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. 2012 Feb;93(1):56–69. doi: 10.1111/j.1365-2613.2011.00801.x

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

Sirilaksana Kunjara *, A Leslie Greenbaum *, Milena Sochor *, Murad Ali *, Allan Flyvbjerg †, Henning Grønbaek †, Patricia McLean *
PMCID: PMC3311022  PMID: 22264286

Abstract

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.

Keywords: adrenal hypertrophy, Angiopeptin, experimental diabetes (STZ), Insulin, phosphoribosylpyrophosphate formation and utilization, Sandostatin

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.

Scheme 1

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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 of diabetes with STZ. The pivotal position of PRPP in relationship to nucleotide synthesis, NAD+ (via nicotinamide mononucleotide (NMN) and nicotinamide phosphoribosyl transferase (Nampt)), NADP+ and NADPH formation is shown, together with the expanded recognition of the role of NAD in DNA repair, immune response, NAD-histone deacetylase and calcium mobilization.

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; Grønbaek 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; Grønbaek 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

Control Diabetic Diabetic/control
C1–C6 C1–C6 Percent
Over-utilization
 Adrenal 0.015 ± 0.002 0.055 ± 0.004 367
 Kidney 1.33 ± 0.40 3.49 ± 0.22 262
Under-utilization
 Mammary gland 31.9 ± 2.6 3.31 ± 0.67 10
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The pentose phosphate pathway was measured by the difference in 14CO2 yields from glucose specifically labelled on carbon 1 or 6. The results are for day 7 after induction of diabetes with STZ and are calculated from yields as μmoles/two adrenals/h and μmoles/g wet weight tissue/h for kidney and lactating rat mammary gland. Data derived from Kunjara et al. (1986a,b, 1992).

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.

Materials and methods

Animals

Male Wistar rats (Taconic, Eiby, Denmark) with an initial mean body weight of 230 g were used. Rats were housed, three per cage, in a room with 12:12-h (06.00–18.00 h) artificial light cycle, temperature 21 ± 2 °C and humidity 55 ± 2%. The animals had free access to standard rat chow (Altromin, Lage, Germany) and tap water throughout the experiment. Diabetes was induced by intravenous injection of STZ (55 mg/kg body weight) in acidic 0.154 M NaCl (pH 4.0) following 12 h of food deprivation. Eighteen hours after the administration of STZ, and daily thereafter, the animals were weighed, urinalysis performed for glucose and ketones using Neostix (Ames Limited, Stoke Poges, Slough, UK) and tail-vein blood glucose determined by Haemoglucotest 1–44 and Reflolux II reflectance meter (Boehringer Ingelheim, Mannheim, Germany). Only animals with blood glucose levels above 11 mM and without ketonuria were included in the study.

The rats were distributed randomly into 15 groups matched for body weight, each containing six or seven animals, and were treated as follows: two groups of non-diabetic rats killed on day 0 and day 7 respectively; five groups of diabetic rats, injected with saline subcutaneously (s.c.) twice daily, were killed successively on days 1, 2, 3, 4 and 7 of the experiment; five groups of diabetic rats were given AGP s.c. and killed on days 1, 2, 3, 4 and 7 of the experiment; three groups of diabetic rats were insulin treated (s.c.) with a very long-acting, heat-treated Ultralente Insulin (Novo-Nordisk, Bagsvaerd, Denmark) and killed on days 2, 4 and 7 of the experiment.

Angiopeptin treatment was initiated 2–4 h after injection with STZ and was given in a dose of 100 μg (in 0.5 ml 0.154 M NaCl) twice daily while placebo rats received 0.5 ml 0.154 M NaCl twice daily. Insulin treatment was initiated 18 h after the administration of STZ and was given in an initial dose of 46 U, followed by 1–3 U thereafter, depending on blood glucose values. In a separate experiment, designed to investigate the effect of the second analogue, SMS, on the same parameters as in the AGP experiment, two further groups of controls, killed on day 0 and 7 of the experiment, three groups of diabetic rats treated with placebo (0.5 ml 0.154 M NaCl) twice daily; three groups of diabetic rats treated with 100 μg SMS s.c. (in 0.5 ml acidic 0.154 M NaCl (pH 5.5) twice daily and three groups of insulin-treated diabetic rats were set up. One group of each of these treated animals was killed on days 1, 2 and 7 of the experiment.

