Improved Afternoon Hepatic Glucose Disposal and Storage Requires Morning Engagement of Hepatic Insulin Receptors.

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 insulin's delivery route affects the second meal response.

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 insulin's delivery route affects the second meal response.

Duration of morning hyperinsulinemia determines 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 h 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.

Duration of Morning Hyperinsulinemia Determines 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.

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

Glucagon rapidly and profoundly stimulates hepatic glucose production (HGP), but for reasons that are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course of glucagon-mediated molecular events and their relevance to metabolic flux in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a sixfold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies.

A high-fat and fructose diet in dogs mirrors insulin resistance and β-cell dysfunction characteristic of impaired glucose tolerance in humans.

This study examined the impact of a hypercaloric high-fat high-fructose diet (HFFD) in dogs as a potential model for human impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). The HFFD not only led to weight gain but also triggered metabolic alterations akin to the precursors of human T2DM, notably insulin resistance and β-cell dysfunction. Following the HFFD intervention, the dogs exhibited a 50% decrease in insulin sensitivity within the first four weeks, paralleling observations in the progression from normal to IGT in humans.

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.

A physiologic increase in brain glucagon action alters the hepatic gluconeogenic/glycogenolytic ratio but not glucagon's overall effect on glucose production.

It has been proposed that brain glucagon action inhibits glucagon-stimulated hepatic glucose production (HGP), which may explain, at least in part, why glucagon's effect on HGP is transient. However, the pharmacologic off-target effects of glucagon in the brain may have been responsible for previously observed effects. Therefore, the aim of this study was to determine if central glucagon action plays a physiologic role in the regulation of HGP.

Profound Sensitivity of the Liver to the Direct Effect of Insulin Allows Peripheral Insulin Delivery to Normalize Hepatic but Not Muscle Glucose Uptake in the Healthy Dog.

Endogenous insulin secretion is a key regulator of postprandial hepatic glucose metabolism, but this process is dysregulated in diabetes. Subcutaneous insulin delivery alters normal insulin distribution, causing relative hepatic insulin deficiency and peripheral hyperinsulinemia, a major risk factor for metabolic disease. Our aim was to determine whether insulin's direct effect on the liver is preeminent even when insulin is given into a peripheral vein.

Importance of the route of insulin delivery to its control of glucose metabolism.

Pancreatic insulin secretion produces an insulin gradient at the liver compared with the rest of the body (approximately 3:1). This physiological distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding.

Liver glycogen-induced enhancements in hypoglycemic counterregulation require neuroglucopenia.

Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic control in patients with diabetes, in part due to dampened counterregulatory hormone responses. It has been demonstrated that elevated liver glycogen content can enhance these hormonal responses through signaling to the brain via afferent nerves, but the role that hypoglycemia in the brain plays in this liver glycogen effect remains unclear. During the first 4 h of each study, the liver glycogen content of dogs was increased by using an intraportal infusion of fructose to stimulate hepatic glucose uptake (HG; = 13), or glycogen was maintained near fasting levels with a saline infusion (NG; = 6).

Safety of surgical denervation of the common hepatic artery in insulin-resistant dogs.

The objective of this study was to assess the safety of surgical common hepatic artery denervation (CHADN). This procedure has previously been shown to improve glucose tolerance in dogs fed a high-fat high-fructose (HFHF) diet. We assessed the hypoglycemic response of dogs by infusing insulin at a constant rate (1.

The Importance of the Mechanisms by Which Insulin Regulates Meal-Associated Liver Glucose Uptake in the Dog.

Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein-to-arterial glucose gradient).

The kinetics of glucagon action on the liver during insulin-induced hypoglycemia.

Glucagon's effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones.

Aerobic exercise training improves hepatic and muscle insulin sensitivity, but reduces splanchnic glucose uptake in obese humans with type 2 diabetes.

