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Review
. 2022 May;10(9):e15263.
doi: 10.14814/phy2.15263.

Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty

Robert L Rodgers  1
Affiliations
Review

Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty

Robert L Rodgers. Physiol Rep. 2022 May.

Abstract

For at least 50 years, the prevailing view has been that the adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A pathway is the predominant signal mediating the hepatic glucose-mobilizing actions of glucagon. A wealth of evidence, however, supports the alternative, that the operative signal most of the time is the phospholipase C (PLC)/inositol-phosphate (IP3)/calcium/calmodulin pathway. The evidence can be summarized as follows: (1) The consensus threshold glucagon concentration for activating AC ex vivo is 100 pM, but the statistical hepatic portal plasma glucagon concentration range, measured by RIA, is between 28 and 60 pM; (2) Within that physiological concentration range, glucagon stimulates the PLC/IP3 pathway and robustly increases glucose output without affecting the AC/cAMP pathway; (3) Activation of a latent, amplified AC/cAMP pathway at concentrations below 60 pM is very unlikely; and (4) Activation of the PLC/IP3 pathway at physiological concentrations produces intracellular effects that are similar to those produced by activation of the AC/cAMP pathway at concentrations above 100 pM, including elevated intracellular calcium and altered activities and expressions of key enzymes involved in glycogenolysis, gluconeogenesis, and glycogen synthesis. Under metabolically stressful conditions, as in the early neonate or exercising adult, plasma glucagon concentrations often exceed 100 pM, recruiting the AC/cAMP pathway and enhancing the activation of PLC/IP3 pathway to boost glucose output, adaptively meeting the elevated systemic glucose demand. Whether the AC/cAMP pathway is consistently activated in starvation or diabetes is not clear. Because the importance of glucagon in the pathogenesis of diabetes is becoming increasingly evident, it is even more urgent now to resolve lingering uncertainties and definitively establish glucagon's true mechanism of glycemia regulation in health and disease.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Distribution of hepatic portal plasma glucagon concentrations (pM) in fed or fasted humans, dogs, rats, and miniature pigs, measured by radioimmunoassay (RIA). Durations of fasting or starvation were 12–48 h. The 36 values are means determined by RIA between 1976 and 2017. Plasma samples were obtained from fed, fasted, starved, conscious, or anesthetized animals. Twenty of the 36 mean values were obtained using “Unger’s 30K antibody”, with most of the remainder using commercial RIA kits. Statistical values: Composite mean = 43.9 pM; SD = 19.8; SEM =3.3; and the 99.9999% confidence interval =16.1, for a statistical range of 27.8 – 60.0 pM. There were no obvious correlations between plasma concentration and species, nutritional state, or RIA method. Note that all 36 values are below the consensus TC of 100 pM for activating AC (see Figure 4). The 36 sources were: Kraft et al. (2017), Lewis et al. (1997), Saccà et al., (1979) and Vaitkus et al., (1984), (10–19); Berger et al. (1994), Blommaart et al. (1995), Curnow et al. (1976), Fries et al. (1982), Hickman et al. (1992), Imai et al. (2003) and Wasserman et al. (1993) (20–29); Androgué et al. (1985), Baumann et al. (1981), Cersosimo et al. (1989), Rao (1995) and Sherwin et al. (1977) (30–39); Francavilla et al. (1980), Holst et al. (1980), Langhans et al. (1984) and Müller et al. (1984) (40–49); Demigné et al. (1985), Goldstein and Curnow (1978), Horikawa et al. (1998), Jaspan et al. (1984), Silva et al. (1990) and Wolf and Eisenstein (1981), (50–59); Balks and Jungermann (1984), Gannon and Nuttall (1993), Ishida et al. (1981), Kinoshita et al. (1985), McLeod et al. (1983), Rabouti et al. (1989) and Silva et al. (1990) (60–69); Hussein et al. (1986), Latour et al. (1999) and Okuda et al. (1994) (70–79)
