Plasma insulin response to various secretagogues in insulinoma

Since the development of radioimmunoassay for insulin, the diagnosis of insulinoma has been made easily. However, it has been assumed that insulinoma is heterogenous in the histological structure as well as in clinical findings. Therefore, the present study was performed to investigate the insulin response to various stimuli and to evaluate the various insulin response tests in 19 patients with insulinoma. The fasting blood glucose was 19 to 90 mg/100 ml in insulinoma and 81 +/- 5 (mean +/- S.D.) mg/100 ml in normal controls. Plasma insulin (IRI) in insulinoma ranged from 10 to 255 microU/ml, while in the control it was 14 +/- 9 microU/ml. However, insulin/blood glucose ratio increased in insulinoma (0.2-11.2) compared with the normal control (0.18 +/- 0.11). In oral glucose tolerance tests, plasma IRI increased and reached peak levels of 48-244 microU/ml, remaining elevated in most cases. In the intravenous tolbutamide test, plasma IRI increased conspicuously to 82-1,330 microU/ml and hypoglycemic coma was provoked in 54%. Plasma IRI was elevated in the intravenous glucagon test and reached the peak levels of 85-400 microU/ml, which exceeded those of the control group. Plasma IRI increased to more than 100 microU/ml after arginine infusion and formed bizarre curves. There were no correlations between plasma IRI response to various stimuli and malignancy, type of B-granule or insulin content of insulinoma tumors. It is concluded that fasting plasma IRI, insulin/glucose ratio, tolbutamide test and glucagon test are highly valuable for the diagnosis of insulinoma.     

Interactions between glucagon and other counterregulatory hormones during normoglycemic and hypoglycemic exercise in dogs.

Somatostatin (ST)-induced glucagon suppression results in hypoglycemia during rest and exercise. To further delineate the role of glucagon and interactions between glucagon and the catecholamines during exercise, we compensated for the counterregulatory responses to hypoglycemia with glucose replacement. Five dogs were run (100 m/min, 12 degrees) during exercise alone, exercise plus ST infusion (0.5 micrograms/kg-min), or exercise plus. ST plus glucose replacement (3.5 mg/kg-min) to maintain euglycemia. During exercise alone there was a maximum increase in immunoreactive glucagon (IRG), epinephrine (E), norepinephrine (NE), FFA, and lactate (L) of 306 +/- 147 pg/ml, 360 +/- 80 pg/ml, 443 +/- 140 pg/ml, 541 +/- 173 mu eq/liter, and 6.3 +/- 0.7 mg/dl, respectively. Immunoreactive insulin (IRI) decreased by 10.2 +/- 4 micro/ml and cortisol (C) increased only slightly (2.1 +/- 0.3 micrograms/dl). The rates of glucose production (Ra) and glucose uptake (Rd) rose markedly by 6.6 +/- 2.2 mg/kg-min and 6.2 +/- 1.5 mg/kg-min. In contrast, when ST was given during exercise, IRG fell transiently by 130 +/- 20 pg/ml, Ra rose by only 3.6 +/- 0.5 mg/kg-min, and plasma glucose decreased by 29 +/- 6 mg/dl. The decrease in IRI was no different than with exercise alone (10.2 +/- 2.0 microU/ml). As plasma glucose fell, C, FFA, and L rose excessively to peaks of 5.4 +/- 1.3 micrograms/dl, 1,166 +/- 182 mu eq/liter and 15.5 +/- 7.0 mg/dl. The peak increment in E (765 +/- 287 pg/ml) coincided with the nadir in plasma glucose and was four times greater than during normoglycemic exercise. Hypoglycemia did not affect the rise in NE. The increase in Rd was attenuated and reached a peak of only 3.7 +/- 0.8 mg/kg-min. During glucose replacement, IRG decreased by 109 +/- 30 pg/ml and the IRI response did not differ from the response to normal exercise. Ra rose minimally by 1.5 +/- 0.3 mg/kg-min. The changes in E, C, Rd, and L were restored to normal, whereas the FFA response remained excessive. In all protocols increments in Ra were directly correlated to the IRG/IRI molar ratio while no correlation could be demonstrated between epinephrine or norepinephrine and Ra. In conclusion, (a) glucagon controlled approximately 70% of the increase of Ra during exercise. This became evident when counterregulatory responses to hypoglycemia (E and C) were obviated by glucose replacement; (b) increments in Ra were strongly correlated to the IRG/IRI molar ratio but not the plasma catecholamine concentration; (c) the main role of E in hypoglycemia was to limit glucose uptake by the muscle; (d) with glucagon suppression, glucose production was deficient but a further decline of glucose was prevented through the peripheral effects of E, (e) the hypoglycemic stimulus for E secretion was facilitated by exercise; and (f) we hypothesize that an important role of glucagons during exercise could be to spare muscle glycogen by stimulating glucose production by the liver.     

Gastric inhibitory polypeptide (GIP) responses after oral glucose ingestion in hyperthyroidism

Gastric inhibitory polypeptide (GIP) is a gastrointestinal hormone stimulated after oral nutrient ingestion, but not after intravenous nutrient administration. GIP stimulates insulin release in the presence of hyperglycemia and as such is considered a major enteroinsular hormone. Since elevated glucose and insulin levels are found in hyperthyroidism, we compared the GIP responses to oral glucose ingestion in 12 hyperthyroid patients and 10 age-matched controls. Seventy-five grams of oral glucose was ingested after overnight fasting and samples were obtained at 0, 30, 60, 90, 120, and 180 min for serum glucose and immunoreactive insulin (IRI) and GIP (IRGIP). The mean serum glucose levels in hyperthyroid subjects were significantly higher (P less than or equal to 0.05) at every time studied except at 180 min. At 60 min, peak mean glucose was 171 +/- 14 mg/dl versus 128 +/- 7 mg/dl in controls (P less than 0.02). Except for fasting, mean IRI levels were significantly higher (P less than 0.001) in hyperthyroid subjects than in controls at all times studied. At 60 min, IRI rose to a peak of 125 +/- 11 microU/ml in hyperthyroid subjects versus 50 +/- 9 microU/ml in controls (P less than 0.001). Mean fasting, stimulated, and incremental IRGIP levels were slightly higher but not statistically different in the hyperthyroid subjects versus controls. Glucose and IRI responses are exaggerated in hyperthyroidism after oral glucose ingestion. Even though GIP has insulinotropic action, its role in the hyperinsulinism found in hyperthyroid subjects appears to be minimal.     

An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects.

Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 microCi/min) was performed for 120 min before and during a euglycemic clamp repeated at approximately 100, approximately 1,000, and approximately 10,000 microU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 +/- 7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5 +/- 2.1 vs. 83.7 +/- 1.9 mg/dl) and mean fasting plasma insulin values (17.8 +/- 1.2 vs. 14.3 +/- 0.8 microU/ml) were significantly higher (P less than 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P less than 0.001) after prednisone at all three steady state plasma insulin levels: 2.8 +/- 0.3 vs. 7.4 +/- 1.1 at approximately 100 microU/ml; 6.0 +/- 0.5 vs. 12.2 +/- 1.1 at approximately 1,000 microU/ml; 7.4 +/- 0.6 vs. 14.4 +/- 0.5 at approximately 10,000 microU/ml. Fasting glucose production (in mg/kg per min) was significantly higher after prednisone: 3.7 +/- 0.2 vs. 2.9 +/- 0.2, P less than 0.001. Suppression of glucose production at steady state plasma insulin level of approximately 100 microU/ml was less after prednisone (1.01 +/- 0.35 vs. 0.14 +/- 0.13, NS), and total at approximately 1,000 and approximately 10,000 microU/ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40 +/- 8 yr (10 treated with placebo and 6 with prednisone as above). No significant difference was observed with regard to specific insulin binding (tested with 1 ng/ml hormone only), whereas significant transport differences were noted at the basal level (0.40 +/- 0.10 vs. 0.54 +/- 0.12 pmol/10(5) cells, P less than 0.05), and at increasing concentrations up to the maximum stimulation values (5 ng/ml): 0.59 +/- 0.04 vs. 0.92 +/- 0.12 pmol/10(5) cells, P less than 0.005. These results suggest that (a) administration of an anti-inflammatory dose of prednisone for 7 d induces insulin resistance in man; (b) this is more dependent on depressed peripheral glucose utilization than on increased endogenous production; (c) total insulin binding on isolated adipocytes is not significantly affected; (d) insulin resistance is primarily the outcome of postreceptor defect (impaired glucose transport).     

