Stimulation Of Glucose Utilization Research Articles

Effect of mono-(2-ethylhexyl) phthalate on the metabolism of energy-yielding substrates in rat sertoli cell-enriched cultures

The effect of the testicular toxin mono-(2-ethylhexyl) phthalate (MEHP) on the metabolism of energy-yielding substrates in Sertoli cell-enriched cultures has been studied. MEHP stimulated glucose utilization and oxidation. Stimulation of 14CO 2 production was greater with [1- 14C]- than with [6- 14C]glucose. Oxidation of [1- 14C]pyruvate and [U- 14C]acetate to 14CO 2 was reduced by MEHP treatment in the presence but unaffected in the absence of glucose. MEHP increased the incorporation of radioactivity from [1- 14C]- and [6- 14C]glucose but not from [U- 14C]acetate into fatty acids. MEHP markedly increased the production of lactate by Sertoli cells cultured in the presence of 5.5 m m-glucose and 0.5 m m-pyruvate. Decreasing the glucose concentration reduced this stimulatory effect. In glucose-free medium containing 0.5 or 2.5 m m-pyruvate MEHP had no effect on Sertoli cell lactate production. Thus, MEHP appears to stimulate the utilization of glucose by the Sertoli cell but does not appear to have a direct effect on the conversion of pyruvate to lactate, on the conversion of pyruvate to acetyl CoA or a direct effect on the metabolism of acetyl CoA through the Krebs cycle. Increased glucose utilization appears to be a consequence of the increased metabolism of glucose that occurs through the glycolytic and pentose phosphate pathways. These results suggest that in contrast to its effects on the liver, MEHP does not exert a primary effect on the Sertoli cell mitochondrion.

Thyrotropin-releasing hormone (TRH): Insulin-like action on glucoregulation

Normoglycemia is maintained through a complex interplay between the glucoregulatory hormones, glucagon, epinephrine. the glucocorticoids and insulin [l, 21, and it is under the controlling influence of various neurotransmitters and peptides acting upon the endocrine pancreas, the liver or at the level of the central nervous system (CNS) [3-6]. Most of the hormones and neural factors implicated in glucoregulation are called into play in response to hypoglycemia resulting from diminished supply or increased expenditure of metabolic fuel, and they act to normalize glucose levels by directly or indirectly promoting sugar production [7]. For example, glucagon is released from alpha-cells in the pancreas whenever plasma glucose levels fall below normal, and it stimulates glucose production in the liver through direct action [ 1,8] or, additionally, by acting within the CNS [9]. Similarly, epinephrine is released from the adrenal medulla in response to hypoglycemia, and it promotes glucose production through direct action on muscle or liver [ 1, 101 as well as indirectly, through CNS action [ll]. Other factors, such as cholecystokinin, bombesin, the opioid peptides and corticotropin-releasing factor (CRF), influence glucoregulation in part by modulating pancreatic function and in part by indirectly stimulating glucose production through CNS action [4, 12-151. In contrast to the multitude of apparently redundant counterregulatory mechanisms set in motion by hypoglycemia, only one peptide hormone, insulin. serves to counteract hyperglycemia. Insulin is released from pancreatic beta-cells in response to high glucose, and it normalizes sugar levels partly by stimulating glucose utilization in muscle and adipose tissues and partly by inhibiting glucose output from the liver [16, 171. In addition, insulin can lower circulating glucose levels by indirectly modulating the production and utilization of sugar through action in the CNS [lS-211. Thyrotropin-releasing hormone (TRH) is a hypothalamic tripeptide (pGlu-His-Pro-NH,) implicated in the regulation of pituitary thyrotropin and prolactin synthesis and secretion [22,23]. In addition. it is known for its many extrapituitary actions. Most

Somatotropin antagonism of insulin-stimulated glucose utilization in 3T3-L1 adipocytes.

