Vella, Adrian

In prediabetes, anthropometric characteristics as well as insulin action do not alter the hepatic response to glucagon. The postprandial suppression or lack of suppression of glucagon secretion is an important factor governing postprandial glucose tolerance independent of insulin secretion.

Abstract Context Insulinoma is a pancreatic neuroendocrine tumor that causes hyperinsulinemic hypoglycemia. Symptomatic hypoglycemia related to hepatic insulinoma metastases may be addressed with liver-directed therapies such as hepatic artery embolization. Objective This work aimed to determine the safety and effectiveness of bland hepatic artery embolization (HAE) for palliation of symptomatic hypoglycemia in patients with hepatic insulinoma metastases refractory to medical management. Methods An institutional review board–approved retrospective review was undertaken of all patients with a tissue (n = 18) or imaging (n = 2) diagnosis of hepatic insulinoma metastases and symptomatic hyperinsulinemic hypoglycemia refractory to medical management who underwent bland HAE at a single center between January 1, 1998 and November 1, 2020. Twenty patients (10 women, 10 men; mean age, 56 years; range, 18-84 years) were identified who individually underwent 1 (n = 7), 2 (n = 5), 3 (n = 5), 4 (n = 2), or 5 (n = 1) HAEs, for an overall total of 45 HAEs. Post-HAE hypoglycemia recurrence was defined as onset of adrenergic symptoms (eg, sweating, weakness, tremor), neuroglycopenic symptoms (eg, confusion, loss of consciousness), and/or documented serum glucose of less than 50 mg/dL, in the absence of an alternative explanation. Median time to first hypoglycemia recurrence, hypoglycemia-free survival (HFS), and overall survival (OS) were calculated using Kaplan-Meier method. Results Before HAE, all patients experienced adrenergic or neuroglycopenic symptoms alleviated by glucose intake, and 60% (n = 12) of patients had documented serum glucose of less than 50 mg/dL within 1 week of the first treatment. Median post-HAE follow-up was 9.4 months (mean, 26 months; range, 0.1-190 months). Postprocedural hypoglycemic symptom relief after the first HAE was reported in 100% (n = 20) of patients before discharge or at follow-up. Post-HAE hypoglycemia recurrence occurred in 60% (n = 12) of patients with a median time to first hypoglycemia recurrence of 2 months (mean, 14 months; range, 0.2-60 months). After the first HAE, median HFS was 14.5 months, and median OS was 16 months. One patient experienced labile postprocedure blood glucose levels requiring intensive care unit admission for intravenous dextrose. Otherwise, no major procedure-related complications occurred. Conclusion Bland HAE is a safe, effective, and repeatable procedure for palliation of symptomatic hypoglycemia in patients with hepatic insulinoma metastases refractory to medical management.

BACKGROUND Epidemiological cohorts can assist with post-marketing surveillance as they provide community-based outcomes data. Concern was raised about the adverse impact of sulfonylureas (SU) drugs on the outcome of diabetes after myocardial infarction (MI). We evaluated the outcome of MI according to treatment among diabetic persons compared to non-diabetic counterparts in a community-based cohort. METHODS All MIs that occurred in Olmsted County, MN between 1979 and 2002 were validated by standardized epidemiological including cardiac pain, biomarkers and ECG Minnesota coding. Diabetes mellitus (DM) was defined by the National Diabetes Data Group criteria. RESULTS Among 2732 persons with MI (mean age 70 ± 12 years, 44% men), 486 (18%) had DM. Subjects with DM were treated with second generation SU (SU2) (24%), insulin (47%) or diet alone (22%) Diabetic subjects were more likely to be overweight, hyperlipidemic and to receive reperfusion therapy during hospitalization than non-diabetic subjects. One year after the MI, 518 subjects died. Diabetic subjects taking SU2 experienced better survival than subjects without diabetes, while subjects treated with diet alone or insulin experienced worse survival. (Figure ). After adjusting for age, sex, reperfusion and duration of DM, an excess risk of death was detected among persons with insulin-treated DM, particularly those with long-standing DM. No association was found for DM patients treated with SU2 or diet. CONCLUSION These data do not support the concern for an adverse impact of SU2 on survival and underscore the potential role of community studies for population surveillance.

Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, and secretory parameters, such as pulse amplitude, time interval and frequency distribution, are impaired in obesity, aging and type 2 diabetes. In this review, we detail the mechanisms of insulin production and β-cell synchronization that regulate pulsatile insulin secretion, and we discuss the challenges to consider when measuring fast oscillatory secretion in vivo. These include the anatomical difficulties of measuring portal vein insulin noninvasively in humans before the hormone is extracted by the liver and quickly removed from the circulation. Peripheral concentrations of insulin or C-peptide, a peptide cosecreted with insulin, can be used to estimate their secretion profile, but mathematical deconvolution is required. Parametric and nonparametric approaches to the deconvolution problem are evaluated, alongside the assumptions and trade-offs required for their application in the quantification of unknown insulin secretory rates from known peripheral concentrations. Finally, we discuss the therapeutical implication of targeting impaired pulsatile secretion and its diagnostic value as an early indicator of β-cell stress.

Adipose inflammation is proposed to be at the nexus of the systemic inflammation and metabolic derangements associated with obesity. The present study provides evidence to support adipose inflammation as a central feature of the pathophysiology of obesity. Adipose inflammation is associated with systemic and peripheral metabolic derangements, including increased systemic inflammation, reduced insulin sensitivity and reduced skeletal muscle mitochondrial respiration.

Abstract Objective Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. Methods We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. Results In univariate analysis, basal insulin secretion (R2 = 0.16) and insulin pulse amplitude (R2 = 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. Conclusions Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.