Peter H. Forsham

Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect

Despite excessive glucagon responses to infusion of arginine, plasma glucagon did not rise in six juvenile-type diabetics during severe insulin-induced hypoglycemia, whereas glucagon in the controls rose significantly. Thus in diabetics pancreatic alpha cells are insensitive to glucose even in the presence of large amounts of circulating insulin. An intrinsic defect common to both alpha and beta pancreatic cells—failure to recognize (or respond to) plasma glucose fluctuations—may be operative in juvenile diabetes.

Tissue effects of glucocorticoids

Abstract Glucocorticoids affect the metabolism of most tissues. Frequently, they influence a number of functions in the same tissue which together produce a pattern of metabolic changes. Many effects result from the stimulation by glucocorticoids of synthesis of specific enzymes. In eliciting such responses, glucocorticoids penetrate the cell membrane and bind to receptor proteins. The hormone-receptor complex binds in the cell nucleus, thereby influencing ribonucleic acid (RNA) and protein synthesis. Thus, macromolecular synthesis may be required for even inhibitory or catabolic steroid actions. Other types of steroids may also act as glucocorticoids or antiglucocorticoids by interacting with the glucocorticoid receptors. In many tissues, including muscle, skin, lymphoid, connective and adipose, the catabolic actions of glucocorticoids result in decreased synthesis and increased degradation of protein and RNA. Glucocorticoids inhibit glucose and amino acid uptake in many instances and enhance lipolysis in adipose tissue. The inhibitory actions form a basis for glucocorticoid suppression of immunologic and inflammatory responses, wound healing, blood lymphocytes and eosinophils, and bone matrix. In liver, these steroids stimulate a number of enzymes and an increase in protein and glycogen content, while inhibiting only a few functions. There is an enhanced hepatic capacity for gluconeogenesis, which with substrate from catabolism elsewhere, results in increased glucose production. The integrated effects of glucocorticoids thus result in hyperglycemia, negative nitrogen balance and fat loss. However, glucocorticoid actions are countered by other hormones, most notably insulin, which is stimulated in response to the hyperglycemia, thus partly reversing some of the metabolic changes. Glucocorticoids enhance or permit certain actions of other hormones. The latter usually stimulate the production of cyclic adenosine 3′,5′-monophosphate (cyclic AMP). In fact, the patterns of glucocorticoid and cyclic AMP actions in conserving glucose are generally parallel. As with cyclic AMP and other types of steroids, glucocorticoids may play a more important role in fetal cellular and tissue differentiation than previously appreciated.

Prevention of human diabetic ketoacidosis by somatostatin. Evidence for an essential role of glucagon.

To evaluate the role of glucagon in the pathogenesis of diabetic ketoacidosis in man, we studied the effect of suppression of glucagon secretion by somatostatin on changes in plasma beta-hydroxybutyrate and glucose concentrations (as well as changes in their precursors) after acute withdrawal of insulin from seven patients with juvenile-type diabetes. Suppression of glucagon secretion prevented the development of ketoacidosis for 18 hours after acute insulin withdrawal, whereas in control studies mild ketoacidosis occurred 10 hours after insulin was stopped. Plasma beta-hydroxybutyrate, glucose, free fatty acid, and glycerol levels were all markedly lower during suppression of glucagon secretion (p smaller than 0.001), whereas plasma alanine levels were higher (p smaller than 0.001). These studies indicate that insulin lack per se does not lead to fulminant diabetic ketoacidosis in man and that glucagon, by means of its gluconeogenic, ketogenic, and lipolytic actions, is a prerequisite to the development of this condition.

Cushing's disease. Selective trans-sphenoidal resection of pituitary microadenomas.

We undertook trans-sphenoidal microsurgical pituitary exploration in 20 consecutive patients with Cushings disease, eight of whom had normal sellar polytomography. Pituitary adenomas were selectively resected in 17 and histologically confirmed in 14. In one patient total hypophysectomy revealed a 1.5-mm basophilic adenoma, and in two patients vascular anomalies prevented sellar exploration. Hypercortisolism was corrected in 17 patients (i.e., in 16 of the 17 undergoing selective tumor removal and in the one with total hypophysectomy). Panhypopituitarism occurred only in this patient, and transient diabetes insipidus occurred in five. Most patients became glucocorticoid deficient and required replacement therapy. We conclude that pituitary tumors are present in the great majority of patient with Cushings disease, even in the absence of demonstrable tomographic changes in the sella turcica, and that selective removal corrects hypercortisolism with little morbidity.

Effects of Somatostatin on Plasma Glucose and Glucagon Levels in Human Diabetes Mellitus: Pathophysiologic and Therapeutic Implications

Abstract To evaluate the role of pancreatic alpha-cell dysfunction in human diabetes mellitus, somatostatin, an inhibitor of glucagon secretion, was infused (1 mg over two hours) in 10 insulin-dependent diabetic subjects. Fasting plasma glucagon fell from 150 ± 15 (mean ± S.E.M.) to 77 ± 10 pg per milliliter (p<0.001), and plasma glucose from 260 ± 20 to 191 ± 21 mg per 100 ml (p<0.001). Similar responses occurred in a hypophysectomized diabetic patient, indicating that these effects of somatostatin were independent of suppression of growth hormone secretion. Somatostatin (4 mg subcutaneously) was active transiently. In additional studies, somatostatin infusion combined with insulin completely abolished post-meal hyperglycemia in four diabetic patients and was more effective than insulin alone. These results indicate that excessive glucagon secretion accounts for about 25 per cent of the fasting plasmaglucose levels in such patients. Furthermore, somatostatin may be a useful adjunct to insulin in treating...

