitors on the 'forgotten' right ventricle.

With the progress in diagnosis, treatment and imaging techniques, there is a growing recognition that impaired right ventricular (RV) function profoundly affects the prognosis of patients with heart failure (HF), irrespective of their left ventricular ejection fraction (LVEF). In addition, right HF (RHF) is a common complication associated with various diseases, including congenital heart disease, myocardial infarction (MI), pulmonary arterial hypertension (PAH) and dilated cardiomyopathy (DCM), and it can manifest at any time after left ventricular assist devices (LVADs). The sodium-glucose cotransporter 2 (SGLT2) inhibition by gliflozins has emerged as a cornerstone medicine for managing type 2 diabetes mellitus (T2DM) and HF, with an increasing focus on its potential to enhance RV function. In this review, we aim to present an updated perspective on the pleiotropic effects of gliflozins on the right ventricle and offer insights into the underlying mechanisms. We can ascertain their advantageous impact on the right ventricle by discussing the evidence obtained in animal models and monumental clinical trials. In light of the pathophysiological changes in RHF, we attempt to elucidate crucial mechanisms regarding their beneficial effects, including alleviation of RV overload, reduction of hyperinsulinaemia and inflammatory responses, regulation of nutrient signalling pathways and cellular energy metabolism, inhibition of oxidative stress and myocardial fibrosis, and maintenance of ion balance. Finally, this drug class's potential application and benefits in various clinical settings are described, along with a prospective outlook on future clinical practice and research directions.

The protective role of shenqi compound in type 2 diabetes: A comprehensive investigation of pancreatic β-cell function and mass

Type 2 diabetes (T2D) is a prevalent metabolic disorder characterized by impaired insulin secretion and insulin resistance, resulting in elevated blood glucose levels. The dysfunction and loss of pancreatic β-cells, responsible for producing insulin, contribute to the development of T2D. Traditional Chinese medicine (TCM) has emerged as a potential source of innovative therapeutic interventions. However, limited research exists on Chinese herbal formulations specifically targeting the protection of pancreatic β-cell function and mass. One such formulation is the Shenqi compound (SQC), widely used in China and consisting of Panax Ginseng, Astragali Radix, Rhizoma Dioscoreae, Corni Fructus, Rehmanniae Radix, Salviae Miltiorrhizae Radix et Rhizoma, Radix Trichosanthis, and Rhei Radix et Rhizoma. Understanding the mechanisms underlying the therapeutic effects of SQC is crucial for developing novel treatment strategies for T2D. This study aims to comprehensively investigate the scientific evidence supporting the role of SQC in alleviating T2D by targeting the protection of pancreatic β-cell function and mass. Spontaneously diabetic GK rats were used as the animal model, receiving SQC (14.4 g/kg/d) for 8 weeks. The results demonstrate multiple beneficial effects of SQC, including significant control of blood glucose levels (P < 0.05), inhibition of insulin resistance (measured by Western Blot), reduction of hyperinsulinemia (P < 0.05), attenuation of oxidative stress (P < 0.05), suppression of inflammation (P < 0.05), protection against islet hypertrophy and beta cell proliferation (evaluated through pathological staining), and inhibition of β-cell apoptosis and senescence (also assessed through pathological staining). These findings indicate the promotion of β-cell survival and function. In vitro experiments using isolated islets further support these results, revealing improvements in insulin secretion (P < 0.05) and β-cell function following SQC therapy (P < 0.05). This represents a significant breakthrough in addressing β-cell dysfunction and preserving mass within the context of TCM. Overall, SQC shows promise as a natural therapeutic approach for T2D, with potential benefits in preserving pancreatic β-cell function and mass. This enhances the practical applicability and significance of the research by bridging the gap between experimental findings and clinical practice, thereby providing important clinical value in TCM treatment of T2D. Further research is necessary to elucidate its precise mechanisms of action and optimize its clinical application.

