Somatostatin: central nervous system actions on glucoregulation.

Somatostatin (SRIF) has been tested for its actions on the central nervous system to affect glucoregulation. In doses ineffective when given systemically , SRIF and SRIF analogs given intracisternally (ic) reduce hyperglycemia and hyperglucagonemia after ic bombesin administration. The SRIF analog, des-AA1, 2, 4, 5, 12, 13-[D-Trp8]SRIF, decreases plasma insulin and elevates plasma glucose and glucagon when given systemically. However, when given ic, this peptide prevents the rise in glucose and glucagon after ic bombesin administration and is 10 times more potent than SRIF in reducing bombesin-induced hyperglycemia. Other analogs of SRIF and various unrelated peptides were found to be ineffective in reducing bombesin-induced hyperglycemia. des-AA1, 2, 4, 5, 12, 13-[D-Trp]SRIF prevented the hyperglycemia induced by surgical stress or by ic administration of beta-endorphin or carbacol. des-AA1, 2, 4, 5, 12, 13-[D-Trp]SRIF given ic did not prevent hyperglycemia induced by systemic administration of epinephrine, arginine, or glucagon. These studies suggest that SRIF and its analogs may act within the brain to affect glucoregulation.     

Involvement of the hippocampus in central nervous system-mediated glucoregulation in rats

To find out whether the hippocampus is involved in central nervous system-mediated glucoregulation, we injected saline, neostigmine, dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, and prostaglandin F2 alpha into the dorsal hippocampus in anesthetized fed rats. After injection of dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, or prostaglandin F2 alpha, the level of hepatic venous plasma glucose did not differ from that in saline-treated control rats. However, neostigmine, an inhibitor of acetylcholine esterase, caused a dose-dependent increase in the hepatic venous plasma glucose concentration. This neostigmine-induced hyperglycemia was dose-dependently suppressed by coadministration of atropine, but not by hexamethonium. Injection of neostigmine (5 X 10(-8) mol) resulted in an increase not only in glucose but also in glucagon, epinephrine, and norepinephrine in hepatic venous plasma. In bilateral adrenalectomized rats, neostigmine-induced hyperglycemia was suppressed, but the hepatic venous plasma glucose concentration still increased significantly. These results indicate that the hippocampus is involved in central nervous system-mediated glucoregulation through cholinergic muscarinic activation, partly via epinephrine secretion.     

Stimulation by bombesin of immunoreactive somatostatin release into rat hypophysial portal blood

Bombesin was injected into the cerebral ventricle of male rats anesthetized with urethane to study its effect on plasma levels of immunoreactive somatostatin (IRS) in hypophysial portal and jugular blood. An intraventricular injection of bombesin (0.2 and 2 micrograms/rat) caused a significant and dose-related increase in plasma IRS in hypophysial portal blood but not in jugular blood. Although bombesin placed into the cerebral ventricle is known to stimulate glucagon and epinephrine release, an iv injection of glucagon (100 micrograms/100 g BW) or epinephrine (2.5 micrograms/100 g BW) did not cause any significant changes in plasma IRS levels in hypophysial portal and jugular blood, suggesting that these substances do not mediate bombesin stimulation of portal IRS release. Pretreatment with naloxone (75 micrograms/100 g BW, iv) failed to affect the portal IRS release induced by bombesin (2 micrograms/rat), indicating that the opiate receptor is not likely to be involved in this reaction. To ascertain whether IRS released by bombesin into hypophysial portal blood is biologically active, the effect of bombesin on the plasma GH level was then examined. Bombesin (2 micrograms/rat) injected intraventricularly completely suppressed the rise of plasma GH after the intraventricular injection of beta-endorphin (1 microgram/rat) or the iv injection of prostaglandin E1 (5 micrograms/100 g BW). Bombesin thus appears to stimulate the secretion of IRS, and probably biologically active somatostatin as well, from the hypothalamus into hypophysial portal blood, thereby inhibiting GH release from the anterior pituitary.     

