RESUMEN
In order to determine whether the A cell may be directly suppressed by glucose in the absence of insulin, canine pancreata were perfused in vitro, both antegrade, through the arterial system and retrograde, through the venous system. Studies of the islet microvasculature have suggested that blood flows from the B cell core to the mantle; thus, the A cell may be tonically inhibited by intra-islet insulin. Retrograde perfusion may then be expected to prevent insulin from reaching the A cell, releasing it from inhibition. Retrograde perfusion with 88 mg/dl glucose markedly increased both insulin and glucagon secretion relative to antegrade levels. In a series of experiments, glucose concentrations were changed from 88 to 200 mg/dl. An antegrade glucose change resulted in increased insulin (134+/-21%; P less than 0.0025) and decreased glucagon (-26+/-9%, P less than 0.025) secretion. A retrograde glucose increase resulted in increased secretion of both insulin (91+/-15%; P less than 0.0005) and glucagon (23+/-9%; P less than 0.0125). To confirm that retrograde perfusion deprived the A cell of endogenous core derived, vascularly delivered insulin, possibly resulting in increased insulin sensitivity, 0.3 mU/ml exogenous porcine insulin was infused. Antegrade, 0.3 mU/ml insulin, had no effect on glucagon secretion (P less than 0.250), while retrograde infusion of 0.3 mU/ml insulin significantly inhibited glucagon secretion (-31 + 8%; P less than 0.0005). The results of our study support the concept that the direction of blood flow and of flow-dependent intra-islet hormone interactions are from the islet B cell core to the mantle. It was further concluded that the normal A cell may not be suppressed by glucose in the absence of insulin.
Asunto(s)
Glucosa/farmacología , Insulina/farmacología , Islotes Pancreáticos/efectos de los fármacos , Animales , Perros , Glucagón/metabolismo , Insulina/metabolismo , Secreción de Insulina , Masculino , Perfusión , Proyectos de Investigación , Tasa de Secreción/efectos de los fármacosRESUMEN
The effects of adrenergic substances on pancreatic insular secretions were studied in a completely isolated canine pancreas with exclusion of the duodenum from the perfusion circuit. To ensure adequate blockade, blockers were infused before agonists. A dose range of beta-receptor blockade was tested, and putative alpha-adrenergic effects were confirmed by combined alpha- and beta-adrenergic receptor blockade.beta-Adrenergic agonism (2 ng/ml isoproterenol) induced a mean integrated increase of 79+/-20% in somatostatin secretion, whereas glucagon and insulin secretion were increased by 185+/-45 and 495+/-146%, respectively. The stimulations of D, A, and B cells were abolished by propranolol.alpha-Adrenergic agonism (10 ng/ml epinephrine) after beta-adrenergic blockade) moderately decreased somatostatin (-37+/-7%) secretion, moderately increased glucagon (91+/-19%), and markedly decreased insulin (-85+/-3%) release. Similar effects on D-, A-, and B-cell secretion were induced with 2 ng/ml epinephrine or 10 ng/ml norepinephrine after beta-adrenergic blockade. The alpha-adrenergic effects on the D and A cell were abolished by either phentolamine or by phenoxybenzamine. This study showed that there are indeed alpha-adrenergic receptors on A cells and that the secretion of glucagon, a "stress" hormone, was stimulated either by alpha- or beta-adrenergic receptor agonism. D-cell secretion, like that of the B cell, was inhibited by alpha-adrenergic agonism and was stimulated by beta-adrenergic agonism. However, beta-adrenergic-induced changes in D-cell secretion were smaller in magnitude than those of B-cell secretion.
