Insulin sensitizer and antihyperlipidemic effects of Cajanus cajan (L.) millsp. root in methylglyoxal-induced diabetic rats.

Cajanus cajan (L.) Millsp., known as pigeon pea, is one of the major grain legume crops of the tropical world. It recognizes as an ethnomedicine to possess various functions, such as helping in healing wound and cancer therapy. We investigated whether 95% ethanol extracts from C. cajan root (EECR) protect against methylglyoxal (MGO)-induced insulin resistance (IR) and hyperlipidemia in male Wistar rats and explored its possible mechanisms. The hypoglycemic potential of EECR was evaluated using α-amylase, α-glucosidase activities, and advanced glycation end products (AGEs) formation. For in vivo study, the rats were divided into six groups and orally supplemented with MGO except for Group 1 (controls). Group 2 was supplemented with MGO only, Group 3: MGO + metformin, Group 4: MGO + Low dose-EECR (L-EECR; 10 mg/kg bw), Group 5: MGO + Middle dose-EECR (M-EECR; 50 mg/kg bw), and Group 6: MGO + High dose-EECR (H-EECR; 100 mg/kg bw). EECR possessed good inhibition of α-glucosidase, α-amylase activities, and AGEs formation (IC50 = 0.12, 0.32, and 0.50 mg/mL), respectively. MGO significantly increased serum levels of blood glucose (GLU), glycosylated hemoglobin, homeostasis model assessment of IR, AGEs, lipid biochemical values, and atherogenic index, whereas EECR decreased these levels in a dose-dependent manner. EECR can also act as an insulin sensitizer, which significantly decreased (47%, P < 0.05) the blood GLU levels after intraperitoneal injection of insulin in the insulin tolerance tests. The hypoglycemic and antihyperlipidemic mechanisms of EECR are likely through several possible pathways including the inhibition of carbohydrate-hydrolyzing enzymes (α-glucosidase and α-amylase) and the enhancement of MGO-trapping effects on inhibition of AGEs formation.

Citrus flavone tangeretin is a potential insulin sensitizer targeting hepatocytes through suppressing MEK-ERK1/2 pathway.

BACKGROUND: Tangeretin, a flavonoid derived from citrus peel, showed anti-diabetic effects. However, the role of tangeretin on liver, the organ that act as target of insulin and play the central role in maintaining the blood glucose level control, is still largely unknown. The current study was designed to assess the effect of tangeretin on liver insulin sensitivity in vitro and in vivo. METHODS: Primary hepatocytes and mice were treated with different dose of tangeretin, parameters of insulin sensitivity, such as blood glucose levels, serum insulin levels, glucose tolerate test (GTT), insulin tolerate test (ITT), insulin stimulated IR-AKT pathway were analyzed. RESULTS: Primary hepatocytes treated with 10/20 µM tangeretin showed up-regulated insulin signaling pathway as well as the glycogen content, while the glucose output were reduced. Intragastric administration of tangeretin (25/50 mg/kg) also ameliorated the liver insulin sensitivity and improved the glucose homeostasis, both in wild type C57 mice and in db/db mice, a diabetic model. Tangeretin treatment dose-dependently suppressed the MEK-ERK1/2 pathway, while forced activation of p-ERK1/2 reversed the insulin sensitized effect of tangeretin. CONCLUSION: These results indicated that tangeretin enhanced the liver insulin sensitivity in vitro and in vivo, through suppressing the MEK-ERK1/2 pathway.

High throughput in vivo phenotypic screening for drug repurposing: Discovery of MLR-1023 a novel insulin sensitizer and novel Lyn kinase activator with clinical proof of concept.

Drug discovery requires the combination of medicinal chemistry and biology. In this article Chris Lipinski, the medicinal chemist, describes the chemical origins at Pfizer of Tolimidone1 the starting point for the repurposed MLR-1023 (Ochman et al., 2012). Andrew Reaume, the biologist, describes his motivation to develop a high quality (i.e. in vivo model) phenotypic screening platform as an ideal drug repositioning platform.

Long-term treatment with α-lipoic acid and myo-inositol positively affects clinical and metabolic features of polycystic ovary syndrome.