Somatostatin analog: plasma catecholamine suppression mediated by the central nervous system

The somatostatin analog, des-AA1,2,4,5,12,13-[D-Trp8]somatostatin (ODT8-SS), acts within the central nervous system to suppress the rise in plasma catecholamines associated with a variety of neural stimuli. Insulin-induced hypoglycemia or stress caused significant elevations in plasma catecholamines that were abolished by intracerebroventricular (icv) administration of ODT8-SS. Bombesin, carbachol, or 2-deoxyglucose, injected icv, evoked marked elevations in plasma epinephrine and norepineprine. These effects were also prevented by ODT8-SS given icv. In all experiments, ODT8-SS appeared to be more effective in lowering plasma epinephrine than in lowering plasma norepinephrine. Systemic administration of ODT8-SS was ineffective in lowering plasma catecholamine levels. Native somatostatin given icv produced inconsistent effects on plasma catecholamine levels. These data suggest that the somatostatin analog, ODT8-SS, acts within the central nervous system to modulate sympathetic nervous system activity. It is suggested, but not established, that this analog acts through the same receptor as native somatostatin.     

Modulation of plasma glucose levels by thyrotropin-releasing hormone administered intracerebroventricularly in the rat

Thyrotropin-releasing hormone (TRH), but not histidyl-proline diketopiperazine (cyclo[His-Pro]), induced transient hyperglycemia associated with hyperglucagonemia and marked hyperinsulinemia when placed intracerebroventricularly (i.c.v.) in anesthetized rats. This TRH-induced hyperglycemia was prevented by acute adrenalectomy. However, adrenalectomy did not prevent TRH-induced hyperinsulinemia or hyperglucagonemia. In streptozotocin-induced diabetic rats, i.c.v. administration of TRH caused progressive and pronounced hyperglycemia. i.c.v. TRH-induced hyperinsulinemia was abolished by vagotomy and by systemic administration of hexamethonium or atropine. These results suggest that TRH induces hyperglycemia mediated by stimulation of the sympathetico-adrenal system and hyperinsulinemia by stimulation of the vagus nerve, and that the rapid decline of plasma glucose levels following transient hyperglycemia is due to hyperinsulinemia.     

Bombesin inhibits thyrotrophin secretion in rats

The effects of peripheral administration of bombesin on thyrotrophin-releasing hormone (TRH) and thyrotrophin (TSH) secretion in rats were studied. Bombesin (200 micrograms/kg) was injected iv, and the rats were serially decapitated. TRH, TSH and thyroid hormone were measured by radioimmunoassay. The hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after bombesin injection, whereas plasma concentrations tended to decrease, but not significantly. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min after the injection. Plasma thyroid hormone levels did not change significantly. Plasma ir-TRH and TSH responses to cold were inhibited by bombesin, but the plasma TSH response to TRH was not affected. In the pimozide- or para-chlorophenylalanine pre-treated group, the inhibitory effect of bombesin on TSH levels was prevented, but not in the L-Dopa- or 5-hydroxytryptophan pre-treated group. These drugs alone had no effect on plasma TSH levels in terms of the dose used. The inactivation of TRH immunoreactivity in plasma or hypothalamus in vitro after bombesin injection did not differ from that of the controls. These findings suggest that bombesin acts on the hypothalamus to inhibit TRH release, and that its effects are at least partially modified by amines of the central nervous system.     

Effect of bombesin on plasma insulin, pancreatic glucagon, and gut glucagon in man

The effect of bombesin on insulin, pancreatic glucagon, and gut glucagon was investigated in eight healthy volunteers and two pancreatectomized patients. Bombesin, infused iv at the constant rate of 5 ng kg-1 min-1, produced a sharp and statistically significant rise in the plasma insulin concentration. The peak was reached at 5 min (26 +/- 2.17 microU/ml; P less than 0.005 vs. basal values), followed by a prolonged and statistically significant (P less than 0.05) decrease in blood glucose. Pancreatic glucagon rapidly rose to a maximal value of 80.5 +/- 7.6 pmol/liter (P less than 0.005 vs. basal values). In contrast with the prompt increase in insulin and glucagon plasma levels, the peak in gut glucagon concentration (55.8 +/- 4.6 pmol/liter; P less than 0.005 vs. basal values) was reached 30 min after bombesin infusion was discontinued. In the two pancreatectomized patients, bombesin induced an increase in gut glucagon concentrations only. The results presented indicate that bombesin acts directly on the A and B cells of the pancreas, influencing glucose homeostasis; however, more complex mechanisms seem to be involved in gut glucagon secretion.     