Asunto(s)
Glucagón/metabolismo , Páncreas/inervación , Receptores Adrenérgicos alfa/fisiología , Receptores Adrenérgicos beta/fisiología , Receptores Adrenérgicos/fisiología , Somatostatina/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Perros , Insulina/metabolismo , Secreción de Insulina , Masculino , Páncreas/citología , Páncreas/efectos de los fármacos , Páncreas/metabolismoRESUMEN
Canine pancreata were perfused in vitro to examine whether hormone cycles could be demonstrated without hepatic or central nervous influence. Insulin, glucagon, and somatostatin demonstrated regular sustained cyclic secretion from the in vitro canine pancreas. Oscillations were noted for over 200 min during the infusion of a constant glucose concentration. Insulin demonstrated a 10-min period with a range of 8-12 min/cycle. Somatostatin had a 10-min period with a range of 8-11 min. Glucagon had a period of 8.6 min with range of 6-10 min. These periods do not allow glucagon to be consistently 90 degrees out of phase with insulin and somatostatin. When glucose was increased from 88 to 200 mg/dl, insulin cycles persisted but on an elevated base line, demonstrating that cycles react to glucose changes but are not dependent upon them. Cycles were disrupted by infusions of dopamine, apomorphine, epinephrine, and acetylcholine, but were reestablished. Autonomic blockade by both single and combined infusions of atropine (cholinergic), propranolol, and dibenzyline (adrenergic) had no effect on cycles. These results suggest that, in vitro, there is an intrinsic rhythm of hormone secretion by the pancreas despite a constant glucose level. The production of in vitro cycles requires the presence of a driving oscillator or pacemaker within the pancreas and the coordination of islets by pace-maker-islet communication, presumably by a non-adrenergic neural system. In vitro oscillations may Indicate that the pancreas is the driver or Zeitgeber of in vivo glucose-insulin cycles.
Asunto(s)
Glucagón/metabolismo , Glucosa/farmacología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Somatostatina/metabolismo , Animales , Perros , Técnicas In Vitro , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , PeriodicidadRESUMEN
To test whether insulin secretion is self-regulatory, canine pancreata were isolated and perfused in vitro and were infused with 0.3, 0.6, or 1.2 mU/ml exogenous insulin. Basal and arginine-stimulated concentrations of C-peptide, glucagon, and somatostatin were measured. There were no significant differences between basal secretion nor the increment of arginine-stimulated secretion for each respective hormone at each exogenous insulin concentration. The second preparation studied was a vascularly isolated, yet innervated, in situ perfused pancreas. Exogenous insulin (1 mU/kg per min) was infused "systemically"; the pancreas received no insulin. Endogenous pancreatic insulin and C-peptide secretion was suppressed, while pancreatic glucagon secretion increased during systemic insulin infusion. No changes in pancreatic hormone secretion occurred after the sympathetic nerves were sectioned. These results suggest that exogenous insulin does not directly suppress the B cell, but can suppress insulin secretion through an indirect neurally mediated, insulin-dependent nerve mechanism.
Asunto(s)
Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Animales , Arginina/farmacología , Péptido C/metabolismo , Perros , Femenino , Glucagón/farmacología , Homeostasis , Técnicas In Vitro , Insulina/farmacología , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Cinética , Perfusión , Somatostatina/metabolismoRESUMEN
In order to determine whether microvascular blood flow is important in the regulation of intra-islet cellular interactions, rat pancreata were isolated and perfused in vitro, both anterogradely or retrogradely, with and without anti-insulin or anti-somatostatin gamma-globulin. Expressed as percent change, anterograde infusion of insulin antibody increased efflux concentrations of glucagon (110 +/- 20%, P less than 0.0005) and somatostatin (2,112 +/- 73%, P less than 0.0005) above their respective control. Retrograde infusion of insulin antibody did not affect efflux concentrations of glucagon (P less than 0.50) or somatostatin (P less than 0.50). The anterograde infusion of anti-somatostatin antibody had no effect upon insulin (P less than 0.50) or glucagon (P less than 0.50) efflux concentrations, whereas retrograde anti-somatostatin antibody infusion produced immediate increases in efflux concentrations of both insulin (115 +/- 33%, P less than 0.0005) and glucagon (77 +/- 8%, P less than 0.0005). These results strongly suggest that (a) the vascular compartment is important in the regulation of intra-islet cellular interactions and further suggest that (b) the order of islet cellular perfusion and interaction is from the B cell core outward to the mantle, and (c) the mantle is further subordered with the majority of D cells downstream or distal to the majority of A cells. Thus, in the vascular compartment, B cells inhibit A-cell secretion and A cells stimulate D-cell secretion.
