Somatostatin Infusion Research Articles

Renal Contribution to Increased Clearance of Exogenous Growth Hormone in Obese Hypertensive Patients

To evaluate the possible role of the kidney in the enhanced metabolic clearance rate (MCR) of GH in obesity, we studied the kinetics of GH and renal fractional extraction of GH (RFEGH) in 12 male hypertensive patients over a wide range of body weights (71.7-129 kg) while undergoing contrast angiography on suspicion of renal artery stenosis. A continuous infusion of recombinant human GH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. After 2 h of GH infusion, when plasma GH had reached a steady state at concentrations that were still in the physiological range, blood was sampled from the left and right renal arteries and veins for determination of GH levels. Subsequently, the GH infusion was stopped, and GH kinetics were investigated with noncompartmental analysis. In none of the patients was hemodynamically significant renal artery stenosis present. Whole body MCR of GH averaged 375 +/- 142 ml/min. Average GH levels were significantly higher in arterial plasma than in simultaneously sampled renal venous plasma (P < 0.001). RFEGH was 8.6 +/- 6.8%. The MCRs of both GH and RFEGH correlated significantly with body weight, body fat mass, and endogenous creatinine clearance. Renal uptake of GH per 100 g kidney tissue correlated inversely with MCR. These results suggest that RFEGH rises with increasing adiposity, but per unit of renal mass, the capacity of the kidney to remove GH from the circulation falls at high MCR values.

Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans

An increase in capillary blood flow and pressure in response to diabetes mellitus may lead to microangiopathy. We hypothesize that these haemodynamic changes are caused by a decreased activity of the sympathetic nervous system due to episodes of sustained hyperglycaemia. Twelve healthy volunteers consecutively underwent a hyperglycaemic experiment (HYPER), with the plasma glucose level maintained at 20 mmol.l(-1) for 6 h by combined infusion of somatostatin, insulin and glucose; and a normoglycaemic experiment (NORMO), with similar infusions but with the plasma glucose maintained at fasting level. During both experiments, sympathetic nervous system (SNS) activity was measured by assessing the plasma catecholamine levels, microneurography, power spectral analysis and forearm blood flow (FBF). In an age- and weight matched group, fasting and 6-h sympathetic activity was measured without infusion of somatostatin and insulin (CONTROL). During HYPER, forearm blood flow increased from 2.45 (0.21) to 3.10 (0.48) ml.dl(-1).min(-1) ( P <0.05), but did not change in NORMO or CONTROL. The HYPER conditions did not change the plasma noradrenaline levels or the muscle sympathetic nerve activity [42 (4), 50 (10) and 45 (5) bursts/100 beats, HYPER, NORMO and CONTROL respectively]. Also, the power spectral analysis was similar under all experimental conditions. All results are expressed as the mean (SEM). In conclusion, sustained hyperglycaemia in normal subjects induces moderate vasodilation in skeletal muscle, but this increased blood flow can not be attributed to a decreased sympathetic tone.

Exercise-Induced Changes in Insulin and Glucagon Are Not Required for Enhanced Hepatic Glucose Uptake After Exercise but Influence the Fate of Glucose Within the Liver

To test whether pancreatic hormonal changes that occur during exercise are necessary for the postexercise enhancement of insulin-stimulated net hepatic glucose uptake, chronically catheterized dogs were exercised on a treadmill or rested for 150 min. At the onset of exercise, somatostatin was infused into a peripheral vein, and insulin and glucagon were infused in the portal vein to maintain basal levels (EX-Basal) or simulate the response to exercise (EX-Sim). Glucose was infused as needed to maintain euglycemia during exercise. After exercise or rest, somatostatin infusion was continued in exercised dogs and initiated in dogs that had remained sedentary. In addition, basal glucagon, glucose, and insulin were infused in the portal vein for 150 min to create a hyperinsulinemic-hyperglycemic clamp in EX-Basal, EX-Sim, and sedentary dogs. Steady-state measurements were made during the final 50 min of the clamp. During exercise, net hepatic glucose output (mg x kg(-1) x min(-1)) rose in EX-Sim (7.6 +/- 2.8) but not EX-Basal (1.9 +/- 0.3) dogs. During the hyperinsulinemic-hyperglycemic clamp that followed either exercise or rest, net hepatic glucose uptake (mg x kg(-1) x min(-1)) was elevated in both EX-Basal (4.0 +/- 0.7) and EX-Sim (4.6 +/- 0.5) dogs compared with sedentary dogs (2.0 +/- 0.3). Despite this elevation in net hepatic glucose uptake after exercise, glucose incorporation into hepatic glycogen, determined using [3-3H]glucose, was not different in EX-Basal and sedentary dogs, but was 50 +/- 30% greater in EX-Sim dogs. Exercise-induced changes in insulin and glucagon, and consequent glycogen depletion, are not required for the increase in net hepatic glucose uptake after exercise but result in a greater fraction of the glucose consumed by the liver being directed to glycogen.

Suppression of Beta-Cell Secretion by Somatostatin Does Not Fully Reverse the Disproportionate Proinsulinemia of Type 2 Diabetes

Disproportionate hyperproinsulinemia is a feature of beta-cell dysfunction in type 2 diabetes. It has been hypothesized that this abnormality represents an intrinsic abnormality of the beta-cell and/or may result from an increase in beta-cell secretory demand. To address this, six patients with type 2 diabetes and six age- and BMI-matched normal subjects received a combined 3-h insulin and somatostatin clamp to decrease beta-cell secretory demand. An arginine stimulation test was performed before and at the end of the clamp to measure beta-cell peptide release. In keeping with the reduction in secretory demand, C-peptide levels were suppressed by 60-80% during the clamp, as were proinsulin (PI) levels. The arginine-stimulated PI/C-peptide ratio decreased in the diabetic subjects from 4.4 +/- 1.5% before to 1.8 +/- 0.5% after the clamp (P < 0.01). This latter ratio was similar to that observed in the normal subjects before the somatostatin infusion (1.5 +/- 0.3%). In the normal subjects, after the clamp the PI/C-peptide ratio had decreased to 0.8 +/- 0.3% (P <0.01). Thus, the postclamp PI/C-peptide ratio in the subjects with type 2 diabetes was elevated compared with that in the normal subjects (P <0.05). Based on these observations, while relief of secretory demand on beta-cells by somatostatin decreases the disproportionate elevation in PI levels in patients with type 2 diabetes, the failure to normalize this measure suggests that an intrinsic abnormality of beta-cell function exists in subjects with type 2 diabetes that may be aggravated by increased secretory demand.

Portal Vein Caffeine Infusion Enhances Net Hepatic Glucose Uptake during a Glucose Load in Conscious Dogs

We determined whether intraportal caffeine infusion, at rates designed to create concentrations similar to that seen with normal dietary intake, would enhance net hepatic glucose uptake (NHGU) during a glucose load. Dogs (n = 15) were implanted with sampling and infusion catheters as well as flow probes >16 d before the studies. After a basal sampling period, dogs were administered a somatostatin infusion (0-150 min) as well as intraportal infusions of glucose [18 micromol/(kg . min)], basal glucagon [0.5 ng/(kg . min)], and insulin [8.3 pmol/(kg . min)] to establish mild hyperinsulinemia. Arterial glucose was clamped at 10 mmol/L with a peripheral glucose infusion. At 80 min, either saline (Control; n = 7) or caffeine [1.5 micromol/(kg . min); n = 8] was infused into the portal vein. Arterial insulin, glucagon, norepinephrine, and glucose did not differ between groups. In dogs infused with caffeine, NHGU was significantly higher than in controls [21.2 +/- 4.3 vs. 11.2 +/- 1.6 micromol/(kg . min)]. Caffeine increased net hepatic lactate output compared with controls [12.5 +/- 3.8 vs. 5.5 +/- 1.5 micromol/(kg . min)]. These findings indicate that physiologic circulating levels of caffeine can enhance NHGU during a glucose load, and the added glucose consumed by the liver is in part converted to lactate.

Prophylaxis of ERCP-related pancreatitis: A randomized, controlled trial of somatostatin and gabexate mesylate

Background & Aims: It still is debated whether post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis can be prevented by administering either somatostatin or gabexate mesylate. The aim of the study is to assess the efficacy of a 6.5-hour infusion of somatostatin or gabexate mesylate in preventing ERCP-related complications. Methods: In a double-blind multicenter trial, 1127 patients undergoing ERCP were randomly assigned to intravenous administration of somatostatin (750 μg; n = 351), gabexate mesylate (500 mg; n = 381), or placebo (saline; n = 395). The drug infusion started 30 minutes before and continued for 6 hours after endoscopy. Patients were evaluated clinically, and serum amylase levels were determined at 4, 24, and 48 hours after endoscopy. Results: No significant differences in incidences of pancreatitis, hyperamylasemia, or abdominal pain were observed among the placebo (4.8%, 32.6%, and 5.3%, respectively), somatostatin (6.3%, 26.8%, and 5.1%, respectively), and gabexate mesylate groups (5.8%, 31.5%, and 6.3%, respectively). Univariate analysis of patient characteristics and endoscopic maneuvers showed that a Freeman score >1 ( P < 0.0001), ≥3 pancreatic injections ( P < 0.00001), and precut sphincterotomy ( P = 0.01) were significantly associated with post-ERCP pancreatitis. At multiple logistic regression analysis, ≥3 pancreatic injections (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.45–2.63) and a Freeman score >1 (OR, 1.47; 95% CI, 1.11–1.94) retained their predictive power. Conclusions: Long-term (6.5-hr) administration of either somatostatin or gabexate mesylate is ineffective for the prevention of post-ERCP pancreatitis. Pancreatic injury seems to be related to difficulty in common bile duct access.

Modulation of basal glucose metabolism and insulin sensitivity by growth hormone and free fatty acids during short-term fasting.

The metabolic response to fasting involves an increase in circulating levels of growth hormone (GH) and free fatty acids, and resistance to insulin's actions on glucose metabolism. Stimulation of lipolysis and insulin resistance are well-described effects of GH. The present study was designed to test the degree to which the insulin antagonistic effects of GH on glucose metabolism are mediated through stimulation of lipolysis during fasting. Seven normal subjects were examined on three occasions during a 40-h fast with infusion of somatostatin, insulin and glucagon for the final 18 h: (expt. i) with GH replacement, (expt. ii) with GH replacement and antilipolysis with acipimox, and (expt. iii) without GH and with antilipolysis. Basal glucose turnover was significantly reduced by addition of acipimox (rate of disappearance (Rd) glucose (mg/kg/min): 1.91+/-0.08 (expt. i), 1.69+/-0.05 (expt. ii), 1.61+/-0.08 (expt. iii); P<0.01), whereas insulin-stimulated glucose uptake was significantly increased (glucose infusion rate (M-value) (mg/kg/min): 1.66+/-0.22 (expt. i), 2.47+/-0.10 (expt. ii), 2.00+/-0.31 (expt. iii); P<0.05). Addition of GH during inhibition of lipolysis failed to affect basal and insulin-stimulated glucose metabolism significantly. Thus, the present data provide strong evidence that the insulin antagonistic effects of GH on fasting glucose metabolism are causally linked to concomitant stimulation of lipolysis.

Modulating amylase and lipase secretion in the pancreatic graft by somatostatin administration: preliminary results of a prospective, randomized trial

Pancreas transplantation is a routine method for the treatment of diabetes mellitus. One of the main challenges of a transplant with extraperitoneal placement of the pancreatic graft is impaired wound healing due to massive amylase and lipase secretion by the pancreatic graft, evoking edemtous fluid. From February 2002 through January 2003, we performed pancreatic transplant procedures in 21 patients who were prospectively and randomly assigned to two groups: 8 organ donors and the recipients were administered somatostatin by continuous infusion. Thirteen grafts were harvested and transplanted without somatostatin infusion. The two groups did not show significantly differences in mean donor or recipient ages, weights, of serum amylase and lipase content values or drain output until day 6. There was a significantly lower lipase in the drain output of transplant recipients given somatostatin (12.5 and 54.2 μmol/L, respectively; P < .05). Neither the post-pancreatic transplant wound healing nor the number of rejection episodes were affected by somatostatin administration.

Somatostatin (SS) and Gabexate (GM) Are Ineffective in Preventing Post-ERCP Complications

Background: The issue whether it is possibile to prevent pancreatic damage by the prophylactic administration of SS or GM is still debated. Aim of this study was to assess the efficacy of these drugrs for prevention of post-ERCP pancreatitis. Methods: A double-blind, multicenter, placebo-controlled trial was conducted in 966 patients who after randomization received an intravenous infusion of SS (750 mg, n=290), GM (500 mg, n=327), or placebo (saline, n=349) that was started 30 minutes before endoscopy and continued for 6 hours afterward. Patients were evaluated clinically and serum amylase levels determined at 4 and 24 hours after endoscopy. Results: No significant difference in the occurrence of pancreatitis, hyperamylasemia, or abdominal pain was observed among placebo (6.9%, 33.5%, and 4.0% respectively), SS (7.6%, 26.6%, and 2.8%, respectively), and GM (6.1%, 32.7%, and 4.0% respectively). At univariate analysis of patients characteristics and endoscopic maneuvers, the Freeman score for difficult cannulation (p<0.0001), more than 3 pancreatic injections (p<0.00001), an intradiverticular papilla (p=0.01), and bile duct diameter <8 mm (p=0.04) were associated to post-ERCP pancreatitis. At multivariate logistic analysis only more than 3 pancreatic injections (OR=1.72, 95% CI 1.15-2.59), and the Freeman score (OR=1.41, 95% CI 1.08-1.86) were predictive of post-ERCP pancreatitis. Conclusion: Long-term (6.5 hours) administration of SS or GM is ineffective for prevention of post-ERCP pancreatitis. Pancreatic injury is related to maneuvers used to obtain biliary access rather than any patient characteristics.

Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals

Obese individuals tend to be both insulin resistant and at increased risk to develop cardiovascular disease (CVD). Given the increased prevalence of obesity in the US population, we thought it important to define the relationship between degree of obesity and insulin-mediated glucose disposal in the population at large, as well as the relationship between obesity, insulin resistance, and CVD risk in these individuals. To do this we quantified insulin-mediated glucose disposal in 465 healthy volunteers by determining the steady-state plasma glucose (SSPG) concentrations at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Adiposity was estimated by body mass index (BMI) and the relationship between BMI and SSPG defined. In addition, a series of CVD risk factors were measured, including blood pressure, plasma glucose, and insulin concentrations, before and after 75 g of oral glucose, and fasting plasma lipid and lipoprotein concentrations. The results indicated that SSPG concentration and BMI were significantly correlated ( r = 0.54, P > .001), and 36% of individuals in the most insulin-resistant tertile were obese (BMI ≥ 30.0 kg/m 2). However, 16% of those in the most insulin-resistant tertile were of normal weight (BMI < 25.0 kg/m 2). Although CVD risk factors were accentuated in general with progressive increases in either BMI or SSPG concentration, important differences were noted. Thus, the higher the SSPG concentration, the more the increase in plasma glucose, insulin, and triglyceride (TG) concentrations, whereas the greater the BMI, the higher the low-density lipoprotein concentration. Furthermore, while CVD risk factors increased significantly with each tertile of insulin resistance, significant differences in CVD risk were only apparent when the lowest BMI tertile was compared with the other 2, with the values in the middle and upper BMI differing from each other. These results show that while BMI and insulin resistance are related, they are not synonymous, and that they make independent and different contributions to increasing CVD risk.

Expression of somatostatin receptors 1 and 2 in the adult mouse kidney

Systemic infusion of somatostatin in humans and rodents alters renal glomerular filtration rate, solute transport, and water clearance. Among the five different G-protein-coupled somatostatin receptors (SSTRs), SSTR1 is expressed in human kidney collecting ducts and SSTR2 is expressed in rat and human collecting ducts and glomeruli. Our laboratory recently localized SSTRs 3, 4, and 5 to mouse kidney proximal tubules. Our aim was to characterize the expression of somatostatin receptors 1 and 2 in mouse kidneys. We detected mRNA for somatostatin receptors 1 and 2 in the mouse kidney by reverse transcriptase-polymerase chain reaction (RT-PCR), with confirmation by Southern blotting. In contrast to the data in human kidneys, we localized SSTR1 proteins to mouse proximal tubules and glomerular podocytes. Similar to the reports in human and rat kidneys, we detected SSTR2 proteins in the murine glomerulus and collecting duct; we were further able to identify the specific SSTR2-positive cells as podocytes and principal cells, respectively. Thus, taken with our previously published results, the kidney expresses all five somatostatin receptors. Furthermore, the expression of the SSTRs in the mouse kidney correlates well with the known actions of somatostatin in the kidney.

Hyperglycemia Downregulates Total Lipoprotein Lipase Activity in Humans.