FIGURE 2
FIGURE 2
Plasma glucagon concentrations as measured by radioimmunoassay (RIA). Mean values ±SEM are grouped by species (a), vascular bed (b), and conditions (c and d), gathered from a large sampling published between 1969 and 2020. (a) Mean peripheral venous plasma concentrations in fed and short‐term fasting (less than 24 h) adult humans (H), dogs (D), rats (R), and mice (M). When fasted, the durations were 8–12 hours in humans, 13–24 h in dogs, 12–16 h in rats, and 14–16 h in mice. (b) Plasma levels in hepatic portal (HP; see Figure 1), peripheral venous (PV), and arterial (AR) circulations. The mean values in the peripheral venous and arterial circulations are 67% and 32%, respectively, of those in the hepatic portal plasma. (c) Mean peripheral venous plasma glucagon levels in type 1 diabetes (T1D; STZ‐ or alloxan‐induced diabetes in mice and rats), type 2 diabetes or obesity with insulin resistance in humans (T2D), and in starvation (S) of more than 24 h. Durations of starvation were 2.25–6 days in rats and 3–7 days in humans. (d) Mean peripheral venous plasma glucagon levels in neonates (N) and exercising adults (E). The ages of neonates ranged between newborn and 4 days in humans (n = 5) and between newborn and 14 days in mice and rats (n = 8). Durations of exercise in rats, dogs, and humans varied from 1 h to exhaustion. The numbers in parentheses indicate the number of publications from which the data were averaged. Data from some references applied to more than one grouping. Plasma concentrations are divided here into four zones based on RIA estimates: Zone 1 (normal physiological) between 0 and 60 pM, spanning the statistical range of mean glucagon concentrations of normal, unstressed adult mammals (Figure 1); Zone 2 (transitional) between 60 and 100 pM, the upper limit of which is the consensus TC for activating AC in dose‐response curves generated ex vivo (see text and Figure 4); Zone 3 (physiological hyperglucagonemia) between 100 and 800 pM, includes the highest mean plasma glucagon concentration in neonates (600 pM) (Blommaart et al., 1995) or exercising adults (732 pM) (Seitz et al., 1999) among the references cited here; and Zone 4 (pharmacological) between 800 and 1,000,000 pM, the highest glucagon concentration reported to maximally activate AC in dose‐response curves generated ex vivo (see text and Figure 4). One value in B (PV) was obtained by ELISA instead of RIA (Hussein et al., 1986). The data were compiled from the following references: A (Species)–Humans (H): Bolli et al. (1984), Borghi et al. (1984), Brodows (1985), Evans et al. (2004), Fujita et al. (1975), Gosmanov et al. (2005), Hamaguchi et al. (1991), Hansen et al. (1982), Heise et al. (2004), (2004), Henkel et al. (2005), Jaspan et al. (1984), Kalkhoff et al. (1973), Livingston et al. (1985), Okba et al. (2020), Petersen and Sullivan (2001), Porcellati et al. (2003), Raju and Cryer (2005), Sherwin et al. (2005), Tasaka et al. (1980), Verillo et al. (1988); Dogs (D): Cersosimo et al.(1998), Coker, Koyama, Brooks, et al. (1999), Kraft et al. (2017), Ishida et al. (1983), Moore et al. (2014), Sherck et al. (2001), Sindelar et al. (1998), and Vaitkus et al. (1984); Rats (R): Balks and Jungermann (1984), Charbonneau et al. (2005), Langhans et al. (1984), Latour et al. (1999), Mayor and Calle, (1988), Omer et al. (2004), Powell et al. (1993), Ruiter et al. (2003), Unger (1985), Widmaier et al. (1991) and Winzell et al. (2007), Mice (M): Green et al. (2016), Karlsson et al. (2002), Marty et al. (2005), Parker et al. (2002), Perry et al. (2020), Winzell et al. (2007) and Zhang et al. (2018) B (Vascular Bed) ‐ Hepatic Portal (HP): See legend, Figure 1, Peripheral Venous (PV): Balks and Jungermann (1984), Bolli et al. (1984), Cersosimo et al. (1998), Charbonneau et al. (2005), Coker, Koyama, Brooks, et al. (1999), Hamaguchi et al. (1991), Hansen et al. (1982), Heise et al. (2004), Henkel et al. (2005), Ichikawa et al. (2019), Ishida et