A. R. Moossa

Metabolic Effects of Troglitazone on Fructose-Induced Insulin Resistance in the Rat

Troglitazone is a new orally active hypoglycemic agent that has been shown to reduce insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of fructose-induced insulin resistance and related abnormalities, we studied the effects of troglitazone on the insulin resistance induced by fructose feeding in rats. Normal male Sprague-Dawley rats were fed a high-fructose diet for 3 weeks with and without troglitazone as a food admixture (0.2%) or were fed normal chow to serve as a control group. In vivo insulin resistnace was measured by the euglycemic hyperinsulinemic clamp technique at two different insulin infusion rates, 29 (submaximal stimulation) and 290 (maximal stimulation) pmol.kg−1 · min−1. Fructose feeding markedly reduced submaximal glucose disposal rate (GDR) (113.8 ± 8.3 vs. 176.0 ± 5.6 µmol.kg−1 · min−1 P < 0.05) and maximal GDR (255.9 ± 5.6 vs. 313.6 ± 10.5 µmol.kg−1 · min−1 P < 0.05), reduced the suppressibility of submaximal hepatic glucose production (HGP; 45.5 ± 5.0 vs. 11.7 ± 5.0 µmol.kg−1 · min−1 P < 0.05), and resulted in hypertriglyceridemia and hypertension. Troglitazone treatment completely restored the GDR (submaximal 158.2 ± 5.6, maximal 305.3 ± 6.1 µmol.kg−1 · min−1) and submaximal HGP (9.4 ± 2.8 µmol.kg−1 · min−1) to control levels and also normalized the elevated plasma triglyceride concentration and systolic blood pressure levels in fructose-fed rats. These results suggest that troglitazone treatment could completely prevent the insulin resistance, hypertension, and hypertriglyceridemia induced by a diet high in fructose and that the drug might prove useful in the treatment and/or prevention of nonhyperglycemic insulin-resistant states as well as in the treatment of established NIDDM.

Isolated splenic vein thrombosis

AbstractIsolated splenic vein thrombosis is being recognized more frequently as a complication of pancreatic disease and as the cause of gastrointestinal hemorrhage in patients without liver disease. The increased incidence reflects advances in diagnostic radiology and a higher index of suspicion for the diagnosis.nSplenic vein thrombosis should be suspected in: (a) a patient with a history of pancreatitis and gastrointestinal blood loss; (b) a patient with splenomegaly in the absence of portal hypertension, cirrhosis, or hematologic disease; and (c) in the setting of isolated gastric varices.nCeliac angiography has replaced splenoportography as the definitive diagnostic tool for splenic vein thrombosis and is indicated prior to operation for suspected portal hypertension or for complications of pancreatitis. The importance of making the diagnosis lies in differentiating the lesion from the more common case of hepatic and extrahepatic portal hypertension. The treatment of choice is splenectomy.RésuméLa thrombose isolée de la veine splénique est reconnue avec une plus grande fréquence quelle complique une affection pancréatique ou quelle soit la cause dune hémorragie digestive chez des malades dont le foie est normal. Ce fait reflète les progrès dans le diagnostic radiologique et dans la connaissance de sa relative fréquence.La thrombose de la veine splénique doit être envisagée: (a) chez un malade qui présente une histoire de pancréatite ou dune hémorragie gastrointestinale; (b) chez un sujet porteur dune splénomégalie en labsence dhypertension portale, de cirrhose ou de maladie hématologique; et (c) en présence de varices gastriques isolées.Langiographie coeliaque a pris la place de la splénoportographie pour porter le diagnostic; elle est indiquée avant toute opération pour hypertension portale ou pancréatite compliquée. Cette exploration capitale permet de distinguer la thrombose de la veine splénique de causes plus courantes à lorigine de lhypertension portale dorigine hépatique ou extrahépatique. Le traitement de choix est la splénectomie.ResumenLa trombosis aislada de la vena esplénica viene siendo reconocida con mayor frecuencia como consecuencia de enfermedad pancreática y como causa de hemorragia gastrointestinal en pacientes libres de enfermedad hepática. La aumentada incidencia es un reflejo de los avances en radiología y de un más alto índice de sospecha en el proceso diagnóstico.Se debe sospechar la presencia de trombosis de la vena esplénica en: (a) un paciente con historia de pancreatitis y de sangrado gastrointestinal; (b) un paciente con esplenomegalia en ausencia de hipertensión portal, cirrosis o enfermedad hematológica, y (c) en presencia de várices gástricas aisladas.La angiografía celiaca ha suplantado a la esplenoportografía como método definitivo de diagnóstico en casos de trombosis de la vena esplénica, y se halla indicado antes de la operación por sospecha de hipertensión portai y por complicaciones de la pancreatitis. La importancia de hacer el diagnóstico reside en diferenciar esta lesión de otras causas más comunes de hipertensión portal hepática y extrahepática. El tratamiento de elección es la esplenectomía.

Kinetics of insulin action in vivo : identification of rate-limiting steps

To examine the kinetic steps in insulins in vivo action, we have assessed the temporal relationship between arterial insulin, interstitial insulin, glucose disposal rate (GDR), and insulin receptor kinase (IRK) activity in muscle and between portal insulin, hepatic glucose production (HGP), and IRK activity in liver. Interstitial insulin, as measured by lymph-insulin concentration (muscle only), and IRK activity were used as independent methods to determine the arrival of insulin at its tissue site of action. Euglycemic clamps were conducted in seven mongrel dogs and consisted of an activation phase with a venous insulin infusion (7.2 nmol · kg−1 · min−1,100 min) and a deactivation phase. Liver and muscle biopsies were taken to assess IRK activity. Arterial, portal, and lymph insulin rose to 636 ± 12, 558 ± 18, and 402 ± 24 pmol/1, respectively. GDR increased from 13.9 ± 0.6 to 41.7 ± 2.8, and HGP declined from 14.4 ± 0.6 to 1.1 ± 0.6 μmol · kg−1 · min−1. Muscle and liver IRK activity increased significantly from 5.9 ± 0.9 to 14.6 ± 0.6 and 5.5 ± 0.7 to 23.7 ± 1.9 fmol P/fmol insulin receptor (IR), respectively. The time to half-maximum response (t½a) for stimulation of GDR (19.8 ± 4.8 min) and suppression of HGP (21.5 ± 3.7 min) were similar. The t½a for stimulation of GDR, muscle IRK, and rise in lymph insulin were not significantly different from one another and were all markedly greater than that for the approach to steady state of arterial insulin (2.3 ± 1.2 min, P < 0.01). The t½a for portal insulin (1.8 ± 0.8 min) was less than that for activation of liver IRK (11.3 ± 4.3, P < 0.05), which in turn was less than that for suppression of HGP (21.5 ± 3.7 min, P < 0.05). In skeletal muscle, the delay in insulin-stimulated GDR occurs before IR binding and is due to the time required for plasma insulin to gain access to the interstitial compartment. In liver, however, identification of the site(s) of delay in insulins effects to suppress HGP is dependent on whether insulin acts directly or indirectly on the liver. If its action is direct, there are two separate sites of delay: a prereceptor and a postreceptor delay. If, however, insulins effect on suppressing HGP is indirect, then a single extrahepatic site of delay is likely, which represents the time-limiting step of insulins ability to stimulate GDR and suppress HGP. Then, the locus of the site involves transendothelial passage of insulin to the interstitial space.

Metabolic effects of troglitazone on fat-induced insulin resistance in the rat.

Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of diet-induced insulin resistance and related abnormalities, we studied its effect on insulin resistance induced by high-fat feeding in rats. Normal male Sprague-Dawley rats were fed a high-fat diet for 3 weeks with and without troglitazone as a food mixture (0.2%) or were fed normal chow. In vivo insulin action was measured using a euglycemic-hyperinsulinemic clamp at two different insulin infusion rates, 4 (submaximal stimulation) and 40 (maximal stimulation) mU/kg/min. Fat feeding markedly reduced the submaximal glucose disposal rate ([GDR], 26.4 +/- 1.3 v 37.5 +/- 1.4 mg/kg/min, P < .01) and maximal GDR (55.9 +/- 1.3 v 64.5 +/- 1.3 mg/kg/min, P < 0.5), reduced the suppressibility of submaximal hepatic glucose production ([HGP], 3.2 +/- 0.9 v 1.5 +/- 0.5 mg/kg/min, P < .05), and resulted in hyperlipidemia. Troglitazone treatment did not affect any of these parameters. Insulin resistance induced by fat feeding is the first experimental model in which troglitazone failed to correct or partially correct the insulin resistance.

The place of total and extended total pancreatectomy in pancreatic cancer.