It is well established that somatotropin (GH) antagonizes insulin action in vivo and that supraphysiologic concentrations of GH frequently result in insulin resistance and glucose intolerance. However, the demonstration of an anti-insulin activity by GH in vitro has been difficult. This study, therefore, set out to determine whether cultures of 3T3-L1 adipocytes could be used to examine the anti-insulin activity of GH. The ability of insulin to stimulate glucose utilization by 3T3-L1 adipocytes increases approximately five-fold during the first 4 days following treatment of the cells with a differentiation medium. It was found that glucose utilization in 3T3-L1 adipocytes is regulated in a reciprocal fashion by insulin and GH. Bovine or human GH directly inhibit up to 50% of insulin-stimulated [14C]-glucose incorporation into lipids in a concentration-dependent manner. The 3T3-L1 sensitivity to GH appears to be at the maximum (50% inhibition of an insulin response) immediately following removal of the cells from the differentiation medium and remains essentially constant during the subsequent 4 days. The GH inhibition of insulin action does not appear to be due GH enhancement of cellular degradation of insulin, competitive binding of GH to the insulin receptor, or GH-induced decrease in cell number. The 3T3-L1 adipocyte system appears to be a sensitive and reliable in vitro model with which to study the molecular mechanisms involved in both GH antagonism of insulin action and development of hormone responsiveness during cellular differentiation into adipocytes.

Effects of nonesterified fatty acid availability on tissue-specific glucose utilization in rats in vivo.

The pathophysiological significance of the glucose-fatty acid cycle in skeletal muscle in vivo is uncertain. We have examined the short term effects of increased availability of nonesterified FFA on tissue-specific glucose uptake and storage in rat tissues in vivo basally and during a hyperinsulinemic (150 mU/liter) euglycemic clamp. Circulating FFA were elevated to 2 mmol/liter (FFA 1) or 4 mmol/liter (FFA 2). Elevated FFA produced a dose-dependent inhibition of myocardial glucose utilization in both basal (FFA1, 42%; FFA2, 68%; P less than 0.001, by analysis of variance) and clamp groups (FFA1, 39%; FFA2, 49%; P less than 0.001) and also suppressed brown adipose tissue glucose utilization during the clamp (-42%, P less than 0.001). In contrast to heart, glucose utilization in skeletal muscle was suppressed by FFA only in the FFA1 basal group (-36%, P less than 0.001); in other groups (e.g., FFA2 clamp) elevated FFA produced increased skeletal muscle glucose utilization (+68%, P less than 0.001) that was directed toward glycogen (+175%, P less than 0.05) and lipid deposition (+125%, P less than 0.005). FFA stimulated basal glucose utilization in white (e.g., FFA2, +220%, P less than 0.005) and brown adipose tissue (e.g., FFA2, +200%, P less than 0.005). Thus elevated FFA can acutely inhibit glucose utilization in skeletal muscle in addition to cardiac muscle in vivo supporting a possible role for the glucose-fatty acid cycle in skeletal muscle in acute insulin resistance. However, at high levels or with elevated insulin, FFA stimulates glucose utilization and storage in skeletal muscle. By promoting accumulation of glucose storage products, chronic elevation of FFA may lead to skeletal muscle (and therefore whole body) insulin resistance.

Effects of subacute capsaicin treatment on local cerebral glucose utilization in the rat

The autoradiographic 2-deoxy- d-[1- 14C] glucose method was used to map the effect of subacute capsaicin administration on local cerebral glucose utilization, an index of brain function. After treatment with an 80 mg/kg, subcutaneous, cumulative dose of capsaicin over 3 days, a challenge dose of 20 mg/kg capsaicin stimulated glucose utilization in dorsal column and brainstem nuclei which receive primary sensory afferent input or are important in autonomic functions. Glucose utilization in the medial septum was simultaneously reduced. Following a 280 mg/kg cumulative dose of capsaicin over 5 days, a capsaicin challenge dose of 20 mg/kg did not stimulate glucose utilization in the hindbrain, but the decrement in the medial septum was maintained and extended into the lateral septum. The findings provide evidence for a central component of the stimulation and subsequent insensitivity observed with continued capsaicin treatment, and suggest that the deoxyglucose procedure is useful in elucidating the neuroanatomical areas involved in several of the sensory and autonomie effects of capsaicin.

Phosphate feeding to permit growth while maintaining secondary product synthesis

Summary. Maintaining high metabolic activities for extended periods by feeding small amounts of the growth limiting nutrient was examined for the production of cycloheximide by Streptomyces griseus. Batch studies indicated that increased initial phosphate levels led to increased cell concentrations, stimulated glucose utilization, and over a limited range (<0.6 g/1 KH2PO4) did not adversely affect cycloheximide production rates. Semi-continuous phosphate feeding was observed to permit limited cell growth, and to enhance metabolic activities (i. e. glucose utilization). The effect of semi-continuous phosphate feeding on antibiotic production depended on the feed rate, with high feed rates suppressing production.

