Type 2 diabetes and oral antihyperglycemic drugs.

Type II diabetes is a heterogeneous disease where environment and genetics are important factors for the expression of the disease. The high cost for treating complications of diabetes is a burden for public health systems and governments worldwide. Type II diabetes has been causing debilitation worldwide for many decades, and a single drug that safely treats the disease has yet to be discovered. Sulfonylureas, biguanides, alpha-glucosidase, meglitinides, DPP-4 inhibitors and thiazolidinediones are among the classes of oral hypoglycemic drugs available to treat Type II diabetes, but concerns exist regarding safety and efficacy of these drugs. In this article we present the pros and cons of the six classes and discuss some of the latest advances towards the development of new drugs for the treatment of Type II diabetes.

Endothelial function and urine albumin levels among asymptomatic Mexican-Americans and non-Hispanic whites.

BACKGROUND: Mexican-Americans (MA) exhibit increases in various cardiovascular disease (CVD) risk factors compared to non-Hispanic Whites (NHW), yet are reported to have lower CVD mortality rates. Our aim was to help explain this apparent paradox by evaluating endothelial function and urine albumin levels in MA and NHW. METHODS: One hundred-five MA and 100 NHW adults were studied by brachial artery flow-mediated dilatation (FMD), blood and urine tests. Participants were studied by ultrasound-determined brachial artery flow-mediated dilatation (FMD), blood and urine tests, at a single visit. RESULTS: Despite higher BMI and triglycerides in MA, MA demonstrated higher FMD than did NHW (9.1 +/- 7.3% vs. 7.1 +/- 6.3%, p < 0.04). Among MA, urinary albumin was consistently lower in participants with FMD >or= 7% FMD versus < 7% FMD (p < 0.006). In multivariate analyses in MA men, urinary albumin was inversely related to FMD (r = -0.26, p < 0.05), as were BMI and systolic blood pressure. In MA women, urinary albumin:creatinine ratio was an independent inverse predictor of FMD (p < 0.05 ). CONCLUSION: To our knowledge, this is the first study to analyze, in asymptomatic adults, the relation of MA and NHW ethnicity to FMD and urine albumin levels. The findings confirm ethnic differences in these important subclinical CVD measures.

Treating the metabolic syndrome using angiotensin receptor antagonists that selectively modulate peroxisome proliferator-activated receptor-gamma.

The metabolic syndrome, defined as a cluster of visceral obesity, insulin resistance, dyslipidemia and elevated blood pressure, is associated with pro-thrombotic, pro-atherogenic and inflammatory risk factors that predispose to cardiovascular disease. Although activators of the peroxisome proliferator-activated receptors (PPARalpha,gamma,delta) in various combinations are under development for treating the metabolic syndrome, they are hampered by adverse effects related to increased adipogenesis, weight gain, fluid overload and carcinogenesis. The recent discovery that telmisartan and irbesartan, antihypertensive angiotensin II type 1 receptor (AT1-R) blockers (ARBs), were uniquely capable of activating PPARgamma, has provided a novel approach to addressing the multifactorial components of the metabolic syndrome. Both drugs have established favorable safety profiles and can activate PPARgamma at concentrations potentially achievable at therapeutic doses. Emerging studies have revealed that both these drugs have beneficial metabolic profiles. This information provides a strategic rationale and pharmacological platform for the development of novel dual ARB/PPARgamma agonists to target the metabolic syndrome and its cardiovascular sequelae, for which therapy is presently insufficient or non-existent. Beneficial effects of these agents include increased energy expenditure, improved lipid profile, increased insulin sensitivity, blood pressure reduction, and amelioration of the associated pro-inflammatory and pro-atherogenic risk profiles. The potential benefit for treatment of the metabolic syndrome, cardiovascular protection, and prevention of related end-organ complications could be of immense clinical value.

Design and synthesis of the first generation of dithiolane thiazolidinedione- and phenylacetic acid-based PPARgamma agonists.

A series of novel derivatives of potent antioxidant vitamin, alpha-lipoic acid, and related analogues were designed, synthesized, and evaluated for their PPARgamma agonist activities. Compounds 9a and the water soluble analogue11e were found to be potent PPARgamma agonists. Compound 9a appeared to have a significant role in improving insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and inflammatory skin diseases.