After completion of the treatment period, the rats were anaesthetized with sodium barbital (50 mg/kg body weight i.p.) and the adrenals removed, trimmed and snap-frozen in liquid nitrogen. They were stored at −80 °C until required for measurement of either PRPP content or assay of enzyme activity.

PRPP content

For the measurement of PRPP content, one frozen adrenal was taken and extracted as described by Kunjara et al. (1992) using 1.2 ml of 100 mM KH2PO4/1 mM EDTA, pH 7.4, and heated for 5 min at 95 °C in a heating block. The PRPP content was measured as described by Kunjara et al. (1986a).

Enzyme assays

The second adrenal gland was homogenized, 1:10, in 10 mM KH2PO4 containing 1 mM mercaptoethanol, pH 7.4, and centrifuged at 27,000 g for 20 min. The supernatant was dialysed for 2 h against the homogenizing medium at 4 °C and used for enzyme assays as described below.

PRPP synthetase (EC 2.7.6.1)

This was measured as described for adrenal glands by Kunjara et al. (1992) using 20 μl of the above extract. A unit of activity is 1 μmol of 14CO2 formed from [carboxyl-14C]-orotic acid/h at 37 °C.

Glucose 6-phosphate dehydrogenase (EC 1.1.1.49) (G6PDH) and six phosphogluconate dehydrogenase (EC 1.1.1.44) (6PGDH)

These activities were measured as described for adrenal glands by Kunjara et al. (1992) using 10 μl of the above extract. A unit of activity is 1 μmol of substrate converted/min at 25 °C.

Statistics

Comparison of the experimental groups (diabetes, diabetes + AGP, diabetes + SMS or diabetes + insulin) vs. control or of treated groups (diabetes, diabetes + AGP, diabetes + SMS or diabetes + insulin) vs. untreated diabetics was by Student's t-test, with two-tailed values of <0.05 being considered statistically significant. The InStat 2.01 programme for Mackintosh was used.

Results

Adrenal gland growth

Changes in the adrenal weight are shown in Figures 1 and 2. As previously reported by Kunjara et al. (1992), the adrenal gland increased in weight following the induction of diabetes (+40% at 3 days and +25% at 7 days). Treatment with AGP decreased the increment of adrenal growth by the second day of treatment and restored adrenal gland weight to control levels by the third day (Figure 1). Sandostatin treatment also returned the adrenal gland to control levels, but this occurred as early as 1 day after treatment. Notably, the growth of the adrenal gland was less marked in the STZ diabetic rats used in the SMS experiment (Figure 2). The elevated blood glucose in the STZ diabetic group was unaffected by treatment with AGP but was restored to normal by insulin (Figure 3). Similarly, SMS had no significant effect upon blood glucose of the diabetic groups as described previously (Steer et al. 1988).

Figure 1.

Figure 1

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Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on adrenal gland weights. The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the adrenal gland weight of the control group was 42.8 ± 1.48 mg. The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Figure 2.

Figure 2

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Effect of STZ diabetes and treatment of diabetic rats with Sandostatin (SMS) or insulin on adrenal gland weights. The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the adrenal gland weight of the control group was 51.2 ± 1.22 mg. The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Figure 3.

Figure 3

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Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on blood glucose. The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the blood glucose of the control group was 6.7 ± 0.2 mM. The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

PRPP content

Diabetes caused a sharp rise in the adrenal content of PRPP either as nmol/g tissue (+100%) or as total adrenal content per two glands (+200%) by day 2. This high level was sustained for the duration of the experiment (Figures 4a,b and 5a,b). AGP limited this increase as early as the second day, when PRPP content was decreased to +40% higher than the controls. Further exposure to AGP for 5 days caused no further change. Similar changes were seen with SMS. Insulin also prevented the rise in PRPP concentration, following approximately the same time course as AGP and SMS. However, it is noteworthy that the effect of diabetes was not totally prevented in either case.

Figure 4.

Figure 4

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(a) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on the phosphoribosyl pyrophosphate (PRPP) content of the adrenal gland (nmol/g). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP concentration of the control group was 180 ± 4 nmol/g. The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on the PRPP content of the adrenal glands (nanomole per two glands). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP content of the control group was 7.6 ± 0.3 nmol/two glands. The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Figure 5.