Asunto(s)
Islotes Pancreáticos/irrigación sanguínea , Microcirculación , Perfusión , Animales , Sitios de Unión de Anticuerpos , Glucagón/metabolismo , Sueros Inmunes/administración & dosificación , Insulina/inmunología , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/citología , Masculino , Unión Proteica , Ratas , Ratas Endogámicas , Somatostatina/inmunología , Azul de Tripano/administración & dosificación , gammaglobulinas/administración & dosificaciónRESUMEN
Autonomic ganglia may be regulated, in part, by nicotinic receptors. To test whether basal insulin secretion may be modulated by an endogenous pancreatic ganglionic mechanism, the effects of ganglionic pre- and postsynaptic nicotinic receptor antagonism were studied in the in vitro canine pancreas. Combined infusion of atropine, phentolamine, and propranolol had no affect on insulin secretion (P less than .30). Presynaptic nicotinic receptor blockade by beta-bungarotoxin (beta-BuTX) in combination with atropine and phentolamine reduced mean insulin secretion (78 +/- 18 U/ml, P less than .0025) from preinfusion concentrations (287 +/- 43 U/ml). The decrease in insulin secretion resulting from BuTX, atropine, and phentolamine was prevented by the addition of either specific postsynaptic nicotinic receptor blockade by alpha-bungarotoxin (P less than .05) or propranolol (P less than .005). Because it is known that postsynaptic nicotinic receptor agonism may stimulate the intraganglionic release of norepinephrine, these results suggest that nicotinic receptors are present at the ganglionic level in the pancreas and modulate insulin secretion by a complex intraganglionic mechanism. The postulated ganglionic nicotinic receptor-mediated mechanism may operate by the interaction of a beta-adrenergic inhibitory component, which may be activated by intraganglionic norepinephrine, and a stimulatory nonmuscarinic nonadrenergic (possibly peptidergic) component, which may be activated in the absence of intraganglionic norepinephrine.
Asunto(s)
Insulina/metabolismo , Islotes Pancreáticos/inervación , Receptores Nicotínicos/fisiología , Animales , Atropina/farmacología , Bungarotoxinas/farmacología , Perros , Hexametonio , Compuestos de Hexametonio/farmacología , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Fentolamina/farmacología , Receptores Nicotínicos/efectos de los fármacosRESUMEN
The metabolic consequences of hemipancreatectomy in living pancreas donors were tested in a dog model in which a 50% lobe-specific pancreatectomy was performed. Removal of the dorsal lobe (analogous to a donor, n = 4) resulted in a progressive increase in fasting glucose during 12 mo from 5.32 +/- 0.16 to 8.17 +/- 0.28 mM and a decrease in fasting insulin from 54 +/- 3 to 6.0 +/- 2.4 pM and glucose clearance (Kg) from 3.00 +/- 0.22 to 1.00 +/- 0.06 mM. Removal of the ventral lobe (analogous to a recipient, n = 5) did not result in a change in fasting glucose or Kg during 12 mo, although fasting insulin was reduced from 36.0 +/- 1.8 to 18.00 +/- 1.93 pM. In vitro perfusion of the remnants after 1 yr showed a deterioration in glucose-stimulated insulin secretion (5-11 mM) by the dorsal remnant (18 +/- 11 vs., 232 +/- 37%) and the ventral remnant (2.6 +/- 19 vs. 87 +/- 13%). The dorsal remnant had a higher response than the ventral remnant (46 +/- 23 vs. -16 +/- 10%, respectively) to severe hyperglucosuria (11-27.7 mM). Insulin content was unchanged in the dorsal remnant (224 +/- 16 vs. 180 +/- 14 micrograms/g), but was reduced in the ventral remnant (65 +/- 14 vs. 154 +/- 15 micrograms/g). In vitro insulin pulse intervals were reduced in both remnants (5.3 +/- 0.2 min vs. control 7.00 +/- 0.18 min). Because of the above effects on the donor when the dorsal lobe is removed, the continued use of hemipancreatectomy as a source of transplantable tissue must be questioned.
Asunto(s)
Islotes Pancreáticos/fisiología , Pancreatectomía , Animales , Glucemia/análisis , Perros , Glucosa/farmacología , Técnicas In Vitro , Insulina/análisis , Islotes Pancreáticos/química , Masculino , Páncreas/química , Páncreas/fisiología , Páncreas/cirugíaRESUMEN
The vascular order of pancreatic islet cellular perfusion is important in the intraislet regulation of hormone secretion. Establishment of the sequence of interaction is fundamental to understanding the physiology and pathophysiology of the human islet. Intraislet insulin from the beta-cell regulates both net hormone secretion and pulsatile secretion from alpha- and delta-cells. In terms of vascular perfusion, the delta-cell is perfused last and does not directly affect alpha- or beta-cells in humans.
