Gerald R. Faloona

Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion.

Abstract The effect of large carbohydrate or protein meals upon plasma glucagon was compared in 14 nondiabetic and 24 diabetic patients. In nondiabetic subjects carbohydrate suppressed mean glucago...

Elevated Plasma and Tissue Levels of Vasoactive Intestinal Polypeptide in the Watery-Diarrhea Syndrome Due to Pancreatic, Bronchogenic and Other Tumors

The actions of the vasoactive intestinal polypeptide make it a potential candidate for mediating certain manifestations of the watery-diarrhea syndrome. Peptide levels were measured by radioimmunoassay in 25 controls and 30 patients with chronic watery diarrhea. Plasma levels were too low to measure (smaller 200 pg per milliliter) in 22 of the controls, averaging 79 plus or minus 64 pg per milliliter (S.D.). Levels were elevated in 26 of 28 plasma samples (5.1 plus or minus 2.5 ng per milliliter), and in each of 13 tissue extracts (5.1 plus or minus 10.9 mug per gram); in all, 28 patients had elevated levels in plasma or tissue or both. Thirteen patients had pancreatic islet-cell adenoma, four islet-cell hyperplasia, five bronchogenic carcinoma, and one each pheochromocytoma and ganglioneuroblastoma. The findings indicate that the peptide is a probable mediator of the watery-diarrhea syndrome, that the syndrome may result from a variety of non-pancreatic tumors, and that this or a related peptide may also be secreted by these tumors.

The effect of experimental insulin deficiency on glucagon secretion

Suppression of pancreatic glucagon secretion by hyperglycemia is a characteristic of normal alpha cell function. However, in diabetic subjects, plasma glucagon is normal or high despite hyperglycemia. It seemed possible that the presence of glucose or its metabolites within the alpha cell might be essential for suppression of glucagon secretion, and that in diabetes an intracellular deficiency of glucose secondary to insulin lack might be responsible for the nonsuppressibility. The present study was designed to determine the effect upon glucagon secretion of blockade of glucose metabolism and of experimental insulin deficiency. Blockade of glucose metabolism was induced in dogs by administration of 2-deoxyglucose or mannoheptulose. A striking rise in glucagon was observed despite accompanying hyperglycemia and hyperinsulinemia, which, in the case of mannoheptulose, was induced by infusing crystalline insulin. To determine if insulin lack also causes paradoxical hyperglucagonemia, dogs were made severely diabetic by alloxan. Fasting glucagon levels ranged from 3 to 22 times normal despite severe hyperglycemia, and were quickly restored to normal by infusing insulin. Diabetes induced in rats by anti-insulin serum was also associated with significant elevation in plasma glucagon. However, diazoxide-induced insulin lack did not increase glucagon in dogs. It is concluded that normal suppression of glucagon secretion by hyperglycemia does not occur when glucose metabolism is blocked or when severe insulin deficiency is produced. It is suggested that normal glucose metabolism within the alpha cell may be an insulin-requiring process without which hyperglycemic suppression of glucagon release cannot occur.

Glucagon-stimulating activity of 20 amino acids in dogs

The effect of 20 L-amino acids upon pancreatic glucagon secretion has been studied in conscious dogs. Each amino acid was administered intravenously over a 15 min period in a dose of 1 mmole/kg of body weight to a group of four or five dogs. Pancreatic glucagon and insulin were measured by radioimmunoassay. 17 of the 20 amino acids caused a substantial increase in plasma glucagon. Asparagine had the most glucagon-stimulating activity (GSA), followed by glycine, phenylalanine, serine, aspartate, cysteine, tryptophan, alanine, glutamate, threonine, glutamine, arginine, ornithine, proline, methionine, lysine, and histidine. Only valine, leucine, and isoleucine failed to stimulate glucagon secretion, and isoleucine may have reduced it. No relationship between glucagon-stimulating activity and insulin-stimulating activity was observed. The amino acids which enter the gluconeogenic pathway as pyruvate and, which are believed to provide most of the amino acid-derived glucose, had a significantly greater GSA than the amino acids which enter as succinyl CoA or as alpha-ketoglutarate. However, pyruvate itself did not stimulate glucagon secretion. The R-chain structure of the amino acid did not appear to be related to its GSA, except that the aliphatic branched chain amino acids, valine, leucine, and isoleucine, were devoid of GSA.