Association of LH/FSH ratio with menstrual cycle regularity and clinical features of patients with polycystic ovary syndrome

BackgroundUnderstanding the global prevalence and phenotypic features of polycystic ovary syndrome (PCOS) is important as geographic factors and ethnic variations can significantly alter the clinical syndrome. The aim of this study was to determine and evaluate the luteinizing hormone/follicle-stimulating hormone ratio (LH/FSH) in women with PCOS during therapy on selected endocrine and biochemical parameters.ResultsWomen with PCOS were included in the study and were classified into two groups: women without therapy (de novo) and women with therapy for PCOS. ESHERE/ASRM criteria that require the presence of two out of three criteria: ovulatory dysfunction, hyperandrogenism, and morphological PCOS detected by ultrasound diagnostics. Electrochemiluminescence immunoassay (ECLIA) was used for FSH and insulin analysis. The enzymatic method was used to analyze the biochemical profile. There was a significant difference between the two groups in terms of the LH/FSH ratio (2.56 vs. 2.41, P=0.043), glucose (6.23 vs. 5.12, P=0.003), insulin (19.21 vs. 7.35, P=0.000), IR (3.22 vs. 1.42, P=0.000), cholesterol (5.97 vs. 4.92, P=0.002), and LDL (3.56 vs. 2.56, P=0.001). The data suggest that patients with PCOS therapy have reduced hyperinsulinemia and insulin resistance. There was a significant correlation between the LH and FSH in the de novo group, as well as the correlation between hormone levels and LH/FSH ratio in both groups. Patients with PCOS therapy have a tendency for normal body weight and reduction of severe obesity compared to patients without therapy. Clinical features such as regular menstrual cycle and the prevalence of acne and hirsutism are not significantly different between groups.ConclusionPCOS cause irregularities of the menstrual cycle, the appearance of clinical manifestations, especially changes of LH/FSH ratio. Therapy for PCOS contributes to better regulation of endocrine and biochemical parameters, especially in the reduction of hyperinsulinemia, insulin resistance, and reduced LH/FSH ratio.

The use of inositol stereoisomers for the treatment of patients with clinical and biochemical signs of hyperandrogenism

For many years, the use of combined oral contraceptives (COC) with antiandrogenic effects was the main treatment of clinical and biochemical hyperandrogenism in patients with polycystic ovary syndrome (PCOS). At the same time, the creation of an alternative therapy regimen for patients who have contraindications to taking hormonal drugs, as well as planning pregnancy, is obvious. Various combinations of inositol stereoisomers (myoinositol ― MI, and D-chiro-inositol ― DCI) are being actively studied. The review reflects the current understanding of the etiology, pathogenesis of hyperinsulinemia and androgen-dependent dermatological manifestations of polycystic ovary syndrome. The mechanisms of action of inositols at the molecular level are normalization of carbohydrate metabolism in the body and the reduction of hyperinsulinemia, as well as the levels of male sex hormones in PCOS. A comparative analysis of studies with various combinations of inositols was conducted on the effectiveness of treatment of clinical manifestations of hyperandrogenism, such as hirsutism and acne. The use of MI in conjunction with DCI reduces the risk of developing metabolic syndrome and improves the endocrine profile and manifestations of insulin resistance, but further multicenter studies on this problem are required.

Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review

Low-carbohydrate high-fat (LCHF) diets are a highly contentious current topic in nutrition. This narrative review aims to provide clinicians with a broad overview of the effects of LCHF diets on...

IL-33 Reverses an Obesity-Induced Deficit in Visceral Adipose Tissue ST2+ T Regulatory Cells and Ameliorates Adipose Tissue Inflammation and Insulin Resistance.

