J Korean Diabetes Assoc.  2007 Jan;31(1):33-43. 10.4093/jkda.2007.31.1.33.

Thiazolidinediones on Insulin Resistance and Insulin Secretion in Obese Diabetic OLETF Rats

• Noh JH
• Hong SH
• Lee KH
• Min KM
• Yang TY
• Lee MS
• Kim KW
• Lee MK

• KMID: 2008094
• DOI: http://doi.org/10.4093/jkda.2007.31.1.33

Abstract

BACKGROUND: Thiazolidinediones are synthetic peroxisome proliferator-activated receptor-gamma agonists that decrease insulin resistance but, as in vitro and in vivo studies suggest, may have direct beneficial effects on pancreatic beta cells. Here, we investigated the effects of thiazolidinediones (TZDs) on the insulin resistance, beta-cell mass and insulin secretion in obese diabetic OLETF rats.
METHODS
We studied insulin resistance (by hyperinsulinemic euglycemic clamp) and insulin secretion (by hyperglycemic clamp) in TZDs administered OLETF and LETO rats. Histologic alterations of the islets were observed and beta-cell mass was also measured by point counting method.
RESULTS
Chronic administration of troglitazone (TGZ, 0.15%) or pioglitazone (PGZ, 0.02%) prevented the development of glucose intolerance in OLETF rats, as assessed by oral glucose tolerance test. There was significant difference in submaximal glucose infusion rate between TGZ-treated and untreated OLETF rats during euglycemic clamp studies at 24 weeks of age. At 16 and 24 weeks of ages, beta-cell mass significantly increased in TGZ-treated OLETF rats compared to untreated animals. At 19 weeks and 30 weeks of age, first-phase insulin secretion was not different in PGZ-treated OLETF rats from untreated OLETF rats during hyperglycemic clamp study. At 30 weeks of age, late-phase insulin secretion was decreased in PGZ-treated OLETF rats compared to untreated OLETF rats. The expression of alpha-smooth muscle actin, a marker of activated pancreatic stellate cells that are involved in the fibrosis of the pancreas, in the islets was suppressed by TGZ treatment at 24 weeks of age.
CONCLUSION
The treatment of TGZ prevented the development of diabetes, and increased insulin sensitivity and pancreatic beta-cell mass in OLETF rats. These results might be related with the suppression of pancreatic stellate cells. Insulin secretion was not affected by PGZ treatment.

Keyword

Euglycemic clamp; Hyperglycemic clamp; OLETF rats; Thiazolidinediones

MeSH Terms

Actins
Animals
Fibrosis
Glucose
Glucose Clamp Technique
Glucose Intolerance
Glucose Tolerance Test
Insulin Resistance*
Insulin*
Insulin-Secreting Cells
Pancreas
Pancreatic Stellate Cells
Peroxisomes
Rats
Rats, Inbred OLETF*
Thiazolidinediones*
Actins
Glucose
Insulin
Thiazolidinediones

Figure

• 

  Fig. 1 Body weight and food intake in age-matched control and TGZ-treated LETO and OLETF rats. Results are the mean ± SEM of 6~12 rats.

• 

  Fig. 2 Fasting plasma total cholesterol, LDL-cholesterol, HDL-cholesterol, free fatty acid and triglyceride levels at 16 and 24 weeks of age (6 and 14 weeks of treatment). Results are the mean ± SEM of 6~12 rats.

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  Fig. 3 Hyperinsulinemic-euglycemic clamp in OLETF and LETO rats with or without TGZ treatment. Following 1 h for stabilization, the GIR necessary to maintain blood glucose at 5 to 6 mmol/L was measured. Results are the mean ± SEM for each group over 1 h.

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  Fig. 4 Changes of concentrations of plasma insulin during hyperglycemic clamp studies. Results are the mean ± SEM.

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  Fig. 5 Insulin staining of pancreatic islets in untreated OLETF rats (A), TGZ-treated OLETF rats (B), untreated LETO rats (C) and TGZ-treated LETO rats (D), and glucagon staining of pancreatic islets in untreated OLETF rats (E), TGZ-treated OLETF rats (F), untreated LETO rats (G) and TGZ-treated LETO rats (H) at 24 weeks of age.

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  Fig. 6 Changes in pancreatic β-cell mass in OLETF and LETO groups at 16 and 24 weeks of age. Total β-cell area was measured using a point-counting procedure with a 48-point transparent overlay.

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  Fig. 7 α-SMA staining of pancreatic islets in untreated OLETF rats (A) and TGZ-treated OLETF rats (B) at 24 weeks of age.

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