Combined Insulin Deficiency and Endotoxin Exposure Stimulate Lipid Mobilization and Alter Adipose Tissue Signaling in an Experimental Model of Ketoacidosis in Subjects With Type 1 Diabetes: A Randomized Controlled Crossover Trial

Svart, Mads; Kampmann, Ulla; Voss, Thomas Schmidt; Pedersen, Steen B.; Johannsen, Mogens; Rittig, Nikolaj; Poulsen, Per Løgstrup; Nielsen, Thomas S.; Jessen, Niels; Møller, Niels

doi:10.2337/db15-1645

Cited by 13 publications

(19 citation statements)

References 25 publications

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“…During the HI, cortisol decreased in KET, while no effect of hyperinsulinaemia was observed in CTR. Glucagon remained elevated by 50% in KET pH, glucose, NEFA and 3-hydroxybutyrate have all been published previously [13] (48.9 ± 5.0 pg/ml) compared with CTR (31.3 ± 4.7 pg/ml; p < 0.01) during the HI, while adrenalin was unaffected.…”

Section: Resultsmentioning

confidence: 51%

“…There was a 100-200-fold increase in TNF-α, IL-6 and IL-10 during KET [13]. The key metabolic variables from the preconditioning period are presented in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…The characteristics of the nine participants and details of the inflammatory response have been published previously [13]. In summary, the participants had an average HbA 1c of 7.7% (61 mmol/mol), diabetes duration of 14 ± 2 years, daily insulin of 0.7 ± 0.4 U kg…”

Section: Resultsmentioning

confidence: 99%

“…Study design and participants The present study was designed as a randomised, controlled, crossover trial consisting of two experimental days, separated by at least 3 weeks, characterised by: (1) euglycaemic control conditions and a bolus of saline (154 mmol/l NaCl) (CTR) and (2) hyperglycaemic ketotic conditions (KET) induced by LPS administration combined with insulin deprivation, as previously described in detail [13]. The study was not blinded.…”

Section: Methodsmentioning

confidence: 99%

“…This, in combination with differences in substrate metabolism between rodents and humans, limits the clinical impact of these studies. Therefore, we have established a human model of DKA by combining insulin deprivation and lipopolysaccharide (LPS) injection in individuals with type 1 diabetes [13]. Using this approach, we aimed to investigate the mechanisms regulating glucose disposal in human skeletal muscle under the hypothesis that early phases of DKA are complicated by impaired insulin action in skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic effects of insulin in a human model of ketoacidosis combining exposure to lipopolysaccharide and insulin deficiency: a randomised, controlled, crossover study in individuals with type 1 diabetes

et al. 2017

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Aims/hypothesis Diabetic ketoacidosis (DKA) is often caused by concomitant systemic inflammation and lack of insulin. Here we used an experimental human model to test whether and how metabolic responses to insulin are impaired in the early phases of DKA with a specific focus on skeletal muscle metabolism. Methods Nine individuals with type 1 diabetes from a previously published cohort were investigated twice at Aarhus University Hospital using a 120 min infusion of insulin (3.0/1.5 mU kg) after an overnight fast under: (1) euglycaemic conditions (CTR) or (2) hyperglycaemic ketotic conditions (KET) induced by an i.v. bolus of lipopolysaccharide and 85% reduction in insulin dosage. The primary outcome was insulin resistance in skeletal muscle. Participants were randomly assigned to one of the two arms at the time of screening using www.randomizer.org. The study was not blinded. Results All nine volunteers completed the 2 days and are included in the analysis. Circulating concentrations of glucose and 3-hydroxybutyrate increased during KET (mean ± SEM 17.7 ± 0.6 mmol/l and 1.6 ± 0.2 mmol/l, respectively), then decreased after insulin treatment (6.6 ± 0.7 mmol/l and 0.1 ± 0.07 mmol/l, respectively). Prior to insulin infusion (KET vs CTR) isotopically determined endogenous glucose production rates were 17 ± 1.7 μmol kg (p = 0.77) and urea excretion rates were 16.9 ± 2.4 g/day vs 7.3 ± 1.7 g/day (p = 0.01). Insulin failed to stimulate forearm glucose uptake and glucose oxidation in KET compared with CTR (p < 0.05). Glycogen synthase phosphorylation was impaired in skeletal muscle. Conclusions/interpretation In KET, hyperglycaemia is primarily driven by increased endogenous glucose production. Insulin stimulation during early phases of DKA is associated with reduced glucose disposal in skeletal muscle, impaired glycogen synthase function and lower glucose oxidation. This underscores the presence of muscle insulin resistance in the pathogenesis of DKA.

