Hepatic and extrahepatic splanchnic glucose metabolism in the postabsorptive and glucose fed dog

In awake dogs we measured the glucose balance across the liver and extrahepatic splanchnic tissues in the postabsorptive state and during two hours of IV infusion of glucose or for three hours following ingestion of oral glucose and during four hours of sequential intraportal followed by oral glucose. The IV glucose infusion rate was adjusted to maintain a steady state glucose concentration of either euglycemic levels (insulin clamp, group 1, N = 4), 125 mg/100 mL above the postabsorptive glucose concentration (+125 mg glucose clamp, group 2, N = 3) or 200 mg/100 mL above basal glucose levels (+200 mg glucose clamp, group 3, N = 7). Oral glucose was given at a dose of either 1.5 g/kg (group 4, N = 7) or 2.5 g/kg (group 5, N = 12). In dogs that received IV glucose, basal gut glucose uptake (0.5 +/- 0.1 mg/min X kg) was stimulated by hyperglycemia (1.5 +/- 0.5 and 1.4 +/- 0.1 mg/min X kg for group 2 and 3, respectively, P less than 0.05). In these same animals basal hepatic glucose output (-2.7 +/- 0.3 mg/min X kg) was promptly suppressed and net hepatic glucose uptake occurred (2.8 +/- 0.2 and 2.4 +/- 0.5 mg/min X kg in group 2 and 3 respectively). Euglycemic hyperinsulinemia (group 1) suppressed postabsorptive hepatic glucose release but did not enhance glucose removal by either the liver or gut tissues. After oral glucose gut tissues released absorbed glucose into portal blood. Over three hours following the glucose meal 74% and 59% of the ingested glucose was absorbed in group 4 and 5, respectively. As with IV glucose, postabsorptive hepatic glucose production was suppressed and over the first two hours after feeding the liver took up glucose (3.4 +/- 1.0 and 3.1 +/- 0.7 mg/min X kg groups 4 and 5, respectively) at a rate similar to that seen with IV glucose. To further examine the effect of the route of glucose administration on liver glucose handling, hepatic glucose balance was measured serially over four hours in three dogs that received IV glucose into a mesenteric vein to produce portal hyperglycemia (+125 mg/dL portal glucose clamp N = 3). Oral glucose (2.5 mg/kg) was given at two hours, and the rate of the mesenteric glucose infusion adjusted to maintain portal glycemia constant. The hepatic glucose balance averaged 5.5 mg/min X kg over the 0 to 2 hour period and 4.2 +/- 1.0 mg/min X kg over the 2 to 4 hour time.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of acute exercise on insulin binding to monocytes in obesity

The effect of 3 hr of cycle erogmeter exercise on ¹²⁵I-insulin binding to monocytes was studied in 8 obese and 10 nonobese control subjects. In the basal state before exercise, total specific ¹²⁵I-insulin binding to monocytes in obese subjects (4.8% ± 0.3%) was 25% lower than in control subjects (6.6% ± 0 0.4%, p < 0.01). During exercise, insulin binding increased in both groups (p < 0.05), but the rise in obese subjects was minimal (13% ± 1%) and was 60%–70% lower than in controls (36% ± 3%, p < 0.01). The data indicate that the increment in insulin binding to monocytes induced by acute exercise is diminished in obesity.     

Vitamin D metabolism and bone histomorphometry in a patient with antacid-induced osteomalacia

A patient with hypophosphatemic osteomalacia secondary to ingestion of large amounts of phosphate-binding antacids is presented. Vitamin D metabolites were measured during the course of his illness and recovery and demonstrated an initially elevated concentration of 1,25-dihydroxyvitamin D, an undetectable level of 24,25-dihydroxyvitamin D, and a normal level of 25-hydroxyvitamin D. These metabolites returned to normal levels when the hypophosphatemia was corrected. Bone histomorphometry showed osteomalacia with increased resorption. The possible role of altered vitamin D metabolism in the pathogenesis of this disorder is discussed.     

The role of fractional glucose extraction in the regulation of splanchnic glucose metabolism in normal and diabetic man

In order to express in equivalent terms seemingly divergent results obtained with isotopic tracer studies as compared to hepatic venous catheter studies on the role of the liver in the metabolism of oral glucose, our previously published studies using the hepatic venous catheter technique in normals and diabetics given intravenous and/or oral glucose were analyzed with respect to the splanchnic fractional extraction of glucose, total splanchnic glucose influx, and the proportion of total glucose metabolism accounted for by net splanchnic glucose uptake. In normal subjects during extreme hyperinsulinemia (plasma insulin, 500–1,200 μU/ml) induced by i.v. insulin while maintaining the blood glucose concentration at basal levels (insulin clamp), total glucose metabolism rose to 10.5 ± 0.9 mg/min · kg, while splanchnic fractional extraction of glucose was 4.2 ± 1.1%, and net splanchnic glucose uptake accounted for only 5 ± 2% of total glucose turnover. During hyperglycemic (blood glucose, 200 mg/dl) hyperinsulinemia induced by i.v. glucose, net splanchnic glucose uptake was twice that observed with euglycemic hyperinsulinemia, and the proportion of total glucose metabolism occurring in the splanchnic bed rose to 14 ± 4%. These increments were due entirely to a rise in splanchnic glucose influx since the fractional extraction (3.4 ± 0.5%) remained unchanged from that observed with euglycemic hyperinsulinemia. After oral glucose (100 g), splanchnic glucose influx was comparable to hyperglycemic hyperinsulinemia induced with i.v. glucose, but splanchnic fractional extraction rose to 13.1 ± 1.9% (p < 0.001 versus i.v. glucose), a value comparable to that observed with isotopic studies of oral glucose metabolism. Total glucose turnover was, however, 30% lower than after i.v. insulin (p < 0.01), so that net splanchnic glucose uptake accounted for 54 ± 5% of total glucose metabolism. In maturity-onset diabetics, after 100 g oral glucose splanchnic glucose influx was 69% greater than in controls (p < 0.001), but net splanchnic glucose uptake was 44% below controls (2.3 ± 0.5 versus 4.1 ± 0.5 mg/min · kg, p < 0.02). This reduction in glucose uptake could be accounted for by a splanchnic fractional extraction ratio (4.7 ± 1.4%) that was 64% lower than in controls given oral glucose (p < 0.001). It is concluded that: (1) in normal subjects, the ability of the splanchnic area to extract circulating glucose (as reflected by the splanchnic fractional extraction) is 2–3-fold greater after oral glucose than after intravenous glucose; (2) the rise in splanchnic fractional extraction to levels of 13% in association with only moderate increases in total glucose turnover fully accounts for the predominance of the splanchnic area in the metabolism of oral as compared to intravenous glucose; and (3) in maturity-onset diabetics, oral glucose fails to induce a rise in splanchnic fractional extraction of glucose comparable to that observed in normal subjects.     

Metabolic, endocrine, and drug-induced interference with pituitary function tests: a review.

Data are summarized concerning some common disease-induced and drug-induced alterations of pituitary function tests. These factors must be kept in mind in order to avoid errors in the diagnosis and treatment of pituitary disease.     

Urinary 3-methylhistidine/creatinine ratio as a clinical tool: Correlation between 3-methylhistidine excretion and metabolic and clinical states in healthy and stressed premature infants

We have investigated the role of the urinary 3-methylhistidine (3MH) excretion, a measure of protein catabolism, in the evaluation of the metabolic state of premature infants. Two-hundred and twenty-two 24 hr urine collections and $\text{3}\text{MH}\text{Cr}$ ratio determinations (expressed as μmoles of 3MH per mg creatinine) were carried out in 36 infants (average gestational age 32.7 ± 0.7 wk, weight 1640 ± 120 grams) and the relationship between the $\text{3}\text{MH}\text{Cr}$ ratios and the metabolic and clinical state has been investigated. Five or more $\text{3}\text{MH}\text{Cr}$ measurements were carried out on each of 19 infants and serial determinations on four of those babies are presented. The urinary $\text{3}\text{MH}\text{Cr}$ ratio of healthy infants with adequate caloric intake and normal growth curve was .148 ± .039 (S.D.) μmol/mg, about 35% higher than the $\text{3}\text{MH}\text{Cr}$ ratio in healthy adults. As long as the premature infants were healthy the degree of prematurity had no effect on the $\text{3}\text{MH}\text{Cr}$ ratio. The relationship between $\text{3}\text{MH}\text{Cr}$ ratio and nitrogen balance was highly significant (p < .001). $\text{3}\text{MH}\text{Cr}$ ratio also correlates very well with the metabolic status of the infants: in the group with normal $\text{3}\text{MH}\text{Cr}$ ratios ≤.175 (.148 + 1 S.D., n = 90) there were four clinically stressed infants (4.4% false negative rate) while in the group with elevated $\text{3}\text{MH}\text{Cr}$ ratios >.225 (.148 + 2 S.D.; n = 79) there were only three clinically well infants (3.8% false positive rate). In comparing the clinical status and $\text{3}\text{MH}\text{Cr}$ ratios, we found that in the group of infants who could not be clearly defined as clinically well or stressed (n = 108) the $\text{3}\text{MH}\text{Cr}$ ratio was more useful than clinical judgment in the prediction of metabolic status. It can be concluded that $\text{3}\text{MH}\text{Cr}$ ratio is a potentially useful clinical tool which describes with high accuracy the clinical and metabolic status of premature infants. This conclusion is further supported by the data of serial $\text{3}\text{MH}\text{Cr}$ determinations.     

Biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes

Oral glucose tolerance was examined in five maturity-onset diabetics during the infusion of somatostatin or saline. Somatostatin inhibited glucose-stimulated insulin release and reduced plasma glucagon by 50%--65%. The rise in plasma glucose after glucose ingestion was initially (at 30--120 min) reduced by somatostatin. However, beyond 3 hr, plasma glucose levels were 50--200 mg/100 ml higher, with somatostatin reaching concentrations at 6 hr that were twofold higher than those observed with saline ( p less than 0.005). The degree of late glucose intolerance was inversely related to postglucose plasma insulin concentrations (p less than 0.01). These findings demonstrate a biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes. The exaggerated later hyperglycemia is related to suppression of insulin secretion. The initial blunting of postprandial hyperglycemia may reflect decreased carbohydrate absorption and/or hypoglucagonemia-mediated enhancement of glucose disposal.     

Insulin binding to monocytes and insulin sensitivity in anorexia nervosa

In six female patients with anorexia nervosa, we examined specific binding of ¹²⁵I-insuIin to monocytes and in vivo sensitivity to insulin before and after treatment. Insulin sensitivity was determined by the rate of glucose disappearance during an intravenous insulin tolerance test (K_ITT).In the untreated state, the patients with anorexia nervosa were 26 to 41 per cent below ideal weight and amenorrheic. Fasting plasma glucose and insulin levels were, respectively, 20 per cent and 55 per cent below those observed in healthy controls. Insulin binding to monocytes was 70 per cent greater than that in controls. Scatchard analysis of the insulin binding data revealed an increase in binding capacity with no change in binding affinity. During the insulin tolerance test, K_ITT (9.7 ± 0.7 per cent · min^?1) was 50 per cent greater in untreated patients than in healthy controls.Following treatment with behavior modification, there was a gain in body weight to within 2 to 11 per cent of ideal body weight, and menstrual function returned. Plasma glucose and insulin levels rose to values similar to those in healthy controls. Insulin binding declined by 40 per cent to values comparable to those in the controls. The decrease in insulin binding was due to a reduction in binding capacity. The plasma glucose response to the insulin tolerance test (K_ITT) fell 50 per cent below pretreatment values to levels comparable to those in healthy controls.Both before and after treatment, an inverse correlation was observed between plasma insulin concentration and insulin binding to monocytes whereas a direct correlation was demonstrable between insulin binding to monocytes and k_ITT.The data indicate that in anorexia nervosa insulin binding to monocytes and in vivo sensitivity to insulin are increased. The increase in insulin binding may be a consequence of a decrease in plasma insulin and may, in turn, be responsible for the increase in insulin sensitivity. The increases in insulin binding and insulin sensitivity return to normal following regain of body weight.     

Incidence of pancreatitis with the use of immune checkpoint inhibitors (ICI) in advanced cancers: A systematic review and meta-analysis

BackgroundSystemic immune side effects including pancreatitis have been reported with the use of Immune Checkpoint Inhibitors (ICI) (CTLA-4, PD-1 and PDL-1). However, the true incidence, risk, causes (tumor or drug specific) of pancreatitis and relation to other immune side effects, especially diabetes mellitus (DM) are unknown.MethodsWe performed a systematic review and meta-analysis of all clinical trials using ICI for the incidence of any grade lipase elevation, pancreatitis or DM.ResultsThe incidence of asymptomatic lipase elevation after ICI use is 2.7% (211/7702) and grade 2 pancreatitis is 1.9% (150/7702). No pancreatitis related mortality has been reported in these clinical trials. Patients treated with CTLA-4 inhibitors have increased incidence of pancreatitis when compared to patients treated with PD1 inhibitors 3.98% (95% CI: 2.92 to 5.05) vs 0.94% (95% CI: 0.48 to 1.40); P value < 0.05. Patients treated with ICI for melanoma have increased incidence of pancreatitis when compared to non-melanoma cancers. We also noted an additive increase in incidence of pancreatitis with combination of CTLA4 and PD-1 inhibitors (10.60; 95% CI: 7.89 to 13.32) compared with either CTLA-4 or PD-1 inhibitors alone.ConclusionsOur study provides precise data for the incidence of pancreatitis among patients using ICI based on tumor types and ICI regimens. ICI use for solid tumors is associated with increased incidence of all grades of lipase elevation and pancreatitis, especially for CTLA-4 agents and ICI combination. Although it does not appear to be associated with mortality, ICI related pancreatitis should be recognized early for appropriate treatment and to potentially reduce long term complications.     