al. (1981), Jaspan et al. (1984), Karlsson et al. (2002), Langhans et al. (1984), Latour et al. (1999), Livingston et al. (1985), Marty et al. (2005), Mayor and Calle (1988), Nair et al. (1987), Omer et al. (2004), Parker et al. (2002), Perry et al. (2020), Powell et al. (1993), Raju and Cryer (2005), Shi et al. (1996), Wall et al. (2005) and Winder, Arogyasami, et al. (1988), Arterial (AR): Balks and Jungermann, (1984), Carlson and Winder (1999), Coker, Koyama, Brooks, et al. (1999), Jackson et al. (2004), Moore et al. (2014), Patel (1984), Pencek et al. (2004) and Sherck et al. (2001), C (Diabetes or Starvation) ‐Type 1 Diabetes (T1D): Chamras et al. (1980), Green et al. (2016), Hermida et al. (1994), Mayor and Calle (1988), Meek et al. (2015), Patel (1984), Shi et al. (1996), Srikant et al. (1977), Walsh and Dunbar (1984), Widmaier et al. (1991), Yamashita et al. (1980) and Zhang et al. (2018), Type 2 Diabetes (T2D): Bolli et al. (1984), Borghi et al. (1984), Hamaguchi et al. (1991), Henkel et al. (2005), Knop et al. (2005), Marliss et al. (1970), Nair et al. (1970); Starvation: Aguilar‐Parada et al. (1969), Bois‐Joyeux et al. (1986), Brodows (1985), Goldstein et al. (1978b), Hamaguchi et al. (1991), Henkel et al. (2005), Knop et al. (2007), Marliss et al. (1970), Mlekusch et al. (1981), Nair et al. (1987), Seitz et al. (1976), Smadja et al. (1990), Srikant et al. (1977), Verrillo et al. (1988), D (Neonates or Exercising Adults) ‐ Neonates (N): Blommaart et al. (1995), Fernández‐Milán et al. (2013), Girard et al. (1973), Luyckx et al. (1972), Lyonnet et al. (1988), Milner et al. (1972), Movassat et al. (1997), Nurjhan et al. (1985), Ogata et al. (1988), Salle and Ruiton‐Ugliengo (1977) and Sperling et al. (1974), Exercise (E): Carlson and Winder (1999), Charbonneau et al. (2005), Coker, Koyama, Lacy, et al. (1999), Latour et al. (1999), Sellers et al. (1988), Winder, Arogyasami, et al. (1988), Winder et al. (1981) and Winder, Yang, et al. (1988)
FIGURE 3
FIGURE 3
Comparison of plasma glucagon concentrations measured by RIA, double‐antibody sandwich enzyme‐linked immunosorbent assay (ELISA), and liquid chromatography/mass spectrometry (LC/MS). Values were obtained from peripheral venous blood samples taken from 13 healthy human volunteers. The authors included sitagliptin, an inhibitor of dipeptidyl peptidase‐4, in their assay solution, a precaution not always taken. They did not specify whether they assayed fresh or frozen‐thawed samples. Notably, the mean values as assessed by ELISA and LC/MS were 50% and 33%, respectively, of those measured by RIA. The figure is adapted from Miyachi et al. (2017). The data clearly reveal the profound influence of assay technique on estimates of plasma glucagon concentrations
FIGURE 4
FIGURE 4
Glucagon concentrations required to stimulate glucose mobilization compared to those required to activate the PLC/IP3 and AC/cAMP pathways. The shaded vertical bar is the statistical range of mean glucagon concentrations, determined by RIA, in the hepatic portal system of humans, rats, dogs, and pigs, 27.8–60.0 (101.44–101.78) pM, with a mean (dotted line) of 43.9 pM (101.64) pM (see Figure 1). The glucose mobilization curve (glucose output, glycogenolysis, or gluconeogenesis) is a composite of 11 dose‐response curves published between 1971 and 1999 (Bizeau and Hazel (1999), Cárdenas‐Tanús et al. (1982), Chan et al. (1979), Corvera and García‐Sáinz (1984), Exton, Lewis, et al. (1971), Felíu et al. (1976), Fleig et al. (1984), Hermsdorf et al. (1989), Ikezawa et al. (1998), Khan et al. (1980) and Wernette Hammond and Lardy (1985)), determined in rat hepatocytes or isolated perfused rat livers. The composite AC/cAMP curve is the average of 15 individual curves generated in rat hepatocytes, liver membranes, or cell lysates (Clark and Jarrett (1978), Corvera and García‐Sáinz (1984), Dich and Gluud (1976), Dighe et al. (1984), England et al. (1983), Exton, Robison, et al. (1971), Hermsdorf et al. (1989), Lynch et al. (1989), Pohl et al. (1972), Robberecht et al. (1988), Rodbell et al. (1971), Soman and Felig (1978), Sonne et al. (1978), Unson et al. (1989) and Yagami (1995)). The inositol‐phosphate data are from Wakelam et al. (1986) (filled triangles) and Unson et al. (1989) (open triangles). The bar below the X axis indicates the four concentration zones as depicted in Figure 2. Glucagon clearly activates the PLC/IP3 pathway in zones 1–4. However, in vivo it does not activate AC in zone 1, inconsistently activates it in zone 2 (see text), and predictably activates AC in zones 3 and 4. The TC for activating AC ex vivo,100 pM, is 2.5 times greater than the aggregate mean hepatic portal plasma concentration of 44 pM, and 100‐fold greater than the 10 pM TC for increasing glucose mobilization. The data clearly show that a substantial fraction of the maximum stimulation of hepatic glucose mobilization, around 40%, is produced by glucagon at physiological (zone 1) concentrations and mediated exclusively by the PLC/IP3 pathway. An additional 35%, generated by supraphysiological, zone 3 concentrations, is mediated by maximal activation of the PLC/IP3 pathway together with a submaximal activation AC/cAMP pathway. The resulting boost in glucose output within zone 3 may be an adaptive response to elevated systemic glucose demand in vivo (see text)
FIGURE 5
FIGURE 5
Comparisons of glucagon concentration‐effect curves, generated in rat hepatocyte preparations, for selected components and targets of the PLC/IP3 pathway. (a) glycogen phosphorylase (GPase) activity and intracellular calcium levels (Ca2+ i); (b) fructose‐1,6‐bisphosphatase (F‐1,6‐BP) activity and phosphorylation; (c) phosphoenolpyruvate carboxykinase (PEPCK) activity and gluconeogenesis; and (d) activities of pyruvate kinase (PyrK) and glycogen synthase (GS). The shaded vertical bars represent the statistical range of plasma glucagon concentrations in the hepatic portal system (see legends of Figures 1 and 4). At the upper limit, mediated exclusively by the PLC/IP3 pathway, glucagon increased Ca2+i 68% and GPase activity 93% (a), F‐1,6‐BPase activity 87% and its phosphorylation 53% (b), and PEPCK expression (activity) 94% and gluconeogenesis 57% (c) of the maximum response produced by higher concentrations. It also decreased PyrK activity by 37% and GS activity by 19% (d). Effects produced by concentrations above 100 pM are mediated by the activation of both the PLC/IP3 and AC/cAMP pathways simultaneously. The data are adapted from Aggarwal et al. (1995), Ekdahl and Ekman (1987), Fleig et al. (1984), Marks and Parker Botelho, (1986) and Staddon and Hansford (1989). See also El‐Maghrabi et al. (1982), Felíu et al. (1976), Ikezawa et al. (1998) and Studer et al. (1984). The data are consistent with the hypothesis that glucagon, at physiological concentrations, exerts substantial effects on intracellular targets involved in glucose mobilization by activating the PLC/IP3 pathway without activating the AC/cAMP pathway
FIGURE 6
FIGURE 6
Hepatic PEPCK activity (a) and G6P activity (b) of fed or fasted (24 h) wild‐type mice (open and shaded bars) and mice with liver‐specific inhibition of PKA (cross‐hatched bars). The mutation suppressed basal cellular PKA activity by approximately 55%. The data show that substantial inhibition of hepatic PKA activity had no effect on fasting‐induced stimulation of hepatic PEPCK or G6Pase activity. The results are consistent with the hypothesis that fasting increases expressions and activities of PEPCK and G6Pase activity by activating the PLC/IP3/CaM pathway without activating the AC/cAMP pathway. However, alternative interpretations are possible because the mutation did not result in complete inhibition of PKA activity (see text). The data are from Willis et al. (2011). Note also that PKA inhibition substantially decreased constitutive (basal) expressions of PEPCK and G6Pase, suggesting that basal AC/cAMP activity is involved in regulating hepatic glucose mobilization in the absence of the activation of the pathway by glucagon.
