Hormonal control of metabolism: regulation of plasma glucose

The control of plasma glucose needs to be tightly monitored because hyperglycaemia and hypoglycaemia can lead to severe clinical problems, including death. In this article the major mechanism for the transport of glucose into and out of the blood and how that mechanism is used to monitor the circulating concentrations of glucose are discussed. A number of hormones regulate glucose in response to changes in plasma concentrations. Insulin promotes the removal of glucose and its conversion to glycogen. Glucagon, in response to falling glucose concentrations, increases the breakdown of glycogen and the release of glucose from the liver. There are many other hormones that play a part in assisting the functions of insulin and glucagon. Failures in the appropriate production of such hormones may lead to the unregulated changes in plasma glucose and subsequent health problems.     

Compensation by fetal erythrocytes of plasma glucose changes in rats

Changes in plasma glucose and glucose and glycogen content in fetal erythrocytes (FRBCs) were studied in rats between days 15 and 21 of gestation and in adult rats. Plasma and FRBC glucose concentrations increased during fetal life and were higher in erythrocytes than in plasma. Glycogen was higher in FRBCs than in adult erythrocytes and tended to decrease from day 15 to 19 of gestation and to increase again on day 21. When FRBCs were incubated in vitro in different glucose concentrations to study their capacity to compensate for changes in plasma glucose concentration, younger cells showed better glucose-buffering capacities. Glucose and glycogen levels in FRBCs increased when they were incubated in high-glucose medium, and the glycogen concentration reached was higher in the early fetal stage than by the end of gestation. Nevertheless, adult erythrocytes accumulated more glycogen in high-glucose medium than cells from any of the fetal-aged erythrocytes. When glucose was injected intraperitoneally into fetuses of different ages, there was an increase of 3.7 microM/ml in glucose concentration in blood from the umbilical artery and 2.5 microM/ml in blood from the umbilical vein. FRBCs buffered some of this change, as evident by an increase in glycogen content. Again, buffering capacity was greater for erythrocytes in younger fetuses. Epinephrine diminished glycogen concentration in venous FRBCs on days 19 and 21 of gestation even in hyperglycemia. Insulin diminished glucose concentration in arterial plasma on days 17 and 21 of gestation, but there were no changes in glucose and glycogen in FRBCs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of gestational hyperglycemia on glucose metabolism and its hormonal control in the fasted, newborn rat during the early postnatal period

To evaluate the effects of gestational hyperglycemia on glucose metabolism and its regulation in the fasted rat during the early postnatal period, unrestrained rats were continuously infused with glucose during the last week of pregnancy. Control rats were infused with distilled water. Newborns were studied during the first six postnatal hours. At birth, newborns from glucose-infused rats, compared with controls, showed higher plasma glucose levels, increased plasma insulin, and lower plasma glucagon and catecholamine concentrations. Between birth and 2 h postpartum, newborn rats from both groups exhibited a marked hypoglycemia, which was, however, more severe in newborns from glucose-infused rats (15 mg/dl) than in controls (26 mg/dl). During the first four postnatal hours, plasma insulin concentration remained higher, while plasma glucagon and catecholamine concentrations remained lower in newborns from hyperglycemic rats. At 6 h, the glycemia reached normal values and the concentrations of the different hormones were similar in controls and newborns from glucose-infused mothers. Concurrently, in the newborns from glucose-infused rats, hepatic glucose production was altered, as they were unable to mobilize liver glycogen stores during the six postnatal hours. Despite slightly delayed phosphoenolpyruvate carboxykinase induction, the rate of gluconeogenesis from 10 mmol/L lactate estimated on isolated hepatocytes was higher in newborns from hyperglycemic mothers than in controls. These results show that gestational hyperglycemia compromises the metabolic and hormonal adaptation of the newborn rat to early extrauterine life; the striking feature of these neonates is the absence of mobilization of liver glycogen stores, which can probably be explained by fetal and neonatal hyperinsulinism associated with the defect of counterregulatory hormones.     