The results of surgical treatment of pancreatic exocrine cancer are poor. There exists a definite small group of patients with early cancers in the head of the pancreas that are potentially curable. It is generally agreed that prolonged survival is obtained only with resection as opposed to a palliative bypass procedure. The only real controversy that remains concerns the extent of the resection. The 3 options available to the surgeon are Whipple pancreatoduodenectomy, total pancreatectomy, and the more radical regional pancreatectomy. Our opinion, based on previous experience, is that total pancreatectomy is the operation of choice for cancer in the head of the pancreas. This operation excludes many of the risk factors associated with the Whipple operation, with no evidence of increased morbidity or mortality. We feel that the case for extended total pancreatectomy is tenuous and yet to be proven, and that there is little or no place for this operation.RésuméLes résultats globaux du traitement chirurgical du cancer du pancréas sont décevants mais il existe un petit groupe de cancers de la tête peu évolués qui sont susceptibles dêtre guéris. Il est admis que la survie la plus longue est obtenue davantage par les méthodes radicales dexérèse que par les méthodes palliatives de drainage. Le point qui prête encore à controverse est létendue de lexérèse. Trois possibilités soffrent au chirurgien: la duodénopancréatectomie type Whipple, la pancréatectomie totale, la pancréatectomie régionale. Daprès notre expérience, la pancréatectomie totale représente lopération de choix pour traiter le cancer de la tête du pancréas. Elle permet déviter les risques inhérents à lopération de Whipple sans augmentation du taux de la morbidité et de la mortalité. En revanche, la pancréatectomie totale élargie na pas fait ses preuves et ses indications sont des plus limitées.ResumenLos resultados del tratamiento quirúrgico del cáncer pancreático exocrino son pobres. Existe un pequeño grupo definido de pacientes con cánceres tempranos de la cabeza del páncreas que son potencialmente curables. Generalmente se acepta que una supervivencia prolongada sólo puede lograrse con la resección quirúrgica en contraposición a los procedimientos paliativos de derivación. La real controversia reside en lo referente a la magnitud de la resección. Las tres opciones disponibles para el cirujano son: 1) la pancreatoduodenectomía o procedimiento de Whipple, 2) la pancreatectomía total y, 3) la pancreatectomía regional o super-radical propuesta por Fortner.Nuestra opinión basada en experiencia previa, es que la pancreatectomía total es la operación de escogencia para cáncer de la cabeza del páncreas. Esta operación excluye muchos de los factores de riesgo asociados con el procedimiento de Whipple, sin que haya evidencia de una mayor mortalidad o morbilidad. Creemos que las razones para favorecer la pancreatectomía regional super-radical son débiles y aún no comprobadas, y que existe una indicación muy limitada, o ninguna, para esta operación.The results of surgical treatment of pancreatic exocrine cancer are poor. There exists a definite small group of patients with early cancers in the head of the pancreas that are potentially curable. It is generally agreed that prolonged survival is obtained only with resection as opposed to a palliative bypass procedure. The only real controversy that remains concerns the extent of the resection. The 3 options available to the surgeon are Whipple pancreatoduodenectomy, total pancreatectomy, and the more radical regional pancreatectomy. Our opinion, based on previous experience, is that total pancreatectomy is the operation of choice for cancer in the head of the pancreas. This operation excludes many of the risk factors associated with the Whipple operation, with no evidence of increased morbidity or mortality. We feel that the case for extended total pancreatectomy is tenuous and yet to be proven, and that there is little or no place for this operation. Les résultats globaux du traitement chirurgical du cancer du pancréas sont décevants mais il existe un petit groupe de cancers de la tête peu évolués qui sont susceptibles dêtre guéris. Il est admis que la survie la plus longue est obtenue davantage par les méthodes radicales dexérèse que par les méthodes palliatives de drainage. Le point qui prête encore à controverse est létendue de lexérèse. Trois possibilités soffrent au chirurgien: la duodénopancréatectomie type Whipple, la pancréatectomie totale, la pancréatectomie régionale. Daprès notre expérience, la pancréatectomie totale représente lopération de choix pour traiter le cancer de la tête du pancréas. Elle permet déviter les risques inhérents à lopération de Whipple sans augmentation du taux de la morbidité et de la mortalité. En revanche, la pancréatectomie totale élargie na pas fait ses preuves et ses indications sont des plus limitées. Los resultados del tratamiento quirúrgico del cáncer pancreático exocrino son pobres. Existe un pequeño grupo definido de pacientes con cánceres tempranos de la cabeza del páncreas que son potencialmente curables. Generalmente se acepta que una supervivencia prolongada sólo puede lograrse con la resección quirúrgica en contraposición a los procedimientos paliativos de derivación. La real controversia reside en lo referente a la magnitud de la resección. Las tres opciones disponibles para el cirujano son: 1) la pancreatoduodenectomía o procedimiento de Whipple, 2) la pancreatectomía total y, 3) la pancreatectomía regional o super-radical propuesta por Fortner. Nuestra opinión basada en experiencia previa, es que la pancreatectomía total es la operación de escogencia para cáncer de la cabeza del páncreas. Esta operación excluye muchos de los factores de riesgo asociados con el procedimiento de Whipple, sin que haya evidencia de una mayor mortalidad o morbilidad. Creemos que las razones para favorecer la pancreatectomía regional super-radical son débiles y aún no comprobadas, y que existe una indicación muy limitada, o ninguna, para esta operación.

