Diabetes - Plasma Glucose a Causative Factor?

9/30/02

Question: What is the effect of high serum glucose levels on the pancreas and its ability to produce insulin?

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Unique Identifier:11272169

Authors: Grill V. Bjorklund A.

Institution: Department of Internal Medicine, University Hospital of Trondheim, Norway. valdemar.grill@medisin.ntnu.no

Title: Overstimulation and beta-cell function.

Source: Diabetes. 50 Suppl 1:S122-4, 2001 Feb.

Abstract: Previous and present evidence ascribes an important role to overstimulation of beta-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 Ca2+ 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 Ca2+ levels, which persists after normalization of the glucose levels. Persistent elevation of cytoplasmic Ca2+ may trigger apoptosis, thus participating in long-term irreversible deterioration of beta-cell function. These data provide sufficient rationale for clinical studies to test the beneficial effects of relative beta-cell rest in type 2 diabetic patients. CAS Registry/EC Number 11061-68-0 (Insulin). 364-98-7 (Diazoxide). 50-99-7 (Glucose). 7440-70-2 (Calcium).

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Unique Identifier:10717000

Authors: Liu K. Paterson AJ. Chin E. Kudlow JE.

Institution: Department of Medicine/Endocrinology, University of Alabama, 1808 Seventh Avenue South, Room 756, Birmingham, AL 35294, USA.

Title: Glucose stimulates protein modification by O-linked GlcNAc in pancreatic beta cells: linkage of O-linked GlcNAc to beta cell death.

Source: Proceedings of the National Academy of Sciences of the United States of America. 97(6):2820-5, 2000 Mar 14.

Abstract: The pancreatic beta cell can respond in the long term to hyperglycemia both with an increased capacity for insulin production and, in susceptible individuals, with apoptosis. When glucose-induced apoptosis offsets the increasing beta cell capacity, type 2 diabetes results. Here, we tested the idea that the pathway of glucose metabolism that leads to the modification of intracellular proteins with the O-linked monosaccharide N-acetylglucosamine (O-GlcNAc) is involved in the glucose-induced apoptosis. This idea is based on two recent observations. First, the beta cell expresses much more O-GlcNAc transferase than any other known cell, and second, that the beta cell-specific toxin, streptozotocin (STZ), itself a GlcNAc analog, specifically blocks the enzyme that cleaves O-GlcNAc from intracellular proteins. As a consequence, we now show that hyperglycemia leads to the rapid and reversible accumulation of O-GlcNAc specifically in beta cells in vivo. Animals pretreated with STZ also accumulate O-GlcNAc in their beta cells when hyperglycemic, but this change is sustained upon re-establishment of euglycemia. In concert with the idea that STZ toxicity results from the sustained accumulation of O-GlcNAc after a hyperglycemic episode, we established a low-dose STZ protocol in which the beta cells' toxicity of STZ was manifest only after glucose or glucosamine administration. Transgenic mice with impaired beta cell glucosamine synthesis treated with this protocol are resistant to the diabetogenic effect of STZ plus glucose yet succumb to STZ plus glucosamine. This study provides a causal link between apoptosis in beta cells and glucose metabolism through glucosamine to O-GlcNAc, implicating this pathway of glucose metabolism with beta cell glucose toxicity. CAS Registry/EC Number 0 (Antibiotics, Aminoglycoside). 0 (Blood Glucose). 18883-66-4 (Streptozocin). 3416-24-8 (Glucosamine). 50-99-7 (Glucose). 7512-17-6 (Acetylglucosamine).

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Unique Identifier:8928761

Authors: Byrne MM. Sturis J. Sobel RJ. Polonsky KS.

Institution: Department of Medicine, Pritzker School of Medicine, University of Chicago, Illinois 60637, USA.

Title: Elevated plasma glucose 2 h postchallenge predicts defects in beta-cell function.

Source: American Journal of Physiology. 270(4 Pt 1):E572-9, 1996 Apr.

Abstract: Studies were performed in subjects with no known family history of diabetes, normoglycemic subjects who have first-degree relatives with non-insulin-dependent diabetes mellitus (NIDDM), and subjects with nondiagnostic oral glucose tolerance tests (NDX) or impaired glucose tolerance (IGT). Insulin sensitivity index (SI) was similar in all four groups. However, a number of defects in insulin secretion were seen in the NDX and IGT groups, including reduced first-phase insulin secretory responses in intravenous glucose in relation to the degree of insulin resistance, and reduced normalized spectral power of insulin secretion during oscillatory glucose infusion. The latter finding demonstrates a decreased ability of the beta-cell to detect and respond to the successive increases and decreases in glucose and therefore to be entrained by the exogenous glucose infusion. The ability of a low-dose glucose infusion to prime the insulin secretory response to a subsequent glucose stimulus was normal in subjects with IGT but reduced or absent in subjects with overt NIDDM. These studies demonstrate that a number of alterations in beta-cell function are detectable in nondiabetic first-degree relatives of subjects with NIDDM with mild elevations in the 2-h postchallenge glucose level, and these abnormalities antedate the onset of overt hyperglycemia and clinical diabetes. CAS Registry/EC Number 0 (Blood Glucose). 11061-68-0 (Insulin). 50-99-7 (Glucose).

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Unique Identifier:2676476

Authors: Giroix MH. Serradas P. Portha B.

Institution: Laboratoire de Physiologie du Developpement et CNRS UA 307, Universite Paris 7, France.

Title: The desensitization of normal B-cells to glucose in vitro is transient and not related to high glucose levels.

Source: Endocrinology. 125(4):1999-2007, 1989 Oct.

Abstract: To examine the postulated phenomenon of glucotoxicity toward the B-cell, islets isolated from normal adult rats were cultured for 1-6 days in RPMI medium at various glucose concentrations. Insulin release and (pro)insulin biosynthesis by these islets were then measured in short term incubations. The 1-day cultured islets (at 9.7 mM glucose) displayed a deficient glucose-stimulated insulin release which was partially restored in the presence of forskolin (5 microM). By contrast they exhibited a consistent insulin release in response to ketoisocaproate (10 mM), 12-O-tetradecanoylphorbol-13-acetate (2 microM), or the combination of Ba2+ (2 mM) and theophylline (1.4 mM) in the absence of extracellular Ca2+. Desensitization of their B-cells was not specific for glucose, since glyceraldehyde (10 mM) or leucine (10 mM) also failed to stimulate insulin release. Desensitization was not related to glucose concentration (5.6, 9.7, or 16.7 mM) in the medium during the 1-day culture period and was restricted to the secretory function, with no impairment of the biosynthesis process. The desensitization to glucose was transient, and high glucose levels (9.7 and 16.7 mM) in the culture medium favored restoration of the subsequent secretory response to the hexose. Under conditions of recovery of B-cell sensitivity to glucose in vitro (5 days at 9.7 mM glucose), the secretory response to acute glucose was in fact significantly enhanced after an additional exposure (1 day) to very high glucose levels (22 or 55 mM). The present results argue against 1) the possibility that islets suffer from some unspecific decreased viability after a 1-day culture period; and 2) the hypothesis that glucose insensitivity in the 1-day cultured islets is primarily caused by a direct deleterious effect of high glucose concentrations on the B-cells. They, rather, reinforce the view that high glucose levels are actually crucial in the preservation of the insulin secretory response to glucose of islets maintained in tissue culture. CAS Registry/EC Number 0 (Blood Glucose). 50-99-7 (Glucose).

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Unique Identifier:5793931

Authors: Zajtchuk R. Amato JC. Shoemaker WC. Baker RJ.

Title: The relationship between blood glucose levels and external pancreatic secretion in man.

Source: Journal of Trauma-Injury Infection & Critical Care. 9(7):629-37, 1969 Jul.

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