Temporary reversal by topotecan of marked insulin resistance in a patient with myelodysplastic syndrome: case report and possible mechanism for tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance.

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor. We report here a remarkable degree of insulin resistance in a patient with adult respiratory distress syndrome and myelodysplasia.

Patient-reported experience with Velosulin human insulin in continuous subcutaneous insulin infusion.

A multicenter, retrospective survey of 339 patients with insulin-dependent diabetes mellitus was done to evaluate patient experience with Velosulin Human insulin, a regular insulin in a phosphate buffer, used in continuous subcutaneous insulin infusion. Patients had used this insulin exclusively for 3 months preceding the survey. Responses were elicited through interviews conducted by physicians or nurses. Patients were queried as to the occurrence of specific complications associated with pump therapy that occurred while using Velosulin Human insulin, including hypoglycemia, diabetic ketoacidosis, unexplained hyperglycemia, tubing obstruction, and infection or abscess at the infusion site. Most patients reported that they did not experience any of these complications during the preceding 3 months. The most frequently cited complication was hyperglycemia unexplained by dosage, exercise, or dietary changes, reported by 110 (32%) patients. The second most frequently reported complication was tubing obstruction, reported by 99 (29%) patients. The reported frequencies of the other complications were: severe hypoglycemia, 45 (13%) patients; diabetic ketoacidosis, 28 (8%) patients; and infection or abscess at the infusion site, 26 (8%) patients. The low morbidity reported by the patients in this survey probably was due in large part to careful patient selection, a high level of motivation on the part of the patients, and experience and education on the part of the health care team, as well as to the use of buffered regular human insulin.

Changes in cognitive and social functioning of diabetic patients following initiation of insulin infusion therapy.

Functional health outcomes resulting from intensive insulin regimens may differ depending upon the age of the diabetic patient. This study tested the hypothesis that health functioning is poorer for younger insulin-dependent diabetic (IDDM) patients following a change to the insulin infusion pump regimen, with progressive improvements occurring in functional health status at higher age levels. Thirty IDDM patients aged 10-47 years were administered health status instruments prior to changing to the new regimen, and again six months later. The instruments assessed physical, cognitive, psychological, and social health functioning. When compared at six months to an age-matched control group on conventional insulin therapy, declines in social activities were found for younger insulin pump patients, with improvements occurring linearly as age increased. Lower performance levels were also found for the younger patients in Conceptual Quotient (CQ), an indicator of cognitive functional status, with progressive improvements with age through the early 30s. However, corresponding declines in function occurred at the oldest age levels. Adaptation to an intensive diabetes regimen appears to be more difficult at younger and older age levels.

Toxic shock syndrome from Staphylococcus aureus infection at insulin pump infusion sites. Report of two cases.

Two young diabetic females using insulin infusion pump therapy became ill with toxic shock syndrome secondary to Staphylococcus aureus infection at the insulin infusion pump site. Physicians need to be aware of this potential complication in diabetic patients using insulin infusion pump therapy so proper management can be initiated early. Infections at insulin infusion sites are common. Patients need to be instructed in the importance of preventing infections at the pump infusion site and proper management of any abscesses that should develop. Controlled studies evaluating proper management of insulin infusion pump sites to prevent infections are needed.

Insulin as a mediator of hepatic glucose uptake in the conscious dog.

The aim of this study was to determine whether a physiological increment in plasma insulin could promote substantial hepatic glucose uptake in response to hyperglycemia brought about by intravenous glucose infusion in the conscious dog. To accomplish this, the plasma glucose level was doubled by glucose infusion into 36-h fasted dogs maintained on somatostatin, basal glucagon, and basal or elevated intraportal insulin infusions. In the group with basal glucagon levels and modest hyperinsulinemia (33 +/- 2 micro U/ml), the acute induction of hyperglycemia (mean increment of 120 mg/dl) caused marked net hepatic glucose uptake (3.7 +/- 0.5 mg . kg-1 . min-1). In contrast, similar hyperglycemia brought about in the presence of basal glucagon and basal insulin levels described net hepatic glucose output in 56%, but did not cause net hepatic glucose uptake. The length of fast was not crucial to the response because similar signals (insulin, 38 +/- 6 micro U/ml; glucose increment, 127 mg/dl) promoted identical net hepatic glucose uptake (3.8 +/- 0.6 mg . kg-1 . min-1) in dogs fasted for only 16 h. In conclusion, in the conscious dog, a) physiologic increments in plasma insulin have a marked effect on the ability of hyperglycemia to stimulate net hepatic glucose uptake, and b) it is not necessary to administer glucose orally to promote substantial net hepatic glucose uptake.