Insulin action in non-insulin-dependent diabetes mellitus: The relationship between hepatic and extrahepatic insulin resistance and obesity

To determine the contribution of obesity to the insulin resistance of non-insulin-dependent diabetes mellitus, insulin dose response curves for suppression of glucose production and stimulation of glucose utilization were generated in lean and obese diabetic patients and compared to those observed in weight-matched nondiabetic subjects. Glucose utilization during 0.4, 1.0, and 10.0 mU/kg × min insulin infusions (producing insulin concentrations ranging from ∼50 to 2,000 μU/mL) was lower (p < .02 to .001) in lean and obese diabetic patients compared to weight-matched nondiabetic subjects indicating insulin resistance. Glucose utilization was not correlated with obesity in the diabetic subjects. Suppression of glucose production was impaired ( P < .03 and .001) in both the lean and obese diabetic subjects at physiologic but not supraphysiologic insulin concentrations. We conclude that patients with NIDDM have both hepatic and extrahepatic insulin resistance, the severity of which appears to be independent of the degree of obesity.

Use of a variable insulin infusion to assess insulin action in obesity: defects in both the kinetics and amplitude of response.

To determine whether the severity of insulin resistance in obesity, as assessed by the traditional hyperinsulinemic glucose clamp, reflects the severity of resistance present during changing insulin concentrations, such as occur after meal ingestion, 9 moderately obese and 12 lean subjects were studied on 2 occasions: once during a primed continuous insulin infusion and once during a variable 8-step insulin infusion. Identical amounts of insulin were given on each occasion, and euglycemia was maintained by a glucose infusion. Stimulation of isotopically determined glucose utilization above the basal value was lower in the obese than in the lean subjects during the variable [2.4 +/- 0.5 (+/- SEM) vs. 5.4 +/- 0.7 g/m2; P = 0.004] and the constant (2.9 +/- 0.7 vs 4.2 +/- 0.9 g/m2; P = 0.32) insulin infusions; however, the differences were only significant with the variable insulin infusion. The variable insulin infusion also was associated with lower rates of activation of glucose utilization (slope, 0-90 min, 0.27 +/- 0.05 vs. 0.55 +/- 0.09 mg/m2 X min 2; P = 0.01) in obese compared to lean subjects. In contrast, rates of activation during the low constant infusion (0.24 +/- 0.05 vs. 0.29 +/- 0.06 mg/m2 X min 2; P = 0.51) did not differ in the lean and obese subjects. Despite identical amounts of insulin, stimulation of glucose utilization was greater (P less than 0.03) during the variable than during the constant insulin infusion in the lean subjects. In contrast, stimulation during the variable and constant insulin infusions was equal in the obese subjects. These observations indicate that insulin resistance in obesity is due to a defect in the rate as well as absolute response achieved and suggest that under conditions of daily living the contribution of insulin resistance to impaired carbohydrate tolerance is greater than that previously estimated by a constant insulin infusion.

Effects of Guanosine 3′,5′-Monophosphate on Glucose Utilization in Isolated Islets of Langerhans*

Dynamic changes in total glucose utilization in isolated islets of Langerhans of the rat were determined by quantitation of the formation of 3H2O from D-[5-3H]glucose. The addition of 8-bromo-cGMP (8-Br-cGMP) or monobutyryl cGMP to the islets during a linear phase of glucose utilization resulted in concentration- and time-dependent increases in glucose utilization. Effects of the analogs of cGMP on glucose utilization were noted as early as 5 min after the onset of stimulation in the presence of 10 mM glucose. 8-Br-cGMP also increased the utilization of 1 mM glucose within 20 min. Stimulatory effects of 8-Br-cGMP were observed in the presence of cycloheximide or N-acetylglucosamine. Neither 8-bromo-cAMP (8-Br-cAMP) nor monobutyryl cAMP induced significant changes in glucose utilization at 1 or 10 mM glucose. In the presence of 3-isobutyl-1-methylxanthine (IBMX), 8-Br-cGMP, but not 8-Br-cAMP, induced a rapid change in glucose utilization. N-Methyl-N'-nitro-N-nitrosoguanidine, which activates guanylate cyclase, also stimulated glucose utilization in the presence of IBMX by 3-fold. IBMX alone did not change glucose utilization. In contrast, 8-Br-5'-GMP reduced glucose utilization, whereas 8-bromoinosine 3',5'-monophosphate and 8-bromoguanosine did not change glucose utilization. Sodium bromide did not affect glucose utilization. Glucose-stimulated insulin release was potentiated by 8-Br-cGMP, whereas insulin release from islets incubated in the absence of glucose or the presence of glyceraldehyde or 2-ketoisocaproic acid was not altered by 8-Br-cGMP. Thus, glucose utilization in pancreatic islets is modulated by cGMP, and the secretory response to 8-Br-cGMP is glucose dependent.

A possible hypoglycemic agent “glucose tolerance factor” stimulates glucose utilization both at transport and post-transport stages in isolated rat adipocytes

A possible hypoglycemic agent “glucose tolerance factor” stimulates glucose utilization both at transport and post-transport stages in isolated rat adipocytes

P-6-3 A possible hypoglycemic agent “glucose tolerance factor” stimulates glucose utilization both at transport and post-transport stages in isolated rat adipocytes

P-6-3 A possible hypoglycemic agent “glucose tolerance factor” stimulates glucose utilization both at transport and post-transport stages in isolated rat adipocytes

Effects of POCA on metabolism and function in the ischemic rat heart.

Sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) inhibits carnitine palmityltransferase I and fatty acid oxidation. The effects of POCA on cardiac function and on tissue levels of carnitine and coenzyme A esters were studied in the isolated rat heart subjected to 90 minutes of ischemia with and without 15 minutes of reperfusion. The perfusion medium contained 1.2 mM palmitate and 5.5 mM glucose plus or minus 0.5 mM POCA. This compound prevented accumulation of long-chain acylcarnitine and coenzyme A esters during ischemia and significantly improved the recovery of cardiac output after ischemia and reperfusion. Short-chain acylcarnitine levels were increased during ischemia by POCA. No effects were noted on tissue ATP and lactate levels. POCA may protect the ischemic heart by preventing accumulation of these toxic metabolites and by stimulating glucose utilization during ischemia.

Insulin-mediated glucose uptake in nondialyzed and dialyzed uremic insulin-dependent diabetic subjects.

A three-step euglycemic insulin clamp was performed in six matched groups: nine healthy subjects, 10 insulin-dependent diabetic (IDD) subjects with normal kidney function, 10 nondiabetic uremic subjects, six nondialyzed uremic IDD subjects, seven uremic IDD subjects on chronic hemodialysis (HD), and six uremic IDD subjects on chronic ambulatory peritoneal dialysis (CAPD). Insulin was infused sequentially at rates of 0.5 (step 1), 2.0 (step 2), and 4.0 (step 3) mU X kg-1 X min-1. Each dose was given for 120 min; however, in the IDD subjects with fasting hyperglycemia, step 1 of the clamp was slightly extended. Average serum free insulin levels at steady state ranged from 22 to 342 microU/ml and were comparable in all groups. Step 3 glucose infusion rate (GIR), the last 30 min of the infusion period, was extremely suppressed in nondialyzed uremic IDD subjects, amounting to 53% of that in healthy subjects (7.7 +/- 0.7 versus 14.4 +/- 0.9 mg X kg-1 X min-1, P less than 0.001) indicating severe insulin resistance in peripheral tissues. As expected, step 3 glucose disposal was also reduced in IDD subjects with normal kidney function (12.4 +/- 0.6 mg X kg-1 X min-1) and nondiabetic uremic subjects (9.2 +/- 0.6 mg X kg-1 X min-1) as compared with healthy subjects (P = 0.06 and P less than 0.001, respectively). The pronounced impairment of insulin responsiveness in nondialyzed uremic IDD subjects was almost equal to the sum of the defects in nondiabetic uremic and IDD subjects with normal kidney function.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of insulin-mediated and glucose-mediated glucose disposal in patients with insulin-dependent diabetes mellitus and in nondiabetic subjects.

