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1.  Influence of uremia and hemodialysis on the turnover and metabolic effects of glucagon. 
Journal of Clinical Investigation  1976;57(3):722-731.
To evaluate the mechanism and role of hyperglucagonemia in the carbohydrate intolerance of uremia, 19 patients with chronic renal failure (12 of whom had undergone chronic hemodialysis for at least 11 mo) and 35 healthy control subjects were studied. Plasma glucagon, glucose, and insulin were measured in the basal state, after glucose ingestion (100 g), after intravenous alanine (0.15 g/kg), and during a 3-h continuous infusion of glucagon (3 ng/kg per min) which in normal subjects, raised plasma glucagon levels into the upper physiological range. Basal concentrations of plasma glucagon, the increment in glucagon after infusion of alanine, and post-glucose glucagon levels were three- to fourfold greater in uremic patients than in controls. The plasma glucagon increments after the infusion of exogenous glucagon were also two- to threefold greater in the uremics. The metabolic clearance rate (MCR) of glucagon in uremics was reduced by 58% as compared to controls. In contrast, the basal systemic delivery rate (BSDR) of glucagon in uremics was not significantly different from controls. Comparison of dialyzed and undialyzed uremics showed no differences with respect to plasma concentrations, MCR, or BSDR of glucagon. However, during the infusion of glucagon, the increments in plasma glucose in undialyzed uremics were three- to fourfold greater than in dialyzed uremics or controls. When the glucagon infusion rate was increased in controls to 6 ng/kg per min to produce increments in plasma glucagon comparable to uremics, the glycemic response remained approximately twofold greater in the undialyzed uremics. The plasma glucose response to glucagon in the uremics showed a direct linear correlation with oral glucose tolerance which was also improved with dialysis. The glucagon infusion resulted in 24% reduction in plasma alanine in uremics but had no effect on alanine levels in controls. It is concluded that (a) hyperglucagonemia in uremia is primarily a result of decreased catabolism rather than hypersecretion of this hormone; (b) sensitivity to the hyperglycemic effect of physiological increments in glucagon is increased in undialyzed uremic patients; and (c) dialysis normalizes the glycemic response to glucagon, possibly accounting thereby for improved glucose tolerance despite persistent hyperglucagonemia. These findings thus provide evidence of decreased hormonal catabolism contributing to a hyperglucagonemic state, and of altered tissue sensitivity contributing to the pathophysiological action of this hormone.
PMCID: PMC436707  PMID: 1249205
2.  Glucagon and insulin have opposite effects on tissue chromium distribution in an obese mouse model 
Previous studies have suggested that chromium (Cr) is an essential cofactor for normal carbohydrate metabolism and affects insulin sensitivity, especially in rodent models. Several factors, such as insulin challenge, high carbohydrate intake, and response to stress (e.g., in obesity), alter Cr excretion or distribution. Glucagon is known to regulate carbohydrate metabolism and hyperglucagonemia plays a role in the development of hyperglycemia in diabetic subjects.
Materials and Methods
In the present study we investigated possible modulation of Cr levels by glucagon using an obese mouse model. Mice were kept on a high‐fat diet and then used as an obesity model. These obese mice were injected with one dose of glucagon or insulin and Cr levels in their tissues were determined.
In obese mice, glucagon challenge significantly increased Cr levels in bone but decreased them in the fat and liver. In contrast, insulin challenge significantly decreased Cr levels in bone but increased them in the fat, liver and muscle.
The results show that glucagon and insulin have opposite effects on Cr levels in bone, fat, liver, and muscle.
PMCID: PMC4020246  PMID: 24843705
Chromium; Glucagon; Insulin
3.  Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin. 
Journal of Clinical Investigation  1976;57(4):875-884.
To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal. Infusion of glucagon (1 ng/kg-min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94 +/- 8 to 126 +/- 12 mg/100 ml over 1 h (P less than 0.01); growth hormone, beta-hydroxy-butyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, beta-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P less than 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. Infusion of growth hormone (1 mug/kg-h) during suppression of its endogenous secretion with somastostatin produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma beta-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P less than 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin.
PMCID: PMC436731  PMID: 820717
4.  The Glycogenolytic Activity of Immunoreactive Pancreatic Glucagon in Plasma 
Journal of Clinical Investigation  1971;50(8):1650-1655.
Conclusions concerning the physiologic role of pancreatic glucagon in health and its contribution to disorders of carbohydrate metabolism, such as diabetes mellitus, are based entirely on measurements of plasma glucagon by radioimmunoassay. The changes in plasma immunoreactive glucagon can have the metabolic and clinical significance which has been implied, only if the glucagon detected by immunoassay has biological activity. The present study was designed to determine if a relationship between the immunoassayable glucagon and glycogenolytic activity of plasma could be demonstrated.
Plasma specimens obtained from normal and diabetic subjects under widely varying circumstances of alpha cell activity were extracted by a modification of the Kenny technique and the recovery of immunoreactive glucagon was calculated. Glycogenolytic activity of each extract was determined by perfusion in the Mortimore rat liver system, modified so as to detect as little as 1 ng of crystalline glucagon.