Obesity is associated with insulin resistance and inflammation thought to be caused by a visceral adipose tissue (VAT)-localized reduction in immunoregulatory cells and increase in proinflammatory immune cells. We previously found that VAT regulatory T cells (Tregs) normally express high levels of IL-10 and that expression of this cytokine in VAT Tregs is specifically reduced in mice fed a high-fat diet. In this study, we further investigated the phenotype of VAT Tregs and found that the majority of IL-10-expressing Tregs in the VAT of lean mice also expressed the ST2 chain of the IL-33R. In addition to high expression of IL-10, ST2(+) Tregs in lean VAT expressed higher proportions of Th2-associated proteins, including GATA3 and CCR4, and Neuropillin-1 compared with ST2(-) Tregs. The proportion of ST2(+) Tregs in VAT was severely diminished in obese mice that had been fed a high-fat/sucrose diet, and this effect could be completely reversed by treatment with IL-33. IL-33 treatment also reversed VAT inflammation in obese mice and resulted in a reduction of hyperinsulinemia and insulin resistance. These data suggest that IL-33 contributes to the maintenance of the normal pool of ST2(+) Tregs in the VAT, and that therapeutic administration of IL-33 results in multiple anti-obesity effects, including the reversal of VAT inflammation and alleviation of insulin resistance.

MP55-15 INVOLVEMENT OF MIR-181B-MEDIATED EZH2/IGF-1R SIGNALLING PATHWAY IN THE GROWTH AND ENERGY METABOLISM OF PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Metformin has received considerable attention as a potential anti-cancer agent. Animal and invitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. This may include increased AMPK activity or a reduction of hyperinsulinemia and insulin signaling. We studied the effect of pharmacologic metformin dosages on prostate gland expression of AMPK, insulin and IGF-1 receptor activity. METHODS: Subjects were identified from a clinical and tissue database from the Seattle-Puget Sound Veteran’s Affairs Medical Center. Cases included men who were continuously taking metformin ( 500mg daily) for at least 6 months prior to the biopsy compared to controls not taking metformin. Controls were matched 1:1 to cases on age, race, BMI and whether PCa was detected. AMPK, insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-IR) and AKT protein expression was assessed by immunohistochemistry. Differences in the mean IHC scores between the two groups were compared with linear regression adjusted for age, race, BMI and fasting glucose based on (1) presence or absence of prostate cancer and (2) metformin exposure. RESULTS: We identified 48 patients taking metformin and 41 controls who underwent prostate biopsy. Of these, 46% had cancer detected. The majority of men were Caucasian (82%), obese (59%) and over the age of 65 (58%). In patients with PCa detected at biopsy, significant increases in IGF-1R (p1⁄40.002), IR (p<0.001), AKT (p<0.001) and AMPK (p<0.001) were found compared to men with negative prostate biopsies. Among metformin users, IGF-1R remained significantly elevated (p1⁄40.01) in men with cancer detected whereas pAMPK expression (p1⁄40.05) was greater only in those without prostate cancer. CONCLUSIONS: In men undergoing prostate needle biopsy, AMPK, IR, and IGF-1R are increased in those with PCa detected compared to those with negative biopsies. When stratified by metformin, AMPK was elevated in negative biopsies while IGF-1R remained elevated in those with cancer. This suggests a mechanistic affect of metformin use on decreased insulin signaling/reception while maintaining elevated AMPK signaling. This may provide a therapeutic benefit in prostate cancer development by decreasing downstream activation of mammalian target of rapamycin (mTOR) signaling and subsequent proliferation. Further longitudinal study is needed to assess dose response and confirm this relationship.

