Splanchnic Glucose Uptake Research Articles

Aerobic exercise training improves hepatic and muscle insulin sensitivity, but reduces splanchnic glucose uptake in obese humans with type 2 diabetes

BackgroundAerobic exercise training is known to have beneficial effects on whole-body glucose metabolism in people with type 2 diabetes (T2D). The responses of the liver to such training are less well understood. The purpose of this study was to determine the effect of aerobic exercise training on splanchnic glucose uptake (SGU) and insulin-mediated suppression of endogenous glucose production (EGP) in obese subjects with T2D.MethodsParticipants included 11 obese humans with T2D, who underwent 15 ± 2 weeks of aerobic exercise training (AEX; n = 6) or remained sedentary for 15 ± 1 weeks (SED; n = 5). After an initial screening visit, each subject underwent an oral glucose load clamp and an isoglycemic/two-step (20 and 40 mU/m2/min) hyperinsulinemic clamp (ISO-clamp) to assess SGU and insulin-mediated suppression of EGP, respectively. After the intervention period, both tests were repeated.ResultsIn AEX, the ability of insulin to suppress EGP was improved during both the low (69 ± 9 and 80 ± 6% suppression; pre-post, respectively; p < 0.05) and high (67 ± 6 and 82 ± 4% suppression, respectively; p < 0.05) insulin infusion periods. Despite markedly improved muscle insulin sensitivity, SGU was reduced in AEX after training (22.9 ± 3.3 and 9.1 ± 6.0 g pre-post in AEX, respectively; p < 0.05).ConclusionsIn obese T2D subjects, exercise training improves whole-body glucose metabolism, in part, by improving insulin-mediated suppression of EGP and enhancing muscle glucose uptake, which occur despite reduced SGU during an oral glucose challenge.

Decreased basal hepatic glucose uptake in impaired fasting glucose.

This research aimed to define the pathophysiological defects responsible for the elevated fasting plasma glucose (FPG) concentration and excessive rise in post-load plasma glucose observed in individuals with impaired fasting glucose (IFG). We used tracer techniques to quantify basal splanchnic (primarily hepatic) glucose uptake and glucose fluxes following glucose ingestion in individuals with normal glucose tolerance (NGT; n=10) and IFG (n=10). Individuals with IFG had a comparable basal rate of hepatic glucose production to those with NGT (15.2±0.2 vs 18.0±0.8μmolmin-1[kg lean body mass (LBM)]-1; p=0.09). However, they had a significantly reduced glucose clearance rate during the fasting state compared with NGT (2.64±0.11 vs 3.62±0.20ml min-1[kgLBM]-1; p<0.01). The difference between the basal rate of glucose appearance measured with [3-3H]glucose and [1-14C]glucose, which represent basal splanchnic glucose uptake, was significantly reduced in IFG compared with NGT (1.39±0.28 vs 3.16±0.44μmolmin-1[kgLBM]-1; p=0.02). Following glucose ingestion, the total amount of exogenous glucose that appeared in the systemic circulation was not significantly different between groups. However, suppression of endogenous glucose production (EGP) was markedly impaired in individuals with IFG. These results demonstrate that decreased tissue (liver) glucose uptake, not enhanced EGP, is the cause for elevated FPG concentration in individuals with IFG, while the excessive rise in plasma glucose concentration following a glucose load in these individuals is the result of impaired suppression of hepatic glucose production.

Comparison of the effects of slowly and rapidly absorbed carbohydrates on postprandial glucose metabolism in type 2 diabetes mellitus patients: a randomized trial

Isomaltulose attenuates postprandial glucose and insulin concentrations compared with sucrose in patients with type 2 diabetes mellitus (T2DM). However, the mechanism by which isomaltulose limits postprandial hyperglycemia has not been clarified. The objective was therefore to assess the effects of bolus administration of isomaltulose on glucose metabolism compared with sucrose in T2DM. In a randomized, double-blind, crossover design, 11 participants with T2DM initially underwent a 3-h euglycemic-hyperinsulinemic (0.8 mU · kg(-1) · min(-1)) clamp that was subsequently combined with 1 g/kg body wt of an oral (13)C-enriched isomaltulose or sucrose load. Hormonal responses and glucose kinetics were analyzed during a 4-h postprandial period. Compared with sucrose, absorption of isomaltulose was prolonged by ∼50 min (P = 0.004). Mean plasma concentrations of insulin, C-peptide, glucagon, and glucose-dependent insulinotropic peptide were ∼10-23% lower (P < 0.05). In contrast, glucagon-like peptide 1 (GLP-1) was ∼64% higher (P < 0.001) after isomaltulose ingestion, which results in an increased insulin-to-glucagon ratio (P < 0.001) compared with sucrose. The cumulative amount of systemic glucose appearance was ∼35% lower after isomaltulose than after sucrose (P = 0.003) because of the reduction in orally derived and endogenously produced glucose and a higher first-pass splanchnic glucose uptake (SGU). Insulin action was enhanced after isomaltulose compared with sucrose (P = 0.013). Ingestion of slowly absorbed isomaltulose attenuates postprandial hyperglycemia by reducing oral glucose appearance, inhibiting endogenous glucose production (EGP), and increasing SGU compared with ingestion of rapidly absorbed sucrose in patients with T2DM. In addition, GLP-1 secretion contributes to a beneficial shift in the insulin-to-glucagon ratio, suppression of EGP, and enhancement of SGU after isomaltulose consumption. This trial was registered at clinicaltrials.gov as NCT01070238.

An interesting case with obese and ketosis-prone type 2 diabetes suggesting metformin action on the adipose tissue

We report a 63-year-old obese ketosis-prone diabetic woman who was being treated with metformin and a low dose of insulin. We performed two hyperinsulinemic-euglycemic clamp studies followed by an oral glucose load (clamp-OGL) with and without administration of metformin. These clamp studies revealed that her splanchnic glucose uptake (SGU) was increased from 27.6 to 64.4% by metformin administration, though the glucose infusion rate (GIR) was not altered. Further investigation indicated that the intrahepatic lipid (IHL) content was low in this patient. After she stopped metformin, the fasting plasma glucose, free fatty acid, and ketone body levels were elevated, while these were decreased by re-administration of the drug. Our results suggest that metformin might not only act on the liver, but also on adipose tissue, and it could be an adjunctive treatment for obese patients with ketosis-prone type 2 diabetes.

Effect of Exenatide on Splanchnic and Peripheral Glucose Metabolism in Type 2 Diabetic Subjects

Our objective was to examine the mechanisms via which exenatide attenuates postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). Seventeen T2DM patients (44 yr; seven females, 10 males; body mass index = 33.6 kg/m(2); glycosylated hemoglobin = 7.9%) received a mixed meal followed for 6 h with double-tracer technique ([1-(14)C]glucose orally; [3-(3)H]glucose i.v.) before and after 2 wk of exenatide. In protocol II (n = 5), but not in protocol I (n = 12), exenatide was given in the morning of the repeat meal. Total and oral glucose appearance rates (RaT and RaO, respectively), endogenous glucose production (EGP), splanchnic glucose uptake (75 g - RaO), and hepatic insulin resistance (basal EGP × fasting plasma insulin) were determined. After 2 wk of exenatide (protocol I), fasting plasma glucose decreased (from 10.2 to 7.6 mm) and mean postmeal plasma glucose decreased (from 13.2 to 11.3 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.9 to 10.8 μmol/kg · min, P < 0.05), and hepatic insulin resistance declined (both P < 0.05). RaO, gastric emptying (acetaminophen area under the curve), and splanchnic glucose uptake did not change. In protocol II (exenatide given before repeat meal), fasting plasma glucose decreased (from 11.1 to 8.9 mm) and mean postmeal plasma glucose decreased (from 14.2 to 10.1 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.4 to 10.7 μmol/kg · min, P = 0.05). RaT and RaO decreased markedly from 0-180 min after meal ingestion, consistent with exenatide's action to delay gastric emptying. Exenatide improves 1) fasting hyperglycemia by reducing basal EGP and 2) postmeal hyperglycemia by reducing the appearance of oral glucose in the systemic circulation.

Importance of changes in gastric emptying for postprandial plasma glucose fluxes in healthy humans

Regulation of postprandial (pp) plasma glucose excursions is complex. Insulin and glucagon are thought to play the predominant role. Nevertheless, only 50% of the variation in pp plasma glucose excursions is explained by variations by the latter. Theoretically, gastric emptying (GE) should be another important factor. However, its impact on pp glucose homeostasis is unknown. We examined the consequences of pramlintide-induced delay in GE on pp glycemia and glucose fluxes, determined isotopically. GE was recorded by scintigraphy. Fourteen healthy subjects (8 men, 6 women; age 40 +/- 3 yr, body mass index 27.8 +/- 1.1 kg/m2) ate a mixed meal, and 30 microg of pramlintide (PRAM) or placebo (PBO) were injected subcutaneously. At 60 min, greater proportions of the initial gastric contents remained in the stomach (PBO vs. PRAM). Thereafter, GE slopes paralleled until 240 min. Fifty percent retention times were lower when PBO was given (P < 0.001). GE was greater from 240 min to the end of the PRAM experiments, so that only slightly greater proportions of the meal remained in the stomach at 330 min. Reductions of GE lowered pp glucose (7.5 +/- 0.3 vs. 6.0 +/- 0.2 mmol/l, P < 0.001), even though plasma insulin was lower with PRAM (164 +/- 13 vs. 138 +/- 13 pmol/ml, both P < 0.01). Reduction in total glucose appearance (P < 0.001) was due to reduced meal-derived glucose appearance (10.2 +/- 0.5 vs. 7.0 +/- 0.4 micromol.kg(-1).min(-1), P < 0.001). Endogenous glucose appearance was greater with PRAM (P < 0.001). Splanchnic glucose uptake was greater with PRAM (26.5 +/- 1.6 vs. 32.5 +/- 2.1%, P = 0.014). These data support the concept that GE is an important physiological regulator of pp glucose homeostasis in humans.

Effects of Diet-Induced Moderate Weight Reduction on Intrahepatic and Intramyocellular Triglycerides and Glucose Metabolism in Obese Subjects

Although moderate weight reduction is recommended as primary therapy of metabolic syndrome, little information is known regarding metabolic changes associated with moderate weight reduction in nondiabetic obese subjects. The aim of this study was to determine the effects of a moderate weight reduction program on intracellular lipid and glucose metabolism in muscle and liver. Data for 13 nondiabetic obese subjects were evaluated. Subjects were put on a 3-month mildly hypocaloric diet therapy (approximately 35 kcal/kg of ideal body weight). Intrahepatic lipid (IHL) and intramyocellular lipid were measured by using (1)H magnetic resonance spectroscopy. Peripheral insulin sensitivity and splanchnic glucose uptake were evaluated by euglycemic-hyperinsulinemic clamp with oral glucose load. Diet therapy for 3 months resulted in 6% reduction in body weight (from 99.9 +/- 7.3 to 93.8 +/- 6.6 kg, P < 0.0001). This change was accompanied by reduction of plasma glucose and insulin excursions during 75-g oral glucose tolerance tests, decrease in diastolic blood pressure, glycated hemoglobin, serum low-density lipoprotein cholesterol, and triglyceride. These changes were also accompanied by a decrease in IHL (from 12.9 to 8.2%, P < 0.01) and increase in splanchnic glucose uptake (from 13.5 to 35.0%, P < 0.03). On the other hand, the diet program did not affect intramyocellular lipid or glucose infusion rate during euglycemic hyperinsulinemic clamp. Our results suggest that moderate weight reduction in obese subjects decreased IHL and augmented splanchnic glucose uptake. This mechanism is at least in part involved in improvement of glucose metabolism by moderate weight reduction in obese subjects.

Spotlight on Pioglitazone in Type 2 Diabetes Mellitus1

Pioglitazone (Actos(trade mark)) is an antihyperglycemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake. Pioglitazone is generally well tolerated, weight gain and edema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin, or a sulfonylurea, induced both long- and short-term improvements in glycemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.

Pioglitazone

Pioglitazone is an antihyperglycaemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake. Pioglitazone is generally well tolerated, weight gain and oedema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin or a sulphonylurea, induced both long- and short-term improvements in glycaemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.

Effects of Type 2 Diabetes on the Regulation of Hepatic Glucose Metabolism

Glucose production is inappropriately increased in people with type 2 diabetes both before and after food ingestion. Excessive postprandial glucose production occurs in the presence of decreased and delayed insulin secretion and lack of suppression of glucagon release. These abnormalities in hormone secretion, coupled with impaired insulin-induced suppression of glucose production and stimulation of splanchnic glucose uptake, likely account in large part for the excessive amounts of glucose that reach the systemic circulation for disposal by peripheral tissues following food ingestion. In contrast, when adequate basal insulin concentrations are present, neither glucagon-induced stimulation of glucose production nor glucose-induced suppression of glucose production differs in diabetic and nondiabetic subjects matched for gender, age, and degree of obesity. However, when insulin secretion is defective, lack of suppression of glucagon can cause substantial hyperglycemia by enhancing rates of glucose production. Therefore, normalization of hepatic glucose metabolism in people with type 2 diabetes mellitus likely will require normalization of insulin and glucagon secretion as well as hepatic insulin action.

Evaluation of hepatic and whole body glycogen metabolism in humans during repeated administrations of small loads of 13C glucose

Postprandial suppression of endogenous glucose production and regulation of glucose homeostasis involve alterations of whole body and hepatic glycogenolysis and glycogen breakdown. These parameters can be estimated by the simultaneous measurement of net total and exogenous, (13)C-labeled, glucose oxidation. Eight subjects were studied on 3 occasions, while receiving oral loads of 60 mg, 120 or 180 mg (13)C glucose/kg every hour for 4 consecutive hours. Net glucose oxidation was calculated from indirect calorimetry, and exogenous glucose oxidation from (13)CO(2) production. These parameters were evaluated during the hour following the fourth glucose load. Whole body endogenous glycogen breakdown was calculated as (net glucose oxidation) - (exogenous glucose oxidation). Total glycogen synthesis was calculated as (glucose load) - (exogenous glucose oxidation). Whole body glucose turnover was measured with 6.6 (2)H(2) glucose. The systemic appearance of oral, (13)C labeled glucose was monitored, and the suppression of endogenous glucose production was calculated. Plasma glucose tracers had reached near steady state during the hour following the fourth glucose load. Glucose ingestion dose-dependently suppressed endogenous glycogen breakdown and stimulated total glycogen synthesis. Endogenous glycogen breakdown was completely inhibited with 180 mg oral glucose/kg. Endogenous glucose production was suppressed in a dose-dependent way, but remained positive with all 3 doses. The first pass splanchnic glucose uptake averaged 25-35%. Repeated administration of small doses of (13)C labeled glucose allow to reach near steady state conditions after four hours, and to non-invasively evaluate whole body glycogen turnover and hepatic glucose metabolism.

Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients

The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation. Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,6 2H2 glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide(GIP) concentrations were compared after intravenous and oral glucose. After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P<0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P<0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose. First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the beta-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

Splanchnic tissues play a crucial role in uremic glucose intolerance

Objective: Determine the mechanism of glucose intolerance in chronically uremic subjects. Design: Comparison of doubly labeled oral glucose tolerance tests. Subjects: Seven nondialyzed chronically uremic subjects (creatinine, 420 ± 104 μmol/L) and 7 healthy subjects, matched for age and body mass index. Intervention: Plasma glucose was labeled by an infusion of dideuterated glucose started 120 minutes before ingestion of 1 g/kg of naturally 13C-enriched corn starch glucose. Glucose levels and oxidation were monitored for 330 minutes after glucose ingestion. Results: Uremic subjects had normal fasting plasma glucose levels and impaired glucose tolerance with high plasma insulin ( P < .001 versus controls). Glucose tolerance was impaired because of an increased total rate of appearance of glucose (cumulated on 330 minutes: uremic, 1,231 ± 42 mg/kg/330 min, controls, 1,031 ± 64; P < .05). Peripheral glucose uptake was increased ( P < .05) because of an increased nonoxidative disposal ( P = .051). Conclusions: Although peripheral glucose uptake resisted the stimulatory effect of the high insulin levels, glucose tolerance was impaired through splanchnic metabolic disturbances: reduced splanchnic glucose uptake and increased endogenous glucose production. The respective contribution of these abnormalities remains to be determined.

Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes.

The effect of pioglitazone on splanchnic glucose uptake (SGU), endogenous glucose production (EGP), and hepatic fat content was studied in 14 type 2 diabetic patients (age 50 +/- 2 years, BMI 29.4 +/- 1.1 kg/m(2), HbA(1c) 7.8 +/- 0.4%). Hepatic fat content (magnetic resonance spectroscopy) and SGU (oral glucose load- insulin clamp technique) were quantitated before and after pioglitazone (45 mg/day) therapy for 16 weeks. Subjects received a 7-h euglycemic insulin (100 mU. m(-2). min(-1)) clamp, and a 75-g oral glucose load was ingested 3 h after starting the insulin clamp. Following glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4 h 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 EGP and glucose disappearance (R(d)). Pioglitazone reduced fasting plasma glucose (10.0 +/- 0.7 to 7.5 +/- 0.6 mmol/l, P < 0.001) and HbA(1c) (7.8 +/- 0.4 to 6.7 +/- 0.3%, P < 0.001) despite increased body weight (83 +/- 3 to 86 +/- 3 kg, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, pioglitazone improved R(d) (6.9 +/- 0.5 vs. 5.2 +/- 0.5 mg. kg(-1). min(- 1), P < 0.001) and insulin-mediated suppression of EGP (0.21 +/- 0.04 to 0.06 +/- 0.02 mg. kg(-1). min(-1), P < 0.01). Following pioglitazone treatment, hepatic fat content decreased from 19.6 +/- 3.6 to 10.4 +/- 2.1%, (P < 0.005), and SGU increased from 33.0 +/- 2.8 to 46.2 +/- 5.1% (P < 0.005). Pioglitazone treatment in type 2 diabetes 1) decreases hepatic fat content and improves insulin-mediated suppression of EGP and 2) augments splanchnic and peripheral tissue glucose uptake. Improved splanchnic/peripheral glucose uptake and enhanced suppression of EGP contribute to the improvement in glycemic control in patients with type 2 diabetes.

Mechanism of Increased Plasma Glucose Levels after Oral Glucose Ingestion in Normal-Weight Middle-Aged Subjects

Background/Aims: To determine the decline in glucose tolerance in normal-weight middle-aged subjects, we performed a cross-sectional study using double-labelled oral glucose tolerance tests in 8 middle-aged (46.3 ± 0.9 years) and in 8 young (23.6 ± 0.5) subjects with similar normal body weight. Methods: Plasma glucose was labelled by an infusion of dideuterated glucose started 120 min before ingestion of 1 g/kg of naturally ¹³C-enriched corn starch glucose. Glucose levels, substrate oxidation (indirect calorimetry) and exogenous glucose oxidation (¹³C enrichment of expired CO₂) were monitored for 330 min. Results: In the middle-aged subjects, the appearance of exogenous glucose was reduced (723 ± 52 mg/kg/330 min) compared to young subjects (864 ± 38; p < 0.05), and systemic glucose production was normal. Plasma glucose levels were increased due to a reduced glucose disappearance rate (middle aged: 1,046 ± 61 mg/kg/330 min vs. young 1,242 ± 67; p < 0.05), concerning both oxidative and non-oxidative disposal. This reduction was no longer apparent when the results were normalized for fat-free mass. Insulin levels were similar in young and middle-aged subjects. Conclusion: In normal-weight middle-aged individuals, glucose intolerance is mainly due to the reduction in the mass of fat-free glucose-utilizing tissues. The higher plasma glucose levels enable normal glucose supply to peripheral tissues, and increase splanchnic glucose uptake.

Fat-induced liver insulin resistance.

In vitro studies have established that free fatty acids (FFAs) are important regulators of hepatic glucose metabolism. FFAs can increase hepatic glucose release by increasing the amount and activity of glucose-6-phosphatase and multiple gluconeogenic enzymes. Elevated FFAs can also potentially decrease hepatic glucose uptake by decreasing hepatic glucokinase activity. In vivo studies in both animals and humans have shown a close correlation between changes in plasma FFAs and endogenous glucose production (EGP). Intervention studies have established that changes in plasma FFAs are accompanied by changes in the relative contribution of gluconeogenesis and glycogenolysis to EGP. The effects of a change in FFAs on EGP itself are more evident when compensatory changes in insulin secretion are prevented or when insulin secretion is impaired (eg, diabetes mellitus). The effects of elevated FFAs on splanchnic glucose uptake are less clear, in that they appear to have no effect in nondiabetic humans and may impair uptake in people with type 2 diabetes.

Influence of metabolic control on splanchnic glucose uptake, insulin sensitivity, and the time required for glucose absorption in patients with type 1 diabetes.

The relationship between splanchnic glucose uptake (SGU) after oral glucose administration and metabolic control in type 1 diabetic patients is controversial. We estimated SGU as well as peripheral glucose uptake and the time required for glucose absorption by a validated method, the oral glucose (OG) clamp, in type 1 diabetic patients with different levels of long-term glycemic control. An OG clamp (which combines a hyperinsulinemic clamp [120 mU. m(-2). min(-1)] with an OR load [75 g] during steady-state glucose uptake) was performed in eight type 1 diabetic patients with good metabolic control (DG) (HbA(1c) 6.1 +/- 0.2%, BMI 23.1 +/- 0.7 kg/m(2)), eight type 1 diabetic patients with poor metabolic control (DP) (HbA(1c) 8.5 +/- 0.3%, BMI 25.4 +/- 1.4 kg/m(2)), and eight healthy matched control subjects (C) (HbA(1c) 5.1 +/- 0.1%, BMI 25 +/- 1.3 kg/m(2)) to determine SGU, glucose uptake, and glucose absorption. Glucose uptake calculated from 120 to 180 min during the clamp was 9.13 +/- 0.55 mg. kg(-1). min(-1) in C, 8.18 +/- 0.71 mg. kg(-1). min(-1) in DG, and 7.42 +/- 0.96 mg. kg(-1). min(-1) in DP (NS). Glucose absorption was 140 +/- 6 min in C, 156 +/- 4 min in DG, and 143 +/- 7 min in DP (NS). The respective calculated SGU was 14.5 +/- 5.6% in C, 17.8 +/- 3.1% in DG, and 18.8 +/- 4.2% in DP (NS) and did not correlate with HbA(1c) values. Peripheral glucose uptake, SGU after oral glucose administration, and the glucose absorption time were not different in type 1 diabetic patients independent of glycemic control when compared with healthy subjects.

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.

Effect of enteral vs. parenteral glucose delivery on initial splanchnic glucose uptake in nondiabetic humans.

To determine if enteral delivery of glucose influences splanchnic glucose metabolism, 10 subjects were studied when glucose was either infused into the duodenum at a rate of 22 micromol x kg(-1) x min(-1) and supplemental glucose given intravenously or when all glucose was infused intravenously while saline was infused intraduodenally. Hormone secretion was inhibited with somatostatin, and glucose (approximately 8.5 mmol/l) and insulin (approximately 450 pmol/l) were maintained at constant but elevated levels. Intravenously infused [6,6-(2)H(2)]glucose was used to trace the systemic appearance of intraduodenally infused [3-(3)H]glucose, whereas UDP-glucose flux (an index of hepatic glycogen synthesis) was measured using the acetaminophen glucuronide method. Despite differences in the route of glucose delivery, glucose production (3.5 +/- 1.0 vs. 3.3 +/- 1.0 micromol x kg(-1) x min(-1)) and glucose disappearance (78.9 +/- 5.7 vs. 85.0 +/- 7.2 micromol x kg(-1) x min(-1)) were comparable on intraduodenal and intravenous study days. Initial splanchnic glucose extraction (17.5 +/- 4.4 vs. 14.5 +/- 2.9%) and hepatic UDP-glucose flux (9.0 +/- 2.0 vs. 10.3 +/- 1.5 micromol x kg(-1) x min(-1)) also did not differ on the intraduodenal and intravenous study days. These data argue against the existence of an "enteric" factor that directly (i.e., independently of circulating hormone concentrations) enhances splanchnic glucose uptake or hepatic glycogen synthesis in nondiabetic humans.

Effects of free fatty acids and glycerol on splanchnic glucose metabolism and insulin extraction in nondiabetic humans.

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To do so, FFAs were increased in 10 subjects to approximately 1 mmol/l by an 8-h Intralipid/heparin (IL/Hep) infusion, whereas they fell to levels near the detection limit of the assay (<0.05 mmol/l) in 13 other subjects who were infused with glycerol alone at rates sufficient to either match (n = 5, low glycerol) or double (n = 8, high glycerol) the plasma glycerol concentrations observed during the IL/Hep infusion. Glucose was clamped at approximately 8.3 mmol/l, and insulin was increased to approximately 300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. Leg glucose uptake (21.7 +/- 3.5 vs. 48.3 +/- 9.3 and 57.8 +/- 11.7 micromol x kg(-1) leg x min(-1)) was lower (P < 0.001) during IL/Hep than the low- or high-glycerol infusions, confirming that elevated FFAs caused insulin resistance in muscle. IL/Hep did not alter splanchnic glucose uptake or the contribution of the extracellular direct pathway to UDP-glucose flux. On the other hand, total UDP-glucose flux (13.2 +/- 1.7 and 12.5 +/- 1.0 vs. 8.1 +/- 0.5 micromol x kg(-1) x min(-1)) and flux via the indirect intracellular pathway (8.4 +/- 1.2 and 8.1 +/- 0.6 vs. 4.8 +/- 0.05 micromol x kg(-1) x min(-1)) were greater (P < 0.05) during both the IL/Hep and high-glycerol infusions than the low-glycerol infusion. In contrast, only IL/Hep increased (P < 0.05) splanchnic glucose production, indicating that elevated FFAs impaired the ability of the liver to autoregulate. Splanchnic insulin extraction, directly measured using the arterial and hepatic vein catheters, did not differ (67 +/- 3 vs. 71 +/- 5 vs. 69 +/- 1%) during IL/Hep and high- and low-glycerol infusions. We conclude that elevated FFAs exert multiple effects on glucose metabolism. They inhibit insulin- and glucose-induced stimulation of muscle glucose uptake and suppression of splanchnic glucose production. They increase the contribution of the indirect pathway to glycogen synthesis and impair hepatic autoregulation. On the other hand, they do not alter either splanchnic glucose uptake or splanchnic insulin extraction in nondiabetic humans.