Sudden onset of diabetes with ketoacidosis in a patient treated with FK506/tacrolimus

Toyonaga, Tetsushi; Kondo, Tatsuya; Miyamura, Nobuhiro; Sekigami, Taiji; Sonoda, Kazuhiro; Kodama, Shintaro; Shirakami, Atsuhisa; Shirotani, T.; Araki, Eiichi

doi:10.1016/s0168-8227(01)00354-0

Cited by 19 publications

(12 citation statements)

References 8 publications

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“…Thus, we investigated glucose/BHBA ratio of w4:1 and w1:1 respectively. The high glucose/BHBA ratio used in our study might be comparable with high plasma glucose concentrations (glucose/BHBA ratio of w4:1) observed in patients with diabetic ketosis (Sheikh-Ali et al 2008), a metabolic situation associated with hyperphagia (Toyonaga et al 2002). Similarly, streptozotocin-treated rats are hyperglycaemic, ketoacidotic and hyperphagic (Goodman 1987, Friedman & Ramirez 1994, although this might also be due to insulin deficiency.…”

Section: The Glucose/bhba Ratio and Food Intakesupporting

confidence: 79%

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The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1-7 cells

Laeger

Pöhland²,

Metges³

et al. 2012

Journal of Endocrinology

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b-Hydroxybutyric acid (BHBA) acts in the brain to influence feeding behaviour, but the underlying molecular mechanisms are unclear. GT1-7 hypothalamic cells expressing orexigenic agouti-related peptide (AGRP) were used to study the AMPactivated protein kinase (AMPK) pathway known to integrate dietary and hormonal signals for food intake regulation. In a 25 mM glucose culture medium, BHBA increased intracellular calcium concentrations and the expression of monocarboxylate transporter 1 (MCT1 (SLC16A1)). Phosphorylation of AMPK-a (PRKAA1 and PRKAA2) at Thr 172 was diminished after 2 h but increased after 4 h. Its downstream target, the mammalian target of rapamycin, was increasingly phosphorylated on Ser 2448 after 2 h but not changed after 4 h of BHBA treatment. After 4 h, BHBA treatment also increased Agrp mRNA expression. This increase was prevented by preincubation with the AMPK inhibitor Compound C. The inhibition of MCT1 activity by p-hydroxymercuribenzoate suppressed BHBA-stimulated AMPK phosphorylation but did not prevent BHBA-induced Agrp mRNA expression. This finding demonstrates that BHBA triggers the AMPK pathway resulting in orexigenic signalling under 25 mM glucose culture conditions. Under conditions of 5 . 5 mM glucose, however, BHBA marginally increased intracellular calcium but significantly decreased AMPK phosphorylation and Agrp mRNA expression, demonstrating that under physiological conditions BHBA reduces central orexigenic signalling.

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Section: The Glucose/bhba Ratio and Food Intakesupporting

confidence: 79%

“…In contrast to diabetic hyperketonaemia, which is usually associated with hyperphagia (Goodman 1987, Friedman & Ramirez 1994, Toyonaga et al 2002, i.c.v. application of BHBA rather diminishes food intake (Sakata et al 1982, Arase et al 1988.…”

Section: Introductionmentioning

confidence: 99%

The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1-7 cells

Laeger

Pöhland²,

Metges³

et al. 2012

Journal of Endocrinology

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“…Furthermore, the decrease in insulin secretion caused by those agents may also explain the requirement of exogenous insulin administration a few months after successful islet transplantation in subjects with type 1 diabetes (21).…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-Mediated XIAP Gene Transfer Reverses the Negative Effects of Immunosuppressive Drugs on Insulin Secretion and Cell Viability of Isolated Human Islets

et al. 2005

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Immunosuppressive drugs are routinely used to provide tolerance after whole pancreas and islet cell transplantations. While they are essential in inhibiting graft rejection, little is known about their effect on islet function and ␤-cell viability. In this study, we report that tacrolimus, sirolimus, and mycophenolic acid, when added to cultures of freshly isolated human islets, induce a downregulation of the synthesis and secretion of insulin. These functional changes are associated with decreased islet cell viability. All three agents induce a decrease of intracellular levels of Bcl-2 and Bcl-xL, with an increased level of Smac, indicating that they are capable of promoting a downregulation of anti-apoptotic factors and an accumulation of pro-apoptotic mediators. Transduction of islet cells with the antiapoptotic gene XIAP prevents the negative effects of these drugs on the function and viability of islets. XIAP-infected cells show a higher expression of phospho-CREB (cAMP-responsive element binding protein) and a reduced level of Smac, resulting in a significant reduction of apoptotic cells and a preservation of the glucose-dependent secretion of insulin. In conclusion, the present study demonstrates that genetically modified human islets expressing XIAP are resistant to the negative effects of immunosuppressive drugs on insulin secretion and cell viability. Diabetes 54: 424 -433, 2005

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“…However, it is difficult to reconcile reduced neuroprotective efficacy in the face of hyperglycaemia by both the nitric oxide donor 3-morpholinosydnonimine (184) and the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (185). Similarly, FK506 is reported to be neuroprotective in hyperglycaemic rats (186), and, yet, it can induce hyperglycaemia and diabetes after transplant surgery (187,188). Nicotinamide (189) and oestrogen (172) treatments are both reported to reduce infarct volume in hyperglycaemic rats.…”

Section: Diabetesmentioning

confidence: 99%

The Influence of Stroke Risk Factors and Comorbidities on Assessment of Stroke Therapies in Humans and Animals

Ankolekar

Rewell

Howells

et al. 2012

International Journal of Stroke

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The main driving force behind the assessment of novel pharmacological agents in animal models of stroke is to deliver new drugs to treat the human disease rather than to increase knowledge of stroke pathophysiology. There are numerous animal models of the ischaemic process and it appears that the same processes operate in humans. Yet, despite these similarities, the drugs that appear effective in animal models have not worked in clinical trials. To date, tissue plasminogen activator is the only drug that has been successfully used at the bedside in hyperacute stroke management. Several reasons have been put forth to explain this, but the failure to consider comorbidities and risk factors common in older people is an important one. In this article, we review the impact of the risk factors most studied in animal models of acute stroke and highlight the parallels with human stroke, and, where possible, their influence on evaluation of therapeutic strategies.

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Sudden onset of diabetes with ketoacidosis in a patient treated with FK506/tacrolimus

Cited by 19 publications

References 8 publications

The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1-7 cells

The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1-7 cells

Adenovirus-Mediated XIAP Gene Transfer Reverses the Negative Effects of Immunosuppressive Drugs on Insulin Secretion and Cell Viability of Isolated Human Islets

The Influence of Stroke Risk Factors and Comorbidities on Assessment of Stroke Therapies in Humans and Animals

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