The aim of this retrospective study was to evaluate the effects of a long-term treatment with α-lipoic acid (ALA) combined with myo-inositol (MI) on clinical and metabolic features of women with polycystic ovary syndrome (PCOS). Fifty-seven women with PCOS and a history of oligoamenorrhea were treated with MI and ALA (800 mg + 2000 mg per day). Forty-four of them had complete clinical charts and were considered eligible for the study. Information about cycle length and body mass index (BMI) was checked after 6, 12, and 24 months. After 12 months ovarian volume, total testosterone plasma levels and changes in hirsutism were also evaluated. The metabolic parameters were evaluated in 16 women after 6 and 18 months of the treatment. Cycle length was significantly reduced at 6 (p < .001), 12, and 24 months of treatment (p < .01). BMI showed a reduction only at 6 months (p < .05), thereafter returning similar to the basal values. No changes of testosterone and ovarian volume were observed. HOMA-IR and fasting insulin were unchanged, but the insulin response to a 3 h OGTT was improved after 6 (p < .01) and 18 months (p < .05) of treatment. No individual suffered from any adverse event. In conclusion, the combination of ALA and MI showed to be useful as long-term therapy in PCOS women, providing a normalization of the menstrual cycle and an amelioration of insulin levels with a high tolerability.

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome.

BGP-15 is a new insulin sensitizer drug candidate, which was developed by Hungarian researchers. In recent years, numerous research groups have studied its beneficial effects. It is effective in the treatment of insulin resistance and it has protective effects in Duchenne muscular dystrophy, diastolic dysfunction, tachycardia, heart failure, and atrial fibrillation, and it can alleviate cardiotoxicity. BGP-15 exhibits chemoprotective properties in different cytostatic therapies, and has also proven to be photoprotective. It can additionally have advantageous effects in mitochondrial-stress-related diseases. Although the precise mechanism of the effect is still unknown to us, we know that the molecule is a PARP inhibitor, chaperone co-inducer, reduces ROS production, and is able to remodel the organization of cholesterol-rich membrane domains. In the following review, our aim was to summarize the investigated molecular mechanisms and pharmacological effects of this potential API. The main objective was to present the wide pharmacological potentials of this chemical agent.

Molecules Isolated from Mexican Hypoglycemic Plants: A Review.

Like in many developing countries, in Mexico, the use of medicinal plants is a common practice. Based on our own field experience, there are at least 800 plants used for treating diabetes nowadays. Thus, their investigation is essential. In this context, this work aims to provide a comprehensive and critical review of the molecules isolated from Mexican hypoglycemic plants, including their source and target tested. In the last few years, some researchers have focused on the study of Mexican hypoglycemic plants. Most works describe the hypoglycemic effect or the mechanism of action of the whole extract, as well as the phytochemical profile of the tested extract. Herein, we analyzed 85 studies encompassing 40 hypoglycemic plants and 86 active compounds belonging to different classes of natural products: 28 flavonoids, 25 aromatic compounds, other than flavonoids, four steroids, 23 terpenoids, 4 oligosaccharides, and 1 polyalcohol. These compounds have shown to inhibit α-glucosidases, increase insulin secretion levels, increase insulin sensitivity, and block hepatic glucose output. Almost half of these molecules are not common metabolites, with a narrow taxonomic distribution, which makes them more interesting as lead molecules. Altogether, this analysis provides a necessary inventory useful for future testing of these active molecules against different hypoglycemic targets, to get a better insight into the already described mechanisms, and overall, to contribute to the knowledge of Mexican medicinal plants.

Metformin, beyond an insulin sensitizer, targeting heart and pancreatic ß cells.

Metformin, a biguanide derivate, is known as the first-line antidiabetic agent for type 2 diabetes mellitus (T2DM) treatment. It reduces insulin resistance and decreases blood glucose concentration by inhibiting gluconeogenesis and suppressing hepatic glucose production with improved peripheral tissue insulin sensitivity. As an insulin sensitizer, metformin takes pleiotropic actions and exerts protective effects on multiple organs mainly in insulin-targeted tissues such as liver, muscle, and adipose tissues. Recent studies discover that metformin also plays essential roles in heart and pancreatic ß cells - two important organs in metabolic regulation. Metformin not only protects T2DM patients from cardiovascular diseases and heart failure, but also restores insulin secretion activities and protects pancreatic ß cells from lipotoxicity or glucotoxicity. Although accumulated evidence shed light on the metformin action, the precise mechanism of metformin is still under investigation. Further laboratory investigations and clinical trials are needed to pinpoint a map of metformin action. Based on recent findings, this review characterizes the beneficial role of metformin in cardiovascular diseases and pancreatic ß cells.