Asunto(s)
Glucagón/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/irrigación sanguínea , Páncreas/irrigación sanguínea , Somatostatina/metabolismo , Adulto , Anticuerpos , Humanos , Anticuerpos Insulínicos , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Cinética , Perfusión , Somatostatina/inmunologíaRESUMEN
Intraislet communication between alpha-, beta-, and delta-cells and their secretory products may theoretically occur via the paracrine (interstitial) and/or vascular routes. Recently, we have shown that there is a directed microvascular circulation in the rat islet with a cellular order of perfusion of beta----alpha----delta. The direction of microvascular perfusion of cells within the dog islet has been controversial. Anterograde (arterial) perfusion and retrograde (reversed or venous) perfusion of a segment of isolated dog pancreas with potent insulin antibodies yielded results similar to those found in the rat pancreas (anterograde, 158 +/- 44% increase in glucagon and 65 +/- 20% increase in somatostatin; retrograde, no change in glucagon or somatostatin). Anterograde infusion of glucagon antibody (no change in insulin, -33.5 +/- 3% decrease in somatostatin) or somatostatin antibody (no change in insulin or glucagon) also yielded the same results as in the rat pancreas. Anterograde infusion of 500 pg/ml glucagon caused a larger increase in insulin secretion (245 +/- 10%) than retrograde infusion (45 +/- 4%), whereas somatostatin was stimulated more retrogradely (339 +/- 17%) than anterogradely (121 +/- 9%). Anterograde infusion of somatostatin produced a larger decrease in insulin and glucagon than did retrograde perfusion (P less than .0001 for both comparisons). The retrograde infusion of 0.3 mU/ml insulin caused a decrease in glucagon but was without effect anterogradely. The results from the infusion of exogenous hormones suggest that the sensitivity of the alpha-, beta-, and delta-cells to insulin, glucagon, and somatostatin is determined by the beta----alpha----delta order of perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Islotes Pancreáticos/irrigación sanguínea , Animales , Perros , Glucagón/metabolismo , Glucagón/farmacología , Insulina/metabolismo , Anticuerpos Insulínicos , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Microcirculación , Somatostatina/metabolismoRESUMEN
The isolated perfused canine pancreas with duodenal exclusion was used to examine islet hormone output in response to arginine and exogenous glucagon and insulin. Exogenous glucagon (100 ng/ml) stimulated insulin and somatostatin secretion, which occurred in a biphasic pattern. The insulin response to glucagon was markedly enhanced by increased perfusate glucose, unlike the somatostatin response, which was little affected. The insulin and somatostatin responses were seen between 15 and 45 s after the glucagon stimulus. Pancreatic polypeptide secretion was uninfluenced by exogenous glucagon. Biphasic release of glucagon, somatostatin, and pancreatic polypeptide was evoked by 10 mM arginine, the responses first being apparent within less than 30 s. Exogenous insulin (50 mU/ml) infused for 10 min had no statistically significant effect on glucagon, somatostatin, or pancreatic polypeptide secretion. This study suggests that these four islet hormones may all be involved in the dynamic mechanisms of nutrient metabolism. In addition, potential intra-islet paracrine effects are identified.