To determine whether glucose-mediated as well as insulin-mediated regulation of glucose utilization and glucose production is impaired in patients with insulin-dependent diabetes mellitus (IDDM), six nonobese, diabetic patients and seven age-, sex-, and weight-matched nondiabetic subjects were studied. Despite slightly higher free insulin concentrations in the diabetic patients than in the nondiabetic subjects during 0.2 mU/kg X min (22 +/- 3 versus 15 +/- 2 microU/ml) and 1.0 mU/kg X min (98 +/- 10 versus 75 microU/ml) insulin infusions, glucose utilization at plasma glucose concentrations of 95, 135, and 175 mg/dl was lower in the diabetic patients than in the nondiabetic subjects. The increment in glucose utilization per increment in plasma glucose (i.e., slope) in the diabetic and nondiabetic subjects, respectively, did not differ significantly during either the 0.2 (1.7 +/- 1.3 versus 1.4 +/- 0.5 dl/kg X min) or 1.0 (4.4 +/- 1.1 versus 6.2 +/- 1.0 dl/kg X min) mU/kg X min insulin infusions, although they tended to be higher in the nondiabetic subjects during the latter infusion. Thus, although stimulation of glucose utilization by insulin is impaired in patients with IDDM, the ability of an increase in glucose concentration to increase glucose utilization does not appear to differ from that present in nondiabetic subjects, at insulin concentrations in the low physiologic range. Whether differences exist in the high physiologic range remains to be determined.

Effect of hyperoxia on the carbohydrate metabolism of human lymphocytes.

Lymphocytes incubated under high oxygen tensions have impaired lymphoblastic transformation to nonspecific mitogens. Since carbohydrate metabolism may be essential for an optimal proliferation of these cells following an antigenic stimulus, we have characterized the effect of hyperoxia on the glucose metabolism of human lymphocytes in vitro. The mean rates of glucose utilization, Krebs cycle activity, and hexose monophosphate shunt activity were determined for unstimulated and phytohemagglutinin (PHA)-stimulated cultures incubated for 3 days. In unstimulated cultures, hyperoxia stimulated glucose utilization and markedly impaired Krebs cycle activity but did not alter HMPS activity. These observations suggest that hyperoxia impairs the mitochondrial activity of lymphocytes and that increased glycolysis compensates for the loss of cellular energy normally produced by this organelle. Under high oxygen tension PHA-stimulated cultures failed to show the burst in HMPS activity and increased Krebs cycle activity characteristic of cultures incubated under physiological oxygen tensions and consumed less glucose. Our results indicate that hyperoxia alters the glucose metabolism of lymphocytes. This metabolic alteration may be related to the impaired function of the cells under hyperoxic conditions.

Insulin resistance in Cushing's syndrome.

It is well established that cortisol excess causes insulin resistance in man, but the mechanisms responsible for this insulin resistance are poorly understood. We studied five women with Cushing's syndrome with impaired oral glucose tolerance tests and seven normal subjects, plotting the shape of the insulin-induced disposal dose-response curve obtained by means of the euglycemic clamp procedure during four different plasma insulin plateaus at four infusion rates of 21, 73, 760, and 1200 mU/M2 . min. Glucose disposal (M = mg/M2 . min) was calculated as glucose amount infused to maintain euglycemia. In Cushing's syndrome the dose-response curve was shifted to the right in comparison with normal subjects, with a significantly lower M (337 +/- 35 vs. 657 +/- 76 P less than 0.01) during the highest insulin infusion rate [maximal glucose disposal (MGD)] without any significant difference in the levels of insulin half-maximally effective in the stimulation of glucose utilization. Neither erythrocyte nor monocyte maximum insulin receptor binding were different between the two populations. Four Cushing's syndrome patients were studied again after surgical treatment. A marked improvement of MGD was observed without any significant change in insulin-binding capacity. These results, particularly the marked decrease in MGD, a typical feature of postreceptor defects, indicate that cortisol-induced insulin resistance in man is due to an impairment of peripheral insulin action located beyond the hormone-receptor binding step.

Quantification of insulin secretion and in vivo insulin action in nonobese and moderately obese individuals with normal glucose tolerance.

Insulin secretion and in vivo insulin action were quantified in nonobese and moderately obese subjects (approximately 35% above desirable body weight) with normal glucose tolerance. Insulin secretion was estimated by determining plasma insulin responses to a 75-g oral challenge, and in vivo insulin-stimulated glucose uptake by the euglycemic clamp technique. Plasma glucose levels of the two groups were identical during the glucose tolerance test, but the plasma insulin response was significantly greater (P less than 0.01) in the obese subjects. However, insulin-stimulated glucose utilization by the two groups was equal during the euglycemic clamp studies. These results were supported by the fact that degree of obesity correlated significantly with insulin response (r = 0.61, P less than 0.005), but not with insulin-stimulated glucose utilization (r = -0.25, P greater than 0.2). Thus, indirect evidence that moderately obese subjects were more insulin-resistant based on measurement of plasma insulin response was not supported by direct quantification of insulin action. One explanation for these findings is that the height of the plasma insulin response bears no relationship to loss of in vivo insulin action, but that seems unlikely in view of the fact that there was a significant correlation (r = -0.52, P less than 0.01) between these two variables in the group as a whole. Therefore, it appears that the hyperinsulinemia seen in obese individuals may not be a simple function of insulin resistance, and that ability of insulin to stimulate glucose utilization is not significantly impaired in moderately obese subjects with normal glucose tolerance. Alternatively, the degree of impairment in insulin action seen in these individuals is insufficient to be detected by the euglycemic clamp technique.