Abnormal pancreatic alpha-cell function in bacterial infections.

Abstract To determine the effect of infection on pancreatic alpha-cell function, plasma glucagon was measured in 22 nondiabetic patients hospitalized with bacterial infection. Glucagon averaged 409 ± 129 pg per milliliter(mean ± S.E.M.) in six patients with severe infection and 185 ± 31 pg per milliliter in 11 with moderate infection, values significantly greater than the mean fasting concentration of 75 ± 4 pg per milliliter found in healthy subjects. The elevated value in all groups returned to normal with recovery. Experimental pneumonococcal pneumonia in dogs was also associated with hyperglucagonemia. Hyperglucagonemia induced in alloxan-diabetic dogs by zinc glucagon given in addition to their usual insulin produced hyperglycemia, glycosuria and an increase in urine volume and urea excretion. Thus, in man and in dogs, infection appears to be accompanied by hyperglucagonemia. In diabetic dogs the glucagon elevation can cause worsening of the diabetic state. This effect may explain infection-induced d...

The Influence of the Antecedent Diet upon Glucagon and Insulin Secretion

Abstract The effect of varying carbohydrate intake upon plasma insulin and glucagon was tested in five volunteers. One week of carbohydrate restriction lowered fasting insulin from 18 to 11 μU per milliliter, whereas fasting glucagon rose from 100 to 136 pg per milliliter, a decline in insulin-glucagon ratio (I/G) of 3.9 to 1.6. One week of isocaloric restoration of carbohydrate to the diet increased fasting insulin to 14 μU per milliliter, and glucagon declined to 65 pg per milliliter, a return of I/G to 4.4. A week of carbohydrate restriction changed the response of insulin and glucagon to protein, insulin rising only to 15 μU per milliliter, whereas glucagon rose from 126 to 218 pg per milliliter, I/G remaining unchanged. After one week of a carbohydrate-containing diet insulin rose to 38 μU, and glucagon to only 167 pg per milliliter, I/G rising from 4.35 to 8.2. The results support the key glucoregulatory role of the alpha and beta cells in influencing hepatic glucose production from both endogenous ...

Hyperglucagonemia of Renal Failure

Elevation of plasma glucagon concentration has been observed in starvation and illnesses associated with increased catabolism such as diabetes mellitus and severe infections. Thus, we examined plasma glucose, immunoreactive insulin (IRI, microunits per milliliter) and glucagon (IRG, picograms per milliliter) responses to a beef meal (1 g/kg body wt) and intravenous glucose (1.5 g/min for 45 min) in patients with chronic renal failure (CRF). After the beef meal (n = 6), plasma glucose did not change, IRI rose from 10.1+/-1.2 to 16.3+/-1.1 (P < 0.01), and IRG rose from a fasting value of 225+/-26 to 321+/-40 (P < 0.01) by 90 min (mean+/-SEM). Intravenous infusion of glucose in CRF patients resulted in significant elevations and prolonged disappearance of plasma glucose and insulin when compared to control subjects (P < 0.01). Glucose infusion failed to suppress elevated plasma glucagon concentrations to normal levels.6 wk of chronic hemodialysis in five patients resulted in normal plasma glucose and insulin responses to the same intravenous glucose load. In contrast, plasma glucagon concentration remained unchanged after hemodialysis and there was no correlation of plasma glucagon levels with carbohydrate intolerance.