Prostaglandins affect the central nervous system to produce hyperglycemia in rats

The influence of prostaglandins (PG) on central nervous system regulation of blood sugar homeostasis was studied in rats. Substances were injected into the third cerebral ventricle of anesthetized rats while rectal temperature and hepatic venous plasma glucose concentration were recorded. Stereotaxic microinjection of PGD2, E1, E2, and F2 alpha produced hyperglycemia and hyperthermia. The relative order of potency in hyperglycemia, PGF2 alpha greater than D2 greater than E1 greater than E2, was not consistent with that of hyperthermia, PGE2 greater than F2 alpha greater than E1 greater than D2, which suggests that hyperglycemia was a primary, not secondary, response to hyperthermia. Injection of PGF2 alpha caused a dose dependent (5-200 micrograms) increase in the hepatic venous plasma glucose level. Neither the injection of PGF2 alpha (50 micrograms) into the cortex nor into the systemic vein caused hyperglycemia. The injection of PGF2 alpha into the ventricle resulted in the increase of not only glucose, but also glucagon, epinephrine, and norephinephrine in the hepatic venous plasma. However, constant infusion of somatostatin through the femoral vein completely prevented the increase of glucagon after administration of PGF2 alpha, although the increase of plasma glucose level was still observed. PGF2 alpha-induced hyperglycemia did not occur in adrenodemedullated rats. Intravenous injection of naloxone or propranolol did not affect the hyperglycemia, but phentolamine significantly prevented the hyperglycemic effect of PGF2 alpha. These results suggest that intraventricular PGF2 alpha affects the central nervous system to produce hyperglycemia by increasing epinephrine secretion from the adrenal medulla.     

Thyrotropin-releasing factor-induced adrenocorticotropin secretion is mediated by corticotropin-releasing factor

TSH-releasing factor (TRF), administered into the lateral cerebroventricle of adult male rats, elevated plasma concentrations of ACTH, epinephrine, and norepinephrine. TRF given iv was devoid of these activities. The CRF receptor antagonist, alpha-helical CRF9-41 (CRF9-41) given iv suppressed the TRF-induced increase in ACTH, but did not alter TRF-induced changes in plasma catecholamines. Intravenous administration of CRF antiserum totally blocked TRF-induced elevation of plasma ACTH concentrations. CRF receptor antagonists administered icv attenuated CRF-induced, but not TRF-induced elevation of plasma concentrations of ACTH, epinephrine, and norepinephrine. It is concluded from these results that TRF acts within the central nervous system to stimulate ACTH release through a CRF-dependent mechanism.     

Autoregulation of endogenous glucose production during hyperglucagonemia

Increased endogenous glucose production (EGP) contributes to fasting hyperglycemia in type II diabetes. In nondiabetic subjects, increased gluconeogenesis from lactate does not increase EGP. Type 2 diabetes is associated with hyperglucagonemia. The present study was undertaken to examine whether physiologic elevation of plasma glucagon overrides autoregulation of EGP. Eight healthy volunteers were studied on 2 occasions, once during a 3-hour infusion of 30 micromol/kg/min Na-lactate and once during a control infusion of Na-bicarbonate. Plasma glucagon, insulin, and growth hormone were clamped at identical levels in both experiments. Rates of appearance of glucose, lactate, and gluconeogenesis from lactate were measured by tracer techniques. Glucagon infusion rate was elevated when the lactate or bicarbonate infusions were started to induce physiologic hyperglucagonemia. Plasma glucagon increased from baseline levels (234 +/- 21 ng/L and 211 +/- 23 ng/L) to 313 +/- 47 ng/L (bicarbonate experiments) and 329 +/- 43 ng/L (lactate experiments, means +/- SE, P >.3). Lactate infusion increased plasma lactate concentrations from 1.1 +/- 0.9 to 4.6 +/- 0.5 mmol/L (P =.0003). Lactate conversion to glucose increased from 1.5+/-0.3 to 2.8+/-0.8 micromol/kg/min (P =.03) and from 1.7 +/- 0.3 to 8.1 +/- 0.8 micromol/kg/min (P =.0003) in the bicarbonate and lactate experiments, respectively. The increments in lactate conversion to glucose differed significantly (P =.0008). Nevertheless, plasma glucose and EGP were not different in the bicarbonate and lactate experiments: 5.4 +/- 0.5 versus 6.6 +/- 0.7 mmol/L (P =.21), and 10.5 +/- 0.6 versus 11.6 +/- 0.6 micromol/kg/min (P =.19). We conclude that in normal volunteers, neither hyperglucagonemia nor the combination of hyperglucagonemia and increased substrate availability alters the autoregulation of EGP.     