Carbohydrate metabolism in potassium-depleted rats

Carbohydrate metabolism was examined in different organs of rats with dietary potassium deprivation for 4 weeks. Thereafter, a 24- or 48-hour starvation period caused a significant decrease of skeletal muscle and liver glycogen content in K+-depleted (KD) rats, whereas kidney glycogen concentration increased and heart glycogen remained unchanged. In contrast, liver glucose concentration was significantly higher in starved KD animals without changes in muscle, heart, and kidney glucose concentrations. Potassium depletion caused a highly significant decrease of plasma and muscle potassium concentrations, metabolic alkalosis, reduced plasma insulin, and increased creatine phosphokinase levels. Blood lactate, pyruvate, and oxoglutarate levels were significantly enhanced in fasted KD rats, whereas blood citrate, beta-hydroxybutyrate, and glucose concentrations were unchanged. Blood acetoacetate level, however, was significantly reduced following potassium depletion. Therefore, beta-hydroxybutyrate/acetoacetate ratio increased significantly, whereas lactate/pyruvate ratio was not influenced. Our results clearly indicate impaired carbohydrate metabolism in potassium-depleted rats.     

Hormonal dysregulations in severe burns

Measurements of the concentrations of pituitary, thyroid and gonadal hormones have been made under both basal conditions and after adequate stimulation using a combined arginine TRH-LHRH stimulation test in 10 patients with deep burns covering between 30 and 70 per cent of the body surface during the first 20 days after injury.The most remarkable changes were found in the pituitary-gonadal system with testosterone concentrations significantly decreased at all times during the periods of study. Stimulation with LHRH resulted in a prompt response of FSH and LH during the first 10 days after burning whereas between 10 and 20 days after injury the basal concentrations for both hormones were significantly lower and showed a delayed response to stimulation.During the period of early fluid therapy large amounts of glucose without additional insulin were given, resulting in elevated blood glucose and high plasma insulin levels. It is concluded that normal pancreatic insulin production is sufficient to avoid excessive hyperglycaemia even during the period soon after burning. Compared with the findings in control patients the HGH levels in burned patients were not significantly different at any time during the periods of study.     

Effects of hyperglycemia on glucose production and utilization in humans. Measurement with [23H]-, [33H]-, and [614C]glucose

Studies with tritiated isotopes of glucose have demonstrated that hyperglycemia per se stimulates glucose utilization and suppresses glucose production in humans. These conclusions rely on the assumption that tritiated glucose provides an accurate measure of glucose turnover. However, if in the presence of hyperglycemia the isotope either loses its label during "futile" cycling or retains its label during cycling through glycogen, then this assumption is not valid. To examine this question, glucose utilization and glucose production rates were measured in nine normal subjects with a simultaneous infusion of [23H]glucose, an isotope that may undergo futile cycling but does not cycle through glycogen; [614C]glucose, an isotope that may cycle through glycogen but does not futile cycle; and [33H]glucose, an isotope that can both undergo futile cycling and cycle through glycogen. In the postabsorptive state at plasma glucose concentration of 95 mg X dl-1, glucose turnover determined with [614C]glucose (2.3 +/- 0.1 mg X kg-1 X min-1) was greater than that determined with [33H]glucose (2.1 +/- 0.1 mg X kg-1 X min-1, P = 0.002) and slightly less than that determined with [23H]glucose (2.7 +/- 0.2 mg X kg-1 X min-1, P = 0.08). Plasma glucose was then raised from 95 to 135 to 175 mg X dl-1 while insulin secretion was inhibited, and circulating insulin, glucagon, and growth hormone concentrations were maintained constant by infusion of these hormones and somatostatin. Glucose production and utilization rates determined with [614C]glucose continued to be less than those determined with [23H]glucose and greater than those seen with [33H]glucose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Galactose assimilation in pups of diabetic canine mothers

The effects of enteric galactose alimentation on neonatal glucose turnover and hepatic glycogen synthesis were investigated in a newborn animal model of diabetic pregnancy. Control pups and pups of diabetic dogs were studied in the basal state and after each group of pups was randomly fed equivalent amounts of galactose or glucose by oral-gastric tubes. Basal fasting blood glucose levels were not statistically different between the groups, whereas basal plasma insulin levels were 2-3 times higher in pups born to diabetic mothers. Blood glucose levels at each time point in response to glucose or galactose feeding in pups of diabetic mothers were not statistically different; however, the rise of plasma insulin concentrations was attenuated in pups of diabetic mothers fed galactose. The increase in the systemic rate of appearance of glucose and in glucose clearance were attenuated in pups of diabetic mothers fed galactose compared with those fed glucose. Hepatic glycogen content was augmented above basal levels in pups of diabetic mothers. Although glycogen synthase activity was not different between glucose- or galactose-fed pups of diabetic mothers, the active component of glycogen phosphorylase was reduced by both glucose and galactose feedings. Galactose alimentation had a greater effect on glycogen phosphorylase than did glucose alimentation. The observed increase in glycogen synthesis and reduced systemic glucose appearance after galactose alimentation could not be accounted for by the previously proposed excess of galactokinase over glucokinase activities when the latter enzyme was assayed at saturation. Indeed, neonatal hepatic glucokinase activity appeared to be induced during diabetic pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of increasing carbohydrate intake on glucose kinetics in injured patients.

