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Viral infections are recognized as contributing factors in the pathogenesis of metabolic diseases. Viruses causing chronic infection are particularly important due to their capacity to induce sustained inflammation. Especially individuals with obesity - who exhibit preexisting metabolic abnormalities, low-grade inflammation, and altered antiviral responses - are at increased risk of viral infection-induced metabolic complications. Despite these associations, the specific metabolic consequences of chronic viral infections in obesity remain insufficiently characterized.

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Current Issue

Characterization of LY3324954 a long-acting glucagon-receptor agonist

William Roell, Tamer Coskun, Teayoun Kim, Libbey O’Farrell, ... Kirk M. Habegger

Characterization of LY3324954 a long-acting glucagon-receptor agonist

 

Objective

Glucagon is a crucial regulator of glucose and lipid metabolism as well as whole-body energy balance. Thus, modulation of glucagon receptor (GCGR) activity in the context of single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity and obesity-associated metabolic dysfunction. To better elucidate the role of GCGR-signaling when paired with incretin receptor signaling or on its own, we developed, LY3324954, a GCGR agonist with improved potency and selectivity as compared to the native glucagon peptide.

Methods

LY3324954 was administered to DIO mice, rats, dogs, and monkeys to evaluate pharmacokinetic (PK) profile. Biweekly treatments were conducted in lean and DIO mice to characterize LY3324954-effects on glucose homeostasis and energy balance. Single dose studies were also conducted in liver Gcgr-deficient mice to establish receptor specificity.

Results

LY3324954 also exhibited extended PK profile in DIO mice, rats, dogs, and monkeys. When administered every 72 h, LY3324954 treatment stimulated transient glucose and insulin excursions in lean mice. In diet-induced obese mice, LY3324954 treatment stimulates energy expenditure, weight loss, and a reduction of adiposity in a dose-dependent manner. Benefit to whole-body lipid homeostasis was likewise observed in these mice.

Conclusions

Taken together, these studies characterize a long-acting and potent GCGR-agonist and its regulation of glucose and lipid metabolism as well as whole-body energy balance following both acute and chronic treatment in mice.

 

 

Articles in Press

Characterization of LY3324954 a long-acting glucagon-receptor agonist

William Roell, Tamer Coskun, Teayoun Kim, Libbey O’Farrell, ... Kirk M. Habegger

Characterization of LY3324954 a long-acting glucagon-receptor agonist

 

Objective

Glucagon is a crucial regulator of glucose and lipid metabolism as well as whole-body energy balance. Thus, modulation of glucagon receptor (GCGR) activity in the context of single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity and obesity-associated metabolic dysfunction. To better elucidate the role of GCGR-signaling when paired with incretin receptor signaling or on its own, we developed, LY3324954, a GCGR agonist with improved potency and selectivity as compared to the native glucagon peptide.

Methods

LY3324954 was administered to DIO mice, rats, dogs, and monkeys to evaluate pharmacokinetic (PK) profile. Biweekly treatments were conducted in lean and DIO mice to characterize LY3324954-effects on glucose homeostasis and energy balance. Single dose studies were also conducted in liver Gcgr-deficient mice to establish receptor specificity.

Results

LY3324954 also exhibited extended PK profile in DIO mice, rats, dogs, and monkeys. When administered every 72 h, LY3324954 treatment stimulated transient glucose and insulin excursions in lean mice. In diet-induced obese mice, LY3324954 treatment stimulates energy expenditure, weight loss, and a reduction of adiposity in a dose-dependent manner. Benefit to whole-body lipid homeostasis was likewise observed in these mice.

Conclusions

Taken together, these studies characterize a long-acting and potent GCGR-agonist and its regulation of glucose and lipid metabolism as well as whole-body energy balance following both acute and chronic treatment in mice.

 

 

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13th
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You are what you eat

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