Dual Peroxisome Proliferator-Activated Receptor-alpha/gamma Agonists : In the Treatment of Type 2 Diabetes Mellitus and the Metabolic Syndrome.

The metabolic syndrome consists of a combination of cardiovascular risk factors that include hyperglycemia with or without type 2 diabetes mellitus, visceral obesity, elevated blood pressure, and atherogenic dyslipidemia. These interrelated disorders and their associated lipotoxicity, oxidative stress, and inflammatory state predispose to a constellation of cardiovascular conditions leading to high risk of heart attack, stroke, renal failure, blindness, and lower extremity amputation. Visceral obesity, a prime risk factor for type 2 diabetes and a major component of the metabolic syndrome, potentiates atherogenesis, atherosclerosis, organ lipotoxicity, and oxidative tissue damage.Peroxisome proliferator-activated receptors (PPARs) are relatively recently discovered nuclear transcription factors that are modulated by dietary fatty acids, including the essential polyunsaturated fatty acids, arachidonic acid and its metabolites, and are essential to the control of energy metabolism. Of the three PPAR isoforms (alpha, gamma, and delta), synthetic pharmaceutical ligands that activate PPARalpha (the antidyslipidemic fibric acid derivatives ['fibrates']) and PPARgamma (the antidiabetic thiazolidinediones) have been studied extensively. Recently developed dual PPARalpha/gamma agonists may combine the therapeutic effects of these drugs, creating the expectation of greater efficacy, and perhaps other advantages in the treatment of type 2 diabetes and the metabolic syndrome. However, thiazolidinediones are hampered by adverse effects related to increased weight gain and fluid overload. It remains to be seen whether the dual PPARalpha/gamma agonists currently under development have similar limitations. Nevertheless, existing clinical data imply that the combined effects of thiazolidinediones and fibrates are likely to be emulated by dual PPARalpha/gamma agonists, providing superior efficacy to these classes for the treatment of type 2 diabetes, the metabolic syndrome, and their cardiovascular and other end-organ complications.

Improvement in psoriasis with rosiglitazone in a diabetic and a nondiabetic patient.

The authors conducted a prospective, open-label, pilot trial of the effects of the antidiabetic thiazolidinedione (TZD) rosiglitazone in two patients with moderate to severe plaque psoriasis. Case 1: A lean, euglycemic 43-year-old nondiabetic man with a 2-year history of plaque psoriasis presented with lesions involving 10% of his body surface (Figures 1A, 1B, 1C). He had no other chronic or acute medical problems. He had previously been managed sporadically with topical triamcinolone acetonide, an intermediate-strength glucocorticoid, and was off antipsoriatic medication for 5 months. He was started on rosiglitazone p.o., 8 mg q.d. After 10 weeks on rosiglitazone, the lesions developed increased erythema, spreading, and shedding of scale (Figures 2A, 2B, 2C). After an additional 26 weeks, the lesions had largely disappeared (Figures 3A, 3B, 3C). The patient remained euglycemic throughout the study. His liver function enzymes (alanine transferase [ALT] and aspartate transferase [AST]) remained normal throughout the study: ALT, 23 IU/L; AST, 47 IU/L before treatment; ALT, 25 IU/L; AST, 33 IU/L after treatment. There were no adverse events. Case 2: An overweight 68-year-old woman (body mass index, 29 kg/m2; with a 12-year history of type 2 diabetes and 5-year history of psoriasis presented with generalized plaque psoriasis over 20% of her body, including two large, thick, silvery plaques with the texture of leather over the lower part of the back (Figure 4A). She was given rosiglitazone p.o., 4 mg b.i.d. for 24 weeks, which resulted in significant improvement in psoriasis (Figure 4B). After an additional 26 weeks on rosiglitazone, the plaques had cleared on her back (Figure 4C) and over her entire body, including scalp, ears, and posterior forearms (not shown). Her glycemic control improved (hemoglobin A1c decreased from 7.7% to 7.2%) and liver function remained normal throughout the study (ALT, 24 IU/L; AST, 14 IU/L before treatment; and ALT, 26 IU/L; AST, 15 IU/L after treatment). There were no adverse events.

Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes.

