Combination peroxisome proliferator-activated receptor gamma and alpha agonist treatment in Type 2 diabetes prevents the beneficial pioglitazone effect on liver fat content.
OBJECTIVE
Peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha agonists individually reduce intra-organ triglyceride content and improve insulin sensitivity. However, the precise effects of combined PPAR-gamma and PPAR-alpha therapy on intra-organ triglyceride content and insulin sensitivity in subjects with Type 2 diabetes have not yet been determined.


METHODS
Diet-controlled Type 2 subjects (n = 9) were studied before and after 16 weeks of combined PPAR-gamma [pioglitazone (PIO), 45 mg daily] and PPAR-alpha [bezafibrate (BEZA), modified release 400 mg daily] agonist therapy. Glucose metabolism and endogenous glucose production were measured following a standard liquid test meal. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy.


RESULTS
Combined PIO and BEZA therapy reduced mean fasting (7.5 +/- 0.5 vs. 6.5 +/- 0.2 mmol/l, P = 0.04) and peak postprandial plasma glucose (15.3 +/- 1.1 vs. 11.7 +/- 0.6 mmol/l, P = 0.007). No significant change in hepatic or muscle triglyceride content was observed. Postprandial suppression of endogenous glucose production remained similar on both study days. Both subcutaneous and visceral fat content increased following therapy.


CONCLUSIONS
Combined PIO and BEZA therapy in Type 2 diabetes does not decrease intrahepatic triglyceride content or postprandial endogenous glucose production. This study demonstrates an unexpected adverse interaction of PPAR-alpha with PPAR-gamma agonist therapy.
Balasubramanian
R
R
Newcastle Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Gerrard
J
J
Dalla Man
C
C
Firbank
M J
MJ
Lane
A
A
English
P T
PT
Cobelli
C
C
Taylor
R
R
D000009:Abdominal Muscles / Q000378:metabolism; D000328:Adult; D000368:Aged; D001629:Bezafibrate / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight; D002096:C-Peptide / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000378:metabolism*
D001629:Bezafibrate; D001786:Blood Glucose; D002096:C-Peptide; D005934:Glucagon; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D047493:PPAR alpha; D047495:PPAR gamma; D000077205:Pioglitazone; D045162:Thiazolidinediones; D014280:Triglycerides