Insulin resistance in noninsulin-dependent diabetes mellitus: Does it exist and can it be measured?

Several techniques that have been used to quantify in vivo insulin-stimulated glucose uptake in patients with noninsulin-dependent diabetes mellitus (NIDDM) have been critically reviewed. An attempt has been made to outline both the advantages and disadvantages of the specific approaches, as well as to summarize the results of the application of these methods in assessment of insulin action in patients with NIDDM. Although the details of the techniques that have been used vary considerably, the results obtained with all of them are quite consistent, and demonstrate unequivocally that the ability of insulin to stimulate glucose utilization is markedly reduced in patients with NIDDM.

Insulin receptor binding and insulin action in human fat cells: Effects of obesity and fasting

We have studied ( 125I)-insulin binding and insulin dose response relationships of ( 14C)-methylglucose transport conversion of ( 14C)-glucose to CO 2 and total lipids, and lipolysis at 37°C and pH 7.4 in adipocytes from obese patients before ( n = 15) and after fasting for 10 days ( n = 6). Studies of adipocytes from obese before fasting showed a significant reduction of insulin binding when expressed to cell surface area and rightward shifts of the insulin dose response curves (decreased insulin sensitivity) for glucose transport, glucose oxidation, lipogenesis and antilipolysis. The decreased insulin sensitivity of adipocytes from obese was most likely the functional consequence of the impaired insulin binding. Moreover, decreased maximal glucose transport capacities were present in fat cells from obese both in the basal and maximally insulin stimulated states. Similarly, the percentage response above basal level to maximal insulin stimulation of glucose oxidation and lipogenesis was impaired in these cells. The latter findings suggest post receptor defects localized both to the transport system per se and to intracellular mechanisms involved in the metabolism of glucose. Conversely, the post receptor pathways for the insulin induced antilipolysis was intact in fat cells from obese man. Studies after fasting showed an increase of adipocyte insulin binding accompanied by an increased sensitivity to the antilipolytic effect of insulin with unchanged maximal responsiveness. However, due to marked post receptor alterations, the insulin stimulated glucose utilization was severely blunted. Thus, the glucose transport system of adipocytes from all fasted subjects was totally unresponsive to insulin, while some of the fasted patients had a slight response of glucose oxidation and lipogenesis in the presence of insulin in maximally effective concentrations.

Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization.

The present studies were undertaken to assess the mechanisms responsible for growth hormone-induced insulin resistance in man. The insulin dose-response characteristics for suppression of glucose production and stimulation of glucose utilization and their relationship to monocyte insulin binding were determined in six normal volunteers after 12-h infusion of growth hormone and 12-h infusion of saline. The infusion of growth hormone (2 micrograms . kg-1 . h-1) increased plasma growth hormone nearly threefold (to congruent to 9 ng/ml) within the range observed during sleep and exercise. This increased plasma insulin (14 +/- 1 versus 8 +/- 1 microunits/ml, P less than 0.005) concentrations without significantly altering plasma glucose concentrations or basal rates of glucose production and utilization. Insulin dose-response curves for both suppression of glucose production (half-maximal response at 37 +/- 3 versus 20 +/- 3 microunits/ml, P less than 0.01) and stimulation of glucose utilization (half-maximal response at 98 +/- 8 versus 52 +/- 8 microunits/ml, P less than 0.01) were shifted to the right with preservation of normal maximal responses to insulin. Monocyte insulin binding was unaffected. Thus, except at near maximal insulin receptor occupancy, the action of insulin on glucose production and utilization per number of monocyte insulin receptors occupied was decreased. These results indicate that increases in plasma growth hormone within the physiologic range can cause insulin resistance in man, which is due to decreases in both hepatic and extrahepatic effects of insulin. Assuming that insulin binding to monocytes reflects insulin binding in insulin sensitive tissues, this decrease in insulin action can be explained on the basis of a postreceptor defect.