Islet Amyloid Polypeptide (Amylin) Increases the Renal Excretion of Calcium in the Conscious Dog

Islet amyloid polypeptide (IAPP) is a member of the calcitonin/CGRP family and has been isolated from the β-cell of pancreatic islets. Recent evidence suggests that this peptide may be involved in calcium metabolism in that its administration resulted in lowering of serum calcium levels. To determine the mechanism of IAPP-induced hypocalcemia, the peptide was infused at 50 pmol/min/kg for 90 minutes in conscious male mongrel dogs. Infusion of the peptide resulted in a modest decline in the total serum calcium concentration (10.4±0.2 to 9.4±0.2 mg/dl; P<0.05) and a concomitant increase in urinary calcium excretion (3.6±0.6 to 6.9±2.0 mg/dl; P<0.01). Based on an extracellular volume of 7 liter in a 28 kg dog, the total decrement in calcium due to IAPP was 41.3±2.4 mg, whereas the total increase in urinary calcium was 3.2±0.7 mg. There were no detectable changes in calcitonin. We conclude that IAPP lowers serum calcium and increases the renal excretion of calcium independently of calcitonin. However, the calciuria can only account for a small component of the hypocalcemic effect and therefore, an additional calcium lowering effect of IAPP exits.

Effects of cyclosporin A on the splenic tissue of rats: A histomorphometric analysis

Histological studies demonstrated that long-term cyclosporin A treatment of nonantigenically challenged (untransplanted and unimmunized) Lewis rats markedly reduces the total percentage of splenic white pulp when compared to untreated control spleens (mean = 24 vs 34%, P less than 0.001). Direct measurements of periarteriolar sheaths and marginal zones demonstrated a marked reduction in size of these compartments in cyclosporin A-treated rats compared to untreated controls (P less than 0.001). In addition, there was a striking reduction in cellular density of the periarteriolar sheaths (P less than 0.001) and a minimal reduction in cellular density of the marginal zones (P less than 0.1) in the cyclosporin A-treated group when compared to untreated controls. There was no significant difference in total splenic size between the cyclosporin A-treated and the control groups, as indicated by total cross section measurements (mean = 33.3 vs 35.0, P less than 0.4). Qualitative observations of methyl green-pyroninophilic cells within and surrounding the marginal zones of the cyclosporin A-treated spleens revealed a much greater proportion of large pyroninophilic lymphocytes, which suggests that they are B immunoblasts. We conclude that long-term cyclosporin A treatment depletes splenic periarteriolar sheaths and marginal zones, compartments known to contain primary T lymphocytes, and induces an immunoblastic cell proliferation within the marginal zones and red pulp as well.

Histometric investigations of the effect of cyclosporin A on the testicular tissue of rats

The effect of cyclosporin A (CsA) on rat testes was assessed in Lewis rats which were given 10 mg/kg of CsA im per day. The rats were divided into 13 subgroups, and 1 subgroup was sacrificed each month. The rat testes were measured and examined for histometrical and morphological changes in comparison to controls. Histometrical analysis included testicular cross-sectional surface area, tubular density, tubular diameter, and the amounts of testicular germinal epithelium, lumen, and interstitial tissue. In the parameters examined, there were no overall differences between CsA-treated animals and controls. CsA does not affect rat testicular tissue.