Background: Aerobic exercise training is known to have beneficial effects on whole-body glucose metabolism in people with type 2 diabetes (T2D). The responses of the liver to such training are less well understood. The purpose of this study was to determine the effect of aerobic exercise training on splanchnic glucose uptake (SGU) and insulin-mediated suppression of endogenous glucose production (EGP) in obese subjects with T2D.

Effect of portal glucose sensing on incretin hormone secretion in a canine model.

It is unknown whether activation of hepato-portal vein (PV) glucose sensors plays a role in incretin hormone amplification of oral glucose-stimulated insulin secretion (GSIS). In previous studies, PV glucose infusion increased GSIS through unknown mechanisms, perhaps neural stimulation of pancreatic β-cells and/or stimulation of gut incretin hormone release. Thus, there could be a difference in the incretin effect when comparing GSIS with portal rather than leg vein (LV) glucose infusion.

Sympathetic Denervation of the Common Hepatic Artery Lessens Glucose Intolerance in the Fat- and Fructose-Fed Dog.

This study assessed the effectiveness of surgical sympathetic denervation of the common hepatic artery (CHADN) in improving glucose tolerance. CHADN eliminated norepinephrine content in the liver and partially decreased it in the pancreas and the upper gut. We assessed oral glucose tolerance at baseline and after 4 weeks of high-fat high-fructose (HFHF) feeding.

Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery.

Peripheral hyperinsulinemia resulting from subcutaneous insulin injection is associated with metabolic defects which include abnormal glucose metabolism. The first aim of this study was to quantify the impairments in liver and muscle glucose metabolism that occur when insulin is delivered via a peripheral vein compared to when it is given through its endogenous secretory route (the hepatic portal vein) in overnight fasted conscious dogs. The second aim was to determine if peripheral delivery of a hepato-preferential insulin analog could restore the physiologic response to insulin that occurs under meal feeding conditions.

Glucose autoregulation is the dominant component of the hormone-independent counterregulatory response to hypoglycemia in the conscious dog.

The contribution of hormone-independent counterregulatory signals in defense of insulin-induced hypoglycemia was determined in adrenalectomized, overnight-fasted conscious dogs receiving hepatic portal vein insulin infusions at a rate 20-fold basal. Either euglycemia was maintained () or hypoglycemia (≈45 mg/dl) was allowed to occur. There were three hypoglycemic groups: one in which hepatic autoregulation against hypoglycemia occurred in the absence of sympathetic nervous system input (), one in which autoregulation occurred in the presence of norepinephrine (NE) signaling to fat and muscle (), and one in which autoregulation occurred in the presence of NE signaling to fat, muscle, and liver ().

Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.

Insulin can inhibit hepatic glucose production (HGP) by acting directly on the liver as well as indirectly through effects on adipose tissue, pancreas, and brain. While insulin's indirect effects are indisputable, their physiologic role in the suppression of HGP seen in response to increased insulin secretion is not clear. Likewise, the mechanisms by which insulin suppresses lipolysis and pancreatic α cell secretion under physiologic circumstances are also debated.

Hepatic and Whole-Body Insulin Metabolism during Proestrus and Estrus in Mongrel Dogs.

Insulin resistance occurs during various stages of the estrus cycle in dogs. To quantify the effects of proestrus-estrus (PE) and determine whether PE affects liver insulin sensitivity, 11 female mongrel dogs were implanted with sampling and intraportal infusion catheters. Five of the dogs (PE group) entered proestrus after surgery; those remaining in anestrus were controls.

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis.

Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion.

Effects of Habitat Complexity on Pair-Housed Zebrafish.

Sexually mature zebrafish were housed as single male-female pairs with or without plastic vegetation for 1, 5, or 10 d for comparison of whole-body cortisol measured by radioimmunoassay. Individually housed male zebrafish were used as controls. In the fish that were pair-housed without vegetation (NVeg), one animal died in 5 of 24 pairs, and one animal was alive but wounded in an additional pair.

Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes.

Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal.