Improvement of impaired postoperative insulin action by bradykinin

The effect of bradykinin on insulin-stimulated glucose metabolism was studied in 5 operated patients using the euglycemic insulin clamp technique and the forearm catheter technique. Insulin infusion [1.0 mU/(kg b.w. X min)] raised plasma insulin levels up to 73 muU/ml. Euglycemia was maintained by a computerized glucose infusion rate, amounting to 2.9 mg/(kg b.w. X min). Addition of bradykinin [1.5 micrograms/(kg b.w. X h)] resulted in a significant increase of the glucose infusion rate [+ 1.0 mg/(kg b.w. X min)] indicating elevated whole body glucose uptake. This was related to an enhanced forearm glucose uptake [+ 1.16 mumol/(100 g X min)]. Forearm blood flow remained stable.     

Utilization of fluorescence tracer in hyperinsulinemic-euglycemic clamp test in mice

The hyperinsulinemic–euglycemic clamp test is considered to be a gold standard for the evaluation of insulin sensitivity. Here, a new version of the clamp test that used the fluorescence tracer 2-NBDG was tested. C57BL/6J mice were induced insulin resistant (IR) with a high-calorie diet. Rosiglitazone was administrated to IR mice and diabetic db/db mice. Insulin resistance was estimated with the oral glucose tolerance test (OGTT), the insulin tolerance test (ITT), the serum insulin level and the homeostasis model assessment of insulin resistance (HOMA-IR), and then confirmed by the hyperinsulinemic–euglycemic clamp test with 2-NBDG. The 2-NBDG content was measured by the fluorescence intensity. The characteristics of insulin resistance were shown remarkably with the increased values of serum insulin and HOMA-IR in IR mice, and with the results from OGTT and ITT in both IR and db/db mice. In the hyperinsulinemic–euglycemic clamp test, the glucose infusion rate and amount of 2-NBDG taken up into the liver, adipose, and skeletal muscle were decreased significantly in IR mice and db/db mice, respectively. The clearing rates of 2-NBDG from the circulation were much slower in both mouse models. All markers were reversed significantly by rosiglitazone treatment. The results indicate that with the fluorescence tracer 2-NBDG, the hyperinsulinemic–euglycemic clamp test can be used to estimate insulin sensitivity in vivo.     

Changes in insulin sensitivity precede changes in body composition during 14 days of step reduction combined with overfeeding in healthy young men

A lifestyle characterized by inactivity and a high-calorie diet is a known risk factor for impaired insulin sensitivity and development of Type 2 diabetes mellitus. To investigate possible links, nine young healthy men (24 ± 3 yr; body mass index of 21.6 ± 2.5 kg/m(2)) completed 14 days of step reduction (10,000 to 1,500 steps/day) and overfeeding (+50% kcal). Body composition (dual X-ray absorptiometry, MRI), aerobic fitness (maximal O(2) consumption), systemic inflammation and insulin sensitivity [oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp] were assessed before (day 0), during (days 3 and 7), and immediately after the intervention (day 14), with follow-up tests (day 30). Body weight had increased at days 7 and 14 (P < 0.05). The amount of visceral fat had increased at day 14 compared with day 0 (P < 0.05). The insulin response to the OGTT had increased at days 7 and 14 (P < 0.05). Insulin sensitivity, estimated using the Matsuda index, had decreased at days 3 and 7 (P < 0.01). At day 14, glucose infusion rates had decreased by ～44% during the euglycemic clamps (P < 0.05). Also, plasma levels of leptin and adiponectin had increased (P < 0.05), whereas no changes were seen in inflammatory markers. At day 30, body weight and whole body adiposity were still elevated compared with day 0 (P < 0.05), whereas the insulin sensitivity as well as the insulin response to the OGTT did not differ from baseline. The glucose response to the OGTT was only affected at day 30, with a decrease compared with day 0. Our data show that insulin sensitivity was impaired after 3 days of inactivity and overfeeding. Impairments in insulin sensitivity occurred before changes in body composition, supporting the notion that the initial steps in impairment of insulin sensitivity may be linked directly to the effects of inactivity and a high calorie intake.     

The pancreatic glucagon and C-peptide secretion during hyperinsulinemia in euglycemic glucose clamp with or without somatostatin infusion in normal man

6 normal subjects received two times of 2 hr euglycemic glucose clamp studies (insulin infusion rate 40 mU/M2/min) one with and the other without somatostatin (SRIF) infusion (500 microgram/hr). Serum C-peptide and glucagon levels were measured during clamp to study the sensitivity of pancreatic alpha and beta cells to the suppressive effects of exogenous hyperinsulinemia during normoglycemia in normal subjects and to find whether SRIF had any modulative effects on endocrine pancreas secretion at the status of hyperinsulinemia. The results showed that in normal man the degree of suppression of pancreatic glucagon secretion by hyperinsulinemia (approximately 100 uU/ml) during euglycemic glucose clamp without SRIF infusion was less than that of C-peptide with mean value of 62 +/- 4% of basal glucagon remained at the end of clamp study; while only about 30 +/- 2% of basal C-peptide concentrations remained. But during SRIF infused glucose clamp studies (SRIF was infused from 60 to 120 min), 32 +/- 2% of mean basal C-peptide concentrations and 38 +/- 6% of mean basal glucagon concentrations left at the end of 2 hr clamp studies when serum insulin level was about 100 uU/ml. For the glucose infusion rate (M value), it was significantly greater in our normal subjects in response to insulin + SRIF as compared to insulin alone (12.0 + 0.9 vs 8.8 +/- 1.4; P less than 0.01). We concluded: during hyperinsulinemia (100 uU/ml), the sensitivity of pancreatic alpha cells to insulin seems less than that of beta cells in normal man at normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

The euglycemic clamp in patients with thalassaemia intermedia

In order to evaluate the influence of haemosiderosis on the glucose metabolism we studied tissue sensitivity to insulin and the metabolic clearance rate (M.C.R.) of this hormone by means of euglycemic clamp technique using an artificial endocrine pancreas in 8 patients with thalassaemia intermedia and 8 control subjects. During the steady-state of euglycemic-hyperinsulinemic clamp (40 mU/m2/min) plasma insulin values were significantly lower and the insulin M.C.R. was significantly higher in thalassaemic patients compared to the controls. To achieve a comparable steady-state insulin concentration to the controls, we performed for a second time the euglycemic clamp in the thalassaemic patients increasing the insulin infusion rate to 80/mU/m2/min. The insulin M.C.R., the M index and the M/IRIs-s ratio were significantly higher in the thalassaemic patients compared to the controls. These results are indicative of an increased tissue peripheral sensitivity to insulin as well as the metabolic clearance rate of this hormone.     

A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A(1) adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly (P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.     

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.     

Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage

Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance.     

Sulfonylurea therapy fails to diminish insulin resistance in type I-diabetic subjects

To assess whether extrapancreatic effects of sulfonylureas in vivo are detectable in the absence of endogenous insulin secretion, insulin sensitivity was determined in six insulin-deficient type 1-diabetic subjects. Peripheral uptake and hepatic production of glucose and lipolysis were measured during hyperinsulinemia using the euglycemic clamp technique and 3-3H-glucose infusions twice, once during a period with glibornuride treatment (50 mg b.i.d.), and once without. Hepatic glucose production decreased in diabetic subjects during hyperinsulinemia (insulin infusion of 20 mU/m2 X min; plasma free insulin levels of 40 +/- 4 mU/l) from 2.9 +/- 0.6 mg/kg min to 0.2 +/- 0.1 mg/kg X min after 120 min, and plasma free fatty acid (FFA) concentrations decreased from 1.33 +/- 0.29 to 0.38 +/- 0.08 mmol/l. Hepatic production, peripheral uptake of glucose and plasma FFA concentrations before and during hyperinsulinemia were not influenced by pretreatment with glibornuride. Compared to 8 non-diabetic subjects, type 1-diabetics demonstrated a diminished effect of hyperinsulinemia on peripheral glucose clearance (2.4 +/- 0.04 vs 4.2 +/- 0.5 ml/kg X min, P less than 0.01), whereas hepatic glucose production and plasma FFA levels were similarly suppressed by insulin. The data indicate that sulfonylurea treatment did not improve the diminished insulin sensitivity of peripheral glucose clearance in type 1-diabetic subjects; insulin action on hepatic glucose production and lipolysis was unimpaired in diabetics and remained uninfluenced by glibornuride. Thus, extrapancreatic effects of sulfonylureas in vivo are dependent on the presence of functioning beta-cells.     

Effect of leptin on insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat

Leptin has been proposed to be a sensor of energy storage in adipose tissues, and is capable of mediating a feedback signal to the hypothalamus, which is involved in the regulation of energy homeostasis and body weight. In order to investigate the issue of whether resistance to the activity of leptin on insulin sensitivity is observed in young Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 8 weeks of age, leptin (50 nmol/kg/h) was administered intravenously for 16 h to OLETF and Long-Evans Tokushima Otsuka (LETO) (lean controls) rats, followed by a measurement of insulin-stimulated glucose uptake in hindlimb muscles during hyperinsulinemic euglycemic clamp technique. In the case of LETO rats, the administration of leptin significantly decreased plasma insulin levels prior to the clamp test, but did not change plasma glucose levels. Furthermore, leptin led to an increase in insulin-stimulated glucose uptake in hindlimb muscles. However, in the case of OLETF rats, leptin administration changed neither plasma insulin levels nor insulin-stimulated glucose uptake. These data demonstrate that OLETF rats at 8 weeks of age have already become resistant to high concentration of peripheral leptin.     

Insulin sensitivity by oral glucose minimal models: validation against clamp

Measuring insulin sensitivity in the presence of physiological changes in glucose and insulin concentrations, e.g., during a meal or OGTT, is important to better understand insulin resistance in a variety of metabolic conditions. Recently, two oral minimal models have been proposed to measure overall insulin sensitivity (S(I)) and its selective effect on glucose disposal (S(I)*) from oral tests. S(I) and S(I)* have been successfully validated against multiple tracer meal estimates, but validation against euglycemic hyperinsulinemic clamp estimates is lacking. Here, we do so in 21 subjects who underwent both a multiple-tracer OGTT and a labeled euglycemic hyperinsulinemic clamp. Correlation between minimal-model S(I), S(I) and corresponding clamp estimates S(I)(*clamp), S(I)(*clamp) was satisfactory, respectively r = 0.81, P < 0.001, and r = 0.71, P < 0.001. S(I) was significantly lower than S(I)(clamp) (8.08 +/- 0.89 vs. 13.66 +/- 1.69 10(-4) dl.kg(-1).min(-1) per microU/ml, P = 0.0002), whereas S(I) and S(I)(*clamp) were very similar (8.17 +/- 1.59 vs. 8.84 +/- 1.39 10(-4) dl.kg(-1).min(-1) per microU/ml, P = 0.52). These results add credibility to the oral minimal-model method as a simple and reliable physiological tool to estimate S(I) and S(I)*, also in large-scale clinical trials.     

The effect of etomoxir on insulin sensitivity in type 2 diabetic patients.

Oral application of 50 mg Etomoxir caused a significant rise (33.1%) of insulin-mediated glucose uptake. This was shown in a placebo-controlled, double-blind randomized study in 8 type 2 diabetic patients by using the euglycemic clamp technique. The mean metabolic clearance rate of glucose (MCR) was raised from 4.1 +/- 0.9 mg/(kg.min) to 5.4 +/- 1.2 mg/(kg.min) (x +/- SEM, P = 0.039). Plasma levels of free fatty acids (FFA), glucose counterregulatory hormones, lipids and C-peptide values during the clamps were not different after verum and placebo. We conclude that Etomoxir improves insulin sensitivity in type 2 diabetic patients.     

Urinary C‐Peptide Excretion: A Novel Alternate Measure of Insulin Sensitivity in Physiological Conditions

Insulin sensitivity (IS) is measured by the euglycemic–hyperinsulinemic clamp under a nonphysiological condition. Daily C‐peptide urinary excretion may be a physiological index of IS, because C‐peptide is co‐secreted with insulin as a function of nutrient intake and IS. The amount of ²H₂O released from glycolytic glucose metabolism after [6,6‐²H₂]‐glucose ingestion was recently proposed as a physiological measure of IS. We compared these IS surrogates to the gold standard (euglycemic–hyperinsulinemic clamp). Thirty (15 male/15 female) sedentary, nondiabetic participants (27.2 ± 4.0 (s.d.) kg/m², 35 ± 12 years) were admitted for 3 days to our in‐patient unit. After a 10‐h fast, they received 60 g of glucose and 15 g of [6,6‐²H₂]‐glucose. Before glucose ingestion and hourly thereafter for 4 h, plasma glucose and insulin concentrations, and plasma deuterium enrichment were determined. Plasma ²H₂O production divided by insulin response was used as the glycolytic index. On day 2, subjects spent 23 h in a metabolic chamber (eucaloric diet, 50% carbohydrate, 30% fat). Urinary C‐peptide excretion was divided by energy intake yielding the C‐peptide to energy intake ratio (CPEP/EI). After leaving the chamber (day 3, 10‐h fast), IS was measured by a 2‐h clamp (120 mU/m²/min). Average IS (clamp) was 7.3 ± 2.6 mg glucose/kg estimated metabolic body size/min (range: 3.6–13.2). These values were inversely correlated with CPEP/EI (r = ?0.62; P < 0.01) and positively with the glycolytic rate (r = 0.60; P < 0.01). In nondiabetic subjects, two novel estimates of IS—daily urinary C‐peptide urinary excretion and glycolytic rate during an oral glucose tolerance test —were related to IS by a clamp.     