Myo-inositol administration positively effects ovulation induction and intrauterine insemination in patients with polycystic ovary syndrome: a prospective, controlled, randomized trial.

Objective: The aim of the study is to investigate the effect of myo-inositol (MYO) on pregnancy rates of patients diagnosed with polycystic ovary syndrome (PCOS) who undergone controlled ovulation induction and intrauterine insemination (IUI). METHODS: A total of 196 infertile patients diagnosed with PCOS and admitted to Dokuz Eylul University Faculty of Medicine were included in the study between March 2013 and May 2016. The patients in group 1 (n = 98) were given 4 g MYO and 400 µg folic acid before and during ovulation induction. The patients undergone controlled ovarian hyperstimulation (COH) with recombinant FSH and IUI. The patients in group 2 (n = 98), were given recombinant FSH directly and 400 µg folic acid. The primary outcome measure of this study was the clinical pregnancy rate. RESULTS: In group 1, 9 patients conceived spontaneous pregnancy. During COH + IUI treatment three cycles were canceled in group 1 and 8 cycles in group 2. Total rFSH dose and cycle duration were significantly lower and clinical pregnancy rates were higher in group 1. The pregnancy rate for group 1 was %18.6 and for group 2 was %12.2. Conclusions: This study shows that MYO should be considered in the treatment of infertile PCOS patients. MYO administration increases clinical pregnancy rates, lowers total rFSH dose and the duration of the ovulation induction.

Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS).

Insulin resistance (IR) plays a pivotal role in PCOS. Insulin-sensitizer agents such as metformin and inositols have been shown to improve the endocrine and metabolic aspects of PCOS. The purpose of this study is to compare their effects on the clinical and metabolic features of the women with PCOS. Fifty PCOS women with IR and/or hyperinsulinemia were randomized to treatment with metformin (1500 mg/day) or myo-inositol (4 g/day). IR was defined as HOMA-IR >2.5, while hyperinsulinemia was defined as a value of AUC for insulin after a glucose load over the cutoff of our laboratory obtained in normal women. The Matsusa Index has been calculated. The women have been evaluated for insulin secretion, BMI, menstrual cycle length, acne and hirsutism, at baseline and after 6 months of therapy. The results obtained in both groups were similar. The insulin sensitivity improved in both treatment groups. The BMI significantly decreased and the menstrual cycle was normalized in about 50% of the women. No significant changes in acne and hirsutism were observed. The two insulin-sensitizers, metformin and myo-inositol, show to be useful in PCOS women in lowering BMI and ameliorating insulin sensitivity, and improving menstrual cycle without significant differences between the two treatments.

Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep.

Women with polycystic ovary syndrome often manifest insulin resistance. Using a sheep model of polycystic ovary syndrome-like phenotype, we explored the contribution of androgen and insulin in programming and maintaining disruptions in insulin signaling in metabolic tissues. Phosphorylation of AKT, ERK, GSK3beta, mTOR, and p70S6K was examined in the liver, muscle, and adipose tissue of control and prenatal testosterone (T)-, prenatal T plus androgen antagonist (flutamide)-, and prenatal T plus insulin sensitizer (rosiglitazone)-treated fetuses as well as 2-yr-old females. Insulin-stimulated phospho (p)-AKT was evaluated in control and prenatal T-, prenatal T plus postnatal flutamide-, and prenatal T plus postnatal rosiglitazone-treated females at 3 yr of age. GLUT4 expression was evaluated in the muscle at all time points. Prenatal T treatment increased mTOR, p-p70S6K, and p-GSK3beta levels in the fetal liver with both androgen antagonist and insulin sensitizer preventing the mTOR increase. Both interventions had partial effect in preventing the increase in p-GSK3beta. In the fetal muscle, prenatal T excess decreased p-GSK3beta and GLUT4. The decrease in muscle p-GSK3beta was partially prevented by insulin sensitizer cotreatment. Both interventions partially prevented the decrease in GLUT4. Prenatal T treatment had no effect on basal expression of any of the markers in 2-yr-old females. At 3 yr of age, prenatal T treatment prevented the insulin-stimulated increase in p-AKT in liver and muscle, but not in adipose tissue, and neither postnatal intervention restored p-AKT response to insulin stimulation. Our findings provide evidence that prenatal T excess changes insulin sensitivity in a tissue- and development-specific manner and that both androgens and insulin may be involved in the programming of these metabolic disruptions.