Effects of pharmacologic hyperglucagonemia on plasma amino acid concentrations in normal and diabetic man.

Four normal and five insulin dependent diabetic men received a 2 h pharmacologic glucagon infusion (50 ng/kg/min) resulting in plasma glucagon levels (4400 pg/ml) similar to those seen in glucagonoma patients. In normal subjects in whom plasma insulin concentrations rose significantly (239 uU/ml) and the blood level of 15 of the 18 amino acids measured fell significantly. In contrast, in the diabetic men who secreted no insulin in response to glucagon (no rise in C-peptide levels), only 10 of 18 amino acid levels fell significantly. The branched chain amino acids valine, leucine and isoleucine, as well as tyrosine and phenylalanine were among the 8 amino acids which showed no change in response to glucagon in the diabetics. Thus, glucagon appears to have no acute affect on branched chain amino acid levels in man.

Retardant effect of hyperglycemia on the rise in plasma fatty acids following insulin withdrawal in man.

The present study was undertaken to examine the influence of hyperglycemia in retarding the rise in circulating FFA noted after acute insulin withdrawal in man. The arterial FFA response to somatostatin administration was measured in the presence of (a) euglycemia and (b) hyperglycemia. In seven normal men who received somatostatin (0.9 mg/h) with euglycemia maintained by exogenous glucose infusion plasma insulin levels fell to levels 4 uU/ml and plasma FFA concentrations rose from 659 +/- 123 to 2057 +/- 268 uEq/l. When somatostatin was infused with hyperglycemia maintained at approximately 230 mg/dl, plasma insulin levels were again maintained at levels 4 uU/ml. Despite similar insulinopenia plasma FFA concentrations rose from 510 +/- 56 to only 1125 +/- 180 uEq/l, significantly less than in the previous protocol (p less than 0.01). These data indicate that hyperglycemia per se significantly attenuates the rise in circulating FFA caused by acute insulin withdrawal in man.

A familial glucagonoma syndrome: genetic, clinical and biochemical features.

A family with multiple endocrine neoplasia type I (MEN-I) is described in which three members had A-cell pancreatic tumors. Two of these members had classic glucagonoma syndromes. The proband, a 62 year old woman, had a high (less than or equal to 9.2 ng/ml) basal plasma glucagon level, most of which eluted in the 3,500 dalton fraction. Plasma glucagon increased following the ingestion of mixed meals and arginine. Secretin, which, in the dog, has been reported to inhibit normal glucagon secretion, provoked a twofold increase in 3,500 dalton plasma glucagon concentration. Increased plasma glucagon in the proband was associated with mild hyperglycemia and insulin resistance. Somatostatin infusion suppressed peripheral glucagon and insulin levels, and increased blood glucose levels. The unique responses to secretin and somatostatin observed in this patient may be diagnostically important in syndromes of inappropriate or autonomous glucagon secretion.

Effects of insulin at two dose levels on gluconeogenesis from alanine in fasting man.

We have determined the effect of insulin infused at 1 and 5 mU/kg/min on gluconeogenesis from alanine in 48-hr fasted men. The conversion of alanine to glucose was measured by the arterial-hepatic venous catheterization technique combined with the infusion of 14C-alanine. During insulin infusion, euglycemia was maintained by variable glucose infusion. When insulin was infused at 1 mU/kg/min the net splanchnic production of 14C-glucose was suppressed by 80% but glucagon infused at the end of the study resulted in substantial release of 14C-glucose from the liver suggesting marked accumulation of labeled glucose in glycogen. When insulin was infused at 5 mU/kg/min the splanchnic release of 14C-glucose was also markedly suppressed but in contrast to the lower insulin dose very little labeled glucose accumulated in glycogen. Neither the high nor the low dose insulin infusion had any effect on net splanchnic alanine uptake and plasma glucagon levels fell by 35% in both protocols. These data demonstrate that in 48-hr fasted man, (1) a small increment in insulin concentration will suppress glucose production but mostly by diverting the newly formed glucose into glycogen; (2) at higher concentrations, insulin will inhibit glucose production mainly by suppressing glucoeogenesis; and (3) this insulin-induced suppression of gluconeogenesis is due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine.

