Abstract
Albert Renold strived to gain insight into the abnormalities of human diabetes by defining the pathophysiology of the disease peculiar to a given animal. He investigated the Israeli desert-derived spiny mice (Acomys cahirinus), which became obese on fat-rich seed diet. After a few months hyperplasia and hypertrophy of β-cells occurred leading to a sudden rupture, insulin loss and ketosis. Spiny mice were low insulin responders, which is probably a characteristic of certain desert animals, protecting against insulin oversecretion when placed on an abundant diet. We have compared the response to overstimulation of several mutant diabetic species and nutritionally induced nonmutant animals when placed on affluent diet. Some endowed with resilient β-cells sustain long-lasting oversecretion, compensating for the insulin resistance, without lapsing into overt diabetes. Some with labile beta cells exhibit apoptosis and lose their capacity of coping with insulin resistance after a relatively short period. The wide spectrum of response to insulin resistance among different diabetes prone species seems to represent the varying response of human beta cells among the populations. In search for the molecular background of insulin resistance resulting from overnutrition we have studied the Israeli desert gerbil Psammomys obesus (sand rat), which progresses through hyperinsulinemia, followed by hyperglycemia and irreversible beta cell loss. Insulin resistance was found to be the outcome of reduced activation of muscle insulin receptor tyrosine kinase by insulin, in association with diminished GLUT4 protein and DNA content and overexpression of PKC isoenzymes, notably of PKCε. This overexpression and translocation to the membrane was discernible even prior to hyperinsulinemia and may reflect the propensity to diabetes in nondiabetic species and represent a marker for preventive action. By promoting the phosphorylation of serine/threonine residues on certain proteins of the insulin signaling pathway, PKCε exerts a negative feedback on insulin action. PKCε was also found to attenuate the activity of PKB and to promote the degradation of insulin receptor, as determined by co-incubation in HEK 293 cells. PKCε overexpression was related to the rise in muscle diacylglycerol and lipid content, which are prevalent on lascivious nutrition especially if fat-rich. Thus, Psammomys illustrates the probable antecedents of the development of worldwide diabetes epidemic in human populations emerging from food scarcity to nutritional affluence, inappriopriate to their metabolic capacity.
Highlights
This lecture is dedicated to the memory of Albert Renold (Fig. 1)
Several Protein kinase C (PKC) isoenzymes were reported to reduce the tyrosine kinase (TK) catalyzed phosphorylation of the insulin receptor (IR) ]3-subunit and insulin receptor substrate (IRS)-1.I55-61 We have found that PKCe overexpression was associated with reduced binding of insulin by muscle IR (Fig. 19)
To examine whether PTP 1B is involved in the susceptibility to insulin resistance or diabetes in Psammomys, Ikeda et al.[921 have measured its expression and activity towards the isolated IR of skeletal muscle of diabetic animals from diabetes prone (DP) line and control animals from the diabetes resistant (DR) line
Summary
This lecture is dedicated to the memory of Albert Renold (Fig. 1). I shall not dwell on his biography, which is well known to most of us. We have devoted particular attention to the gerbil Psammomys obesus (often nicknamed sand rat) The main native nutrient of Psammomys is a leafy halophilic plant, Atriplex halimus, (saltbush) (Fig. 6) This gerbil never exhibits diabetes in its native desert habitat but was known to develop fatal diabetes when transferred from the Nile Delta in Egypt to the USA.[9] In the 1980s Adler and colleagues have transferred Psammomys from the desert shores of the Dead Sea to the laboratory,I1,111 maintaining the animals on low energy (LE) diet, and succeeded to establish a stable, reproducible colony. Psammomys maintained on HE diet for a few weeks undergoes massive /3-cell degranulation, loss of insulin immunostaining, apoptosis and necrosis set in.[23,24,25,26,27] J6rns and colleagues[281 have followed in recent ultrastructural studies the time course of progression of Psammomys to diabetes. The/3-cells in the pancreas removed from hyperglycemic, insulin deficient animals (stage D), after several weeks on HE diet were found to exhibit apoptosis and DNA cleavageI21,251 (Fig. 10). The recovery was partial when hyperglycemia was corrected but the insulin
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