A significant correlation between the calculated quantity of immunoreactive glucagon and the glycogenolytic activity of plasma extracts was observed for both normal and diabetic subjects. Most of the glycogenolytic activity was abolished by incubating the extract with antiglucagon serum.
It was concluded that the glycogenolytic activity of extractable glucagon is proportional to its immunoreactivity as calculated from its original concentration in plasma. This would tend to support the view that all or most of the immunoreactive glucagon of plasma is biologically active.
PMCID: PMC442065  PMID: 5097572
5.  Opposite Effects of Glucagon and Insulin on Compensation for Spectacle Lenses in Chicks 
Chick eyes compensate for defocus imposed by positive or negative spectacle lenses. Glucagon may signal the sign of defocus. Do insulin (or IGF-1) and glucagon act oppositely in controlling eye growth, as they do in metabolic pathways and in control of retinal neurogenesis?
Chicks, wearing either lenses or diffusers or neither over both eyes, were injected with glucagon, a glucagon antagonist, insulin, or IGF-1 in one eye (saline in other eye). Alternatively, chicks without lenses received insulin plus glucagon in one eye, and either glucagon or insulin in the fellow eye. Ocular dimensions, refractive errors and glycosaminoglycan synthesis were measured over 2-4 days.
Glucagon attenuated the myopic response to negative lenses or diffusers by slowing ocular elongation and thickening the choroid; in contrast, with positive lenses, it increased ocular elongation to normal levels and reduced choroidal thickening, as did a glucagon antagonist. Insulin prevented the hyperopic response to positive lenses by speeding ocular elongation and thinning the choroid. In eyes without lenses, both insulin and IGF-1 speeded, and glucagon slowed, ocular elongation, but either glucagon or insulin increased the rate of thickening of the crystalline lens. When injected together, insulin blocked choroidal thickening by glucagon, at a dose that did not, by itself, thin the choroid.
Glucagon and insulin (or IGF-1) cause generally opposite modulations of eye-growth, with glucagon mostly increasing choroidal thickness and insulin mostly increasing ocular elongation. These effects are mutually inhibitory and depend on the visual input.
PMCID: PMC2755053  PMID: 18791176
emmetropization; glucagon; insulin; myopia; hyperopia; choroid; IGF, insulin-like growth factor
6.  The effect of experimental insulin deficiency on glucagon secretion 
Journal of Clinical Investigation  1971;50(9):1992-1999.
Suppression of pancreatic glucagon secretion by hyperglycemia is a characteristic of normal alpha cell function. However, in diabetic subjects, plasma glucagon is normal or high despite hyperglycemia. It seemed possible that the presence of glucose or its metabolites within the alpha cell might be essential for suppression of glucagon secretion, and that in diabetes an intracellular deficiency of glucose secondary to insulin lack might be responsible for the nonsuppressibility. The present study was designed to determine the effect upon glucagon secretion of blockade of glucose metabolism and of experimental insulin deficiency.
Blockade of glucose metabolism was induced in dogs by administration of 2-deoxyglucose or mannoheptulose. A striking rise in glucagon was observed despite accompanying hyperglycemia and hyperinsulinemia, which, in the case of mannoheptulose, was induced by infusing crystalline insulin.
To determine if insulin lack also causes paradoxical hyperglucagonemia, dogs were made severely diabetic by alloxan. Fasting glucagon levels ranged from 3 to 22 times normal despite severe hyperglycemia, and were quickly restored to normal by infusing insulin. Diabetes induced in rats by anti-insulin serum was also associated with significant elevation in plasma glucagon. However, diazoxide-induced insulin lack did not increase glucagon in dogs.
It is concluded that normal suppression of glucagon secretion by hyperglycemia does not occur when glucose metabolism is blocked or when severe insulin deficiency is produced. It is suggested that normal glucose metabolism within the alpha cell may be an insulin-requiring process without which hyperglycemic suppression of glucagon release cannot occur.
PMCID: PMC292125  PMID: 4935445
7.  The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis 
BMC Biology  2009;7:24.
We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed.
We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.
These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.
PMCID: PMC2698822  PMID: 19460132
8.  Effects of glucagon on plasma amino acids. 
Journal of Clinical Investigation  1984;73(3):785-793.