Inositol's and other nutraceuticals' synergistic actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: state-of-the-art and future perspectives.

The incidence of metabolic syndrome (MetS), type II diabetes (T2D) and polycystic ovarian syndrome (PCOS) has been progressively increasing. Insulin resistance (InsR) seems to play a key role in a majority of phenotypes of these conditions, altering metabolic homeostasis, within muscle, liver, adipose and other tissues. Hyperinsulinemia is often associated with InsR and causes hormonal imbalances especially within ovaries and adrenals. Inositol is a polyalcohol, naturally occurring as nine stereoisomers, including D-chiro-inositol (DCI) and myo-inositol (MI), which have prominent roles in the metabolism of glucose and free fatty acids. MI and DCI have been classified as insulin-sensitizers and seem to adequately counteract several InsR-related metabolic alterations with a safe nutraceutical profile. Based on our analysis of selected studies that investigated MI and/or DCI, we conclude that supplementation with MI and/or DCI complement each other in their metabolic actions and act in synergy with other insulin sensitizing drugs and/or nutraceuticals. Nevertheless, considering the possible severe bias due to different methodologies across published studies, we conclude that there is a need for further studies on larger cohorts and with greater statistical power. These should further clarify outcomes and suitable therapeutic dosages of MI and DCI, possibly based on each patient's clinical status.

Metabolic profile of Diane-35 versus Diane-35 plus metformin in Chinese PCOS women under standardized life-style changes.

OBJECTIVE: The aim of this study was to compare the effect of Diane-35 versus Diane-35 + metformin on metabolic parameters in Chinese PCOS patients. METHODS: Patients getting individualized life-style modification were treated with Diane-35. Metformin was added according to its indication. Within a 3-month prospective study, metabolic parameters were assessed. RESULTS: Eighty-three patients were recruited, 45 using Diane-35 and 38 Diane-35 plus metformin. Using Diane-35, triglycerides (TG) (p < 0.05) and tendencially (p < 0.1) total cholesterol (TC) increased, but significant positive effects on BMI, high-density lipoprotein cholesterol (HDL-C), and HDL-C/TC ratio were observed. Other lipids and the parameters for glucose metabolism remained unchanged. In the combination group, no negative effect on TG and TC was seen, other lipid fractions improved, as well as BMI, % body fat, and all parameters for glucose metabolism like fasting plasma glucose (FPG), fasting insulin, HOMA-insulin-resistance index, and insulin sensitivity index (ISI), whereby the beneficial effect of metformin got significance compared with Diane-35 for BMI, FPG, and ISI. CONCLUSION: With the exception of increasing triglycerides, Diane-35 had no relevant negative effects in the metabolic system. It does not negatively impact the beneficial effects of metformin in lipids and glucose metabolism. Diane-35 plus metformin is effective in improving the metabolic profile of Chinese PCOS patients.

Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients.

Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects fertility through oligo-ovulation, hyperandrogenism and polycystic morphology of the ovaries. Since it has been demonstrated a high incidence of insulin resistance in PCOS patients, our study aimed to evaluate the efficacy of the integrative treatment with D-chiro-inositol (DCI) (500 mg die, per os, for 12 weeks) on hormonal parameters and insulin sensitivity in a group of overweight/obese PCOS patients (body mass index; BMI > 26). After the treatment, interval several endocrine parameters improved (luteinizing hormone [LH], LH/follicle stimulating hormone [FSH], androstenedione and insulin), insulin response to oral glucose tolerance test reported the significant improvement of insulin sensitivity as well as the gonadotropin-releasing hormone (GnRH)-induced (10 µg, in bolus) LH response. BMI decreased, though no lifestyle modification was requested. When data were analyzed according to the presence or absence of first-grade diabetic relatives, PCOS patients with diabetic relatives showed greater improvement after DCI administration. In conclusion DCI administration is effective in restoring better insulin sensitivity and an improved hormonal pattern in obese hyperinsulinemic PCOS patients, in particular, in hyperinsulinemic PCOS patients who have diabetic relatives.

Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long-acting dual amylin and calcitonin receptor agonist improves insulin-mediated glycaemic control and controls body weight.

BACKGROUND AND PURPOSE: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D. EXPERIMENTAL APPROACH: Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg-1) to induce T1D. Humulin (1 U/200 g·day-1 or 2 U/200 g·day-1) was continuously infused, while half of the rats received additional KBP-336 (4.5 nmol·kg-1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study. KEY RESULTS: Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation. CONCLUSION AND IMPLICATIONS: The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits.