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal. Infusion of glucagon (1 ng/kg-min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94 +/- 8 to 126 +/- 12 mg/100 ml over 1 h (P less than 0.01); growth hormone, beta-hydroxy-butyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, beta-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P less than 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. Infusion of growth hormone (1 mug/kg-h) during suppression of its endogenous secretion with somastostatin produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma beta-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P less than 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin.

An Overnight High-Dose Dexamethasone Suppression Test for Rapid Differential Diagnosis of Cushing's Syndrome

We have developed a high-dose dexamethasone suppression test that can be administered overnight with a single 8-mg dose and used the new procedure in the differential diagnosis of 83 patients with Cushings syndrome. In 76 patients with surgically or pathologically proven cause--60 with Cushings disease, 7 with the ectopic adrenocorticotrophic hormone syndrome, and 9 with adrenal tumors--suppression of plasma cortisol levels to less than 50% of baseline indicated a diagnosis of Cushings disease. The test had a sensitivity of 92%, a specificity of 100%, and a diagnostic accuracy of 93%. These values equal or exceed those of the standard 2-day test whether based on suppression of urinary 17-hydroxycorticosteroids or plasma cortisol. We conclude that this overnight, high-dose dexamethasone suppression test is practical and reliable in the differential diagnosis of Cushings syndrome.

Selective Venous Sampling for ACTH in Cushing's Syndrome: Differentiation Between Cushing's Disease and the Ectopic ACTH Syndrome

We performed selective venous catheterization and sampling for ACTH in six patients with ACTH-secreting pituitary adenomas (Cushings disease) and four patients with occult ectopic ACTH-secreting neoplasms. In five patients with Cushings disease in whom the inferior petrosal sinus could be catheterized, ACTH levels were unequivocally higher than simultaneous peripheral values: The ratio was greater than 2.0, with a range of 2.2 to 16.7. In contrast, the inferior petrosal sinus-to-peripheral ACTH ratio in three patients with ectopic ACTH secretion was less than 1.5. In the fourth patient, an arteriovenous gradient of 6.8 was shown 2 years before a bronchial carcinoid tumor was clinically apparent. Central-to-peripheral ACTH ratios at the level of the jugular bulb and jugular vein were not diagnostic. We conclude that selective venous ACTH sampling from the inferior petrosal sinus is a reliable and useful aid in the differential diagnosis of Cushings syndrome when standard clinical and biochemical studies are inconclusive.

Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: Studies with somatostatin☆

To study the role of glucagon in human glucose homeostasis, experimental glucagon deficiency was produced by infusing somatostatin (i. v. 250 mug bolus, followed by infusion of 500 mug/hr) in six normal subjects and in two hypophysectomized patients-an insulin-dependent diabetic and a nondiabetic. In normal subjects, somatostatin lowered plasma glucagon from a mean (plus or minus SE) basal level of 85 plus or minus 15 to 33 plus or minus 10 pg/ml, p smaller than 0.001. Concurrently, plasma glucose fell from 90 plus or minus 2 to 73 plus or minus 3 mg/100 ml, p smaller than 0.001. Serum insulin and growth hormone fell slightly during somatostatin infusion, while plasma free fatty acids rose. In both hypophysectomized patients, somatostatin lowered plasma glucagon and glucose levels. In all subjects, after stopping somatostatin infusions, plasma glucagon and glucose returned promptly to control values, while serum growth hormone did not change. In additional in vitro studies, somatostatin (1 mug/ml) had no effect on muscle glucose uptake. Since it is known that somatostatin has no direct effect on hepatic glucose production, these results suggest that the fall in plasma glucose during somatostatin infusion resulted from inhibition of glucagon secretion, thus providing evidence that this hormone plays a physiologic role in the maintenance of fasting euglycemia in man.

Early Phase of Insulin Release

The early phase of insulin release in the first five minutes after intravenous administration of glucose, glucagon, and glucose-plus-glucagon was investigated systematically in various clinical conditions. In normal subjects there is an immediate release of insulin after glucose, glucagon, and glucose-plus-glucagon infusions. The latter combination produced the highest insulin levels. Of a group of nonobese subjects with diabetic heritage, some had impaired early release of insulin, but0 their mean response did not differ significantly from the normal group. Investigation of nonobese potential diabetics (offspring of two diabetic parents) revealed that as a group average they had decreased insulin levels during the early phase of insulin release, even though intravenous glucose tolerance was normal. Four of ten subjects had a normal response. Nonobese, noninsulin-dependent diabetics had no insulin response to infused glucose, but when glucagon was added to glucose a significant and rapid insulin discharge was observed. However, the magnitude of this response was about half that seen in normal subjects after glucose-plusglucagon. Finally, the early phase of insulin release was studied in obese nondiabetic subjects who demonstrated an exaggerated insulin release to each stimulus. Again, glucose-plusglucagon was the most potent stimulator of insulin release. It is postulated that impairment in the early phase of insulin release may be the first detectable abnormality of insulin secretion in diabetes mellitus and that glucagon has the capability of restoring this toward normal.