The effects of glucagon deficiency and excess on plasma concentrations of 21 amino acids were studied in six normal human subjects for 8 h. During glucagon deficiency, produced by intravenous infusion of somatostatin (0.5 mg/h) and insulin (5 mU/kg per h), amino acid concentration (sum of 21 amino acids) rose from 2,607 +/- 76 to 2,922 +/- 133 microM after 4 h (P less than 0.025). The largest increases occurred in lysine (+26%), glycine (+24%), alanine (+23%), and arginine (+23%) concentrations. During glucagon excess produced by intravenous infusion of somatostatin (0.5 mg/h), insulin (5 mU/kg per h), and glucagon (60 ng/kg per h), amino acid concentration decreased from 2,774 +/- 166 to 2,388 +/- 102 microM at 8 h (P less than 0.01). The largest decreases occurred in citrulline (-37%), proline (-32%), ornithine (-30%), tyrosine (-23%), glycine (-20%), threonine (-21%), and alanine (18%) concentrations. Urinary urea nitrogen and total nitrogen excretions were lower during glucagon deficiency than during glucagon excess (3.1 +/- 0.2 vs. 6.3 +/- 2.3 g/8 h, P less than 0.05 and 4.8 +/- 1.0 vs 7.0 +/- 2.6 g/8 h, respectively, P less than 0.05). Biostator-controlled euglycemic glucagon deficiency was produced in four normal subjects for 4 h to eliminate possible effects of changes in glucose concentration on amino acids. Amino acid concentration (sum of 18 amino acids) increases occurred in arginine (+42%), alanine (+28%), glutamine (+25%), and glycine (+16%) concentrations. The data show that small changes (-66 pg/ml and +50 pg/ml) in basal glucagon concentrations cause plasma amino acid concentrations to change in opposite directions. The finding that urinary excretion of nitrogen and urea nitrogen was greater during glucagon excess than during glucagon deficiency suggested alterations in the rate of gluconeogenesis from amino acids as one mechanism by which glucagon controls blood amino acid levels.
PMCID: PMC425081  PMID: 6142902
9.  Synergistic Interactions of Physiologic Increments of Glucagon, Epinephrine, and Cortisol in the Dog 
Journal of Clinical Investigation  1979;63(1):114-123.
To evaluate the role of anti-insulin hormone actions and interactions in the pathogenesis of stress-induced hyperglycemia, the counterregulatory hormones, glucagon, epinephrine, and cortisol were infused alone as well as in double and triple combinations into normal conscious dogs in doses that were designed to simulate changes observed in severe stress. Infusion of glucagon, epinephrine, or cortisol alone produced only mild or insignificant elevations in plasma glucose concentration. In contrast, the rise in plasma glucose produced by combined infusion of any two counterregulatory hormones was 50-215% greater (P < 0.005-0.001) than the sum of the respective individual infusions. Furthermore, when all three hormones were infused simultaneously, the increment in plasma glucose concentration (144±2 mg/dl) was two- to fourfold greater than the sum of the responses to the individual hormone infusions or the sum of any combination of double plus single hormone infusion (P < 0.001).
Infusion of glucagon or epinephrine alone resulted in a transient rise in glucose production (as measured by [3-3H]glucose). While glucagon infusion was accompanied by a rise in glucose clearance, with epinephrine there was a sustained, 20% fall in glucose clearance. When epinephrine was infused together with glucagon, the rise in glucose production was additive, albeit transient. However, the inhibitory effect of epinephrine on glucose clearance predominated, thereby accounting for the exaggerated glycemic response to combined infusion of glucagon and epinephrine. Although infusion of cortisol alone had no effect on glucose production, the addition of cortisol markedly accentuated hyperglycemia produced by glucagon and(or) epinephrine primarily by sustaining the increases in glucose production produced by these hormones. The combined hormonal infusions had no effect on β-hydroxybutyrate concentration.
It is concluded that (a) physiologic increments in glucagon, epinephrine, and cortisol interact synergistically in the normal dog so as to rapidly produce marked fasting hyperglycemia; (b) in this interaction, epinephrine enhances glucagon-stimulated glucose output and interferes with glucose uptake while cortisol sustains elevations in glucose production produced by epinephrine and glucagon; and (c) these data indicate that changes in glucose metabolism in circumstances in which several counterregulatory hormones are elevated (e.g., “stress hyperglycemia”) are a consequence of synergistic interactions among these hormones.
PMCID: PMC371925  PMID: 762240
10.  The Proprotein Convertase Encoded by amontillado (amon) Is Required in Drosophila Corpora Cardiaca Endocrine Cells Producing the Glucose Regulatory Hormone AKH 
PLoS Genetics  2010;6(5):e1000967.
Peptide hormones are potent signaling molecules that coordinate animal physiology, behavior, and development. A key step in activation of these peptide signals is their proteolytic processing from propeptide precursors by a family of proteases, the subtilisin-like proprotein convertases (PCs). Here, we report the functional dissection of amontillado (amon), which encodes the Drosophila homolog of the mammalian PC2 protein, using cell-type specific inactivation and rescue experiments, and we show that amon is required in the islet-like adipokinetic hormone (AKH)–producing cells that regulate sugar homeostasis. In Drosophila, AKH acts analogously to vertebrate glucagon to increase circulating sugar levels from energy stores, while insulin-like peptides (DILPs) act to decrease sugar levels. amon mutant larvae have significantly reduced hemolymph sugar levels, and thus phenocopy larvae where the AKH–producing cells in the corpora cardiaca have been ablated. Reduction of amon expression in these cells via cell-specific RNA inactivation also results in larvae with reduced sugar levels while expression of amon in AKH cells in an amon mutant background rescues hypoglycemia. Hypoglycemia in larvae resulting from amon RNA inactivation in the AKH cells can be rescued by global expression of the akh gene. Finally, mass spectrometric profiling shows that the production of mature AKH is inhibited in amon mutants. Our data indicate that amon function in the AKH cells is necessary to maintain normal sugar homeostasis, that amon functions upstream of akh, and that loss of mature AKH is correlated with loss of amon activity. These observations indicate that the AKH propeptide is a proteolytic target of the amon proprotein convertase and provide evidence for a conserved role of PC2 in processing metabolic peptide hormones.
