NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion

Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Insulin secretion and action and the response of endogenous glucose production to a lack of glucagon suppression in non-diabetic subjects

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and Endogenous Glucose Production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 non-diabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (non-suppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to non-suppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action.

L-arabinose co-ingestion delays glucose absorption derived from sucrose in healthy men and women: a double-blind, randomized crossover trial

Dietary interventions to delay carbohydrate digestion or absorption can effectively prevent hyperglycemia in the early postprandial phase. L-arabinose can specifically inhibit sucrase. It remains to be assessed whether co-ingestion of L-arabinose with sucrose delays sucrose digestion, attenuates subsequent glucose absorption, and impacts hepatic glucose output. In this double-blind, randomized crossover study, we assessed blood glucose kinetics following ingestion of a 200-mL drink containing 50 g sucrose with 7.5 g L-arabinose (L-ARA) or without L-arabinose (CONT) in twelve young, healthy participants (24±1 y; BMI: 22.2±0.5 kg/m2). Plasma glucose kinetics were determined by a dual stable isotope methodology involving ingestion of [U-13C6]-glucose-enriched sucrose, and continuous intravenous infusion of [6,6-2H2]-glucose. Peak glucose concentrations reached 8.18±0.29 mmol/L for CONT 30 min after ingestion. In contrast, the postprandial rise in plasma glucose was attenuated for L-ARA, because peak glucose concentrations reached 6.62±0.18 mmol/L only 60 min after ingestion. The rate of exogenous glucose appearance for L-ARA was 67 and 57% lower compared with CONT at t = 15 min and 30 min, respectively, whereas it was 214% higher at t = 150 min, indicating a more stable absorption of exogenous glucose for L-ARA compared with CONT. Total glucose disappearance during the first hour was lower for L-ARA compared with CONT (11±1 versus 17±1 g, p<0.0001). Endogenous glucose production was not differentially affected at any time point (p=0.27). Co-ingestion of L-arabinose with sucrose delays sucrose digestion, resulting in a slower absorption of sucrose-derived glucose without causing adverse effects in young, healthy adults.

Acute effects of the food preservative propionic acid on glucose metabolism in humans

IntroductionPropionic acid (PA) is a common food preservative generally recognized as safe by the US Food and Drug Administration; however, exogenous PA has effects on glucose metabolism that are not fully understood. Our preclinical studies demonstrated exogenous PA increases glucagon, norepinephrine, and endogenous glucose production (EGP).Research design and methodsWe performed a randomized, placebo-controlled, crossover study in 28 healthy men and women to determine the effect of PA (1500 mg calcium propionate) on these factors. Subjects had two study visits, each preceded by a 1 week, PA-free diet. During each visit, glucose, insulin, glucagon, norepinephrine, epinephrine, and EGP were assessed for 2 hours after oral administration of PA/placebo under resting conditions (protocol 1) and during either a euglycemic (~85–90 mg/dL) or hypoglycemic (~65–70 mg/dL) hyperinsulinemic clamp (protocol 2).ResultsPA, as compared with placebo, significantly increased: (1) glucagon and norepinephrine during protocol 1; (2) glucagon, norepinephrine, and epinephrine under euglycemic conditions in protocol 2; and (3) norepinephrine, epinephrine, and EGP under hypoglycemic conditions in protocol 2.ConclusionOral consumption of PA leads to inappropriate activation of the insulin counterregulatory hormonal network. This inappropriate stimulation highlights PA as a potential metabolic disruptor.

Estimating Enhanced Endogenous Glucose Production in Intensive Care Unit Patients with Severe Insulin Resistance

Background: Critically ill ICU patients frequently experience acute insulin resistance and increased endogenous glucose production, manifesting as stress-induced hyperglycemia and hyperinsulinemia. STAR (Stochastic TARgeted) is a glycemic control protocol, which directly manages inter- and intra- patient variability using model-based insulin sensitivity (SI). The model behind STAR assumes a population constant for endogenous glucose production (EGP), which is not otherwise identifiable. Objective: This study analyses the effect of estimating EGP for ICU patients with very low SI (severe insulin resistance) and its impact on identified, model-based insulin sensitivity identification, modeling accuracy, and model-based glycemic clinical control. Methods: Using clinical data from 717 STAR patients in 3 independent cohorts (Hungary, New Zealand, and Malaysia), insulin sensitivity, time of insulin resistance, and EGP values are analyzed. A method is presented to estimate EGP in the presence of non-physiologically low SI. Performance is assessed via model accuracy. Results: Results show 22%-62% of patients experience 1+ episodes of severe insulin resistance, representing 0.87%-9.00% of hours. Episodes primarily occur in the first 24 h, matching clinical expectations. The Malaysian cohort is most affected. In this subset of hours, constant model-based EGP values can bias identified SI and increase blood glucose (BG) fitting error. Using the EGP estimation method presented in these constrained hours significantly reduced BG fitting errors. Conclusions: Patients early in ICU stay may have significantly increased EGP. Increasing modeled EGP in model-based glycemic control can improve control accuracy in these hours. The results provide new insight into the frequency and level of significantly increased EGP in critical illness.