Effects of Glucocorticoids on Carbohydrate Metabolism M. McMahon, J. Gerich,* and R. Rizzat Endocrine Research Unit, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota I. INTRODUCTION As is evident from their name, it has long been known that glucocorticoids have important effects on carbohydrate metabolism.' Glucocorticoid deficiency results in an increased sensitivity to insulin and glucocorticoid excess results in a decreased sensitivity to insulin. These agents modulate pancreatic insulin secretion as well as hepatic and extrahepatic responses to insulin. They influence insulin action both directly at the receptor and postreceptor level, and indirectly by altering fatty acid and amino acid metabolism. Glucocorticoids are important stress hormones whose hyperglycemic effects are enhanced in disease states, such as diabetes mellitus, where insulin secretion is limited. This article attempts to briefly review the in vitro and in vivo data upon which these statements are based. 11. HISTORY The involvement of adrenocortical hormones in intermediary metabolism was recognized as early as 1908 when investigators reported a decrease in fasting plasma glucose concentrations in adrenalectomized dogs.' Two years later, hypoglycemia was described in association with Addison's disease.2By 1927, it was evident that hypoglycemia was accompanied by hepatic glycogen d e p l e t i ~ n . ~ Injection of the newly available adrenocortical extracts resulted in an increase in blood glucose and replenishment of hepatic glycogen store^.^-^ Gluconeogenesis was felt to be responsible for these * Present address: Clinical Research Center, 3488 Presbyterian University Hospital, University of Pittsburgh, Pittsburgh, PA 15261. t To whom correspondence should be addressed. Diabeteshletabolism Reviews, Vol. 4, No. 1, 17-30 (1988) 0 1988 by John Wiley & Sons, Inc. changes, since the production of urea, a by-product of the conversion of amino acids to glucose, increased in proportion to the increased carbohydrate a~ailability.~ In the early 1940s, it was recognized that glucocorticoids altered extrahepatic as well as hepatic glucose m e t a b ~ l i s m . The ~ - ~ amount of glucose excreted in the urine was greater in cortisone-treated rats than could be attributed to increased gluconeogenesis,6 suggesting an extrahepatic site of action. Furthermore, cortisol slowed the rate of fall of blood glucose in adrenalectomized rats, despite the fact that the liver had been removed by evisceration. Glucocorticoids also appeared important in the pathogenesis of diabetes mellitus. Hypophysectomy or adrenalectomy resulted in an improvement of pancreatic diabetes.' Conversely, in a study of 9000 routine autopsies, the prevalence of diabetes mellitus was approximately five times higher in persons with adenomas of the adrenal cortex than in a control group who did not have a d e n ~ m a sThese . ~ and similar studies led to intensive investigation into the factors regulating cortisol secretion, and into the mechanisms by which steroids altered carbohydrate metabolism. 111. REGULATION OF CORTISOL SECRETION Cortisol, a product of the cells of the zona fasciculata and zona reticularis of the adrenal cortex, is the main glucocorticoid in humans. Cortisol secretion is determined by a balance of excitatory and inhibitory substances." Adrenocorticotropic hormone (ACTH), a peptide produced in basophilic cells of the pituitary gland, is the most potent regulator of cortisol secretion." ACTH, by interacting with a specific adrenal cell plasma membrane receptor, stimulates adenylate cyclase activity, cyclic AMP production, and steroidogenesis. 'OJ' ACTH secretion is known to follow a circadian CCC 0742-4221/88/01017-14$04.00 18 GLUCOCORTICOIDS AND GLUCOSE METABOLISM and ultradian rhythm.12 Its secretion is increased by corticotropin releasing hormone (CRH), vasopressin, oxytocin, angiotensin 11, catecholamines, vasoactive intestinal polypeptide (VIP), and opia t e ~ .Neurons '~ that secrete CRH arise from cells in the hypothalamic paraventricular nucleus and project to the median eminen~e.'