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Recent Exposure to Hypoglycemia Increases Glucose Variability Following a Hyper/Hypoglycemic Metabolic Challenge in T1D.

ABSTRACT: AIMS:In type 1 diabetes (T1D), repeated hypoglycemic episodes may reduce hormonal defenses and increase the risk for severe hypoglycemia. In this work, we investigate the effect of a structured hyper/hypoglycemic metabolic challenge on the postintervention glucose variability in T1D subjects studied at home. METHODS:Thirty T1D subjects using insulin pump were monitored with blood glucose meters (SMBG) during a 1-month observation period. After 2 weeks of monitoring, participants were admitted at the University of Virginia Clinical Research Unit to undergo an 8-hour metabolic challenge. The intervention was designed to create hyperglycemia shortly followed by hypoglycemia, mimicking a real-life scenario of underbolused meal followed by overcorrection. After the intervention, subjects were monitored for 2 more weeks. Glycemic variability was assessed before and after the challenge using the low blood glucose index (LBGI). Glucagon counterregulation (GCR) response to induced hypoglycemia was also measured. LBGI variation and GCR were linked to prior exposure to hypoglycemia. RESULTS:Subjects significantly exposed to hypoglycemia in the 2 weeks before the intervention had a significant increase of postchallenge LBGI ( P < .001) and lower GCR response ( P < .05). Recent occurrence of hypoglycemia and number of years not using an insulin pump were identified as significant predictors of postchallenge LBGI ( P < .001). CONCLUSION:Glycemic swings, a common result of suboptimal insulin treatment, have a significant impact on future (days) glycemic control in T1D subjects with a recent history of hypoglycemia, as measured in the field. Choice of past insulin therapy may also mediate this effect.

SUBMITTER: Fabris C

PROVIDER: S-EPMC5851215 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Recent Exposure to Hypoglycemia Increases Glucose Variability Following a Hyper/Hypoglycemic Metabolic Challenge in T1D.

Fabris Chiara C Farhy Leon S LS Anderson Stacey M SM Nass Ralf M RM Kovatchev Boris P BP Breton Marc D MD

Journal of diabetes science and technology 20170925 2

<h4>Aims</h4>In type 1 diabetes (T1D), repeated hypoglycemic episodes may reduce hormonal defenses and increase the risk for severe hypoglycemia. In this work, we investigate the effect of a structured hyper/hypoglycemic metabolic challenge on the postintervention glucose variability in T1D subjects studied at home.<h4>Methods</h4>Thirty T1D subjects using insulin pump were monitored with blood glucose meters (SMBG) during a 1-month observation period. After 2 weeks of monitoring, participants w ...[more]

PMID: 28942668

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Project description:Hemorrhagic shock (HS) may contribute to organ failure, by profoundly altering mitochondrial function. Resveratrol (RSV), a naturally occurring polyphenol, has been shown to promote mitochondrial function and regulate glucose homeostasis in diabetes. We hypothesized that RSV during resuscitation would ameliorate HS-induced mitochondrial dysfunction and improve hyperglycemia following acute blood loss.With the use a decompensated HS model, male Long-Evans rats (n = 6 per group) were resuscitated with lactated Ringer's solution with or without RSV (30 mg/kg) and were killed before hemorrhage (sham), at severe shock, following resuscitation, and 18 hours after resuscitation. At each time point, the liver and kidney mitochondria were isolated to assess individual respiratory complexes (CI, CII, and CIV) and the production of reactive oxygen species (ROS). Blood samples were assayed for glucose, insulin, corticosterone, total glucagon-like peptide (GLP-1), glucagon, and serum cytokine levels. The Homeostatic Model Assessment-Insulin Resistance index was used to quantify insulin resistance.RSV supplementation following HS significantly improved mitochondrial function and decreased mitochondrial ROS production in both liver and kidney. RSV-treated animals had significantly lower blood glucose levels following resuscitation when compared with sham animals (116.0 ± 20.2 mg/dL vs. 227.7 ± 8.3 mg/dL, p < 0.05) or those resuscitated with lactated Ringer's solution (116.0 ± 20.2 mg/dL vs. 359.0 ± 79.5 mg/dL, p < 0.05). RSV supplementation was associated with significantly decreased plasma insulin levels (1.0 ± 0.4 ng/mL vs. 6.5 ± 3.7 ng/mL, p < 0.05), increased total GLP-1 levels (385.8 ± 56.6 ng/mL vs. 187.3 ± 11.1 ng/mL, p < 0.05), and a lower natural Log Homeostatic Model Assessment-Insulin Resistance index (1.30 ± 0.42 vs. 4.18 ± 0.68, p < 0.05) but had minimal effect on plasma corticosterone, glucagon, or cytokine levels.Resuscitation with RSV restores mitochondrial function and decreases insulin resistance but may be associated with increased hypoglycemia. The observed antiglycemic effects of RSV may be mediated by decreased mitochondrial ROS and increased GLP-1 secretion.

Project description:Glucose supply from blood is mandatory for brain functioning and its interruption during acute hypoglycemia or cerebral ischemia leads to brain injury. Alternative substrates to glucose such as the ketone bodies (KB), acetoacetate (AcAc), and β-hydroxybutyrate (BHB), can be used as energy fuels in the brain during hypoglycemia and prevent neuronal death, but the mechanisms involved are still not well understood. During glucose deprivation adaptive cell responses can be activated such as autophagy, a lysosomal-dependent degradation process, to support cell survival. However, impaired or excessive autophagy can lead to cell dysfunction. We have previously shown that impaired autophagy contributes to neuronal death induced by glucose deprivation in cortical neurons and that D isomer of BHB (D-BHB) reestablishes the autophagic flux increasing viability. Here, we aimed to investigate autophagy dynamics in the brain of rats subjected to severe hypoglycemia (SH) without glucose infusion (GI), severe hypoglycemia followed by GI (SH + GI), and a brief period of hypoglycemic coma followed by GI (Coma). The effect of D-BHB administration after the coma was also tested (Coma + BHB). The transformation of LC3-I to LC3-II and the abundance of autophagy proteins, Beclin 1 (BECN1), ATG7, and ATG12-ATG5 conjugate, were analyzed as an index of autophagosome formation, and the levels of sequestrosome1/p62 (SQSTM1/p62) were determined as a hallmark of autophagic degradation. Data suggest that autophagosomes accumulate in the cortex and the hippocampus of rats after SH, likely due to impaired autophagic degradation. In the cortex, autophagosome accumulation persisted at 6 h after GI in animals exposed to SH but recovered basal levels at 24 h, while in the hippocampus no significant effect was observed. In animals subjected to coma, autophagosome accumulation was observed at 24 h after GI in both regions. D-BHB treatment reduced LC3-II and SQSTM1/p62 content and reduced ULK1 phosphorylation by AMPK, suggesting it stimulates the autophagic flux and decreases AMPK activity reducing autophagy initiation. D-BHB also reduced the number of degenerating cells. Together, data suggest different autophagy dynamics after GI in rats subjected to SH or the hypoglycemic coma and support that D-BHB treatment can modulate autophagy dynamics favoring the autophagic flux.

Dataset Information

Recent Exposure to Hypoglycemia Increases Glucose Variability Following a Hyper/Hypoglycemic Metabolic Challenge in T1D.

Publications

Recent Exposure to Hypoglycemia Increases Glucose Variability Following a Hyper/Hypoglycemic Metabolic Challenge in T1D.

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