Author Summary
Peptide hormones are important signaling molecules that coordinate physiology, behavior, and development. A key step in production of peptide hormones is the proteolytic cleavage of larger inactive precursors by prohormone convertases (PCs). Studies in a variety of organisms, including humans, have shown that deficiencies in PC genes lead to complex and detrimental changes. We used fruitfly genetics to dissect the function of Drosophila PC2, encoded by the amon gene, in the regulation of carbohydrate metabolism. We found that amon is expressed in endocrine cells of the corpora cardiaca that produce the sugar-mobilizing adipokinetic hormone (AKH), a functional analog of vertebrate glucagon. Previous studies suggest that the AKH–producing cells are homologs of the glucagon-producing islet alpha-cells in the pancreas. We found that flies with amon deficiency had significantly reduced hemolymph (insect “blood”) sugar levels. Using cell-type specific inactivation and rescue experiments, we show that amon expression in the AKH cells is necessary and sufficient for normal sugar regulation. We also demonstrate that AKH production is inhibited in amon mutants. Our results indicate that amon is necessary to maintain normal hemolymph sugar levels by activating AKH and suggest a conservation of PC2 function in processing peptide hormones between flies and mammals.
PMCID: PMC2877730  PMID: 20523747
11.  Glucagon induces translocation of glucokinase from the cytoplasm to the nucleus of hepatocytes by transfer between 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase-2 and the glucokinase regulatory protein 
Biochimica et Biophysica Acta  2014;1843(6):1123-1134.
Glucokinase activity is a major determinant of hepatic glucose metabolism and blood glucose homeostasis. Liver glucokinase activity is regulated acutely by adaptive translocation between the nucleus and the cytoplasm through binding and dissociation from its regulatory protein (GKRP) in the nucleus. Whilst the effect of glucose on this mechanism is well established, the role of hormones in regulating glucokinase location and its interaction with binding proteins remains unsettled. Here we show that treatment of rat hepatocytes with 25 mM glucose caused decreased binding of glucokinase to GKRP, translocation from the nucleus and increased binding to 6-phosphofructo 2-kinase/fructose 2,6 bisphosphatase-2 (PFK2/FBPase2) in the cytoplasm. Glucagon caused dissociation of glucokinase from PFK2/FBPase2, concomitant with phosphorylation of PFK2/FBPase2 on Ser-32, uptake of glucokinase into the nucleus and increased interaction with GKRP. Two novel glucagon receptor antagonists attenuated the action of glucagon. This establishes an unequivocal role for hormonal control of glucokinase translocation. Given that glucagon excess contributes to the pathogenesis of diabetes, glucagon may play a role in the defect in glucokinase translocation and activity evident in animal models and human diabetes.
•Hepatic glucokinase activity is acutely regulated by its cellular location.•High glucose translocates glucokinase from nuclear GKRP to cytoplasmic PFK2/FBPase2.•Here we show that glucagon counteracts glucokinase translocation by elevated glucose.•This effect of glucagon is reversed by novel glucagon receptor antagonists.•This study supports a role for glucagon in regulating glucokinase translocation.
PMCID: PMC4024195  PMID: 24566088
BiFC, bimolecular fluorescence complementation; cAMP, cyclic adenosine monophosphate; EPAC, exchange protein directly activated by cAMP; F26P2, fructose 2,6-bisphosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GK, glucokinase; GKRP, glucokinase regulatory protein; G6pc, glucose 6-phosphatase; mRFP, red fluorescent protein; N/C ratio, nuclear-to-cytoplasmic ratio; PepO, desHis1Pro4Glu9-glucagon; PepR, desHis1Pro4Glu9Lys12(γ-glutamyl PAL)glucagon-amide; Phos-a, glycogen phosphorylase; PFK2/FBPase2, 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase-2; PKA, protein kinase A; PLA, proximity ligation assay; YFP, yellow fluorescent protein; Glucokinase; Glucokinase regulatory protein; 6-phosphofructo 2-kinase/fructose 2,6 bisphosphatase-2; Hepatocyte; Glucagon
12.  Effects of endotoxin on carbohydrate metabolism in inbred mice. 
Effects of endotoxin on carbohydrate metabolism were studied in A/HeJ (endotoxin-sensitive) and C3H/HeJ (endotoxin-resistant) inbred mice. A/HeJ mice developed hypoglycemia within two hours after endotoxin injection, yet liver glycogen content did not differ from controls. Similarly treated C3H/HeJ mice did not develop significant hypoglycemia. Administration of glucagon to endotoxin-treated A/HeJ mice failed to elevate their blood glucose concentrations, while endotoxin-treated mice of the same strain did respond to dibutyryl cyclic AMP with a significant elevation of blood glucose. C3H/HeJ mice on the other hand responded to glucagon and dibutyryl cyclic AMP with elevated blood glucose. Endotoxin-treated C3H/HeJ but not A/HeJ mice were able to carry out gluconeogenesis induced by prednisolone, while both inbred strains showed active glycogenesis after administration of an exogenous glucose load. Administration of glucagon resulted in diminished liver glycogen concentrations in A/HeJ endotoxin-treated mice suggesting no impairment of glycogenolysis. The inability of endotoxin-treated A/HeJ mice to respond to glucagon could be due to impairment of gluconeogenesis. Although endotoxin interfered with the capacity of both inbred strains to respond to glucagon administration with elevation of liver cyclic AMP, the effect was significantly more severe in A/HeJ mice. The susceptibility of A/HeJ mice to the lethal effect of endotoxin may be related to the apparent sensitivity of carbohydrate metabolic pathways to disturbance by endotoxin.
PMCID: PMC1277578  PMID: 187306
13.  Somatostatin Receptor Type 2 Antagonism Improves Glucagon Counterregulation in Biobreeding Diabetic Rats 
Diabetes  2013;62(8):2968-2977.
Impaired counterregulation during hypoglycemia in type 1 diabetes (T1D) is partly attributable to inadequate glucagon secretion. Intra-islet somatostatin (SST) suppression of hypoglycemia-stimulated α-cell glucagon release plays an important role. We hypothesized that hypoglycemia can be prevented in autoimmune T1D by SST receptor type 2 (SSTR2) antagonism of α-cells, which relieve SSTR2 inhibition, thereby increasing glucagon secretion. Diabetic biobreeding diabetes-prone (BBDP) rats mimic insulin-dependent human autoimmune T1D, whereas nondiabetic BBDP rats mimic prediabetes. Diabetic and nondiabetic rats underwent a 3-h infusion of vehicle compared with SSTR2 antagonist (SSTR2a) during insulin-induced hypoglycemia clamped at 3 ± 0.5 mmol/L. Diabetic rats treated with SSTR2a needed little or no glucose infusion compared with untreated rats. We attribute this effect to SSTR2a restoration of the attenuated glucagon response. Direct effects of SSTR2a on α-cells was assessed by resecting the pancreas, which was cut into fine slices and subjected to perifusion to monitor glucagon release. SSTR2a treatment enhanced low-glucose–stimulated glucagon and corticosterone secretion to normal levels in diabetic rats. SSTR2a had similar effects in vivo in nondiabetic rats and promoted glucagon secretion from nondiabetic rat and human pancreas slices. We conclude that SST contributes to impaired glucagon responsiveness to hypoglycemia in autoimmune T1D. SSTR2a treatment can fully restore hypoglycemia-stimulated glucagon release sufficient to attain normoglycemia in both diabetic and prediabetic stages.
PMCID: PMC3717832  PMID: 23630299
14.  Interactions of Fat and Carbohydrate Metabolism—New Aspects and Therapies 
NO one has so far produced anything approaching a clear picture of either fat or carbohydrate metabolism and the interactions of the two are still more involved and elusive although they clearly exist. Plants and animals build up reserves of fat from carbohydrate, but the reverse process (fat into carbohydrate), proved in plant seeds, is still unproven in animals, although theoretically possible.
In normal human metabolism fat-carbohydrate interactions are almost hidden. The disturbances shown in the metabolism of a diabetic seem to give us the clearest indications of these interactions. Either carbohydrate or fat can be used as the main source of body fuel, but their metabolic course is very different, both as regards chemistry and function. It is only whep carbohydrate is not available, either in starvation or severe diabetes, that fat provides the fuel of the body; this contrast is also manifest in the blood and internal organs, especially the liver. Under the commonest normal conditions of diet carbohydrate is predominantly and preferentially used for metabolism. The liver is rich in glycogen, poor in fat; the blood fat is minimal and ketone bodies, although perhaps present in small amount in the blood at most times, are absent on common tests. As soon as carbohydrate is insufficiently available for the needs of metabolism, depot fat flows to the liver and is there catabolized to ketone bodies which recent proof has shown to be burned peripherally in the muscles independent of carbohydrate metabolism. This is a normal process, harmful only in diabetes, and especially harmful when it occurs suddenly, e.g. when insulin is cut off from a fat diabetic dog or human patient. A diabetic supports with ease a prolonged severe ketosis but suffers from one of sudden onset, although of milder severity. Insulin in the diabetic and sugar in the starved switches metabolism from fat to carbohydrate usage very quickly and ketonuria usually disappears in three to six hours.
“Diabetic obesity” is very common and is often seen in the earliest stages and again after insulin treatment. It seems probable that hyperglycæmia causes this obesity and this has been clearly established by observations on an unusual case of lipæmia, diabetes and lipodystrophy.
Lipæcmia may occur in two opposite phases of metabolism, one anabolic—when fat is on its way to storage, the other catabolic—when it is flowing from stores to the liver. The latter is the usual condition obvious in disease.
Work has also been done which suggests that other lipotropic factors—choline, lipocaic, &c., exert an influence on carbohydrate-fat balance, more specifically the glycogen-fat balance in the liver.