Figure 5

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(a) Effect of STZ diabetes and treatment of diabetic rats with Sandostatin (SMS) or insulin on the phosphoribosyl pyrophosphate (PRPP) content of the adrenal gland (nanomole per gram). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP concentration of the control group was 147 ± 17.4 nmol/g. The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with SMS or insulin on the PRPP content of adrenal glands (nanomole per two glands). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP content of the control group was 7.27 ± 1.07 nmol/two glands. The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

PRPP synthetase

Diabetes caused a rise in the activity of PRPP synthetase reaching a plateau value some +50% and +100% greater (units per gram tissue and total units/two adrenals respectively) than the control value 2–3 days after induction of diabetes in the AGP group (Figure 6a,b). AGP and SMS prevented this rise completely from the earliest time studied. With AGP, after 7 days of treatment, PRPP synthetase levels were decreased significantly below control values. This decrease was much less marked with SMS (Figure 7a,b; Tables S1 and S2)

Figure 6.

Figure 6

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(a) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on the phosphoribosyl pyrophosphate (PRPP) synthetase of the adrenal gland (μmol/g/h). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP synthetase activity per g tissue in the control group was 10.89 ± 0.34 (μmol/g/h). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on the PRPP synthetase of the adrenal gland (μmol/two glands/h). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP synthetase activity per two glands in the control group was 0.497 ± 0.034 (μmol/two glands/h). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Figure 7.

Figure 7

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(a) Effect of STZ diabetes and treatment of diabetic rats with Sandostatin (SMS) or insulin on the phosphoribosyl pyrophosphate (PRPP) synthetase of the adrenal gland (μmol/g/h). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP synthetase activity per g tissue in the control group was 11.6 ± 0.3 (μmol/g/h). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with SMS or insulin on the PRPP synthetase of the adrenal glands (μmol/two glands/h). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the PRPP synthetase activity per two glands in the control group was 0.59 ± 0.02 (μmol/two glands/h). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Insulin treatment, initiated on day 2 post-STZ, was also effective in preventing the increase in PRPP synthetase, although the activity of the enzyme was not decreased below control levels (Figure 6a,b). Essentially the pattern of change was the same whether the results are considered as activity per gram or as total activity in the two glands.

G6P dehydrogenase and 6PG dehydrogenase

Only minor changes were found in the activities of the oxidative enzymes of the pentose phosphate pathway when expressed as activities per gram tissue (Figures 8a,b and 9a,b). The effect of diabetes and AGP is seen more clearly when the total enzyme activity in the two glands is considered. In terms of total activity, STZ diabetes caused a +40% to +50% rise in G6PDH and 6PGDH commencing after 1 day of diabetes. Both AGP and insulin limited this rise restoring the activity to a value close to the control value. Notably, AGP treatment for 7 days caused a significant fall in G6PDH activity in the diabetic group to −21% of control value. The effects of SMS on the oxidative enzymes of the pentose phosphate pathway in STZ diabetic rats were less marked but essentially similar to those seen for the AGP series. (Figures 10a,b and 11a,b).

Figure 8.

Figure 8

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(a) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on G6P dehydrogenase activity of the adrenal gland (μmol/g/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the G6P dehydrogenase activity per g tissue in the control group was 6.23 ± 0.21 (μmol/g/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on G6P dehydrogenase of the adrenal gland (μmol/two glands/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the G6P dehydrogenase activity per two glands in the control group was 0.279 ± 0.009 (μmol/two glands/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Figure 9.

Figure 9

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(a) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on 6PG dehydrogenase activity of the adrenal gland (μmol/g/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the 6PG dehydrogenase activity per g tissue in the control group was 8.3 ± 0.33 (μmol/g/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with angiopeptin or insulin on 6PG dehydrogenase of the adrenal gland (μmol/two glands/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the 6PG dehydrogenase activity per two glands in the control group was 0.373 ± 0.015 (μmol/two glands/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with angiopeptin 100 μg twice daily (D + AGP); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Figure 10.

Figure 10

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(a) Effect of STZ diabetes and treatment of diabetic rats with Sandostatin (SMS) or insulin on G6P dehydrogenase activity of the adrenal gland (μmol/g/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the G6P dehydrogenase activity per g tissue in the control group was 7.0 ± 0.28 (μmol/g/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with Sandostatin (SMS) or insulin on G6P dehydrogenase of the adrenal glands (μmol/two glands/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the G6P dehydrogenase activity per two glands in the control group was 0.36 ± 0.02 (μmol/two glands/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Figure 11.