This study was undertaken to evaluate the effects of thiazolidinediones (TZD) on keratinocyte proliferation, motility, and matrix metalloproteinase (MMP) production. Rosiglitazone (a potent TZD) inhibited both proliferation and motility as well as elaboration of MMP-1 and MMP-9. Inhibition was obtained with keratinocytes in monolayer culture and human skin in organ culture. There were significant concentration-response differences in sensitivity of the three keratinocyte responses to treatment with rosiglitazone. In contrast to keratinocytes, dermal fibroblasts were resistant to the effects of rosiglitazone. Treatment of keratinocytes with rosiglitazone did not suppress epidermal growth factor receptor autophosphorylation, but inhibited signaling through the extracellular regulated kinase mitogen-activated protein kinase pathway without a concomitant effect on pathways that lead to c-jun activation. Pioglitazone, another TZD, also suppressed keratinocyte proliferation, although it was less effective than rosiglitazone. An experimental TZD (BP-1107) inhibited keratinocyte proliferation at a much lower concentration than either rosiglitazone or pioglitazone. Because enhanced keratinocyte motility and increased MMP production as well as increased keratinocyte proliferation are thought to contribute to the phenotype of psoriatic lesional skin, we propose that interference with these keratinocyte responses contributes to the previously reported antipsoriatic activity of TZD.

Effect of pioglitazone treatment in a patient with secondary multiple sclerosis.

BACKGROUND: Ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinical studies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARgamma agonist used to treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). We therefore tested the safety and therapeutic potential of oral pioglitazone in a patient with secondary MS. CASE PRESENTATION: The rationale and risks of taking pioglitazone were carefully explained to the patient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increased by 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed by measurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms were assessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks the patient exhibited increased appetite, cognition and attention span. After 12 months treatment, body weight increased from 27.3 to 35.9 kg (32%) and maintained throughout the duration of the study. Upper extremity strength and coordination improved, and increased fine coordination was noted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, the patient demonstrated improvement in orientation, short-term memory, and attention span. MRIs carried out after 10 and 18 months of treatment showed no perceptible change in overall brain atrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, the patient continues to be clinically stable, with no adverse events. CONCLUSIONS: In a patient with secondary progressive MS, daily treatment with 45 mg p.o. pioglitazone for 3 years induced apparent clinical improvement without adverse events. Pioglitazone should therefore be considered for further testing of therapeutic potential in MS patients.

Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis?

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-gamma may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-gamma agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-gamma-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-gamma-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.

Alpha-Lipoic acid-based PPARgamma agonists for treating inflammatory skin diseases.

Novel thiazolidinedione derivatives of the potent antioxidant, alpha-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-[4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy]ethyl)-5-(1,2-dithiolan-3-yl)- N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARgamma) (EC(50) range 15-101 nM) and modest activators of PPARalpha (EC(50) 5 microM). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its water-soluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.

Relation of metabolic syndrome components to left ventricular mass in Mexican Americans versus non-Hispanic whites.

Metabolic syndrome (MetS) is associated with increased risk for cardiovascular disease (CVD). Mexican Americans (MA) exhibit increases in CVD risk factors compared with non-Hispanic whites (NHW), but few data exist comparing the relation of MetS to subclinical CVD, for example, left ventricular (LV) mass. Asymptomatic subjects (104 MA and 101 NHW, 52.2% female, aged 48 ± 12 years) were studied by echocardiography (echo) and by blood and urine tests. Metabolic syndrome was defined based on the American Heart Association/National Heart, Lung, and Blood Institute definition. Echo LV mass was compared with the presence or absence of MetS and with the number of MetS components. Multiple linear regression also examined the association of MetS with LV mass adjusted for non-MetS risk factors. Left ventricular mass was lower in MA (145.5 ± 43.9 g) compared with NHW (160.2 ± 49.9 g) (P < .05), although this difference was attenuated after adjusting for MetS and other risk factors. Left ventricular mass was higher in those with vs without MetS in both MA and NHW men and women (P < .05 to P < .01). There was a significant (P < .001) graded increase in echo LV mass with increasing number of MetS components both in MA (108.3 to 153.8 g) and NHW (144.3 to 215.1 g). In multiple regression analysis, male sex and MetS remained independently associated (P < .0001) with LV mass; however, body mass index explained much of this association, indicating the strong association of obesity with LV mass. Mean LV mass in both MA and NHW adults was higher in those with vs without MetS and with increasing number of MetS components, with body mass index the principal component of MetS associated with LV mass. The prognostic significance of LV mass in persons with MetS requires further study.

Do differences in subclinical cardiovascular disease in mexican americans versus European americans help explain the Hispanic paradox?

Mexican Americans have exhibited increases in various coronary heart disease risk factors compared to European Americans but have also had reportedly lower coronary heart disease mortality from vital statistics studies. We hypothesized this apparent paradox might relate to lower levels of subclinical disease in Mexican Americans. A total of 105 adult Mexican Americans (42 men and 63 women, age 46 +/- 14 years) and 100 European Americans (59 men and 41 women, age 50 +/- 11 years) were studied using blood tests, transthoracic echocardiography, and computed tomography coronary artery calcium (CAC) scans. Despite a greater body mass index and triglycerides in Mexican Americans (p <0.001), the Mexican Americans demonstrated less subclinical disease than did the European Americans (14.4% vs 25.7% with CAC scores >0, p <0.05 and mean left ventricular mass [LV] of 146 vs 160 g, p <0.05). Also, the LV mass was significantly greater in Mexican Americans with than in those without CAC (mean 172 vs 140 g, p <0.05). On logistic regression analysis, age and diastolic blood pressure were associated with an increased likelihood of CAC (p <0.001 and p <0.01, respectively), and Mexican-American ethnicity was associated with a decreased likelihood of CAC (odds ratio 0.33, 95% confidence interval 0.12 to 0.87, p <0.05). On multiple regression analysis, male gender, body surface area, and systolic blood pressure were independently associated with an increased LV mass (all p <0.001). The body mass index was less strongly related to the LV mass than was the body surface area and was not related to CAC. In conclusion, Mexican-American ethnicity is associated with both a lower LV mass and a lower prevalence of CAC, although the differences in LV mass did not remain after adjustment for other factors. Although systolic blood pressure, body surface area, and male gender were most strongly associated with the LV mass, age and diastolic blood pressure, in addition to Mexican-American ethnicity, were the most important indicators of CAC.

Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome.

In addition to lowering blood pressure, telmisartan, an angiotensin (AT(1)) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPAR gamma active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPAR gamma agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT(1) receptor with a K(i) = 13.4 nM, but it was devoid of PPAR gamma activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPAR gamma transactivation assay (69% activation) with no affinity for the AT(1) receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARgamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 microM).

PPARgamma Agonists: Potential as Therapeutics for Neovascular Retinopathies.

The angiogenic, neovascular proliferative retinopathies, proliferative diabetic retinopathy (PDR), and age-dependent macular degeneration (AMD) complicated by choroidal neovascularization (CNV), also termed exudative or "wet" AMD, are common causes of blindness. The antidiabetic thiazolidinediones (TZDs), rosiglitazone, and troglitazone are PPARgamma agonists with demonstrable antiproliferative, and anti-inflammatory effects, in vivo, were shown to ameliorate PDR and CNV in rodent models, implying the potential efficacy of TZDs for treating proliferative retinopathies in humans. Activation of the angiotensin II type 1 receptor (AT1-R) propagates proinflammatory and proliferative pathogenic determinants underlying PDR and CNV. The antihypertensive dual AT1-R blocker (ARB), telmisartan, recently was shown to activate PPARgamma and improve glucose and lipid metabolism and to clinically improve PDR and CNV in rodent models. Therefore, the TZDs and telmisartan, clinically approved antidiabetic and antihypertensive drugs, respectively, may be efficacious for treating and attenuating PDR and CNV humans. Clinical trials are needed to test these possibilities.

Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome.

In animal experiments, the potent antioxidant and free radical scavenger alpha-lipoic acid has been shown to cause weight loss, ameliorate insulin resistance and atherogenic dyslipidemia, as well as to lower blood pressure, all of these being components of the metabolic syndrome. Recent investigations on its mechanisms of action indicate that alpha-lipoic acid can affect central and peripheral modulation of 5'-AMP-activated protein kinase, activate PPAR-alpha and PPAR-gamma, modulate PPAR-regulated genes and upregulate the expression of PPAR-gamma mRNA and protein in cardiac tissue and aorta smooth muscle. To a large extent, these findings can explain the observed beneficial metabolic effects of alpha-lipoic acid, supporting its potential application as a therapeutic agent for the treatment of the metabolic syndrome.