The metabolic and hormonal effect of glucose loads, ranging from 125 to 504 g/70 kg/day, were studied in severely injured patients. There was little or no correlation of glucose intake with nitrogen balance, plasma glucose, fatty acid concentrations, or epinephrine excretion. Increased norepinephrine excretion correlated with and may have resulted from increased glucose intake. Serum glucagon concentrations averaged 320 pg/ml and were not depressed by glucose intake. Insulin concentrations rose with glucose intake but were low for the level of plasma glucose. Glucose oxidation and non-oxidative metabolism, including glycogen deposition, correlated well with glucose intake. Gluconeogenesis from alanine was much higher than normal but was completely suppressed at very high intakes. The data imply that cycling of glucose, with glycerol, glycogen, or both, increased with increasing glucose intake.     

Erythrocytes and glucose homeostasis in rats

The capacity of erythrocytes to modify their glycogen stores to compensate for changes in glucose concentration in plasma was studied. Experiments in vitro and in vivo demonstrated that erythrocytes absorbed and incorporated glucose into their glycogen stores when glucose concentration in the medium was high and liberated it when the concentration was low. Epinephrine administration inhibited glucose absorption by erythrocytes, and in its presence, erythrocytes liberated glucose from their glycogen stores, being unable to compensate for this rise in glucose concentration in plasma. Similar results were obtained when endogenous secretion of epinephrine was enhanced by carotid sinus-chemoreceptor stimulation. Insulin had no effect on the capacity of erythrocytes to absorb glucose. These data suggest a role for erythrocytes in the transport of glucose to different regions in the organism's circulation and in the regulation of glucose concentration in plasma.     

Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients

We searched for metabolic crossover points in muscle glucose metabolite profiles during maintenance of matched glucose fluxes across forearm muscle in insulin-resistant type I (insulin-dependent) diabetic patients and nondiabetic subjects. To classify subjects as insulin sensitive or insulin resistant, whole-body and forearm glucose disposal, oxidative and nonoxidative glucose disposal (indirect calorimetry), and glycogen synthesis (muscle glycogen content in needle biopsies) were measured under euglycemic conditions at two insulin concentrations. Whole-body and forearm muscle glucose disposal were significantly reduced in diabetic patients compared with control subjects. The reduction in total glucose disposal was due to similar relative reductions in oxidative and nonoxidative glucose disposal, pointing toward rate limitation early in glucose metabolism. The defect in nonoxidative glucose disposal was at least partly due to a defect in muscle glycogen synthesis, because muscle glycogen content failed to increase in response to an increase in the plasma insulin concentration in the diabetic patients. The most-insulin-resistant type 1 diabetic patients were restudied under conditions where, by glucose mass action, whole-body glucose disposal was forced to be similar to that in the control subjects. Matching glucose fluxes in the two groups resulted in similar rates of forearm and whole-body oxidative and nonoxidative glucose disposal and muscle glycogen synthesis, but it did not result in accumulation of free intracellular glucose, glucose-6-phosphate, glucose-1-phosphate, fructose-6-phosphate, or lactate in muscle. These data imply that the rate-limiting defect for glucose disposal in skeletal muscle of type I diabetic patients is at the level of glucose transport.     

Banting lecture 1988. Role of insulin resistance in human disease

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)     

Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.

To examine the mechanism by which free fatty acids (FFAs) induce insulin resistance in vivo, awake chronically catheterized rats underwent a hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insulin resistance as reflected by a approximately 35% reduction in the glucose infusion rate (P < 0.05 vs. control). The insulin resistance was associated with a 40-50% reduction in 13C nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs. control) and muscle glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a approximately 25% reduction in glucose transport activity as assessed by 2-[1,2-3H]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a approximately 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). We conclude that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.     

The effect of hemorrhagic shock on plasma amino acids and tissue energy substrates in the primate.