Figure 11

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(a) Effect of STZ diabetes and treatment of diabetic rats with Sandostatin (SMS) or insulin on 6PG dehydrogenase activity of the adrenal gland (μmol/g/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the 6PG dehydrogenase activity per g tissue in the control group was 10.3 ± 0.38 (μmol/g/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section. (b) Effect of STZ diabetes and treatment of diabetic rats with SMS or insulin on 6PG dehydrogenase of the adrenal gland (μmol/two glands/min). The results over the 7-day period are shown as a percentage change relative to that of the normal control group that is shown by the horizontal dotted line; the 6PG dehydrogenase activity per two glands in the control group was 0.53 ± 0.03 (μmol/two glands/min). The results are presented as follows: •-•, STZ diabetic rats (D); ○-○, STZ diabetic rats treated with SMS 100 μg twice daily (D + SMS); △-△, STZ diabetic rats treated with Ultralente insulin (D + INS). The vertical lines represent the SEM of each group. The significance of difference between groups is shown at the foot of each column: *P < 0.05; **P < 0.01; ***P < 0.001; each group contained not <6 values. For details of treatment, see Materials and methods section.

Interrelationships among pathways

The results presented in Figure 12 show the percentage changes in several different parameters over duration of diabetes of 1–7 days. There is close correlation between adrenal gland weight and activity of PRPP synthetase. Phosphoribosyl pyrophosphate concentration shows a more striking increase to close to 200% of the control value; a plateau level is reached approximately 3 days after diabetes induction. The oxidative enzymes of the PPP show less marked increases. Based on these findings, Scheme 2 summarizes the potential interrelationships between the various hormonal and metabolite changes found in experimental diabetes and reflecting the central importance of steroid synthesis and the redox state of NADP+/NADPH in PRPP formation.

Figure 12.

Figure 12

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The interrelationships among phosphoribosyl pyrophosphate (PRPP) concentration, PRPP synthetase, the oxidative enzymes of the pentose phosphate pathway and adrenal gland growth in STZ diabetic rats. The results are presented as percentage change relative to the normal non-diabetic control group set at 100%. The symbols shown are: adrenal gland weight (g), ▪-▪; PRPP synthetase (units/g), △-△; PRPP concentration (g), Inline graphic; G6P dehydrogenase (units/g), Inline graphic; GPG dehydrogenase (units/g), Inline graphic.

Scheme 2.

Scheme 2

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The interrelationship between steroid synthesis and activity of the pentose phosphate pathway (PPP) in adrenal gland, showing the changes in experimental diabetes leading to increased phosphoribosyl pyrophosphate (PRPP) formation shown by vertical black arrows and the proposed site of action of somatostatin analogues, Sandostatin (SMS) and Angiopeptin (AGP).

Notably, both oxidative and non-oxidative routes along the PPP lead to R5P formation and have markedly higher activity in the adrenal relative to other tissues examined, with the exception of the lactating rat mammary gland (Novello & McLean 1968). There is approximately 20-fold higher specific activity of the oxidative enzymes of the PPP in the normal adrenal gland relative to the kidney, and two to threefold higher specific activity of the non-oxidative enzymes, transketolase and transaldolase (Novello & McLean 1968). These enzyme profiles and responses to diabetes and the two somatostatin analogues may be related to the differences in the sequence of regulatory factors involved in adrenal and renal growth in experimental diabetes (Steer et al.1988; Kunjara et al.1992).

Discussion

The present study extends our previous work on the adrenal gland in diabetes (Kunjara et al. 1992) to the critical earlier period of 1–3 days after treatment with STZ during which the adrenal gland weight increased by more than 50%. It also seeks to elucidate whether control at the level of PRPP production is a result of diabetic hyperglycaemia or because of changes in other hormonal factors. To examine this question, two different long-acting somatostatin analogues and insulin were used and adrenal growth measured and correlated with biochemical findings (Ezzat & Melmed 1992; Ørskov et al. 1992; Von Werder & Foglia 1992; Rutter 2009).

