Streptozotocin Diabetes: Time Course of Irreversible B-Cell Damage; Further Observations on Prevention by Nicotinamide

Stauffacher, Werner; Burr, Ian M.; Gutzeit, A.; Beaven, D. W.; Velemínský, J.; Renold, A. E.

doi:10.3181/00379727-133-34439

Cited by 62 publications

(48 citation statements)

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“…As previously reported (Schein and Bates, 1 968; Stauffacher et al, 1970) and confirmed by the present study, diabetes onset after i.v. injection of Sz, 65mg/kg, is followed by a triphasic pattern with an early Fig.1, the injection of a diabetogenic dose, 65mg/kg, of Sz was followed by the triphasic pattern in not only blood glucose and plasma insulin but also plasma glucagon level fluctuations, and the pattern of plasma glucagon fluctuations was similar to that of blood glucose responses.…”

Section: Discussionsupporting

confidence: 79%

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The effect of streptozotocin on the pancreatic a cell function.

et al. 1979

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SynopsisThe effect of a single i.v. injection of30, 50, and65mg of streptozotocin (Sz) per kg of body weight on blood glucose, plasma insulin and glucagon levels was studied in rats. Responses to glucose of these three parameters were also examined in rats one week after the administration of various doses of Sz alone, Sz with nicotinamide or with picolinamide.Nicotinamide, 500mg/kg, and picolinamide, 250 mg/kg, were given i.p. 15m in before the injection of 65mg/kg of Sz.The triphasic pattern was observed after the injection of 65mg/kg of Sz not only in blood glucose and plasma insulin but also in plasma glucagon level fluctuations, the last of which showed a similar pattern to that of blood glucose responses.Further, the initial hyperglucagonemia had a delay of2hr in onset, when treated with30 and50mg/kg of Sz, respectively. Oral glucose loading resulted in a significant increase of plasma glucagon levels in rats injected with 30 and 50mg/kg of Sz, respectively.The paradoxical rise of plasma glucagon and glucose intolerance was observed in rats given Sz with nicotinamide, and Sz with picolinamide, as well as in those given Sz alone, 65mg/kg, while there was no significant difference in insulin responses between the pretreated groups of rats and controls.These results suggest that streptozotocin, even in a nondiabetogenic dose, has effect(s) on the A cell function, and that nicotinamide and picolinamide are active in protecting B cells against the cytotoxic effect, but they do not modify the effect of Sz on the A cell function.

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Section: Discussionsupporting

confidence: 79%

“…It has further been shown that nicotinamide protects B cells against the cytotoxic effect (Schein et al, 1967;Schein and Bates, 1968;Dulin and Wyse, 1969;Stauffacher et al, 1970). Picolinamide was found to prevent a diabetogenic effect of Sz (Doi, 1975 …”

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confidence: 99%

The effect of streptozotocin on the pancreatic a cell function.

et al. 1979

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“…In an attempt to explain the mechanism of action it has been suggested that diabetogenic activity of streptozotocin is mediated through its ability to lower pancreatic NAD+ concentrations significantly (Schein et al, 1967;Schein & Loftus, 1968;Schein & Bates, 1968;Junod et al, 1969;Ho & Hashim, 1972;Lazarus & Shapiro, 1973). This postulate is based on the observation that nicotinamide given either 10min before or up to 2h after streptozotocin prevents the development of diabetes (Dulin & Wyse, 1969a,b;Stauffacher et al, 1970;Lazarus & Shapiro, 1973).…”

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The synthesis of [14C]streptozotocin and its distribution and excretion in the rat

Karunanayake

Hearse

Mellows

1974

Biochemical Journal

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[14C]Streptozotocin was synthesized specifically labelled at three positions in the molecule. The biological activity ofsynthetic streptozotocin was characterised by studies in vivo ofits diabetogenic activity and its dose-response curves. After this characterization the excretion pattern of all three labelled forms of streptozotocin was studied. With [1-14C]-streptozotocin and [2'-14C]streptozotocin the injected radioactivity was excreted (approx.70% and 80% respectively) mainly in the urine, the greater part of the excretion occurring in the first 6h period; small amounts (approx. 9% and 8 % respectively) were found in the faeces. In contrast, with [3'-methyl-'4C]streptozotocin a much smaller proportion (approx.42 %) of the injected radioactivity was excreted in the urine, the major proportion appearing in the first 6h, whereas approx. 53 % of the injected radioactivity was retained in the carcasses. In whole-body radioautographic studies very rapid renal clearance and hepatic accumulation of the injected radioactivity was observed with all three labelled forms of the drug. There was some evidence for biliary and intestinal excretion. Major differences were apparent in the tissue-distribution studies, with each of the three labelled forms, particularly with [3'-methyl-14C]streptozotocin. There was no accumulation of [1-_4C]streptozotocin in the pancreas for the 6h period after administration. However, with [3'-methyl-14C]-streptozotocin (and also [2'-'4C]streptozotocin) there was evidence of some pancreatic accumulation after 2h. The results indicate that streptozotocin is subjected to considerable metabolic transformation and to rapid renal clearance. The implication of these suggestions is evaluated with particular reference to the diabetogenic action of streptozotocin.

