Control of Glucose Production in vivo by Insulin and Glucagon

Abstract

Effects of basal glucagon Effects of increments in glucagon Insulin and Glucose ProductionEffects of insulin deficiency Effects of increases in insulin Integration of insulin and glucagon's effects INSULIN AND GLUCAGON have been known to regulate glucose production by the liver for almost 40 yr. In 1959 Shoemaker et al. (115) used arteriovenous difference techniques to first demonstrate the ability of glucagon to stimulate net hepatic glucose output in vivo. This observation was eventually confirmed by others (21, 36, 71) using tracer methods. Since gluconeogenesis could not be measured at that time, it was not possible to determine whether the hormone was working through an action on glycogenolysis or gluconeogenesis. Likewise, since it was not possible to remove glucagon selectively, it was also unclear what the consequences of glucagon deficiency, if any, would be.The first consistent inhibitory effect of insulin on glucose production by the liver in vivo was reported by Madison et al. in 1960 (83). This finding was soon confirmed by Starzl et al. (122,123) and Steele et al. (124) using isotopic techniques. Unlike the case with glucagon, it was possible to demonstrate the consequences of acute insulin deficiency. In experiments on partially or totally depancreatized conscious dogs, sudden cessation of endogenous or exogenous insulin input resulted in a rapid increase in glucose production (134,141). As was the case for glucagon, it was not possible to determine the extent to which insulin's action resulted from changes in glycogenolysis or gluconeogenesis.In summary, by the early 1970s, both insulin and glucagon had been convincingly shown to regulate hepatic glucose production in vivo in animal models. Little was known, however, about their action in the human, about the dose-response relationships between their plasma lev-els and hepatic glucose output, or about the time courses of their effects on glucose production. In addition, it was unclear to what extent their actions involved effects on glycogenolysis and gluconeogenesis. The purpose of this chapter is to address these issues. ASSESSMENT OF GLUCOSE PRODUCTION IN VNOTo fully appreciate the effects of insulin and glucagon on glucose production in the whole animal, it is first necessary to discuss the methods used to measure glucose entry into the blood in vivo. The techniques employed have improved considerably over the past four decades. That should be kept in mind as one considers the quantitative aspects of some of the early studies of insulin and glucagon action in vivo. In general, two main approaches have been used: the arteriovenous (A-V) difference technique and the isotope dilution technique. The former consists of the measurement of glucose in the blood entering and leaving the liver and the simultaneous assessment of hepatic arterial and portal vein blood flows. The product of the A-V difference for glucose and hepatic blood flow yields the net hepatic glucose balance. The isotopic technique consists of infusion or injection of an isotope o...

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

“…In fact, after an overnight fast, the basal glucagon level accounted for up to 70% of glucose production (16). In addition, a rise in plasma glucagon of only 100 pg/ml in the liver sinusoids tripled glucose production (19,20). Thus, the control strength of glucagon is profound, with a dynamic range of approximately 5 mg/kg/min over the physiologic range of plasma glucagon concentrations (Figure 1 and refs.…”

Minireview: Glucagon in the Pathogenesis of Hypoglycemia and Hyperglycemia in Diabetes

“…From there the hormone is secreted into the hepatic portal vein from which it acts on G protein-coupled receptors in the liver to stimulate glucose production (1)(2)(3). By itself, glucagon largely stimulates hepatic glycogenolysis.…”

Glucagon and hyperglycaemia in diabetes

“…Therefore the general concept is that of relative hyperglucagonaemia in diabetes, since glucagon levels might be expected to be reduced in the setting of hyperglycaemia. Given a body of physiological evidence that glucagon supports the postabsorptive and postprandial plasma glucose concentrations [1,2,11] and an array of studies, including but not limited to those of glucagon suppression with somatostatin in experimental animals and humans without and with diabetes by Gerich and co-workers and by others (reviewed in [1]), the involvement of glucagon in the pathogenesis of hyperglycaemia in diabetes is plausible, perhaps even probable. However, much of the supportive evidence is from short-term studies extrapolated to the long-term condition.…”

“…The hormone increases hepatic glucose production by stimulating glycogenolysis and, particularly when gluconeogenic precursors are abundant, gluconeogenesis [1,2]. Glucagon secretion in vivo is stimulated by decreased glucose and increased amino acid levels; it is inhibited by increased glucose, insulin and non-esterified fatty acid levels as well as by somatostatin.…”

“…Glucagon secretion in vivo is stimulated by decreased glucose and increased amino acid levels; it is inhibited by increased glucose, insulin and non-esterified fatty acid levels as well as by somatostatin. It is also stimulated by β 2 -adrenergic receptor activation [by sympathetic neural noradrenaline (norepinephrine)] and by muscarinic cholinergic receptor activation (by parasympathetic neural acetylcholine), but at least the glucagon response to hypoglycaemia is not critically dependent on pancreatic innervation [2]. Findings, ranging from elegant studies of isolated rat α-cells [3] to studies in healthy humans [4], have provided renewed interest in the concept of Samols et al [5] that β-cell insulin, perhaps among other secretory products, acting via the islet microcirculation, regulates α-cell glucagon secretion in a reciprocal fashion: a decrease in insulin signals an increase in glucagon secretion and an increase in insulin signals a decrease in glucagon secretion.…”