Levels of plasma amino acids and muscle concentrations of energy substrates and metabolites after shock in the Macaca mulatta Rhesus monkey were investigated. The hemodynamic response to shock is similar to that of previously reported studies of primates in shock. Plasma glucose and ASAT increased significantly, while levels of ALAT and pyruvic acid did not change. Lactic acid was elevated. Muscle glycogen and concentrations of lactic acid were increased, and levels of pyruvic acid, creatine phosphate, and malate fell during shock. Levels of ATP in muscle were unchanged. Nine of the 23 arterial plasma amino acids analyzed decreased significantly. Aspartic acid was increased during shock. The increased levels of tissue carbohydrates and decreased concentrations of plasma amino acids observed in this study differ from results previously reported for other animal shock models. Changes in amino acid levels are similar to the results of some clinical studies.     

Plasma glucagon and the insulin:glucagon ratio in gestational diabetes.

The influence of pregnancy on serum glucose, serum insulin, and plasma glucagon concentrations was studied in eight normal women and 14 nonobese gestational diabetics. Each normal individual was subjected to an oral glucose tolerance test in midpregnancy, and all subjects were investigated late in pregnancy and again four to six weeks postpartum. As compared with the postpartum values, fasting glucose concentration decreased during gestation in the normals and increased in the gestational diabetics, but the changes were small and insignificant. In contrast, fasting insulin concentration increased equally and significantly in pregnancy in both groups. Likewise, the glucagon concentration was enhanced in the fasting state in both groups in pregnancy. However, the molar insulin-to-glucagon ratio was significantly elevated in both normals and gestational diabetics. In late pregnancy the magnitude of the insulin response to oral glucose (i.e., the incremental insulin area above fasting baseline) was equally and significantly enhanced in the normals and the gestational diabetics. However, when the insulin response during the first 60 minutes of the OGTT was expressed per unit of glucose stimulus (i.e., the delta insulin/delta glucose ratio) a significantly higher mean response was found in the normal pregnants than in the gestational diabetics. In pregnancy and postpartum, plasma glucagon always decreased to levels significantly below fasting levels after glucose ingestion. In normal midpregnancy the degree of suppression of glucagon was close to that of postpartum, whereas an exaggerated and prolonged suppression was found in late pregnancy in the normals as well as the gestational diabetics. These findings indicate that plasma glucagon and serum insulin concentrations are profoundly influenced by pregnancy. As the changes, however, lead to an increased insulin-to-glucagon ratio, the diabetogenicity of pregnancy is not explained by this relationship.     

Control of glycogen synthesis by glucose, glycogen, and insulin in cultured human muscle cells

A key feature of type 2 diabetes is impairment in the stimulation of glycogen synthesis in skeletal muscle by insulin. Glycogen synthesis and the activity of the enzyme glycogen synthase (GS) have been studied in human myoblasts in culture under a variety of experimental conditions. Incubation in the absence of glucose for up to 6 h caused an approximately 50% decrease in glycogen content, which was associated with a small decrease in the fractional activity of GS. Subsequent reincubation with physiological concentrations of glucose led to a dramatic increase in the rate of glycogen synthesis and in the fractional activity of GS, an effect which was both time- and glucose concentration-dependent and essentially additive with the effects of insulin. This effect was seen only after glycogen depletion. Inhibitors of signaling pathways involved in the stimulation of glycogen synthesis by insulin were without significant effect on the stimulatory action of glucose. These results indicate that at least two distinct mechanisms exist to stimulate glycogen synthesis in human muscle: one acting in response to insulin and the other acting in response to glucose after glycogen depletion, such as that which results from exercise or starvation.     

Mechanism of amino acid-induced skeletal muscle insulin resistance in humans

Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 microg/l) somatostatin clamp tests in the presence of low (approximately 1.6 mmol/l) and increased (approximately 4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with D-[6,6-(2)H(2)]glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using (13)C and (31)P nuclear magnetic resonance spectroscopy, respectively. A approximately 2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180--315 min, 24 plus minus 3; control, 67 plus minus 10 micromol center dot l(-1) center dot min(-1); P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (DeltaG6P(260--300 min), 18 plus minus 19; control, 103 plus minus 33 micromol/l; P < 0.05). In conclusion, plasma amino acid elevation induces skeletal muscle insulin resistance in humans by inhibition of glucose transport/phosphorylation, resulting in marked reduction of glycogen synthesis.     