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“…In characterizing the effects of streptozotocin, it was of interest to know whether nicotinamide or methylnicotinamide could protect against the streptozotocin-induced inhibition of proinsulin and total protein synthesis, just as they have been reported to protect the insulin release capability [17][18][19][20][21][22][23][24]. In one experiment, 10 mM nicotinamide or 4 mM methyl nicotinamide were included in the incubation medium with or without 2.2 mM streptozotocin.…”

Section: The Effects Of Streptozotocin Concentration and Time Of Expomentioning

confidence: 99%

“…Certainly, the administration of nicotinamide, a precursor of NAD in many tissues, protects against the diabetogenic effects of subsequently administered streptozotocin [17][18][19][20][21][22][23][24][25]. This protection may, however, unmask a long term oncogenic effect of the drug [26,27].…”

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Effects of streptozotocin in vitro on proinsulin biosynthesis, insulin release and ATP content of isolated rat islets of Langerhans

et al. 1976

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Summary. Proinsulin synthesis, insulin release and intracellular ATP concentrations were measured in isolated rat islets of Langerhans under control conditions of in vitro incubation and after treatment with several concentrations of streptozotocin for different periods of time. It was found that streptozotocin inhibited proinsulin synthesis, as well as insulin release, in a time and concentration dependent manner. The characteristics of the inhibition of these two processes were similar in general terms, but one dissimilarity was noted, i.e. after 60 min exposure to a high concentration of streptozotocin, proinsulin synthesis was inhibited more than insulin release. ATP content was reduced by high concentrations of streptozotocin, but it was found that proinsulin synthesis and insulin release could be inhibited without any effect on ATP content by a low (0.22 mM) concentration of streptozotocin. The effect of streptozotocin on proinsulin synthesis was judged to be the result of a target specificity for the B-cell rather than a specific effect on proinsulin relative to total protein synthesis. [4] activity, has been structurally characterized as 2-deoxy-2-(3'-methyl-3'-nitrosoureido)-D-glucopyranose [5]. The compound has been used extensively for the induction of experimental diabetes in laboratory animals and may, because of the reproducibility of its effects, be the agent of choice for this purpose [6][7][8][9][10][11][12][13][14][15][16].The mechanism by which streptozotocin selectively destroys ttie B-cells of the islets of Langerhans is not known, although lowering of intracellular nicotinamide adenine dinucleotide (NAD) levels may be involved. Certainly, the administration of nicotinamide, a precursor of NAD in many tissues, protects against the diabetogenic effects of subsequently administered streptozotocin [17][18][19][20][21][22][23][24][25]. This protection may, however, unmask a long term oncogenic effect of the drug [26,27].Studies of the effects of streptozotocin on islets of Langerhans have shown a correlation between the extent of B-cell destruction and the decrease in islet NAD [25]; decreased oxidation of glucose by islets isolated after in vivo administration of a diabetogenic dose of streptozotocin [28]; and a dose-related inhibition of glucose-induced insulin secretion during two hours of incubation, when the drug was added in vitro to isolated islets [29]. The purpose of the present study was that of investigating the effects of streptozotocin on proinsulin synthesis, while simultaneously measuring its effects upon insulin release. Only one preliminary report dealing with proinsulin synthesis and streptozotocin has appeared [30].

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Streptozotocin Diabetes: Time Course of Irreversible B-Cell Damage; Further Observations on Prevention by Nicotinamide

Cited by 62 publications

References 0 publications

The effect of streptozotocin on the pancreatic a cell function.

The effect of streptozotocin on the pancreatic a cell function.

The synthesis of [14C]streptozotocin and its distribution and excretion in the rat

Effects of streptozotocin in vitro on proinsulin biosynthesis, insulin release and ATP content of isolated rat islets of Langerhans

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