The effect of somatostatin on the intestinal transport of glucose in vivo and in vitro in the rat.

The possibility that somatostatin has a direct inhibitory effect on intestinal D-glucose absorption was studied in rats using intact intestinal loops and everted jejunal segments. Somatostatin infusion in vivo produced a significant fall in plasma glucose concentration (P less than 0.001) and a fall in pooled plasma insulin concentration to 51% of control values. However, somatostatin infusion did not alter significantly from control values the rate of glucose disappearance from the perfused jejunal lumen in vivo or the appearance of gut-derived plasma glucose. The lack of an inhibitory effect of somatostatin on glucose absorption in vivo was confirmed using two in vitro studies. When increasing concentrations of somatostatin (0-10(4) ng/ml-1) were added to both mucosal and serosal solutions, no significant differences were seen for net transmural flux or unidirectional flux of D-glucose in everted jejunal segments. These studies suggest that somatostatin in the rat does not influence plasma glucose concentration by inhibiting intestinal glucose transport at physiological concentrations of glucose and over a wide range of somatostatin concentrations.

Effect of hyperglycemia independent of changes in insulin or glucagon on lipolysis in the conscious dog.

In the face of fixed basal levels of insulin (9 microunits/ml) and glucagon (63 pg/ml) maintained by the infusion of somatostatin and replacement amounts of the two pancreatic hormones, the mean arterial plasma glucose concentration was elevated from 102 to 217 mg/dl by continuous glucose infusion. Hyperglycemia resulted in a significant decrease in the arterial blood glycerol (35%) and plasma free fatty acid concentrations (46%). The drop in the blood glycerol level was paralleled by a decline in hepatic glycerol uptake indicating that hyperglycemia did not alter the fractional extraction of glycerol by the liver. These results support the view that glucose has a direct antilipolytic effect in vivo.

Effect of glucose, independent of changes in insulin and glucagon secretion, on alanine metabolism in the conscious dog.

To study the effects of hyperglycemia on the metabolism of alanine and lactate independent of changes in plasma insulin and glucagon, glucose was infused into five 36-h-fasted dogs along with somatostatin and constant replacement amounts of both insulin and glucagon. Hepatic uptakes of alanine and lactate were calculated using the arteriovenous difference technique. [14C]Alanine was infused to measure the conversion of alanine and lactate into glucose. Hyperglycemia (delta 115 mg/dl) of 2 h duration caused the plasma alanine level to increase by over 50%. This change was caused by an increase in the inflow of alanine into plasma since the net hepatic uptake of the amino acid did not change. Taken together, the above findings indicate that glucose per se can significantly impair the fractional extraction of alanine by the liver. Hepatic extraction of lactate was also affected by hyperglycemia and had fallen to zero within 90 min of starting the glucose infusion. This fall was associated with a doubling of arterial lactate level. Conversion of [14C]-alanine and [14C]lactate into [14C]glucose was suppressed by 60 +/- 11% after 2 h of hyperglycemia, and because this fall could not be entirely accounted for by decreased lactate extraction an inhibitory effect of glucose on gluconeogenesis within the liver is suggested. These studies indicate that the plasma glucose level per se can be an important determinant of the level of alanine and lactate in plasma as well as the rate at which they are converted to glucose.

Lack of a role for glucagon in the disposal of an oral glucose load in normal man.

The present study was undertaken to determine the role of glucagon in determining the disposition of an oral glucose load in normal man. To accomplish this, the plasma glucose response to an oral glucose load was determined in four normal men who were studied on two occasions. During one study, glucagon (3 ng/kg.min) was administered to prevent the fall in plasma glucagon noted after oral glucose ingestion. Despite elevation of plasma glucagon levels to 350 pg/ml in this protocol, the plasma insulin and glucose levels achieved were virtually identical to those obtained after oral glucose alone. These results indicate that neither physiological elevations of plasma glucagon nor the suppression of plasma glucagon seen during oral glucose administration alter glucose tolerance in normal man. Thus, in a normal man capable of secreting appropriate amounts of insulin in response to the ingestion of glucose, glucagon plays no appreciable role in the disposition of this glucose load.

