Excessive Insulin Therapy: Biochemical Effects and Clinical Repercussions

Wilson, Dana E.

doi:10.7326/0003-4819-98-2-219

Cited by 29 publications

(6 citation statements)

References 62 publications

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“…Insulin-dependent diabetes mellitus is marked not only by a decrease in insulin levels but also by an increase in the circulating levels of the so-called counterregulatory hormones, glucocorticoids and glucagon (16,17). To evaluate whether insulin and its counter-regulatory hormones exert a direct and specific effect on liver cells, we used hepatoma cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous work has shown that the plasma homocysteine level was also decreased in the streptozotocin-induced rat diabetic model with a concomitant increase in hepatic CBS enzyme activity; insulin administration reversed these effects (15). Insulin-dependent diabetes mellitus is characterized not only by insufficient circulating levels of insulin but also by elevated levels of counterregulatory hormones such as glucagon and glucocorticoids (15)(16)(17). Moreover, cyclic AMPelevating agents and glucocorticoids have been shown to increase the level of CBS enzyme activity in rat hepatoma cells (18).…”

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confidence: 99%

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Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

Ratnam

Maclean

Jacobs

et al. 2002

Journal of Biological Chemistry

144

127

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Homocysteine metabolism is altered in diabetic patients. Cystathionine ␤-synthase (CBS), a key enzyme involved in the transsulfuration pathway, which irreversibly converts homocysteine to cysteine, catalyzes the condensation of serine and homocysteine to cystathionine. Studies in streptozotocin-induced diabetic rats have shown that CBS enzyme activity is elevated in the liver but not in the kidney, and this effect is reversed by insulin treatment. To determine whether these effects resulted from alterations at the level of gene transcription, CBS mRNA was measured in diabetic and insulin-treated diabetic rats. CBS mRNA levels were found to be markedly higher in streptozotocin-induced diabetic rat livers; these were reduced by insulin administration. In H4IIE cells, a rat hepatoma cell culture model, glucocorticoids increased the cellular levels of CBS enzyme protein and CBS mRNA; insulin inhibited this stimulatory effect. Treatment with insulin also decreased CBS levels in HepG2 cells, a human hepatoma cell line. Nuclear run-on experiments in the rat cells confirmed that stimulation of CBS gene expression by glucocorticoids and the inhibition by insulin occurred at the transcriptional level. Transient transfections of HepG2 cells with a CBS-1b promoter luciferase reporter construct showed that the promoter activity was decreased by 70% after insulin treatment. These results show that insulin has a direct role in regulating homocysteine metabolism. Altered insulin levels in diseases such as diabetes may influence homocysteine metabolism by regulating the hepatic transsulfuration pathway.Cystathionine ␤-synthase (CBS) 1 (EC 4.2.1.22) catalyzes the first committed step in cysteine biosynthesis, the irreversible condensation of homocysteine with serine to form cystathionine (1). Homocysteine, a sulfur-containing nonprotein amino acid, is an intermediate in the metabolism of methionine. It is at a metabolic crossroads between its synthesis from methionine and its removal through the transsulfuration or remethylation pathways (2). Two pyridoxal 5Ј-phosphate-dependent enzymes comprise the transsulfuration pathway: CBS, which catalyzes the condensation of serine and homocysteine to cystathionine, and cystathionine ␥-lyase, which catalyzes the formation of cysteine, ␣-ketobutyrate, and ammonia (3, 4). The regulation of CBS gene expression is important in a number of physiological situations. Feeding rats a high protein diet or a high methionine diet increases CBS activity (5). It is also known that flux through the transsulfuration pathway provides cysteine for glutathione synthesis, so that altered CBS levels may be of importance in oxidative stress (6). The well known sparing effect of cysteine on methionine requirements is mediated, at least in part, via alterations in CBS activity. Our own recent work shows that glucagon administration to rats increases hepatic CBS enzyme activity and mRNA levels (7). CBS enzyme deficiency, an autosomal recessively inherited disorder, is the leading cause of homocystinuria. Partial d...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

Ratnam

Maclean

Jacobs

et al. 2002

Journal of Biological Chemistry

144

127

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“…Finally, the fact that system x c − contributes to injury might seem paradoxical given its importance in the biosynthesis of the antioxidant molecule glutathione ( Watanabe and Bannai, 1987 ; Bannai et al., 1989 ; Miura et al., 1992 ; Sato et al., 1995 ; Bridges et al., 2001 ; Dun et al., 2006 ; Lewerenz et al., 2009 ). Ironically, while this pathway allows the CNS to rapidly upregulate glutathione production in response to cellular stress, we and others demonstrate its potential to exacerbate CNS pathology both in vitro and in vivo (for reviews, see Bridges et al., 2012 ; Lewerenz et al., 2013 ; Massie et al., 2015 ).…”

