Amelioration by KRP-297, a new thiazolidinedione, of impaired glucose uptake in skeletal muscle from obese insulin-resistant animals

Murakami, Koji; Tsunoda, Masaki; Ide, Tomohiro; Ohashi, Mitsuo; Mochizuki, Toru

doi:10.1016/s0026-0495(99)90158-0

Cited by 17 publications

(10 citation statements)

References 18 publications

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“…We studied db/db mice on a C57BL/6J genetic background and characterized mitochondrial performance in key tissues for insulin action, including glycolytic and oxidative skeletal muscle and liver. Obese diabetic db/db mice are characterized by insulin resistance in glycolytic (22,43,52) and oxidative (6,19,35) skeletal muscle and liver (19,28,53). We provide evidence for tissue-specific changes in mitochondrial function in db/db mice, indicating that mitochondrial adaptations to an excessive nutrient supply and inactivity are influenced by the metabolic plasticity and function of each organ or cell type.…”

mentioning

confidence: 75%

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Holmström

Iglesias‐Gutiérrez

Zierath

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

118

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The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (ϩ/?) and obese diabetic (db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissuespecific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1␣ and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction. mitochondrial dysfunction; mitochondrial biogenesis; oxidative capacity; energy metabolism OBESITY IS A MAJOR RISK FACTOR for development of insulin resistance and type 2 diabetes mellitus (T2DM) (49). Insulin resistance in skeletal muscle and liver, coupled with ␤-cell failure, represents underlying defects in T2DM. Thus, there is a growing appreciation that defects in insulin action in multiple tissues contribute to whole body insulin resistance, disturbances in energy balance, and T2DM.Mitochondrial dysfunction has been implicated in the development of insulin resistance and the pathogenesis of T2DM (32,37,38). The vast majority of mitochondrial proteins, as well as factors controlling the expression and proliferation of the mitochondrial genome, are encoded in the nucleus. Studies of rodent tissues, including analysis of mitochondrial DNA copy number, cytochrome c oxidase activity, and mitochondrial mass in liver, cardiac muscle, and oxidative and glycolytic skeletal muscle (8,9,14,50,51) provide evidence for marked tissue-specific differences in mitochondrial properties, concurrent with varying metabolic characteristics and demands unique to each specific tissue. Furthermore, quantitative mass spectrometry and 2-D gel electrophoresis of the mitochondrial proteome reveal tissue-specific mitochondrial protein programs (13,24,34). Mitochondria are finely tuned to meet the specific needs of the tissue as well as the environmental or pathophysiological state that the specific tissue encounters (1...

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confidence: 75%

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Holmström

Iglesias‐Gutiérrez

Zierath

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

118

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“…We speculate that this is due to the effects of a dual agonist that enhances lipid catabolism and reduces fat mass by PPAR␣ activation, as previously suggested (2, 5a). We consider that KRP-297 ameliorated obesity most, so that pancreatic insulin content of the KRP-297-treated group was almost the same as that in normal mice (26), and the islets of the KRP-297-treated group were not Values are means Ϯ SE. GSIS, glucose-stimulated insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…Some literature has reported that PPAR␣ agonists also ameliorated insulin resistance (6,7,14,19,24,28,36), but the effect on insulin secretion is unclear. Dual agonists of PPAR␥ and -␣, 25,26) and , have been developed, and their utility for diabetes and/or metabolic syndrome has been suggested. However, studies of combination therapy with a PPAR␥ agonist and a PPAR␣ agonist are rare (2, 21), and their effect on insulin secretion has not been reported.…”

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confidence: 99%

Combination therapy with PPARγ and PPARα agonists increases glucose-stimulated insulin secretion in db/dbmice

Yajima

Hara²,

Fujita

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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. Combination therapy with PPAR␥ and PPAR␣ agonists increases glucose-stimulated insulin secretion in db/db mice. Am J Physiol Endocrinol Metab 284: E966-E971, 2003; 10.1152/ ajpendo.00149.2002.-Although peroxisome proliferator-activated receptor (PPAR)␥ agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPAR␥ agonist, pioglitazone, and a PPAR␣ agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone ϩ bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPAR␥ agonist-treated groups. Also, PPAR␥ agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPAR␥ and -␣ agonists. We conclude that combination therapy with PPAR␥ and PPAR␣ agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.peroxisome proliferator-activated receptor; glucose-stimulated insulin secretion; glucolipotoxicity; insulin resistance; type 2 diabetes with obesity PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)␥ agonists have been used for the treatment of type 2 diabetic patients, especially those with obesity, all over the world. They ameliorate insulin resistance of peripheral tissues, such as skeletal muscle, liver, and adipocytes, by various suggested mechanisms. Although some literature has suggested effects of PPAR␥ agonists on the pancreas (13, 32), only a few studies have investigated this issue (23,29,30). Because the expression of PPAR␥ is confirmed not only in rodent (1) but also in human islets (5), an effect of PPAR␥ agonists on the pancreas has been suggested.On the other hand, fibrates are PPAR␣ agonists and have been used for patients with dyslipidemia. Some literature has reported that PPAR␣ agonists also ameliorated insulin resistance (6,7,14,19,24,28,36), but the effect on insulin secretion is unclear. Dual agonists of PPAR␥ and -␣, 25,26) and , have been developed, and their utility for diabetes and/or metabolic syndrome has been suggested. However, studies of combination therapy with a PPAR␥ agonist and a PPAR␣ agonist are rare (2, 21), and their effect on insulin secretion has not been reported.We hypothesized that combination therapy with PPAR␥ and -␣ agonists would be useful for reducing lipotoxicity (10, 20, 37) in type 2 diabetes with obesity by augmenting the lipid-lowering effects. We used the PPAR␥ agonist pioglitazone (PIO), combination therapy with the PPAR␥ agonist PIO and the PPAR␣ agonist bezabibrate (P...

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“…MCC-555 (24) has low binding potency, but is a highly effective PPARγ activator [102][103][104][105]. While some have entered preclinical development, such as the new preclinical (25) [108], T-174 (26) [109] and KRP-297 (27) which has an amide bond in the bridge moiety [110]. [114].…”

Section: Thiazolidinediones (Tzds)mentioning

confidence: 99%

Current Therapies and Emerging Targets for the Treatment of Diabetes

Wagman¹,

Nuss²

2001

CPD

155

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Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the world's population. The number of diabetics is increasing by 4-5% per year with an estimated 40-45% of individual's over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impaired glucose tolerance resulting in the prevalence of beta-cell dysfunction and macrovascular complications. In addition to increased medical vigilance, diabetes is being combatted through aggressive treatment directed at lowering circulating blood glucose and inhibiting postprandial hyperglycemic spikes. Current strategies to treat diabetes include reducing insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of small molecules are being investigated which exhibit improved efficacy and safety profiles. Promising biological targets are also emerging such as (1) insulin sensitizers including protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), (2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by means of beta 3-adrenoceptor agonists. Also important are alternative routes of glucose disposal such as Na+-glucose cotransporter (SGLT) inhibitors, combination therapies, and the treatment of diabetic complications (eg. retinopathy, nephropathy, and neuropathy). With may new opportunities for drug discovery, the prospects are excellent for development of innovative therapies to effectively manage diabetes and prevent its long term complications. This review highlights recent (1997-2000) advances in diabetes therapy and research with an emphasis on small molecule drug design (275 references).

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Amelioration by KRP-297, a new thiazolidinedione, of impaired glucose uptake in skeletal muscle from obese insulin-resistant animals

Cited by 17 publications

References 18 publications

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

Combination therapy with PPARγ and PPARα agonists increases glucose-stimulated insulin secretion in db/dbmice

Current Therapies and Emerging Targets for the Treatment of Diabetes

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