To address the question whether an increase in insulinemia and/or glycemia affects the total activity of lipoprotein lipase (LPL) in circulation, the enzyme activity was measured after periods of hyperinsulinemia (HI), hyperglycemia (HG), and combined hyperinsulinemia and hyperglycemia (HIHG) induced by euglycemic hyperglycemic clamp, hyperglycemic clamp with the infusion of somatostatin to inhibit endogenous insulin secretion, and hyperglycemic clamp, respectively. The results obtained were compared to those after saline infusion (C). Twelve healthy normolipidemic and non-obese men with normal glucose tolerance were included in the study. At the end of each clamp study, LPL activity was determined first in vivo using an intravenous fat tolerance test and then in vitro in postheparin plasma. Whereas isolated HI had no effect on LPL activity in postheparin plasma, both HG and HIHG reduced LPL activity to 60 % and 56 % of that observed after saline infusion. Similarly, the k2 rate constant determined in intravenous fat tolerance test was reduced to 95 %, 84 %, and 54 % after periods of HI, HG, and HIHG, respectively. The activity of hepatic lipase, another lipase involved in lipoprotein metabolism, was not affected by hyperinsulinemia and/or hyperglycemia. In conclusion, our data suggest that hyperglycemia per se can downregulate the total LPL activity in circulation.

Interaction of insulin and prior exercise in control of hepatic metabolism of a glucose load.

To determine if prior exercise enhances insulin-stimulated extraction of glucose by the liver, chronically catheterized dogs were submitted to 150 min of treadmill exercise or rest. After exercise or rest, dogs received portal glucose (18 micro mol x kg(-1) x min(-1)), peripheral somatostatin, and basal portal glucagon infusions from t = 0 to 150 min. A peripheral glucose infusion was used to clamp arterial blood glucose at 8.3 mmol/l. Insulin was infused into the portal vein to create either basal levels or mild hyperinsulinemia. Prior exercise did not increase whole-body glucose disposal in the presence of basal insulin (25.5 +/- 1.5 vs. 20.3 +/- 1.7 micro mol x kg(-1) x min(-1)), but resulted in a marked enhancement in the presence of elevated insulin (97.2 +/- 15.1 vs. 64.4 +/- 7.4 micro mol x kg(-1) x min(-1)). Prior exercise also increased net hepatic glucose uptake in the presence of both basal insulin (7.5 +/- 1.2 vs. 2.9 +/- 2.4 micro mol x kg(-1) x min(-1)) and elevated insulin (22.0 +/- 3.5 vs. 11.5 +/- 1.8 micro mol x kg(-1) x min(-1)). Likewise, net hepatic glucose fractional extraction was increased by prior exercise with both basal insulin (0.04 +/- 0.01 vs. 0.01 +/- 0.01 micro mol x kg(-1) x min(-1)) and elevated insulin (0.10 +/- 0.01 vs. 0.05 +/- 0.01). Hepatic glycogen synthesis was increased by elevated insulin, but was not enhanced by prior exercise. Although the increase in glucose extraction after exercise could be ascribed to increased insulin action, the increase in hepatic glycogen synthesis was independent of it.

Methods for quantifying insulin resistance in human immunodeficiency virus-positive patients

Various indirect indices have been used in human immunodeficiency virus (HIV)-infected individuals to assess insulin resistance, but the validity of these measures has not been rigorously assessed by comparison with physiologic methods of quantifying insulin-mediated glucose uptake (IMGU). We directly measured IMGU in 50 nondiabetic HIV-positive subjects by determining the steady-state plasma glucose (SSPG) concentration in response to a 3-hour continuous infusion of insulin, glucose, and somatostatin. Because steady-state plasma insulin concentrations were similar (∼60 μU/mL) in all subjects, the SSPG concentrations provided direct assessments of insulin action. Relationships between SSPG levels and various surrogate measures of IMGU derived from the 75-g oral glucose tolerance test (OGTT) were determined. The indirect measure of IMGU most closely related to SSPG concentrations was the total integrated insulin response to a 75-g glucose load ( r = 0.78, P < .01), accounting for approximately two thirds of the variability in SSPG ( r 2 = 0.61). Other indirect measures of IMGU, including the homeostasis assessment for insulin resistance (HOMA-IR), were also significantly related to SSPG values, but had lower magnitudes of correlation ( r = 0.43 to 0.61), thereby possessing limited ability to predict SSPG variability ( r 2 = 0.18 to 0.37). In conclusion, indirect measures of IMGU need to be applied with caution when evaluating insulin action in HIV-infected patients.

