Interrelationship of dipeptidyl peptidase IV (DPP4) with the development of diabetes, dyslipidaemia and nephropathy: a streptozotocin-induced model using wild-type and DPP4-deficient rats

Abstract

We examined the role of dipeptidyl peptidase IV (DPP4) in the development of diabetes, dyslipidaemia and renal dysfunction induced by streptozotocin (STZ). F344/ DuCrlCrlj rats, which lack DPP4 activity, and wild-type rats were treated with STZ. Plasma DPP4 activity and biochemical parameters were measured until 42 days after STZ treatment. At the end of the experiment, renal function and DPP4 expressions of the kidney, liver, pancreas and adipose tissues were determined. Increases in blood glucose, cholesterol and triglycerides were evoked by STZ in both rat strains; however, the onset of hyperglycaemia was delayed in DPP4-deficient rats as compared with wild-type rats. By contrast, more severe dyslipidaemia was observed in DPP4-deficient rats than in wild-type rats after STZ treatment. Plasma DPP4 activity increased progressively with time after STZ treatment in wild-type rats. The kidney of wild-type rats showed decreased DPP4 activity with increased Dpp4 mRNA after STZ treatment. In addition, kidney weight, serum creatinine and excreted amounts of urinary protein, glucose and DPP4 enzyme were enhanced by STZ. DPP4-deficient rats showed increased serum creatinine in accordance with decreased creatinine clearance as compared with wild-type rats after STZ treatment. In conclusion, plasma DPP4 activity increased after STZ treatment, positively correlating to blood glucose. DPP4-deficient rats were resistant to developing diabetes, while susceptible to dyslipidaemia and reduction of glomerular filtration rate by STZ. DPP4 activation may be responsible for hyperglycaemia, lipid metabolism and preservation of renal function.

Plasma dipeptidyl peptidase 4 activity correlates with body mass index and the plasma adiponectin concentration in healthy young people

“…Additionally, using Otsuka Long-Evans Tokushima fatty rats, which display a spontaneously hyperphagic and obese phenotype in combination with hyperglycemia and hyperinsulinemia, we showed that plasma DPP4 activity changes in accordance with the progression of hyperinsulinemic obesity and pancreatic islet atrophy [7]. Furthermore, we reported that the plasma DPP4 level and DPP4 mRNA expression in some tissues increased progressively with the development of streptozotocin-induced type 1 diabetes [8].…”

“…Although several clinical studies have investigated whether DPP4 activity is correlated with the onset or severity of diabetes and/or obesity, they have produced mixed results; i.e., plasma DPP4 activity levels were of 7-amino-4-methylcoumarin (AMC) from the synthetic substrate H-glycyl-prolyl-AMC (Gly-Pro-AMC; Sigma, St. Louis, MO, U.S.A.), as described previously [6][7][8]. Briefly, 5 μL of plasma were mixed with 35 μL of assay buffer (25 mmol/L HEPES, 140 mmol/L NaCl, 80 mmol/L MgCl 2 , and 1 % BSA; pH 7.8).…”

Dipeptidyl peptidase-IV is a potential molecular biomarker in diabetic kidney disease

“…DPP IV may be secreted from tubular epithelial cells following renal damage, which is known to cause the leakage of microvascular endothelial DPP IV in the kidney, or there may be some increased cleavage of the DPP IV pro-peptide. 7,[23][24][25] The morphological analysis of the AD-1 antibodyimmunoprecipitated urinary microvesicles by electron microscopy indicated that antibody binding during the isolation process did not perturb the morphology and structure of these vesicles. Based on the ratio of microvesicle-bound DPP IV to total urinary DPP IV, we propose that the microvesicle-bound type is the major form of DPP IV in urine.…”

Dipeptidyl Peptidase IV Inhibition Alters the Hemodynamic Response to Angiotensin-Converting Enzyme Inhibition in Humans With the Metabolic Syndrome

“…This may be important because such effects in the long term are probably not desirable and could accelerate diabetic nephropathy. Indeed, Kirino et al 12 report that in DPP-4 -deficient rats (F344/DuCrlCrlj rats; a strain of rats with a mutation in the DPP-4 gene that results in deficient DPP-4 activity), creatinine clearance 42 days after induction of diabetes (with streptozotocin) is 50% lower in DPP-4 -deficient versus wild-type rats.…”