Oral Glucose Augmentation of Insulin Secretion: INTERACTIONS OF GASTRIC INHIBITORY POLYPEPTIDE WITH AMBIENT GLUCOSE AND INSULIN LEVELS

Gastric inhibitory polypeptide, or GIP, has been postulated as the major enteric hormonal mediator of insulin release. The release of immuno-reactive GIP (IR-GIP) after oral glucose and its role in insulin release was studied in normal men by the glucose clamp technique. In 24 subjects studied with the hyperglycemic clamp, blood glucose was maintained at 125 mg/dl above basal for 2 h via a primed-continuous IV glucose infusion coupled to a servo-controlled negative feedback system. 40 g glucose per m² surface area was ingested at 60 min, and the blood glucose was maintained at the steady-state hyperglycemic level. Plasma IR-GIP and insulin (IRI) levels were measured throughout the 2-h period. IR-GIP levels changed little when IV glucose alone was given; the mean basal value was 305±34 (SEM) pg/ml. After oral glucose, IR-GIP levels began to rise within 10 min and reached a peak within 40 min of 752±105 pg/ml. Plasma IRI responded initially to the square wave of hyperglycemia in the typical biphasic pattern. After oral glucose, plasma IRI levels rose strikingly above the elevated levels produced by hyperglycemia alone, reaching a peak of 170±15 μU/ml within 45 min. The time course of the rise in IR-GIP and IRI was nearly identical.     

Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect.

Insulin resistance in liver cirrhosis may depend on either reduced sensitivity (receptor defect) and/or reduced response to insulin (postreceptor defect). To clarify the mechanism of such resistance, a [3H]glucose infusion (0.2 microCi/min) was performed for 120 min before and during a euglycemic clamp at approximately 100, 1,000, and 10,000 microU/ml steady state plasma insulin concentration in 18 compensated cirrhotics with portal hypertension and impaired glucose tolerance, and 18 healthy volunteers with no family history of diabetes, matched for sex, age, and weight. Mean fasting plasma insulin (29.2 +/- 3.4 SEM vs. 14.8 +/- 1.1 microU/ml) was significantly higher (P less than 0.001) in cirrhotics, while fasting plasma glucose was much the same in the two groups. Glucose use (milligrams per kilogram per minute) was significantly lower in cirrhotics at all three steady state plasma insulin levels: 3.04 +/- 0.34 vs. 7.72 +/- 0.61 (P less than 0.001) at approximately 100; 6.05 +/- 1.07 vs. 11.45 +/- 1.24 (P less than 0.001) at approximately 1,000; and 11.69 +/- 0.69 vs. 14.13 +/- 0.74 (P less than 0.05) at approximately 10,000 microU/ml. Mean plasma C-peptide was significantly higher in cirrhotics both basally and during the steady states (P less than 0.001); it was completely suppressed at approximately 10,000 microU/ml in controls and only 57.5% of the baseline in cirrhotics. Endogenous glucose production (milligrams per kilogram per minute) was much the same in the two groups in the fasting state and almost entirely suppressed in the controls (0.10 +/- 0.05 vs. 0.48 +/- 0.11, P less than 0.001) at approximately 100 microU/ml; at approximately 1,000 microU/ml a residual glucose production, 0.07 +/- 0.05, was observed in the cirrhotics only. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro in six cirrhotics and six controls. Insulin binding to circulating monocytes and isolated adipocytes was significantly lower (P less than 0.025) in cirrhotics in all insulin concentration studies. Glucose transport values on isolated adipocytes were significantly lower in cirrhotics both basally (P less than 0.001) and at maximal insulin concentration (P less than 0.05). These results suggest that insulin resistance in human cirrhosis is more dependent on depressed peripheral glucose use than on increased endogenous glucose production, and that a combined receptor and postreceptor defect in insulin action on target cells seems to be present.     

Effects of cisapride on the secretion of pancreatic polypeptide in healthy volunteers

Plasma human pancreatic polypeptide (hPP) responses to intravenous injections of a new gastric and intestinal motility promoting agent, R51 619 (cisapride), were studied in healthy volunteers. The mean fasting concentrations of plasma hPP (39 +/- 5.4 pg/ml; mean +/- S.E.) were elevated significantly to the peak values of 118 +/- 25.1 pg/ml 30 min after the drug had been given in a dose of 4 mg over 5 min. However, plasma insulin (IRI), glucose and prolactin levels were not elevated. Atropine diminished the cisapride-induced hPP elevation, thereby suggesting that cisapride induced release of acetylcholine but had no antidopaminergic action.     

Dawn phenomenon: its frequency in non-insulin-dependent diabetic patients on conventional therapy

The frequency of the dawn phenomenon has been studied in non-insulin-dependent diabetic (NIDDM) patients while they continued with their conventional therapy. Plasma glucose (PG) and immunoreactive insulin (IRI) were estimated hourly from 0300 to 0900 h in 19 NIDDM patients; 9 patients were treated by diet alone (group 1), and 10 patients were treated by diet and oral hypoglycemic agents (group 2). The dawn rise of plasma glucose was demonstrated in 17 (89.5%) of the 19 patients with mean +/- SE plasma glucose at 0300 h of 7.0 +/- 0.5 mM and at 0800 h of 8.4 +/- 0.6 (P less than .01). IRI in all patients rose from 14.7 +/- 1.3 microU/ml at 0500 h to 18.1 +/- 1.8 microU/ml at 0700 h (P less than .05). The changes in IRI levels at any time from 0300 to 0800 h in groups 1 and 2 when considered separately were insignificant. Thus, the dawn phenomenon occurs commonly in NIDDM patients taking their conventional therapy.     

Evidence that the brain of the conscious dog is insulin sensitive.

The aim of this study was to determine whether a selective increase in the level of insulin in the blood perfusing the brain is a determinant of the counterregulatory response to hypoglycemia. Experiments were carried out on 15 conscious 18-h-fasted dogs. Insulin was infused (2 mU/kg per min) in separate, randomized studies into a peripheral vein (n = 7) or both carotid and vertebral arteries (n = 8). This resulted in equivalent systemic insulinemia (84 +/- 6 vs. 86 +/- 6 microU/ml) but differing insulin levels in the head (84 +/- 6 vs. 195 +/- 5 microU/ml, respectively). Glucose was infused during peripheral insulin infusion to maintain the glucose level (56 +/- 2 mg/dl) at a value similar to that seen during head insulin infusion (58 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and similar hypoglycemia; steady state plasma epinephrine (792 +/- 198 vs. 2394 +/- 312 pg/ml), norepinephrine (404 +/- 33 vs. 778 +/- 93 pg/ml), cortisol (6.8 +/- 1.8 vs. 9.8 +/- 1.6 micrograms/dl) and pancreatic polypeptide (722 +/- 273 vs. 1061 +/- 255 pg/ml) levels were all increased to a greater extent during head insulin infusion (P < 0.05). Hepatic glucose production, measured with [3-3H]glucose, rose from 2.6 +/- 0.2 to 4.3 +/- 0.4 mg/kg per min (P < 0.01) in response to head insulin infusion but remained unchanged (2.6 +/- 0.5 mg/kg per min) during peripheral insulin infusion. Similarly, gluconeogenesis, lipolysis, and ketogenesis were increased twofold (P < 0.001) during head compared with peripheral insulin infusion. Cardiovascular parameters were also significantly higher (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog (a) the brain is directly responsive to physiologic elevations of insulin and (b) the response includes a profound stimulation of the autonomic nervous system with accompanying metabolic and cardiovascular changes.     

Regulation by insulin of myocardial glucose and fatty acid metabolism in the conscious dog.

In vivo small doses of insulin inhibit lipolysis, lower plasma FFA, and stimulate glucose disposal. Lowering of plasma FFA, either in the absence of a change in insulin or during combined hyperglycemia and hyperinsulinemia, promotes glucose uptake by heart muscle in vivo. In the isolated perfused heart, large doses of insulin directly stimulate heart glucose uptake. To assess the effect of physiological elevations of plasma insulin upon myocardial glucose and FFA uptake in vivo independent of changes in plasma substrate concentration, we measured arterial and coronary sinus concentrations of glucose, lactate, and FFA, and coronary blood flow in conscious dogs during a 30 min basal and a 2 h experimental period employing three protocols: (a) euglycemic hyperinsulinemia (insulin clamp, n = 5), (b) euglycemic hyperinsulinemia with FFA replacement (n = 5), (c) hyperglycemic euinsulinemia (hyperglycemic clamp with somatostatin, n = 5). In group 1, hyperinsulinemia (insulin = 73 +/- 13 microU/ml) stimulated heart glucose uptake (7.3 +/- 4.4 vs. 28.2 +/- 2.8 mumol/min, P less than 0.002), lowered plasma FFA levels by 80% (P less than 0.05), and decreased heart FFA uptake (28.4 +/- 4 vs. 1.5 +/- 0.9, P less than 0.01). When the fall in plasma FFA was prevented by FFA infusion (group 2), hyperinsulinemia (86 +/- 10 microU/ml) provoked a lesser (P less than 0.05) stimulation of glucose uptake (delta = 8.2 +/- 4.2 mumol/min) than in group 1, and there was no significant change in FFA uptake (25.3 +/- 16 vs. 16.5 +/- 4). Hyperglycemia (plasma glucose = 186 +/- 8 mg/100 ml) during somatostatin infusion resulted in only a small rise in plasma insulin (delta = 12 +/- 7 microU/ml), and although plasma FFA tended to decline, heart glucose uptake did not rise significantly (delta = 5.5 +/- 3.2 mumol/min, P = NS). There was no significant change in coronary blood flow during any of the three study protocols. We conclude that, in the dog, insulin at physiologic concentrations: (a) stimulates heart glucose uptake, both directly and by suppressing the plasma FFA concentration, and (b) does not alter coronary blood flow. Hyperglycemia per se has little effect on heart glucose uptake.     

Thermic effect of glucose in man. Obligatory and facultative thermogenesis.

The contribution of the sympathetic nervous system to the thermic effect of intravenously infused glucose and insulin was studied in 10 healthy young men before and after beta-adrenergic receptor blockade with propranolol during conditions of normoglycemia (90 mg/dl) at two levels of hyperinsulinemia (approximately 90 microU/ml and approximately 620 microU/ml). During steady state conditions of glucose uptake (0.515 +/- 0.046 and 0.754 +/- 0.056 g/min), significant increases were observed in energy expenditure (0.10 +/- 0.02 kcal/min, P less than 0.001, and 0.21 +/- 0.02 kcal/min, P less than 0.01, respectively). Similarly, glucose oxidation increased from 0.100 +/- 0.015 to 0.266 +/- 0.022 g/min (P less than 0.001) at approximately microU/ml insulin and from 0.082 +/- 0.013 to 0.295 +/- 0.018 g/min (P less than 0.001) at approximately 620 microU/ml insulin. Concomitantly, the rate of nonoxidative glucose disposal or "glucose storage" was 0.249 +/- 0.033 and 0.459 +/- 0.048 g/min, respectively. At this time the thermic effect of infused glucose/insulin was 5.3 +/- 0.9 and 7.5 +/- 0.7%, and the energy cost of "glucose storage" was 0.50 +/- 0.16 kcal/g and 0.47 +/- 0.04 kcal/g at the two different levels of glucose uptake. After beta-adrenergic receptor blockade with propranolol, glucose uptake, oxidation, and "storage" were unchanged in both studies, but significant decreases in energy expenditure were observed (1.41 +/- 0.06-1.36 +/- 0.05 kcal/min, P less than 0.01 at approximately 90 microU/ml insulin, and 1.52 +/- 0.07-1.43 +/- 0.05 kcal/min, P less than 0.005 at approximately 620 microU/ml insulin) causing significant falls in both the estimated thermic effect of infused glucose/insulin and the energy cost of "glucose storage". Regression analysis of the results from both studies indicated a mean energy cost for "glucose storage" of 0.36 kcal/g (r = 0.74, P less than 0.001), which fell significantly (P less than 0.005) to 0.21 kcal/g (r = 0.49, P less than 0.05) during beta-adrenergic receptor blockade with propranolol. The latter is in close agreement with that calculated on theoretical grounds for the metabolic cost of glucose storage as glycogen, i.e., obligatory thermogenesis. It is concluded that beta-adrenergically mediated sympathetic nervous activity is responsible for almost the entire rise in energy expenditure in excess of the obligatory requirements for processing and storing glucose during conditions of normoglycemia and hyperinsulinemia in healthy man, and that the energy cost of "glucose storage" is not different at normal (approximately 90 microU/ml) and supraphysiological (approximately 620 microU/ml) plasma insulin concentrations.     

Mechanisms of glucagon secretion during insulin-induced hypoglycemia in man. Role of the beta cell and arterial hyperinsulinemia

To elucidate the mechanisms controlling the response of glucagon to hypoglycemia, a vital component of the counterregulatory hormonal response, the role of intraislet insulin was studied in seven normal subjects and five subjects with insulin-dependent diabetes mellitus (IDDM) (of less than 15-mo duration). In the normal subjects, hypoglycemia (arterial plasma glucose [PG] 53 +/- 3 mg/dl) induced by an intravenous insulin infusion (30 mU/m2 X min for 1 h, free immunoreactive insulin [FIRI] 58 +/- 2 microU/ml) elicited a 100% fall in insulin secretion and an integrated rise in glucagon of 7.5 ng/ml per 120 min. When endogenous insulin secretion was suppressed by congruent to 50 or congruent to 85% by a hyperinsulinemic-euglycemic clamp (FIRI 63 +/- 1.5 or 147 +/- 0.3 microU/ml, respectively) before hypoglycemia, the alpha cell responses to hypoglycemia were identical to those of the control study. When the endogenous insulin secretion was stimulated by congruent to 100% (hyperinsulinemic-hyperglycemic clamp, FIRI 145 +/- 1.5 microU/ml, PG 132 +/- 2 mg/dl) before hypoglycemia, the alpha cell responses to the hypoglycemia were also superimposable on those of the control study. Finally, in C-peptide negative diabetic subjects made euglycemic by a continuous overnight intravenous insulin infusion, the alpha cell responses to hypoglycemia were comparable to those of normal subjects despite absent beta cell secretion, and were not affected by antecedent hyperinsulinemia (hyperinsulinemic-euglycemic clamp for 2 h, FIRI 61 +/- 2 microU/ml). These results indicate that the glucagon response to insulin-induced hypoglycemia is independent of the level of both endogenous intraislet and exogenous arterial insulin concentration in normal man, and that this response may be normal in the absence of endogenous insulin secretion, in contrast to earlier reports. Thus, loss of beta cell function is not responsible for alpha cell failure during insulin-induced hypoglycemia in IDDM.     

Role of parathyroid hormone in the glucose intolerance of chronic renal failure.

Evidence has accumulated suggesting that the state of secondary hyperparathyroidism and the elevated blood levels of parathyroid hormone (PTH) in uremia participate in the genesis of many uremic manifestations. The present study examined the role of PTH in glucose intolerance of chronic renal failure (CRF). Intravenous glucose tolerance tests (IVGTT) and euglycemic and hyperglycemic clamp studies were performed in dogs with CRF with (NPX) and without parathyroid glands (NPX-PTX). There were no significant differences among the plasma concentrations of electrolytes, degree of CRF, and its duration. The serum levels of PTH were elevated in NPX and undetectable in NPX-PTX. The NPX dogs displayed glucose intolerance after CRF and blood glucose concentrations during IVGTT were significantly (P less than 0.01) higher than corresponding values before CRF. In contrast, blood glucose levels after IVGTT in NPX-PTX before and after CRF were not different. K-g rate fell after CRF from 2.86 +/- 0.48 to 1.23 +/- 0.18%/min (P less than 0.01) in NPX but remained unchanged in NPX-PTX (from 2.41 +/- 0.43 to 2.86 +/- 0.86%/min) dogs. Blood insulin levels after IVGTT in NPX-PTX were more than twice higher than in NPX animals (P less than 0.01) and for any given level of blood glucose concentration, the insulin levels were higher in NPX-PTX than NPX dogs. Clamp studies showed that the total amount of glucose utilized was significantly lower (P less than 0.025) in NPX (6.64 +/- 1.13 mg/kg X min) than in NPX-PTX (10.74 +/- 1.1 mg/kg X min) dogs. The early, late, and total insulin responses were significantly (P less than 0.025) greater in the NPX-PTX than NPX animals. The values for the total response were 143 +/- 28 vs. 71 +/- 10 microU/ml, P less than 0.01. There was no significant difference in the ratio of glucose metabolized to the total insulin response, a measure of tissue sensitivity to insulin, between the two groups. The glucose metabolized to total insulin response ratio in NPX (5.12 +/- 0.76 mg/kg X min per microU/ml) and NPX-PTX (5.18 +/- 0.57 mg/kg X min per microU/ml) dogs was not different but significantly (P less than 0.01) lower than in normal animals (9.98 +/- 1.26 mg/kg X min per microU/ml). The metabolic clearance rate of insulin was significantly (P less than 0.02) reduced in both NPX (12.1 +/- 0.7 ml/kg X min) and NPX-PTX (12.1 +/- 0.9 ml/kg X min) dogs, as compared with normal animals (17.4 +/- 1.8 ml/kg X min). The basal hepatic glucose production was similar in both groups of animals and nor different from normal dogs; both the time course and the magnitude of suppression of hepatic glucose production by insulin were similar in both in groups. There were no differences in the binding affinity, binding sites concentration, and binding capacity of monocytes to insulin among NPX, NPX-PTX, and normal dogs. The data show that (a) glucose intolerance does not develop with CRF in the absence of PTH, (b) PTH does not affect metabolic clearance of insulin or tissue resistance to insulin in CRF, and (c) the normalization of metabolism in CRF in the absence of PTH is due to increased insulin secretion. The results indicate that excess PTH in CRF interferes with the ability of the beta-cells to augment insulin secretion appropriately in response to the insulin-resistant state.     

Role of the endocrine pancreas in the kalemic response to acute metabolic acidosis in conscious dogs.

Metabolic acidosis due to organic acids infusion fails to elicit hyperkalemia. Although plasma potassium levels may rise, the increase is smaller than in mineral acid acidosis. The mechanisms responsible for the different effects of organic acid acidosis and mineral acid acidosis remain undefined, although dissimilar hormonal responses by the pancreas may explain dissimilar hormonal responses by the pancreas may explain the phenomena. To test this hypothesis, beta-hydroxybutyric acid (7 meq/kg) or hydrochloric acid (3 meq/kg) was infused over 30 min into conscious dogs (n = 12) with chronically implanted catheters in the portal, hepatic, and systemic circulation, and flow probes were placed around the portal vein and hepatic artery. Acid infusion studies in two groups of anesthetized dogs were also done to assess the urinary excretion of potassium (n = 14), and to evaluate the effects of acute suppression of renal electrolyte excretion on plasma potassium and on the release/uptake of potassium in peripheral tissues of the hindleg (n = 17). Ketoacid infusion caused hypokalemia and a significant increase in portal vein plasma insulin, from the basal level of 27 +/- 4 microU/ml to a maximum of 84 +/- 22 microU/ml at 10 min, without changes in glucagon levels. By contrast, mineral acid acidosis of similar severity resulted in hyperkalemia and did not increase portal insulin levels but enhanced portal glucagon concentration from control values of 132 +/- 25 pg/ml to 251 +/- 39 pg/ml at 40 min. A significant decrease in plasma glucose levels due to suppression of hepatic release was observed during ketoacid infusion, while no changes were observed with mineral acid infusion. Plasma flows in the portal vein and hepatic artery remained unchanged from control values in both acid infusion studies. Differences in renal potassium excretion were ruled out as determinants of the disparate kalemic responses to organic acid infusion compared with HCl acidosis. Evaluation of the arteriovenous potassium difference across the hindleg during ketoacid infusion demonstrates that peripheral uptake of potassium is unlikely to be responsible for the observed hypokalemia. Although the tissue responsible for the different kalemic responses could not be defined with certainty, the data are compatible with an hepatic role in response to alterations in the portal vein insulin and/or glucagon levels in both acid infusion studies. We propose that cellular uptake of potassium is enhanced by hyperinsulinemia in ketoacid infusion, and release of potassium results from increased glucagon levels in HCl acidosis. Whether the changes in plasma potassium that other types od organic acid acidosis produce are accounted for by a similar hormonal mechanism remains to be determined.     

A case of insulin resistance associated with acanthosis nigricans

We described here a 12-year-old male patient with the syndrome of insulin resistance and acanthosis nigricans type A. Insulin levels at fasting state and after glucose loading were 149 +/- 63 microU/ml (mean +/- S.D.) and over 1,000 microU/ml respectively, while the fasting level of blood glucose was 77.7 +/- 8.9 mg/ml (mean +/- S.D.). A marked resistance to exogenous insulin was observed. Circulating levels of insulin antagonists such as growth hormone, cortisol and glucagon were within the normal range. Proinsulin was less than 5% of the radioimmunoassayable insulin. No insulin antibody or antireceptor antibody was detected. Insulin binding to mononuclear cells was decreased to about 50% of the controls. Analysis of membrane receptors demonstrated the normal average affinity, dissociation kinetics and negative cooperativity with a decreased number of receptors. After two days fasting, plasma IRI levels decreased to 27 microU/ml, while insulin binding kinetics were not affected; which suggests that the receptor decrease was not secondary to hyperinsulinemia. These findings indicate that the decreased number of receptors was one of the causes for insulin resistance in this patient.     

Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.     

Importance of Hepatic Portal Circulation for Insulin Action in Streptozotocin-Diabetic Rats Transplanted with Fetal Pancreases

The importance of the hepatic portal circulation in the response to insulin was assessed in streptozotocin-diabetic rats transplanted with syngeneic fetal pancreases. Partial reversal of diabetes was accomplished by transplantation of two or three fetal pancreases beneath the capsule of the kidney; complete reversal followed shunting of the venous drainage from the transplants to the liver. Plasma glucose after streptozotocin of 509+/-31 mg/dl (mean+/-SEM) fell after transplantation to 395+/-23 and after the shunt to 143+/-5 mg/dl. Urine volume fell from 84+/-4 to 50+/-5 ml/d and then to normal (17+/-1 ml/d) after the shunt. Glucose excretion which was 8.1+/-0.3 g/d after streptozotocin fell after transplantation to 4.8+/-0.3 g/d and after the shunt completely disappeared from the urine. The disappearance rate of glucose injected into the circulation, which was 0.50+/-0.07%/min in untreated diabetes, increased to 1.39+/-0.38%/min after transplantation and to 2.52+/-0.31%/min after the shunt, not different from normal controls (2.79+/-0.25). Plasma immunoreactive insulin (IRI) was below normal (25-35 muU/ml) and unresponsive to glucose in untreated diabetic rats. After transplantation IRI levels ranged from 73-223 muU/ml and there was no rise after glucose injection. After the shunt both the basal IRI (36+/-5 muU/ml) and the peak response to glucose at 10 min (58+/-7 muU/ml) were the same as in normal controls (42+/-4 and 62+/-7 muU/ml, respectively). The fall in IRI after the shunt is explained by increased extraction of insulin passing into the liver and also diminished secretion. After removal of the transplants plasma glucose and urine values returned almost to pretransplant levels.Secretion of insulin by transplanted pancreases into the liver enhances the effectiveness probably by increased extraction and action and reveals the importance of the normal route for insulin delivery.     

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.     

Effects of morphine on glucose homeostasis in the conscious dog.

This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon. In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99 +/- 3 to 154 +/- 13 mg/dl (P less than 0.05). Glucose production peaked at 3.9 +/- 0.7 vs. 2.5 +/- 0.2 mg/kg per min basally, while glucose clearance declined to 1.7 +/- 0.2 from 2.5 +/- 0.1 ml/kg per min (both P less than 0.05). Morphine increased epinephrine (1400 +/- 300 vs. 62 +/- 8 pg/ml), norepinephrine (335 +/- 66 vs. 113 +/- 10 pg/ml), glucagon (242 +/- 53 vs. 74 +/- 14 pg/ml), insulin (30 +/- 9 vs. 10 +/- 2 microU/ml), cortisol (11.1 +/- 3.3 vs. 0.9 +/- 0.2 micrograms/dl), and plasma beta-endorphin (88 +/- 27 vs. 23 +/- 6 pg/ml); all values P less than 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part of a widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis. Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma glucose, P less than 0.05) that is due to inhibition of glucose production (by 25-43%, P less than 0.05). The hypoglycemia was independent of detectable changes in insulin, glucagon, epinephrine and cortisol, and was not reversed by concurrent infusion of a slight molar excess of naloxone. Therefore, we postulate that the hypoglycemic effect of morphine results from the interaction of the opiate with non-mu receptors either in the liver or the central nervous system.     

Insulin resistance in uremia.

Tissue sensitivity to insulin was examined with the euglycemic insulin clamp technique in 17 chronically uremic and 36 control subjects. The plasma insulin concentration was raised by approximately 100 microU/ml and the plasma glucose concentration was maintained at the basal level with a variable glucose infusion. Under these steady-state conditions of euglycemia, the glucose infusion rate is a measure of the amount of glucose taken up by the entire body. In uremic subjects insulin-mediated glucose metabolism was reduced by 47% compared with controls (3.71 +/- 0.20 vs. 7.38 +/- 0.26 mg/kg . min; P less than 0.001). Basal hepatic glucose production (measured with [3H]-3-glucose) was normal in uremic subjects (2.17 +/- 0.04 mg/kg . min) and suppressed normally by 94 +/- 2% following insulin administration. In six uremic and six control subjects, net splanchnic glucose balance was also measured directly by the hepatic venous catheterization technique. In the postabsorptive state splanchnic glucose production was similar in uremics (1.57 +/- 0.03 mg/kg . min) and controls (1.79 +/- 0.20 mg/kg . min). After 90 min of sustained hyperinsulinemia, splanchnic glucose balance reverted to a net uptake which was similar in uremics (0.42 +/- 0.11 mg/kg . min) and controls (0.53 +/- 0.12 mg/kg . min). In contrast, glucose uptake by the leg was reduced by 60% in the uremic group (21 +/- 1 vs. 52 +/- 8 mumol/min . kg of leg wt; P less than 0.005) and this decrease closely paralleled the decrease in total glucose metabolism by the entire body. These results indicate that: (a) suppression of hepatic glucose production by physiologic hyperinsulinemia is not impaired by uremia, (b) insulin-mediated glucose uptake by the liver is normal in uremic subjects, and (c) tissue insensitivity to insulin is the primary cause of insulin resistance in uremia.