Streptozotocin diabetes—further studies on the mechanism of depression of nicotinamide adenine dinucleotide concentrations in mouse pancreatic islets and liver

Schein, Philip S.; Cooney, David A.; McMenamin, Mary G.; Anderson, Tom

doi:10.1016/0006-2952(73)90071-3

Cited by 92 publications

(43 citation statements)

References 12 publications

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“…Recently, Yamamoto and Okamoto [27] demonstrated an increased activity ofpolyadenosine diphosphoribose (poly (ADP-rib)) synthetase, an enzyme participating in DNA-repair, in nuclei from rat pancreatic islets exposed to SZ in vitro. This enzyme uses NAD as a substrate, which is concordant with the documented observation that SZ depletes the NAD content of pancreatic islets [28][29]. It has been demonstrated that enzymically generated oxygen radicals in vitro can cause DNA single strand breaks [30], which presumably activates the enzyme.…”

Section: Discussionsupporting

confidence: 78%

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

Sandler

Andersson

1982

Diabetologia

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Summary. The protective effect on streptozotocin-induced diabetes of dimethyl urea, a hydroxyl radical scavenger, has been evaluated in vivo and in vitro. Pretreatment with dimethyl urea before a single diabetogenic dose of streptozotocin partially protected NMRI mice from hyperglycaemia, whereas the serum glucose of C57BL/KsJ mice increased during week 2 of observation. When the pancreases of these latter mice were examined histologically, insulitis was found in 15 out of 22 animals. The protective effect of dimethyl urea in the NMRI mice was not due to short-term hyperglycaemia induced by the drug, since pretreatment with glucose did not protect from streptozotocin but potentiated its diabetogenic effect. Dimethyl urea reduced the inhibition caused by streptozotocin on proinsulin biosynthesis of NMRI islets in vitro. It is suggested that streptozotocin-induced diabetes in mice may involve generation of hydroxyl radicals which are toxic to islet B cells. If this immediate cytotoxicity is reduced by a scavenger, a more slowly developing hyperglycaemia and an accompanying insulitis may occur in particularly susceptible animals.

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Section: Discussionsupporting

confidence: 78%

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

Sandler

Andersson

1982

Diabetologia

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“…The toxin has a half-life of 5-15 min (19) and is taken up via GLUT2 expressed in ␤-cells and hepatocytes (20). The toxin has a glucose moiety and a reactive methyl group and is known to induce a rapid depletion of NAD in the islets (21). NAD is essential for redox reactions involved in the generation of ATP via glycolysis and mitochondrial oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

Kullin

Hansen

et al. 2000

Diabetes

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We examined the influence of two K ATP channel openers, diazoxide and an analog (NNC 55-0118), on experimental ␤-cell damage induced by streptozotocin (STZ; 0.5 mmol/l). Rat pancreatic islets were exposed to diazoxide or NNC 55-0118 for 30 min and were further incubated for 30 min after the addition of STZ. The islets were then washed and cultured for 24 h. Islets exposed to STZ alone showed extensive morphological damage, reduced glucose oxidation, low insulin content, and severely impaired glucose-stimulated insulin secretion and proinsulin biosynthesis. Islets treated with STZ in the presence of the channel openers (0.03-0.30 mmol/l) showed dose-dependent preservation of the morphology and improved glucose oxidation rates, insulin content, and secretion. NNC 55-0118 was capable of fully counteracting the STZ impairment, whereas diazoxide had a less protective effect. NNC 55-0118 did not counteract STZ-induced depression of islet NAD levels when examined 2 h after STZ exposure, which suggests that the mechanism of action by NNC 55-0118 is not through an inhibition of poly(ADP-ribose) polymerase. The results illustrate that K ATP channel openers can protect insulinproducing cells against toxic damage, an effect that may be of use in subjects with ongoing insulitis. Diabetes 49:1131-1136, 2000 I n human autoimmune diabetes, the insulin-producing ␤-cells are generally thought to be destroyed by cytotoxic T-cells that are driven by an antigen-specific process (1,2). In experiments with isolated islets, we have found that glucose increases the expression of ␤-cell autoantigens (3) and that diazoxide lowers the antigen amount (4). Against this background, we conducted a clinical trial and observed that a 3-month supplementary treatment with diazoxide had a beneficial effect on residual ␤-cell function in patients with new-onset type 1 diabetes (5). "␤-cell rest" may thus protect islet cells from autoimmune destruction (6) and may help to explain the remission phenomenon often noted subsequent to the initiation of insulin treatment.Diazoxide and other K ATP channel openers such as cromakalim and pinacidil have been used in experimental studies of the ischemic heart, and beneficial cardioprotective effects have been observed (7-9). Although the exact mechanism of this phenomenon is not understood, an opening of mitochondrial K + channels seems to be involved that results in dissipation of the inner mitochondrial membrane potential. This leads to net oxidation of the mitochondria with an apparent reduction in energy wastage (7,9,10).Diazoxide is known to act on K ATP channels in the plasma membrane of ␤-cells (11). It hyperpolarizes the membrane and inhibits the energy-consuming process of insulin secretion (12). Recently, exposure of ␤-cells to diazoxide has also been found to engage mitochondrial K ATP channels (13). In the present study, we examined the influence of diazoxide and NNC 55-0118, a new K ATP channel opener analog, on experimental ␤-cell damage induced by streptozotocin (STZ), an agent known to cause ene...

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“…On the other hand, phosphorylation of even restricted amounts of Dglyceraldehyde will lead to ATP production and a flux of intermediates through the lower span of the glycolytic pathway. Our previous work (Dean & Matthews, 1972) has shown that to remain an effective stimulant D-glyceraldehyde requires an intact NAD+/NADH redox system, for the electrical activity elicited by glyceraldehyde (and by glucose) is obliterated by streptozotocin, a diabetogenic agent which severely reduces NAD levels in islet cells (Schein, Cooney, McMenamin & Anderson, 1973). Furthermore, glucose metabolism in islet cells is normally associated with a very rapid and marked increase in reduced pyridine nucleotides (Panten, Dal Ri, Poser & Hasselblatt, 1971) which is not seen in the absence of Ca2+.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic islet cells: effects of monosaccharides, glycolytic intermediates and metabolic inhibitors on membrane potential and electrical activity.

Dean¹,

Matthews²,

Sakamoto³

1975

The Journal of Physiology

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SUMMARY1. The effects of monosaccharides, glycolytic intermediates, metabolic inhibitors and anoxia, have been studied on the membrane electrical activity of mouse pancreatic islet cells in vitro using a single intracellular micro-electrode for both voltage recording and current injection. 4. Electrical activity induced by D-glucose 28 mm, was progressively inhibited by phloridzin, 10 mm, if the cells were exposed to D-glucose and inhibitor simultaneously, and abolished on pretreatment with inhibitor for 30-60 min. Phloridzin also caused depolarization of the islet cells which was independent of extracellular glucose.5. Anoxia completely blocked the electrical activity induced by glucose but not that evoked by D-glyceraldehyde, L-leucine, tolbutamide or glibenclamide.6. Jodoacetic acid, 5 mm, rapidly blocked glucose-induced electrical activity whilst that elicited by tolbutamide was relatively resistant to inhibition. 7. The nature and possible location of the glucoreceptor in pancreatic

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Streptozotocin diabetes—further studies on the mechanism of depression of nicotinamide adenine dinucleotide concentrations in mouse pancreatic islets and liver

Cited by 92 publications

References 12 publications

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro

K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

Pancreatic islet cells: effects of monosaccharides, glycolytic intermediates and metabolic inhibitors on membrane potential and electrical activity.

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