Activation of the Somatotropic Axis by Testosterone in Adult Men: Evidence for a Role of Hypothalamic Growth Hormone-Releasing Hormone

Testosterone (T) is known to affect the growth hormone (GH) axis. However, the mechanisms underlying the activation of GH secretion by T still remain to be clarified. Available data in animals and humans have shown that withdrawal of somatostatin (SRIH) infusion induces a GH-releasing hormone (GHRH)-mediated rebound release of GH, and there is accumulating evidence that SRIH infusion withdrawal may be a useful test to probe the GHRH function in vivo. With the aim of investigating whether the stimulatory effect of androgens on GH release in man could be accounted for by activation of the hypothalamic GHRH tone, we evaluated the plasma GH response to SRIH withdrawal in 10 patients aged 29.6 ± 2.4 years (mean ± SEM), diagnosed with hypergonadotropic hypogonadism, before and after a 6-month replacement therapy with T enanthate (250 mg every 3 weeks, i.m.), and in 10 healthy men, aged 26.7 ± 2.8 years. To verify whether the modulation of GH secretion by T could also be mediated through changes in SRIH tone and/or pituitary releasable pool, we examined GH secretory responses to combined GHRH and L-arginine (ARG) in the same individuals. Basal plasma concentrations of GH (0.48 ± 0.11 µg/l) and IGF-I (23.79 ± 1.83 nmol/l) were significantly lower in untreated hypogonadal patients than in healthy men, and significantly increased after T replacement therapy (GH 1.13 ± 0.28 µg/l; IGF-I 28.71 ± 1.46 nmol/l). The mean ΔGH peak after SRIH withdrawal recorded in untreated hypogonadal men (2.65 ± 0.86 µg/l) was significantly (p < 0.05) lower than that observed in healthy men (6.53 ± 1.33 µg/l) and significantly increased after T replacement therapy (5.52 ± 1.25 µg/l). The GH responses to GHRH combined with ARG (a functional SRIH antagonist) were not significantly different between healthy men and untreated hypogonadal patients, and were not significantly affected by T treatment. Plasma T and estradiol (E₂) levels significantly correlated with ΔGH peak after SRIH withdrawal in healthy men and in T-treated hypogonadal patients, whereas in untreated patients they did not. No significant correlation was found between GH areas under the curve after GHRH + ARG test and T and E₂ plasma levels in either healthy men or in hypogonadal patients (both before and after T replacement). These findings are consistent with the view that in humans the stimulatory action of T on the GH axis appears to be mediated at the hypothalamic level primarily by promoting GHRH function.

Chronic hepatic artery ligation does not prevent liver from differentiating portal vs. peripheral glucose delivery.

Infusion of glucose into the hepatic artery blocks the stimulatory effect of the "portal signal" on net hepatic glucose uptake (NHGU) during portal glucose delivery. We hypothesized that hepatic artery ligation (HAL) would result in enhanced NHGU during peripheral glucose infusion because the arterial glucose concentration would be perceived as lower than that in the portal vein. Fourteen dogs underwent HAL approximately 16 days before study. Conscious 42-h-fasted dogs received somatostatin, intraportal insulin, and glucagon infusions at fourfold basal and at basal rates, respectively, and peripheral glucose infusion to create hyperglycemia. After 90 min (period 1), seven dogs (HALpo) received intraportal glucose (3.8 mg. kg-1. min-1) and seven (HALpe) continued to receive only peripheral glucose for 90 min (period 2). These two groups were compared with nine non-HAL control dogs (control) treated as were HALpe. During period 2, the arterial plasma insulin concentrations (24 +/- 3, 20 +/- 1, and 24 +/- 2 microU/ml) and hepatic glucose loads (39.1 +/- 2.5, 43.8 +/- 2.9, and 37.7 +/- 3.7 mg. kg-1. min-1) were not different in HALpe, HALpo, and control, respectively. HALpo exhibited greater (P < 0.05) NHGU than HALpe and control (3.1 +/- 0.3, 2.0 +/- 0.4, and 2.0 +/- 0.1 mg. kg-1. min-1, respectively). Net hepatic carbon retention was approximately twofold greater (P < 0.05) in HALpo than in HALpe and control. NHGU and net hepatic glycogen synthesis during peripheral glucose infusion were not enhanced by HAL. Even though there exists an intrahepatic arterial reference site for the portal vein glucose concentration, the failure of HAL to result in enhanced NHGU during peripheral glucose infusion suggests the existence of one or more comparison sites outside the liver.

