Critical low catastrophe: a case report of treatment-refractory hypoglycemia following overdose of long-acting insulin.
BLOOD sugar; DEXTROSE; HYPOGLYCEMIA; INSULIN; INSULINOMA; PARENTERAL infusions
Overdose of long-acting insulin can cause unpredictable hypoglycemia for prolonged periods of time. The initial treatment of hypoglycemia includes oral carbohydrate intake as able and/or parenteral dextrose infusion. Refractory hypoglycemia following these interventions presents a clinical challenge in the absence of clear guidelines for management. Octreotide has sometimes been used, but its use is generally limited to sulfonylurea overdose. In this case report, we present a case of refractory hypoglycemia following an overdose of 900 units of long-acting insulin glargine that failed to respond to usual modes of therapy mentioned above. Stress-dose corticosteroids were then initiated, followed by subsequent improvement in IV dextrose and glucagon requirements and blood glucose levels. Hence, corticosteroids may serve as an adjunctive therapy in managing hypoglycemia and can be considered earlier in the course of treatment in patients with refractory hypoglycemia to prevent volume overload, especially when large volumes of dextrose infusions are required.
Sandooja R;Moorman JM;Priyadarshini KM;Detoya K
Case Reports in Endocrinology
2020
1905-07
journalArticle
<a href="http://doi.org/10.1155/2020/8856022" target="_blank" rel="noreferrer noopener">10.1155/2020/8856022</a>
Ampk-dependent Repression Of Hepatic Gluconeogenesis Via Disruption Of Creb Center Dot Crtc2 Complex By Orphan Nuclear Receptor Small Heterodimer Partner
activated protein-kinase; binding-protein; Biochemistry & Molecular Biology; creb coactivator crtc2; gene-expression; insulin; metformin; phosphorylation; shp; torc2; transcriptional activity
Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of gluconeogenic enzyme gene expression. Here, we show that SHP inhibited protein kinase A-mediated transcriptional activity of cAMP-response element-binding protein (CREB), a major regulator of glucose metabolism, to modulate hepatic gluconeogenic gene expression. Deletion analysis of phosphoenolpyruvate carboxykinase (PEPCK) promoter demonstrated that SHP inhibited forskolin-mediated induction of PEPCK gene transcription via inhibition of CREB transcriptional activity. In vivo imaging demonstrated that SHP inhibited CREB-regulated transcription coactivator 2 (CRTC2)-mediated cAMP-response element-driven promoter activity. Furthermore, overexpression of SHP using adenovirus SHP decreased CRTC2-dependent elevations in blood glucose levels and PEPCK or glucose-6-phosphatase (G6Pase) expression in mice. SHP and CREB physically interacted and were co-localized in vivo. Importantly, SHP inhibited both wild type CRTC2 and S171A (constitutively active form of CRTC2) coactivator activity and disrupted CRTC2 recruitment on the PEPCK gene promoter. In addition, metformin or overexpression of a constitutively active form of AMPK (Ad-CA-AMPK) inhibited S171A-mediated PEPCK and G6Pase gene expression, and hepatic glucose production and knockdown of SHP partially relieved the metformin- and Ad-CA-AMPK-mediated repression of hepatic gluconeogenic enzyme gene expression in primary rat hepatocytes. In conclusion, our results suggest that a delayed effect of metformin-mediated induction of SHP gene expression inhibits CREB-dependent hepatic gluconeogenesis.
Lee J M; Seo W Y; Song K H; Chanda D; Kim Y D; Kim D K; Lee M W; Ryu D; Kim Y H; Noh J R; Lee C H; Chiang J Y L; Koo S H; Choi H S
Journal of Biological Chemistry
2010
2010-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1074/jbc.M110.134890" target="_blank" rel="noreferrer noopener">10.1074/jbc.M110.134890</a>
Hepatocyte Growth Factor Family Negatively Regulates Hepatic Gluconeogenesis via Induction of Orphan Nuclear Receptor Small Heterodimer Partner in Primary Hepatocytes
signaling pathway; mice; hyperglycemia; Biochemistry & Molecular Biology; gene-expression; promoter; activated protein-kinase; insulin; diabetic-nephropathy; hepg2 liver-cells; upstream
Hepatic gluconeogenesis is tightly balanced by opposing stimulatory (glucagon) and inhibitory (insulin) signaling pathways. Hepatocyte growth factor (HGF) is a pleiotropic growth factor that mediates diverse biological processes. In this study, we investigated the effect of HGF and its family member, macrophage-stimulating factor (MSP), on hepatic gluconeogenesis in primary hepatocytes. HGF and MSP significantly repressed expression of the key hepatic gluconeogenic enzyme genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (Glc-6-Pase) and reduced glucose production. HGF and MSP activated small heterodimer partner (SHP) gene promoter and induced SHP mRNA and protein levels, and the effect of HGF and MSP on SHP gene expression was demonstrated to be mediated via activation of the AMP-activated protein kinase (AMPK) signaling pathway. We demonstrated that upstream stimulatory factor-1 (USF-1) specifically mediated HGF effect on SHP gene expression, and inhibition of USF-1 by dominant negative USF-1 significantly abrogated HGF-mediated activation of the SHP promoter. Elucidation of the mechanism showed that USF-1 bound to E-box-1 in the SHP promoter, and HGF increased USF-1 DNA binding on the SHP promoter via AMPK and DNA-dependent protein kinase-mediated pathways. Adenoviral overexpression of USF-1 significantly repressed PEPCK and Glc-6-Pase gene expression and reduced glucose production. Knockdown of endogenous SHP expression significantly reversed this effect. Finally, knockdown of SHP or inhibition of AMPK signaling reversed the ability of HGF to suppress hepatocyte nuclear factor 4 alpha-mediated up-regulation of PEPCK and Glc-6-Pase gene expression along with the HGF- and MSP-mediated suppression of gluconeogenesis. Overall, our results suggest a novel signaling pathway through HGF/AMPK/USF-1/SHP to inhibit hepatic gluconeogenesis.
