Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU x kg(-1) x min(-1)) clamp and a two-step euglycemic IGF-I (26 and 52 pmol x kg(-1) x min(-1)) clamp with [3-(3)H]glucose, [1-(14)C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (R(d)) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of R(d) (second clamp step) in response to both insulin and IGF-I was reduced by approximately 40-50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin (P < 0.01-0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects (P < 0.05-0.01). CONCLUSIONS: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.     

Free fatty acid-induced peripheral insulin resistance augments splanchnic glucose uptake in healthy humans

To investigate the effect of elevated plasma free fatty acid (FFA) concentrations on splanchnic glucose uptake (SGU), we measured SGU in nine healthy subjects (age, 44 +/- 4 yr; body mass index, 27.4 +/- 1.2 kg/m(2); fasting plasma glucose, 5.2 +/- 0.1 mmol/l) during an Intralipid-heparin (LIP) infusion and during a saline (Sal) infusion. SGU was estimated by the oral glucose load (OGL)-insulin clamp method: subjects received a 7-h euglycemic insulin (100 mU x m(-2) x min(-1)) clamp, and a 75-g OGL was ingested 3 h after the insulin clamp was started. After glucose ingestion, the steady-state glucose infusion rate (GIR) during the insulin clamp was decreased to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in GIR during the period after glucose ingestion from the ingested glucose load. [3-(3)H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of endogenous glucose production (EGP) and glucose disappearance (R(d)). During the 3-h euglycemic insulin clamp before glucose ingestion, R(d) was decreased (8.8 +/- 0.5 vs. 7.6 +/- 0.5 mg x kg(-1) x min(-1), P < 0.01), and suppression of EGP was impaired (0.2 +/- 0.04 vs. 0.07 +/- 0.03 mg x kg(-1) x min(-1), P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly increased during the LIP vs. Sal infusion study (30 +/- 2 vs. 20 +/- 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs whole body glucose R(d) and insulin-mediated suppression of EGP in healthy subjects but augments SGU.     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

Acute inhibition of lipolysis does not affect postprandial suppression of endogenous glucose production

To test the hypothesis that intrahepatic availability of fatty acid could modify the rate of suppression of endogenous glucose production (EGP), acipimox or placebo was administered before and during a test meal. We used a modified isotopic methodology to measure EGP in 11 healthy subjects, and (1)H magnetic resonance spectroscopic measurement of hepatic triglyceride stores was also undertaken. Acipimox suppressed plasma free fatty acids markedly before the meal (0.05 +/- 0.01 mmol/l at -10 min, P = 0) and throughout the postprandial period (0.03 +/- 0.01 mmol/l at 150 min). Mean peak plasma glucose was significantly lower after the meal on acipimox days (8.9 +/- 0.4 vs. 10.1 +/- 0.5 mmol/l, P < 0.01), as was mean peak serum insulin (653.1 +/- 99.9 vs. 909 +/- 118 pmol/l, P < 0.01). Fasting EGP was similar (11.15 +/- 0.58 micromol.kg(-1).min(-1) placebo vs. 11.17 +/- 0.89 mg.kg(-1).min(-1) acipimox). The rate of suppression of EGP after the meal was almost identical on the 2 test days (4.36 +/- 1.52 vs. 3.69 +/- 1.21 micromol.kg(-1).min(-1) at 40 min). There was a significant negative correlation between the acipimox-induced decrease in peak plasma glucose and liver triglyceride content (r = -0.827, P = 0.002), suggesting that, when levels of liver fat were low, inhibition of lipolysis was able to affect glucose homeostasis. Acute pharmacological sequestration of fatty acids in triglyceride stores improves postprandial glucose homeostasis without effect on the immediate postprandial suppression of EGP.     

FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with (2)H(2)O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (~450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 micromol/l (P < 0.001), EGP from 15.7 to 2.0 micromol x kg(-1) x min(-1) (P < 0.01), GNG from 8.2 to 3.7 micromol x kg(-1). min(-1) (P < 0.05), and GL from 7.4 to -1.7 micromol x kg(-1). min(-1) (P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 micromol/l (P < 0.001). EGP decreased 64% less than during insulin alone (-5.1 +/- 0.7 vs. -13.7 +/- 3.4 micromol x kg(-1). min(-1)). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (-2.6 vs. -4.5 micromol x kg(-1). min(-1), not significant). In contrast, GL decreased 66% less than during insulin alone (-3.1 vs. -9.2 micromol x kg(-1). min(-1), P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.     

A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes

Effect of stimulation of glucokinase (GK) export from the nucleus by small amounts of sorbitol on hepatic glucose flux in response to elevated plasma glucose was examined in 6-h fasted Zucker diabetic fatty rats at 10 wk of age. Under basal conditions, plasma glucose, insulin, and glucagon were approximately 8 mM, 2,000 pmol/l, and 60 ng/l, respectively. Endogenous glucose production (EGP) was 44 +/- 4 micromol x kg(-1) x min(-1). When plasma glucose was raised to approximately 17 mM, GK was still predominantly localized with its inhibitory protein in the nucleus. EGP was not suppressed. When sorbitol was infused at 5.6 and 16.7 micromol x kg(-1) x min(-1), along with the increase in plasma glucose, GK was exported to the cytoplasm. EGP (23 +/- 19 and 12 +/- 5 micromol x kg(-1) x min(-1)) was suppressed without a decrease in glucose 6-phosphatase flux (145 +/- 23 and 126 +/- 16 vs. 122 +/- 10 micromol x kg(-1) x min(-1) without sorbitol) but increased in glucose phosphorylation as indicated by increases in glucose recycling (122 +/- 17 and 114 +/- 19 vs. 71 +/- 11 microl x kg(-1) x min(-1)), glucose-6-phosphate content (254 +/- 32 and 260 +/- 35 vs. 188 +/- 20 nmol/g liver), fractional contribution of plasma glucose to uridine 5'-diphosphate-glucose flux (43 +/- 8 and 42 +/- 8 vs. 27 +/- 6%), and glycogen synthesis from plasma glucose (20 +/- 4 and 22 +/- 5 vs. 9 +/- 4 mumol glucose/g liver). The decreased glucose effectiveness to suppress EGP and stimulate hepatic glucose uptake may result from failure of the sugar to activate GK by stimulating the translocation of the enzyme.     

Assessment of postprandial glucose metabolism: conventional dual- vs. triple-tracer method

The dual-tracer method has been used conventionally for assessment of postprandial fluxes, i.e., appearance in plasma of ingested glucose (R(a meal)), endogenous glucose production (EGP), and disposal (R(d)). To quantify the magnitude of errors affecting the calculations and their dependence on model assumptions, this method was assessed and compared with the triple-tracer method, which provides model-independent estimates. For this purpose, the dual-tracer protocol was performed twice in eight normal subjects, with [1-(13)C]glucose to trace ingested glucose and [6,6-(2)H(2)]glucose constantly infused. A third tracer, [6-(3)H]glucose, was infused at variable rates to render the calculation of R(a meal) and EGP virtually model independent. The dual-tracer method analyzed with a one-compartment model performed poorly, since R(a meal) peak was significantly lower and delayed compared with triple-tracer reference, resulting in a significantly lower estimation of the amount of absorbed glucose (9,036 +/- 558 vs. 11,316 +/- 823 micromol/kg, P = 0.0117). EGP showed a paradoxical pattern, with an initial overshoot followed by a rapid decay to negative values, resulting in a significant underestimation of EGP suppression (57 +/- 3 vs. 65 +/- 4%, P = 0.0117). A two-compartment model performed better but did not overcome the limitations of the dual-tracer approach, since the amount of absorbed glucose was still significantly underestimated (10,231 +/- 661 vs. 12,169 +/- 838 micromol/kg, P = 0.0117) and EGP still showed a paradoxical behavior. R(d), estimated from R(a meal) and EGP, was significantly underestimated with the dual-tracer method, irrespective of adopted model. We conclude that three suitably infused tracers are required for accurate assessment of postprandial R(a meal), EGP, and R(d).     