FIGURE 7
FIGURE 7
Variable effects of STZ‐induced diabetes in vivo on the concentration‐dependent stimulation of adenylate cyclase (AC) by glucagon in rat hepatocyte membrane preparations. The data are expressed as the % of the maximum produced by the nondiabetic (ND) control group. Diabetes either (a) enhanced Lynch et al. (1989); (b) suppressed Dighe et al. (1984); or (c) had no effect on Srikant et al. (1977) the activation of AC by glucagon. The doses of STZ were 100 mg/kg (a and b) or 65 mg/kg (c), and the durations of diabetes were 3 days (a) or 5 days (b and c). Note that diabetes had no effect on the sensitivity to glucagon, that is, on the TC required to activate AC (estimated to be 300 pM in a and b, and 100 pM in c), regardless of its attendant effect on the magnitude or direction of the response to increasing concentrations of glucagon but see Walsh & Dunbar, (1984). However, influences of co‐regulators such as insulin or corticosteroids, at least in STZ‐induced diabetes, may variably affect sensitivity to AC‐activating effects of glucagon in vivo (see text). For additional examples in each category, see (Allgayer et al. (; Soman & Felig, (1978); Walsh & Dunbar, (1984) (increased responsiveness); Chamras et al. (1980) and Yamashita et al. (1980) (decreased responsiveness); and Pilkis et al. (1974) (no effect on responsiveness). These results highlight the uncertainties with regard to the effects of T1D on the relationship between glucagon concentrations and the activation of AC/cAMP
FIGURE 8
FIGURE 8
Variable effects of starvation on plasma glucagon and hepatic tissue cAMP levels or AC activity in rats. Depending on the study (see Table 4B), starvation was reported to increase both plasma glucagon and tissue cAMP levels (a), increase plasma glucagon but decrease hepatic AC activity (b), or have no effect on either plasma glucagon or tissue cAMP levels (c). The peak plasma glucagon levels in A and B are 56 and 57 pM, within zone 1 (Figure 2). The durations of starvation were 2 days (a), 6 days (b) and 3 days (c). The results highlight the uncertainty regarding the effect of starvation on the relationship between plasma glucagon and hepatic tissue cAMP levels or AC activity. Adapted from Seitz et al. (1976) (a), Srikant et al. (1977) (b), and Goldstein et al. (1978b) (c)
FIGURE 9
FIGURE 9
Comparison of the concentration‐dependent effects of glucagon on cAMP levels in neonatal and adult rat hepatocytes, adapted from Beaudry et al. (1977). (a) The data are expressed as reported, in relative terms (% of basal). (b) The same data when converted here to absolute levels (pmoles/mg wet wt.). The shaded bar depicts the full hepatic portal glucagon concentration in the adult from Figure 1, and the crosshatched bar corresponds to the range of peripheral venous plasma glucagon concentrations from just after birth to 16 h after birth (Girard et al., ; Sperling et al., 1974). The latter was adjusted to estimate the hepatic portal plasma concentration range according to the hepatic portal/peripheral venous ratio of 1.49 as depicted in Figure 2B. Note that the responsiveness to glucagon appears to be depressed in the neonate when expressed in relative terms (A), but that both basal and glucagon‐stimulated cAMP levels are revealed to be elevated in neonatal hepatocytes when expressed in absolute terms (B). The results in B are consistent with the view that both the constitutive and glucagon‐stimulated AC/cAMP pathway are adaptively enhanced in the neonate (see text)
FIGURE 10
FIGURE 10