Chanda D; Li T G; Song K H; Kim Y H; Sim J G; Lee C H; Chiang J Y L; Choi H S
Journal of Biological Chemistry
2009
2009-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1074/jbc.M109.022244" target="_blank" rel="noreferrer noopener">10.1074/jbc.M109.022244</a>
Hepatic Cannabinoid Receptor Type 1 Mediates Alcohol-Induced Regulation of Bile Acid Enzyme Genes Expression Via CREBH
metabolism; Ohio; mice; Signaling; Signal transduction; liver; Homeostasis; transcription factor; Genes; exposure; Acids; er stress; endoplasmic-reticulum stress; Science & Technology - Other Topics; insulin-resistance; cholesterol 7-alpha-hydroxylase; human hepatocytes; Rodents; Bile acids; alcohol; element-binding protein; gene-expression; endocannabinoid system; bound; cb1 receptors; leptin resistance; Liver diseases; Diabetes mellitus; insulin-resistance; insulin; Fatty liver; hepatocytes; Sciences: Comprehensive Works; Alcohols; Bile; activation; Damage prevention; Deregulation; Muridae; Regulatory mechanisms (biology); RNA extraction; Synthesis
Bile acids concentration in liver is tightly regulated to prevent cell damage. Previous studies have demonstrated that deregulation of bile acid homeostasis can lead to cholestatic liver disease. Recently, we have shown that ER-bound transcription factor Crebh is a downstream effector of hepatic Cb1r signaling pathway. In this study, we have investigated the effect of alcohol exposure on hepatic bile acid homeostasis and elucidated the mediatory roles of Cb1r and Crebh in this process. We found that alcohol exposure or Cb1r-agonist 2-AG treatment increases hepatic bile acid synthesis and serum ALT, AST levels in vivo alongwith significant increase in Crebh gene expression and activation. Alcohol exposure activated Cb1r, Crebh, and perturbed bile acid homeostasis. Overexpression of Crebh increased the expression of key bile acid synthesis enzyme genes via direct binding of Crebh to their promoters, whereas Cb1r knockout and Crebh-knockdown mice were protected against alcohol-induced perturbation of bile acid homeostasis. Interestingly, insulin treatment protected against Cb1r-mediated Crebh-induced disruption of bile acid homeostasis. Furthermore, Crebh expression and activation was found to be markedly increased in insulin resistance conditions and Crebh knockdown in diabetic mice model (db/db) significantly reversed alcohol-induced disruption of bile acid homeostasis. Overall, our study demonstrates a novel regulatory mechanism of hepatic bile acid metabolism by alcohol via Cb1r-mediated activation of Crebh, and suggests that targeting Crebh can be of therapeutic potential in ameliorating alcohol-induced perturbation of bile acid homeostasis.
Chanda D; Kim Y H; Li T; Misra J; Kim D K; Kim J R; Kwon J; Jeong W I; Ahn S H; Park T S; Koo S H; Chiang J Y L; Lee C H; Choi H S
PLOS ONE
2013
2013-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1371/journal.pone.0068845" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0068845</a>
INSITU HYBRIDIZATION STUDY OF OBESITY-ASSOCIATED ALTERATION IN GROWTH-HORMONE MESSENGER-RNA LEVELS
differentiation; Endocrinology & Metabolism; expression; fetal-rat; gene-transcription; glucocorticoid hormones; growth hormone; insitu hybridization; insulin; lean zucker rats; messenger-rna; Nutrition & Dietetics; pituitary-tumor cells; ribonucleic-acid; triiodothyronine
In order to investigate whether the impaired GH secretion associated with obesity is due to a pituitary disorder we studied GH mRNA levels by in situ hybridization in genetically obese and lean Zucker rats. The levels of GH mRNA were at least two fold lower in obese rats in comparison to that in lean controls as quantified by both the scanning of autoradiographs of tissue sections and Northern blot analysis. Quantification of somatotrophs revealed no significant difference in their number between lean and obese rat pituitaries. It is therefore likely that the attenuated GH mRNA levels in genetically obese Zucker rats are due to a decrease in GH transcripts per somatotroph rather than a result of a pituitary defect involving a preferential decrease in somatotroph population.
Ahmad I; Steggles A W; Finkelstein J A
International Journal of Obesity
1992
1992-06
Journal Article or Conference Abstract Publication
n/a