In America attention has been drawn to the frequent and persistenzt occurrence of fatty enlargement of the liver in diabetic children. The author has seen many diabetic children (usually in a state of chronic ketosis) with enlarged livers, but such enlargement has rapidly disappeared with better management of the diabetes. Only two out of some 500 diabetic children have clearly shown the unmistakable syndrome of “hepatomegalic dwarfism ”. In these two cases choline and lipocaic were given over prolonged periods without any effect: the liver, however, of one of these cases has since become normal by the addition of zinc protamine insulin.
PMCID: PMC1998199  PMID: 19992415
15.  Metabolic Studies in the African Pygmy 
Journal of Clinical Investigation  1972;51(2):395-401.
Major metabolic effects of human growth hormone (HGH) were assessed in the African Babinga pygmy. Plasma free fatty acid (FFA) and glucose concentrations were measured in pygmies, HGH-deficient dwarfs, Bantu tribesmen, and Caucasian controls after each received 4 mg of HGH intravenously over a 20 min period. Pygmies had an early decrease of plasma FFA and glucose concentration, but did not exhibit a later lipolytic response.
In neighboring Bantu tribesmen, American controls, and HGH-deficient dwarfs, both the early and late responses to intravenous HGH were present. The failure of plasma FFA concentration to increase in the pygmy after intravenous HGH was not due to a generalized defect in lipolysis since a normal lipolytic response was obtained with epinephrine (2 μg/min for 20 min).
Pygmies, like HGH-deficient dwarfs, had significantly reduced insulin responses to both oral glucose and arginine. Insulin secretion was significantly reduced when compared with either Bantu tribesmen or American controls and was not altered by 2 wk of a high carbohydrate/high protein diet. HGH treatment in pygmies (5 mg b.i.d. for 5 days) failed to augment either glucose or arginine-induced insulin secretion. Glucagon consistently caused normal insulin secretion in HGH-deficient dwarfs and was, likewise, effective in each pygmy studied. In two offspring from different pygmy mothers and Bantu fathers, insulin responses to glucose were initially normal and increased in a normal manner after HGH treatment.
In previous studies, HGH failed to reduce serum urea nitrogen concentration in pygmies. Sulfation factor was found to be normal. A consideration of the data in toto is consistent with a hypothesis that the metabolic findings in the pygmy may result from partial nonresponsiveness to either HGH or to a factor generated by HGH. This defect is not transmitted as either an autosomal or sex-linked dominant trait.
PMCID: PMC302138  PMID: 5009122
16.  Effects of Acute Hyperglucagonemia on Hepatic and Intestinal Lipoprotein Production and Clearance in Healthy Humans 
Diabetes  2011;60(2):383-390.
The metabolism of hepatic- and intestinally derived lipoproteins is regulated in a complex fashion by nutrients, hormones, and neurologic and other factors. Recent studies in animal models suggest an important role for glucagon acting via the glucagon receptor in regulating hepatic triglyceride (TG) secretion. Here we examined the direct effects of glucagon on regulation of hepatic and intestinal lipoprotein metabolism in humans.
Eight healthy men underwent two studies each, in random order, 4–6 weeks apart in which de novo lipogenesis, kinetics of larger VLDL1 TG, and kinetics of VLDL1 and smaller VLDL2 apolipoprotein (apo)B100 and B48 were studied using established stable isotope enrichment methods. Subjects were studied in the constant fed state under conditions of a pancreatic clamp (with infusion of somatostatin, insulin, and growth hormone) at either basal glucagon (BG study, 64.5 ± 2.1 pg/mL) or hyperglucagonemia (high glucagon [HG] study, 183.2 ± 5.1 pg/mL).
There were no significant differences in plasma concentration of VLDL1 or VLDL2 TG, apoB100 or apoB48 between BG and HG studies. There was, however, lower (P < 0.05) VLDL1 apoB100 fractional catabolic rate (−39%) and production rate (−30%) in HG versus BG, but no difference in de novo lipogenesis or TG turnover, and glucagon had no effect on intestinal (B48-containing) lipoprotein metabolism.
Glucagon acutely regulates hepatic but not intestinal lipoprotein particle metabolism in humans both by decreasing hepatic lipoprotein particle production as well as by inhibiting particle clearance, with no net effect on particle concentration.
PMCID: PMC3028336  PMID: 20980459
17.  In vivo inhibition of glucagon secretion by paracrine beta cell activity in man. 
Journal of Clinical Investigation  1981;68(1):314-318.
The close anatomical relationships betaeen pancreatic alpha and beta cells makes possible their interaction at a local (paracrine) level. To demonstrate this in vivo, we have compared the acute glucagon response to intravenous arginine in the basal state and after beta cell suppression by infusions of insulin. The plasma glucose concentration was maintained by the glucose clamp technique. In six normal weight nondiabetics, infusion of insulin at 0.2 mU/kg per min (rate 1) raised the mean +/- SEM plasma insulin levels from 10 +/- 3 to 32 +/- 4 mU/liter and at 1 mU/kg per min (rate 2) raised plasma insulin to 84 +/- 8 mU/liter. This resulted in beta cell suppression, as shown by a diminution in the acute insulin response (incremental area under the insulin response curve, 0-10 min): basal = 283 +/- 61, 199 +/- 66 (rate 1) and 143 +/- 48 mU/liter per 10 min (rate 2) and a fall in prestimulus C-peptide from 1.05 +/- 0.17 to 0.66 +/- 0.15 and to 0.44 +/- 0.15 mM/liter (all P less than 0.01). This beta cell suppression was associated with increased glucagon responses to arginine: 573 +/- 75 (basal), 829 +/- 114 (rate 1), and 994 +/- 136 ng/liter per 10 min (rate 2) and increased peak glucagon responses 181 +/- 11 (basal), 214 +/- 16 (rate 1), and 259 +/- 29 ng/liter (rate 2) (all P less than 0.01). In all subjects, there was a proportional change between the rise in he acute glucagon response to arginine and the fall in the prearginine C-peptide level. To demonstrate that augmented glucagon response was due to betw cell suppression, and not to the metabolic effect of infused insulin, similar studies were performed in C-peptide-negative-diabetics. Their acute glucagon response to arginine was inhibited by the insulin infusion: 701 +/- 112 (basal), 427 +/- 33 (rate 1), and 293 +/- 67 ng/liter per 10 min (rate 2) as was their peak glucagon response: 268 +/- 69, 170 +/- 36, and 115 +/- 33 ng/liter (all P less than 0.01). Thus, hyperinsulinemia, within the physiological range achieved by insulin infusion, inhibits beta cell secretion which, via a paracrine mechanism, potentiates glucagon secretion.
PMCID: PMC370801  PMID: 7019246
18.  Evidence for a catabolic role of glucagon during an amino acid load. 
Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations.
PMCID: PMC507404  PMID: 8690809
19.  UCP2 Regulates the Glucagon Response to Fasting and Starvation 
Diabetes  2013;62(5):1623-1633.
Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2−/−) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell–specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia.
PMCID: PMC3636632  PMID: 23434936
20.  Regulation of glucose homeostasis in humans with denervated livers. 
Journal of Clinical Investigation  1997;100(4):931-941.
The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, (a) minimal alteration of endogenous glucose production, (b) increased concentration of insulin and glucagon, and (c) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denervation of the transplanted graft.
PMCID: PMC508266  PMID: 9259593
21.  Effect of a LoBAG30 diet on protein metabolism in men with type 2 diabetes. A Randomized Controlled Trial 
We previously reported that a weight-maintenance diet with a carbohydrate:protein:fat ratio of 30:30:40%, ingested for 5 weeks, improved blood glucose control in subjects with untreated type 2 diabetes. In this study we also determined that insulin and insulin-like growth factor-I (IGF-I) were increased. In this report we provide further information. Specifically, 24-hour total and individual amino acids, glucagon and cortisol data are provided. In addition, we determined whether these multiple effectors resulted in a positive nitrogen balance and an increase in fat-free mass. Insulin and IGF-I should stimulate protein accumulation. An increase in amino acids, particularly branched chain amino acids, should facilitate this, whereas glucagon and cortisol could have adverse effects in this regard.
Eight men with untreated type 2 diabetes were studied. A randomized crossover design was used. Data were obtained before and after 5 weeks on a control diet (55% carbohydrate:15% protein:30% fat) and on a 30% carbohydrate:30% protein:40% fat diet. Nitrogen balance and body composition were determined at the beginning and end of each dietary intervention.
As expected, the mean 24-hour total amino acid area response was higher after ingesting the 30:30:40 diet. However, the increase was only statistically significant for the branched chain amino acids, and phenylalanine and tyrosine. The 24-hour cortisol profile was unchanged. Glucagon was increased. Nitrogen balance was positive. Body weight was stable. Body composition and computed tomography data indicate no change in the fat-free mass.
This high protein, low carbohydrate diet induced a metabolic milieu which strongly favors a positive protein balance, and a positive balance was present. However, an increase in lean (protein) mass was not documented. Whether such a diet in people with type 2 diabetes is useful in preventing or delaying the loss of total lean body mass and/or sarcopenia associated with aging remains to be determined.
PMCID: PMC3443440  PMID: 22607113
LoBAG diet; Protein balance; Nitrogen balance; Fat-free mass; Body composition; Amino acids; Cortisol; Glucagon; Sarcopenia
22.  Anti-Diabetic Efficacy and Impact on Amino Acid Metabolism of GRA1, a Novel Small-Molecule Glucagon Receptor Antagonist 
PLoS ONE  2012;7(11):e49572.
Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.
PMCID: PMC3501516  PMID: 23185367
23.  Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by anti-insulin serum and glucagon. 
Journal of Clinical Investigation  1975;55(6):1202-1209.