Treatment with the somatostatin analogues ab initio abolished the adrenal growth, and there was an increase in PRPP formation and the rise of PRPP synthetase activity in the first 7 days following the induction of diabetes, without having any significant effect on the blood glucose value. These results are interpreted as showing that elevated glucose per se is not responsible for the diabetic adrenal hypertrophy and that growth factors or hormones, which are regulated by these somatostatin analogues, may play a significant role in adrenal growth processes.

Among many possibilities, the first to be considered was the possible role of IGF-I in the adrenal response to diabetes. The hypothesis of IGF-I involvement is attractive in view of the known increase of IGF-I concentration seen in the diabetic rat kidney during early renal hypertrophy (Flyvbjerg et al. 1988). Flyvbjerg (1988, 1989, 1997, 2004), have also shown that the increase in IGF-I and the early renal hypertrophy were both abolished by treatment with insulin or a somatostatin analogue; by analogy, it could be argued that the adrenal might show a parallel response.

The finding that AGP, SMS and insulin will all prevent the early growth changes in the diabetic rat adrenal gland supports the suggestion that IGF-I might be involved. This hypothesis is further strengthened by the known presence of IGF-I receptors in adrenal fasciculata cells (Penhoat et al. 1988) and the effect of somatostatin in having both central (via growth hormone) and peripheral local effects on IGF-I levels in tissues, well documented for the kidney (Flyvbjerg et al. 1988; Ezzat & Melmed 1992; Ørskov et al. 1992).

The biological effects of IGF-I are initiated by interaction with cell surface receptors. The similarity of insulin and IGF-I receptors has been established (Tang-Fen et al. 1985; Herner & Farber 1990). In view of the reported effects of IGF-I on the rate of glucose transport and utilization in certain tissues (Dimitriadis et al. 1992), it is possible that some of the insulin-like effects of diabetes on the adrenal gland, for example the increase in the oxidation of glucose via the PPP and the rise in PRPP concentration (Sochor et al. 1984; Kunjara et al. 1992) could be mediated by an increase in adrenal IGF-I levels.

However, while this body of indirect evidence supports the hypothesis that IGF-I is linked to early adrenal growth in diabetes, the manifold effects of somatostatin have also to be considered (Ezzat & Melmed 1992; Ørskov et al. 1992; Von Werder & Foglia 1992; Rutter 2009). The multifunctional properties of somatostatin make it difficult to determine its precise mode of action in maintaining normal parameters of adrenal growth and PRPP content in the diabetic rat. In different clinical and experimental conditions, somatostatin has been shown to depress growth hormone and IGF-I levels, glucagon, thyroid-stimulating hormone and (in Cushing's syndrome), to suppress circulating ACTH and cortisol and urinary cortisol excretion (Ezzat & Melmed 1992; Ørskov et al. 1992; Von Werder & Foglia 1992; Rutter 2009). Of special interest in the interpretation of the present experiments is the effect of somatostatin analogues on the level of IGF-I and IGF-binding protein-1 (IGFBP-1) (Ezzat & Melmed 1992; Drop et al. 1991; Flyvbjerg et al. 1992). Ezzat and Melmed (1992) proposed that somatostatin analogues not only suppress growth hormone and IGF-I but also, by stimulating IGFBP-1, attenuate the local action of IGF-I. Therefore, future experiments must address more directly the question as to whether IGF-I mRNA and IGF-I levels are altered in the adrenal gland in diabetes, in a fashion similar to that used for studies on the kidney (Flyvbjerg et al. 1990), to evaluate the possibility that the putative IGF-1 related changes are not the primary process in the adrenal growth and PRPP changes.