S(G), S(I), and EGP of exercise-trained middle-aged men estimated by a two-compartment labeled minimal model

To examine the effects of physical training on glucose effectiveness (S(G)), insulin sensitivity (S(I)), and endogenous glucose production (EGP) in middle-aged men, stable-labeled frequently sampled intravenous glucose tolerance tests (FSIGTT) were performed on 11 exercise-trained middle-aged men and 12 age-matched sedentary men. The time course of EGP during the FSIGTT was estimated by nonparametric stochastic deconvolution. Glucose uptake-specific indexes of glucose effectiveness (S(2*)(G) x 10(2): 0.81 +/- 0.08 vs. 0.60 +/- 0.05 dl. min(-1). kg(-1), P < 0.05) and insulin sensitivity [S(2*)(I) x 10(4): 24.59 +/- 2.98 vs. 11.89 +/- 2.36 dl. min(-1). (microU/ml)(-1). kg(-1), P < 0.01], which were analyzed using the two-compartment minimal model, were significantly greater in the trained group than in the sedentary group. Plasma clearance rate (PCR) of glucose was consistently greater in the trained men than in sedentary men throughout FSIGTT. Compared with sedentary controls, EGP of trained middle-aged men was higher before glucose load. The EGP of the two groups was similarly suppressed by approximately 70% within 10 min, followed by an additional suppression after insulin infusion. EGP returned to basal level at approximately 60 min in the trained men and at 100 min in the controls, followed by its overshoot, which was significantly greater in the trained men than in the controls. In addition, basal EGP was positively correlated with S(2*)(G) . The higher basal EGP and greater EGP overshoot in trained middle-aged men appear to compensate for the increased insulin-independent (S(2*)(G)) and -dependent (S(2*)(I)) glucose uptake to maintain glucose homeostasis.     

Partitioning glucose distribution/transport, disposal, and endogenous production during IVGTT

We have separated the effect of insulin on glucose distribution/transport, glucose disposal, and endogenous production (EGP) during an intravenous glucose tolerance test (IVGTT) by use of a dual-tracer dilution methodology. Six healthy lean male subjects (age 33 +/- 3 yr, body mass index 22.7 +/- 0.6 kg/m(2)) underwent a 4-h IVGTT (0.3 g/kg glucose enriched with 3-6% D-[U-(13)C]glucose and 5-10% 3-O-methyl-D-glucose) preceded by a 2-h investigation under basal conditions (5 mg/kg of D-[U-(13)C]glucose and 8 mg/kg of 3-O-methyl-D-glucose). A new model described the kinetics of the two glucose tracers and native glucose with the use of a two-compartment structure for glucose and a one-compartment structure for insulin effects. Insulin sensitivities of distribution/transport, disposal, and EGP were similar (11.5 +/- 3.8 vs. 10.4 +/- 3.9 vs. 11.1 +/- 2.7 x 10(-2) ml small middle dot kg(-1) small middle dot min(-1) per mU/l; P = nonsignificant, ANOVA). When expressed in terms of ability to lower glucose concentration, stimulation of disposal and stimulation of distribution/transport accounted each independently for 25 and 30%, respectively, of the overall effect. Suppression of EGP was more effective (P < 0.01, ANOVA) and accounted for 50% of the overall effect. EGP was suppressed by 70% (52-82%) (95% confidence interval relative to basal) within 60 min of the IVGTT; glucose distribution/transport was least responsive to insulin and was maximally activated by 62% (34-96%) above basal at 80 min compared with maximum 279% (116-565%) activation of glucose disposal at 20 min. The deactivation of glucose distribution/transport was slower than that of glucose disposal and EGP (P < 0.02) with half-times of 207 (84-510), 12 (7-22), and 29 (16-54) min, respectively. The minimal-model insulin sensitivity was tightly correlated with and linearly related to sensitivity of EGP (r = 0.96, P < 0.005) and correlated positively but nonsignificantly with distribution/transport sensitivity (r = 0.73, P = 0.10) and disposal sensitivity (r = 0.55, P = 0.26). We conclude that, in healthy subjects during an IVGTT, the two peripheral insulin effects account jointly for approximately one-half of the overall insulin-stimulated glucose lowering, each effect contributing equally. Suppression of EGP matches the effect in the periphery.     