The effect of alanine on glucagon secretion

If glucagon plays a hormonal role in the regulation of gluconeogenesis from endogenous amino acids, its secretion might be stimulated by an increase in the concentration of alanine, which has recently been identified as a principal gluconeogenic precursor. To determine if this is the case, 0.75 mmole of alanine per kilo was infused into conscious dogs immediately after a priming injection of 0.25 mmole per kg for 15 min. A uniform rise in the plasma level of pancreatic glucagon, as determined by a relatively specific radioimmunoassay for pancreatic glucagon, was observed. The rise, which averaged 90 pg per ml, was highly significant at 7(1/2) and 15 min after the start of the infusion. Insulin rose an average of only 8 muU per ml, while glucose rose an average of 10 mg per 100 ml. A lower dose of alanine, 1 mmole per kg, infused over a 1 hr period without an initial priming injection, also elicited a significant rise in glucagon measured in the pancreaticoduodenal venous plasma; glucagon rose from 350 pg per ml to 1066 pg per ml at the end of the infusion. The insulin response was modest and inconsistent, and glucose, again, rose 10 mg per 100 ml. To determine if the availability of exogenous glucose would abolish the alanine-induced rise in glucagon secretion, dogs were made hyperglycemic by a constant intravenous glucose infusion and were then given the high-dose alanine infusion. Under these circumstances, glucagon did not rise above the mean fasting concentration of 75 pg per ml, whereas mean insulin rose dramatically by more than 100 muU per ml. It was concluded that, in the fasting state, alanine does stimulate the secretion of glucagon, while having very little stimulatory effect on insulin secretion. Glucagon could, therefore, be a humoral mediator of gluconeogenesis from endogenous alanine, responding to hyperalaninemia in the fasting state, but not when exogenous glucose is available.

The Effect of Insulin on the Alpha-Cell Response to Hyperglycemia in Long-Standing Alloxan Diabetes

In acute experimental diabetes in animals, alpha-cell unresponsiveness to hyperglycemia can be promptly corrected by insulin, but in human diabetes, even massive doses of insulin have little effect. To determine if this inability of insulin to correct the alpha-cell abnormality in man is merely the consequence of the long duration of the diabetic state (rather than of a difference in mechanism), the effect of insulin was studied in alloxan diabetes of long duration. Alloxan-diabetic dogs were maintained for 7-18 mo and treated daily with insulin. When glucose was infused without insulin, glucagon did not decline but rose paradoxically. However, when insulin was infused at a rate of 9 mU/kg/min together with glucose, a prompt decline in glucagon from a base-line average of 171 pg/ml SEM+/-34 to a nadir of 41 pg/ml SEM+/-9 was observed. This decline indicated that alpha-cell responsiveness to hyperglycemia is completely restored by large quantities of insulin. To determine if small amounts of insulin would similarly restore alpha-cell responsiveness in long-standing experimental diabetes, 1.4 mU/kg/min was infused. By the time the mean insulin level had risen 43 muU/ml, glucagon had declined significantly and ultimately fell to a nadir of 44 pg/ml. It is concluded from these studies that alpha-cell responsiveness to hyperglycemia can be fully restored in long-standing alloxandiabetic dogs as readily as in acutely diabetic dogs. Its ineffectiveness in restoring alpha-cell responsiveness to hyperglycemia in human diabetes may not, therefore, be related to duration of the diabetic state, and may reflect a primary alpha-cell defect.

The Effects of Triglyceride Absorption upon Glucagon, Insulin, and Gut Glucagon-Like Immunoreactivity

The effects of a fat meal upon plasma insulin, glucagon, and glucagon-like immunoreactivity (GLI) have been studied in conscious dogs and in human volunteers. In dogs the intraduodenal instillation of 10 g/kg of peanut oil was accompanied by increases in the mean plasma levels of all three polypeptides that averaged 5 muU/ml, 107 pg/ml, and 2.1 ng/ml, respectively. 3 g/kg of peanut oil, when emulsified with egg yolk, elicited a much greater response of the three hormones, and a physiologic dose of 1 g/kg in emulsified form also caused a significant rise in glucagon and GLI. The islet cell hormone response was not ascribable to chylomicronemia since intravenous infusion of canine chyle failed to stimulate glucagon secretion; moreover, in dogs with a thoracic duct fistula in which chyle was excluded from the circulation, the intraduodenal administration of a fat meal elicited the normal islet cell hormone response, as well as a rise in GLI. 10 g/kg of medium-chain triglycerides failed to elicit these same responses. In six human volunteers the oral administration of 3 g/kg peanut oil was accompanied by increments of 2 muU/ml, 26 pg/ml, and 1.5 ng/ml in the mean levels of insulin, glucagon, and GLI. The changes in insulin and glucagon in man were neither statistically significant nor biologically impressive. It is concluded that in dogs fat absorption is accompanied by prompt and substantial increases in plasma glucagon and GLI and a small transient rise in insulin. The evidence favors an enterogenic signal to the islets of Langerhans rather than their stimulation by chylomicrons. Pancreozymin is qualified to serve as such a signal. The physiologic implications of this study are considered.