PPARγ and the Treatment of Insulin Resistance

doi:10.1016/S1043-2760(00)00306-4

Trends in Endocrinology & Metabolism

Volume 11, Issue 9, 1 November 2000, Pages 362-368

https://doi.org/10.1016/S1043-2760(00)00306-4 Get rights and content

Abstract

Numerous studies across several population groups have indicated that insulin resistance plays a central role in the development of type 2 diabetes mellitus (T2DM). Moreover, this disorder is also strongly associated with other metabolic syndromes, including hypertension, dyslipidemias and polycystic ovarian syndrome (PCOS). Recent advances have demonstrated that pharmacological agents of the thiazolidinedione class can reverse insulin resistance and profoundly improve many of these associated symptoms. These effects have been documented in a variety of genetic and acquired animal models of insulin resistance, as well as in numerous clinical trials in patients with insulin resistance. These compounds appear to enhance insulin action by modulating the activity of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ. This activation results in changes in the expression of a number of genes that are critically involved in glucose and lipid metabolism, as well as in insulin signal transduction. While precise events that occur downstream from PPARγ modulation remain uncertain, new insights are emerging from knockout studies in mice and the identification of genetic variants in humans. These findings indicate that there is still much to learn about the molecular biology and physiology of these interesting receptors, and that research in this area can lead to more effective and safer drugs to treat insulin resistance and associated syndromes.

Section snippets

Thiazolidinediones Improve Insulin Sensitivity

The recent introduction of the thiazolidinedione (TZD) insulin-sensitizing drugs has allowed us to move from the bench to the bedside to test speculations about the pharmacological treatment of insulin resistance⁶. TZDs such as troglitazone, rosiglitazone and pioglitazone improve insulin action in a variety of insulin-resistant obese and diabetic animal models7., 8., 9., 10., 11.. These drugs uniformly improve insulin resistance, reducing plasma glucose levels and concomitantly lowering

Thiazolidinediones Activate the Nuclear Receptor PPARγ

The emergence of TZDs as insulin-sensitizing agents in animals and, more importantly, in humans, has generated intense interest in studying the molecular mechanisms that underlie the pharmacological actions of these drugs. Despite this interest, these mechanisms remained relatively obscure until Grimaldi²¹, Kliever²² and Speigelman²³ and co-workers discovered that TZDs behave as agonists for the peroxisome proliferator-activated receptor (PPAR) γ. PPARγ is a member of the nuclear receptor

Lessons Learned from PPARγ Knockouts and Mutants

To further elucidate the role of PPARγ in glucose homeostasis and insulin resistance, the gene encoding PPARγ has been ablated in mice. Although homozygous PPARγ^−/− null mutants were not viable, owing to intra-uterine lethality, heterozygous PPARγ^+/− mice have been studied39., 40.. These animals, which lack one PPARγ allele, have provided an opportunity to examine the effect of a 50% reduction in the transcription of the PPARγ gene on relevant physiological pathways. At the outset, PPARγ^+/−

References (50)

S.I. Taylor
Deconstructing type 2 diabetes
Cell
(1999)
T. Fujiwara
Characterization of CS-045, a new oral antidiabetic agent. II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice
Metabolism
(1991)
E.W. Kraegen
A potent in vivo effect of ciglitazone on muscle insulin resistance induced by high fat feeding of rats
Metabolism
(1989)
J.M. Lehmann
An antidiabetic thiazlidinedione is a high affinity ligand for PPARγ
J. Biol. Chem.
(1995)
P. Tontonoz
Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor
Cell
(1994)
B.M. Forman
15-DeoxyΔ 12., 14.-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ
Cell
(1995)
C.A. Baumann
Cloning and characterization of a functional PPARγ-responsive element in the promoter of the CAP gene
J. Biol. Chem.
(2000)
T.P. Ciaraldi
In vitro studies on the action of CS-045. A new anti-diabetic agent
Metabolism
(1990)
Y.M.C. Barak
PPARγ is required for placental, cardiac and adipose tissue development
Mol. Cell
(1999)
N.Y. Kubota
PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance
Mol. Cell
(1999)

J.S. Ringel

Pro12Ala missense mutation of the peroxisome proliferator activated receptor γ and diabetes mellitus

Biochem. Biophys. Res. Commun.

(1999)

Y.H. Mori

Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor γ2 gene on adiposity, fat distribution and insulin sensitivity in Japanese men

Biochem. Biophys. Res. Commun.

(1998)

L.H-Y. Nagy

Nuclear receptor repression mediated by a complex containing SMRT, mSIN3AZ, and histone deacetylase

Cell

(1997)

D.P. McDonnell

The molecular pharmacology of SERMs

Trends Endocrinol. Metab.

(1999)

Olefsky, J.M. (1997) Insulin resistance. In Ellenberg and Rifkin's Diabetes Mellitus (5th edn) (Porte, D., Jr and...

G.M. Reaven

Role of insulin resistance in human disease

Diabetes

(1988)

J.H. Warram

Slow glucose removal rate and hyperinsulinemia precede the development of type 2 diabetes in the offspring of diabetic parents

Ann. Int. Med.

(1990)

Kruszynska, Y. et al. Effects of troglitazone on plasminogen activator inhibitor-1 (PAI-1) concentration in blood in...

A.R. Saltiel et al.

Thiazolidinediones in the treatment of insulin resistance and type 2 diabetes

Diabetes

(1996)

T. Fujiwara

Characterization of new oral antidiabetic agent CS-045: studies in KK and ob/ob mice and Zucker fatty rats

Diabetes

(1988)

M.K. Lee

Metabolic effects of troglitazone on fructose-induced insulin resistance in the rat

Diabetes

(1994)

P.D.G. Miles

TNF-α-induced insulin resistance in vivo and its prevention by troglitazone

Diabetes

(1997)

P.G. Miles

Troglitazone prevents hyperglycemia-induced but not glucosamin-induced insulin resistance

Diabetes

(1998)

S. Suter

Metabolic effects of a new oral hypoglycemic agent, CS-045, in non-insulin dependent diabetic subjects

Diabetes Care

(1992)

Y. Iwamoto

Effects of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM

Diabetes Care

(1991)

Cited by (278)

