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G Reach

Publications and source records attributed to G Reach.

At least 19 recordsLinked to original sources
PubMed2001

PPAR-alpha-null mice are protected from high-fat diet-induced insulin resistance.

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the expression of genes involved in lipid metabolism. PPAR-alpha furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-alpha-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-alpha in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-alpha-null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-alpha-null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-alpha-null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat-fed wild-type mice, whereas it remained unchanged in PPAR-alpha-null mice. In contrast, PPAR-alpha deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-alpha dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-alpha deficiency on glucose homeostasis seem not to occur via the pancreas, because glucose-stimulated insulin secretion of islets was not influenced by the PPAR-alpha genotype. These data suggest that PPAR-alpha plays a role for the development of IR in response to a Western-type high-fat diet.

1-Methyl-3-isobutylxanthine↗
PubMed2001

[Towards a cell therapy for diabetes? An epistemiological perspective].

This text describes, in an epistemological perspective, the development of the concept of cellular therapy applied to the treatment of type 1 diabetes. Emphasis is put on three recent papers describing the success of islet allograft in diabetic patients, the development of neo-islets from stem cells isolated from the pancreas of adult mice, and the effect of hepatic cell transfection with an adenovirus bearing the gene coding for PDX-1, a transcription factor involved in the maturation of islets of Langerhans. This text tries to delineate some factors which may be involved in the chances for these techniques to reach the real world of human therapeutics.

Adenoviridae↗
PubMed2001

[Does obesity protect against diabetes? A new controversy].

Obesity is a risk factor for the appearance of type 2 diabetes: this notion, largely based on clinical experience, dictates the essential principles of the treatment of type 2 diabetes. At odds with this conventional wisdom, Elliot Danforth Jr. has recently proposed that "too few adipocytes predisposes to type 2 diabetes". A further thought on this controversy is discussed herein. In the context of the "orthodox" view which links obesity and diabetes, and its relation to the controversy, we analyse on one hand the effects of thiazolidine-diones on insulin sensitivity and on adipogenesis and, on the other hand, those of extreme situations represented by lipoatrophic diabetes and morbid obesity. This analysis shows that fat tissue indeed favors the appearance of diabetes but is also able to be anti-diabetogenic, and a dynamic solution of this paradox is put forward. We propose a dual evolutionist hypothesis leading to the selection of an intermediary adipogenic genotype based on the limitation of both insulin secretion and adipogenic potential, which would explain both the necessity of the existence of adipose tissue in man and the limitations of its development.

Adipocytes↗
PubMed2000

[Application of the causal theory of action through analysis of therapeutic non-observance].

This paper presents an analysis of an aspect of non-observance in the treatment of type 1 diabetes mellitus, the absence of adaptation of insulin dosage in spite of hyperglycemia. The adaptation of insulin dosage by the patient is described as an intentional action, performed as a habit. The problem is analysed through the causal theory of action and the concept of akrasia. These considerations may be useful to understand other aspects of therapeutic non-observance.

Attitude to Health↗
PubMed2000

Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration.

Long-term exposure of pancreatic beta cells to elevated levels of fatty acids (FAs) impairs glucose-induced insulin secretion. However, the effects of FAs on insulin gene expression are controversial. We hypothesized that FAs adversely affect insulin gene expression only in the presence of elevated glucose concentrations. To test this hypothesis, isolated rat islets were cultured for up to 1 week in the presence of 2.8 or 16.7 mmol/L glucose with or without 0.5 mmol/L palmitate. Insulin release, insulin content, and insulin mRNA levels were determined at the end of each culture period. Palmitate increased insulin release at each time point independently of the glucose concentration. In contrast, insulin content was unchanged in the presence of palmitate at 2.8 mmol/L glucose, but was markedly decreased in the presence of 0.5 mmol/L palmitate and 16.7 mmol/L glucose after 2, 3, and 7 days of culture. In the presence of a basal concentration of glucose, insulin mRNA levels were transiently increased by palmitate at 24 hours but were unchanged thereafter. In contrast, palmitate significantly inhibited the stimulatory effects of 16.7 mmol/L glucose on insulin mRNA levels after 2, 3, and 7 days. To determine whether the inhibitory effect of palmitate on glucose-stimulated insulin mRNA levels was associated with decreased insulin promoter activity, HIT-T15 cells were cultured for 24 hours in 11.1 mmol/L glucose in the presence or absence of palmitate, and insulin gene promoter activity was measured in transient transfection experiments using the insulin promoter-reporter construct INSLUC. INSLUC activity was decreased more than 2-fold after 24 hours of exposure to 0.5 mmol/L palmitate. We conclude that long-term exposure of pancreatic beta cells to palmitate decreases insulin gene expression only in the presence of elevated glucose concentrations, in part through inhibition of insulin gene promoter activity.

Animals↗
PubMed2000

Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal streptozotocin-treated rats.

According to the "glucose toxicity" hypothesis, hyperglycemia contributes to defective beta-cell function in type 2, non-insulin-dependent diabetes mellitus. This concept is supported by substantial data in rodent models of diabetes. However, the ability of glucose to stimulate the accumulation of insulin mRNA, a critical feature of normal beta-cell physiology, has not been investigated in in vivo models with chronic hyperglycemia. The aim of this study was to determine whether glucose-induced insulin mRNA accumulation is impaired in the neonatal streptozotocin-treated rat (n0-STZ rat), a model of non-obese, non-insulin-dependent diabetes mellitus. Islets of Langerhans isolated from n0-STZ and control rats were cultured for 24 h in the presence of 2.8 or 16.7 mmol/l glucose, and insulin mRNA levels were measured by Northern analysis. Insulin mRNA levels were increased more than twofold by glucose in control islets. In contrast, no significant effect of glucose was found on insulin mRNA levels in n0-STZ islets. We conclude that insulin gene regulation by glucose is impaired in n0-STZ rat islets.

Animals↗
PubMed2000

Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal streptozotocin-treated rats.

According to the glucose toxicity hypothesis, hyperglycemia contributes to defective beta-cell function in type 2, non-insulin-dependent diabetes mellitus. This concept is supported by substantial data in rodent models of diabetes. However, the ability of glucose to stimulate the accumulation of insulin mRNA, a critical feature of normal beta-cell physiology, has not been investigated in in vivo models of chronic hyperglycemia. The aim of this study was to determine whether glucose-induced insulin mRNA accumulation is impaired in the neonatal streptozotocin-treated rat (n0-STZ rat), a model of non-obese, non-insulin-dependent diabetes mellitus. Islets of Langerhans isolated from n0-STZ and control rats were cultured for 24 h in the presence of 2.8 or 16.7 mmol/L glucose, and insulin mRNA levels were measured by Northern analysis. Insulin mRNA levels were increased more than twofold by glucose in control islets. In contrast, no significant effect of glucose was found on insulin mRNA levels in n0-STZ islets. We conclude that insulin gene regulation by glucose is impaired in n0-STZ rat islets.

Animals↗
PubMed2000

Interstitial glucose concentration and glycemia: implications for continuous subcutaneous glucose monitoring.

The changes in plasma glucose concentration and in interstitial glucose concentration, determined with a miniaturized subcutaneous glucose sensor, were investigated in anesthetized nondiabetic rats. Interstitial glucose was estimated through two different calibration procedures. First, after a glucose load, the magnitude of the increase in interstitial glucose, estimated through a one-point calibration procedure, was 70% of that in plasma glucose. We propose that this is due to the effect of endogenous insulin on peripheral glucose uptake. Second, during the spontaneous secondary decrease in plasma glucose after the glucose load, interstitial glucose decreased faster than plasma glucose, which may also be due to the effect of insulin on peripheral glucose uptake. Third, during insulin-induced hypoglycemia, the decrease in interstitial glucose was less marked than that of plasma glucose, suggesting that hypoglycemia suppressed transfer of glucose into the interstitial tissue; subsequently, interstitial glucose remained lower than plasma glucose during its return to basal value, suggesting that the stimulatory effect of insulin on peripheral glucose uptake was protracted. If these observations obtained in rats are relevant to human physiology, such discrepancies between plasma and interstitial glucose concentration may have major implications for the use of a subcutaneous glucose sensor in continuous blood glucose monitoring in diabetic patients.

Animals↗
PubMed2000

[Clinical perspectives of xenotransplantation of islets of Langerhans].

This paper describes the rationale and different approaches for developing islets of Langerhans xenotransplantation. Implementing this therapeutic strategy in the treatment of human diabetes mellitus requires careful consideration of its potential risks and benefits, taking into account the current status of the treatment of this disease.

Animals↗
PubMed1999

Cryopreservation of specific pathogen-free (SPF) pig islet cells: effect of culture time before cryopreservation and after thawing.

UNLABELLED: The aim of this study was to determine the optimal conditions (effect of culture time before and after cryopreservation) for cryopreservation of specific pathogen-free pig islet cells. METHODS: (1) Glucose-induced insulin secretion by fresh islet cells cultured for 10 days was compared to that by islet cells cryopreserved 7 days after isolation and cultured 3 days after thawing. (2) Islet cells were cryopreserved 1, 7, or 14 days after isolation and cultured 3, 7, 14, or 21 days after thawing. Islet cell number, insulin content, and insulin response under perifusion tests were investigated. RESULTS: (1) Insulin response by cryopreserved islet cells was identical to that by fresh islet cells (basal/stimulation index: 2. 13 +/- 0.19 vs 2.17 +/- 0.16, n = 4, NS), although the amount of secreted insulin was reduced by 40% (area under the curve: 2136 +/- 198 pM/10(4) cells/180 min vs 3564 +/- 636 pM/10(4) cells/180 min, P = 0.104). (2) Cell number 6 days after thawing was reduced by 54, 40, and 63% when cryopreservations were carried out at D1, D7, and D14. (3) Insulin content in cultured or cryopreserved islet cells increased between 7 and 14 days of culture. (4) Whatever the culture time before and after cryopreservation, insulin secretion in response to glucose was maintained. The insulin release was the highest for islet cells cryopreserved 14 days after isolation and cultured 14 days after thawing (stimulation index: 6.19 +/- 2.68). CONCLUSIONS: SPF pig islet cells remained functional after cryopreservation in polyethylene glycol and it may be important to culture islet cells over 14 days before and after cryopreservation.

Animals↗
PubMed1999

Long-term exposure of isolated rat islets of Langerhans to supraphysiologic glucose concentrations decreases insulin mRNA levels.

Chronic hyperglycemia has been postulated to contribute to beta-cell dysfunction in type 2 diabetic patients. A deleterious effect of prolonged exposure to high glucose concentrations on insulin gene expression has been demonstrated in insulin-secreting cell lines. This study was designed to investigate in isolated rat islets the effects of long-term exposure to supraphysiologic glucose concentrations on insulin, GLUT2, and glucokinase gene expression. The acute effects of glucose on gene expression were investigated by culturing rat islets in 2.8 or 16.7 mmol/L glucose for 24 hours. Insulin, GLUT2, and glucokinase mRNA levels were assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). As expected, glucose acutely increased relative insulin and GLUT2 mRNA levels by 2.8- +/- 0.5-fold (n = 5, P < .005) and 1.8- +/- 0.3-fold (n = 5, P < .05), respectively, but had no effect on glucokinase gene expression (1.1- +/- 0.1-fold increase, n = 4, NS). These results validate the use of semiquantitative RT-PCR to detect changes in gene expression in rat islets. Islets were then cultured in 5.6 or 16.7 mmol/L glucose for 2, 4, or 6 weeks. Relative insulin mRNA levels were higher in islets cultured in high glucose after 2 weeks (1.8+/-0.1 v 1.0+/-0.1, n = 4, P < .05), identical after 4 weeks (0.9+/-0.1 v 1.00+/-0.2, n = 4, NS), and significantly lower after 6 weeks (0.6+/-0.1 v 1.0+/-0.2, n = 6, P < .05). Relative GLUT2 mRNA levels were higher in islets cultured in high glucose after 2 weeks (1.7+/-0.2 v 1.0+/-0.2, n = 3, P < .05) and then identical in both groups after 4 weeks (1.0+/-0.1 v 1.0+/-0.1, n = 3, NS) and 6 weeks (1.0+/-0.2 v 1.0+/-0.1, n = 6, NS). Relative glucokinase mRNA levels were identical under both culture conditions at 2 (1.4+/-0.4 v 1.0+/-0.2, n = 3, NS), 4 (0.8+/-0.5 v 1.0+/-0.3, n = 3, NS), and 6 (0.9+/-0.2 v 1.0+/-0.1, n = 6, NS) weeks. These results indicate that a 6-week exposure of rat islets to supraphysiologic glucose concentrations decreases insulin mRNA levels without affecting GLUT2 and glucokinase gene expression. We conclude that the phenomenon of glucose toxicity decreasing insulin gene expression is not restricted to transformed cells, and might provide insight into the mechanisms by which chronic hyperglycemia adversely affects beta-cell function.

Animals↗
PubMed1999

[Possible consequences on the follow up of type 2 diabetic patients of a recent modification of a glycosylated hemoglobin assay].

Glycated hemoglobin assay is considered as the gold standard for the follow-up of diabetic patients, and the assay must now be calibrated on the results of the method used in the DCCT study. It is considered as appropriate to intensify the therapy of type 2 diabetic patients when two consecutive values higher than 8% are observed. We present herein a case report illustrating the possible consequences on the follow up of type 2 diabetic patients of a recent significant modification, not reported elsewhere, aimed to eliminate a bias vs the DCCT method of a system, DCA 2000, largely used to determine HbA1c level in diabetic patients: before this modification, the DCA 2000 method underestimated the glycated hemoglobin level by 0.5% for a 8% value. Such is no more the case.

Adult↗