~ CRH neurons receive regulatory signals from many portions of the brain; excitatory inputs are cholinergic and serotonergic, and inhibitory influences are noradrenergic.12J3 Glucocorticoids interact with the brain and pituitary gland to inhibit the release of CRH and ACTH, forming a closed-loop feedback system. This control system can, however, be overridden by a second control system with a higher priority. When subjected to emotional or physical stresses, CRH and ACTH secretion are vigorously stimulated in spite of high circulating serum cortisol levels.l2 Vasopressin and norepinephrine are synergistic with CRH in response to stress. CRH may release other neurotransmitters in addition to ACTH.l4-I6 Cortisol is transported in the serum bound mainly to corticosteroid-binding globulin.'2 It is bound to a lesser extent to a high-affinity, lowbinding capacity glycoprotein and to albumin.I2 The biological significance of the binding protein rests not as much with rendering the steroid water soluble as with providing a circulating reservoir of biologically active hormones that may be more readily available in times of stress.12Normally, less than 10% of cortisol is free and it is this amount that is biologically active and available for hepatic metabolism and renal excretion.I2 Plasma cortisol clearance is depressed in the presence of renal or hepatic disease, hypothyroidism, advanced age, or infancy.l7-I9 IV. EFFECTS OF GLUCOCORTICOIDS ON INSULIN AND GLUCAGON SECRETION Glucocorticoid excess results in increased basal and glucose-stimulated insulin secretion.zo-" In contrast, a deficiency of these hormones depresses insulin secretion, although concomitant catecholamine deficiency also may contribute when glucocorticoid deficiency is produced by adrenalectomy.25t26 Treatment with glucocorticoids potentiates the response to both glucose and nonglucose secretagogues. As shown in Figure 1, similar increments in glucose lead to greater increments in insulin when individuals are pretreated with de~amethasone.'~ Thus, the diabetogenic in- 2.0. Slope of Potentiation 1.0. 0.5 0.24 / 0.1 Figure 1. Effect of dexamethasone treatment on the slope of glucose potentiation of acute insulin response (AIR) to isoproterenol. The slope is an index of beta cell responsiveness to a change in glucose (AG) (Ref. 27). fluence of glucocorticoid excess is partly compensated for by increased insulin secretion, provided the functional reserve of the pancreas is adequate. Pancreatic islet morphology is altered by glucocorticoid therapy. 28-32 These changes proceed at a slower rate than do changes in insulinemia and glycemia.26 Treatment with glucocorticoids produces hyperglycemia and hyperinsulinemia within one day, p-cell degranulation by two to three days, increased p-cell glycogen content by four days, and p-cell hyperplasia over a period of weeks to Degranulation of the p cells and increased mitotic activity may be followed by partial P-cell regranulation.28,mThese latter changes are consistent with the decreasing functional demand on p cells attributed to the gradual diminution of the hyperglycemia observed with prolonged steroid therapy.26The delayed appearance of islet glycogen has been postulated as due to low islet glycogen synthetase activity.32The morphologic effects of steroids on the pancreatic cells are reversible.26 Steroids appear to have little effect on the number, size, or granulation of A and D However, glucocorticoid excess increases basal and amino acid induced glucagon ~ e c r e t i o n . ~ ~ , ~ ~ V. EFFECT OF GLUCOCORTICOIDS ON INSULIN ACTION: ALTERATIONS IN RECEPTOR AND POSTRECEPTOR FUNCTION (TABLE I) Glucocorticoids modulate insulin action by altering both receptor and postreceptor function. As is evident from Table 1, their effects on insulin receptor binding remain controver- Pred Cort Dex Pred Cort Cort Pred In vitro In vitro In vitro In vitro In vitro In vitro In vitro 3T3-Ll 3T3-Ll Lymphocytes IM-9 IM-9 IM-9 Dex Pred Dex Dex Pred 3T3-C2 3T3-C2 In vivo Rat Dex Invitro In vivo Rat Cortisone (Cort) 3T3-C2 In vitro Human Prednisone (Pred)iDex In vivo In vivo In vivo In vitro Rat Dex Rat Rat Rat Fibroblasts In vitro Rat Dex Dex Invitro Invitro Dex Dex Rat Glucocorticoid Dexamethasone (Dex) Dex Dex In vivo Invivo In vitro In vitro In vivo Liver Rat hepatocytes Rat hepatocytes Rat plasma membrane Rat hepatocytes Rat hepatocytes Adipocytes Rat TX Effects of Glucocorticoids on Insulin Action Source Table I. 1/12 1 1 3-7 1 1-2 1-2 1 3-7 1 1-2 7 7 6-21 1 1 7 1/2-1/4 1/2-2 1/12 1/12 1-2 4 6 21 7-28 1 Days of treatment t t t 1 c, 1 f, t t t f, 1 1 c, t 1 1 f, ++ c, c, f, 1 1 1 t t Insulin binding - 2-Deoxy uptake 2-Deoxy uptake A1B 2-Deoxy uptake 2-Deoxy uptake A1B - Phosphodiesterase Oxidation 2-deoxyglucose uptake Oxidation 2-deoxy uptake Oxidation2-deoxy glucose Oxidation2-deoxyglucose uptake Lipolysis Lipogenesis Oxidation 2-deoxy glucose uptake Oxidation 2-deoxy glucose uptake 38 41 1 1 h 41 1 1 1 .1 1 2 h 1 12h 1 24-48 c, 1 48 h 40 1 46 47 47 45 44 44 44 42 43 37 41 40 1 t 39 J 35 36 34 Ref. 37 34 - - V,,, -1 - A1B t 1 A1B Glycogen synthetase Synthetase Action W L 20 GLUCOCORTICOIDS AND GLUCOSE METABOLISM Table I. (Continued) Effects of Glucocorticoids on Insulin Action Days of Insulin Source TX Glucocorticoid treatment binding Monocytes Human Human Human Human Human Human Human Erythrocytes Human Human Human Human Human Human Human In vivo In vivo Cort In vivo In vivo In vivo In vivo Cushing’s Cort Dex In vivo In vivo In vivo In vivo In vivo Cushing’s Cushing’s Pred Cort Pred 114 114 112 3 3 3 # t # J. J # Cort - * Dex Cort Pred Dex Cort Cort Cort 3 3 3 1-3 1-3 J. J - # J. # # t, Ref. 50 49 51 48 48 47 52 53 53 53 54 54 52 55 sial. Glucocorticoids have been reported to inbinding that is modulated by the prevailing insulin crease,34,35,41,45-47,49 decreaSe,34,36-38,43,44.48.53,54 or not concentration. Chronic steroid excess appears to alter37,39p40,42,44*47,50-55 insulin binding to hepatodecrease insulin binding. cytes, adipocytes, fibroblasts, lymphocytes, monoThese conclusions from in vitro experiments cytes, and erythrocytes. are supported by in vivo studies in nondiabetic Although there is not total agreement, these animals and humans. In vivo, glucocorticoid exdiscrepant observations can in large part be excess is generally accompanied by increased circuplained by an interaction between the effects of lating insulin concentration^.^^-^^ Almost all in vivo glucocorticoids and hyperinsulinemia on insulin studies have reported either no change47,50-55 or a binding. In vivo, steroid-induced insulin resistance d e ~ r e a s e ~in, insulin ~ ~ , ~ binding, presumably reevokes a compensatory increase in insulin secreflecting a balance between insulin-induced downreserve is adequate, hyperinsut i ~ nIf.pancreatic ~~ regulation and steroid-induced upregulation. The linemia ensues. Hyperinsulinemia per se can demore chronic the steroid excess, the more likely crease insulin binding through a process referred insulin binding will be d e ~ r e a s e d . Changes ~ ~ , ~ ~ ,in~ to as downreg~lation.~~,~~ This process is both time circulating cortisol concentration appear to have and concentration dependent.57 the same effect on insulin binding whether proUnder in vitro conditions, where compenduced by exogenous administration or by altering satory hyperinsulinemia cannot occur, incubation endogenous secretion. Cushing’s syndrome is aswith glucocorticoids results in an acute increase in sociated with no ~ h a n g e , and ~ ~ ,adrenalectomy ~~ h e p a t o ~ y t e ,f~i b’ ~ r ~~b l a s tand , ~ ~ l y m p h ~ c y t ein~ ~ , ~ ~with an increase, in insulin bindings8 Virtually sulin binding. Density shift experiments suggest nothing is known about the effects of in vivo corthat, at least in fibroblasts, the enhanced receptor tisol excess on insulin binding to human muscle binding is due to a decrease in the rate of deacand liver. This is of particular importance since tivation rather than to an increase in the rate of these are the insulin-sensitive tissues that are synthesis of insulin receptors.45If steroid-treated mainly responsible for glucose homeostasis in hufibroblasts are coincubated with insulin, a decrease mans. In addition, the effect of steroids on receprather than an increase in insulin receptor binding tor-postreceptor coupling remains uncertain. occurs.44The duration of exposure to glucocortiIn addition to their effects on insulin binding, coids also may be important. Increases in insulin steroids modulate the tissue response to insulin binding have primarily been observed with short through postreceptor mechanisms. This concluwhereas longer exincubations (1-2 days),34f35,45-47 sion is based primarily on the concept of spare posure (3-7 days) generally has resulted in deinsulin receptors. As has been previously reviewcreased insulin binding.34,36-38,43,44 Taken together, ed,59the total number of insulin receptors in most these data are consistent with an acute, direct, tissues is substantially in excess of the number restimulatory effect of glucocorticoids on insulin quired to elicit a maximal response to insulin. A 21 McMAHON, GERICH, AND RIZZA modest decrease in receptor number is accompanied by a decrease in response to submaxima1 but not to maximal insulin concentrations. However, a postreceptor defect, involving a process that is rate limiting at low but not high insulin concentrations, also can decrease the response to submaximal but not to maximal insulin concentraoitn@ s. ' Therefore, a shift in the insulin doseresponse curve can be due to either a receptor or postreceptor defect. In contrast, a decrease in maximal response, in the absence of a severe reduction in binding, provides strong circumstantial evidence for impaired postreceptor function.59 Acute exposure of tissues to glucocorticoids results in an increase,35~39,41r45 whereas more prolonged exposure results in a decrease, in the maximal response to i n s ~ l i n . ~These , ~ ~results ! ~ ~ suggest impaired postreceptor function. This conclusion is supported by the observation that the decrease in insulin acction at low insulin concentrations is out of proportion to that predicted by the concomitant decrease in insulin binding.34,36-41,43-45 Furthermore, despite identical insulin binding, glucocorticoids may have different effects in the same tissue depending on the response assessed (e.g., dexamethasone may simultaneously decrease glucose uptake and increase amino acid t r a n ~ p o r t )As . ~ ~is the case for insulin binding, little is known regarding the effects of glucocorticoids upon postreceptor function in human liver or muscle. such as 2-deoxyglucose, which are transported but not further metab~lized~~; and (c) when cultured with thymocytes, result in a decrease in intracellular glucose-6-phosphate concentration consistent with impaired transport rather than decreased intracellular metabolism.63 Glucocorticoids inhibit glucose transport in young and old rats, but inhibit oxidation only in young rats.& The time required for these steroids to alter glucose transport varies, depending on the tissue studied. A biphasic response (i.e., an acute increase followed by a chronic decrease) may be observed in some tissues.45In thymocytes, the early actions of cortisol can be separated into three stages? The initial stage lasts 5-10 min, during which time nuclear cortisol-receptor complexes are formed requiring RNA but not protein synthesis. After this stage, the presence of the hormone is no longer necessary. The next stage requires neither RNA nor protein synthesis. The final stage, which occurs approximately 15 min after exposure to the steroid, requires protein but not RNA synthesis. Cortisol's effect on glucose uptake is first evident during the final stage. B. In Vivo Studies Glucocorticoids also modulate glucose utilization in vivo. Their administration has been reor to increase basal ported to either not glucose u t i l i ~ a t i o n . ~Interpretation ~,'~ of these results is confounded by concurrent increases in glucose and insulin concentrations, changes that in VI. EFFECT OF GLUCOCORTICOIDS UPON themselves may increase glucose disposal. Glucose GLUCOSE UTILIZATION clearance, calculated by dividing glucose utiliGlucocorticoids impair carbohydrate tolerance zation by glucose concentration, is decreased by by decreasing glucose utilization. This effect has glucocorticoids.68This has been interpreted as sugbeen demonstrated in both in vitro and in vivo gesting a decrease in the efficiency of glucose upstudies. take. However, the use of glucose clearance as an indicator of efficiency of glucose uptake has been challenged on both theoretical and experimental A. In Vitro Studies grounds. 69 Glucocorticoids inhibit insulin-stimulated gluThe effects of glucocorticoids on glucose utilicose metabolism in adipocytes,61,62 t h y m o c y t e ~ , ~ ~ , zation ~ ~ are more clear-cut when changes in glucose and muscle.64Although the muscle is the tissue and insulin concentrations are prevented. Hyperresponsible for the majority of insulin-stimulated cortisolemia, produced by a 24-h infusion of hydroglucose uptake in vivo, the effect of steroids on cortisone, increases postabsorptive plasma glucose adipocyte and thymocyte metabolism has been and insulin concentrations, and the glucose utilimore thoroughly studied. Glucocorticoids dezation rate.51However, when assessed in the prescrease adipocyte glucose