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Section: Resultsmentioning

confidence: 51%

“…There was a 100-200-fold increase in TNF-α, IL-6 and IL-10 during KET [13]. The key metabolic variables from the preconditioning period are presented in Table 1.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolic effects of insulin in a human model of ketoacidosis combining exposure to lipopolysaccharide and insulin deficiency: a randomised, controlled, crossover study in individuals with type 1 diabetes

et al. 2017

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Substrate metabolism, hormone and cytokine levels and adipose tissue signalling in individuals with type 1 diabetes after insulin withdrawal and subsequent insulin therapy to model the initiating steps of ketoacidosis

et al. 2018

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Aims/hypothesis Lack of insulin and infection/inflammation are the two most common causes of diabetic ketoacidosis (DKA). We used insulin withdrawal followed by insulin administration as a clinical model to define effects on substrate metabolism and to test whether increased levels of counter-regulatory hormones and cytokines and altered adipose tissue signalling participate in the early phases of DKA. Methods Nine individuals with type 1 diabetes, without complications, were randomly studied twice, in a crossover design, for 5 h followed by 2.5 h high-dose insulin clamp: (1) insulin-controlled euglycaemia (control) and (2) after 14 h of insulin withdrawal in a university hospital setting. Results Insulin withdrawal increased levels of glucose (6.1 ± 0.5 vs 18.6 ± 0.5 mmol/l), NEFA, 3-OHB (127 ± 18 vs 1837 ± 298 μmol/l), glucagon, cortisol and growth hormone and decreased HCO 3 − and pH, without affecting catecholamine or cytokine levels. Whole-body energy expenditure, endogenous glucose production (1.55 ± 0.13 vs 2.70 ± 0.31 mg kg −1 min −1), glucose turnover, non-oxidative glucose disposal, lipid oxidation, palmitate flux (73 [range 39-104] vs 239 [151-474] μmol/min), protein oxidation and phenylalanine flux all increased, whereas glucose oxidation decreased. In adipose tissue, Ser473 phosphorylation of Akt and mRNA levels of G0S2 decreased, whereas CGI-58 (also known as ABHD5) mRNA increased. Protein levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase phosphorylations were unaltered. Insulin therapy decreased plasma glucose concentrations dramatically after insulin withdrawal, without any detectable effect on net forearm glucose uptake. Conclusions/interpretation Release of counter-regulatory hormones and overall increased catabolism, including lipolysis, are prominent features of preacidotic ketosis induced by insulin withdrawal, and dampening of Akt insulin signalling and transcriptional modulation of ATGL activity are involved. The lack of any increase in net forearm glucose uptake during insulin therapy after insulin withdrawal indicates muscle insulin resistance.

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SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes

Chen

Birnbaum

et al. 2021

Cardiovasc Drugs Ther

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Combined Insulin Deficiency and Endotoxin Exposure Stimulate Lipid Mobilization and Alter Adipose Tissue Signaling in an Experimental Model of Ketoacidosis in Subjects With Type 1 Diabetes: A Randomized Controlled Crossover Trial

Cited by 13 publications

References 25 publications

Metabolic effects of insulin in a human model of ketoacidosis combining exposure to lipopolysaccharide and insulin deficiency: a randomised, controlled, crossover study in individuals with type 1 diabetes

Metabolic effects of insulin in a human model of ketoacidosis combining exposure to lipopolysaccharide and insulin deficiency: a randomised, controlled, crossover study in individuals with type 1 diabetes

Substrate metabolism, hormone and cytokine levels and adipose tissue signalling in individuals with type 1 diabetes after insulin withdrawal and subsequent insulin therapy to model the initiating steps of ketoacidosis

SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes

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