Biomedical subjects
Publications and source records attributed to E Shafrir.
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We investigated the possible relationship between islet amyloid polypeptide (IAPP) and the hyperinsulinemia and/or hyperglycemia that is seen in the desert-adapted gerbil Psammomys obesus, when the animal is transferred from a low-energy (LE) diet to a high-energy (HE) diet. The effects of vanadyl sulfate and transition from a HE to a LE diet on the diabetic state of the Psammomys were also studied. Psammomys maintained on a LE diet, showing normoinsulinemia and normoglycemia (group A), were used as controls. IAPP and insulin immunoreactivity in the islets of Langerhans was studied using the peroxidase-antiperoxidase technique and plasma levels of the two hormones were determined by radioimmunoassays. The islet immunoreactivity of both IAPP and insulin was significantly weaker in the hyperinsulinemic and hyperglycemic Psammomys (group C) compared to group A. Transfer to a LE diet resulted in complete recovery of the IAPP- and insulin-staining pattern to that seen in group A [group A--Rec (nutrition)]. The plasma IAPP levels of the group C animals were not significantly higher than in group A, while after vanadyl sulfate treatment the IAPP levels and IAPP/insulin ratios remained significantly higher [group A--Rec (vanadyl)]. At the same time the circulating levels of glucose and insulin were restored to normal. Conclusively, islet IAPP and insulin immunoreactivity disappeared and reappeared in parallel in Psammomys transferred to a HE diet and back to a LE diet. Furthermore, vanadyl sulfate treatment of the hyperinsulinemic and hyperglycemic animals normalized circulating glucose and insulin levels, but not IAPP levels, possibly due to a negative feedback effect of IAPP on insulin release.
The desert gerbil Psammomys obesus ("sand rat"), a model of nutritionally induced insulin resistance and non-insulin-dependent diabetes mellitus, was treated after weaning with exogenous insulin implants in the normoglycaemic, normoinsulinaemic state. Albino rats matched for weight and age served as high energy diet adjusted reference animals. Insulin administration, elevating the serum insulin to 6000 pmol/l resulted in only a mild reduction in blood glucose levels in Psammomys, but caused a severe, often fatal hypoglycaemia in the albino rats. The hepatic response to insulin-induced hypoglycaemia in rats involved a significant loss in glycogen and suppression of phosphoenolpyruvate carboxykinase (PEPCK) activity. In Psammomys under similar hyperinsulinaemia no appreciable changes in liver glycogen and PEPCK activity were evident, indicating that blood glucose was replenished by continuing gluconeogenesis. Euglycaemic, hyperinsulinaemic clamp caused a complete shut-down of hepatic glucose production in albino rats. However, in both diabetes-prone and diabetes-resistant Psammomys lines, mean hepatic glucose production was reduced by only 62 to 53% respectively, despite longer lasting and higher levels of hyperinsulinaemia. These results indicate that Psammomys is characterized by muscle and liver insulin resistance prior to diet-induced hyperglycaemia and hyperinsulinaemia. This is assumed to be a species feature of Psammomys, exemplifying a metabolic adjustment to survival in conditions of food scarcity of both animal and human populations. It may reflect a propensity to insulin resistance and hyperglycaemia in population groups exposed to affluent nutrition.
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Triamcinolone or triiodothyronine (T3) was administered to rats with nephrosis induced by aminonucleoside of puromycin and to control nontreated rats. Triamcinolone produced hyperglycemia, hyperinsulinemia and liver glycogen deposition in control rats and to a lesser extent in nephrotic rats. Triamcinolone treatment did not affect plasma protein and albumin levels but increased the level of plasma triglycerides and cholesterol in the very low density lipoprotein (VLDL) and LDL but not high density lipoprotein fractions. The exacerbation of hyperlipoproteinemia was attributed both to increase hepatic lipid synthesis and delayed removal, since it was associated with the induction of hepatic acetyl-CoA carboxylase, the regulatory enzyme of lipogenesis, as well as with marked suppression of adipose tissue lipoprotein lipase (LPL). The hepatic lipase activity was found to be elevated in nephrotic rats but was suppressed by triamcinolone treatment, indicating a reduced capacity of VLDL to LDL conversion. T3 treatment resulted in serum glucose and insulin increases similar to triamcinolone, but more moderate in nephrotic vs. control rats, and in marked reduction in liver glycogen content. Plasma protein levels were not affected, but contrary to control rats, T3 treatment produced an elevation in serum triglycerides and cholesterol in nephrotic rats. The activity of several hepatic lipogenic enzymes, including acetyl-CoA carboxylase, was markedly elevated, as was the activity of gluconeogenic enzymes. Thus, the hyperlipoproteinemia on T3 treatment appeared to be mainly due to predomination of lipid synthesis over removal, since the activities of enzymes responsible for plasma lipid disposal, adipose tissue LPL and hepatic lipase were enhanced both in control and nephrotic rats. It is remarkable that both T3 and triamcinolone induce the lipogenic enzymes and apolipoproteins in the liver of nephrotic rats, already pronouncedly stimulated to replace the excreted plasma proteins. Thus, the nephrotic liver is able to respond to hormonal stimulation with further specific protein and lipid synthesis. It is also pertinent that the recovery from immunosuppressive treatment of human nephrosis, developing on an immune background, may result in more impressive amelioration of proteinuria and hypoproteinemia than of hyperlipoproteinemia because of the lipidemic effect of glucocorticoids.