Influence of physiologic hyperglucagonemia on urinary glucose,nitrogen, and electrolyte excretion in diabetes

To evaluate the effect of physiologic hyperglucagonemia on nitrogen and glucose metabolism and on urinary electrolyte excretion, pancreatic glucagon was administered as a continuous 3-day infusion to three adult-onset non-insulin-dependent diabetics and two insulin-treated juvenile diabetics while on a constant dietary intake. The glucagon infusion resulted in increases in plasma glucagon which were 4–6-fold greater than control values. Despite prolonged hyperglucagonemia, urinary glucose excretion was unchanged. Similarly, urinary urea nitrogen and total nitrogen excretion were not altered by glucagon administration. Urinary sodium tended to rise, albeit not significantly (P < 0.1), on the first infusion day, but later declined to control values despite increasing plasma glucagon concentrations. Urinary chloride, potassium, calcium, and phophorus excretion remained unchanged. We conclude that continuous physiologic increments in plasma glucagon do not enhance glycosuria or increase protein catabolism and ureagenesis in diabetes when insulin is available. The augmented protein catabolism and gluconeogenesis that accompany diabetic ketoacidosis can not be explained primarily on the basis of hyperglucagonemia.     

Idiopathic thrombocytopenic purpura occurring in a subject previously splenectomized for traumatic splenic rupture: Role of splenosis in the pathogenesis of thrombocytopenia

A 25 year old woman presented with idiopathic thrombocytopenic purpura. She had undergone splenectomy 12 years previously for traumatic splenic rupture. Thrombocytopenia was ultimately resistant to steroid therapy. Howell-Jolly bodies were absent from the peripheral smear and ^99mTC-spleen scan demonstrated foci of increased uptake thought consistent with accessory spleens. However, splenosis alone was demonstrated at laparotomy, and all visible splenotic tissue was surgically removed. The patient responded and adequate platelet counts were maintained after discontinuation of steroid therapy. The functional capacity of splenic implants has been previously demonstrated both in animal and man. However, reports linking splenosis to hematologic disease are rare. In the present case, characteristic splenic function was demonstrated by both the ^99mTc-spleen scan and the absence of the typical peripheral blood findings of asplenia. The hematologic response to the removal of the splenotic tissue attests to its importance in maintaining the thrombocytopenic state. In the setting of prior splenectomy for splenic trauma, splenosis may contribute to hematologic disease. Removal of this splenotic tissue may result in hematologic remission.     

Influence of physical training on the fuel-hormone response to prolonged low intensity exercise

The effects of physical training on the fuel-hormone response to prolonged (3 hr), low intensity cycle ergometer exercise (40% maximal aerobic power) which in the untrained state fails to produce a rise in blood lactate, was examined in six healthy male subjects. The training program consisted of one hour cycle ergometer exercise performed 4 times weekly for 6 weeks and resulted in a 19% increase in maximal aerobic power. Prior to training, prolonged low intensity exercise resulted in a 20% decline in plasma glucose, a 2.5-fold rise in plasma free fatty acids (FFA), a 7-fold rise in plasma epinephrine, a 3-fold elevation in plasma norepinephrine, and a 2.5-fold rise in plasma glucagon. Following training, the exercise-induced decline in glucose was 60% less than before training, the elevations in plasma FFA and norepinephrine were respectively, 45% and 90% less than before training and no significant increment in plasma norepinephrine and glucagon was observed. Training also blunted the exercise-induced elevations in circulating ketones and growth hormone and resulted in a lower respiratory exchange ratio during exercise. The data indicate that training markedly diminishes the fuel-hormone perturbations associated with low intensity exercise and in the face of a lessened increment in plasma FFA results in a greater utilization of fat and less dependence on carbohydrate during the exercise.     

Pharmacokinetics of digoxin and digitoxin in patients undergoing hemodialysis

The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population.Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dlalyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin.When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (± SE) of 0.84 ± 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 ± 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the pharmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.