MP55-14 METFORMIN USE AND METABOLIC SIGNALING IN MEN UNDERGOING PROSTATE NEEDLE BIOPSY

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2015MP55-14 METFORMIN USE AND METABOLIC SIGNALING IN MEN UNDERGOING PROSTATE NEEDLE BIOPSY Brian Winters, Sarah Holt, Xiaotun Zhang, Colm Morrissey, Daniel Lin, Stephen Plymate, and Jonathan Wright Brian WintersBrian Winters More articles by this author , Sarah HoltSarah Holt More articles by this author , Xiaotun ZhangXiaotun Zhang More articles by this author , Colm MorrisseyColm Morrissey More articles by this author , Daniel LinDaniel Lin More articles by this author , Stephen PlymateStephen Plymate More articles by this author , and Jonathan WrightJonathan Wright More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2057AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Metformin has received considerable attention as a potential anti-cancer agent. Animal and in-vitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. This may include increased AMPK activity or a reduction of hyperinsulinemia and insulin signaling. We studied the effect of pharmacologic metformin dosages on prostate gland expression of AMPK, insulin and IGF-1 receptor activity. METHODS Subjects were identified from a clinical and tissue database from the Seattle-Puget Sound Veteran's Affairs Medical Center. Cases included men who were continuously taking metformin (≥ 500mg daily) for at least 6 months prior to the biopsy compared to controls not taking metformin. Controls were matched 1:1 to cases on age, race, BMI and whether PCa was detected. AMPK, insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-IR) and AKT protein expression was assessed by immunohistochemistry. Differences in the mean IHC scores between the two groups were compared with linear regression adjusted for age, race, BMI and fasting glucose based on (1) presence or absence of prostate cancer and (2) metformin exposure. RESULTS We identified 48 patients taking metformin and 41 controls who underwent prostate biopsy. Of these, 46% had cancer detected. The majority of men were Caucasian (82%), obese (59%) and over the age of 65 (58%). In patients with PCa detected at biopsy, significant increases in IGF-1R (p=0.002), IR (p<0.001), AKT (p<0.001) and AMPK (p<0.001) were found compared to men with negative prostate biopsies. Among metformin users, IGF-1R remained significantly elevated (p=0.01) in men with cancer detected whereas p-AMPK expression (p=0.05) was greater only in those without prostate cancer. CONCLUSIONS In men undergoing prostate needle biopsy, AMPK, IR, and IGF-1R are increased in those with PCa detected compared to those with negative biopsies. When stratified by metformin, AMPK was elevated in negative biopsies while IGF-1R remained elevated in those with cancer. This suggests a mechanistic affect of metformin use on decreased insulin signaling/reception while maintaining elevated AMPK signaling. This may provide a therapeutic benefit in prostate cancer development by decreasing downstream activation of mammalian target of rapamycin (mTOR) signaling and subsequent proliferation. Further longitudinal study is needed to assess dose response and confirm this relationship. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e678 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brian Winters More articles by this author Sarah Holt More articles by this author Xiaotun Zhang More articles by this author Colm Morrissey More articles by this author Daniel Lin More articles by this author Stephen Plymate More articles by this author Jonathan Wright More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Patients with type 2 diabetes mellitus failing on oral agents and starting once daily insulin regimen; a small randomized study investigating effects of adding vildagliptin.

BackgroundThe addition of a DDP4-inhibitor to existing insulin therapy reduces HbA1c. However, no data exist about the addition of these agents at the beginning of insulin treatment in type 2 diabetes while this could especially be interesting because it is during this period that considerable residual beta cell function is still present. The benefit of such a strategy could be a lower insulin dose required for glycemic control. The hypothesis of our study was that adding a DPP4-inhibitor at the beginning of insulin treatment could lead to less exogenous insulin requirement, a reduction of hyperinsulinemia and side effects (hypoglycemia and weight gain), less glucose variability and improvement of insulin and glucagon dynamics during a mixed meal test.ResultsIn this small clinical trial (trial registration NTR2022) 9 patients were randomized to receive vildagliptin and 6 to receive placebo in addition to start of once daily insulin treatment. Unfortunately, due to a difficult inclusion, the preset sample size of 40 patients could not be met. Median units of insulin at the end of the study was 47 U in the placebo group and 34 U in the vildagliptin group. Median glycemic variability (SD) at the end of study was 2.1 in the placebo group and 1.5 in the vildagliptin group. Median weight gain at the end of study was 3 kg in the placebo and 0.5 kg in the vildagliptin group. Occurrence of hypoglycemia was low in both groups. Insulin, C-peptide, glucose and glucagon levels were comparable during mixed meal tests.ConclusionsThis small randomized study did not have sufficient power to detect effects of the addition of vildagliptin to the start of once daily long-acting insulin. However in our opinion adding a DPP4-inhibitor, especially in this group remains a very interesting approach. This study could be used as a guidance for larger studies that are required to investigate the effects of this intervention on insulin requirements, glycemic variability, hypoglycemia and weight gain.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-579) contains supplementary material, which is available to authorized users.

A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome.

Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake. A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography. PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08). Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

Evaluation of two dietary treatments in obese hyperinsulinemic adolescents

Hyperinsulinemia increases the risk of cardiovascular disease in obese children. Only a few treatments are available to decrease insulin resistance. The reduction of hyperinsulinemia by dietary means would be a simple, physiologic and economic way to reduce the risk of metabolic disease. To compare the effects of two low-energy diets on serum insulin concentrations and weight loss in obese hyperinsulinemic adolescents. Eighty-six randomly assigned insulin-resistant obese adolescents completed a 16 week calorie-restricted diet. The experimental diet had a reduced glycemic index designed to evoke a low insulin response (LIR), with carbohydrates and proteins ingested in separate meals. The control diet was a conventional (CD) with similar proportions (60%, 20% and 20%). Variables studied were blood glucose and insulin concentrations after an oral glucose load, body mass index, waist circumference, and insulin resistance (homeostasis model assessment, HOMA). Mean weight [+/- Standard Deviation (SD)] was significantly reduced after the LIR (-0.53 +/- 0.5) and the CD (-0.54 +/- 0.4), but a greater decrease of waist circumference (cm) was observed after the LIR (-9.1 +/- 4.8 vs. -6.6 +/- 4.6, p = 0.02). Fasting insulin concentrations (-17.9 +/- 27.9 vs. -9.4 +/- 14.8, p = 0.01) and HOMA dropped significantly more after the LIR than after the CD (-3.5 +/- 4.9SD vs. -2.4 +/- 1SD, p < 0.0001). The LIR diet reduces serum insulin concentrations and waist circumference more than conventional treatment and appears to be a promising alternative to a conventional diet in insulin-resistant obese adolescents. Long-term follow-up is needed to evaluate the maintenance of weight loss and metabolic parameters.

Ectopic expression of Wnt10b decreases adiposity and improves glucose homeostasis in obese rats

The Wnt family of secreted glycoproteins had previously been shown to regulate diverse processes during early development. Wnt signaling also plays a key role in the homeostasis of adult tissues maintaining stem cell pluripotency and determining differentiating cell fate. The age-related decrease in Wnt signaling may contribute to increased muscle adiposity and diminished bone strength. In the current study, we investigated the long-term metabolic consequences of the upregulated Wnt/beta-catenin signaling in skeletal muscles of adult diet-induced obese (DIO) rats. To this end, we generated a recombinant adeno-associated virus (rAAV) vector encoding murine Wnt10b cDNA. The long-term expression of rAAV1-Wnt10b was tested after intramuscular injection in the female DIO rat. Animals fed high-fat diet and treated with rAAV1-Wnt10b showed a sustained reduction in body weight compared with controls, and expression of Wnt10b was accompanied by a reduction in hyperinsulinemia and triglyceride plasma levels as well as improved glucose homeostasis. Nuclear magnetic resonance methods revealed that ectopic expression of Wnt10b resulted in a decrease in both global and muscular fat deposits in DIO rats. The long-range effect of locally expressed Wnt10b was also manifested through the increased bone mineral density. The detailed analysis of molecular markers revealed fibroblast growth factor-4 and vascular endothelial growth factor as possible mediators of the systemic effect of Wnt10b transgene expression. Our data demonstrate that altering Wnt/beta-catenin signaling in the skeletal muscle of an adult animal invokes moderate responses with favorable metabolic profile, bringing the notion of alternative therapeutic modality in the treatment of obesity, diabetes, and osteoporosis.

Effect of rosiglitazone on endocrine, metabolism and ovulatory performance in patients with polycystic ovary syndrome and insulin resistance.