Both fasting glucose production and disappearance are abnormal in people with "mild" and "severe" type 2 diabetes

To determine whether regulation of fasting endogenous glucose production (EGP) and glucose disappearance (R(d)) are both abnormal in people with type 2 diabetes, EGP and R(d) were measured in 7 "severe" (SD), 9 "mild" (MD), and 12 nondiabetic (ND) subjects (12.7 +/- 0.6 vs. 8.1 +/- 0.4 vs. 5.1 +/- 0.4 mmol/l) after an overnight fast and during a hyperglycemic pancreatic clamp. Fasting insulin was higher in both the SD and MD than ND subjects, whereas fasting glucagon only was increased (P < 0.05) in SD. Fasting EGP, glycogenolysis, gluconeogenesis, and R(d) all were increased (P < 0.05) in SD but did not differ in MD or ND. On the other hand, when glucose ( approximately 11 mmol/l), insulin ( approximately 72 pmol/l), and glucagon ( approximately 140 pg/ml) concentrations were raised to values similar to those observed in the severe diabetic subjects, EGP was higher (P < 0.001) and R(d) lower (P < 0.01) in both SD and MD than in ND. The higher EGP in the SD and MD than ND during the clamp was the result of increased (P < 0.05) rates of glycogenolysis (4.2 +/- 1.7 vs. 3.5 +/- 1.0 vs. 0.0 +/- 0.8 micromol.kg(-1).min(-1)), since gluconeogenesis did not differ among groups. We conclude that neither glucose production nor disappearance is appropriate for the prevailing glucose and insulin concentrations in people with mild or severe diabetes. Both increased rates of gluconeogenesis (likely because of higher glucagon concentrations) and lack of suppression of glycogenolysis contribute to excessive glucose production in type 2 diabetics.     

Characterization of hepatic and brain metabolism in young adults with glycogen storage disease type 1: a magnetic resonance spectroscopy study

In glycogen storage disease type 1 (GSD1), children present with severe hypoglycemia, whereas the propensity for hypoglycemia may decrease with age in these patients. It was the aim of this study to elucidate the mechanisms for milder hypoglycemia symptoms in young adult GSD1 patients. Four patients with GSD1 [body mass index (BMI) 23.2 +/- 6.3 kg/m, age 21.3 +/- 2.9 yr] and four healthy controls matched for BMI (23.1 +/- 3.0 kg/m) and age (24.0 +/- 3.1 yr) were studied. Combined (1)H/(31)P nuclear magnetic resonance spectroscopy (NMRS) was used to assess brain metabolism. Before and after administration of 1 mg glucagon, endogenous glucose production (EGP) was measured with d-[6,6-(2)H(2)]glucose and hepatic glucose metabolism was examined by (1)H/(13)C/(31)P NMRS. At baseline, GSD1 patients exhibited significantly lower rates of EGP (0.53 +/- 0.04 vs. 1.74 +/- 0.03 mg.kg(-1).min(-1); P < 0.01) but an increased intrahepatic glycogen (502 +/- 89 vs. 236 +/- 11 mmol/l; P = 0.05) and lipid content (16.3 +/- 1.1 vs. 1.4 +/- 0.4%; P < 0.001). After glucagon challenge, EGP did not change in GSD1 patients (0.53 +/- 0.04 vs. 0.59 +/- 0.24 mg.kg(-1).min(-1); P = not significant) but increased in healthy controls (1.74 +/- 0.03 vs. 3.95 +/- 1.34; P < 0.0001). In GSD1 patients, we found an exaggerated increase of intrahepatic phosphomonoesters (0.23 +/- 0.08 vs. 0.86 +/- 0.19 arbitrary units; P < 0.001), whereas inorganic phosphate decreased (0.36 +/- 0.08 vs. -0.43 +/- 0.17 arbitrary units; P < 0.01). Intracerebral ratios of glucose and lactate to creatine were higher in GSD1 patients (P < 0.05 vs. control). Therefore, hepatic defects of glucose metabolism persist in young adult GSD1 patients. Upregulation of the glucose and lactate transport at the blood-brain barrier could be responsible for the amelioration of hypoglycemic symptoms.     

Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans

Prolonged infusions of lipid and heparin that achieve high physiological free fatty acid (FFA) concentrations inhibit hepatic (and peripheral) insulin sensitivity in humans. These infusions are composed largely of polyunsaturated fatty acids (PUFA; linoleic and linolenic). It is not known whether fatty acid composition per se affects hepatic glucose metabolism in humans. To address this issue, we examined the impact of enteral infusions of either palm oil (48% palmitic, 35% oleic, and 8% linoleic acids) or safflower oil (6% palmitic, 12% oleic, 74% linoleic acids) in 14 obese nondiabetic subjects. (2)H(2)O was administered to determine the contribution of gluconeogenesis to endogenous glucose production (EGP), and a primed continuous infusion of [6,6-(2)H]glucose was administered to assess glucose appearance. As a result of the lipid infusions, plasma FFA concentrations increased significantly in both the palm oil (507.5 +/- 47.4 to 939.3 +/- 61.3 micromol/l, P < 0.01) and safflower oil (588.2.0 +/- 43.0 to 857.8 +/- 68.7 micromol/l, P < 0.01) groups after 4 h. EGP was similar at baseline (12.4 +/- 1.8 vs. 11.2 +/- 1.0 micromol x kg FFM(-1) x min(-1)). During a somatostatin-insulin clamp, the glucose infusion rate was significantly lower (AUC glucose infusion rate 195.8 +/- 50.7 vs. 377.8 +/- 38.0 micromol/kg FFM, P < 0.01), and rates of EGP were significantly higher (10.7 +/- 1.4 vs. 6.5 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < 0.01) after palm oil compared with safflower oil, respectively. Baseline rates of gluconeogenesis and glycogenolysis were also similar. However, after lipid infusion, rates of glycogenolysis were suppressed by safflower oil but not by palm oil. Thus these studies demonstrate, for the first time in humans, a differential effect of saturated fatty acids and PUFA on hepatic glucose metabolism.     

Increased insulin receptor signaling and glycogen synthase activity contribute to the synergistic effect of exercise on insulin action.

The purpose of this study was to determine the factors contributing to the ability of exercise to enhance insulin-stimulated glucose disposal. Sixteen insulin-resistant nondiabetic and seven Type 2 diabetic subjects underwent two hyperinsulinemic (40 mU x m-2 x min-1) clamps, once without and once with concomitant exercise at 70% peak O2 consumption. Exercise was begun at the start of insulin infusion and was performed for 30 min. Biopsies of the vastus lateralis were performed before and after 30 min of insulin infusion (immediately after cessation of exercise). Exercise synergistically increased insulin-stimulated glucose disposal in nondiabetic [from 4.6 +/- 0.4 to 9.5 +/- 0.8 mg x kg fat-free mass (FFM)-1x min-1] and diabetic subjects (from 4.3 +/- 1.0 to 7.9 +/- 0.7 mg. kg FFM-1x min-1) subjects. The rate of glucose disposal also was significantly greater in each group after cessation of exercise. Exercise enhanced insulin-stimulated increases in glycogen synthase fractional velocity in control (from 0.07 +/- 0.02 to 0.22 +/- 0.05, P < 0.05) and diabetic (from 0.08 +/- 0.03 to 0.15 +/- 0.03, P < 0.01) subjects. Exercise also enhanced insulin-stimulated glucose storage (glycogen synthesis) in nondiabetic (2.9 +/- 0.9 vs. 4.9 +/- 1.1 mg x kg FFM-1x min-1) and diabetic (1.7 +/- 0.5 vs. 4.2 +/- 0.8 mg x kg FFM-1. min-1) subjects. Increased glucose storage accounted for the increase in whole body glucose disposal when exercise was performed during insulin stimulation in both groups; effects of exercise were correlated with enhancement of glucose disposal and glucose storage (r = 0.93, P < 0.001). Exercise synergistically enhanced insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase activity (P < 0.05) and Akt Ser473 phosphorylation (P < 0.05) in nondiabetic subjects but had little effect in diabetic subjects. The data indicate that exercise, performed in conjunction with insulin infusion, synergistically increases insulin-stimulated glucose disposal compared with insulin alone. In nondiabetic and diabetic subjects, increased glycogen synthase activation is likely to be involved, in part, in this effect. In nondiabetic, but not diabetic, subjects, exercise-induced enhancement of insulin stimulation of the phosphatidylinositol 3-kinase pathway is also likely to be involved in the exercise-induced synergistic enhancement of glucose disposal.     

