B cell insensitivity in a rat model of non-insulin-dependent diabetes. Evidence for a rapidly reversible effect of previous hyperglycemia.

Grill, V.; Westberg, M.; Östenson, Claes Göran

doi:10.1172/jci113119

Cited by 51 publications

(33 citation statements)

References 35 publications

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“…In contrast, perfusate containing 5.5 mmol/1 glucose (well below the normal plasma glucose value in rats) failed to achieve the same effect, indicating that the return of glucose-induced insulin secretion was not simply an effect of removing hyperglycaemia but instead depended on the absence (or possibly extremely low level) of glucose. The same observation has been made in other hyperglycaemic rodent models [15,22,23] suggesting that rapid restoration of glucose responsiveness in the presence of profound glucopoenia is a fundamental characteristic of hyperglycaemia-associated Beta-cell dysfunction. Some aspects of these findings need to be emphasized.…”

Section: Discussionsupporting

confidence: 71%

“…Animal models should theoretically provide a way to investigate this question, but reversal studies in hyperglycaemic rat models have provided conflicting results. Using in vitro techniques, glucose-induced insulin secretion has been restored in as little as 40 min [15]. In contrast, in vivo insulin injections have proved to be of varying success and require days to work [16][17][18].…”

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confidence: 99%

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Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Leahy

Weir

1991

Diabetologia

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Summary. Glucose-induced insulin secretion is lost in the face of chronic hyperglycaemia. The same defect is present when normal rats are made hyperglycaemic by 48-h glucose infusions. Insulin secretory responses were mapped out during the post-infusion period in order to determine how long it takes for normal Beta-cell function to recover, and to identify factors which influence the rate of recovery. Male Sprague Dawley rats weighing 200-250 g were infused with 50% glucose or 77 mmol/1 NaC1 for 48 h. The glucose-infused rats were mildly hypoglycaemic for 14 h after the infusion ceased. Glucose-induced insulin secretion, absent at the end of the glucose infusion, was normal 6 h post-infusion. Such rapid recovery was not because of the short duration of hyperglycaemia; mild hypoglycaemia from a 5-h insulin infusion in 90% pancreatectomized rats resulted in a four-fold rise in glucose-induced insulin secretion. Under in vitro conditions, extreme glucose deprivation caused by perfusing the pancreas of glucose-infused rats with buffer devoid of glucose restored glucose-induced insulin secretion in just 37 min. Therefore, the suppression of glucose-induced insulin release by chronic hyperglycaemia is a dynamic situation that requires ongoing hyperglycaemia to prevent the reappearance of glucose responsiveness. This study shows recovery of glucose-induced insulin secretion after just 6 h of mild hypoglycaemia in vivo and even faster recovery with more severe glucose deprivation in vitro. Our results suggest that there is an inverse relationship between the rate of return of Betacell glucose responsiveness and the ambient glucose concentration.Key words: Animal models, Type 2 (non-insulin-dependent) diabetes mellitus, insulin secretion, insulin treatment, hypoglycaemia, islets of Langerhans.Normally, the plasma glucose concentration exerts the dominant influence over insulin secretion. Type 2 (noninsulin-dependent) diabetes mellitus is characterized by Beta cells which no longer respond to a changing glucose level [1][2][3][4]. We have proposed that glucose-induced insulin secretion is lost as a direct result of Beta cells being exposed to a chronically elevated glucose concentration [4,5]. Support for this idea has come from animal studies in which normal rats made hyperglycaemic through a variety of mechanisms develop a similar defect [6.9], and also that normalizing the plasma glucose concentration in these rats with phloridzin restores glucose-induced insulin secretion [10,11].Little is known about reversal of secretory defects in non-insulin-dependent diabetes mellitus except that restoration of euglycaemia often results in the reappearance of glucose-induced insulin release [4, 12-14]. The recovery time has not been mapped out, nor has much been learned about what conditions speed up or retard recovery. Animal models should theoretically provide a way to investigate this question, but reversal studies in hyperglycaemic rat models have provided conflicting results. Using in vitro techniques, glucose-induced insuli...

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Leahy

Weir

1991

Diabetologia

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“…However, the basic features are well worth presenting because the insights gained from investigations on glucose desensitization are also shaping the lines of thought in investigations of the desensisitization by nonnutrient, pharmacological insulin secretagogues. The main feature that distinguishes glucose desensitization from glucose toxicity is the reversibility of the diminished secretory responsiveness (8). This reversibility can be suprisingly rapid: it was described to occur in vitro within minutes after changing from a moderately elevated glucose concentration back to a nonstimulatory concentration (9).…”

Section: Glucose Desensitization: Concepts and Controversiesmentioning

confidence: 99%

Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

et al. 2004

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Prolonged stimulation of insulin secretion by depolarization and Ca2؉ influx regularly leads to a reversible state of decreased secretory responsiveness to nutrient and nonnutrient stimuli. This state is termed "desensitization." The onset of desensitization may occur within 1 h of exposure to depolarizing stimuli. Desensitization by exposure to sulfonylureas, imidazolines, or quinine produces a marked cross-desensitization against other ATP-sensitive K ؉ channel (K ATP channel)-blocking secretagogues. However, desensitized ␤-cells do not necessarily show changes in K ATP channel activity or Ca 2؉ handling. Care has to be taken to distinguish desensitization-induced changes in signaling from effects due to the persisting presence of secretagogues. The desensitization by depolarizing secretagogues is mostly accompanied by a reduced content of immunoreactive insulin and a marked reduction of secretory granules in the ␤-cells. In vitro recovery from a desensitization by the imidazoline efaroxan was nearly complete after 4 h. At this time point the depletion of the granule content was partially reversed. Apparently, recovery from desensitization affects the whole lifespan of a granule from biogenesis to exocytosis. There is, however, no direct relation between the ␤-cell granule content and the secretory responsiveness. Even though a prolonged exposure of isolated islets to depolarizing secretagogues is often associated with the occurrence of ultrastructural damage to ␤-cells, we could not find a cogent link between depolarization and Ca 2؉ influx and apoptotic or necrotic ␤-cell death. Diabetes 53 (Suppl. 3)

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“…14) Other authors confirmed these findings and showed that neonatally-STZ treated rats in adulthood display some of the typical characteristics of diabetes. [15][16][17][18] We demonstrated in a previous study that responses of mesenteric microvessels of n-STZ diabetic rats to endothelium-dependent vasodilator acetylcholine and to sodium nitroprusside, an endothelium-independent vasodilator, were significantly reduced compared with non-diabetic rats. We concluded that the impaired vasodilatation is, in part, due to a reduced sensitivity of vessels to NO and to a reduced production and/or bioavailability of NO.…”

mentioning

confidence: 86%

Constrictor Responses to Noradrenaline, Hemodynamic Profile, and Superoxide Levels Measured by Hydroethidine Oxidation in Diabetic Rats

Sartoretto

Oliveira

Nigro

et al. 2007

Biological & Pharmaceutical Bulletin

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Vascular complications are more frequent and severe among diabetics as compared with healthy populations. 1-3)Cardiovascular disease is one of the leading causes of death in the Western world and diabetes mellitus is a major factor underlying its development.4) The pathogenesis of diabetesassociated hypertension is not completely understood, but may involve insulin resistance, which is associated with hypertension in both diabetic and non-diabetic individuals. 5,6) Most of the complications in diabetes are due to increased serum glucose and increased generation of oxygen-derived free radicals, which lead to endothelial dysfunction. Prolonged exposure to hyperglycemia is recognized as a major factor in the pathogenesis of atherosclerosis in diabetic patients, by inducing a large number of alterations at the cellular level of vascular tissue.7) The most important mechanisms involved in this process are glycation end products accumulating in vessel wall 8) and oxidative stress by impairment of oxidative defensive capacity as well as by an overproduction of reactive oxygen species (ROS). 9-11)The neonatal streptozotocin (n-STZ) rat model firstly described by Portha et al. (1974) 12) ; Weir et al. (1981) 13) is an alternate model that presents pancreatic b-cell destruction followed by partial b-cell regeneration and glucose intolerance.14) Other authors confirmed these findings and showed that neonatally-STZ treated rats in adulthood display some of the typical characteristics of diabetes. [15][16][17][18] We demonstrated in a previous study that responses of mesenteric microvessels of n-STZ diabetic rats to endothelium-dependent vasodilator acetylcholine and to sodium nitroprusside, an endothelium-independent vasodilator, were significantly reduced compared with non-diabetic rats. We concluded that the impaired vasodilatation is, in part, due to a reduced sensitivity of vessels to NO and to a reduced production and/or bioavailability of NO. 19) Reduction in bioavailability and/or sensitivity of NO in n-STZ diabetic rats may be causing several other alterations in vascular function. Therefore, the goal of the present study was to test the hypothesis that vascular dysfunction in neonatal streptozotocin-induced diabetic rats could be associated with alterations in blood pressure, hemodynamic profile, and levels of superoxide anion. MATERIALS AND METHODS Induction of DiabetesDiabetes mellitus was induced in male newborn (2-d-old, weighing 8 to 10 g) Wistar rats with bolus injection of STZ (160 mg/kg, i.p.) dissolved in citrate buffer (10 mM, pH 4.5). Control rats were sham injected with the same volume of citrate buffer. The n-STZ diabetic rats and matching controls were housed according to institutional guidelines (room temperature 22Ϯ0.5°C, 12 h light/dark cycle, 60% humidity, standard rat chow and water ad libitum). The experimental protocols were approved and performed in accordance with the guidelines of the Institute of Biomedical Sciences Ethical Committee.Characterization of the n-STZ Diabetic Rats The n-ST...

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B cell insensitivity in a rat model of non-insulin-dependent diabetes. Evidence for a rapidly reversible effect of previous hyperglycemia.

Cited by 51 publications

References 35 publications

Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

Constrictor Responses to Noradrenaline, Hemodynamic Profile, and Superoxide Levels Measured by Hydroethidine Oxidation in Diabetic Rats

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