RESUMO
BACKGROUND: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. AIMS: To update disease-causing mutations and current clinical knowledge of the disease. MATERIALS AND METHODS: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. RESULTS: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. CONCLUSIONS: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.
Assuntos
Efeito Fundador , Estudos de Associação Genética , Mutação , Fenótipo , Tirosinemias/diagnóstico , Tirosinemias/genética , Adolescente , Idade de Início , Alelos , Criança , Pré-Escolar , Feminino , Loci Gênicos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Tirosina Transaminase/genética , Tirosinemias/dietoterapia , Adulto JovemRESUMO
AIMS/HYPOTHESIS: We evaluated the incidence of insulin-requiring diabetes in a rural area of sub-Saharan Africa. METHODS: Health surveillance data from a chronic disease programme in two zones of Ethiopia, Gondar and Jimma, were studied. The two zones have a population of more than 5,000,000 people. RESULTS: In Gondar Zone (1995-2008) and Jimma Zone (2002-2008) 2,280 patients presented with diabetes, of whom 1,029 (45%) required insulin for glycaemic control at diagnosis. The annual incidence of insulin-requiring diabetes was 2.1 (95% CI 2.0-2.2) per 100,000 and was twice as high in men (2.9 per 100,000) as in women (1.4 per 100,000). In both sexes incidence rates peaked at the age of 25 to 29 years. Incidence rates in the urban areas of Gondar and Jimma were five times higher than in the surrounding rural areas. Patients with insulin-requiring diabetes from rural and urban areas had a very low BMI and most were subsistence farmers or unemployed. CONCLUSIONS/INTERPRETATION: The typical patient with diabetes in rural Ethiopia is an impoverished, young adult male with severe symptoms requiring insulin for glycaemic control. The low incidence rates in rural compared with urban areas suggest that many cases of this disease remain undiagnosed. The disease phenotype encountered in this area of Africa is very different from the classical type 1 diabetes seen in the West and most closely resembles previous descriptions of malnutrition-related diabetes, a category not recognised in the current WHO Diabetes Classification. We believe that the case for this condition should be reopened.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus/epidemiologia , Desnutrição/epidemiologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Criança , Diabetes Mellitus/etiologia , Diabetes Mellitus Tipo 1/classificação , Diabetes Mellitus Tipo 1/etiologia , Etiópia/epidemiologia , Feminino , Humanos , Incidência , Masculino , Desnutrição/complicações , Pessoa de Meia-Idade , População Rural/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Adulto JovemRESUMO
Do functional linkages between islet endocrine cells exist? The effect of differences in frequency and distribution of islet endocrine cells on B cell function was examined in islets from the ventral (ventral islets) and dorsal (dorsal islets) areas of the rat pancreas. Dorsal islets contained 10 times as much glucagon as ventral islets, whereas insulin and total protein contents were similar. Basal rates of insulin secretion and proinsulin biosynthesis were similar in the two types of islet, but, under conditions of glucose stimulation, both insulin secretion and proinsulin biosynthesis were significantly greater in the glucagon-rich dorsal islets. Similarly, glucose utilization rates an ATP levels were greater in dorsal islets. In contrast, the rates of processing of newly synthesized proinsulin were similar in ventral and dorsal islets. That the islet glucagon content may have affected B cell function is inferred from two independent findings. Firstly, basal and glucose-stimulated cyclic AMP contents of glucagon-rich dorsal islets were greater than those of ventral islets. Secondly, in the presence of excess exogenous glucagon (1 microgram/ml), the differences in glucose-induced insulin secretion and proinsulin biosynthesis rates between the two types of islets were eliminated. These results strongly suggest that changes in the relative proportions of the different islet endocrine cells exert marked effects on islet function. In particular, a greater A cell and glucagon content is associated with higher rates of glucose-induced insulin secretion and biosynthesis.
Assuntos
Linfócitos B/fisiologia , Ilhotas Pancreáticas/fisiologia , 1-Metil-3-Isobutilxantina/farmacologia , Trifosfato de Adenosina , Animais , AMP Cíclico , Glucagon/farmacologia , Glucose/metabolismo , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/análise , Masculino , Polipeptídeo Pancreático , Proinsulina/biossíntese , Proinsulina/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Islets of 5-mo-old obese Zucker rats secreted 50% more somatostatin (SRIF) in response to 8.3 mM or 16.7 mM glucose than did islets from lean controls; the islet SRIF contents of obese and lean rats were similar. As expected, islets of obese rats demonstrated a greater basal and a fivefold greater glucose-induced insulin release and also a twofold greater insulin content than did islets from lean rats. Obese rats were pair fed with lean animals from the age of 9 wk until killed, when 5 mo old. While this curtailed the weight gain of obese rats to that of lean controls, it caused no reduction in the percent body weight found in the form of lipid. The responses of the pancreatic delta and beta cells to pair feeding were markedly different. Pair feeding caused no alteration in either SRIF content or glucose-induced SRIF release, while the expected reductions in both islet insulin content and glucose-induced insulin secretion were observed. Islets from older obese Zucker rats (15--18 mo old) had four to five times greater contents of both SRIF and insulin than did islets from age-matched lean controls. The obese rats of this age had a moderate glucose intolerance. SRIF secretion from the islets of such rats was distinctly greater than from those of lean controls at all glucose concentrations tested (range, 1.0--16.7 mM). The delta cells of the older obese rats had lost their sensitivity to glucose, while those of lean controls remained sensitive. Beta cells of islets from both obese and lean 15-mo-old rats remained glucose sensitive. Under all conditions tested, secretion of SRIF and insulin was greater from islets of obese than lean rats. The results demonstrate a marked difference in pancreatic delta and beta cell responses to pair feeding in the obese Zucker rat. At present, the role played by hypersecretion of pancreatic SRIF in the obesity syndrome of the Zucker rat remains obscure.
Assuntos
Ilhotas Pancreáticas/metabolismo , Obesidade/fisiopatologia , Somatostatina/metabolismo , Envelhecimento , Animais , Peso Corporal , Dieta Redutora , Ingestão de Energia , Teste de Tolerância a Glucose , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/crescimento & desenvolvimento , Lipídeos/análise , Ratos , Ratos EndogâmicosRESUMO
Synthetic human pancreatic polypeptide stimulated pancreatic somatostatin secretion by isolated rat islets and by the isolated perfused rat pancreas. In contrast, synthetic bovine pancreatic polypeptide and the C-terminal hexapeptide had no effect on somatostatin secretion. Synthetic human pancreatic polypeptide had only a mild stimulatory effect on glucagon secretion at the highest concentration of the peptide used (2.2 x 10(-6) M0 and in the presence of 16.7 mM glucose.
Assuntos
Glucagon/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Polipeptídeo Pancreático/farmacologia , Fragmentos de Peptídeos/farmacologia , Somatostatina/metabolismo , Animais , Técnicas In Vitro , Ilhotas Pancreáticas/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
In islets removed from untreated streptozotocin-diabetic rats, the somatostatin-containing cells were unresponsive to changes in glucose concentration, while they did respond to raised cyclic AMP levels. By contrast, in vivo insulin treatment restored the glucose sensitivity of the somatostatin secreting cells. In addition, in vivo insulin treatment resulted in a lowering of the high basal somatostatin secretion rate found in islets from untreated diabetic rats. These changes were made without any alteration of islet insulin content or enhancement of the in vitro insulin secretion. These results indicate that there is not a basic defect in the glucoreceptor of the somatostatin cell in diabetes.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Insulina/uso terapêutico , Ilhotas Pancreáticas/fisiopatologia , Somatostatina/metabolismo , 1-Metil-3-Isobutilxantina/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Masculino , Ratos , Ratos Endogâmicos , Taxa Secretória/efeitos dos fármacosRESUMO
It is well known that, in diabetes, there is an abnormality of both pancreatic beta and alpha cell secretion. Since islet transplantation can markedly improve the diabetic state in streptozotocin-treated rats, we investigated the effects of intraportal transplantation on the beta and alpha cell secretion of the transplanted tissue. In addition we examined the effects of transplantation on the hormone content of both the transplanted tissue and the endogenous pancreas. Animals were examined 6 and 20 wk after transplantation. Isolated perfusions of the perfusions of the islet-containing livers showed that both glucagon and insulin secretion could be promptly stimulated by arginine. The hormone content of the livers at death revealed that, while the insulin content of transplanted tissue was well maintained, there was a marked reduction in glucagon content. An increase in pancreatic glucagon content was found in rats with untreated diabetes of five months' duration; this was partially or fully prevented by islet transplantation. There was also a moderate increase in insulin content of the pancreases of animals that received islet transplants.