Studies involving genetically and nutritionally induced diabetes in animals indicate that early hyperinsulinaemia is the causative factor of tissue insulin resistance, leading to compensatory insulin oversecretion and pancreatic beta-cell dysfunction. The models for this syndrome, which occurs in association with obesity (thus termed "diabesity" here), concern either species with a sturdy pancreas, capable of long-lasting oversecretion, or those with labile beta cells which cannot sustain the initial oversecretion due to genomic modifiers enhancing gluco- or lipotoxicity. Examples of the latter are db/db mice mutants and desert gerbils susceptible to overnutrition, i.e. Psammomys obesus (sand rats). The latter also comprise spiny mice (Acomys cahirinus) which do not manifest resistance. They are low insulin secretors and accumulate insulin in beta cells which may disintegrate, producing insulin-deficiency. P. obesus is characterised by low insulin-receptor density. On a high energy diet, the capacity of insulin to activate receptor tyrosine kinase (TK) is reduced, concomitant with hyperinsulinaemia. With subsequent hyperglycaemia, a vicious circle of insulinaemia-glycaemia accentuates TK activation failure. This is attributable to multisite phosphorylation, including serine and threonine on the receptor b-subunit, which are inhibitory to TK activity. The compromised TK activation is reversible by diet restriction and normoinsulinaemia restoration. Similar receptor TK malfunction is seen in other animal species with diabesity. Hyperinsulinaemia has also been shown to cause a variety of detrimental effects in vitro and in vivo. The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin-resistance syndrome and non-insulin-dependent diabetes mellitus, particularly in populations emerging into nutritional abundance. It is postulated that the "thrifty gene" is focused on receptor TK, whose reduced function is the primary phenotypic expression of protracted hyperinsulinaemia.
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The insulin receptor was evaluated at different disease stages in the sand rat (Psammomys obesus), a model for nutrition-induced diabetes. Nondiabetic sand rats showed markedly low receptor number in liver compared with albino rats. Their receptor had an intact tyrosine kinase activity but a higher Km for ATP in the phosphorylation reaction of exogenous substrates. The initial effects of overeating (i.e., development of hyperinsulinemia without hyperglycemia) were associated in the sand rat with a dramatic decrease in in vitro and in vivo insulin-induced receptor tyrosine kinase activity in both liver and muscle. In muscle, this coincided with a decrease in receptor number and an increase in basal tyrosine kinase activity. Similar changes were observed upon development of hyperinsulinemia with hyperglycemia. Upon recovery from the diabetic state by diet restriction, the impaired receptor kinase activation was corrected. Complete restoration occurred only in animals that fully recovered from the diabetic state and became normoinsulinemic. These observations indicate that loss and gain of receptor tyrosine kinase activity were dependent on insulin levels. Thus, overeating may lead to the development of hyperinsulinemia through ineffective extraction of excess insulin by the scarce liver receptors. Hyperinsulinemia, in turn, causes a reversible reduction in receptor kinase activity, leading to insulin resistance. This sequence of events may be relevant to diet-related changes in human non-insulin-dependent diabetes mellitus.
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Patients with noninsulin-dependent diabetes mellitus exhibit increased proportions of plasma proinsulin and proinsulin conversion intermediates. We used hyperinsulinemic diabetic and nondiabetic Psammomys obesus to study the possible relationship between steady state pancreatic insulin stores and the proportion of proinsulin-related peptides in the plasma and pancreas. Insulin-like peptides were separated by reverse phase HPLC and identified by pulse-chase experiments. A marked increase in the proportions of proinsulin and proinsulin conversion intermediates in the plasma and pancreas of diabetic nonfasted Psammomys was associated with 90% reduction in insulin stores of the pancreas. After a 16- to 20-h fast, the depletion of pancreatic insulin in the diabetic animals was partially corrected, and the proinsulin/insulin ratio was normalized. In contrast, nondiabetic Psammomys showed only 50% reduction in pancreatic insulin stores under nonfasting conditions, with no change in the proinsulin/insulin ratio. These findings suggest that in the diabetic Psammomys obesus, the pancreatic capacity for storage of insulin may be limited; the metabolic consequences of this limitation are amplified by increased secretory demand secondary to insulin resistance, thus facilitating the establishment of hyperglycemia, which may in itself further exacerbate pancreatic dysfunction.
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