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.

Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk.

Unlabelled: The risk of hypoglycemia and its serious medical sequelae restrict insulin replacement therapy for diabetes mellitus. Such adverse clinical impact has motivated development of diverse glucose-responsive technologies, including algorithm-controlled insulin pumps linked to continuous glucose monitors ("closed-loop systems") and glucose-sensing ("smart") insulins. These technologies seek to optimize glycemic control while minimizing hypoglycemic risk.

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.

In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins.

The glucose-responsive insulin (GRI) MK-2640 from Merck was a pioneer in its class to enter the clinical stage, having demonstrated promising responsiveness in in vitro and preclinical studies via a novel competitive clearance mechanism (CCM). The smaller pharmacokinetic response in humans motivates the development of new predictive, computational tools that can improve the design of therapeutics such as GRIs. Herein, we develop and use a new computational model, IMPACT, based on the intersection of human and animal model glucoregulatory systems, to investigate the clinical translatability of CCM GRIs based on existing preclinical and clinical data of MK-2640 and regular human insulin (RHI).

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.

100 years of glucagon and 100 more.

The peptide hormone glucagon, discovered in late 1922, is secreted from pancreatic alpha cells and is an essential regulator of metabolic homeostasis. This review summarises experiences since the discovery of glucagon regarding basic and clinical aspects of this hormone and speculations on the future directions for glucagon biology and glucagon-based therapies. The review was based on the international glucagon conference, entitled 'A hundred years with glucagon and a hundred more', held in Copenhagen, Denmark, in November 2022.

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.

Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin analog, as part of a basal-bolus regimen in type 2 diabetes: a randomized, active-controlled phase 2/3 study.

Background: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin.

Research Design And Methods: In this open-label, active-controlled trial, patients with T2D, HbA ≥7%-≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, = 30; 45 mg, = 31) and IAsp, = 30. Primary outcome was change from baseline (CFB) in HbA at week 24.

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.

COVID-19 Exacerbates Insulin Resistance During Diabetic Ketoacidosis in Pediatric Patients With Type 1 Diabetes.

Objective: Although mortality from coronavirus disease 2019 (COVID-19) among youth with type 1 diabetes is rare, severe acute respiratory syndrome coronavirus 2 is associated with increased pediatric hospitalizations for diabetic ketoacidosis (DKA). To clarify whether the relationship between COVID-19 and DKA is coincidental or causal, we compared tissue glucose disposal (TGD) during standardized treatment for DKA between pediatric patients with COVID-19 and those without COVID-19.

Research Design And Methods: We retrospectively compared TGD during standardized therapy for DKA in all children with preexisting type 1 diabetes with or without COVID-19.

A Gut-Centric Model of Metabolic Homeostasis.

Modern changes in diet and lifestyle have led to an explosion of insulin resistance and metabolic diseases around the globe which, if left unchecked, will become a principal driver of morbidity and mortality in the 21st century. The nature of the metabolic homeostatic shift within the body has therefore become a topic of considerable interest. While the gut has long been recognized as an acute nutrient sensor with signaling mechanisms to the other metabolic organs of the body, its role in regulating the body's metabolic status over longer periods of time has been underappreciated.

Insulin Infusion Is Linked to Increased Expression in Muscle and Plasma C-type Natriuretic Peptide in Male Dogs.

The purpose of this study was to assess insulin-stimulated gene expression in canine skeletal muscle with a particular focus on , the gene that encodes C-type natriuretic peptide, a key hormonal regulator of cardiometabolic function. Four conscious canines underwent hyperinsulinemic, euglycemic clamp studies. Skeletal muscle biopsy and arterial plasma samples were collected under basal and insulin-stimulated conditions.

C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions.

Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5 male/4 female). After a 2-hour basal period, an intravenous (IV) infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hours.

Voices: Insulin and beyond.

Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph.

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.

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).

Molecular engineering of safe and efficacious oral basal insulin.

Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure.

Bromocriptine mesylate improves glucose tolerance and disposal in a high-fat-fed canine model.

Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4 wk on HFD, daily bromocriptine (Bromo; = 6) or vehicle (CTR; = 5) injections were administered. Oral glucose tolerance tests were performed before beginning HFD (OGTT1), 4 wk after HFD began (Bromo only), and after 7.