Effects of long-acting somatostatin analogues on redox systems in rat lens in experimental diabetes.

The effects of long-acting somatostatin analogues, angiopeptin (AGP) and Sandostatin (SMS), on the early decline in the lens content of glutathione (GSH), ATP and NADPH and increase in sorbitol were studied in STZ diabetic rats, and comparison was made with the effect of insulin. Three factors prompted this study: (i) the known increase in IGF-1 in ocular tissue in diabetes and antagonistic effect of somatostatins, (ii) the known effect of IGF-1 in increasing lens aldose reductase and (iii) the lack of effect of somatostatins on diabetic hyperglycaemia, the latter enabling a differentiation to be made between effects of hyperglycaemia per se and site(s) of IGF-1/somatostatins. All four metabolites studied showed a significant restoration towards the normal control level after 7 days of treatment with AGP and SMS, and AGP was more effective on levels of GSH and ATP. A significant correlation was found between GSH and ATP across all groups at 7 days treatment. The redox state changes in diabetes include both NADP+/NADPH and NAD+/NADH in the conversion of glucose to sorbitol and via sorbitol dehydrogenase to fructose with a linked decrease in ATP formation via NAD+/NADH regulation of the glycolytic pathway. The interlinked network of change includes the requirement for ATP in the synthesis of GSH. The present study points to possible loci of action of somatostatins in improving metabolic parameters in the diabetic rat lens via effects on aldose reductase and/or glucose transport at GLUT 3.

Effects of long-term experimental diabetes on adrenal gland growth and phosphoribosyl pyrophosphate formation in growth hormone-deficient dwarf rats.

The availability of growth hormone (GH)-deficient dwarf rats with otherwise normal pituitary function provides a powerful tool to examine the relative role of hyperglycaemia and the reordering of hormonal factors in the hypertrophy-hyperfunction of the adrenal gland that is seen in experimental diabetes. Here, we examine the effects of long-term (6 months) experimental diabetes on the growth of the adrenal glands; their content of phosphoribosyl pyrophosphate (PRPP); and the activity of the PRPP synthetase, G6P dehydrogenase and 6PG dehydrogenase enzymes in GH-deficient dwarf rats compared to heterozygous controls. These parameters were selected in view of the known role of PRPP in both de novo and salvage pathways of purine and pyrimidine synthesis and in the formation of NAD, and in view of the role of the oxidative enzymes of the pentose phosphate pathway in both R5P formation and the generation of the NADPH that is required in reductive synthetic reactions. This study shows that GH deficiency prevents the increase in adrenal gland weight, PRPP synthetase, PRPP content and G6P dehydrogenase and 6PG dehydrogenase. This contrasts sharply with the heterozygous group that showed the expected increase in these parameters. The blood glucose levels of the groups of long-term diabetic rats, both GH-deficient and heterozygous, remained at an elevated level throughout the experiment. These results are fully in accord with earlier evidence from studies with somatostatin analogues which showed that the GH-insulin-like growth factor I (IGF-I)-axis plays a key role in the adrenal diabetic hypertrophy-hyperfunction syndrome.

Effects of long-acting somatostatin analogues on adrenal growth and phosphoribosyl pyrophosphate formation in experimental diabetes.

Adrenal growth and increased adrenal function occur in experimental diabetes. Previously, we have shown that phosphoribosyl pyrophosphate (PRPP) and PRPP synthetase increased rapidly between 3 and 7 days after induction of diabetes with streptozotocin (STZ), with less marked changes in enzymes of the pentose phosphate pathway. The present study examines the earlier phase of 1-3 days following induction of diabetes, seeking to elucidate whether control of PRPP production is a result of diabetic hyperglycaemia, or to a more general re-ordering of hormonal factors. To investigate this question, the role of insulin and two different long-acting somatostatin analogues, Angiopeptin and Sandostatin, were used in a well-established animal model. PRPP was chosen specifically as a target for these studies in view of its central role in nucleotide formation and nicotinamide mononucleotide synthesis via Nampt which is the rate-limiting step in the synthesis of NAD and which has been shown to have multiple roles in cell signalling in addition to its known function in glycolysis and energy production. Treatment with the somatostatin analogues ab initio effectively abolished the adrenal growth, the increase in PRPP formation and the rise of PRPP synthetase activity in the first 7 days of diabetes, without having any significant effect on blood glucose values. This suggests that elevated glucose per se is not responsible for the diabetic adrenal hypertrophy and implies that growth factors/hormones, regulated by somatostatin analogues, play a significant role in adrenal growth processes.

Age-related changes in the response of rat adipocytes to insulin: evidence for a critical role for inositol phosphoglycans and cAMP.

Adipose tissue plays a pivotal role in ageing and longevity; many studies, both human and animal, have focussed on the effects of food limitation. Here we present a new model based on striking differences between two 'normal' inbred strains of albino Wistar rats the Charles River (CR) and Harlan Olac (HO) that have marked differences in age-related accumulation of fat and insulin-stimulated rates of glucose incorporation into lipid in the epididymal fat pads (EFP). The incorporation [U-(14)C]glucose into lipid by adipocytes showed that the CR group had a twofold higher basal rate of lipogenesis and a greater response to insulin in vitro, exceptionally, adipocytes from CR group maintained the high response to insulin to late adulthood while retaining the lower EFP weight/100 g body weight. Inositol phosphoglycan A-type (IPG-A), a putative insulin second messenger, was 3.5-fold higher and cAMP significantly lower per EFP in the CR versus HO groups. Plasma insulin levels were similar and plasma leptin higher in CR versus HO groups. The anomaly of a higher rate of lipogenesis and response to insulin and lower EFP weight in the CR group is interpreted as the resultant effect of a faster turnover of lipid and stimulating effect of leptin in raising fatty acid oxidation by muscle, potentially key to the lower accumulation of visceral fat. The metabolic profile of the CR strain provides a template that could be central to therapies that may lead to the lowering of both adipose and non-adipocyte lipid accumulation in humans in ageing.

Reciprocal control of pyruvate dehydrogenase kinase and phosphatase by inositol phosphoglycans. Dynamic state set by "push-pull" system.

Reversible phosphorylation of proteins regulates numerous aspects of cell function, and abnormal phosphorylation is causal in many diseases. Pyruvate dehydrogenase complex (PDC) is central to the regulation of glucose homeostasis. PDC exists in a dynamic equilibrium between de-phospho-(active) and phosphorylated (inactive) forms controlled by pyruvate dehydrogenase phosphatases (PDP1,2) and pyruvate dehydrogenase kinases (PDK1-4). In contrast to the reciprocal regulation of the phospho-/de-phospho cycle of PDC and at the level of expression of the isoforms of PDK and PDP regulated by hormones and diet, there is scant evidence for regulatory factors acting in vivo as reciprocal "on-off" switches. Here we show that the putative insulin mediator inositol phosphoglycan P-type (IPG-P) has a sigmoidal inhibitory action on PDK in addition to its known linear stimulation of PDP. Thus, at critical levels of IPG-P, this sigmoidal/linear model markedly enhances the switchover from the inactive to the active form of PDC, a "push-pull" system that, combined with the developmental and hormonal control of IPG-P, indicates their powerful regulatory function. The release of IPGs from cell membranes by insulin is significant in relation to diabetes. The chelation of IPGs with Mn2+ and Zn2+ suggests a role as "catalytic chelators" coordinating the traffic of metal ions in cells. Synthetic inositol hexosamine analogues are shown here to have a similar linear/sigmoidal reciprocal action on PDC exerting push-pull effects, suggesting their potential for treatment of metabolic disorders, including diabetes.