Upregulated hexokinase activity in isolated islets from diabetic 90% pancreatectomized rats

Hosokawa, Hitoshi; Hosokawa, Yuka; Leahy, Jack L.

doi:10.2337/diabetes.44.11.1328

Cited by 24 publications

(21 citation statements)

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“…Severely hyperglycemic rats were then divided in 3 groups. The first one was sacrificed 2 weeks after Px, and the other two were randomly assigned to phlorizin treatment However, the increase in HK I mRNA found in our Px rats is consistent with the increased HK activity reported in diabetic animals which probably accounts for the lower threshold for glucose-stimulated insulin secretion in Px islets and in islets overexpressing HK I (41)(42)(43). The progressive decrease of VDCC␣ 1D and SERCA3 could also contribute to the alteration of glucose-induced [Ca 2ϩ ] i rise and stimulation of insulin release in type 2 diabetes (7,44,45).…”

Section: Discussionsupporting

confidence: 74%

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

Jonas¹,

Sharma²,

Hasenkamp

et al. 1999

Journal of Biological Chemistry

531

474

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Differentiated pancreatic ␤ cells are unique in their ability to secrete insulin in response to a rise in plasma glucose. We have proposed that the unique constellation of genes they express may be lost in diabetes due to the deleterious effect of chronic hyperglycemia. To test this hypothesis, Sprague-Dawley rats were submitted to a 85-95% pancreatectomy or sham pancreatectomy. One week later, the animals developed mild to severe chronic hyperglycemia that was stable for the next 3 weeks, without significant alteration of plasma nonesterified fatty acid levels. Expression of many genes important for glucose-induced insulin release decreased progressively with increasing hyperglycemia, in parallel with a reduction of several islet transcription factors involved in ␤ cell development and differentiation. In contrast, genes barely expressed in sham islets (lactate dehydrogenase A and hexokinase I) were markedly increased, in parallel with an increase in the transcription factor c-Myc, a potent stimulator of cell growth. These abnormalities were accompanied by ␤ cell hypertrophy. Changes in gene expression were fully developed 2 weeks after pancreatectomy. Correction of blood glucose by phlorizin for the next 2 weeks normalized islet gene expression and ␤ cell volume without affecting plasma nonesterified fatty acid levels, strongly suggesting that hyperglycemia triggers these abnormalities. In conclusion, chronic hyperglycemia leads to ␤ cell hypertrophy and loss of ␤ cell differentiation that is correlated with changes in c-Myc and other key transcription factors. A similar change in ␤ cell differentiation could contribute to the profound derangement of insulin secretion in human diabetes.Pancreatic ␤ cells are highly specialized cells that secrete insulin in response to a variety of stimuli, the most important being glucose (1, 2). Their correct function is dependent on the expression of a unique set of genes that allow ␤ cells to respond to even small increases in plasma glucose levels by releasing appropriate amounts of insulin into the circulation (3). Type 2 diabetes is characterized by the combination of insulin resistance and profound alteration in glucose-stimulated insulin secretion (4). The latter can be ascribed, at least in part, to the deleterious effect of even mild chronic hyperglycemia and elevated plasma nonesterified fatty acids (NEFA) 1 on pancreatic ␤ cell function, a process often referred to as "gluco-lipotoxicity" (5, 6). In islets isolated from animal models of diabetes, several defects have been identified at the level of gene expression and/or enzymatic activity, but none by itself can entirely account for the ␤ cell defect characteristic of type 2 diabetes (5,7,8).Recently, the study of the transcriptional regulation of the insulin gene has led to the identification of several ␤ cell/islet transcription factors that are important for the development of the endocrine pancreas, the tissue-specific expression of key ␤ cell genes and maintenance of ␤ cell differentiation (9, 10). In islets ...

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Section: Discussionsupporting

confidence: 74%

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

Jonas¹,

Sharma²,

Hasenkamp

et al. 1999

Journal of Biological Chemistry

531

474

View full text Add to dashboard Cite

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“…The maximal glucose phosphorylation rate is higher in DP-HE than DP-LE islets, largely due to a rise in the maximal velocities of hexokinase 1 more than glucokinase, with no change in the K m of these enzymes (16). A similar shift to the left of the glucose concentration-response curve for insulin secretion characterizes islets from hyperglycemic 90% pancreatectomized rats (26,27). …”

Section: Discussionmentioning

confidence: 94%

Increased Glucose Sensitivity of Stimulus-Secretion Coupling in Islets FromPsammomys obesusAfter Diet Induction of Diabetes

