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    • As glucagon stimulated hepatic glucose production is a key

    2021-09-02

    As glucagon-stimulated hepatic GSK2606414 mg production is a key component of the normal response to hypoglycemia, the potential of a GCGr antagonist to delay or prevent recovery from a hypoglycemic state is a critical safety issue that must be addressed. Studies of the effects on time to recovery from a hypoglycemic state have been reported for MK-0893 and LY2409021., , Time to recovery from a hypoglycemic clamp (blood glucose maintained at 50mg/dL for 30min) to blood glucose ⩾70mg/dL after single doses of MK-0893 was measured in healthy subjects. Doses of 200mg and 1g MK-0893 were associated with mean recovery times of 45.0min and 59.1min, respectively. Mean recovery time for placebo treatment was 33.3min. In a separate study, administration of single-dose 1g MK-0893 to type-2 diabetic patients also receiving the β-blocker propranolol (80mg b.i.d.) resulted in a mean recovery time (defined as time to blood glucose ⩾65mg/dL after discontinuation of a hypoglycemic clamp at 50mg/dL) of 103min. Mean recovery time in subjects receiving propranolol plus placebo was 71min. Similar mean recovery times to blood glucose ⩾63mg/dL from insulin-induced hypoglycemia (∼40mg/dL) in type-2 diabetics receiving either 90mg LY2409021 or placebo 12h prior to initiation of the hypoglycemic clamp were observed. Observed LS mean time to recovery in each treatment group was 65.87min for subjects receiving LY2409021 on a metformin background, 54.26min for placebo on a metformin background, 51.40min for LY2409021 without metformin background, and 52.65min for placebo without metformin background. Overall LS mean recovery time was 58.19min for subjects receiving LY2409021 and 53.45min for those receiving placebo. These data indicate the delay in recovery from a hypoglycemic state due to GCGr antagonism is minimal. While neither MK-0893 nor MK-3577 is currently listed in Merck’s development pipeline, clinical development of LY2409021 is ongoing, and other small-molecule GCGr antagonists are progressing in the clinic. In recently disclosed results from a phase 1 clinical study, administration of the small-molecule GCGr antagonist LGD-6972 (structure not disclosed) to healthy volunteers was associated with dose-dependent decreases in FPG 24h and 48h post-dose. In type-2 diabetic subjects, a single dose of 40mg LGD-6972 was associated with a 57mg/dL placebo-adjusted decrease in mean FPG 24h post-dose. Pfizer currently has small-molecule GCGr antagonist, PF-06291874 (structure not disclosed) listed in its phase 2 development pipeline. No clinical data concerning PF-06291874 has yet been disclosed.
    Introduction Glucagon responds to low blood glucose levels by stimulating hepatic glucose output. A key step in this process is that glucagon promotes the uptake and metabolism of amino acids in the liver. These amino acid metabolites are used as substrates in the process of gluconeogenesis to produce glucose. This is supported by the observation that small changes in basal glucagon levels in man cause plasma amino acid concentrations to change in the opposite direction (Boden et al., 1984). Glucagon has also been shown to stimulate amino acid transport in hepatocytes (Fehlman et al., 1979, Kelley et al., 1980, Mallet et al., 1969). Consistent with this, hyperglucagonemia promotes hepatic amino acid transport, metabolism, and conversion of degraded amino acids into glucose in humans (Boden et al., 1990). On the contrary, inhibition of glucagon signaling in humans reduces the expression of liver genes involved in the uptake and conversion of amino acids to metabolites available for gluconeogenesis and increases circulating amino acid levels (Charlton et al., 1996). This is supported by the observations that patients with glucagonoma have elevated plasma glucagon and hypoaminoacidemia (Mallinson et al., 1974, Boden et al., 1977) whereas totally pancreatectomized patients present hyperaminoacidemia. The latter could be normalized by infusion of glucagon (Boden et al., 1980, Muller et al., 1979). Finally, it is well established that hyperglucagonemia occurs in a variety of catabolic conditions, including trauma, burns, sepsis, cirrhosis, the postoperative state, and poorly controlled type 1 diabetes (Rocha et al., 1972, Wilmore et al., 1974, Meguid et al., 1978, McCullough et al., 1992, Russell et al., 1975). These data show that glucagon is a pivotal hormone in the control of amino acid disposal and blood glucose levels as discussed recently (Holst et al., 2017).