Effects of acute changes in fasting glucose and free fatty acid concentrations on indices of ß-cell function and glucose metabolism in subjects without diabetes.

Elevated fasting free fatty acids (FFAs) and fasting glucose are additively associated with impaired glucose tolerance (IGT) and decreased ß-cell function [quantified as disposition index (DI)]. We sought to examine how changes in fasting FFA and glucose alter islet function. We studied 10 subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT) on two occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG/IGT. In addition, we studied seven subjects with IFG/IGT on two occasions. On one occasion, insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG/NGT. The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and ß-cell function. Elevation of overnight fasting FFA and glucose in NFG/NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 h, Saline vs. Intralipid/glucose, P = 0.55). Although overall ß-cell function quantified by the Disposition Index was unchanged, the dynamic component of ß-cell responsivity (ϕd) was decreased by Intralipid and glucose infusion (9 ± 1 vs. 16 ± 3 10-9, P = 0.02). In people with IFG/IGT, insulin did not alter postprandial glucose concentrations or indices of ß-cell function. Endogenous glucose production and glucose disappearance were also unchanged in both groups. We conclude that acute, overnight changes in FFA, and glucose concentrations do not alter islet function or glucose metabolism in prediabetes.NEW & NOTEWORTHY This experiment studied the effect of changes in overnight concentrations of free fatty acids (FFAs) and glucose on ß-cell function and glucose metabolism. In response to elevation of these metabolites, the dynamic component of the ß-cell response to glucose was impaired. This suggests that in health overnight hyperglycemia and FFA elevation can deplete preformed insulin granules in the ß-cell.

Improving Intravenous and Subcutaneous Insulin Overlap During Treatment of Diabetic Ketoacidosis: A Quality Improvement Project.

Objective: To reduce the frequency of insufficient overlap of intravenous (IV) and subcutaneous (SC) insulin during the treatment of diabetic ketoacidosis (DKA) as a quality improvement project. Patients and Methods: Rates of insufficient IV and SC insulin overlap (< 2-hour overlap, SC insulin given after IV insulin discontinuation, or no SC insulin given after IV insulin discontinuation) were assessed in adults with DKA treated with IV insulin at a large tertiary care referral center in Rochester, Minnesota, from July 1, 2021, to March 15, 2023. After a preintervention analysis period, an electronic medical record-based best practice advisory was introduced to notify hospital providers discontinuing IV insulin if SC long-acting insulin had not been given in the previous 2-6 hours. Demographic characteristics and clinical outcomes before and after intervention were compared. Results: A total of 352 patient encounters were included (251 in the preintervention phase and 101 in the postintervention phase). The rate of insufficient IV to SC insulin overlap decreased from (88 of 251) 35.1% before intervention to (20 of 101) 19.8% after intervention (P=.005). The rate of posttransition hypoglycemia (<70 mg/dL; to convert to mmol/L, multiply by 0.0259) decreased from (27 of 251) 10.7% to (4 of 101) 4% after intervention (P=.04). Rates of posttransition hyperglycemia (>250 mg/dL), rebound DKA, length of hospital stay, and duration of IV insulin therapy were similar before and after intervention. Conclusion: Using quality improvement methodology, the rates of insufficient IV to SC insulin overlap during treatment of DKA in a large tertiary care referral center were measured and reduced through an electronic medical record-based best practice advisory targeting hospital providers.

The Effect of Glucagon-Like Peptide 1 Receptor Blockade on Glucagon-Induced Stimulation of Insulin Secretion.

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signaling through the glucagon-like peptide 1 receptor (GLP-1R) present on ß-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied individuals without diabetes in two separate experiments. Each subject was studied on two occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4 ng/kg/min, increasing by 0.2 ng/kg/min every hour for 5 h. On one day, exendin-9,39 (300 pmol/kg/min) was infused to block GLP-1R, while on the other, saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production and glucose disappearance were measured using the tracer-dilution technique. Glucagon concentrations, by design, did not differ between study days. Integrated ISR was lower during exendin-9,39 infusion (213 ± 26 vs. 191 ± 22 nmol/5 h, saline vs. exendin-9,39, respectively; P = 0.02). In the separate experiment, exendin-9,39 infusion, compared with saline infusion, also decreased the ß-cell secretory response to a 1-mg glucagon bolus. These data show that, in humans without diabetes, glucagon partially stimulates the ß-cell through GLP-1R.

Glucagon-like peptide-1 receptor blockade impairs islet secretion and glucose metabolism in humans.

BACKGROUNDProglucagon can be processed to glucagon-like peptide1 (GLP-1) within the islet, but its contribution to islet function in humans remains unknown. We sought to understand whether pancreatic GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes.METHODSWe therefore studied individuals with and without type 2 diabetes on two occasions in random order. On one occasion, exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other, saline was infused. The tracer dilution technique ([3-3H] glucose) was used to measure glucose turnover during fasting and during a hyperglycemic clamp.RESULTSExendin 9-39 increased fasting glucose concentrations; fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed. In people with type 2 diabetes, fasting glucagon concentrations were markedly elevated and persisted despite hyperglycemia. This impaired suppression of endogenous glucose production by hyperglycemia.CONCLUSIONThese data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes.TRIAL REGISTRATIONThis study was registered at ClinicalTrials.gov NCT04466618.FUNDINGThe study was primarily funded by NIH NIDDK DK126206. AV is supported by DK78646, DK116231 and DK126206. CDM was supported by MIUR (Italian Minister for Education) under the initiative "Departments of Excellence" (Law 232/2016).