An important alternative possibility is that the action of somatostatin on ACTH secretion may prevent the adrenal hypertrophy and hyperfunction in diabetes (De Nicola et al. 1976, 1977; Rhees et al. 1983). In this regard, the studies of McKerns (1969) and McKerns and Ryschkewitsch (1963), showing a direct action of ACTH on bovine adrenal gland G6PDH activity, on the bioavailability of PRPP and in stimulating purine and pyrimidine synthesis in adrenal preparations, are of special relevance. The observations of McKerns and Ryschkewitsch (1963), Criss and Mckerns (1968) and McKerns (1969), taken together with the established evidence for an increased corticosterone production by the adrenal gland in diabetes (De Nicola et al. 1976, 1977; Rhees et al. 1983) and the effects of somatostatin analogues in decreasing ACTH secretion (Ezzat & Melmed 1992; Von Werder & Foglia 1992), supports the view that the significant target site for somatostatin analogues is ACTH secretion, and that this affects adrenal growth in diabetes. A feature of these results that supports the notion of later involvement of ACTH in the adrenal changes in diabetes in vivo is that no marked changes were found in the G6PDH activity in the period of most rapid adrenal growth. Over the first 4 days of diabetes, the activity of G6PDH and 6PGDH kept pace with adrenal growth and did not change in activity per gram tissue; the increase of these enzymes was, as shown previously (Kunjara et al. 1992), a later manifestation of the diabetic syndrome. This delayed response, when seen in relationship to the striking changes found by Criss and Mckerns (1968) in G6PDH activity in the adrenal gland to ACTH in vitro, certainly suggests the possibility of a sequential pattern of change in hormonal regulation of the adrenal gland (Revsin et al. 2008). Thus a unifying hypothesis is that both IGF-I and ACTH may be involved in the adrenal response at different time intervals; and both the effects could be diminished by somatostatin analogues. The insulin-like effects of diabetes reported here could well be explained by the rise of IGF-1 in the adrenal gland, while an increase in ACTH would be compatible with the view advanced by McKerns & Ryschkewitisch (1976) that trophic hormone stimulation of PRPP in target tissues could be an important mechanism regulating ribonucleotide synthesis. Further studies on sequential changes in IGF-1 and ACTH and somatostatin analogues in relation to metabolic events in the adrenal gland will be needed to evaluate the role of each hormone signal in diabetes.

There are other signalling pathways that may be involved in the observed effects of somatostatin analogues on metabolic pathways in the adrenal gland in diabetes. Somatostatin is known to block glucagon secretion from the pancreas (Rutter 2009). However, the present experiments do not suggest major changes in glucagon secretion, because blood glucose remained elevated in the somatostatin-treated groups throughout the experiments (Figure 3) – a decrease in blood glucose would be anticipated if decreased glucagon secretion was a major factor, in view of the effects of this hormone on hepatic gluconeogenesis. The role of cAMP was not investigated directly here, but Chambers et al. (1974) reported that cyclic nucleotides induce PRPP synthetase activation by 2- to 10-fold in lymphocytes, and there is known to be augmentation of pituitary adenylate cyclase activating polypeptide (PACAP) in STZ-induced diabetes in rats (Tamakawa et al. 1998; Vaudry et al. 2009).

In untreated diabetic rats, PRPP increases more rapidly than the activity of the oxidative enzymes of the PPP (Figure 12). There are two factors in this: increase in PRPP synthetase activity and enhanced supply of R5P from the combined activity of G6P dehydrogenase and 6PG dehydrogenase. Flux through the PPP is regulated by rate of utilization of NADPH and thus the supply of NADP+. The increase in steroid secretion by the adrenal gland in diabetes uses NADPH in this reductive synthetic process, thus increasing availability of NADP+ and thereby increasing G6P flux through the oxidative reactions of the PPP. This increases the bioavailability of R5P (Scheme 2). The pivotal role of regulation of the PPP by the rate of reoxidation of NADPH to NADP+ has been reported previously in many studies (McLean 1959; Kunjara et al. 1986b; Sochor et al. 1989). With regard to R5P, it is notable that there is a relatively high Km value for R5P for both isoforms of PRPP synthetase, 52 and 83 μM respectively (Becker 2001); the adrenal gland has predominantly the type 1 isoform of PRPP synthetase (Taira et al. 1989). Becker (2001) summarized this potential ‘A role for R5P as a regulator as well as a substrate in the PRPP synthetase reaction provides an attractive means to regulate sugar and purine metabolic pathway activities’.

A caveat about the present experiments is that, because of the small size of the rat adrenal, only studies on the whole gland were undertaken, despite the structural complexity of the tissue. It is known that the various elements and zones of the adrenal gland exhibit different responses to diabetes. Thus, while the zona fasciculata, which has receptors for IGF-I, increases in the diabetic rat adrenal (Penhoat et al. 1988), the zona glomerulosa decreases, as does the secretion of aldosterone (Rebuffat et al. 1988). The present experiments also leave unanswered the question of the response to diabetes of the adrenal medulla, which also has a high concentration of PRPP, which could be required as a precursor and activator of the de novo synthesis of ATP, which is involved in the packaging and secretion of catecholamines in the rat adrenal gland (Kunjara et al. 1992).

