The glucose intolerance of acute pancreatitis: hormonal response to arginine.

Patients with acute pancreatitis were studied by arginine infusion at 48--72 h. 7--10 days, and 18--21 days after onset of their illness. Plasma glucose, insulin, and glucagon values were determined. Acute pancreatitis was characterized by fasting hyperglycemia and hyperglucagonemia, associated with relative hyoinsulinemia. Arginine stimulation early in the disease (48--72 h) demonstrated hyperglycemia and hyperglucagonemia, which normalized by 18--21 days. Both phases of the normal biphasic insulin response to arginine were decreased during the initial arginine infusion. By 18--21 days, although the first phase was completely normal, the second phase of insulin secretion remained depressed. Acute pancreatitis is associated with damage to both the endocrine and exocrine pancreas. Glucose intolerance seen with this disease appears to be the result of hyperglucagonemia and relative hypoinsulinemia. Although the healing process at 3 wk is associated with return of plasma glucose and glucagon concentrations to normal, the impaired second phase insulin secretion persists.

Hemodynamic response to vasopressin in dehydrated human subjects.

BACKGROUND: Despite the known potent vasoconstrictor effects of vasopressin, the role of this hormone in the maintenance of blood pressure is incompletely understood. In studies performed in animals with increased plasma vasopressin concentrations, several complex cardiovascular effects have been noted, including decreases in heart rate and cardiac output, which may account for a lack of effect on arterial pressure despite the vasopressin-induced increase in total peripheral resistance. Only a few studies have been done to assess the cardiovascular effects of vasopressin in human subjects, and most of these have been limited to measurement of heart rate and arterial pressure only. The present study was designed to identify more fully the cardiovascular effects of vasopressin when plasma vasopressin concentrations are increased by osmotic stimulation without the superimposition of major nonosmotic stimuli associated with severe volume depletion. METHOD: Studies were performed on 11 normal human subjects in supine and erect posture before and after 24 hours of fluid deprivation, and following administration of a selective V1 receptor antagonist, [d(CH2)5Tyr(ME)]AVP, after dehydration. Cardiovascular parameters were measured noninvasively by thoracic electrical bioimpedance cardiography and blood samples for measurements of plasma concentrations of vasopressin and other hormones affected by dehydration and differences in posture were collected for subsequent analysis. RESULTS: After 24 hours of fluid restriction, plasma osmolality was increased from 287 +/- 0.9 to 294 +/- 0.7 mosm/kg H20 and plasma vasopressin concentrations (Pavp) were increased in both supine and erect posture. Mean arterial (MAP) and systolic blood pressure (SBP) were reduced by fluid restriction but were higher in erect than in supine posture both before and after fluid restriction. Heart rate (HR), diastolic blood pressure (DBP), and systemic vascular resistance (SVRI) were also higher in erect than in supine posture, while cardiac index (CI), stroke index (SI), end-diastolic index (EDI), and an index of total thoracic fluid content (TFC) were all reduced in erect posture, both before and after dehydration. Plasma renin activity (PRA) and plasma norepinephrine concentrations (Pne) were increased in erect posture, both before and after dehydration, but there was no effect of erect posture on plasma vasopressin concentrations (Pavp), either before or after dehydration. Administration of the V1 receptor antagonist after dehydration had no effect on hemodynamic parameters other than small reductions in DBP and cardiac preload. CONCLUSION: It is concluded from these studies that small increases in Pavp associated with moderate dehydration do not play a role in the maintenance of arterial pressure in normal human subjects in either supine or erect posture.

Hormonal responses to intravenous glucose and arginine in patients with pancreatitis.

19 subjects with an acute episode of pancreatitis, and 5 patients with chronic pancreatitis received intravenous glucose tolerance tests with measurement of glucose, insulin and glucagon. Patients recovering from acute pancreatitis demonstrated defects in their ability to dispose of a glucose load. 10 patients had overt glucose intolerance; of these, 4 were insulin-deficient, 3 had a loss of an acute insulin response to glucose, and 3 had marked hyperglucagonemia with normal to increased insulin levels. These abnormalities were seen in response both to intravenous glucose and intravenous arginine. Therefore, according to this study, at least three factors are clearly implicated in the production of glucose intolerance after an acute episode of pancreatitis: hypoinsulinemia, delayed insulin secretory response and hyperglucagonemia.

Growth hormone and carbohydrate intolerance in cirrhosis.

Patients with cirrhosis of the liver often have insulin resistance and elevated circulating growth hormone levels. This study was undertaken (a) to evaluate glucose intolerance, insulin resistance and abnormal growth hormone secretion and (b) to determine if GH suppression improves insulin resistance. Glucose tolerance tests (GTT), intravenous insulin tolerance tests (IVITT), arginine stimulation tests (AST) and glucose clamp studies before and during GH suppression with somatostatin were performed in a group of patients with alcohol-induced liver cirrhosis. During GTT cirrhotic subjects had a 2-hour plasma glucose of 200 +/- 9.8 ng/dl (N = 14) compared to 128 +/- 8.0 ng/dl in normal controls (N = 15), P less than 0.001. Basal GH was elevated in cirrhotic patients and in response to arginine stimulation reached a peak of 17.0 +/- 5.4 ng/ml (N = 7), compared to a peak of 11.3 +/- 1.8 ng/ml in 5 normal controls (P = NS). During IVITT patients with cirrhosis had a glucose nadir of 60.0 +/- 4.0 mg/dl (N = 9), compared to 29.0 +/- 7.0 mg/dl in controls (N = 5), P less than 0.001. Peak GH levels during IVITT were not significantly different in cirrhotics and controls. Glucose utilization rates in 4 patients with cirrhosis of the liver before somatostatin mediated GH suppression was 3.1 +/- 0.5 mg/kg/min and 6.5 +/- 1.5 mg/kg/min during somatostatin infusion, P less than 0.025. We conclude that patients with alcohol induced cirrhosis have sustained GH elevations resulting in insulin resistance which improves after GH suppression.