Flavokawain B is an effective natural peroxisome proliferator-activated receptor γ-selective agonist with a strong glucose-lowering effect.

Rosiglitazone, a full PPARγ agonist and a classical insulin sensitizer, was once used as a powerful weapon in the treatment of T2DM. However, its applications have been restricted recently because of its multiple side effects. Here, a natural compound, flavokawain B (FKB), which was screened in our previous experiments, was investigated for its potential as a preferable insulin sensitizer because it has no or few side effects. Using the surface plasmon resonance (SPR) technique, we confirmed that FKB is a natural ligand for PPARγ with high binding affinity. In in vitro experiments, FKB significantly increased 2-NBDG uptake in HepG2 and 3T3-L1 cells, which partially stimulated PPARγ transcriptional activity. Compared with rosiglitazone, FKB had little effect on the adipose differentiation of 3T3-L1 cells, and all of these features suggest that FKB is a selective modulator of PPARγ (SPPARγM). Moreover, FKB increased the mRNA expression levels of most genes related to insulin sensitivity and glucose metabolism but had no obvious effect on those related to adipose differentiation. In vivo experiments confirmed that FKB effectively decreased abnormal fasting blood glucose and postprandial blood glucose levels and reduced glycated hemoglobin levels, similar to rosiglitazone, in HFD-fed/STZ-treated and db/db mice, two T2DM animal models, but did not cause side effects, such as weight gain or liver or kidney damage. Further investigation revealed that FKB could inhibit PPARγ-Ser273 phosphorylation, which is the key mechanism involved in improving insulin resistance. Together, FKB is a well-performing SPPARγM that exerts a powerful glucose-lowering effect without causing the same side effects as rosiglitazone, and it may have great potential for development.

Quantitative risk-benefit profiles of oral contraceptives, insulin sensitizers and antiandrogens for women with polycystic ovary syndrome: A model-based meta-analysis.

Oral contraceptives (OCs), insulin sensitizers, and antiandrogens (AAs), alone or in combination, are commonly used for treating non-fertility indications in polycystic ovary syndrome (PCOS). However, unclear risk-benefit profiles jeopardize their appropriate clinical applications. This study aimed to quantitatively evaluate the effects of the aforementioned medications and to compare their risk-benefit profiles. Randomized controlled trials published until 14th March 2022 were searched in PubMed and Embase. A model-based meta-analysis was developed to examine the time-effect profiles of each medication. The maximal percentage change of the effect (Emax) and time to achieve half of Emax (T50) were estimated. Primary outcomes included menstruation, hirsutism score, free androgen index (FAI), body mass index (BMI), insulin sensitivity, and lipid profiles. Overall, 200 studies (9,685 patients and 385 arms) were identified for modeling. OCs performed exceptionally well in improving menstruation (Emax: 149%; T50: 7.44 weeks), hirsutism score (Emax: 66.2%; T50: 26.2 weeks), and FAI (Emax: 75.7%; T50: 0.51 weeks). However, OCs elevated the triglyceride (TG) level (Emax: 12.6%; T50:1.19 weeks). After 12-week OC treatment, the TG level of approximately 30% of patients, whose baselines were normal, exceeded the reference limit. This suggested that OC-induced dyslipidemia should be routinely monitored. The maximal BMI-lowering effect of metformin was similar to that of placebo (Emax: 3.80%); however, metformin had a shorter T50 (6.67 weeks versus 12.9 weeks). Further, active lifestyle intervention plus placebo significantly decreased BMI (Emax: 8.78%). Adding metformin to active lifestyle intervention accelerated the BMI-lowering effect within 24 weeks, whereas with the extension of this addition beyond 24 weeks, BMI did not reduce further, which indicated that benefits were limited from this prolonged addition. AAs were less potent in reducing hirsutism score (Emax: 40.2% versus 66.2%) and FAI (Emax: 34.5% versus 75.7%) compared to OCs. OC plus metformin combined OC-derived androgen-suppressing effects and metformin-derived insulin-sensitizing effects, and partially relieved the OC-induced TG increase (Emax: 9.76%). Baseline dependency was found in most clinical responses, implying that pharmacotherapies tailored based on baselines achieved more clinical improvements. This study presents new quantitative evidence on pharmacotherapies for PCOS. Currently, long-term risk-benefit profiles and emerging therapies are inadequately reported and require more further research.