Asunto(s)
Arginina/farmacología , Glucagón/farmacología , Insulina/farmacología , Páncreas/efectos de los fármacos , Polipéptido Pancreático/metabolismo , Somatostatina/metabolismo , Animales , Perros , Glucosa/administración & dosificación , Técnicas In Vitro , Páncreas/metabolismoRESUMEN
The impairment of glucose-potentiated insulin secretion present in non-insulin-dependent diabetes mellitus (NIDDM) can be approximated in normal subjects by an epinephrine infusion. Therefore, we sought to determine the role of the endogenous sympathetic nervous system in glucose-potentiated insulin secretion in both NIDDM (n = 6) and normal (n = 6) subjects. Glucose-potentiated insulin secretion was calculated as the slope of the curve relating increasing ambient glucose levels to the acute insulin response to an intravenous pulse of 5 g of L-arginine. Glucose-potentiated insulin secretion was determined on separate days during alpha-, beta-, and combined alpha- plus beta-adrenergic blockade and compared with a saline control. In normal subjects, there was no effect of alpha-, beta-, or alpha- plus beta-blockade on the slope of glucose potentiation. In NIDDM, the initially decreased slope of glucose potentiation (0.25 +/- 0.06 microU X ml-1 X mg-1 X dl, mean +/- SE; P less than .01) was not affected by beta-blockade but increased during alpha-blockade (0.91 +/- 0.22 microU X ml-1 X mg-1 X dl; P less than .05). However, this improvement was abolished by combined alpha- plus beta-blockade (0.32 +/- 0.07 microU X ml-1 X mg-1 X dl). Plasma norepinephrine was increased above basal levels in both normal (+260 +/- 89 pg/ml) and NIDDM (+438 +/- 162 pg/ml) subjects during alpha-blockade (P less than .05 for both). This increase in plasma norepinephrine strongly suggests that there is an increase in synaptic cleft norepinephrine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Glucemia/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Adulto , Arginina , Glucemia/metabolismo , Catecolaminas/sangre , Humanos , Insulina/sangre , Secreción de Insulina , Masculino , Persona de Mediana Edad , Fentolamina/farmacología , Propranolol/farmacologíaRESUMEN
OBJECTIVE: To compare the efficacy and safety of two daily doses of the new sulfonylurea, glimepiride (Amaryl), each as a once-daily dose or in two divided doses, in patients with NIDDM. RESEARCH DESIGN AND METHODS: Of the previously treated NIDDM patients, 416 entered this multicenter randomized double-blind placebo-controlled fixed-dose study. After a 3-week placebo washout, patients received a 14-week course of placebo or glimepiride 8 mg q.d., 4 mg b.i.d., 16 mg q.d., or 8 mg b.i.d. RESULTS: Fasting plasma glucose (FPG) and HbA1c values were similar at baseline in all treatment groups. The placebo group's FPG value increased from 13.0 mmol/l at baseline to 14.5 mmol/l at the last evaluation endpoint (P < or = 0.001). In contrast, FPG values in the four glimepiride groups decreased from a range of 12.4-12.9 mmol/l at baseline to a range of 8.6-9.8 mmol/l at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change [vs. placebo] from baseline). Two-hour postprandial plasma glucose (PPG) findings were consistent with FPG findings. In the placebo group, the HbA1c value increased from 7.7% at baseline to 9.7% at endpoint (P < or = 0.001), whereas HbA1c values for the glimepiride groups were 7.9-8.1% at baseline and 7.4-7.6% at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change from baseline). There were no meaningful differences in glycemic variables between daily doses of 8 and 16 mg or between once- and twice-daily dosing. Adverse events and laboratory data demonstrate that glimepiride has a favorable safety profile. CONCLUSIONS: Glimepiride is an effective and well-tolerated oral glucose-lowering agent. The results of this study demonstrate maximum effectiveness can be achieved with 8 mg q.d. of glimepiride in NIDDM subjects.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Glucemia/metabolismo , Péptido C/sangre , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Esquema de Medicación , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , Insulina/sangre , Masculino , Persona de Mediana Edad , Periodo Posprandial , Compuestos de Sulfonilurea/efectos adversos , Factores de TiempoRESUMEN
In the canine pancreas alpha and beta adrenergic receptors exist on D cells with α stimulation inhibiting and ß stimulation increasing somatostatin release. There are no dopaminergic receptors on D cells. Stimulation of muscarinic receptors causes mild inhibition of somatostatin secretion. Autonomic receptors on the D cell may be physiologically stimulated in vivo via local ganglionic and/or central autonomic drivers.
RESUMEN
To determine whether the insulinotropic effects of dopamine were mediated through the adrenergic system, dogs were infused with dopamine before or after various combinations of adrenergic and cholinergic blockade. Plasma glucose levels did not change significantly throughout the individual experiments, although cardiovascular effects from both blockade and dopamine infusion were demonstrated. The pronounced in vivo insulinotropic effects of dopamine were abolished by beta-adrenergic blockade with propranolol and all subsequent combinations of propranolol, phentolamine, and atropine. These results contrast with the in vitro suppression of insulin by dopamine, which is abolished by alpha-adrenergic blockade by phentolamine. Therefore, it may be concluded that the prevention of dopamine effects on insulin secretion by adrenergic antagonism is evidence that dopamine exerts its effects on the B cell directly or indirectly through the adrenergic system.
Asunto(s)
Antagonistas Adrenérgicos beta/metabolismo , Dopamina/farmacología , Insulina/metabolismo , Animales , Atropina/farmacología , Glucemia/metabolismo , Perros , Secreción de Insulina , Masculino , Fentolamina/farmacología , Propranolol/farmacología , Factores de TiempoRESUMEN
Insulin has emerged as a regulator of sex hormone-binding globulin (SHBG) production in vitro and in vivo. A role for insulin in regulating SHBG exists in insulin resistant states such as obesity and polycystic ovary syndrome. The relationship of in vivo insulin secretion rates to SHBG levels in healthy normal men is less well documented. Hepatic synthesis of SHBG may be influenced by quantitative insulin exposure as well as qualitative characteristics such as frequency and amplitude of insulin secretory pulses. The present study was undertaken to assess these relationships in 10 normal men. Adiposity was determined by the body mass index and fat distribution by the waist hip ratio. Peripheral insulin sensitivity was determined by the euglycemic clamp technique at an insulin infusion rate of 287 pmol/min.m2. SHBG levels were determined in the fasting state by RIA. Arterialized venous samples for C-peptide were obtained every 2 min for 90 min in the basal state. Individual C-peptide kinetics were derived after a bolus injection of biosynthetic human C-peptide and a previously validated two compartmental model. Insulin secretion rates at each time point were calculated using the plasma C-peptide values and the C-peptide kinetics. Insulin secretion rates were unrelated to SHBG concentrations (r = -0.29, P > 0.05). The insulin secretory pulse interval had a significant positive association with SHBG levels (r = 0.86, P < 0.05). Insulin secretory pulse amplitude, body mass index, waist hip ratio, and peripheral insulin sensitivity were not associated with SHBG concentrations in a regression analysis. We postulate that insulin secretory pulse frequency may be an important determinant of SHBG synthesis in normal man.
Asunto(s)
Insulina/metabolismo , Globulina de Unión a Hormona Sexual/metabolismo , Tejido Adiposo , Adulto , Composición Corporal , Índice de Masa Corporal , Péptido C/sangre , Péptido C/farmacocinética , Humanos , Secreción de Insulina , Cinética , Masculino , Periodicidad , Análisis de RegresiónRESUMEN
Abdominal fat distribution is associated with insulin resistance in healthy young men. Factors modulating this phenomenon remain unclear. Pulsatile insulin release has been implicated as a potential regulator of insulin action. The relationship of pulsatility of peripheral insulin levels to fat distribution and peripheral insulin sensitivity was examined in 10 healthy men. Fat distribution was determined by the waist to hip ratio. Peripheral insulin sensitivity was assessed by the euglycemic clamp at an insulin infusion rate of 287 pmol/min.m2. Pulsatility of insulin was assessed by sampling every 2 min for 90 min in the basal state. The characteristics of insulin pulses were assessed by the computer program Pulsar. The waist to hip ratio was negatively associated with insulin sensitivity (r = -0.70, P less than 0.05) and insulin pulse interval (r = -0.66, P less than 0.05). The insulin pulse interval was positively correlated with peripheral insulin sensitivity (r = 0.73, P less than 0.05). The insulin interpulse interval was the primary determinant of insulin sensitivity. The increased frequency of insulin pulses may play a role in inducing insulin resistance in individuals with abdominal fat distribution.
Asunto(s)
Tejido Adiposo/metabolismo , Insulina/sangre , Abdomen , Adulto , Glucemia/análisis , Índice de Masa Corporal , Prueba de Tolerancia a la Glucosa , Humanos , Lípidos/análisis , MasculinoRESUMEN
Intra-islet regulation of islet cells by one another is theoretically possible by two routes: (1) paracrine (i.e., interstitial, which is unproved); and (2) direct cellular perfusion through the islet microvasculature. The latter was tested in in vitro rat pancreases by anterograde and retrograde perfusion with or without anti-insulin or antisomatostatin antibody. Anterograde infusion of insulin antibody increased glucagon and somatostatin secretion (p less than 0.0005), whereas retrograde insulin antibody infusion was without effect. Anterograde infusion of somatostatin antibody had no effect upon insulin or glucagon secretion. In contrast, retrograde infusion of somatostatin antibody increased both insulin and glucagon secretion (p less than 0.0005). In comparison, anterograde infusion of antiglucagon antibody decreased somatostatin secretion without influencing insulin, whereas retrograde antiglucagon antibody infusion decreased insulin without changing somatostatin secretion. These results establish a "directed" functional microvascular circulation with a strict sequence of perfusion, first of B cells, then A cells, then D cells. The B cell microvascularly is the primary glucose sensor and its insulin plays a vital role in inhibiting glucagon secretion. The abnormalities in glucagon secretion in diabetes mellitus can now be explained by a deficiency in intra-islet microvascular insulin.