Effect of intrahypothalamic injection of neostigmine on the secretion of epinephrine and norepinephrine and on plasma glucose level.

We previously reported that the injection of neostigmine, an inhibitor of acetylcholinesterase, into the third cerebral ventricle of fasted rats produced hyperglycemia associated with the secretion of epinephrine and norepinephrine. However, the central nervous system site of action of neostigmine by which the plasma catecholamine and glucose concentrations were increased is not known. In this study we injected neostigmine into the ventromedial hypothalamus, lateral hypothalamus, paraventricular hypothalamus, median site of the lateral-preoptic area, lateral site of the lateral-preoptic area, anterior site of the anterior hypothalamic area, mammillary body (posterior mamillary nucleus), and cortex of anesthetized fasted rats and measured the plasma levels of glucose, epinephrine, and norepinephrine. It was found that the ventromedial hypothalamus, lateral hypothalamus, paraventricular hypothalamus, and median site of the lateral-preoptic area were involved in increasing the plasma levels of glucose and epinephrine. From this evidence we conclude that neostigmine acts on selected regions known to be involved in glucoregulation in the hypothalamus to increase the plasma levels of epinephrine and glucose.     

Uncontrolled diabetes mellitus and hyperglucagonemia associated with an islet cell carcinoma.

A 53 year old woman presented with diabetes mellitus, hyperglucagonemia (600 to 1,500 pg/ml), clinical hyperparathyroidism and an abdominal mass diagnosed on biopsy as an islet cell carcinoma. Glucagon content of the tumor was 0.78 mug/g wet weight. Hourly blood samples during a 24 hour period revealed a direct correlation between plasma glucose and glucagon. The oral administration of glucose paradoxically increased whereas the intravenous administration decreased plasma glucagon. Circulating glucagon levels were markedly increased with arginine and epinephrine infusion. Both short- and long-term administration of alpha adrenergic blockade depressed the glucagon response to epinephrine infusion. In contrast, long-term alpha adrenergic blockade increased glucagon secretion despite improved glucose tolerance during a second 24 hour study. Although the patient demonstrated overt clinical and chemical findings of hyperparathyroidism, parathyroid hormone (PTH) was not detected in her plasma. The pattern of tumor growth was consistent with an origin from pancreatic islets. We conclude that (1) the tumor was responsive to physiologic stimuli known to affect glucagon secretion; (2) elevations of plasma glucagon levels with oral and dietary glucose suggest regulation of secretion by intestinal factors; and (3) improvement of glucose tolerance with alpha adrenergic blockade may be related to increased insulin secretion.     

Influence of physiologic hyperglucagonemia on urinary glucose,nitrogen, and electrolyte excretion in diabetes

To evaluate the effect of physiologic hyperglucagonemia on nitrogen and glucose metabolism and on urinary electrolyte excretion, pancreatic glucagon was administered as a continuous 3-day infusion to three adult-onset non-insulin-dependent diabetics and two insulin-treated juvenile diabetics while on a constant dietary intake. The glucagon infusion resulted in increases in plasma glucagon which were 4–6-fold greater than control values. Despite prolonged hyperglucagonemia, urinary glucose excretion was unchanged. Similarly, urinary urea nitrogen and total nitrogen excretion were not altered by glucagon administration. Urinary sodium tended to rise, albeit not significantly (P < 0.1), on the first infusion day, but later declined to control values despite increasing plasma glucagon concentrations. Urinary chloride, potassium, calcium, and phophorus excretion remained unchanged. We conclude that continuous physiologic increments in plasma glucagon do not enhance glycosuria or increase protein catabolism and ureagenesis in diabetes when insulin is available. The augmented protein catabolism and gluconeogenesis that accompany diabetic ketoacidosis can not be explained primarily on the basis of hyperglucagonemia.     

Role of insulin in the blunted glucose metabolic response of septic rats to epinephrine

Epinephrine produces smaller incremental increases in plasma glucose concentration and rate of glucose appearance (Ra) in septic rats compared with nonseptic animals. In the present study, we investigated the role of insulin in the diminished response of septic rats to epinephrine-induced increases in glucose turnover. Glucose kinetics were assessed by the infusion of [6-3H]-glucose in conscious catheterized rats made septic by subcutaneous injections of live Escherichia coli. Epinephrine was infused at 1 micrograms/min/kg for 2 hours in the presence and absence of somatostatin and mannoheptulose (SRIF + MH). In comparison to nonseptic control animals, epinephrine-induced increases in plasma glucose concentration and glucose Ra were blunted by more than 50% in the septic rats. Infusion of SRIF + MH with epinephrine restored the blunted response to normal. During the infusion of epinephrine alone, the plasma insulin concentration in the septic rats was 2.8-fold higher than the nonseptic controls. SRIF + MH lowered the plasma insulin concentrations in both the nonseptic and septic rats to less than 10 microU/mL. SRIF + MH reversed the sepsis-induced hyperglucagonemia, but did not prevent a slight increase in glucagon levels during the epinephrine infusion in the nonseptic rats. In a second study, septic rats infused with SRIF + MH and replacement insulin showed a smaller increase in glucose concentration and glucose production in response to epinephrine than did septic animals administered SRIF + MH and no insulin. These results indicate that insulin plays an important role in the diminished response of septic rats to epinephrine.     

Effects of neuropeptides on adenohypophyseal hormone response to acute stress in male rats.

The effects of bombesin and other unrelated oligopeptides on hormonal changes induced by stress were studied in conscious adult male rats. Restraint in the cold for 1 h increased plasma corticosterone and PRL levels and decreased GH values but had no effect on LH levels. Bombesin (5 microgram), given intracerebroventricularly (ivt) before stress, inhibited the PRL rise without affecting corticosterone, GH, or LH response. A complete blockade of PRL rise was observed with doses of bombesin ranging from 5 microgram to 100 ng ivt, regardless of the duration (15, 30, 45, or 60 min) or the nature (cold exposure or restraint at room temperature) of the stressor agents. Bombesin was 10(3) more potent as a PRL inhibitor when given ivt than when given iv, and its ivt effect was not reversed by naloxone (1 or 10 mg/kg). Among other unrelated peptides tested (beta-endorphin, neurotensin, substance P, and TRH; 5 microgram ivt), only neurotensin decreased plasma PRL levels in rats subjected to restraint in the cold for 1 h. These results show that in conscious male rats, centrally administered bombesin has a very potent and long acting inhibitory effect on PRL release induced by acute stress. Since a bombesin-like peptide has been found in rat brain, its physiological role in PRL regulation remains to be elucidated.     

Thyrotropin-releasing hormone-induced hyperglycemia: possible involvement of cholinergic receptors in the lateral hypothalamus

The influence of the site of action of thyrotropin-releasing hormone (TRH) on the production of hyperglycemia was studied in rats by comparing the effectiveness of TRH administered by different routes. Administration of TRH (5 micrograms) into the lateral hypothalamus (LH) produced a hyperglycemia with a peak elevation of blood glucose of 140 mg/dl. Injection of 5 micrograms TRH into the ventromedial hypothalamus (VMH) produced a blood glucose elevation of 44 mg/dl, while injection of the same dose of TRH into the anterior hypothalamus (AH) produced a blood glucose elevation of 23 mg/dl. These findings indicate an LH site of action of TRH. Indeed, intra-LH administration of TRH (1-10 micrograms) caused dose-related increases in blood glucose. Administration of acetylcholine into the same site was also shown to induce hyperglycemia. The hyperglycemic effects of TRH and acetylcholine were antagonized by previous treatment of the LH site with atropine, a cholinergic receptor antagonist. Furthermore, the TRH-induced hyperglycemia was not observed or was greatly reduced in spinal rats or in adrenalectomized rats. The results indicate that TRH may act through the cholinergic receptor mechanisms within the LH region to induce hyperglycemia by promoting an increase in the sympathetic-adrenal medullary efferent activity.     

Attenuation of endotoxin-induced increase in glucose metabolism by platelet-activating factor antagonist

Platelet-activating factor (PAF) has recently been proposed as a putative mediator of various pathophysiologic events during endotoxemia. The aim of the present study was to determine the relative importance of PAF in producing the alterations in carbohydrate metabolism following endotoxin. Chronically catheterized conscious rats were treated with SRI 63-441, a specific PAF receptor antagonist, or saline prior to Escherichia coli endotoxin (100 micrograms/100 g body weight, LD10) administration. Hemodynamic and whole-body glucose kinetic changes, the latter assessed by a constant intravenous infusion of [6-3H] glucose, were determined throughout the 4-hr experimental protocol. Endotoxin induced a transient 30-35% reduction in mean arterial blood pressure (MABP) in animals treated with saline. The PAF-antagonist attenuated this hypotensive effect, and MABP was only reduced by 14-18%. Endotoxin increased plasma glucose and lactate levels, as well as the rate of glucose appearance (Ra) in saline-treated rats. The PAF antagonist reduced the hyperglycemia by 60-75% and tended to prevent the hyperlactacidemia. The endotoxin-induced elevation in glucose Ra was also attenuated by 55%. A similar degree of hyperglucagonemia was observed following endotoxin in both groups, and plasma insulin concentrations were not different. However, plasma catecholamine levels were significantly lower (30-70%) in endotoxemic rats treated with the PAF antagonist. These results suggest that the enhanced production of PAF following endotoxin may be responsible, at least in part, for the early hemodynamic changes. The role of PAF as a mediator of endotoxin-induced glucose dyshomeostasis, however, may be secondary to its hemodynamic effects.     

Increased responsiveness to the hyperglycemic, hyperglucagonemic and hyperinsulinemic effects of circulating norepinephrine in ob/ob mice

OBJECTIVE: Several studies have implicated increased sympathetic tone as a contributing factor to the hyperglycemia and hyperglucagonemia of ob/ob mice. However, the responsiveness of plasma glucose, insulin and glucagon to circulating norepinephrine (NE) in ob/ob vs normal lean mice has never been described. Therefore, the present study investigated the effect of a 15 min intravenous NE infusion (1 pmol/min/g) on plasma glucose, insulin and glucagon in anesthetized lean, ob/ob, ob/ob-concurrent yohimbine (alpha(2) antagonist) treated, and ob/ob-chronically sympatholytic dopamine agonist treated (for 14 days prior to infusion) mice. In an effort to gain insight into a possible relation between norepinephrine, hyperglucagonemia and hyperinsulinemia in ob/ob mice, this study also examined the isolated islet responses to NE and glucagon in lean, ob/ob and ob/ob-sympatholytic dopamine agonist treated mice. RESULTS: Basal humoral values of glucose, insulin and glucagon were all elevated in ob/ob vs lean mice (by 63, 1900 and 63%, respectively, P<0.01). However, NE infusion further increased levels of glucose, insulin and glucagon in ob/ob (by 80, 90 and 60%, respectively, P<0.05) but not in lean mice (between group difference for all parameters P<0.05). Acute concurrent yohimbine treatment as well as chronic prior sympatholytic dopamine agonist treatment (bromocriptine plus SKF38393) simultaneously strongly aborgated or abolished all these humoral hypersensitivity responses to intravenous NE in ob/ob mice (P<0.05). Clamping the plasma glucose level in untreated ob/ob mice at a high level (30 mM) established by NE infusion did not significantly alter the plasma insulin level, suggesting that some other influence of NE was responsible for this insulin effect. Direct NE administration at 1 microM to islets from lean and ob/ob mice inhibited 15 mM glucose-stimulated insulin secretion in both groups, but at 0.1 microM it was inhibitory only in islets from ob/ob mice. However, glucagon (10 nM) increased 15 mM glucose-stimulated insulin secretion in ob/ob (by 170%, P<0.05) but not lean mice (between group difference P<0.05). CONCLUSION: These findings suggest that hypersensitivity to circulating NE may potentiate hyperglycemia and hyperglucagonemia in ob/ob mice, and the subsequent hyperglucagonemia coupled with increased islet beta-cell insulin secretory responsiveness to glucagon in ob/ob mice may support hyperinsulinemia, thus explaining the increased plasma insulin level response to intravenous NE in these animals. These findings further support a role for increased peripheral noradrenergic activities in the development and maintenance of the hyperglycemic, hyperglucagonemic and hyperinsulinemic state, characteristic of type 2 diabetes.     

