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.

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Altered dipeptidyl peptidase-4 (DPP4) activity during the progression of late-stage type 2 diabetes was measured in Otsuka Long-Evans Tokushima fatty (OLETF) rats. Compared with OLETF rats subjected to 30% food restriction, food-satiated OLETF rats exhibited spontaneous hyperphagic obesity, insulin resistance, hyperglycemia, hyperinsulinemia, and increased plasma DPP4 activity during the early phase of the experiment (up to ∼30 wk). Subsequently, their plasma DPP4 activity as well as their body weight, body fat, and plasma insulin concentration declined to control levels during the late phase, resulting in excessive polyuria, proteinuria, dyslipidemia, pancreatic islet atrophy, hypoinsulinemia, and diabetes, which changed from insulin-resistant diabetes to hypoinsulinemic diabetes secondary to progressive islet insufficiency, and their fasting blood glucose level remained high. Since plasma DPP4 activity demonstrated significant positive correlations with body weight and the fasting plasma insulin level but not with the fasting blood glucose level during the late stage of diabetes, body fat and fasting plasma insulin levels may be useful factors for predicting the control of plasma DPP4 activity. In contrast, pancreatic DPP4 activity was significantly increased, and the expression of pancreatic insulin was significantly reduced in late-stage diabetic OLETF rats, suggesting that a relationship exists between the activation of pancreatic DPP4 and insulin depletion in pancreatic islet atrophy. In conclusion, it is suggested that plasma DPP4 activity changes in accordance with the progression of hyperinsulinemic obesity and pancreatic islet atrophy. DPP4 activity may play an important role in insulin homeostasis.

Several studies have investigated whether dipeptidyl peptidase IV (DPP IV) activity is correlated to the severity of diabetes; however, it remains unclear. To investigate the roles of DPP IV activity in metabolic abnormalities, impaired glucose tolerance rats were produced using a high-fat (HF) or high-sucrose (HS) diet. HF dietfed rats obviously exhibited impaired glucose tolerance, with increases in subcutaneous and epididymal fat mass, insulin resistance and dyslipidaemia. In rats fed a HS diet rather than a normal diet, lower body weight and fasting blood glucose were observed temporarily in the early period after HS diet feeding; however, impaired glucose tolerance was evoked to some extent with an increase in epididymal fat mass. Both HF and HS diet-fed rats showed significantly higher plasma DPP IV activity than normal diet-fed rats, in the order of HF dietϾHS dietϾnormal diet. HF and HS diets did not significantly affect DPP IV activity and mRNA expression in the kidney. On the other hand, HF, but not HS, diet caused a significant decrease in DPP IV activity in the liver as compared to the control. Of note, both HF and HS diets caused a significant decrease in DPP IV activity in epididymal fat, even though they did not change DPP IV activity in subcutaneous fat. In conclusion, HF or HS diet-induced impaired glucose tolerance with visceral fat accumulation may be interrelated with increased plasma DPP IV activity and decreased DPP IV activity of visceral but not subcutaneous adipose tissue.