Full-length nuclear receptor allosteric regulation
2023, Journal of Lipid Research
Nuclear receptors are a superfamily of transcription factors regulated by a wide range of lipids that include phospholipids, fatty acids, heme-based metabolites, and cholesterol-based steroids. Encoded as classic two-domain modular transcription factors, nuclear receptors possess a DNA-binding domain (DBD) and a lipid ligand-binding domain (LBD) containing a transcriptional activation function. Decades of structural studies on the isolated LBDs of nuclear receptors established that lipid–ligand binding allosterically regulates the conformation of the LBD, regulating transcriptional coregulator recruitment and thus nuclear receptor function. These structural studies have aided the development of several FDA-approved drugs, highlighting the importance of understanding the structure-function relationships between lipids and nuclear receptors. However, there are few published descriptions of full-length nuclear receptor structure and even fewer descriptions of how lipids might allosterically regulate full-length structure. Here, we examine multidomain interactions based on the published full-length nuclear receptor structures, evaluating the potential of interdomain interfaces within these nuclear receptors to act as inducible sites of allosteric regulation by lipids.
Kutkin, iridoid glycosides enriched fraction of Picrorrhiza kurroa promotes insulin sensitivity and enhances glucose uptake by activating PI3K/Akt signaling in 3T3-L1 adipocytes
2022, Phytomedicine
Citation Excerpt :
PPARγ and CEBPα are the key transcriptional factor and therapeutic targets used in the treatments of metabolic disorders like obesity, heart failure, and hepatic steatosis. These studies provide ample evidences that PPARγ activators upregulate lipid metabolism and alleviate insulin resistance by enhancing insulin sensitivity, thus stimulating glucose uptake in peripheral tissue (Olefsky and Saltiel, 2000). Nowadays plant based therapies are in trends to treat numerous health disorders such as jaundice, fever, liver ailments etc.
Therapeutic failure and drug resistance are common sequelae to insulin resistance associated with type 2 diabetes mellitus (T2DM). Consequently, there is an unmet need of alternative strategies to overcome insulin resistance associated complications.
To demonstrate whether Kutkin (KT), iridoid glycoside enriched fraction of Picrorhiza kurroa extract (PKE) has potential to increase the insulin sensitivity vis à vis glucose uptake in differentiated adipocytes.
Molecular interaction of KT phytoconstituents, picroside-I (P-I) & picroside- II (P-II) with peroxisome proliferator-activated receptor gamma (PPARγ), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were analyzed in silico. Cellular viability and adipogenesis were determined by following 3-(4, 5-Dimethylthiazol-2-Yl)-2, 5-Diphenyltetrazolium bromide (MTT) assay and Oil Red-O staining. Further, ELISA kit based triglycerides and diacylglycerol-O-Acyltransferase-1 (DGAT1) were assessed in differentiated adipocytes. ELISA based determination were performed to check the levels of adiponectin and tumor necrosis factor alpha (TNF-α). However, Flow cytometry and immunofluorescence based assays were employed to measure the glucose uptake and glucose transporter 4 (glut4) expression in differentiated adipocytes, respectively. Further to explore the targeted signaling axis, mRNA expression levels of PPARγ, CCAAT/enhancer binding protein α (CEBPα), and glut4 were determined using qRT-PCR and insulin receptor substrate-1 (IRS-1), Insulin receptor substrate-2 (IRS-2), PI3K/Akt, AS160, glut4 followed by protein validation using immunoblotting in differentiated adipocytes.
In silico analysis revealed the binding affinities of major constituents of KT (P-I& P-II) with PPARγ/PI3K/Akt. The enhanced intracellular accumulation of triglycerides with concomitant activation of PPARγ and C/EBPα in KT treated differentiated adipocytes indicates augmentation of adipogenesis in a concentration-dependent manner. Additionally, at cellular level, KT upregulated the expression of DAGT1, and decreases fatty acid synthase (FAS), and lipoprotein lipase (LPL), further affirmed improvement in lipid milieu. It was also observed that KT upregulated the levels of adiponectin and reduced TNFα expression, thus improving the secretory functions of adipocytes along with enhanced insulin sensitivity. Furthermore, KT significantly promoted insulin mediated glucose uptake by increasing glut4 translocation to the membrane via PI3/Akt signaling cascade. The results were further validated using PI3K specific inhibitor, wortmannin and findings revealed that KT treatment significantly enhanced the expression and activation of p-PI3K/PI3K and p-Akt/Akt even in case of treatment with PI3K inhibitor wortmannin alone and co-treatment with KT in differentiated adipocytes and affirmed that KT as activator of PI3K/Akt axis in the presence of inhibitor as well.
Collectively, KT fraction of PKE showed anti-diabetic effects by enhancing glucose uptake in differentiated adipocytes via activation of PI3K/Akt signaling cascade. Therefore, KT may be used as a promising novel natural therapeutic agent for managing T2DMand to the best of our knowledge, this is the first report, showing the efficacy and potential molecular mechanism of KT in enhancing insulin sensitivity and glucose uptake in differentiated adipocytes.
Structural characterization and hypoglycemic effect of green alga Ulva lactuca oligosaccharide by regulating microRNAs in Caenorhabditis elegans
2020, Algal Research
The novel oligosaccharides from Ulva lactuca were obtained and characterized by nuclear magnetic resonance, Fourier-transformed infrared and liquid chromatography-quadrupole time-of-flight tandem mass spectrometry. U. lactuca oligosaccharides were composed by β-D-Glcp-(1 → 4)-α-L-Rhap (2SO₃⁻)-(1 → 2)-β-D-GlcpA-(1 → 6)-β-D-Galp-(1 → 5)-α-L-Arap-(1→ and α-L-Rhap-(1 → 2)-α-L-Rhap(3SO₃⁻)-(1 → 6)-β-D-Glcp-(1 → 2)-β-D-Xylp-(1→ with a branch of β-D-GlcpA that connected in C4 of β-D-Glcp, respectively. After U. lactuca oligosaccharide treatment, the mean lifespan, glucose levels, and insulin resistance were improved in Caenorhabditis elegans. It has significantly enhanced the total superoxide dismutase levels and ameliorated the intracellular reactive oxygen species accumulation. U. lactuca oligosaccharides could prevent the DNA and mitochondrial damage induced by high glucose. The gene expression levels of abnormal dauer formation 16 (DAF-16), protein kinase B (AKT-1), protein skinhead-1 (SKN-1), adenosine monophosphate-activated kinase 2 (AAK-2), DAF-15, and superoxide dismutase 3 (SOD-3) were up-regulated though inhibiting the expressions of miR-48-5p, miR-67-3p, miR-124-3p, and miR-85-3p, while the gene expression levels of DAF-2, LEThal 363 (LET-363), and signal element on X 1 (SEX-1) were also up-regulated. U. lactuca oligosaccharides might be applied in the functional foods to improve glucose metabolism disorders and antioxidant systems in vivo mediated by modulation of microRNAs.
Schwann cells apoptosis is induced by high glucose in diabetic peripheral neuropathy
2020, Life Sciences
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus that affects approximately half of patients with diabetes. Current treatment regimens cannot treat DPN effectively. Schwann cells (SCs) are very sensitive to glucose concentration and insulin, and closely associated with the occurrence and development of type 1 diabetic mellitus (T1DM) and DPN. Apoptosis of SCs is induced by hyperglycemia and is involved in the pathogenesis of DPN. This review considers the pathological processes of SCs apoptosis under high glucose, which include the following: oxidative stress, inflammatory reactions, endoplasmic reticulum stress, autophagy, nitrification and signaling pathways (PI3K/AKT, ERK, PERK/Nrf2, and Wnt/β-catenin). The clarification of mechanisms underlying SCs apoptosis induced by high glucose will help us to understand and identify more effective strategies for the treatment of T1DM DPN.
Role of acupuncture in the treatment of insulin resistance: A systematic review and meta-analysis
2019, Complementary Therapies in Clinical Practice
and purpose Acupuncture has gained increasing attention in the treatment of insulin resistance (IR). This study systematically reviews the efficacy of acupuncture on clinical IR outcomes.
Cochrane Central Register of Controlled Trials, Embase, Medline (via OVID), China National Knowledge Infrastructure (CNKI), Wan Fang and China Science and Technology Journal Database (VIP) were searched to collect randomized controlled trials (RCTs) of patients with IR treated by acupuncture. Meta-analysis was performed by RevMan 5.3.
With acupuncture, the homeostasis model assessment of insulin resistance (homa-IR) significantly decreased (mean difference (MD) = -1.04, 95% confidence interval (CI) −1.37 to −0.71; P < 0.00001), as did fasting blood glucose (FBG) (MD = −0.56, 95% CI -0.88 to −0.25; P = 0.0005), 2 h postprandial blood glucose (2hPG) (MD = −0.91, 95% CI -1.62 to −0.20; P = 0.01), and fasting insulin (FINS) (MD = −3.23, 95% CI -4.14 to −2; P < 0.00001). Meanwhile, the insulin sensitivity index (ISI) (MD = 0.36, 95% CI 0.18 to 0.53; P < 0.0001) increased, and fewer adverse events occurred.
Acupuncture may improve homa-IR, ISI, FBG, 2hPG and FINS with fewer adverse events than other treatments, making it a viable treatment for IR.
Egg white hydrolysate enhances insulin sensitivity in high-fat diet-induced insulin-resistant rats via Akt activation
2019, British Journal of Nutrition