The effect of rosiglitazone on endocrine, metabolism and ovulatory performance in the paitents with polycystic ovary syndrome (PCOS) and insulin resistance was investigated. Twenty-five patients diagnosed as having polycystic ovary syndrome (PCOS) combined with insulin resistance were treated with rosiglitazone for 12 weeks. Before and after treatment, serum luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), testosterone (T), androstenedione (A), sex hormone binding globulin (SHBG), insulin and glucose concentration, total cholesterol, triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholestero (LDL-C), apolipoprotein A, apolipoprotein B levels and ovulatory performance were determined. The results showed that after treatment serum insulin levels was decreased significantly (P<0.01). The HDL-C was increased while LDL-C decreased significantly (P<0.05, P< 0.01). The serum LH, T, A concentrations and the ratio of LH/FSH were decreased, while SH-BG levels increased significantly (P<0.01). The ovulation rate during clomiphene citrate therapy was 72%, significantly higher than that before treatment. It is likely that reduction of hyperinsulinemia that is produce by rosiglitazone may effectively improve the endocrine, metabolism and ovulatory performance in the patients with PCOS and insulin resistance.

Biochemical and morphological effects of K-111, a peroxisome proliferator-activated receptor (PPAR)α activator, in non-human primates

K-111 has been characterized as a potent peroxisome proliferator-activated receptor (PPAR)α activator. Antidiabetic potency and amelioration of disturbed lipid metabolism were demonstrated in rodents, which were accompanied by elevations of peroxisomal enzymes and liver weight. To examine the possible therapeutic application of K-111 we have now assessed its efficacy in non-human primates with high transferability to humans. For this purpose obese, hypertriglyceridaemic, hyperinsulinaemic prediabetic rhesus monkeys were dosed sequentially with 0, 1, 3 and 10 mg/kg per day orally over a period of 4 weeks each. In addition, the effect of K-111 on the peroxisome compartment was analyzed in cynomolgus monkeys using liver samples obtained following a 13-week oral toxicity study. In prediabetic monkeys, the reduction of hyperinsulinaemia and improvement of insulin-stimulated glucose uptake rate indicated amelioration of insulin resistance. These effects were nearly maximal at a dose of 3 mg/kg per day, while triglycerides and body weight were lowered significantly in a dose-dependent manner. This reduction of body weight contrasts sharply with the adipogenic response observed with thiazolidinediones, another family of insulin-sensitizing agents. In young cynomolgus monkeys at a dosage of 5 mg/kg per day and more, K-111 induced an up to three-fold increase in lipid β-oxidation enzymes with an 1.5- to 2-fold increase in peroxisome volume density. This moderate increase in peroxisomal activity by K-111 in monkeys is consistent with its role as an PPARα activator and corresponds to the observations with fibrates in other low responder mammalian species. The increase in β-oxidation may explain, at least in part, the lipid modulating effect as well as the antidiabetic potency of K-111. This pharmacological profile makes K-111 a highly promising drug candidate for clinical applications in the treatment of type 2 diabetes, dyslipidaemia, obesity and the metabolic syndrome.

Biochemical and morphological effects of K-111, a peroxisome proliferator-activated receptor (PPAR)$alpha; activator, in non-human primates

K-111 has been characterized as a potent peroxisome proliferator-activated receptor (PPAR)α activator. Antidiabetic potency and amelioration of disturbed lipid metabolism were demonstrated in rodents, which were accompanied by elevations of peroxisomal enzymes and liver weight. To examine the possible therapeutic application of K-111 we have now assessed its efficacy in non-human primates with high transferability to humans. For this purpose obese, hypertriglyceridaemic, hyperinsulinaemic prediabetic rhesus monkeys were dosed sequentially with 0, 1, 3 and 10 mg/kg per day orally over a period of 4 weeks each. In addition, the effect of K-111 on the peroxisome compartment was analyzed in cynomolgus monkeys using liver samples obtained following a 13-week oral toxicity study. In prediabetic monkeys, the reduction of hyperinsulinaemia and improvement of insulin-stimulated glucose uptake rate indicated amelioration of insulin resistance. These effects were nearly maximal at a dose of 3 mg/kg per day, while triglycerides and body weight were lowered significantly in a dose-dependent manner. This reduction of body weight contrasts sharply with the adipogenic response observed with thiazolidinediones, another family of insulin-sensitizing agents. In young cynomolgus monkeys at a dosage of 5 mg/kg per day and more, K-111 induced an up to three-fold increase in lipid β-oxidation enzymes with an 1.5- to 2-fold increase in peroxisome volume density. This moderate increase in peroxisomal activity by K-111 in monkeys is consistent with its role as an PPARα activator and corresponds to the observations with fibrates in other low responder mammalian species. The increase in β-oxidation may explain, at least in part, the lipid modulating effect as well as the antidiabetic potency of K-111. This pharmacological profile makes K-111 a highly promising drug candidate for clinical applications in the treatment of type 2 diabetes, dyslipidaemia, obesity and the metabolic syndrome.

