Psammomys Obesus, a Model for Environment-Gene Interactions in Type 2 Diabetes

Abstract

Type 2 diabetes is characterized by insulin resistance and progressive ␤-cell failure. Deficient insulin secretion, with increased proportions of insulin precursor molecules, is a common feature of type 2 diabetes; this could result from inappropriate ␤-cell function and/or reduced ␤-cell mass. Most studies using tissues from diabetic patients are retrospective, providing only limited information on the relative contribution of ␤-cell dysfunction versus decreased ␤-cell mass to the "␤-cell failure" of type 2 diabetes. The gerbil Psammomys obesus is a good model to address questions related to the role of insulin resistance and ␤-cell failure in nutritionally induced diabetes. Upon a change from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops moderate obesity associated with postprandial hyperglycemia. Continued dietary load, superimposed on its innate insulin resistance, results in depletion of pancreatic insulin stores, with increased proportions of insulin precursor molecules in the pancreas and the blood. Inadequate response of the preproinsulin gene to the increased insulin needs is an important cause of diabetes progression. Changes in ␤-cell mass do not correlate with pancreatic insulin stores and are unlikely to play a role in disease initiation and progression. The major culprit is the inappropriate insulin production with depletion of insulin stores as a consequence. Similar mechanisms could operate during the evolution of type 2 diabetes in humans. Diabetes 54 (Suppl. 2):S137-S144, 2005 NUTRITION-INDUCED DIABETES IN PSAMMOMYS OBESUSPsammomys obesus is a diurnal gerbil that lives in North African and Eastern Mediterranean semi-desert regions. The Israeli P. obesus colony was established at the Hebrew University ϳ30 years ago from animals collected from the arid shores of the Dead Sea. In its native habitat, feeding mainly on the low-calorie Atriplex halimus plant, P. obesus is neither obese nor hyperglycemic. However, in captivity, when fed ad libitum calorie-rich rodent food, it exhibits a tendency to develop moderate obesity and postprandial hyperglycemia (1,2). The observation that not all animals develop hyperglycemia on the calorie-rich diet enabled the selection of two outbred lines of P. obesus by assorted breeding: a diabetes-prone (DP) line, in which Ͼ70% of the animals develop postprandial hyperglycemia within 4 -7 days of calorie-rich diet, and a diabetesresistant (DR) line, in which 60 -70% of the animals are normoglycemic despite the calorie-rich diet (3,4).Once postprandial hyperglycemia develops (nonfasted blood glucose Ͼ8.3 mmol/l), progression of diabetes is very rapid, reaching the end-stage of the disease, characterized by severe hypoinsulinemia, hyperlipidemia, and ketosis, within 4 -6 weeks of initiating the calorie-rich diet ( Fig. 1) (5,6). Although islet destruction is clearly demonstrated at this terminal stage, no signs of autoimmunity are evident at any time (6,7). Hyperglycemia in P. obesus is reversible, except for the hypoinsulinemic end...

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

“…Also in vitro studies have shown a synergistic toxic effect of high glucose and saturated NEFA, a process termed glucolipotoxicity, leading to beta cell dysfunction and death [19,20]. However, most of the in vivo data were obtained in animals such as the Zucker diabetic fatty rat (ZDF) [21], the db/db mouse [22] or the gerbil Psammomys obesus [23], which are obese and hyperlipidaemic, and have extreme hyperglycaemia. Very high glycaemia alone can negatively impact on these processes in the absence of hyperlipidaemia [24,25], so there is a need to better understand the biochemical basis of beta cell failure in milder models of type 2 diabetes.…”

Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus—an adaptive response to hyperglycaemia?

“…When these animals are transferred from their natural low-energy saltbush diet to more energy-dense rodent laboratory chow, the initial response is an increase in BCM to compensate for the increased insulin demand, followed by development of hyperglycaemia. This animal model is characterised by fast depletion of insulin stores as hyperglycaemia becomes manifest [23,24]. Not all animals become hyperglycaemic as some are resistant to the high-energy diet and stay normoglycaemic (non-responders).…”

Genome sequence of a diabetes-prone rodent reveals a mutation hotspot around the ParaHox gene cluster

“…1B). P. obesus has emerged as a model for research into diet-induced type II diabetes because, if provided with high carbohydrate diets, the majority of individuals become obese and develop classic diabetes symptoms, in the most extreme cases leading to pancreatic failure and death (1)(2)(3)(4).…”