Thiazolidinediones: potential as therapeutics for psoriasis and perhaps other hyperproliferative skin disease.

The thiazolidinediones constitute a family of synthetic compounds that act as high-affinity ligands for persoxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor family. Although originally developed to facilitate glucose control in patients with Type 2 diabetes, a number of studies showed that these agents effectively inhibited epithelial cell proliferation and tissue inflammation. Many of the initial cell growth inhibition studies were conducted with malignant epithelial cells from various sites; however, in addition to malignant epithelial cells, other studies showed that rapidly proliferating epidermal keratinoctyes in culture were also sensitive to the growth-inhibiting action of these moieties. Additional studies subsequently demonstrated that some patients with plaque psoriasis responded to treatment with one or another member of the thiazolidinedione family. Due to the potential therapeutic benefit of these compounds in diseases such as psoriasis, studies have been conducted to elucidate mechanisms by which growth inhibition is achieved. Interference with a number of growth-influencing signalling pathways has been demonstrated. Of interest, some of the growth-inhibiting effects are seen under conditions in which PPAR-gamma activation may not be responsible for the activity. Based on therapeutic potential, additional ongoing studies are aimed at developing novel thiazolidinediones that may have better efficacy than the currently available agents. Other studies are aimed at identifying optimal ways to use these agents in the treatment of hyperplastic skin diseases such as psoriasis.

BP-1107 [{2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide]: a novel synthetic thiazolidinedione that inhibits epidermal hyperplasia in psoriatic skin-severe-combined immunodeficient mouse transplants after topical application.

Recent studies have demonstrated that orally administered thiazolidinedione ligands of the peroxisome proliferator-activated receptor-gamma can ameliorate clinical features of psoriasis in humans. Thiazolidinediones also inhibit the proliferation of psoriatic keratinocytes in monolayer and organ culture, and at least one of these agents (troglitazone) inhibits epidermal hyperplasia of human psoriatic skin transplanted to severe-combined immunodeficient (SCID) mice. In the present study, we show that a novel, synthetic, thiazoladinedione derivative, BP-1107 ({2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide), is capable of inhibiting psoriatic hyperplasia in the SCID mouse transplant model after topical application. Like other thiazolidinediones, BP-1107 inhibits proliferation of rapidly growing keratinocytes in monolayer culture, but compared with these agents, the effective dose of BP-1107 needed to suppress keratinocyte proliferation is much lower. Concentrations of BP-1107 that effectively inhibit keratinocyte function have no detrimental effect on dermal fibroblasts. These data suggest that effective topical antipsoriatic therapy may be provided with this agent.

Inhibition of corneal neovascularization by a peroxisome proliferator-activated receptor-gamma ligand.

PURPOSE: To determine the efficacy of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in inhibiting corneal neovascularization. METHODS: Twenty-six adult male Sprague-Dawley rats were randomly divided into three groups. Each group received intrastromal polymer micropellets containing one of the following: Group 1, no active ingredient (n=10); Group 2, vascular endothelial growth factor (VEGF) (n=7); Group 3, VEGF and pioglitazone (n=9). Neovascularization was evaluated 7 days after pellet implantation. After systemic India ink injection, digital photographs of the eyes were taken. The area and density of neovascularization were measured using imaging software. RESULTS: Mean area of neovascularization was 0.43+/-0.18 mm2 for Group 1, 2.87+/-0.48 mm2 for Group 2 and 2.10+/-0.22 mm2 for Group 3. Statistical analysis showed significant differences between Groups 1 and 2 and Groups 1 and 3. There was no significant difference between Groups 2 and 3. Mean density of neovascularization was 2.16+/-0.66 for Group 1, 27.14+/-2.93 for Group 2 and 12.02+/-2.24 for Group 3. All comparisons between groups were statistically significant (P<0.01). CONCLUSIONS: Pioglitazone is effective in decreasing the density of angiogenesis in a VEGF-induced neovascular rat cornea model. There is possibility of even greater effect with higher doses of the drug. Pioglitazone is a promising drug for the treatment of ocular neovascularization.

Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity.

The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPARgamma; influence the expression of PPARgamma target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPARgamma when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPARgamma have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations.