Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment

Kosáka, Kinori; Kuzuya, Tsunehiko; Akanuma, Yasuo; Hagura, Ryoko

doi:10.1007/bf01228297

Cited by 239 publications

(105 citation statements)

References 21 publications

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“…In humans with diabetes, any treatment that normalizes the plasma glucose profile leads to improvements in insulin secretion (43,44). Our findings suggest that the severity of hyperglycemia plays a critical role in the progressive loss of ␤-cell differentiation with diabetes.…”

Section: ␤-Cell Abnormalities Worsen With Duration Of Hyperglycemiamentioning

confidence: 71%

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Laybutt¹,

Glandt

et al. 2003

Journal of Biological Chemistry

143

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We have proposed that hyperglycemia-induced dedifferentiation of ␤-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. ␤-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1␣), ␤-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC␤, and sarcoplasmic reticulum Ca 2؉ -ATPase 3). Conversely, genes normally suppressed in ␤-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce ␤-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of ␤-cell phenotype with decreased expression of ␤-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the ␤-cell phenotype found in diabetes.Pancreatic ␤-cells maintain specialized pathways of metabolism that efficiently couple the secretion of insulin to circulating glucose levels (1, 2). With the increased demand of insulin resistance and obesity, an adaptation in ␤-cell mass and secretion can keep glucose levels within a narrow range (3-5). The failure of ␤-cells to adequately adapt to increased demand is fundamental to the pathogenesis of all forms of diabetes. We have hypothesized that abnormal ␤-cell function in diabetes is due to the loss of the unique expression pattern of genes that optimize glucose-induced insulin secretion (GIIS) 1 and insulin synthesis (5).The development of the endocrine pancreas and the maintenance of ␤-cell differentiation is regulated by a network of transcription factors, which includes pancreatic and duodenal homeob...

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Section: ␤-Cell Abnormalities Worsen With Duration Of Hyperglycemiamentioning

confidence: 71%

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Laybutt¹,

Glandt

et al. 2003

Journal of Biological Chemistry

143

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“…Inducing better control by intensive insulin treatment in type 2 diabetic patients has repeatedly been shown to improve insulin secretion (26). Furthermore, as already mentioned, short-term treatment with diazoxide improves insulin secretion in type 2 diabetic subjects (16), and this effect may be independent of an effect on blood glucose (17).…”

mentioning

confidence: 94%

Overstimulation and beta-cell function.

Grill¹,

Björklund²

2001

Diabetes

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Previous and present evidence ascribes an important role to overstimulation of ␤-cells for the secretory abnormalities associated with type 2 diabetes. The abnormality most clearly linked to overstimulation is the elevated ratio of circulating proinsulin to insulin. Evidence obtained in human pancreatic islets suggests that aberrations in insulin oscillations that occur in type 2 diabetes could at least in part be linked to abnormalities in cytoplasmic Ca 2+ oscillations induced by overstimulation. Furthermore, in a transplantation model, we have obtained evidence for long-lasting, perhaps irreversible, effects of overstimulation, implying that this is a causative factor for the well-recognized deterioration of insulin secretion with increasing duration of type 2 diabetes. The mechanisms behind the effects of overstimulation are only partly clarified, but it is clear that reduced insulin secretion after overstimulation is only partly explained by decreased insulin stores. In cultured human pancreatic islets, overstimulation by high glucose leads to a rise in cytoplasmic Ca 2+ levels, which persists after normalization of the glucose levels. Persistent elevation of cytoplasmic Ca 2+ may trigger apoptosis, thus participating in long-term irreversible deterioration of ␤-cell function. These data provide sufficient rationale for clinical studies to test the beneficial effects of relative ␤-cell rest in type 2 diabetic patients. Diabetes 50 (Suppl. 1): S122-S124, 2001I n 1986, Leahy et al. (1) reported that 48 h of marked hyperglycemia in normal rats, achieved by massive glucose infusions, produced almost total insensitivity to glucose when insulin release was subsequently measured from the perfused pancreas. This desensitizing effect was specific for glucose and other secretagogues, such as arginine, eliciting normal or even exaggerated responses. Desensitization was reversible within 24 h. One of us (V.G.) later showed that if glucose-induced insulin secretion during glucose infusion was blocked by the simultaneous infusion of diazoxide, no later desensitization occurred; if anything, insulin responses to glucose were enhanced (2) (Fig. 1). Because the levels of hyperglycemia were kept similar with or without diazoxide, it was concluded that the desensitizing effect was due to overstimulation of the ␤-cells rather than to effects of hyperglycemia per se.We studied the desensitizing effect of overstimulation further in vitro (3). It was found to be induced in perifused islets by only a few hours of glucose stimulation. The decline of insulin secretion during prolonged in vitro stimulation mimicked that first described by Bolaffi et al. (4) as the third phase of insulin secretion, was proportionate to the degree of stimulation, and could be totally prevented by blocking glucose-induced insulin secretion with diazoxide.Which mechanisms explain desensitization by overstimulation and its prevention by diazoxide? Diazoxide blocks glucose-induced insulin secretion by opening K + -ATP channels (5). An effect of overstimula...

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“…Return to normoglycaemia through interventions such as reduced energy intake, use of insulin-sensitising agents or exogenous insulin results in marked recovery of insulin secretory capacity [4,5]. These observations are suggestive of a cascade whereby metabolic stress against a background of susceptible beta cells results in early glucose intolerance, which in turn worsens insulin secretory function and causes more dysmetabolism, more acquired beta cell defects and so on.…”

Section: Introductionmentioning

confidence: 99%

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Delghingaro-Augusto¹,

Nolan

Gupta

et al. 2009

Diabetologia

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Aims/hypothesis The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model. Methods Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured. Results ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression. Conclusions/interpretation Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.

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Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment

Cited by 239 publications

References 21 publications

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Overstimulation and beta-cell function.

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

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