Treatment with rosiglitazone reduces hyperinsulinemia and improves arterial elasticity in patients with type 2 diabetes mellitus

Objective The aim of this study was to determine whether reduction of hyperinsulinemia with rosiglitazone will improve vascular elasticity in patients with non-insulin dependent diabetes mellitus. Methods In an open label study 52 patients with non-insulin dependent diabetes mellitus and at least one additional cardiovascular risk factor, were treated for 6 months with 4 mg of rosiglitazone, and uptitrated to 8 mg after 3 months of treatment, if needed. At the beginning of the study and at its end, blood was drawn for insulin, C- peptide, and 24-h urine collected for microalbuminuria/proteinuria. Glucose, chemistry, lipid profile, and hemoglobin A1C were determined at 0, 3, and 6 months. Vascular compliance was measured in monthly intervals. Results Treatment increased significantly small artery elasticity from 1.45 to 2.43 mL/mm Hg × 100. Large artery elasticity tended to increase toward the end of the study ( P = not significant). Systolic blood pressure decreased from 144 to 124 mm Hg and diastolic blood pressure decreased from 80 to 68 mm Hg, despite mild weight gain. Heart rate tended to decrease from 76.3 to 74.7 beats/min ( P = not significant). Systemic vascular resistance decreased from 1789.8 to 1329.4 dyne sec/cm 5. Plasma insulin, in patients not treated with insulin, decreased from 42.45 ± 24.90 to 27.86 ± 14.86 IU/mL ( P = .0001). Conclusions Treatment with rosiglitazone reduced hyperinsulinemia and improved small artery elasticity with a tendency to improve large artery elasticity, in hypertensive and in normotensive patients. Because rosiglitazone improves insulin receptor sensitivity (IRS), it is logical to assume that the reduction in hyperinsulinemia reflects improvement in IRS. Our data support the hypothesis that hyperinsulinemia and IRS participate in the mechanisms of tissue injury and their improvement induces improvement in arterial elasticity.

Nitric oxide does not participate in the metabolic effects of exogenous bradykinin in fructose-fed rats

The study was carried out to demonstrate the effects of bradykinin (BK) on hypertension, hyperinsulinemia, and hypertriglyceridemia in fructose-fed rats, and to determine whether these actions are mediated through nitric-oxide (NO) formation. Eighteen rats, rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a fructose-enriched diet, were studied. BK (0.2 mg/day) was infused intravenously using osmotic pumps attached by a catheter to the jugular vein of 12 rats for 12 days. BK was administered either alone ( n = 6) or with concomitant inhibition of NO synthase ( n = 6). Six untreated rats served as control. Measurements of systolic blood pressure (indirect method) and levels of insulin and triglyceride in serum were taken every second day. BK infused chronically, induced a marked fall in all parameters as early as the second day of infusion: in blood pressure from 152 ± 7 to 126 ± 12 mmHg, in insulin from 8.7 ± 2.9 to 4.6 ± 5.4 pg/mL, and in triglyceride from 308 ± 94 to 76 ± 19 mg/dL. No such reduction was seen in untreated animals. When BK was administered concurrently with NO synthase inhibitor, blood pressure rose significantly, reaching very high values at the end of treatment. However, the reduction in insulin and triglyceride levels induced by BK was not affected. The capacity of BK to enhance reduction in hyperinsulinemia and hypertriglyceridemia in the fructose-fed rats is not mediated by NO formation. Whether this action of BK is related to a direct effect of this peptide remains to be determined.