Retrospective and prospective viewpoints

Over 50 years ago, Morton (1958) in the introduction to the classic paper in this field stated that ‘It is generally accepted that the cell nucleus carries the genetic determinants of cell behaviour. It must therefore exercise control of cell division, growth and differentiation probably by means of a compound or compounds exclusively in the nucleus but essential for cytoplasmic reactions. Such a compound is coenzyme 1 (nicotinamide adenine dinucleotide)’. As Imai noted (2009a), this concept was expanded by Gholson (1966) who predicted that the active turnover of NAD argued for ‘an important but as yet unknown function’. The low concentration of NAD in cells undergoing rapid division was shown by early work from a number of groups (Jedeikin & Weinhouse 1955; Branster & Morton 1956; Glock & McLean 1957), and it was postulated that a significant decrease in the rate of synthesis of NAD by the nucleus would modify cell division.

These early studies and hypotheses are of interest in relation to the recent exponential growth in studies on the multiple functions of NAD within the cell in addition to the established role in redox systems and glycolysis and as a precursor of NADP; certain of these (Menissier de Murcia et al. 2003); Sir2 and NAD-dependent histone deacetylase) and mono-ADP-ribosyl transferases that regulate a wide range of proteins involved in metabolism, cell survival and immune response (Imai et al. 2000; Landry et al. 2000; Corda & Di Girolamo 2003; Revollo et al. 2004; Michan & Sinclair 2007; Imai 2009b) and the formation of cyclic ADP-ribose involved in calcium signalling (Lee 2001). These functions have further highlighted the significance of the regulation of PRPP and its key role in NAD synthesis.

There is considerable recent interest in the role of growth hormone, IGF-1 and growth hormone-binding proteins in life span extension in both rodents and humans, but there are few that link these studies to the PRPP/NAD axis. Both growth hormone-deficient mice and growth hormone-binding protein knockout mice displayed increased insulin sensitivity while subjects with a genotype associated with reduced concentration of free IGF-1 in plasma were over-expressed among long-lived people (Barbieri et al. 2003; Fontana et al. 2010). It is important to remember that these are all end-points and that the early initiating stages are key events.

It remains to be determined if somatostatin analogues will reverse, as well as prevent, the changes occurring in the adrenal gland in diabetes. Nonetheless, the finding that these compounds have a very powerful effect in prevention of changes in the early diabetic adrenal is indicative of their potential importance. This applies both to the understanding the biochemical processes of diabetic adrenal gland hypertrophy and to the clinical control of metabolic derangements in diabetes, particularly in those linked to glucocorticoid secretion and gluconeogenesis.

Conclusion

Evidence is presented showing that treatment with the somatostatin analogues ab initio 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 the blood glucose values. These results are interpreted as showing that elevated glucose per se is not responsible for the diabetic adrenal hypertrophy and that growth factors or hormones, regulated by somatostatin analogues, play a significant role in adrenal growth processes. In experimental diabetes, the increase in IGF-1 leads to a sequence of linked events summarized in Scheme 2: stimulation of the formation of adrenal steroids, the utilization of NADPH and oxidation to NADP+, an increase in the formation of R5P via the oxidative PPP and thus a rise in PRPP formation via control by Km for R5P, the increased PRPP being a critical factor in the synthesis of NAD, NADPH and nucleotide and nucleic acid synthesis and adrenal gland growth (Scheme 1). From these observations, we conclude that the somatostatin analogues have an ongoing effect on the reoxidation of NADPH, on ribose formation and PRPP synthesis, and that other effects (such as the IGF-1 changes seen in other organs, but not thus far in the adrenal) are secondary to these underlying metabolic changes.

Acknowledgments

We thank Karen Mathiassen and Kirsten Nyborg for their skilled technical help.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was supported by grants from the Basil Samuel Charitable Trust, the British Diabetic Association, the Association for International Cancer Research, the Danish Diabetes Association and the Danish Medical Research Council.

Supporting Information

Additional Supporting Information may be found in the online version of this article:

Table S1. Effect of diabetes, angiopeptin and insulin on adrenal growth, pentose phosphate pathway and PRPP synthesis.

Table S2. Effect of diabetes, Sandostatin (SMS) and insulin on the adrenal growth, pentose.

iep0093-0056-SD1.docx (25.8KB, docx)

Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

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