Intraportal glucose delivery enhances the effects of hepatic glucose load on net hepatic glucose uptake in vivo.

Although the importance of the hepatic glucose load in the regulation of liver glucose uptake has been clearly demonstrated in in vitro systems, the relationship between the hepatic glucose load and hepatic glucose uptake has yet to be defined in vivo. Likewise, the effects of the route of glucose delivery (peripheral or portal) on this relationship have not been explored. The aims of the present study were to determine the relationship between net hepatic glucose uptake (NHGU) and the hepatic glucose load in vivo and to examine the effects of the route of glucose delivery on this relationship. NHGU was evaluated at three different hepatic glucose loads in 42-h fasted, conscious dogs in both the absence (n = 7) and the presence (n = 6) of intraportal glucose delivery. In the absence of intraportal glucose delivery and in the presence of hepatic glucose loads of 50.5 +/- 5.9, 76.5 +/- 10.0, and 93.6 +/- 10.0 mg/kg/min and arterial insulin levels of approximately 33 microU/ml, NHGU was 1.16 +/- 0.37, 2.78 +/- 0.82, and 5.07 +/- 1.20 mg/kg/min, respectively. When a portion of the glucose load was infused into the portal vein and similar arterial insulin levels (approximately 36 microU/ml) and hepatic glucose loads (52.5 +/- 4.5, 70.4 +/- 5.6, and 103.6 +/- 18.4 mg/kg/min) were maintained, NHGU was twice that seen in the absence of portal loading (3.77 +/- 0.40, 4.80 +/- 0.59, and 9.62 +/- 1.43 mg/kg/min, respectively). Thus, net hepatic glucose uptake demonstrated a direct dependence on the hepatic glucose load that did not reach saturation even at elevations in the hepatic glucose load of greater than three times basal. In addition, the presence of intraportal glucose delivery increased net hepatic glucose uptake apparently by lowering the threshold at which the liver switched from net glucose output to net glucose uptake.     

The relationship between endogenous serum insulin concentration and glucose uptake in the forearm muscles of nondiabetics

IN A SERIES OF EXPERIMENTS ON THE HUMAN FOREARM, PREPARATION DESIGNED TO EXAMINE THE EFFECTS OF VARIATIONS IN IMMUNOLOGICALLY DETERMINED ENDOGENOUS SERUM INSULIN LEVELS AND OF BLOOD GLUCOSE CONCENTRATIONS ON MUSCULAR GLUCOSE UPTAKE, THE FOLLOWING RESULTS WERE OBTAINED: (a) A highly significant correlation between muscular glucose uptake and simultaneous arterial serum insulin concentration. (b) No correlation between glucose uptake and simultaneous arterial blood glucose concentration during hyperglycemia. (c) A maximal insulin effect on muscular glucose uptake at arterial serum insulin concentrations at about 200 muU/ml. This observation is, however, based on only a few experiments.     

Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans.

13C NMR spectroscopy was used to assess flux rates of hepatic glycogen synthase and phosphorylase in overnight-fasted subjects under one of four hypoglucagonemic conditions: protocol I, hyperglycemic (approximately 10 mM) -hypoinsulinemia (approximately 40 pM); protocol II, euglycemic (approximately 5 mM) -hyperinsulinemia (approximately 400 pM); protocol III, hyperglycemic (approximately 10 mM) -hyperinsulinemia (approximately 400 pM); and protocol IV; euglycemic (approximately 5 mM) -hypoinsulinemia (approximately 40 pM). Inhibition of net hepatic glycogenolysis occurred in both protocols I and II compared to protocol IV but via a different mechanism. Inhibition of net hepatic glycogenolysis occurred in protocol I mostly due to decreased glycogen phosphorylase flux, whereas in protocol II inhibition of net hepatic glycogenolysis occurred exclusively through the activation of glycogen synthase flux. Phosphorylase flux was unaltered, resulting in extensive glycogen cycling. Relatively high rates of net hepatic glycogen synthesis were observed in protocol III due to combined stimulation of glycogen synthase flux and inhibition of glycogen phosphorylase flux. In conclusion, under hypoglucagonemic conditions: (a) hyperglycemia, per se, inhibits net hepatic glycogenolysis primarily through inhibition of glycogen phosphorylase flux; (b) hyperinsulinemia, per se, inhibits net hepatic glycogenolysis primarily through stimulation of glycogen synthase flux; (c) inhibition of glycogen phosphorylase and the activation of glycogen synthase are not necessarily coupled and coordinated in a reciprocal fashion; and (d) promotion of hepatic glycogen cycling may be the principal mechanism by which insulin inhibits net hepatic glycogenolysis and endogenous glucose production in humans under euglycemic conditions.     

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.     

Glucose ingestion in dogs alters the hepatic extraction of insulin. In vivo evidence for a relationship between biologic action and extraction of insulin.

Oral glucose (25 g) fed to seven healthy, conscious dogs resulted in an increase in peripheral plasma glucose from 109 +/- 3 to 178 +/- 10 mg/dl. Concurrently serum insulin increased in the portal vein to levels approximately threefold greater than those in the periphery. Hepatic insulin delivery rose from 10.8 +/- 0.7 to 59.0 +/- 19.9 m U/min at 60 min. coincident with an increased hepatic insulin extraction from 3.3 to 41.4 mU/min (corresponding to an increase in hepatic extraction from 31 +/- 4 to 59 +/- 7%), both returning to basal at 3 h. In each animal there was a positive correlation between hepatic insulin delivery and extraction (r = 0.80, P less than 0.001 for the seven experiments combined). These changes in heptic insulin delivery and extraction after glucose metabolism associated with insulin action. As hepatic insulin extraction increased, hepatic glucose output declined, both parameters returning to basal levels by 3 h, indicating a negative correlation between hepatic insulin extraction and hepatic glucose output (r = 0.63, P less than 0.001; n = 7). The factors that mediate this marked and rapidly occurring increase in hepatic insulin extraction after oral glucose are unknown, and may include hepatic insulin delivery, glucose levels in the blood flow, and gut factors released by oral glucose intake. The association of changes in hepatic insulin extraction in vivo with an insulin effect on the liver as measured hepatic glucose output is consistent with in vitro observations relating insulin degradation to receptor binding.     

Contribution of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity

OBJECTIVE: The goal of this study was to evaluate the performance of surrogate measures of insulin sensitivity and insulin secretion. RESEARCH DESIGN AND METHODS: The homeostasis model assessment (HOMA) of insulin resistance (IR) and the insulin sensitivity index (S(i)) from oral glucose tolerance test (OGTT) were compared with the M value from a hyperinsulinemic-euglycemic clamp in 467 subjects with various degrees of glucose tolerance. Endogenous glucose production (EGP) and hepatic insulin sensitivity were determined in a subset (n = 143). Insulin secretion was estimated as the HOMA beta-cell index and as the insulinogenic index from the first 30 min of the OGTT (I/G30) and compared with the first-phase insulin response (FPIR) to an intravenous glucose tolerance test (n = 218). RESULTS: The M value correlated with the HOMA-IR (r = -0.591, P < 0.0001) and the S(i) (r = 0.533, P < 0.0001) indexes in the total study group. HOMA-IR correlated with basal EGP in the total study group (r = 0.378, P < 0.0005) and in subjects with diabetes (r = 0.330, P = 0.01). However, neither HOMA-IR nor S(i) correlated significantly with the M value in subjects with impaired fasting glucose (IFG) (r = -0.108, P = 0.5; r = 0.01, P = 0.9) or IFG/impaired glucose tolerance (IGT) (r = -0.167, P = 0.4; r = 0.09, P = 0.6). The HOMA-IR correlated with hepatic insulin sensitivity in the whole study group (r = -0.395, P < 0.005) as well as in the IFG/IGT subgroup (r = -0.634, P = 0.002) and in the diabetic subgroup (r = -0.348, P = 0.008). In subjects with IFG/IGT, hepatic insulin sensitivity was the most important determinant of HOMA-IR, explaining 40% of its variation. The HOMA beta-cell index showed a weak correlation with FPIR in the whole study group (r = 0.294, P = 0.001) but not in the subgroups. In contrast, the I/G30 correlated with FPIR in the whole study group (r = 0.472, P < 0.0005) and in the IFG/IGT subgroup (r = 0.493, P < 0.005). CONCLUSIONS: HOMA-IR is dependent upon both peripheral and hepatic insulin sensitivity, the contribution of which differs between subjects with normal and elevated fasting glucose concentrations. These discrepancies develop as a consequence of a nonparallel deterioration of the variables included in the equations with worsening of glucose tolerance.     

Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses

OBJECTIVE: To determine whether the hyperbolic relationship between insulin sensitivity and the acute insulin response to glucose (AIRg) exists in subjects with impaired fasting glucose (IFG) or decreased glucose tolerance. RESEARCH DESIGN AND METHODS: We studied 219 healthy subjects (88 male and 131 female subjects, aged 26-75 years) with fasting plasma glucose (FPG) <6.11 mmol/l. Subjects underwent an intravenous glucose tolerance test to determine the insulin sensitivity index (Si), AIRg, and the glucose disappearance constant (Kg), the latter a measure of intravenous glucose tolerance. RESULTS: Si and AIRg were inversely related for the entire cohort, and this relationship was not significantly different from hyperbolic. The inverse relationship between Si and AIRg was not significantly different when compared between groups based on fasting glucose (normal fasting glucose [NFG], FPG <5.56 mmol/l vs. IFG, FPG 5.56-6.11 mmol/l) or by the Kg quartile. However, the curve relating Si and AIRg was left shifted in the IFG compared with NFG group (P < 0.001) and was progressively more left shifted with decreasing Kg (P < 0.001), consistent with decreasing beta-cell function. These changes were not observed for the curves relating Si and fasting insulin, suggesting that in the fasting state beta-cell function is maintained even in patients with mild IFG. Finally, the disposition index (DI) (Si x AIRg) was calculated as a measure of beta-cell function. The DI progressively decreased with increasing FPG, even in the group of subjects classified as NFG. CONCLUSIONS: The inverse relationship between insulin sensitivity and AIRg is consistent with a hyperbola not only in subjects with normal glucose tolerance but also with mild IFG or decreased Kg. Based on a hyperbolic relationship, a decrease in beta-cell function can be detected as FPG increases, even in patients who are normal glucose tolerant.     

Effects of atropine and gastric inhibitory polypeptide on hepatic glucose uptake and insulin extraction in conscious dogs.

Previous studies comparing the effects of oral, intraportal, and peripheral venous administration of glucose in conscious dogs demonstrated a significant increase in hepatic extraction of insulin only after oral glucose, but similar hepatic uptake of glucose after oral and intraportal glucose, which was greater than that after peripheral intravenous glucose infusion. This study evaluated the effect of atropine blockade of the parasympathetic nervous system on the increased fractional hepatic extraction of insulin and the role of gastric inhibitory polypeptide (GIP) on augmented hepatic uptake of oral glucose in conscious dogs with chronically implanted Doppler flow probes on the portal vein and hepatic artery, and catheters in the portal and hepatic veins and carotid artery. Since atropine infusion decreased absorption of glucose, and in order to achieve comparable portal vein levels of glucose and insulin, the dogs receiving atropine were given 1.9 +/- 0.1 g/kg glucose, compared with the control dogs who received 1.1 +/- 0.1 g/kg. The percentage of the glucose load that was absorbed was greater in the dogs not given atropine (80 +/- 4 vs. 44 +/- 7%), but because of the different loads, the absolute amount of glucose absorbed was similar in both groups (20.2 +/- 1.6 vs. 21.7 +/- 4.1 g). Although delayed by atropine, the peak portal vein glucose and insulin concentrations and the amounts presented to the liver were similar in both groups. However, the increased portal vein plasma flow and fractional hepatic extraction of insulin observed after oral glucose was not observed in the dogs infused with atropine. The net hepatic glucose uptake after oral glucose was significantly less at 10, 20, and 45 min in the atropine-treated dogs, and the area under the curve over the 180-min period was 44% less. However, the latter was not statistically significant. Infusion of GIP with peripheral intravenous glucose did not increase hepatic uptake of glucose or the fractional hepatic extraction of insulin compared with peripheral intravenous glucose alone. These results indicate an important role for parasympathetic innervation in the augmented fractional hepatic extraction of insulin, and increased portal vein plasma flow after oral glucose. Although a relationship between the augmented fractional extraction of insulin and the net hepatic glucose uptake may exist, it does not necessarily indicate that the former is required for the latter. Such parasympathetic innervation may be involved in the greater removal of glucose by the liver after oral compared with peripheral glucose administration. The augmented hepatic uptake of glucose and fractional hepatic extraction of insulin after oral glucose doesn not appear to be mediated by gastric inhibitory polypeptide.     

肝源性糖尿病及其胰岛素抵抗临床观察

目的 观察肝炎后肝硬化继发糖尿病患者糖代谢紊乱和胰岛素抵抗相关指标。方法 30例既往有肝硬化病文(Child-pugh A、B级)但无糖尿病史，血压正常的肝56性糖尿病患者(组1)，分别检测空腹血糖(FPG)、空腹血浆硬岛素(FPI)、空腹C—肽，糖化血红蛋白(HbAlc)，计算胰岛素敏感性指数(ISI)，并以非糖尿病忠者30例(组2)和26例正常人(组3)为对照研究。结果 与组2组3比较，组1空腹血糖升高(分别为P＜0．05和P＜0．01)，空腹C—肽水平无明显差异，但空腹血浆胰岛素水平升高(P均＜0．05)，胰岛素敏感性指数降低(分别为P＜0．05和P＜0．01)。组2与组3间比较，组2空腹血浆硬岛素水平轻度升高，硬岛素敏感性指数降低，但差异无统计学意义。结论 硬岛素抵抗和高硬岛素血症可能为肝源性糖尿病形成的危险因索。     

Differential effects of oral, peripheral intravenous, and intraportal glucose on hepatic glucose uptake and insulin and glucagon extraction in conscious dogs.

The effect of equal (1.1 +/- 0.1 g/kg body wt) amounts of glucose administered orally, or by peripheral intravenous or intraportal infusion on hepatic glucose uptake and fractional hepatic extraction of insulin and glucagon was studied in conscious dogs with chronically implanted Doppler flow probes on the portal vein and hepatic artery and catheters in the portal vein, hepatic vein, carotid artery, and superior mesenteric vein. Portal vein and hepatic vein plasma flow increased only after oral glucose administration. Arterial plasma glucose increased equally to 150-160 mg/100 ml after all three routes of glucose administration. Portal vein glucose was similar after oral (195 +/- 15 mg/100 ml) and intraportal glucose infusion (215 +/- 11 mg/100 ml) and significantly higher than after peripheral intravenous glucose. Hepatic glucose uptake after oral (68 +/- 4%) and intraportal glucose administration (65 +/- 7%) significantly exceeded that after peripheral intravenous glucose infusion (23 +/- 5%). The amount of insulin above basal presented to the liver during the 180 min after oral glucose was 7.6 +/- 1.3 U, 4.3 +/- 0.6 U after intraportal glucose, and 4.1 +/- 0.6 U after peripheral intravenous glucose. Hepatic extraction of insulin increased significantly after oral glucose (42 +/- 3 to 61 +/- 4%), but was unchanged after intraportal and peripheral intravenous glucose administration. When the portal vein glucose levels achieved during peripheral intravenous glucose infusion for 90 min were maintained by a subsequent 90-min intraportal glucose infusion, hepatic glucose uptake was significantly greater during the intraportal glucose infusion. Glucagon secretion was suppressed equally after oral glucose, intraportal glucose, and peripheral intravenous glucose administration; fractional hepatic extraction of that hormone, which was significantly less than that of insulin, was unchanged. These results indicate that hepatic glucose uptake is significantly greater after oral and intraportal glucose administration than after peripheral intravenous glucose infusion. This difference is not simply related to the amount of glucose or insulin presented to the liver and the increased hepatic glucose uptake did not depend solely upon the augmented fractional hepatic extraction of insulin. Hepatic extraction of insulin and hepatic glucose uptake appear to be regulated independently.     

Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes.

The changes in hepatic glucose production (Ra), tissue glucose disposal (Rd), and plasma glucose and insulin concentration that took place over a 16-h period from 10 to 2 p.m. were documented in 14 individuals; 8 with non-insulin-dependent diabetes mellitus (NIDDM) and 6 with normal glucose tolerance. Values for Ra were higher than normal in patients with NIDDM at 10 p.m. (4.73 +/- 0.41 vs. 3.51 +/- 0.36 mg/kg per min, P less than 0.001), but fell at a much faster rate throughout the night than that seen in normal subjects. As a consequence, the difference between Ra in normal individuals and patients with NIDDM progressively narrowed, and by 2 p.m., had ceased to exist (1.75 +/- 0.61 vs. 1.67 +/- 0.47 mg/kg per min, P = NS). Plasma glucose concentration also declined in patients with NIDDM over the same period of time, but they remained quite hyperglycemic, and the value of 245 +/- 27 mg/dl at 2 p.m. was about three times greater than in normal individuals. Plasma insulin concentrations also fell progressively from 10 to 2 p.m., and were similar in both groups throughout most of the 16-h study period. Thus, the progressive decline in Ra in patients with NIDDM occurred despite concomitant falls in both plasma glucose and insulin concentration. Glucose disposal rates also fell progressively in both groups, but the magnitude of the fall was greater in patients with NIDDM. Consequently, Rd in patients with NIDDM was higher at 10 p.m. (3.97 +/- 0.48 vs. 3.25 +/- 0.13 mg/kg per min, P less than 0.001) and lower the following day at 2 p.m. (1.64 +/- 0.21 vs. 1.97 +/- 0.35 mg/kg per min, P less than 0.01). These results indicate that a greatly expanded pool size can exist in patients with NIDDM at a time when values for Ra are identical to those in normal subjects studied under comparable conditions, which suggests that fasting hyperglycemia in NIDDM is not simply a function of an increase in Ra.     

院前颅脑创伤患者创伤程度与早期血糖相关性分析

目的 检测院前颅脑创伤患者创伤程度与早期血糖之间的关系,以指导院前创伤患者的病情评估与预后.方法 回顾性分析2008-01～2010-12期间43例院前颅脑创伤患者创伤程度与其早期血糖之间的关系,根据格拉斯哥昏迷评分(GCS)分为轻、中、重度颅脑创伤三组,按上海市院前急救质控手册,分为病情判断危重和普通组,用t检验进行组间比较,评估早期血糖与患者伤情、预后的关系.结果 研究显示,轻、中、重度颅脑伤患者出现不同程度的高血糖,平均血糖随着伤情的加重依次升高,其中GCS评分在13～15分之间为轻度创伤组,共21例,血糖为(5.62±0.67)mmol/L;GCS评分在9～12分之间为中度创伤组,共13例,血糖为(6.38±0.44 )mmol/L;GCS评分在3～8分之间为重度创伤组,共9例,血糖为(7.33±1.48)mmol/L;病情危重组血糖值为(7.62±0.54)mmol/L,病情普通组血糖值为 (5.85±0.89)mmol/L.结果 表明,轻、中型颅脑创伤组间差异无统计学意义(P>0.05),其余两两组间差异均有统计学意义(P<0.05);病情判断危重和普通组比较差异有统计学意义(P<0.05).结论 院前颅脑创伤患者创伤严重程度与早期血糖增高有明显正相关性,对院前创伤患者的病情评估与预后有指导意义.     

Relationship of glucagon suppression by insulin and somatostatin to the ambient glucose concentration.

The glucagon-suppressing activity of insulin and somatostatin were compared at high and low glucose concentrations. In normal dogs made hyperglucagonemic by phloridzin pretreatment, insulin and somatostatin suppressed glucagon at rates of 47 +/- 8 and 35 +/- 8%/h (NS), respectively, despite profound hypoglycemia. In severely hyperglycemic alloxan-diabetic dogs, insulin and somatostatin suppressed glucagon at rates of 48 +/- 13 and 54 +/- 6%/h, respectively, not different from the nondiabetic dogs. After phloridzin pretreatment to eliminate hyperglycemia in the diabetic dogs, insulin and somatostatin suppressed 51 +/- 8 and 31 +/- 10%/h (NS), respectively. Glucose infused in the phloridzin-pretreated insulin-deprived group suppressed glucagon only partially; insulin was required to reduce it further. We conclude that insulin and somatostatin suppress glucagon at similar rates irrespective of ambient glucose levels, and that diabetic hyperglucagonemia represents the summation of stimulation by insulin lack minus suppression by the associated hyperglycemia.     

Effect of dexamethasone on hepatic glucose and insulin metabolism after oral glucose in conscious dogs.

To examine whether hyperinsulinemia associated with glucocorticoid treatment results solely from hypersecretion of insulin or also involves altered fractional hepatic extraction, oral glucose (1 g/kg body wt) was administered to dogs with or without dexamethasone treatment (2 mg/d for 2 d). Dexamethasone significantly increased basal glucose and insulin concentrations in the portal vein, hepatic vein, and femoral artery, reduced basal fractional hepatic extraction of insulin from 43 +/- 4% to 22 +/- 4%, and, after oral glucose, increased retention by the liver of net glucose released into the portal system from 27 +/- 4% to 53 +/- 13%. Intraportal insulin infusion (1 and 2 mU/kg per min) after 7 d of dexamethasone treatment (2 mg/d) caused less suppression of endogenous glucose production, and less exogenous glucose was required to maintain an euglycemic clamp than in control animals. Dexamethasone treatment is associated with: decreased basal fractional hepatic insulin extraction contributing to hyperinsulinemia; and less suppression of endogenous glucose production and increase in peripheral uptake in response to insulin, but no reduction in net hepatic glucose uptake after oral glucose.     

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects

The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.     

Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men.

Insulin action and obesity are both correlated with the density of muscle capillary supply in humans. Since the altered muscle anatomy in the obese might affect interstitial insulin concentrations and reduce insulin action, we have cannulated peripheral lymphatic vessels in lean and obese males, and compared peripheral lymph insulin concentrations with whole body glucose uptake during a euglycemic, hyperinsulinemic clamp. Lymph insulin concentrations in the lower limb averaged only 34% of arterial insulin concentrations during 150 min of insulin infusion. Obese subjects had the highest arterial (P < or = 0.0001) and lymph insulin (P < 0.005) concentrations, but the lowest glucose uptake rates (P < 0.002). In contrast to the initial steep rise then plateau of arterial insulins, both lymph insulin and whole body glucose uptake rates rose slowly and did not consistently reach a plateau. In each individual, the glucose uptake closely correlated with peripheral lymphatic insulin concentrations (mean r2 = 0.95). The coupling between glucose uptake and lymph insulin (glucose uptake/pmol insulin) was much steeper in lean subjects than in the obese (P < or = 0.0001). These results indicate that even if insulin diffusion into tissues is rate limiting for insulin action, a tissue defect rather than an insulin diffusion defect causes insulin resistance in obese subjects.