Normalization of insulin sensitivity with lithium in diabetic rats

Lithium salts are commonly used in psychiatric patients and have been shown to have an insulinlike action in vitro. To define the impact of lithium ion on in vivo glucose metabolism, the effect of 2 wk of lithium treatment on plasma glucose and insulin concentrations, insulin-mediated glucose disposal, and skeletal muscle glycogen synthesis in normal and diabetic rats was examined. Our results demonstrated the ability of lithium ions to completely restore insulin sensitivity to normal in diabetic rats. The insulin-mimetic activity of the cation seems to be highly specific for the glycogenic pathway in skeletal muscle. These results raise the possibility that lithium ion may prove effective in reversing the defect in glycogen storage that characterizes non-insulin-dependent diabetes mellitus in humans.     

Metabolic studies in the pyelonephritic rat.

Insulin antagonism characterizes infection, but the mechanism is unknown. Previous studies have been performed during the acute catabolic stage of infection, and the resultant metabolic changes reflect this decreased food intake and weight loss. To delineate metabolic alterations due to infection itself, rats with pyelonephritis induced by tail-vein injection of 1 ml. of Streptococcus faecalis (10(9) bacteria per milliliter) were studied two weeks later during a period of near-normal weight gain and food intake. Fasting growth hormone concentrations (nanograms per milliliter) in the pyelonephritic rats were nearly five times normal (45.8 vs. 9.9). Intra-arterial glucose and insulin tolerance tests were impaired. Early glucose-induced insulin release was depressed. Fat pads from infected rats manifested higher basal lipolysis per cell. Glycerol-mediated gluconeogenesis by liver slices was decreased. This pathway was unaffected by insulin in infected rats but readily inhibited in control rats. The following metabolic parameters were similar in control and infected animals: (in vivo) fasting concentrations of plasma glucose, free fatty acids, triglycerides, total corticoids, creatinine, insulin, glucagon, molar ratios of insulin and glucagon, glucose and insulin responses to tolbutamide, and glucagon and free fatty acid suppression after glucose; (in vitro) glucose metabolism by muscle and fat, epinephrine- and theophylline-stimulated lipolysis and re-esterification by epididymal fat pads, fasting hepatic glycogen content, glucose production by liver slices with and without alanine. No plasma insulin antagonist was found in the infected rats. Metabolic alterations in infected rats can be demonstrated independently of the associated catabolism. Increased growth hormone secretion cannot explain all of these changes.     

Measured energy expenditure and plasma substrate and hormonal changes after severe head injury.

The influence of head trauma on the pattern of response to injury has been studied. Metabolic and hormonal data from brain injured patients over 20 days following injury were compared with an existing data base from non-head-injured patients and control subjects. The results demonstrated elevated concentrations of plasma glucose, lactate, non-esterified fatty acids (NEFA), cortisol, glucagon and insulin above that of control values in both groups after injury. Head injury as a separate factor did not affect the concentrations of any of these plasma substrates and hormones independently of its contribution to the Injury Severity Score (ISS). However, plasma catecholamine concentrations were higher in the head injured initially and at 7 days after injury. All head-injured patients showed an increase in metabolic rate (above predicted values) at some stage after injury. It should be noted, however, that there were some features of head injury (and its treatment) such as paralysis, ventilation and fasting which were not matched in the non-head-injured group. It was concluded that the metabolic changes occurring after head injury are similar to those occurring after extracranial injury and that therapeutic intervention has a major effect on the level of energy expenditure seen in these patients.     

Pancreatic islet hormone response to oral glucose in morbidly obese patients.

Pancreatic islet peptides, as well as other gastrointestinal hormones, have been implicated in both the pathogenesis of obesity and the etiology of associated metabolic derangements. This study evaluated the pancreatic islet and gastrointestinal (GI) hormone response to oral glucose in 20 morbidly obese (151% above ideal body weight) patients. Glucose intolerance, hyperinsulinism, and exaggerated gastric inhibitory polypeptide (GIP) release occurred following glucose ingestion. Significant release of PP occurred in 14 patients, while only six patients had release of somatostatin. No significant changes in plasma concentrations of glucagon occurred. Since GIP is insulinotropic in the presence of hyperglycemia, the hyperinsulinism of morbid obesity may be secondary to the abnormally high glucose-stimulated GIP levels in these patients. Failure of glucagon suppression in response to oral glucose many contribute to the hyperglycemia noted. Somatostatin and pancreatic polypeptide may be responsible for some of the metabolic derangements of morbid obesity.