LOCAL THERMAL CONTROL OF SKIN BLOOD FLOW IN DIABETES

Local temperature has an important role in the control of the skin circulation in humans, and can change skin blood flow from zero to maximal levels. Vasodilation to local warming of the skin includes important roles for sensory nerves and nitric oxide. In individuals with type 2 diabetes mellitus (DM), cutaneous vascular function is impaired, but the mechanisms are not well understood. PURPOSES To test whether local warming vasodilation is altered in type 2 DM, and to test whether hyperglycemia per se has a role in altered local control of skin blood flow in diabetes. METHODS 1. We used nonpainful local warming (42°C) of the skin in combination with laser-Doppler measurement of skin blood flow in individuals with type 2 DM and in age-matched controls. 2. In separate studies, we measured responses to similar local warming in healthy individuals during acute hyperglycemia induced by intravenous infusion of glucose with simultaneous insulin, somatostatin, glucagon and growth hormone infusions to keep all other hormones at baseline physiological levels. RESULTS Preliminary results indicate diminished vasodilation to nonpainful local warming in patients with type 2 DM compared to controls, including a decrease of ∼20% in both the initial peak (sensory nerve mediated) and final plateau (NO dependent) phases of the response. Acute hyperglycemia in healthy subjects did not alter cutaneous vasodilation to local warming. CONCLUSION Cutaneous vasodilation to nonpainful local warming is impaired in type 2 DM. Although one episode of acute hyperglycemia did not affect this response in healthy subjects, this impairment in patients may be a result of repeated episodes or higher levels of hyperglycemia in the development of the disease. Supported by NIH DK-29953, HL-63328, AR-08610 and GCRC grant RR-00585 (to the Mayo Clinic).

Migratory necrolytic erythema and glucagonoma

Surgery 2003;133:449-50.

Somatostatin infusion withdrawal: a study of patients with migraine, cluster headache and healthy volunteers

Migraine and cluster headache are the most common disabling primary headache syndromes and are typically episodic. A reliable method of triggering such headache attacks facilitates the study and treatment of these disorders. There is sufficient clinical and laboratory evidence to suggest that somatostatin withdrawal may be a useful way of triggering headache. We studied 15 subjects, eight migraineurs, four cluster headache sufferers and three healthy controls. Each subject had a standard somatostatin infusion, 250 μg/h for 3.5 h. Subjects were followed for 24 h post-infusion. Growth hormone was suppressed in each subject demonstrating a biologically active infusion of somatostatin. None of the non-headache sufferers had pain. Seven of eight migraine sufferers had no immediate headache and no delayed headache. One migraineur experienced short lasting headache with no migrainous features. Three of four patients with cluster headache had no significant pain with the infusion, while one had pain after 1 h. The results suggest that somatostatin infusion is not a reliable way to produce headache in experimental settings in either migraine or cluster headache. The data do not exclude a role for somatostatinergic mechanisms in primary headache.

Modulation by somatostatin of rat submandibular salivary secretion

Although somatostatin (somatotrophin release inhibitory factor; SRIF) is a well-known inhibitory peptide, there are only a few reports of it acting as a positive modulator. In this work, the action of somatostatin upon rat submandibular protein secretion was studied. In vivo somatostatin infusion (35 μg/(kg h)) raised protein secretion stimulated by adrenergic and peptidergic agents. To rule out possible systemic effects of somatostatin, in vitro experiments were performed. Somatostatin (90 nmol/l) augmented protein release stimulated by noradrenaline (19 μmol/l) and substance P (10 μmol/l), but it did not affect isoprenaline (400 μmol/l)-induced protein release. Phenoxybenzamine (20 μmol/l) reduced the effect of somatostatin on noradrenaline-stimulated protein release. Propranolol (20 μmol/l) increased the noradrenaline-stimulated protein release and this effect was synergistic with the action of somatostatin. The absence of extracellular calcium did not significantly reduce somatostatin enhancement of agonist-induced secretion. Fluorescence measurements of the Ca 2+-sensitive dye fluo3 showed that cytosolic calcium in acinar cells remained elevated during stimuli when somatostatin was present in the medium. It was concluded that somatostatin modulates rat submandibular protein secretion by prolonging the time that the cytosolic calcium signal remains high after stimulus.