Lifestyle prevention in animal diabetes (type 2). Effect of exercise and energy restriction

This PhD dissertation was accepted by the Faculty of Health Sciences, Aarhus University, and defended on February 27, 2004.

Official opponents: Niels Møller, Jens Høiriis Nielsen, and Jørn Wulff Helge.

Tutors: Kjeld Hermansen and Søren Gregersen.

Correspondence: Michele Colombo, Aarhus University Hospital, Tage Hansens Gade 2, DK-8000 Aarhus C. E-mail: mcolombo@dadlnet.dk

Dan Med Bull 2004;51:250.

ABSTRACT

The PhD study was carried out at the Department of Endocrinology and Metabolism, Aarhus Amtssygehus, Aarhus University Hospital.

The abnormal energy balance found in type 2 diabetes can be influenced by lifestyle modifications such as energy restriction (ER) and exercise training (ET). However, only little information exists on the changes at the transcriptional level in insulin-sensitive tissues and pancreatic islets to ER and ET during the development of type 2 diabetes. Although the energy balance is influenced by a number of appetite-regulating neuropeptides, little is known of their possible direct effects on insulin secretion.

The PhD dissertation is based on three studies. In two studies we have investigated the gene expression changes in skeletal muscle, liver, fat, and pancreatic islets after ER and ET in male Zucker Diabetic Fatty (ZDF) rats. Our hypothesis was that prolonged ER or ET would cause alterations at the gene expression level in several metabolically important tissues, thereby counteracting development of type 2 diabetes. We monitored in parallel 27 ZDF rats divided into three groups: control (ad libitum diet), ER (restricted by 30% E compared to control) and ET groups. After five weeks, gene expression was quantified with gene chip technology. As expected, ER and ET ameliorate the development of hyperglycaemia and abnormal intermediary metabolism. The gene expression was clearly changed in skeletal muscle, liver and also influenced in pancreatic islets and visceral adipose tissue. Metabolic pathways (lipid and glucose) as well as signalling pathways (e.g. IGF-1, MAPK) were changed by both interventions.

The aim of the third study was to clarify the dose- and glucose-dependency on the insulin secretion of one of the appetite-regulating peptides, ghrelin, and to compare its effect with that of GLP-1, CART (55-102), CART (55-76), CART (62-76), MCH, orexin A and B. Rat islets were incubated with the neuropetides in the presence of high glucose. The effect of ghrelin was also studied in the beta cell line, INS-1E cells. mRNA expression of the ghrelin receptor using RT-PCR was estimated. We found that ghrelin inhibited insulin secretion in a dose- and glucose-dependent manner. Neither CART fragments, MCH, orexin A nor orexin B changed the insulin secretion at high glucose, while GLP-1 - as expected - stimulated insulin release from the rat islets.

Lifestyle modifications (exercise and caloric restriction) change the expression of multiple genes in skeletal muscle, liver and pancreatic islets and counteract the metabolic derangement otherwise seen in type 2 diabetes. Thus, our results indicate that changes at the gene transcription level may play an important role for the prevention of diabetes.