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

It is well established that, following the induction of diabetes, there is an early increase in adrenal size, with hypertrophy of the zona fasciculata and an increase of steroid production (De Nicola et al. 1976, 1977; Rhees et al. 1983; Penhoat et al. 1988). The most marked changes in adrenal weight and plasma corticosteroid levels were observed 5 days after the induction of diabetes in rats with streptozotocin (STZ), with a less marked, but persistent, adrenal hyperactivity occurring up to 6 weeks after the onset of diabetes (De Nicola et al. 1977). Kunjara et al. (1992) have shown that not only does the rat adrenal gland contain a notably high concentration of phosphoribosyl pyrophosphate (PRPP), some 20-fold greater than a range of normal tissues such as the liver, kidney and heart, but also that this nucleotide precursor is increased markedly within 3 days of STZ induction of diabetes. Phosphoribosyl pyrophosphate is known to play a central role in nucleotide synthesis. It serves as a substrate for the de novo and salvage pathways of purine and pyrimidine synthesis, and as an activator of the first steps in both de novo routes (Becker et al. 1979; Becker 2001). In synthesis of nicotinamide mononucleotide (NMN) via Nampt, PRPP is the rate-limiting step in NAD synthesis (see Garten et al. 2009; Imai 2009a). Recent studies have emphasized the multiple roles of NAD in addition to its established function in redox systems, in glycolysis and energy production. These include a number of signalling pathways: poly ADP ribosylation in DNA repair (Menissier de Murcia et al. 2003), formation of cyclic ADP-ribose involved in calcium signalling (Lee 2001), and of Sir2, an NAD-dependent histone deacetylase and mono-ADP-ribosyl transferases that regulates a wide array of proteins involved in metabolism and cell survival (Imai et al. 2000; Landry et al. 2000; Revollo et al. 2004; Michan & Sinclair 2007; Imai 2009b). The linkages between PRPP formation and the multiple sites of cellular regulation are summarized in Scheme 1. These interrelated functions have highlighted the potential significance of the regulation of PRPP in growth processes such as those seen in the diabetic adrenal and prompted an investigation of PRPP- and PRPP-associated factors involved in the early stages of the adrenal response in experimental diabetes. Scheme 1 Pathways linking phosphoribosyl pyrophosphate (PRPP) formation with multiple sites of cellular regulation and growth. The present study demonstrated the increase in PRPP concentration and PRPP synthetase activity in rat adrenal glands following induction ... The temporal parallelism between the growth response of the adrenal and the kidney in experimental diabetes (Kunjara et al. 1986a, 1992; Flyvbjerg et al. 1988) suggested the hypothesis that common hormonal signals might be involved in the two organs. Using adrenal cortical cell cultures in serum-free defined medium, a number of factors have been shown to be implicated. This includes both insulin and insulin-like growth factor I (IGF-I), which stimulate growth of bovine fasciculata cells (Penhoat et al. 1988). The characteristics of the IGF-I and insulin receptors, and the role of these hormones on adrenal cell function and steroidogenic response, were investigated, and at physiological concentrations IGF-I was shown to be the more potent factor. In fact, there has already been considerable interest in changes in IGF-I during early diabetic renal hypertrophy (Mendley & Toback 1988; Hammerman 1989; Fine et al. 1992). Increasing evidence supports the concept that IGF-I stimulates the initial renal hypertrophy (Flyvbjerg et al. 1988, 1990, 1991; Gronbaek et al. 2002; Flyvbjerg 2004). Flyvbjerg et al. (1991) infused IGF-1 into diabetic rats 5 days after treatment with STZ, that is at the time when the initial rapid growth phase had slowed, and growth acceleration was demonstrated. Administration of a somatostatin analogue prevented both the increase of kidney IGF-I and the initial renal growth in diabetes (Flyvbjerg et al. 1989; Gronbaek et al. 2002). Adrenal levels of IGF-1 were not documented in these studies. The similarities between kidney and adrenal gland responses in STZ diabetes have been related previously to a general and widely held concept of ‘glucose over-utilization’ in those tissues not requiring insulin for glucose uptake. These tissues include the ocular lens and peripheral nerve, and glycosylation of proteins such as haemoglobin A1c and lens α crystalline (Brownlee & Cerami 1981; Sochor et al. 1985) as well as the adrenal and kidney. This contrasts sharply with those tissues dependent upon insulin for glucose uptake and showing aspects of ‘glucose under-utilization’, such as muscle, adipose tissue and lactating mammary gland (Kunjara et al. 1986a,b, 1992) (Table 1). Table 11 Effect of diabetes on the activity of the pentose phosphate pathway in rat adrenal gland, kidney and lactating mammary gland: glucose under- and over-utilization To explore these questions, two different somatostatin analogues, Angiopeptin (AGP, Lantreotide), and Sandostatin (SMS, Octreotide), have been used. These analogues have been shown to have different effects on tissue growth (Alderton et al. 1998). Their effects on the early growth of the adrenal gland, on the tissue concentration of PRPP, on PRPP synthetase activity and on the enzymes of the pentose phosphate pathway (PPP) (which are involved in the provision of R5P, the immediate precursor of PRPP) were compared. In addition, they were also compared with the effect of insulin on the same parameters.