Section: Discussionmentioning

confidence: 99%

A Cytotoxic, Co-operative Interaction Between Energy Deprivation and Glutamate Release From System x_c⁻Mediates Aglycemic Neuronal Cell Death

Thorn

Jackman

et al. 2015

ASN Neuro

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The astrocyte cystine/glutamate antiporter (system xc−) contributes substantially to the excitotoxic neuronal cell death facilitated by glucose deprivation. The purpose of this study was to determine the mechanism by which this occurred. Using pure astrocyte cultures, as well as, mixed cortical cell cultures containing both neurons and astrocytes, we found that neither an enhancement in system xc− expression nor activity underlies the excitotoxic effects of aglycemia. In addition, using three separate bioassays, we demonstrate no change in the ability of glucose-deprived astrocytes—either cultured alone or with neurons—to remove glutamate from the extracellular space. Instead, we demonstrate that glucose-deprived cultures are 2 to 3 times more sensitive to the killing effects of glutamate or N-methyl-D-aspartate when compared with their glucose-containing controls. Hence, our results are consistent with the weak excitotoxic hypothesis such that a bioenergetic deficiency, which is measureable in our mixed but not astrocyte cultures, allows normally innocuous concentrations of glutamate to become excitotoxic. Adding to the burgeoning literature detailing the contribution of astrocytes to neuronal injury, we conclude that under our experimental paradigm, a cytotoxic, co-operative interaction between energy deprivation and glutamate release from astrocyte system xc− mediates aglycemic neuronal cell death.

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“…Despite widespread acceptance of the Somogyi phenomenon and its inclusion in standard texts on diabetes (4-7), its clinical relevance continues to be controversial (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Although individuals with IDDM frequently experience asymptomatic nocturnal hypoglycemia (18)(19)(20)(21)(22)(23), the relevance of antecedent hypoglycemia to early-morning hyperglycemia has been questioned (12,13,(15)(16)(17).…”

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confidence: 98%

Relationship of Nocturnal Hypoglycemia to Daytime Glycemia in IDDM

Lerman

Wolfsdorf²

1988

Diabetes Care

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In view of the continuing debate about the clinical relevance of nocturnal hypoglycemia as an explanation for high blood glucose (BG) levels before breakfast, we prospectively analyzed 281 overnight BG profiles (blood samples obtained at 2100, 0200-0300, and 0700) in 66 consecutive patients with insulin-dependent diabetes mellitus. Nocturnal hypoglycemia (0200-0300 BG concentration less than or equal to 50 mg/dl) occurred in 27 patients (41%) and in 36 profiles (13%). All the patients with nocturnal hypoglycemia received two or more injections of insulin each day. When hypoglycemia occurred at 0200-0300, the preceding BG concentration at 2100 was significantly lower than when nocturnal BG was greater than 100 mg/dl (108 +/- 11 vs. 145 +/- 12 mg/dl; P less than .05; mean +/- SE). A BG less than or equal to 120 mg/dl at 2100 preceded nocturnal hypoglycemia in 24 (67%) of 36 profiles. The mean BG at 0700 was significantly lower in the profiles associated with nocturnal hypoglycemia than in those with nocturnal BG levels greater than 150 mg/dl (156 +/- 10 vs. 201 +/- 11 mg/dl; P less than .05). BG values greater than 180 mg/dl at 0700 were infrequently (11 of 143 or 8% of profiles) preceded by nocturnal hypoglycemia, and no instances of major hyperglycemia (BG greater than 300 mg/dl) at 0700 were preceded by nocturnal hypoglycemia. Furthermore, BG at 0700, 1100, and 1500 on the day before the occurrence of nocturnal hypoglycemia were similar to those on the day after.(ABSTRACT TRUNCATED AT 250 WORDS)

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Excessive Insulin Therapy: Biochemical Effects and Clinical Repercussions

Cited by 29 publications

References 62 publications

Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

A Cytotoxic, Co-operative Interaction Between Energy Deprivation and Glutamate Release From System x_c⁻Mediates Aglycemic Neuronal Cell Death

Relationship of Nocturnal Hypoglycemia to Daytime Glycemia in IDDM

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Excessive Insulin Therapy: Biochemical Effects and Clinical Repercussions

Cited by 29 publications

References 62 publications

Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

A Cytotoxic, Co-operative Interaction Between Energy Deprivation and Glutamate Release From System xc−Mediates Aglycemic Neuronal Cell Death

Relationship of Nocturnal Hypoglycemia to Daytime Glycemia in IDDM

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A Cytotoxic, Co-operative Interaction Between Energy Deprivation and Glutamate Release From System x_c⁻Mediates Aglycemic Neuronal Cell Death