Pertusa¹,

Нешер

Kaiser

et al. 2002

Diabetes

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When fed a high-energy (HE) diet, diabetes-prone (DP) Psammomys obesus develop type 2 diabetes with altered glucose-stimulated insulin secretion (GSIS).␤-Cell stimulus-secretion coupling was investigated in islets isolated from DP P. obesus fed a low-energy (LE) diet (DP-LE) and after 5 days on a HE diet (DP-HE). DP-LE islets cultured overnight in 5 mmol/l glucose displayed glucose dose-dependent increases in NAD(P)H, mitochondrial membrane potential, ATP/ (ATP ؉ ADP) ratio, cytosolic calcium concentration ([Ca 2؉ ] c ), and insulin secretion. In comparison, DP-HE islets cultured overnight in 10 mmol/l glucose were 80% degranulated and displayed an increased sensitivity to glucose at the level of glucose metabolism, [Ca 2؉ ] c , and insulin secretion. These changes in DP-HE islets were only marginally reversed after culture in 5 mmol/l glucose and were not reproduced in DP-LE islets cultured overnight in 10 mmol/l glucose, except for the 75% degranulation. Diabetes-resistant P. obesus remain normoglycemic on HE diet. Their ␤-cell stimulus-secretion coupling was similar to that of DP-LE islets, irrespective of the type of diet. Thus, islets from diabetic P. obesus display an increased sensitivity to glucose at the level of glucose metabolism and a profound ␤-cell degranulation, both of which may affect their in vivo GSIS. Diabetes 51:2552-2560, 2002 S timulation of insulin secretion by glucose requires oxidative metabolism of the sugar in ␤-cells, with acceleration of ATP production and increase of the ATP/ADP ratio (1-4). The subsequent closure of ATP-sensitive K ϩ channels in the plasma membrane is followed by depolarization, opening of voltage-dependent Ca 2ϩ channels, and Ca 2ϩ influx. This leads to a rise with oscillations of the cytosolic calcium concentration ([Ca 2ϩ ] c ), which triggers exocytosis of insulin-containing granules (5-7). Glucose metabolism also amplifies the efficacy of [Ca 2ϩ ] c on exocytosis, but the nature of the coupling factor(s) remains elusive (8).Type 2 diabetes is characterized by the association of insulin resistance and inappropriate insulin secretion by pancreatic ␤-cells (9 -12). The gerbil Psammomys obesus is an attractive model of diet-induced type 2 diabetes because a diabetes-resistant (DR) subgroup has been separated from the diabetes-prone (DP) animals by assorted breeding (9,13). When fed a low-energy (LE) diet, DP P. obesus remain normoglycemic despite their marked insulin resistance. Within a few days on a high-energy (HE) diet, DP P. obesus develop hyperglycemia associated with hyperinsulinemia, rapidly followed by a progressive decline in ␤-cell function leading to absolute insulin deficiency (14,15). In contrast, DR P. obesus are less hyperinsulinemic and remain normoglycemic on HE diet (16). Previous studies have shown that after 5 days on HE diet, glucose-stimulated insulin secretion (GSIS) is markedly altered in islets from DP but not DR P. obesus, possibly as a result of decreased insulin content, lower oxidative capacity, and altered protein kinase C ac...

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“…Studies in ␤-cells suggest that mild hyperglycemia actually lowers the glucose set point for insulin secretion at any glucose level. This is believed to be secondary to upregulation of hexokinase activity relative to glucokinase acitvity (13) and would explain the increased responsiveness of insulin secretion with mildly increased glycemia. It is worth considering, however, whether a chronic mild-to-moderate increase in glycemia can have biologically detrimental consequences.…”

Section: Discussionmentioning

confidence: 99%

Glucose Allostasis

et al. 2003

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In many organisms, normoglycemia is achieved by a tight coupling of nutrient-stimulated insulin secretion in the pancreatic ␤-cell (acute insulin response [AIR]) and the metabolic action of insulin to stimulate glucose disposal (insulin action [M]). It is widely accepted that in healthy individuals with normal glucose tolerance, normoglycemia can always be maintained by compensatorily increasing AIR in response to decreasing M (and vice versa). This has been mathematically described by the hyperbolic relationship between AIR and M and referred to as glucose homeostasis, with glucose concentration assumed to remain constant along the hyperbola. Conceivably, glucose is one of the signals stimulating AIR in response to decreasing M. Hypothetically, as with any normally functioning feed-forward system, AIR should not fully compensate for worsening M, since this would remove the stimulus for the compensation. We provide evidence from cross-sectional, longitudinal, and prospective data from Pima Indians (n ‫؍‬ 413) and Caucasians (n ‫؍‬ 60) that fasting and postprandial glucose concentrations increase with decreasing M despite normal compensation of AIR. For this physiologic adaptation to chronic stress (insulin resistance), we propose to use the term "glucose allostasis." Allostasis (stability through change) ensures the continued homeostatic response (stability through staying the same) to acute stress at some cumulative costs to the system. With increasing severity and over time, the allostatic load (increase in glycemia) may have pathological consequences, such as the development of type 2 diabetes. Diabetes 52:903-909, 2003 I nsulin action and secretion are the principal determinants of glycemia. In people with normal glucose tolerance (NGT), a decrease in insulin action (M) is accompanied by upregulation of insulin secretion (and vice versa). This is interpreted as compensation of insulin secretion for insulin resistance to maintain normoglycemia (1,2). Insulin resistance is a common consequence of obesity, for example, and represents a key factor in the pathogenesis of type 2 diabetes (3). Mathematically, the relationship between insulin secretion and insulin sensitivity is thought to be best expressed twodimensionally by a hyperbola with the product of the two variables equalling a constant (4), named the "disposition index" (DI). The DI is considered to measure the ability of the ␤-cells to compensate for insulin resistance. It decreases when glucose tolerance becomes impaired (5).While the insulin secretion/M hyperbola elegantly conceptualizes many cross-sectional and longitudinal observations (reviewed in 5), the physiologic signal that stimulates the compensatory increase in ␤-cell function in response to decreasing M remains unexplained. Insulin secretion is primarily substrate controlled, and glucose, the preeminent secretagogue among nutrient molecules, would be a good candidate for such a signal. Glucosestimulated insulin secretion is primarily controlled by the enzyme glucokinase, which governs the ge...

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Upregulated hexokinase activity in isolated islets from diabetic 90% pancreatectomized rats

Cited by 24 publications

References 0 publications

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

Increased Glucose Sensitivity of Stimulus-Secretion Coupling in Islets FromPsammomys obesusAfter Diet Induction of Diabetes

Glucose Allostasis

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