View all citing articles on Scopus

View full text

Trends in Endocrinology & Metabolism

ReviewPPARγ and the Treatment of Insulin Resistance

Abstract

Section snippets

Thiazolidinediones Improve Insulin Sensitivity

Thiazolidinediones Activate the Nuclear Receptor PPARγ

Lessons Learned from PPARγ Knockouts and Mutants

Cell

Metabolism

Metabolism

J. Biol. Chem.

Cell

15-DeoxyΔ12., 14.-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ

Cell

J. Biol. Chem.

Metabolism

Mol. Cell

Mol. Cell

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Cell

Trends Endocrinol. Metab.

Role of insulin resistance in human disease

Diabetes

Slow glucose removal rate and hyperinsulinemia precede the development of type 2 diabetes in the offspring of diabetic parents

Ann. Int. Med.

Thiazolidinediones in the treatment of insulin resistance and type 2 diabetes

Diabetes

Characterization of new oral antidiabetic agent CS-045: studies in KK and ob/ob mice and Zucker fatty rats

Diabetes

Metabolic effects of troglitazone on fructose-induced insulin resistance in the rat

Diabetes

TNF-α-induced insulin resistance in vivo and its prevention by troglitazone

Diabetes

Troglitazone prevents hyperglycemia-induced but not glucosamin-induced insulin resistance

Diabetes

Metabolic effects of a new oral hypoglycemic agent, CS-045, in non-insulin dependent diabetic subjects

Diabetes Care

Effects of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM

Diabetes Care

Review
PPARγ and the Treatment of Insulin Resistance

15-DeoxyΔ 12., 14.-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