Asunto(s)
Islotes Pancreáticos/fisiología , Animales , Glucagón/inmunología , Glucagón/metabolismo , Técnicas In Vitro , Islotes Pancreáticos/irrigación sanguínea , Microcirculación , Ratas , Somatostatina/inmunología , Somatostatina/metabolismo , gammaglobulinas/administración & dosificaciónRESUMEN
PURPOSE: Cardiomyopathy, coronary artery atherosclerosis, or autonomic neuropathy may affect the cardiovascular performance of the diabetic patient. To evaluate the role of parasympathetic nervous system activity on cardiovascular performance, 25 diabetic subjects who lacked symptoms, signs, or objective measurements of ischemia or cardiomyopathy were studied. PATIENTS AND METHODS: Diabetic subjects were classified according to their RR variation, an index of cardiac parasympathetic nervous system activity. Fourteen diabetic subjects had a normal RR variation of greater than 30 (D-NOR), and 11 diabetic patients had an abnormal RR variation of less than 20 (D-ABN). Fifteen age- and weight-matched, healthy, nondiabetic subjects (NOR) constituted the control group. All subjects had oxygen consumption, multigated acquisition determination of cardiac output, and work product measured before and during supine bicycle maximum exercise testing. RESULTS: There was no difference in the resting cardiac output among the groups. Resting work product, however, was greatest in the D-ABN group when compared with performance in the other two groups (D-ABN: 11,500 +/- 800; D-NOR: 9,000 +/- 600; NOR: 8,700 +/- 400; p less than 0.0025). This was due to an increase in both heart rate (p less than 0.025) and systolic blood pressure (p less than 0.015). In the diabetic subjects, there was an inverse relationship between the RR variation and resting work product (r = 0.47, n = 25, p less than 0.005). In response to exercise, the percent increase in cardiac output at matched percent maximum oxygen uptake was greatest in the NOR, D-NOR, and D-ABN groups, respectively (analysis of variance, p less than 0.01). In the diabetic subjects, there was a significant relationship between the RR variation and the maximum percent change in cardiac output (r = 0.41, n = 25, p less than 0.02). Compared with the NOR group, the maximum increase in work product was impaired in diabetic subjects (p less than 0.002) and not different between the D-NOR and D-ABN groups. CONCLUSIONS: The increase in resting work product and the poor cardiac output responses to exercise in the D-ABN group are due to a decrease in cardiac parasympathetic nervous system activity and can be suggested by an abnormal RR variation. This index of parasympathetic nervous system activity can help the physician identify that subset of diabetic patients that may need special consideration when exercise training is prescribed.
Asunto(s)
Neuropatías Diabéticas/fisiopatología , Sistema de Conducción Cardíaco/fisiopatología , Adulto , Presión Sanguínea , Gasto Cardíaco , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Neuropatías Diabéticas/sangre , Epinefrina/sangre , Prueba de Esfuerzo , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Sistema Nervioso Parasimpático/fisiopatologíaRESUMEN
This paper describes an inexpensive practical approach for the automated computation of quench corrections in beta-scintillation experiments, using a table-top calculator. This approach applies a second-order fit, ax2 + bx + c = y, where x is the channel A/B ratio for known quench standards and y describes efficiency. There is excellent agreement between measured values and the polynomial expression for most experimental A/B ratios.
Asunto(s)
Procesamiento Automatizado de Datos/métodos , Conteo por CintilaciónRESUMEN
Of 128 euthyroid hospitalized patients with nonthyroidal illnesses (NTI), 33% had a low total thyroxine (T4). Forty-three percent of the latter patients had a low free thyroxine index. In euthyroid patients with NTI, free T4 was, with rare exceptions, within the range for well euthyroid controls. The free T4, as determined by two different radioimmunoassays, was diagnostically low in 34 of 37 hypothyroid patients without NTI. However, in hypothyroid patients with NTI, the free T4 determination was less informative. Only four of ten patients had a low free T4 by the Corning test, and none of ten were low by the Clinical Assays test. Our data suggest that patients with NTI frequently have low T4 and low FT4I, despite being euthyroid. Low free T4 strongly suggests hypothyroidism, but normal free T4 in patients with NTI does not exclude hypothyroidism.