metabolism primarily by ence of comparable glucose and insulin concentrainhibiting glucose transport. This conclusion is tions, using the hyperinsulinemic euglycemic supported by several observations indicating that clamp technique, an inhibitory effect of cortisol on glucocorticoids (a) decrease the number of glucose insulin-induced stimulation of glucose utilization is transportersfi; (b) inhibit the uptake of substances, readily evident (Figure 2). Short-term steroid ex- 22 GLUCOCORTICOIDS AND GLUCOSE METABOLISM GLUCOSE PRODUCTION GLUCOSE UTILIZATION 2.5 2.0 - .k 5 0-0 y 0 I - 10 - 'C 8 MEAN ? SEM 8 Q 12 SALINE w CORTISOL 1.5 - -*z I 1.0 - 6 : Q 5 0.5 - 4 0 - 2 c 10 1 50 ) I 500 2000 10 50 PLASMA INSULIN uU/ml 500 2000 Figure 2. Insulin dose-response curves for suppression of glucose production and stimulation of glucose utilization following a 24-h infusion of either cortisol (2 pg/kg min) or saline (Ref. 51). 1 cess decreases glucose utilization at physiologic but not at supraphysiologic insulin concentrations. In contrast, chronic cortisol excess, as observed in Cushing's syndrome, is associated with an impaired glucose utilization at both physiologic and supraphysiologic insulin concentrations." These data indicate that, despite compensatory changes in glucose and insulin concentration, glucocorticoids decrease the efficiency of glucose uptake. VII. EFFECTS OF GLUCOCORTICOIDS ON HEPATIC CARBOHYDRATE METABOLISM (TABLE 11) Cortisol excess can increase hepatic glucose production. It may do so directly by increasing the gluconeogenic and glycogenic capacity, or indirectly by increasing the gluconeogenic substrate availability. Glucocorticoids also may function in a permissive role by enabling other counterregulatory hormones to exert their effects on the liver. Table 11. Effects of Glucocorticoids on Gluconeogenesis Ref. Increase precursor availability Increase hepatic precursor uptake Facilitate precursor transfer into mitochondria Induce synthesis of gluconeogenic enzymes Increase glucagon secretion Permissive effects of glucagon and epinephrine on p;luconeoeenesis 67,72,73,85,86 72,73 72,73 72,73 24,33 92,93 A. Effects of Glucocorticoids on Gluconeogenesis It has been known since the 1940s that adrenalectomized rats are able to maintain normal plasma glucose concentrations in the fed but not in the fasted state.7 Treatment of adrenalectomized rats with cortisol restores their ability to tolerate a fast by increasing blood glucose and hepatic glycogen levels to n ~ r m a lMultiple .~ subsequent studies have demonstrated that glucocorticoids have potent effects on gluconeogenesis (Table 11); for reviews, see Refs. 72 and 73). They (a) increase the availability and uptake of gluconeogenic substrates, (b) facilitate metabolite transport across the mitochondria1 membrane, (c) induce the synthesis and modulate the activity of critical gluconeogenic enzymes, and (d) potentiate the response to other gluconeogenic hormones such as epinephrine and glucagon. Glucocorticoids increase circulating amino acids levels by increasing the breakdown of protein and decreasing the incorporation of amino acids into skeletal muscle ~ r o t e i n . This ~ ~ , leads ~ ~ to an increase in hepatic amino acid uptake.76 Conversely, adrenalectomy decreases plasma amino acid concentrations. Glucocorticoids increase the availability of the gluconeogenic precursor glycerol by enhancing lipolysis.77,78 They increase the activity of numerous gluconeogenic enzymes including glu~osed-phosphatase,~~ fructose-6-diphosphatase," pyruvate carboxykinase,61,62and pyruvate carboxylase.@Glucocorticoid effects upon gluconeogenesis generally require several hours for full McMAHON, GERICH,AND RIZZA 23 expression and can be blocked by inhibitors of proincreases within three hours of cortisol administratein ~ynthesis.'~ However, recent studies have retion. The glycogenic action of glucocorticoids can ported that dexamethasone can increase the rate of be prevented by the administration of actinomycin conversion of pyruvate to glucose in isolated hepaD, indicating a requirement for protein synthesis.M tocytes within 9 min.