The enhanced capacity for long-chain fatty acid oxidation and ketogenesis that develops in the rat liver between 6 and 9 h after the onset of starvation was shown to be inducible much more rapidly by administration of anti-insulin serum or glucagon to fed rats. After only 1 h of treatment with either agent, the liver had clearly switched from a "nonketogenic" to a "ketogenic" profile, as determined by rates of acetoacetate and b-hydroxybutyrate production on perfusion with oleic acid. As was the case after starvation, the administration of insulin antibodies or glucagon resulted in depletion of hepatic glycogen stores and a proportional increase in the ability of the liver to oxidize long-chain fatty acids and (-)-octanoylcarnitine, suggesting that all three treatment schedules activated the carnitine acyltransferase system of enzymes. In contrast to anti-insulin serum, which produced marked elevations in plasma glucose, free fatty acid, and ketone body concentrations, glucagon treatment had little effect on any of these parameters, presumably due to enhanced insulin secretion after the initial stimulation of glycogenolysis. Thus, after treatment with glucagon alone, it was possible to obtain a "ketogenic" liver from a nonketotic animal. The results are consistent with the possibility that the activity of carnitine acyltransferase, and thus ketogenic capacity, is subject to bihormonal control through the relative blood concentrations of insulin and glucagon, as also appears to be the case with hepatic carbohydrate metabolism.
PMCID: PMC301874  PMID: 1133169
24.  Glucose and ATP levels in pancreatic islet tissue of normal and diabetic rats. 
Journal of Clinical Investigation  1976;58(5):1193-1200.
It has been suggested that the hyperglucagonemia observed in diabetic animals and man may be due to an impairment of glucose uptake and metabolism by the alpha-cells resulting in a decreased production of ATP. To test this hypothesis glucose, ATP, glucagon, and insulin were measured in pancreatic islets of normal and alloxan or streptozotocin diabetic rats. Two experimental approaches were used. In the first, the pancreas was perfused in vitro for assessing insulin and glucagon release due to 10 mM amino acids with and without 5 mM glucose. These perfusions were performed in the presence and absence of insulin. After perfusion, the pancreas was frozen and processed for analysis of islet glucose, ATP, insulin, and glucagon content. The second approach was to investigate the islet sucrose, urea, and glucose spaces together with ATP, insulin, and glucagon content in vivo in normal and in insulin-treated and untreated streptozotocin diabetic rats. Perfusion of the pancreas in vitro with 5 mM glucose resulted in higher glucose content of normal islets than in alloxan and streptozotocin diabetic islets. Similarly in the in vivo studies, the intracellular glucose space of the streptozotocin diabetic islets was 30% the value found in normals. In the in vivo experiments, despite the relatively small intracellular glucose space of alpha-cell islets, the ATP content of these islets was only 15-20% lower than the ATP content of normal islets. In the in vitro experiments, perfusion with glucose resulted in ATP contents of alpha-cell islets and of normal mixed alpha-beta-cell islets which were indistinguishable. However, the ATP content of alpha-cell islets was maintained for prolonged periods in the absence of glucose in contrast to mixed islets, composed primarily of beta-cells, in which the ATP level decreased by 45% when glucose-free medium was perfused for sustained periods. Finally, insulin infused in high concentrations or administered to the diabetic animal had no effect on the glucose spaces or the ATP contents of normal or alpha-cell islets. It can be calculated that in vivo the intracellular glucose level of islets from streptozotocin treated rats is approximately 15 mM. Since in normals an extracellular glucose concentration of this magnitude inhibits stimulated glucagon release completely, it would seem unlikely that a lack of intracellular glucose is the cause of the apparent glucose "blindness" of the alpha-cells in diabetes. In fact, in perfusion studies as little as 2.5 mM free intracellular glucose was sufficient to suppress glucagon secretion from diabetic alpha-cells. The results of the ATP measurements clearly eliminate a possible energy deficit of diabetic alpha-cells as cause of the apparent glucose resistance of alpha-cells.
PMCID: PMC333287  PMID: 136453
25.  Novel Use of Glucagon in a Closed-Loop System for Prevention of Hypoglycemia in Type 1 Diabetes 
Diabetes Care  2010;33(6):1282-1287.
To minimize hypoglycemia in subjects with type 1 diabetes by automated glucagon delivery in a closed-loop insulin delivery system.
Adult subjects with type 1 diabetes underwent one closed-loop study with insulin plus placebo and one study with insulin plus glucagon, given at times of impending hypoglycemia. Seven subjects received glucagon using high-gain parameters, and six subjects received glucagon in a more prolonged manner using low-gain parameters. Blood glucose levels were measured every 10 min and insulin and glucagon infusions were adjusted every 5 min. All subjects received a portion of their usual premeal insulin after meal announcement.
Automated glucagon plus insulin delivery, compared with placebo plus insulin, significantly reduced time spent in the hypoglycemic range (15 ± 6 vs. 40 ± 10 min/day, P = 0.04). Compared with placebo, high-gain glucagon delivery reduced the frequency of hypoglycemic events (1.0 ± 0.6 vs. 2.1 ± 0.6 events/day, P = 0.01) and the need for carbohydrate treatment (1.4 ± 0.8 vs. 4.0 ± 1.4 treatments/day, P = 0.01). Glucagon given with low-gain parameters did not significantly reduce hypoglycemic event frequency (P = NS) but did reduce frequency of carbohydrate treatment (P = 0.05).
During closed-loop treatment in subjects with type 1 diabetes, high-gain pulses of glucagon decreased the frequency of hypoglycemia. Larger and longer-term studies will be required to assess the effect of ongoing glucagon treatment on overall glycemic control.
PMCID: PMC2875438  PMID: 20332355

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