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles

To determine whether, in the presence of constant insulin concentrations, a change in glucose concentrations results in a reciprocal change in endogenous glucose production (EGP), glucagon ( approximately 130 ng/l) and insulin ( approximately 65 pmol/l) were maintained at constant "basal" concentrations while glucose was clamped at approximately 5.3 mM (euglycemia), approximately 7.0 mM (sustained hyperglycemia; n = 10), or varied to create a "postprandial" profile (profile; n = 11). EGP fell slowly over the 6 h of the euglycemia study. In contrast, an increase in glucose to 7.13 +/- 0.3 mmol/l resulted in prompt and sustained suppression of EGP to 9.65 +/- 1.21 micromol x kg-1 x min-1. On the profile study day, glucose increased to a peak of 11.2 +/- 0.5 mmol/l, and EGP decreased to a nadir of 6.79 +/- 2.54 micromol x kg-1 x min-1 by 60 min. Thereafter, the fall in glucose was accompanied by a reciprocal rise in EGP to rates that did not differ from those observed on the euglycemic study day (11.31 +/- 2.45 vs. 12.11 +/- 3.21 micromol x kg-1 x min-1). Although the pattern of change of glucose differed markedly on the sustained hyperglycemia and profile study days, by design the area above basal did not. This resulted in equivalent suppression of EGP below basal (-1,952 +/- 204 vs. -1,922 +/- 246 mmol. kg-1. 6 h-1). These data demonstrate that, in the presence of a constant basal insulin concentration, changes in glucose within the physiological range rapidly and reciprocally regulate EGP.     

Type 2 diabetic patients may have a mild form of an injury response: a clinical research center study

Patients with type 2 diabetes (DM) demonstrate inadequate insulin release, elevated gluconeogenesis, and diminished nonoxidative glucose disposal. Similar metabolic changes occur during systemic injury caused by infection, trauma, or cancer. Described here are metabolic changes occurring in 16 DM and 11 lung cancer patients (CA) and 13 normal volunteers (NV). After a 10-h overnight fast, all subjects had fasting hormone and substrate concentrations determined, along with rates of glucose production, leucine appearance (LA), and leucine oxidation (LO). Fasting insulin (data not shown) and C-peptide concentrations were elevated in DM and CA compared with weight-matched NV (0.72 +/- 0.09 and 0.64 +/- 0.08 vs. 0.51 +/- 0.03 mg/l, P < 0.05). C-reactive protein concentration was elevated in CA compared with DM and NV (23.3 +/- 6.0 vs. 4.2 +/- 1.4 and 2.1 +/- 0.5 mg/l, P < 0.01). All counterregulatory hormones were normal except for serum cortisol (11.4 +/- 1.0 and 12.1 +/- 1.0 vs. 8.9 +/- 0.7 microg/dl, DM and CA vs. NL, respectively, P < 0.05). Glucose production was increased in DM and CA compared with NV (4.22 +/- 0.6 and 3.53 +/- 0.3 vs. 2.76 +/- 0.2 mg x kg lean body wt(-1) x min(-1), P < 0.01). LO and LA were increased in DM and CA compared with NV (LO: 27.3 +/- 1.5 and 19.7 +/- 1.5 vs. 12.5 +/- 1.1 mmol x kg lean body wt(-1) x min(-1), P < 0.05; LA: 91.9 +/- 6.6 and 90.7 +/- 7.0 vs. 79.1 +/- 6.0 mmol. kg lean body wt(-1) x min(-1), P < 0.01). DM share similar metabolic derangements with CA. The increase in LA may be secondary to an increased glucose production where amino acids are mobilized to provide the liver with adequate substrate to make glucose. The increase in glucose production may also be part of the injury response, or it may represent a form of insulin resistance that exists in both the DM and (non-DM) CA patients.     

Autoregulation of glucose production in men with a glycerol load during rest and exercise

Related to hepatic autoregulation we evaluated hypotheses that 1) glucose production would be altered as a result of a glycerol load, 2) decreased glucose recycling rate (Rr) would result from increased glycerol uptake, and 3) the absolute rate of gluconeogenesis (GNG) from glycerol would be positively correlated to glycerol rate of disappearance (R(d)) during a glycerol load. For these purposes, glucose and glycerol kinetics were determined in eight men during rest and during 90 min of leg cycle ergometry at 45 and 65% of peak O2 consumption (.VO2 (peak)). Trials were conducted after an overnight fast, with exercise commencing 12 h after the last meal. Subjects received a continuous infusion of [6,6-(2)H(2)]glucose, [1-(13)C]glucose, and [1,1,2,3,3-(2)H(5)]glycerol without (CON) or with an additional 1,000 mg (rest: 20 mg/min; exercise: 40 mg/min) of [2-(13)C]- or unlabeled glycerol added to the infusate (GLY). Infusion of glycerol dampened glucose Rr, calculated as the difference between [6,6-(2)H(2)]- and [1-(13)C]glucose rates of appearance (R(a)), at rest [0.35 +/- 0.12 (CON) vs. 0.12 +/- 0.10 mg. kg(-1). min(-1) (GLY), P < 0.05] and during exercise at both intensities [45%: 0.63 +/- 0.14 (CON) vs. 0.04 +/- 0.12 (GLY); 65%: 0.73 +/- 0.14 (CON) vs. 0.04 +/- 0.17 mg. kg(-1). min(-1) (GLY), P < 0.05]. Glucose R(a) and oxidation were not affected by glycerol infusion at rest or during exercise. Throughout rest and both exercise intensities, glycerol R(d) was greater in GLY vs. CON conditions (rest: 0.30 +/- 0.04 vs. 0.58 +/- 0.04; 45%: 0.57 +/- 0.07 vs. 1.19 +/- 0.04; 65%: 0.73 +/- 0.06 vs. 1.27 +/- 0.05 mg. kg(-1). min(-1), CON vs. GLY, respectively). Differences in glycerol R(d) (DeltaR(d)) between protocols equaled the unlabeled glycerol infusion rate and correlated with plasma glycerol concentration (r = 0.97). We conclude that infusion of a glycerol load during rest and exercise at 45 and 65% of .VO2(peak) 1) does not affect glucose R(a) or R(d), 2) blocks glucose Rr, 3) increases whole body glycerol R(d) in a dose-dependent manner, and 4) results in gluconeogenic rates from glycerol equivalent to CON glucose recycling rates.     

Impaired substrate oxidation in healthy elderly men after eccentric exercise.

The metabolic response to eccentric exercise in healthy older adults is unknown. Therefore, substrate metabolism was examined in the basal state and after sustained hyperglycemia (180 min, 10 mM) in eight healthy, sedentary older [66 +/- 2 yr; body mass index (BMI) of 25.5 +/- 1.2 kg/m] and nine younger (23 +/- 1 yr; BMI of 23.6 +/- 1.7 kg/m) men, under control conditions and 48 h after eccentric exercise. Indirect calorimetry was performed to evaluate carbohydrate and lipid oxidation (C(ox) and L(ox), respectively). Eccentric exercise caused muscle soreness and increased plasma creatine kinase in both groups of men (P < 0.02). Although a similar level of hyperglycemia was maintained in the two groups, glucose infusion rates were lower (P < 0.001) in the older men. Compared with basal levels, hyperglycemia stimulated an increase in C(ox) and a decrease in L(ox) during the control and exercise trials in the younger group (P < 0.03), but only during the control trial in the older subjects (P < 0.007). C(ox) was unchanged after eccentric exercise in the younger men [4.00 +/- 0.30 vs. 3.54 +/- 0.44 mg x kg fat-free mass (FFM)(-1) x min(-1); exercise vs. control] but was suppressed by 20% in the older group (3.37 +/- 0.37 vs. 4.21 +/- 0.23 mg x kg FFM(-1) x min(-1); P < 0.04). Moreover, L(ox) was reduced by 38% in the younger subjects (0.47 +/- 0.09 vs. 0.76 +/- 0.10 mg x kg FFM(-1) x min(-1); P< 0.03) but was augmented by 89% in the older group (0.68 +/- 0.11 vs. 0.36 +/- 0.08 mg x kg FFM(-1) x min(-1); P < 0.04). In addition, hyperglycemia-stimulated C(ox), L(ox), and respiratory exchange ratio responses to eccentric exercise were related to abdominal adiposity (r = -0.57, P < 0.04, r = 0.68, P < 0.02 and r = -0.60, P < 0.02, respectively). Despite normal glucose tolerance and the absence of obesity per se, older men experience a reduction in carbohydrate oxidation in response to hyperglycemia after eccentric exercise.     

Hormone-independent activation of EGP during hypoglycemia is absent in type 1 diabetes mellitus

It has been suggested that insulin-induced suppression of endogenous glucose production (EGP) may be counteracted independently of increased epinephrine (Epi) or glucagon during moderate hypoglycemia. We examined EGP in nondiabetic (n = 12) and type 1 diabetic (DM1, n = 8) subjects while lowering plasma glucose (PG) from clamped euglycemia (5.6 mmol/l) to values just above the threshold for Epi and glucagon secretion (3.9 mmol/l). Individualized doses of insulin were infused to maintain euglycemia during pancreatic clamps by use of somatostatin (250 microg/h), glucagon (1.0 ng. kg(-1). min(-1)), and growth hormone (GH) (3.0 ng. kg(-1). min(-1)) infusions without need for exogenous glucose. Then, to achieve physiological hyperinsulinemia (HIns), insulin infusions were fixed at 20% above the rate previously determined for each subject. In nondiabetic subjects, PG was reduced from 5.4 +/- 0.1 mmol/l to 3.9 +/- 0.1 mmol/l in the experimental protocol, whereas it was held constant (5. 3 +/- 0.2 mmol/l and 5.5 mmol/l) in control studies. In the latter, EGP (estimated by [3-(3)H]glucose) fell to values 40% of basal (P < 0.01). In contrast, in the experimental protocol, at comparable HIns but with PG at 3.9 +/- 0.1 mmol/l, EGP was activated to values about twofold higher than in the euglycemic control (P < 0.01). In DM1 subjects, EGP failed to increase in the face of HIns and PG = 3.9 +/- 0.1 mmol/l. The decrease from basal EGP in DM1 subjects (4.4 +/- 1.0 micromol. kg(-1). min(-1)) was nearly twofold that in nondiabetics (2.5 +/- 0.8 micromol. kg(-1). min(-1), P < 0.02). When PG was lowered further to frank hypoglycemia ( approximately 3.1 mmol/l), the failure of EGP activation in DM1 subjects was even more profound but associated with a 50% lower plasma Epi response (P < 0. 02) compared with nondiabetics. We conclude that glucagon- or epinephrine-independent activation of EGP may accompany other counterregulatory mechanisms during mild hypoglycemia in humans and is impaired or absent in DM1.     

Use of a novel triple-tracer approach to assess postprandial glucose metabolism

Numerous studies have used the dual-tracer method to assess postprandial glucose metabolism. The present experiments were undertaken to determine whether the marked tracer nonsteady state that occurs with the dual-tracer approach after food ingestion introduces error when it is used to simultaneously measure both meal glucose appearance (R(a meal)) and endogenous glucose production (EGP). To do so, a novel triple-tracer approach was designed: 12 subjects ingested a mixed meal containing [1-(13)C]glucose while [6-(3)H]glucose and [6,6-(2)H(2)]glucose were infused intravenously in patterns that minimized the change in the plasma ratios of [6-(3)H]glucose to [1-(13)C]glucose and of [6,6-(2)H(2)]glucose to endogenous glucose, respectively. R(a meal) and EGP measured with this approach were essentially model independent, since non-steady-state error was minimized by the protocol. Initial splanchnic glucose extraction (ISE) was 12.9% +/- 3.4%, and suppression of EGP (EGPS) was 40.3% +/- 4.1%. In contrast, when calculated with the dual-tracer one-compartment model, ISE was higher (P < 0.05) and EGPS was lower (P < 0.005) than observed with the triple-tracer approach. These errors could only be prevented by using time-varying volumes different for R(a meal) and EGP. Analysis of the dual-tracer data with a two-compartment model reduced but did not totally avoid the problems associated with marked postprandial changes in the tracer-to-tracee ratios. We conclude that results from previous studies that have used the dual-tracer one-compartment model to measure postprandial carbohydrate metabolism need to be reevaluated and that the triple-tracer technique may provide a useful approach for doing so.