@This very short time of onHowever, other studies have suggested a more set and the fact that it is not inhibited by cyclohexrapid stimulation of glycogen synthesis.w The amide suggest that glucocorticoids can act through rapid effect occurs prior to synthetase activation, is pathways that do not require gene transcription independent of protein synthesis, and may be meand subsequent stimulation of protein synthesis. diated by changes in intracellular calcium concenGlucocorticoids also permit the stimulation of glutration.9o coneogenesis by glucagon and epinephrine (see below).70 C. Permissive Effects of Glucocorticoids Although there is general agreement that these hormones inhibit protein synthesis, animal The hypothesis that physiologic concentrastudies have been contradictory as to whether the tions of cortisol are required to allow other horglucocorticoid level capable of causing proteolysis mones to exert their normal metabolic effects was is pharmacologic or p h y s i ~ l o g i cRecent . ~ ~ ~stud~ ~ ~ ~ ~ initially proposed in 1952.91 In vitro studies have ies in humans indicate that modest hypercortisoledocumented the presence of so-called permissive mia (-40 pgldL), produced by an exogenous coreffects of glucocorticoids upon gluconeogenesis, tisol infusion, increases both the rate of appearance glycogenolysis, and l i p ~ l y s i s .The ~ ~ ,term ~ ~ permisand the plasma concentration of l e ~ c i n eSince .~~ sive is used in the sense that glucocorticoids are leucine is an essential amino acid, its sole source in required for the full expression of the cellular rethe postabsorptive state is tissue protein. The insponse to another hormone. The interaction becrease in leucine appearance strongly suggests that tween glucocorticoids and the gluconeogenic efphysiologic concentrations of cortisol are capable fects of epinephrine and glucagon is one such of increasing proteolysis, which in turn results in example. Glucocorticoid deficiency markedly iman increased availability of gluconeogenic amino pairs the ability of glucagon or epinephrine to stimacids. ulate gluconeogenesis or g l y c o g e n ~ l y s i s .Simi~~*~~ larily, the lipolytic effect of epinephrine in vitro and in vivo is reduced in adrenalectomized B. Effects of Glucocorticoids on Glycogen animals.94 Treatment with glucocorticoids, at a Metabolism dose that in itself is not stimulatory, restores reOne of the most dramatic results of the adminsponsiveness to glucagon and epinephrine. Adreistation of cortisol to adrenalectomized animals is nalectomy does not alter the rate of glucagon- or an increase in hepatic and, to a lesser extent, musepinephrine-induced cyclic AMP formation.73 cle glycogen ~ o n t e n tThis . ~ action is due not only to However, adrenalectomy impairs the coupling of stimulation of gluconeogenesis (vida supra), but cyclic AMP with its biologic Glucoalso to an increase in the activity of glycogen syncorticoid deficiency appears to hinder the catecholt h e t a ~ e . ' ~ !Rates ~ of glycogen synthesis and amine modulation of pyruvate kinase and fructose breakdown are dependent upon the activities of 2,6-bisphosphatase Glucocorticoids glycogen synthetase (the enzyme responsible for also increase severalfold the ability of insulin to glycogen synthesis) and glycogen phosphorylase stimulate glycogen ~ y n t h e s i sThus, . ~ ~ these agents (the enzyme responsible for the release of glucose facilitate processes responsible for both increasing from gly~ogen).'~ With steroid exposure, glycogen glycogen storage and hepatic glucose release. synthetase A activity is stimulated both in the basal state and under conditions in which the enzyme D. Effects of Glucocorticoids on Hepatic normally would be ina~tive.'~ Cortisol's glycogenic Glucose Release In Vivo effect is dose dependent and saturable.%Glucocorticoids increase the activity rather than the total Hepatic glycogen stores become depleted duramount of glycogen ~ynthetase.'~ In vitro studies ing glucocorticoid defi~iency.~ An acute excess prosuggest that steroids decrease the inhibition that duces a transient fall in hepatic glucose r e l e a ~ e . ~ ~ , ~ ~ phosphorylase A normally exerts on synthetase The acute decrease in hepatic glucose release does phosphatase (the enzyme that inactivates glycogen not appear insulin mediated since it is observed in synthetase) .89 In vivo, the liver glycogen content pancreatectomized animals.'O A decrease in glu- 24 GLUCOCORTICOIDS AND GLUCOSE METABOLISM cose production has not been observed in humans following an intravenous infusion of cortis01.~~,~ The mechanism for the decrease in glucose production in dogs remains to be defined. Chronic glucocorticoid excess, whether endogenous or exogenous, increases postabsorptive hepatic glucose In dogs, the rate of incorporation of lactate and alanine into glucose is accelerated, suggesting enhanced gluconeogenes ~ s . However, ~' the increase in glucose production ,exceeds the increase in gluconeogenesis, implying concurrent stimulation of glycogenolysis.70 The steroid-induced increase in hepatic glucose release is greater when endogenous insulin secretion is limited, such as occurs with diabetes m e l l i t u ~Ex.~~ ogenous and endogenous cortisol excess causes hepatic insulin r e s i s t a n ~ e . ~Both ' , ~ ~produce a shift to the right in the insulin dose-response curve for suppression of glucose production without altering maximal suppression at supraphysiologic insulin concentrations (Figure 2). As observed in vitro, cortisol potentiates the res onse to glucagon and epinephrine in v ~ v o .JOO~ ~A, ~combined infusion of cortisol, epinephrine, and glucagon (presumably mimicking the hormonal milieu present during stress) results in a greater stimulation of glucose production than accounted for by the sum of the responses to the individual hormones69 (Figure 3). Despite enhanced insulin secretion, the combined infusion produces severe and sustained hyperglycemia. Glucocorticoids also potentiate the lipolytic and lactacidemia action of epinephrine.'" These observations suggest that cortisol may play an important role in the pathogenesis of stress-induced hyperglycemia. E -G*C '-*.*, - -* -,/* Y* 170 Plasma Glucose i I 70L / 4 1 I I I 1 t ra 5 Glucose Product ion ( mg / kg/min 1 /* 4 1 r I O L 30 -4 /4-. r VP I 1 - 2 5 0 I 2 I I I 3 4 5 Time ( h r s ) E. Counterregulation Fasting hypoglycemia may occur in people with chronic glucocorticoid deficiency.lo' As discussed above, hypoglycemia is reversed by small permissive amounts of cortisol."' Further increments in cortisol are not necessary for recovery from acute insulin-induced hypoglycemia. This conclusion is best illustrated by studies of counterregulation in adrenalectomized patients (Figure 4).As long as glucagon secretion is intact, recovery from insulin-induced hypoglycemia is normal in adrenalectomized individuals maintained on replacement doses of glucocorticoid.'02-'05In addition, the observation that the plasma cortisol response to hypoglycemia in normal humans does not occur until well after the compensatory in- Figure 3. Effects of infusion of cortisol (C; 5 mg/M2 min), epinephrine (E; 1.2 &M2 min), or glucagon (G; 3 ng/kg.min) alone or in combination in nondiabetic subjects (Ref. 78). crease in hepatic glucose release has already begun also argues against an important role of cortisol in acute glucose counterregulation. lo6 Furthermore, even if the temporal pattern of secretion were appropriate, cortisol is unlikely to stimulate hepatic glucose release since acute increments in corticosteroid have been reported to decrease rather than to increase glucose p r o d u ~ t i o n . ~ ~ , ~ ~ In contrast, cortisol may play a role in the recovery from prolonged hypoglycemia. Recent studies have demonstrated that subcutaneous in- 25 McMAHON, GERICH, AND RIZZA c .NORMAL SUBJfCTS IN 0-0 INSULIN OSU lOOr Jot- sB :I 1 AORfNALECTOMIZfO SUBJfCrS "'4 ' ko PLASMA NOREPINEPHRINE 800,- I * PI ASMA CORTISOL GROWTH HORMONf PLASMA tPIMPMRINf -- 10 J 10 60 90 MlNUTfS Figure 4. Glucose counterregulation following insulin-induced hypoglycemia in adrenalectomized and nonadrenalectomized (normal) subjects (Ref. 105). jection of insulin results in more severe and prolonged hypoglycemia in patients with insulindependent diabetes mellitus compared to nondiabetic control subjects. Although basal cortisol levels were comparable in both groups, the cortisol response during hypoglycemia was impaired in many of the diabetic person^.'