Effects of bombesin on pancreatic digestive enzyme gene expression.

We examined the effects of bombesin on rat pancreatic digestive enzyme gene expression using cloned complementary DNA probes for amylase, trypsinogen I, chymotrypsinogen B, and lysophospholipase. Rats were injected sc three times daily with 5 nmol/kg body wt bombesin. Pancreata were investigated after 6, 12, 24, 48, and 120 h of hormone treatment. Bombesin administration resulted in a time-dependent increase of pancreatic weight, as well as DNA and protein concentration. Cellular hypertrophy became evident after 48 h, and pancreatic hyperplasia occurred after 5 days of hormone treatment. Bombesin administration resulted in a time-dependent parallel decrease of amylase and lysophospholipase messenger RNA (mRNA) concentrations with maximal inhibition occurring after 120 h of bombesin treatment (13 +/- 1% and 14 +/- 3% of control, respectively, P less than 0.05, n = 6). In contrast, chymotrypsin and trypsin mRNA levels remained unaltered after bombesin treatment for up to 5 days. Amylase and chymotrypsin enzyme levels did not correlate with their respective mRNA concentrations. Both decreased to approximately 50% of control after 12 h and increased to 126 +/- 38% of control and 388 +/- 109% of control (P less than 0.05, n = 6), respectively, after 5 days of bombesin treatment. To test whether the bombesin regulation was mediated by the release of cholecystokinin (CCK), the specific CCK receptor antagonist L-364,718 (1 mg/kg body wt) was injected ip either alone, or 15 min before each bombesin injection for 5 days. Although the antagonist alone significantly reduced the mRNA concentrations for trypsin, chymotrypsin, and lysophospholipase to approximately 50%, it did not block the effects of bombesin on pancreatic digestive enzyme levels. These data therefore indicate that bombesin regulates pancreatic digestive enzyme mRNA and protein concentrations in a nonparallel manner; furthermore, CCK is not involved in mediating the bombesin effects on pancreatic gene expression.     

Contribution of platelet activating factor to hemodynamic and sympathetic responses to bacterial endotoxin in conscious rats

The effect of the platelet activating factor (PAF) antagonist WEB 2086 on blood pressure; heart rate; and plasma glucose, lactate, and catecholamine concentrations were examined following either PAF or endotoxin administration in conscious rats. PAF infusion (50 ng/kg/min for 60 min) resulted in a sustained hypotension, with tachycardia and elevated plasma norepinephrine (NE; 1.8-fold increase), epinephrine (E; 6.7-fold increase), and dopamine (DA; 1.0-fold increase) at 30 min after beginning infusion. Plasma NE, E, and DA became 4.1 (NE)-, 17.4 (E)-, and 3.3 (DA)-fold higher than control at 60 min after beginning infusion. Both the hemodynamic and plasma catecholamine alterations induced with PAF were completely blocked with WEB 2086 pretreatment. Bacterial endotoxin treatment (5 mg/kg, i.v. bolus) produced well-characterized responses of hypotension, tachycardia, hyperglycemia, hyperlactacidemia, and an elevation in plasma catecholamines. Whereas complete blockade of the hypotensive and tachycardic effect of endotoxin was achieved with WEB 2086 at 30 min following endotoxin, the increases in plasma catecholamines and lactate elicited by endotoxin were attenuated but remained significantly higher than control levels. Hyperglycemia following endotoxin was not altered by WEB 2086 treatment. In endotoxic rats pretreated with WEB 2086 there was significant hypotension, tachycardia, and hyperlactacidemia and an elevation in plasma catecholamines at both 60 and 120 min, but all were less severe compared to non-WEB 2086-treated endotoxic animals. The results demonstrate that WEB 2086 completely blocked early endotoxin-induced hypotension and tachycardia but not catecholamine elevation following endotoxin. This work suggests that sympathetic activation following endotoxin may be mediated by factors other than hypotension.