An update on diagnosis and therapeutics for type-2 diabetes mellitus.

Type-2 Diabetes mellitus is a common metabolic disorder. It is combined with co-morbidities, such as obesity, hyperlipidemia, hypertension and cardiovascular disease which taken together, comprise the 'Metabolic Syndrome'. This disease causes crucial morbidity and mortality at considerable expense to patients, their families and society. Different categories of drugs such as insulin secretagogues, insulin sensitizers, alpha-glucosidase inhibitors, GLP-1 agonists, DPP4 inhibitors, dual PPAR agonists and others are used for its management. Therefore, it is of interest to highlight the recent advances in diagnosis and therapeutics used in the treatment of type-2 diabetes mellitus. The classical and online-literature were used to compile data for this study. This includes the electronic search engine such as Scopus, Google Scholar, Sci Finder, PubMed and Web of Science. Data shows that there are different families of oral and injectable drugs at hand for the treatment of T2DM. Hence, we need to develop a novel, safety and effective agents that will improve the quality of life of T2DM patients, considering effectiveness and durability of lowering blood Glucose, risk of hypoglycemia and diabetes complications.

Insulin sensitizers in 2023: lessons learned and new avenues for investigation.

INTRODUCTION: 'Insulin sensitizers' derived discoveries of the Takeda Company in 1970s. Pioglitazone remains the best in class with beneficial pleiotropic pharmacology, although use is limited by tolerability issues. Various attempts to expand out of this class assumed the primary molecular target was the transcription factor, PPARγ. Findings over the last 10 years have identified new targets of thiazolidinediones (TZDs) that should alter the drug discovery paradigm. AREAS COVERED: We review structural classes of experimental insulin sensitizer drugs, some of which have attained limited approval in some markets. The TZD pioglitazone, originally approved in 1999 as a secondary treatment for type 2 diabetes, has demonstrated benefit in apparently diverse spectrums of disease from cardiovascular to neurological issues. New TZDs modulate a newly identified mitochondrial target (the mitochondrial pyruvate carrier) to reprogram metabolism and produce insulin sensitizing pharmacology devoid of tolerability issues. EXPERT OPINION: Greater understanding of the mechanism of action of insulin sensitizing drugs can expand the rationale for the fields of treatment and potential for treatment combinations. This understanding can facilitate the registration and broader use of agents with that impact the pathophysiology that underlies chronic metabolic diseases as well as host responses to environmental insults including pathogens, insulin sensitizer, MPC, mitochondrial target, metabolic reprogramming, chronic and infectious disease.

Reflections on the state of diabetes research and prospects for treatment.

Research on the etiology and treatment of diabetes has made substantial progress. As a result, several new classes of anti-diabetic drugs have been introduced in clinical practice. Nonetheless, the number of patients achieving glycemic control targets has not increased for the past 20 years. Two areas of unmet medical need are the restoration of insulin sensitivity and the reversal of pancreatic beta cell failure. In this review, we integrate research advances in transcriptional regulation of insulin action and pathophysiology of beta cell dedifferentiation with their potential impact on prospects of a durable "cure" for patients suffering from type 2 diabetes.

FAM3D: A gut secreted protein and its potential in the regulation of glucose metabolism.

The number of diabetic patients is rising globally and concomitantly so do the diabetes associated complications. The gut secretes a variety of proteins to control blood glucose levels and/or food intake. As the drug class of GLP-1 agonists is based on a gut secreted peptide and the positive metabolic effects of bariatric surgery are at least partially mediated by gut peptides, we were interested in other gut secreted proteins which have yet to be explored. In this respect we identified the gut secreted protein FAM3D by analyzing sequencing data from L- and epithelial cells of VSG and sham operated as well as chow and HFD fed mice. FAM3D was overexpressed in diet induced obese mice via an adeno-associated virus (AAV), which resulted in a significant improvement of fasting blood glucose levels, glucose tolerance and insulin sensitivity. The liver lipid deposition was reduced, and the steatosis morphology was improved. Hyperinsulinemic clamps indicated that FAM3D is a global insulin sensitizer and increases glucose uptake into various tissues. In conclusion, the current study demonstrated that FAM3D controls blood glucose levels by acting as an insulin sensitizing protein and improves hepatic lipid deposition.