Endocrine and Metabolic Effects of MetforminVersusEthinyl Estradiol-Cyproterone Acetate in Obese Women with Polycystic Ovary Syndrome: A Randomized Study1

Metformin, a biguanide antihyperglycemic drug, has been shown to improve ovarian function and glucose metabolism in women with polycystic ovary syndrome (PCOS), but results concerning its effects on insulin sensitivity are controversial. Oral contraceptive pills are commonly used in the treatment of PCOS; but, like metformin, their influence on insulin sensitivity is not well known. We randomized 32 obese (body mass index > 27 kg/m2) women with PCOS, either to metformin (500 mg x 2 daily for 3 months, then 1,000 mg x 2 daily for 3 months) or to ethinyl estradiol (35 microg)-cyproterone acetate (2 mg) oral contraceptive pills (Diane Nova) for 6 months. Metformin significantly decreased the waist-to-hip ratio, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity, with slight (but nonsignificant) improvements in insulin hepatic extraction and insulin sensitivity. Diane Nova significantly decreased serum testosterone and increased serum sex hormone-binding globulin concentrations and glucose area under the curve during oral glucose tolerance test. It is concluded that metformin, probably by way of its effect on adipose tissue, leads to reduction of hyperinsulinemia and concomitant improvement in the menstrual pattern; and therefore, it offers a useful alternative treatment for obese, anovulatory women with PCOS. Despite slight worsening of glucose tolerance, Diane Nova is an efficient treatment for women with hyperandrogenism and hirsutism.

Discovery of a Potent, Highly Selective, and Orally Efficacious Small-Molecule Activator of the Insulin Receptor

A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and evaluated for their abilities to selectively activate human insulin receptor tyrosine kinase (IRTK). 2, 5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone (2h) was identified as a potent, highly selective, and orally active small-molecule insulin receptor activator. It activated IRTK with an EC(50) of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administration of the compound to hyperglycemic db/db mice (0.1-10 mg/kg/day) elicited substantial to nearly complete correction of hyperglycemia in a dose-dependent manner. In ob/ob mice, the compound (10 mg/kg) caused significant reduction in hyperinsulinemia. A structurally related compound 2c, inactive in IRTK assay, failed to affect blood glucose level in db/db mice at equivalent exposure levels. Results from additional studies with compound 2h, aimed at evaluating classical quinone-related phenomena, provided sufficient grounds for optimism to allow more extensive toxicologic evaluation.

Increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals.

We have recently demonstrated that insulin activates farnesyltransferase (FTase) and thereby increases the amounts of cellular farnesylated p21Ras in 3T3-L1 fibroblasts, adipocytes and vascular smooth muscle cells. We postulated that hyperinsulinaemia might considerably increase the the cellular pool of farnesylated p21Ras available for activation by other growth factors. To examine the role of in vivo hyperinsulinaemia in regulating farnesylated p21Ras, we measured the amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. Liver, aorta, and skeletal muscle of ob/ob mice, and mice made obese and hyperinsulinaemic by injection of gold-thioglucose contained greater amounts of farnesylated p21Ras than tissues of their lean normoinsulinaemic counterparts. Similarly, farnesylated p21Ras was increased (67 vs. 35 % in control animals, p<0.01) in the livers of hyperinsulinaemic Zucker rats (fa/fa). Reduction of hyperinsulinaemia by exercise training (2 h/day for 7-8 weeks) resulted in decreases in the amounts of farnesylated p21Ras in these animals. Increased farnesylated p21Ras in hyperinsulinaemic animals reflected increasing increments in the activity of FTase in ob/ob mice (2-fold increase) and fa/fa Zucker rats (3.5-fold increase), while the total amounts of Ras proteins remained unchanged. In contrast to insulin-resistant hyperinsulinaemic animals, denervated insulin-resistant rat soleus muscle (in the presence of normoinsulinaemia) showed normal amounts of farnesylated p21Ras. In summary, these data confirm increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals.