Glucose Disposal In Man Research Articles

Glucose effectiveness is a critical pathogenic factor leading to glucose intolerance and type 2 diabetes: An ignored hypothesis.

Although the ability of glucose to mediate its own in vivo metabolism is long documented, the quantitative measurement of whole body glucose-mediated glucose disposal at basal insulin levels (glucose effectiveness [GE]), followed the introduction of the Minimal Model intravenous glucose tolerance test technique. A literature review, combined with our own studies, of the role of GE in glucose metabolism in normal and "at risk" individuals, was undertaken to determine GE's contribution to glucose homeostasis. GE accounts for ~45% to 65% of glucose disposal in man. A negative association between GE and insulin meditated glucose disposal (Si), is present in normal subjects without a family history of type 2 diabetes mellitus but is absent in normoglycaemic "at risk" relatives with a positive family history of diabetes mellitus. Intracellular GE disposal is mediated by mass action of glucose through the skeletal muscle membrane via facilitated Glut 4 transporters. However, GE is frequently forgotten as a significant contributor to the development of glucose intolerance in "at risk" individuals. Only limited studies have examined the role of a lower GE in such normoglycemic subjects with preexisting mild insulin resistance and β-cell dysfunction. These studies demonstrate that in "at risk" individuals, an initial low GE is a key contributor and predictor of future glucose intolerance, whereas an initial raised GE is protective against future glucose intolerance. In "at risk" individuals, a low GE and genetically determined vulnerable β-cell function are more critical determinants of future glucose intolerance than their preexisting insulin-resistant state.

Carotid Artery Wall Intima-Media Thickness Is Associated With Insulin-Mediated Glucose Disposal in Men at High and Low Coronary Risk

The aim of this investigation was to examine the relationship between insulin sensitivity and intima-media thickness in the common carotid artery. Ultrasound examinations of the common carotid artery and hyperinsulinemic euglycemic clamp examinations were performed in a group (n = 25) of men aged 57 to 77 years at high risk for atherosclerotic disease (hypertension and at least one of the following factors: hypercholesterolemia and/or smoking) and in an age-matched low-risk group (n = 23) with no cardiovascular risk factors. Subjects with cardiovascular disease or diabetes mellitus were excluded. A significant negative relationship between insulin sensitivity index and common carotid maximum intima-media thickness was observed in both the high-risk group (r = -.45, P < .05) and in the low-risk group (r = -.59, P < .01). Our results suggest that an increase in intimamedia thickness, as a possible expression of early atherosclerosis, is negatively related to insulin sensitivity.

Insulin resistance, body fat distribution, and sex hormones in men.

Although many studies have suggested that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both pre- and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of body mass index (BMI), waist-to-hip ratio (WHR), sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with insulin concentrations and whole-body glucose disposal in 87 men from a population-based study in Kuopio, Finland. BMI was significantly correlated with fasting insulin (r = 0.46), total whole-body glucose disposal (r = -0.30), glucose oxidation (r = -0.21), and nonoxidative glucose disposal (r = -0.25). WHR also was significantly associated with fasting insulin (r = 0.61), total whole-body glucose disposal (r = -0.54), glucose oxidation (r = -0.23), and nonoxidative whole-body glucose disposal (r = -0.50). SHBG and total and free testosterone were significantly associated with insulin concentrations and total and nonoxidative glucose disposal but not with glucose oxidation. DHEA-SO4 and estradiol were not associated with insulin, glucose concentrations, or whole-body glucose disposal in univariate analysis. In multivariate analysis, total whole-body glucose disposal was associated negatively with WHR and positively associated with total testosterone and SHBG; nonoxidative whole-body glucose disposal was associated negatively with WHR and positively associated with total and free testosterone. Glucose oxidation was significantly associated only with WHR. In conclusion, higher WHR and lower testosterone were strongly associated with a decrease in total and nonoxidative whole-body glucose disposal in men.

Level of skeletal muscle glucose transporter protein correlates with insulin-stimulated whole body glucose disposal in man

The content of GLUT4 glucose transporter mRNA and protein were measured in samples of the vastus lateralis muscle of normal volunteers subjected to a 4-h hyperinsulinaemic, euglycaemic clamp. Plasma glucose concentration was clamped at 5.3 +/- 0.1 mmol/l, and serum insulin concentration was maintained at 740 +/- 5 pmol/l. Whole body glucose uptake averaged 38.3 +/- 2.2 mumol.kg-1.min-1, 62% of this being due to disposal via non-oxidative pathways. A significant correlation existed between basal levels of GLUT4 protein and the rate of whole body glucose disposal (r = 0.77, p less than 0.02) and non-oxidative glucose disposal (r = 0.80, p less than 0.02). There was no correlation between GLUT4 protein content and oxidative glucose disposal (r = 0.08, NS). These observations are consistent with an important role for skeletal muscle GLUT4 protein in whole body glucose disposal.

The effects of euglycemic hyperinsulinemia and amino acid infusion on regional and whole body glucose disposal in man

We investigated the effects of amino acid infusion on regional and whole body glucose metabolism in 16 normal volunteers, age 32 to 70 years. Ten subjects underwent 140-minute euglycemic insulin infusions at the rate of 1 mU/kg · min with concomitant 10% amino acid infusion. Six volunteers who underwent identical euglycemic insulin infusions without amino acid infusion served as controls. Whole body glucose disposal was estimated by the rate of exogenous glucose infusion required to maintain euglycemia, and peripheral glucose balance was evaluated by the forearm balance technique. In four subjects from each group, a primed, continuous infusion of [3- 3H]glucose was used to quantify endogenous glucose production (EGP). Comparable states of hyperinsulinemia were achieved with insulin concentrations (μU/mL) of 101 ± 7 observed in the group with amino acid infusion and 95 ± 14 in the control group. Whole body glucose utilization was significantly lower ( P < .001) in the subjects receiving amino acid infusion (5.0 ± 0.4 mg/kg · min) compared with the control group (8.7 ± 0.8 mg/kg · min). Forearm glucose disposal was markedly reduced ( P < .05) in the group receiving amino acid infusion ( 1,385 ± 330 nmol 100 g · min ) compared with controls ( 2,980 ± 460 nmol 100 g · min ). Under comparable conditions of euglycemia and hyperinsulinemia, virtually complete suppression of EGP was observed in both groups. We conclude that infusion of amino acids with insulin under euglycemic conditions reduces whole body glucose utilization primarily by reducing peripheral glucose disposal.

Effects of chronic beta receptor stimulation on glucose metabolism.

The acute administration of a beta receptor-stimulating agent profoundly affects insulin-mediated glucose metabolism; however, little is known about the impact of chronic beta receptor stimulation on glucose metabolism and insulin sensitivity. We therefore investigated the effect of the chronic administration of a beta-2-agonist, terbutaline sulfate (TS), on glucose metabolism in 7 healthy, normal-weight, male volunteers between the ages of 21 and 30 yr. Studies were performed using the euglycemic, hyperinsulinemic (1.0 mU/min X kg) clamp technique before and after the oral administration of 5 mg of TS three times a day for 1 and 2 wk. Basal endogenous glucose production (EGP) (2.54 +/- 0.11 versus 2.64 +/- 0.14 mg/min X kg) and basal glucose oxidation (1.87 +/- 0.16 versus 2.0 +/- 0.2 mg/min X kg) were unchanged by the chronic administration of TS. However, insulin-stimulated total glucose metabolism increased by 29% (7.0 +/- 0.47 versus 9.05 +/- 0.67 mg/min X kg; P less than 0.02). Insulin-stimulated, nonoxidative glucose disposal increased by 45% (3.62 +/- 0.42 versus 5.26 +/- 0.48 mg/min X kg; P less than 0.01), while insulin-stimulated glucose oxidation did not change significantly (3.38 +/- 0.15 versus 3.79 +/- 0.22 mg/min X kg). EGP was completely suppressed under both conditions. Mean basal plasma insulin concentration (41 +/- 9 versus 49 +/- 15 pmol/L) and insulin clearance during the clamp procedure was unchanged (477 +/- 45 versus 474 +/- 37 ml/min X m2). We conclude that chronic beta receptor stimulation with TS improves insulin-stimulated glucose disposal in man, mostly by improving nonoxidative glucose disposal, i.e., "glucose storage."(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of changes in insulin receptor binding during insulin infusions on the shape of the insulin dose-response curve for glucose disposal in man.

To determine the influence of insulin infusions used in dose-response studies on monocyte insulin binding, monocyte insulin binding and glucose disposal were measured in six normal subjects before and at the end of each of four sequential 2-h insulin infusions (0.4, 1.0, 2.0, and 10 mU kg-1 min-1). Monocyte insulin binding was unaltered at the end of the first three infusions (plasma insulin, 31 +/- 2 (SEM), 77 +/- 3, and 184 +/- 10 microU/ml) but was decreased after the last infusion (plasma insulin, 1730 +/- 125 microU/ml) at 0.2 through 10.2 ng/ml insulin concentrations in the binding assay (P less than 0.01). Using a one-site model, this could be ascribed to a decrease in insulin receptor affinity (1.54 +/- 0.26 vs. 2.27 +/- 0.48 X 10(8) M-1, P less than 0.05), whereas in a two-site model this appeared to be due to a decrease in high affinity binding sites (1,868 +/- 228 vs. 2,387 +/- 207, P less than 0.02). Nevertheless, insulin receptor occupancies estimated to occur during the insulin infusions were virtually identical whether preinsulin infusion binding data (745 +/- 72, 1,383 +/- 117, 2,572 +/- 302, and 10,092 +/- 1,708) or binding data at the end of each infusion (702 +/- 56, 1,367 +/- 150, 2,383 +/- 318, and 9,158 +/- 2,023) were used to calculate occupancy. These results indicate that although monocyte insulin binding decreased during dose-response experiments using sequential infusions of insulin, due to the concentrations of insulin at which this occurs this decrease did not alter the shape of the dose-response curve relating glucose disposal to monocyte insulin receptor occupancy.

Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man.

The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg(-1) min(-1)) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg(-1) min(-1); (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg(-1) min(-1)); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg(-1) min(-1)). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls ( approximately 170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 muU/ml at 90 min. NSGB switched from a net output of 1.71+/-0.13 to a net uptake of 1.5-1.6 mg kg(-1) min(-1) due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78+/-0.13 to 1.6-1.8 mg kg(-1) min(-1); P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 muU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 muU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 muU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg(-1) min(-1)). Peripheral glucose uptake rose to the same extent as in controls. IT IS CONCLUDED THAT: (a) the suppressive effect of hyperglycemia on hepatic glucose output is strictly dependent on the degree of hepatic insulinization; (b) insulin plays an essential role in promoting splanchnic glucose uptake after an intravenous glucose load whereas hyperglycemia per se is totally unable to activate this process; (c) peripheral glucose uptake is markedly stimulated by hyperglycemia even in the face of insulin deficiency. Direct evidence also demonstrates that the skeletal muscle is involved in this response. Our data, thus, indicate that insulin rather than hyperglycemia regulates splanchnic glucose disposal in man. On the other hand, hyperglycemia per se appears to be an important regulator of glucose disposal by peripheral tissues.

Synergistic interaction between exercise and insulin on peripheral glucose uptake.

The interaction of exercise and insulin on glucose metabolism was examined in 10 healthy volunteers. Four study protocols were used: study 1: plasma insulin was raised by approximately 100 microunits/ml while plasma glucose was maintained at basal levels for 2 h (insulin clamp). Study 2: subjects performed 30 min of bicycle exercise at 40% of VO2 max. Study 3: an insulin clamp was performed as per study 1. Following 60 min of sustained hyperinsulinemia, however, subjects exercised for 30 min as per study 2. Study 4: subjects were studied as per study 3 except that catheters were inserted into the femoral artery and vein to quantitate leg glucose uptake. During the 60-90 min period of hyperinsulinemia (study 1), glucose uptake averaged 8.73 +/- 0.10 mg/kg per min. With exercise alone (study 2), the increment in peripheral glucose uptake was 1.43 +/- 0.30 mg/kg per min. When hyperinsulinemia and exercise were combined (study 3), glucose uptake averaged 15.06 +/- 0.98 mg/kg per min (P less than 0.01) and this was significantly (P less than 0.001) greater than the sum of glucose uptake when exercise and the insulin clamp were performed separately. The magnitude of rise in glucose uptake correlated closely with the increase in leg blood flow (r = 0.935, P less than 0.001), suggesting that the synergism is the result of increased blood flow and increased capillary surface area to exercising muscle. More than 85% of total body glucose metabolism during studies 1 and 3 was accounted for by skeletal muscle uptake. These results demonstrate that (a) insulin and exercise act synergistically to enhance glucose disposal in man, and (b) muscle is the primary tissue responsible for the increase in glucose metabolism following hyperinsulinemia and exercise.