Splanchnic metabolism of alanine in intact man. Effects of somatostatin and somatostatin plus insulin.

We examined splanchnic metabolism of alanine in 15 normal males under three sets of conditions: infusion of saline (control studies); infusion of somatostatin (SRIF) (bihormonal deficiency of insulin and glucagon); and infusion of somatostatin plus insulin (selective glucagon deficiency). Net splanchnic alanine uptake (NSAU) remained stable over 2 h during infusion of saline. Infusion of SRIF was associated with a fall in estimated hepatic plasma flow (EHPF) whether or not insulin was infused concomitantly. With SRIF only, arterio-hepatic venous alanine differences increased such that NSAU remained stable over 2 h, despite the fall in EHPF. In contrast, with selective glucagon deficiency, NSAU fell significantly after 2 h, an effect consequent on a fall in EHPF and a delayed fall in arterio-hepatic venous (A-HV) alanine differences. Our studies are compatible with a role for basal glucagon in maintenance of splanchnic extraction of alanine in normal man. However, the SRIF-initiated fall in EHPF may exert an influence on A-HV alanine differences independent of changes in pancreatic hormone secretion.

Hyperglycemia per se (insulin and glucagon withdrawn) can inhibit hepatic glucose production in man.

We examined the effect of hyperglycemia per se on net splanchnic glucose balance. In 2 groups of normal postabsorptive men who had undergone hepatic vein catheterization, somatostatin was administered to block endogenous insulin and glucagon secretion. Exogenous glucose was infused in both groups to maintain euglycemia for 2 h in one group (n = 7) and to induce hyperglycemia of 220-240 mg/dl after 30 minutes of euglycemia in the second group (n = 4). In both groups the induction of insulinopenia and glucagonopenia with euglycemia maintained resulted in an initial 75% fall in net splanchnic glucose production (NSGP). In the group in which euglycemia was maintained NSGP returned to basal rates (157 +/- 31 mg/min) within 2 h. However, in the group in which hyperglycemia was induced, NSGP did not return to basal rates but remained suppressed (28 +/- 4 mg/min) for the duration of the study. These data in normal man indicate that hyperglycemia per se with insulin and glucagon acutely withdrawn can suppress splanchnic glucose production but does not induce net splanchnic glucose storage.

Glucose metabolism in intact man: the responsiveness of splanchnic and peripheral tissues to insulin.

Man controls his blood sugar concentration within rather narrow limits, despite wide latitude in the content and timing of meals. Man does not eat constantly; rather, he alternates between periods of "feasting" and "fasting." It is a useful generalization that the metabolic environment is altered such that forces promoting substrate storage are dominant during the postprandial period and forces that encourage substrate mobilization are prominent during food-free intervals. In this report, we shall primarily examine the role of insulin, the hormone of carbon storage, in maintaining glucose homeostasis during a 24-hr period. In particular, we wish to highlight (A) possible important differences in the dose response curves of insulin in splanchnic and peripheral tissues and (B) the modulating influences of hyperglycemia and glucagon on insulin's effects across the splanchnic bed.

Persistent stimulatory effect of glucagon on glucose production despite downregulation.

The rise and subsequent return to basal of glucose production (Ra) during a constant glucagon infusion ("downregulation") has suggested to some workers that glucagon's effects are evanescent. To examine whether glucagon displays persistent biological activity even after downregulation, 6 healthy males received an 8 hour infusion of somatostatin and glucagon, with 3H-3-glucose to measure glucose turnover. Ra rose from 2.8 +/- 0.3 to 4.2 +/- 0.3 mg/kg . min at 90 minutes, returned to basal levels at 150 minutes, and remained at this level for the ensuing 330 minutes. Six additional subjects received an 8 hour somatostatin infusion, with glucagon administered concomitantly for the first 5 hours. Glucagon withdrawal at 5 hours produced an immediate decline in Ra from 1.8 +/- 0.2 to 0.9 +/- 0.2 mg/kg . min. Thus, even after downregulation the maintenance of basal Ra is dependent on circulating glucagon.