Characteristics of vasopressin release during controlled reduction in arterial pressure.

Because of the interruption of the descending sympathetic nervous pathways, individuals with cervical spinal cord injury experience orthostatic hypotension when in an upright posture. The changes in hemodynamic parameters that occur during upright posture can be closely monitored and quantitated during progressive head-up tilting on a tilt table. We have utilized this method to assess the response of vasopressin and other vasoactive hormones to gradual, progressive reductions in arterial pressure and to identify possible threshold responses to baroreceptor stimulation in human subjects. Studies were performed in 12 quadriplegic subjects, 3 paraplegic subjects, and 3 normal control subjects. Data from the studies in paraplegic and normal subjects did not differ and were pooled as control data. In quadriplegic subjects, mean arterial pressure (MAP) decreased from 93 +/- 4 mm Hg to 60 +/- 3 mm Hg in a closely correlated (r = 0.948, p < 0.002) linear relationship with increasing degrees of tilt, whereas in control subjects, MAP increased from 81 +/- 4 to 88 +/- 3 mm Hg. Plasma vasopressin concentrations (Pavp) increased minimally in quadriplegic subjects until MAP was reduced to levels that were 25% to 30% lower than MAP with subjects in the supine posture. Beyond this level of hypotension, Pavp increased markedly. Log-linear regression analysis of these data showed a highly significant correlation (r = 0.85, p < 0.0002) between in Pavp and MAP, which defines Pavp as an exponential function of decreasing MAP. Changes in Pavp in control subjects were minimal during incremental head-up tilting. In contrast, plasma renin activity (PRA) increased in both quadriplegic and control subjects. Log-linear regression analysis of these data showed highly significant correlates between in PRA and degree of tilt in both quadriplegic (r = 0.958, p < 0.0002) and control (r = 0.873, p < 0.0002) subjects. Plasma atrial natriuretic peptide concentrations decreased linearly with increasing degrees of tilt. The rate of decline in Panp was greater in quadriplegic than in control subjects. These studies provide additional evidence that Pavp increases exponentially as a function of decreasing MAP and suggest that a critical threshold level of hypotension exists at which vasopressin release accelerates rapidly in response to baroreceptor stimulation. At this level of reduced MAP, Pavp reaches levels that are potentially capable of exerting a pressor effect.

Studies of glucose intolerance in cirrhosis of the liver.

Patients with hepatic cirrhosis often have demonstrable glucose intolerance. We studied 21 patients with cirrhosis of the liver. Oral glucose tolerance tests (OGTT), intravenous arginine stimulation tests (IVAST), and intravenous insulin tolerance tests (IVITT) were performed, and timed blood samples were obtained for the assay of glucose immunoreactive insulin (IRI), C-peptide (C-P), and immunoreactive glucagon (IRG). The 125I-insulin binding to circulating monocytes was studied in some of the patients. All results were compared to those of similar studies performed on healthy controls. During OGTT significant glucose intolerance was demonstrable in the patients with cirrhosis (2 hr plasma glucose 198.8 +/- 14.3 mg/dl in cirrhosis and 116.4 +/- 4.2 in controls; p less than 0.001). Two-hour plasma IRI, C-P, and IRG were significantly higher in the cirrhotic patients than in controls (p less than 0.001; less than 0.001; less than 0.025). In response to IVAST, the patients with cirrhosis showed a greater first-phase insulin secretion and controls had a slightly better second-phase insulin release. Plasma IRG rose from a basal value of 446 pg/ml to 1100 in the patients with cirrhosis and from 171 pg/ml to 494 in controls. After intravenous insulin administration, there was only a 40% decline in plasma glucose concentration from basal values in the patients with cirrhosis whereas the controls showed a 60% decline, demonstrating that the patients with cirrhosis had significant insulin resistance. Moreover, the half-life of insulin was prolonged in the patients with cirrhosis (t 1/2 = 15.5 min in cirrhosis and 10.3 in controls; p less than 0.001); and the ratio of C-P to insulin during OGTT was also reduced, indicating that the patients with cirrhosis have reduced hepatic clearance of insulin. The specific binding of 125I-insulin to circulating monocytes was 2.7% in cirrhosis, 2% in obese controls, and 4% in lean controls. There was a significant negative correlation between the fasting plasma insulin values and the specific binding of insulin. In conclusion, patients with hepatic cirrhosis have significant glucose intolerance characterized by hyperinsulinemia, hyperglucagonemia, insulin resistance, and down-regulation of insulin receptors. Although hyperinsulinemia is probably caused by reduced hepatic clearance of insulin, hyperglucagonemia is primarily due to increased pancreatic secretion.