Effects of acute dexamethasone administration ex vivo (a) or prior adrenalectomy (b and c) on glucagon concentration‐dependent increases in cAMP generation (a, b), or phosphorylase a (GPase) activity (c) in rat hepatocytes. Administration of dexamethasone “sensitized” the hepatocytes by increasing the maximal response, but did not alter the TC of 630 (102.80) pM (a). Adrenalectomy in vivo had no effect ex vivo on glucagon‐induced increases in cellular cAMP (b) or PKA activity (not shown). However, adrenalectomy did inhibit the stimulation by glucagon of GPase activity (c) and glucose output (not shown). Note that, in the sham‐operated or untreated group, a concentration of 60 (101.78) pM near‐maximally activated GPase (c), but had minimal effects on tissue cAMP levels (a and b). These results suggest that the “sensitizing” effects of exogenous corticosteroids are apparent ex vivo, but may not be consistently induced by endogenous corticosteroids in vivo (see Figures 7 and 8). As a control, endogenous corticosteroids do seem to contribute to the stimulation of phosphorylase activity by zone 1 and zone 2 concentrations of glucagon in vivo (c). Adapted from references Christoffersen et al. (1984) (a) and Chan et al. (1979) (b and c)
FIGURE 11
FIGURE 11
Presumptive model of intracellular events in response to activation of GR1 receptors and phospholipase C (PLC) by glucagon in hepatocytes. Many of the targets of CaMKs depicted here are also targets of PKA, activated by supraphysiological or pharmacological concentrations (see text). The Kd value of 80 pM for the purified receptor is from Andersson et al. (1993). The model for nuclear translocation of CaMKII and its interactions with CaMKK and CaMKIV in the nucleus is from Cohen S et al., 2015 for neurons, and for Fox01 translocation is from Ozcan et al. (2012) for hepatocytes. Possible involvement of AMPK in this model is not firmly established (see text), and therefore is not shown. CaM, calmodulin; CaMKII and IV, calmodulin‐dependent protein kinase II and IV; CBP, CREB‐binding protein; CRE, cyclic adenosine monophosphate response element; CREB, cyclic adenosine monophosphate response element binding protein; CRTC2, CREB transcriptional coactivator 2 (aka TORC2); ER, endoplasmic reticulum; Fox01, forkhead box 01; GR1, glucagon receptor type 1; HDAC5, histone deacetylase 5; IP3, inositol triphosphate; IP3R, inositol triphosphate receptor; IRE, insulin response element; P300, histone acetyltransferase p300; GPasea, glycogen phosphorylase a; GPaseb, glycogen phosphorylase b; PhosK, glycogen phosphorylase kinase; PIP2, phosphoinositol‐bisphosphate; PLC, phospholipase C; SCP4, small C‐terminal domain phosphatase. The figure was constructed (BioRender.com) using information gathered from the following references: GR1(Kd)/ Gαq /PLC/IP3/IP3RI: Andersson et al. (1993), Barucha and Tager (1990), Bill and Vines (2020), Bonnevie‐Nielsen and Tager (1983), Chin & Means, 2000), Goldstein and Hager (2018), Igumenova (2015), Ikezawa et al. (1998), Miura et al. (1992), Newton (2018), Sonne et al. (1978), Takemoto‐Kimura et al. (2017) and Wayman et al. (2011), PhosK/GPase: Brushia and Walsh (1999), Miura et al. (1992) and Vénien‐Bryan et al. (2002), CaMKII: Cohen et al. (2015), Johannessen and Moens (2007) and Takemoto‐Kimura et al. (2017), CaMKIV: Hook and Means (2001), Shaywitz and Greenberg (1999), Skelding and Rostas (2020) and Soderling, 1999), CaMKK: Anderson et al. (2012), Brzozowski and Skelding (2019), Puri (2020), Racioppi and Means (2012) and Skelding and Rostas (2020), Calcineurin/CRTC2: Oh et al. (2013) and Rui (2014), Nuclear translocation of Fox01, CRTC2, CaMKII, and CaMKIV: Cohen et al. (2015), Goldstein and Hager (2018), Ozcan et al. (2012), Skelding and Rostas (2020) and Wayman et al. (2011), Intranuclear: Cohen et al. (2015), Goldstein and Hager (2018), Johannessen and Moens (2007), Müller et al. (2017), Oh et al. (2013), Ozcan et al. (2012), Ravnskjaer et al. (2015), Shaywitz and Greenberg (1999), Soderling, (1999)
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