Troglitazone Ameliorates Insulin Resistance in Patients with Werner’s Syndrome

Izumino, Kiyohiro; Sakamaki, Hiroyuki; Ishibashi, Miwa; Takino, Hirofumi; Yamasaki, Hironori; Yamaguchi, Yoshihiko; Chikuba, Nobuhiro; Matsumoto, Kazunari; Akazawa, Shoichi; Tokuyama, Kumpei; Nagataki, Shigenobu

doi:10.1210/jcem.82.8.4162

Cited by 12 publications

(3 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we have found a lack of significant correlation between the acute insulin response and SG in the present as well as previous studies. 17,18 Based on these findings, we postulate that Japanese subjects probably suffer from impairment of ␤-cell function and glucose-dependent glucose uptake.…”

Section: Discussionmentioning

confidence: 95%

No deterioration in insulin sensitivity, but impairment of both pancreatic β-cell function and glucose sensitivity, in Japanese women with former gestational diabetes mellitus

et al. 1998

View full text Add to dashboard Cite

To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non-obese women with a history of GDM and eight non-obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18+/-0.34 vs 2.26+/-0.29 x 10(-2) min(-1), p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56% of that observed in control subjects (1250+/-87.4 vs 2223+/-304.3 pmol l(-1) min, p < 0.01). Our results indicate that in former GDM patients, who are japanese and non-obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved.

show abstract

Section: Discussionmentioning

confidence: 95%

No deterioration in insulin sensitivity, but impairment of both pancreatic β-cell function and glucose sensitivity, in Japanese women with former gestational diabetes mellitus

et al. 1998

View full text Add to dashboard Cite

show abstract

“…One study revealed insulin‐resistant diabetes mellitus and visceral fat obesity in Werner syndrome patients 14 . The insulin resistance in Werner syndrome is attributed to the intracellular insulin signaling defect 15 . In our case, abdominal computed tomography did not reveal any visceral fat obesity.…”

Section: Discussionmentioning

confidence: 41%

Primary liver tumor associated with Werner syndrome (adult progeria)

Okano¹,

Isono²,

Tanaka³

et al. 2011

Hepatology Research

View full text Add to dashboard Cite

A 57-year-old woman was admitted to our hospital with characteristic aging of the face and thin body. Before admission, she had been treated for diabetes mellitus type 2 and had undergone amputation of the right leg due to ischemic disease. Abdominal computed tomography revealed primary liver tumor. Biopsy of the liver mass revealed poorly differentiated adenocarcinoma, not hepatocellular carcinoma. Genetic sequencing indicated a homozygous mutation in the Werner syndrome gene (WRN) and she was diagnosed with Werner syndrome with primary liver tumor. She declined medications for the liver tumor and eventually died 6 months after diagnosis. Werner syndrome is a rare autosomal recessive disorder associated with premature aging, and most cases of Werner syndrome have been reported from Japan. The main causes of death with Werner syndrome are malignancy and atherosclerotic vascular disease. With respect to malignancy, non-epithelial tumors are more common in Werner syndrome patients than in the general population. Some cases also show complications of epithelial tumors, as in the present case. When a liver tumor of unknown etiology is accompanied by characteristic aging of the face, Werner syndrome should be suspected and a comprehensive search for other tumors and complications of metabolic disorders undertaken.

show abstract

“…It is suggested that MCC-555 may provide a causal therapy of insulin resistance by targeted action on the defective site in the insulin signaling cascade. Further, the drugs may also be suitable for treatment of nondiabetic insulin-resistant states such as obesity (11), the polycystic ovarian syndrome (12), and Werner's syndrome (13). 1 and 2).…”

mentioning

confidence: 99%

The New Antidiabetic Drug MCC-555 Acutely Sensitizes Insulin Signaling in Isolated Cardiomyocytes**This work was supported by the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Bundesministerium für Gesundheit, EU COST Action B5, and a grant from Mitsubishi Chemical (Yokohama, Japan).

et al. 1998

View full text Add to dashboard Cite

Freshly isolated adult rat ventricular cardiomyocytes have been used to characterize the action profile of the new thiazolidinedione antidiabetic drug MCC-555. Preincubation of cells with the compound (100 microM for 30 min or 10 microM for 2 h) did not modify basal 3-O-methylglucose transport, but produced a marked sensitizing effect (2- to 3-fold increase in insulin action at 3 x 10(-11) M insulin) and a further enhancement of maximum insulin action (1.8-fold). MCC-555 did not modulate autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). However, insulin action (10(-10) and 10(-7) M) on IRS-1-associated phosphatidylinositol (PI) 3-kinase activity was enhanced 2-fold in the presence of MCC-555. Association of the p85 adapter subunit of PI 3-kinase to IRS-1 was not modified by the drug. Immunoblotting experiments demonstrated expression of the peroxisomal proliferator-activated receptor-gamma in cardiomyocytes reaching about 30% of the abundance observed in adipocytes. The insulin-sensitizing effect of MCC-555 was lost after inhibition of protein synthesis by preincubation of the cells with cycloheximide (1 mM; 30 min). Cardiomyocytes from obese Zucker rats exhibited a completely blunted response of glucose transport at 3 x 10(-11) M insulin. MCC-555 ameliorates this insulin resistance, producing a 2-fold stimulation of glucose transport, with maximum insulin action being 1.6-fold higher than that in control cells. This drug effect was paralleled by a significant dephosphorylation of IRS-1 on Ser/Thr. In conclusion, MCC-555 rapidly sensitizes insulin-stimulated cardiac glucose uptake by enhancing insulin signaling resulting from increased intrinsic activity of PI 3-kinase. Acute activation of protein expression leading to a modulation of the Ser/Thr phosphorylation state of signaling proteins such as IRS-1 may be underlying this process. It is suggested that MCC-555 may provide a causal therapy of insulin resistance by targeted action on the defective site in the insulin signaling cascade.

show abstract

Troglitazone Ameliorates Insulin Resistance in Patients with Werner’s Syndrome

Cited by 12 publications

References 35 publications

No deterioration in insulin sensitivity, but impairment of both pancreatic β-cell function and glucose sensitivity, in Japanese women with former gestational diabetes mellitus

No deterioration in insulin sensitivity, but impairment of both pancreatic β-cell function and glucose sensitivity, in Japanese women with former gestational diabetes mellitus

Primary liver tumor associated with Werner syndrome (adult progeria)

Contact Info

Product

Resources

About