Assuntos
Diabetes Mellitus Experimental/cirurgia , Insulina/metabolismo , Transplante das Ilhotas Pancreáticas , Pâncreas/metabolismo , Animais , Glicemia , Peso Corporal , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/urina , Glucagon/análise , Glucagon/metabolismo , Teste de Tolerância a Glucose , Injeções Intravenosas , Insulina/análise , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Fígado/análise , Masculino , Pâncreas/análise , Veia Porta , Ratos , Ratos Endogâmicos , Fatores de Tempo , Transplante HomólogoRESUMO
The secretory responses of beta and delta cells were compared in the isolated, perfused, rat pancreas. Insulin release was stimulated 50-fold and somatostatin (SRIF) secretion twofold when the glucose concentration was increased from 100 mg/dl to 300 mg/dl. When islet cyclic AMP (cAMP) was raised by 3-isobutyl-1-methylxanthine (IBMX), the secretion of SRIF was stimulated in a glucose-dependent manner (300 mg/dl greater than 100 mg/dl greater than 25 mg/dl). As expected, insulin release was also potentiated in a similar fashion. A difference in the glucose dependency of the cAMP effect was seen at 25 mg/dl glucose, where 0.25 mM IBMX enhanced the release of SRIF but not that of insulin. In contrast, at 300 mg/dl glucose, IBMX caused a greater potentiation of insulin release than of SRIF release. The release of insulin, when expressed in absolute terms, was stimulated more markedly than that of SRIF under most conditions tested. However, the expression of total hormone released during 30 min of stimulation as a percentage of tissue hormone content allowed a different interpretation of the results. For example, 2.1% and 1.8% of tissue insulin and SRIF contents, respectively, was released during exposure to 300 mg/dl glucose. Surprisingly, under basal conditions (100 mg/dl glucose), 1.0% of total SRIF content was released during 30 min compared with the release of only 0.04% of insulin.
Assuntos
1-Metil-3-Isobutilxantina/farmacologia , AMP Cíclico/metabolismo , Glucose/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Somatostatina/metabolismo , Teofilina/análogos & derivados , Animais , Técnicas In Vitro , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Cinética , Masculino , Perfusão , RatosRESUMO
The effect of constant, controlled hyperinsulinemia on in vivo and in vitro insulin responsiveness has been investigated in rats that have received insulin infusions through chronically implanted jugular vein catheters. Constant rates of insulin infusion during days 1-4 resulted in stable plasma insulin concentrations. The plasma glucose initially fell from 122 +/- 3 to 53 +/- 4 mg/dl. While the infusion rate was maintained constant, the plasma glucose continued to fall over the subsequent days so that on day 4 the plasma glucose, 40 +/- 2 mg/dl, was significantly lower than that in the same animals on day 1 (P less than 0.02). Subsequently, the rate of insulin infusion was decreased to maintain the plasma glucose level in the 35-40 mg/dl range. Plasma catecholamine levels were high in insulin-infused rats. On the eighth day an in vivo insulin tolerance test (0.5 U/kg) was performed. Insulin-infused rats responded with a hypoglycemia that was both more pronounced and longer sustained than in saline-infused controls. Insulin responsiveness in vitro has been measured in isolated adipocytes. Adipocytes from epididymal fat pads were of similar size in the two groups of animals. Glucose uptake by adipocytes from insulin-infused rats was similar to that of controls under basal (zero insulin) conditions, but showed an increase in the maximum response to insulin. Glucose incorporation into total lipid and fatty acid was greater in adipocytes from insulin-infused rats than in controls under both basal (zero insulin) and insulin-stimulated conditions. Activities of the lipogenic enzymes acetyl CoA carboxylase and fatty acid synthetase were markedly increased in epididymal fat pads of insulin-infused rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Insulina/sangue , Acetil-CoA Carboxilase/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Desoxiglucose/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Epinefrina/sangue , Ácido Graxo Sintases/metabolismo , Insulina/farmacologia , Lipídeos/biossíntese , Masculino , Norepinefrina/sangue , Ratos , Ratos EndogâmicosRESUMO
Free radical-mediated damage to vascular cells may be involved in the pathogenesis of diabetic vasculopathy. The aim of this study was to compare the extent of glucose-induced oxidative stress in both vascular smooth muscle cells (VSMCs) and pericytes and the effect on antioxidant enzyme gene expression and activities. Porcine aortic VSMC and retinal pericytes were cultured in either 5 or 25 mmol/l glucose for 10 days. Intracellular malondialdehyde (MDA) was measured as a marker of peroxidative damage, and mRNA expression of CuZn-SOD, MnSOD, catalase, and glutathione peroxidase (GPX) were measured by Northern analysis. Glutathione (GSH) was also measured. There was a significant increase in MDA in VSMCs in 25 mmol/l glucose (1.34 +/- 0.11 vs. 1.88 +/- 0.24 nmol/mg protein, 5 vs. 25 mmol/l D-glucose, mean +/- SE, n = 15, P < 0.01), but not in pericytes (0.38 +/- 0.05 vs. 0.37 +/- 0.05 nmol/mg protein, n = 11). There was a significant decrease in GSH in both cell types (VSMC, 1.40 +/- 0.13 vs. 0.69 +/- 0.12 nmol/mg protein, n = 15, P < 0.001; pericytes, 1.97 +/- 0.17 vs. 0.94 +/- 0.16 nmol/mg protein, n = 11, P < 0.001). mRNA expression of CuZnSOD and MnSOD was increased only in VSMCs (by 58.5 +/- 8.1 and 41.0 +/- 6.9%, respectively, n = 8, P < 0.01). CuZnSOD protein was increased by approximately 120% (P < 0.00001). None of the antioxidant enzyme activities was altered between 5 and 25 mmol/l glucose in either cell type. Both MnSOD activities and GSH concentrations were higher in pericytes compared with VSMC under basal (5 mmol/l) conditions (P < 0.05 and P < 0.02, respectively). These results demonstrate glucose-induced reduction of GSH in both cells, but only in VSMC is there evidence of oxidant damage in the form of lipid peroxidation, implying significant differences in intracellular responses to glucose between contractile cells in the macro- and microvasculature.
Assuntos
Glucose/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Retina/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Aorta/citologia , Aorta/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Microcirculação/efeitos dos fármacos , Músculo Liso Vascular/citologia , Retina/citologia , SuínosRESUMO
OBJECTIVE: To compare the efficacy of an extended insulin regimen using correction of hyperketonemia as endpoint with a more conventional regimen in the treatment of diabetic ketoacidosis. RESEARCH DESIGN AND METHODS: A total of 22 patients admitted to a Belfast teaching hospital with clinical and biochemical features of diabetic ketoacidosis (pH < 7.25 and/or bicarbonate < 16 mmol/l) were randomized to either conventional or extended insulin regimens. In the conventional regimen, insulin was administered at 5 U/h until near-normoglycemia (blood glucose < or = 10 mmol/l) and then administered at a reduced rate until clinical recovery. In the extended regimen, administration of insulin at 5 U/h was continued beyond attainment of normoglycemia, until resolution of hyperketonemia (3-hydroxybutyrate < 0.5 mmol/l). Main outcome measures were 3-hydroxybutyrate and bicarbonate levels during the 24 h after attainment of near-normoglycemia. RESULTS: After near-normoglycemia, correction of hyperketonemia was achieved earlier with the extended treatment (5.9 +/- 0.8 vs. 21.8 +/- 3.4 h, P = 0.0004 [mean +/- SD]). The area under the curve of 3-hydroxybutyrate against time for 24 h after near-normoglycemia was reduced with the extended treatment (24.9 +/- 3.8 vs. 55.9 +/- 6.7 mmol.l-1.h-1, P = 0.001). These differences remained statistically significant after adjustment for higher baseline levels of 3-hydroxybutyrate at near-normoglycemia in the extended treatment group. Bicarbonate levels at 6 and 12 h after near-normoglycemia were not significantly different between groups. CONCLUSIONS: The extended insulin regimen, which was easy to implement at ward level, produced a more rapid resolution of ketosis than the conventional regimen.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/tratamento farmacológico , Hidroxibutiratos/sangue , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Ácido 3-Hidroxibutírico , Adulto , Bicarbonatos/sangue , Bicarbonatos/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/sangue , Eletrólitos/sangue , Eletrólitos/metabolismo , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Intravenosas , Insulina/administração & dosagem , Masculino , Fatores de TempoRESUMO
OBJECTIVE: The hemodynamic, respiratory, and metabolic responses to exercise were studied in IDDM patients and control subjects to detect diabetic cardiomyopathy. RESEARCH DESIGN AND METHODS: Eight subjects aged 25-40 years with diabetes of at least 10 years' duration were compared with eight control subjects aged 21-46 years. All subjects underwent a progressive incremental bicycle exercise test with measurement of gas exchange, blood glucose, lactate, fat metabolite, and catecholamine levels and two steady-state exercise tests with measurement of cardiac output by a CO2 rebreathing method. A new first-pass radionuclide method was used to measure cardiac ejection fractions (EFs) at rest, peak exercise, and steady-state exercise. RESULTS: The peak achieved oxygen consumption was similar in the diabetic and control subjects (29.9 [25.1-34.6] and 31.4 [26.9-35.9] ml.min-1.kg-1, respectively; mean [95% CI]). There were no significant differences in heart rate, double product, ventilation, respiratory exchange ratio, or ventilatory equivalents for oxygen and CO2 during the incremental test. Glucose levels were higher in the diabetic subjects, but there were no significant differences in levels of lactate, catecholamines, free fatty acids, glycerol, or beta-hydroxybutyrate. Left ventricular EF fell from rest to peak exercise within the diabetic group (66.0% [59.6-72.4] at rest; 53.6% [45.6-61.6] at peak; P < 0.05) but this did not differ significantly from the control group (58.7% [52.3-65.1] at rest; 60.3% [48.9-71.7] at peak). Right ventricular EFs were similar in each group, and there was no reduction in peak filling rate to suggest diastolic dysfunction. The cardiac output responses to exercise were also similar in the two groups. CONCLUSIONS: There is no evidence of impairment of the exercise response in subjects with long-standing diabetes, and the apparent fall in left ventricular EF at peak exercise could be related to hemodynamic adaptation.
Assuntos
Débito Cardíaco/fisiologia , Diabetes Mellitus Tipo 1/fisiopatologia , Exercício Físico/fisiologia , Consumo de Oxigênio/fisiologia , Adulto , Metabolismo Basal/fisiologia , Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
Using chronically catheterized, freely moving male Wistar rats, we have shown that the sweet taste of a saccharin solution reliably triggers a rapid cephalic phase insulin response (CPIR), in the absence of any significant change of glycemia. To establish the neural mediation of this reflex response we used rats that were cured from streptozotocin diabetes by intrahepatic islet-transplantation as a denervated B-cell preparation. The complete lack of any saccharin-induced CPIR in these rats suggests that it is indeed mediated by the peripheral autonomic nervous system, and that the insulin-stimulating gastrointestinal hormones are not involved in this response. It was further found that this reflex insulin secretion is not easily extinguishable and thus might have an unconditioned component. To investigate the central neural pathways involved in this reflex response we used both electrophysiological methods in anesthetized and semi-micro CNS manipulations in freely moving rats. On the basis of our preliminary results, and several reports, using the decerebrate rat preparation for measuring behavioral or saliva secretory oral taste reactivity, it appears that CPIR might be organized at the brain stem/midbrain level, receiving strong modulatory influences from the diencephalon. But much further work has to be done to establish the central nervous circuitry. Finally, in two experiments, aiming at the question of how important and physiologically relevant the CPIR might be, we found that, on one hand, its lack can result in pathological oral glucose tolerance and on the other hand its exaggeration might contribute to the behavioral reaction to highly palatable sweet food and the resulting development of dietary obesity.
RESUMO
The object of the present investigation was to determine whether insulin secreted by the endocrine pancreas and carried in the insulo-acinar portal system has a direct effect on pancreatic enzyme secretion. For this purpose, the isolated rat pancreas was perfused in a nonrecirculating system. The perfusate contained 3 mM glucose, and either caerulein or vaso-active intestinal polypeptide was used to stimulate exocrine secretion. The amount of insulin reaching the exocrine pancreas was reduced by two different experimental procedures. In the first, use was made of streptozotocin-diabetic rats treated with insulin in vivo. Treatment was such that the contents of amylase and lipase, vastly altered in the untreated diabetic state, were normalized before the perfusion studies. In the second procedure, insulin reaching the exocrine pancreas was reduced by antiinsulin serum in the perfusate. In these procedures, the reduced insulin bioavailability was associated with a reduction in caerulein- and vasoactive intestinal polypeptide-stimulated enzyme release, which was shown as a reduction of maximum responsiveness to caerulein without alteration of sensitivity. By contrast, in dispersed pancreatic acini where the insulo-acinar axis was completely disrupted, amylase secretion from diabetic and nondiabetic tissue was identical over a wide range of caerulein concentrations, showing that the secretory defect seen in the perfusion studies was not inherent to the exocrine tissue. The results show that basal insulin secretion has a direct effect on pancreatic enzyme output and that the insulo-acinar axis may play an important role in the regulation of acinar cell function.
Assuntos
Ilhotas Pancreáticas/fisiologia , Pâncreas/enzimologia , Amilases/metabolismo , Animais , Ceruletídeo/farmacologia , Diabetes Mellitus Experimental/enzimologia , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Lipase/metabolismo , Masculino , Perfusão , Ratos , Peptídeo Intestinal Vasoativo/farmacologiaRESUMO
We have found that rats with transplanted pancreatic islets, when compared to normal rats, have a delayed onset of insulin release in response to orally, but not to iv administered glucose. Furthermore, while glucose tolerance of the rats with transplanted islets was similar to that of normal controls when the glucose was administered iv, the tolerance was markedly less when it was administered orally. These tests were carried out using permanently implanted cardiac catheters and chronic oral fistulae and were conducted at a time when the body weight of the transplanted animals had returned to levels similar to those of the controls. During the tests the rats were conscious and unrestrained. The difference in the fine control of insulin secretion in transplanted islets from that in the normal pancreas may be due to defective innervation of such islets. These results may have implications for the use of transplanted islets in the control of diabetes mellitus in man. The methods employed can be further used to define other areas in which the response of transplanted islets in rats differs from that of the normal pancreas.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Transplante das Ilhotas Pancreáticas , Veia Porta , Animais , Glicemia/análise , Diabetes Mellitus Experimental/terapia , Teste de Tolerância a Glucose , Insulina/análise , Insulina/sangue , Ilhotas Pancreáticas/análise , Masculino , Ratos , Ratos Endogâmicos Lew , Transplante HomólogoRESUMO
The effects of exogenous insulin on somatostatin secretion from the isolated perfused rat pancreas have been investigated in the presence of 5.6 mM glucose and when somatostatin secretion was stimulated by either glucose (16.7 mM) or arginine (20 mM). Insulin (15 mU/ml) significantly and rapidly suppressed glucose- and arginine-stimulated somatostatin release. However, at 5.6 mM glucose and, in the absence of other stimulators of somatostatin release, insulin had no effect on the somatostatin secretion rate.
Assuntos
Arginina/farmacologia , Glucose/farmacologia , Insulina/farmacologia , Pâncreas/metabolismo , Somatostatina/metabolismo , Animais , Técnicas In Vitro , Cinética , Masculino , Pâncreas/efeitos dos fármacos , Perfusão , RatosRESUMO
Sixteen patients with clinically active acromegaly were investigated; four of these had insulin-independent diabetes mellitus. Those acromegalic subjects who were not diabetic exhibited excessive insulin responses to glucose and arginine stimulation. By contrast, plasma glucagon concentrations in these patients did not differ significantly from those in control subjects. Acromegalic patients who also had insulin-independent diabetes had a markedly reduced insulin response to glucose stimulation, while arginine-induced insulin secretion was relatively well preserved. Although there was a tendency for plasma glucagon concentrations to be higher in the diabetic than in the nondiabetic group of acromegalic subjects, this difference did not achieve statistical significance either in the basal state or during the glucose amd arginine infusion tests.
Assuntos
Acromegalia/sangue , Glucagon/sangue , Insulina/sangue , Acromegalia/complicações , Adolescente , Adulto , Idoso , Arginina , Complicações do Diabetes , Diabetes Mellitus/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The effect of glibenclamide treatment on insulin-mediated glucose disposal was studied in eight C-peptide-negative type I diabetic patients. The patients were studied twice by the euglycemic insulin clamp technique. One of the two experiments was preceded by glibenclamide treatment at the dose of 5 mg, three times daily for 15 days; half of the patients had the first test before and the second test after sulfonylurea treatment, and vice versa. Insulin was infused for four periods of 2 h each sequentially at 0.5, 1.0, 2.0, and 5.0 mU kg-1 min-1; for each insulin infusion period, the steady state plasma free insulin levels were comparable with or without glibenclamide. The mean +/- SEM plasma glucose concentration was 88 +/- 2 mg/dl in both experiments. The insulin-mediated glucose disposal rate was greater with glibenclamide during the first insulin infusion period (which generated plasma free insulin levels within the physiological range) 2.68 +/- 0.32 mg kg-1 min-1 with glibenclamide vs. 1.97 +/- 0.20 mg kg-1 min-1 without glibenclamide (P less than 0.005). However, glucose disposal rates did not differ in the diabetic patients with or without glibenclamide treatment during the second, third, and fourth insulin infusion periods, which generated plasma free insulin levels in the supraphysiological range. These results provide evidence for an extrapancreatic effect of glibenclamide at low insulin concentrations during euglycemic clamping in patients with insulin-dependent diabetes mellitus. However, this effect was not reflected clinically in either an increased rate of hypoglycemic reactions or decreased insulin needs during the short term period of treatment.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/farmacologia , Compostos de Sulfonilureia/farmacologia , Adulto , Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Glucose/administração & dosagem , Glibureto/farmacologia , Humanos , Infusões Parenterais , Insulina/administração & dosagem , Insulina/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
Increased glucose/glucose-6-phosphate (G/G6P) substrate cycle activity may be an early marker of disordered hepatic glucose metabolism. To investigate the effects of glucocorticoids on G/G6P cycle activity and insulin resistance, we studied eight normal subjects using the euglycemic glucose clamp technique with high pressure liquid chromatography-purified [2(3)H]- and [6-3H]glucose tracers at insulin infusion rates of 0.4 and 2.0 mU/kg.min after 24-h cortisol (2 micrograms/kg.min) and saline infusions. Endogenous glucose production ([6-3H]glucose) was greater after cortisol than saline in the postabsorptive state (13.3 +/- 0.5 vs. 12.2 +/- 0.5 mumol/kg.min; P < 0.05) and during 0.4-mU insulin infusion (10.5 +/- 0.7 vs. 5.0 +/- 0.8 mumol/kg.min; P < 0.005). During 2.0-mU insulin infusion, endogenous glucose production was suppressed similarly (5.1 +/- 0.4 vs. 4.1 +/- 0.5 mumol/kg.min), but glucose disappearance was less after cortisol than saline (38.7 +/- 3.5 vs. 64.6 +/- 4.3 mumol/kg.min; P < 0.001). G/G6P cycle activity after cortisol and saline was similar in the postabsorptive state and during 0.4 mU insulin. During 2.0 mU insulin, cycle activity was greater after cortisol than saline (3.6 +/- 0.9 vs. 0.8 +/- 0.5 mumol/kg.min; P < 0.005). In conclusion, cortisol induces hepatic insulin resistance without significantly changing G/G6P cycle activity. At high glucose turnover rates, G/G6P cycle activity is increased by cortisol; however, reduced glucose disappearance is the main cause of impaired insulin action.
Assuntos
Glucose/metabolismo , Glucofosfatos/metabolismo , Hidrocortisona/farmacologia , Insulina/farmacologia , Absorção , Adulto , Glicemia/análise , Feminino , Técnica Clamp de Glucose , Glucose-6-Fosfato , Humanos , MasculinoRESUMO
An increase in oxidative stress may contribute to the development of diabetic complications. The key aqueous-phase chain-breaking antioxidant ascorbate is known to be deficient in diabetes, and we have therefore investigated the effects of ascorbate supplementation on oxidative stress in the streptozotocin diabetic rat. Markers of lipid peroxidation (malondialdehyde [MDA] and diene conjugates) were increased in plasma and erythrocytes of untreated diabetic animals, and levels of the antioxidants ascorbate and retinol were reduced. Plasma tocopherol was unchanged. Insulin treatment normalized MDA and ascorbate levels, although ascorbate metabolism remained disturbed, as indicated by increased levels of dehydroascorbate. High-dose ascorbate supplementation in the absence of insulin treatment restored plasma ascorbate to normal and increased plasma retinol and tocopherol levels. However, MDA and diene conjugate levels remained unchanged, possibly as a result of increased iron availability. High-dose ascorbate supplementation should be approached with caution in diabetes, as ascorbate may exert both antioxidant and prooxidant effects in vivo.