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

Abstract

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.

Metabolomics Profiling of Patients With A−β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis

“…With the exception of the three BCAAs, studies of plasma amino acid concentrations in patients during DKA compared with healthy control subjects have reported no difference in lysine, methionine, phenylalanine, and histidine and lower threonine and tryptophan concentrations (22)(23)(24)(25)28,29). Finally, no change in muscle protein balance has been demonstrated in experimental DKA in T1D patients (30). Together, these findings suggest that elevation of serum BCAA during DKA is due primarily to a marked decrease in BCAA catabolism rather than increased muscle protein breakdown.…”

Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use

“…This results in a favourable cardiovascular profile. In fact, in a randomised controlled trial in humans, the increase in ßOHB induced by lipopolysaccharide infusion was associated with a reduced cerebral glucose uptake and an increased cerebral blood flow, without a tangible effect on cerebral oxygen uptake [53]. Figure 2 illustrates the glucosesparing effect in the brain and in the liver, induced by the presence of ketone bodies.…”

Diabetic Ketoacidosis in adults: Part 1. Pathogenesis and diagnosis

“…[7] Hyperglycaemia, increased glucagon and increased levels of other counter-regulatory hormones such as adrenaline and cortisol all contribute to insulin resistance and decreased glucose uptake in skeletal muscles. [8]…”