^' However, since glucagon secretion was also impaired, the contribution (if any) of the decrease in cortisol secretion to the defect in counterregulation remains uncertain. VIII. GLUCOCORTICOIDS AND DIABETES MELLITUS Plasma concentrations of cortisol and its urinary metabolites have been reported to be normal"' or increased'09-"' in persons with diabetes mellitus; elevated levels have most commonly been observed in the presence of poor glycemic contro1.'08-'12Abnormal diurnal rhythms and exaggerated early morning increases in plasma cortisol also have been observed in persons with diabetes mellitus."' The early morning rise in plasma cortisol does not appear a major determinant of fasting glucose concentrations in patients with diabetes mellitus since there was no correlation with the average fasting glucose or between the nocturnal change in glucose and the nocturnal change in plasma cortisol levels."' Furthermore, the inhibi- tion of cortisol secretion by either metapyrone or dexamethasone does not alter nocturnal insulin requirements .113,114 Intensive insulin therapy may influence cortisol secretion in persons with insulin-dependent diabetes mellitus (IDDM). The cortisol response to hypoglycemia in six patients with IDDM has been reported to be reduced following four to eight months of near normoglycemia produced by intensive insulin therapy.'15 However, no impairment of cortisol response to hypoglycemia has been reported in studies involving diabetic subjects with autonomic neuropathy, studies assessing the response to a lower glucose nadir, or studies performed after a shorter period of intensive insulin control.116-118Cortisol secretion does not appear to influence patient vulnerability to hypoglycemia during intensive insulin therapy. '19 Of perhaps greater pertinence, catecholamine secretion also was impaired in the studies reporting decreased cortisol ~ecretion."~ A decrease in catecholamine secretion has a major impact on counterregulation in disease states such as IDDM when glucagon secretion is also deficient. Increments in plasma cortisol to levels mimicking those observed during stress causes a more marked derangement in carbohydrate metabolism in diabetic than in nondiabetic i n d i v i d ~ a l s As .~~ shown in Figure 5, an infusion of an identical amount of cortisol resulted in a six- to sevenfold GLUCOCORTICOIDS AND GLUCOSE METABOLISM 26 CORTISOL OR SALINE INFUSION . l 1. I PLASMA GLUCOSE mg /d I ,20 90 650 1 l 1 l I DIABETIC CORTISOL\ I 4/ A4,' I 1 I pk NORMAL CORTISOL +&€-P@ &&&q$z$:$-- *-4-4--4--4-f DIABETIC SALINE istration of the identical dose of dexamethasone induced only mild hyperketonemia in nondiabetic subjects.'24 However, when insulin secretion was inhibited by somatostatin, cortisol excess also markedly increased ketone body concentrations in nondiabetic subjects.'25 Conversely, suppression of endogenous cortisol secretion with metapyrone resulted in a 50% reduction in plasma ketone body production.'" Thus, as with glucose metabolism, the effects of glucocorticoids on ketone body metabolism are strongly influenced by the degree of insulin secretory reserve. 26 GLUCOSE OUTPUT mg/kg/min IX. CONCLUSION 22 2o 18 1 I I -30 0 1 60 120 I I 1 I I I I I 180 240 300 360 TIME (min) Figure 5. Effects of infusion of cortisol (5 mg/M2* h) or saline in diabetic or nondiabeticsubjects. The diabetic subjects were maintained on a constant basal insulin infusion throughout the study (Ref. 98). greater rise in plasma glucose in diabetic than in nondiabetic subjects. In the diabetic subjects, the rise in plasma glucose was due to an excessive rate of hepatic glucose release that was not accompanied by an appropriate increase in glucose utilization. This pattern was substantially different from that observed in nondiabetic subjects receiving the same amount of cortisol. Glucocorticoids also have potent ketogenic effects in diabetes mellitus. Their ketogenic action in insulin-deficient states was described as early as Chronic exposure of persons with the 1950~.'~~,'~' insulin-dependent mellitus to glucocorticoids at concentrations equivalent to those present in diabetic ketoacidosis resulted in a fourfold elevation in ketone body production. 122~123 Heparin-stimulated lipoprotein lipase activity did not cause a further rise in ketone body concentration, suggesting that a cortisol-induced increase in free fatty acids was not the cause of the enhanced ketogenesis. Admin- Glucocorticoid excess can decrease glucose utilization, increase hepatic glucose production, and stimulate glucagon secretion, lipolysis, proteolysis, and gluconeogenesis. These hormones also exert a permissive effect on gluconeogenesis, glycogenolysis, and lipolysis. All of these effects are accentuated by insulin deficiency. Hypercortisolemia potentiates the actions of catecholamines and glucagon on glucose production. 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