Biology subjects

Edgerton, D. S.

Publications and source records attributed to Edgerton, D. S..

3 recordsLinked to original sources

bioRxiv2024

Morning Engagement of Hepatic Insulin Receptors Improves Afternoon Hepatic Glucose Disposal and Storage

Glucose tolerance improves significantly upon consuming a second, identical meal later in the day (second meal phenomenon). We previously established that morning hyperinsulinemia primes the liver for increased afternoon hepatic glucose uptake (HGU). Although the route of insulin delivery is an important determinant of the mechanisms by which insulin regulates liver glucose metabolism (direct hepatic vs indirect insulin action), it is not known if insulins delivery route affects the second meal response. To determine whether morning peripheral insulin delivery (as occurs clinically (subcutaneous)) can enhance afternoon HGU, conscious dogs were treated in the morning with insulin delivered via the portal vein, or peripherally (leg vein), while glucose was infused to maintain euglycemia. Consequently, arterial insulin levels increased similarly in both groups, but relative hepatic insulin deficiency occurred when insulin was delivered peripherally. In the afternoon, all animals were challenged with the same hyperinsulinemic-hyperglycemic clamp to simulate identical postprandial-like conditions. The substantial enhancement of HGU in the afternoon caused by morning portal vein insulin delivery was lost when insulin was delivered peripherally. This indicates that morning insulin does not cause the second meal phenomenon via its indirect actions on the liver, but rather through direct activation of hepatic insulin signaling. Article HighlightsO_LIMorning insulin delivery primes the liver for increased hepatic glucose uptake (HGU) later in the day, but the mechanism (direct hepatic and/or indirect insulin action) remains unclear. C_LIO_LIThis study compared insulin infusion via physiologic (hepatic portal vein) and clinical (peripheral) routes to assess their impact on afternoon hepatic glucose disposal. C_LIO_LIMorning peripheral insulin delivery failed to induce a significant enhancing effect on afternoon HGU and glycogen storage, unlike morning hepatic portal vein insulin delivery, which did. C_LIO_LIThese findings highlight the importance of achieving appropriate hepatic insulin exposure in the morning to effectively prime the liver for efficient glucose disposal. C_LI

physiology↗

bioRxiv2024

Duration of Morning Hyperinsulinemia is Key to the Enhancement of Hepatic Glucose Uptake and Glycogen Storage Later in the Day

The second meal phenomenon refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4 hours of morning hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic (HIHG) clamp. Our current aim was to determine if the duration or pattern of morning hyperinsulinemia is important for the afternoon response to a HIHG clamp. To determine this, we administered the same total amount of insulin either over 2h in the first (Ins2h-A) or second (Ins2h-B) half of the morning, or over the entire 4h (Ins4h) of the morning. In the 4h afternoon period, all three groups had 4x-basal insulin, 2x-basal glycemia, and portal glucose infusion to expose the liver to the primary postprandial regulators of hepatic glucose metabolism. During the afternoon clamp, there was a marked increase in HGU and hepatic glycogen synthesis in the Ins4h group compared to the Ins2h-A and Ins2h-B groups, despite matched hepatic glucose loads and total insulin infusion rates. Thus, the longer duration (Ins4h) of lower hyperinsulinemia in the morning seems to be the key to much greater liver glucose uptake during the afternoon clamp. New and noteworthyMorning insulin exposure primes the liver for increased hepatic glucose uptake and glycogen storage during a subsequent hyperinsulinemic-hyperglycemic clamp. This study addressed whether the pattern and/or duration of insulin delivery in the morning influences insulins ensuing priming effect. We found that despite receiving equal total doses of insulin in the morning, a prolonged, lower rate of morning insulin delivery improved afternoon liver glucose metabolism more effectively than a shorter, higher rate of delivery.

physiology↗

bioRxiv2023

Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog

Glucagon rapidly and profoundly simulates hepatic glucose production (HGP), but for reasons which are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course and relevance (to metabolic flux) of glucagon-mediated molecular events in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a 6-fold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group glucose remained at basal while in the other glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) but only partially sustained increase in hepatic cAMP over 4h, a continued elevation in G6P, and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis and HGP increased rapidly, peaking at 30 min, then returned to baseline over the next three hours (although glucagons stimulatory effect on HGP was sustained relative to the hyperglycemic control group). Hepatic gluconeogenic flux did not increase due to lack of glucagon effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, and downregulation of genes involved in extracellular matrix assembly and development.

physiology↗