Sensory nerve inactivation by resiniferatoxin improves insulin sensitivity in male obese Zucker rats

Recent studies have suggested that sensory nerves may influence insulin secretion and action. The present study investigated the effects of resiniferatoxin (RTX) inactivation of sensory nerves (desensitization) on oral glucose tolerance, insulin secretion and whole body insulin sensitivity in the glucose intolerant, hyperinsulinemic, and insulin-resistant obese Zucker rat. After RTX treatment (0.05 mg/kg RTX sc given at ages 8, 10, and 12 wk), fasting plasma insulin was reduced (P < 0.0005), and oral glucose tolerance was improved (P < 0.005). Pancreas perfusion showed that baseline insulin secretion (7 mM glucose) was lower in RTX-treated rats (P = 0.01). Insulin secretory responsiveness to 20 mM glucose was enhanced in the perfused pancreas of RTX-treated rats (P < 0.005) but unaffected in stimulated, isolated pancreatic islets. At the peak of spontaneous insulin resistance in the obese Zucker rat, insulin sensitivity was substantially improved after RTX treatment, as evidenced by higher glucose infusion rates (GIR) required to maintain euglycemia during a hyperinsulinemic euglycemic (5 mU.kg(-1).min(-1)) clamp (GIR(60-120min): 5.97 +/- 0.62 vs. 11.65 +/- 0.83 mg.kg(-1).min(-1) in RTX-treated rats, P = 0.003). In conclusion, RTX treatment and, hence, sensory nerve desensitization of adult male obese Zucker rats improved oral glucose tolerance by enhancing insulin secretion, and, in particular, by improving insulin sensitivity.     

Acute insulin infusion decreases plasma ghrelin levels in uncomplicated obesity

BACKGROUND: Plasma ghrelin levels have been shown to decrease after insulin infusion in lean subjects. Nevertheless, the mechanism of the suggested inhibitory effect of insulin on ghrelin is still unclear and no data about the effect of acute insulin infusion on plasma ghrelin concentration in obese subjects are available. OBJECTIVE: We sight to evaluate plasma ghrelin concentration during an hyperinsulinemic euglycemic clamp in uncomplicated obese subjects. METHODS: 35 uncomplicated obese subjects, body mass index (BMI) 43.3+/-10.1 kg/m(2), 33 women and 2 men, mean age 34.9+/-10, with a history of excess fat of at least 10 years underwent euglycemic hyperinsulinemic clamp. Blood samples for ghrelin were performed at baseline and steady state of euglycemic insulin clamp. RESULTS: Ghrelin concentrations decreased over time to 10.6+/-15% (range 2-39%) of baseline, from a mean of 205.53+/-93.79 pg/ml to 179.03+/-70.43 pg/ml during the clamp (95% CI, 10.69 to 36.44, P<0.01). In a univariate linear regression analysis baseline plasma ghrelin levels were inversely correlated to BMI (r=-0.564, P=0.04). A linear positive trend between whole body glucose utilization (M(FFMkg) index) and ghrelin reduction during the clamp was found (chi(2) 3.05, p=0.05). CONCLUSIONS: Our data seem to suggest that hyperinsulinemia during a euglycemic clamp is able to suppress plasma ghrelin concentrations in uncomplicated obesity. This effect appears to be positively related to insulin sensitivity.     

Impaired insulin action in primary hyperaldosteronism

The presence of insulin resistance is frequently found in essential hypertension. There are, however, only sparse data with respect to the potential presence of insulin resistance in patients with secondary hypertension. We have therefore undertaken a study to reveal the potential occurrence of insulin resistance in primary hyperaldosteronism (PH). The hyperinsulinemic euglycemic clamp technique together with the evaluation of insulin receptor characteristics were used to study insulin resistance in 12 patients with PH. The measured parameters were compared to normal values in control subjects. We have found a significantly lower glucose disposal rate (M, micromol/kg/min) (18.7+/-6 vs. 29.3+/-4), decreased tissue insulin sensitivity index (M/I, micromol/kg/min per mU/l x100) (23.7+/-9.8 vs. 37.5+/-11.6) and also lower metabolic clearance rate of glucose (MCRg, ml/kg/min) (3.8+/-1.5 vs. 7.0+/-1.1) in patients with primary hyperaldosteronism. The insulin receptor characteristics on erythrocytes did not differ in primary hyperaldosteronism as compared to control healthy subjects. We thus conclude that insulin resistance is also present in secondary forms of hypertension (primary hyperaldosteronism) which indicates the heterogeneity of impaired insulin action in patients with arterial hypertension.     

Beta cell function, peripheral sensitivity to insulin and islet cell autoimmunity in cystic fibrosis patients with normal glucose tolerance

Beta cell function, peripheral sensitivity to insulin and specific pancreatic autoimmunity were studied in 30 youngsters with cystic fibrosis (CF) accurately selected in order to fulfill the criteria for normal glucose tolerance. With respect to weight-matched controls, patients with CF exhibited a significantly lower glucose tolerance and a globally preserved, although delayed, insulin response to oral glucose tolerance test, while first-phase insulin secretion after i.v. glucose was blunted. Peripheral sensitivity to insulin, assessed in vivo by both the euglycemic clamp technique and the number of insulin receptors, directly measured in circulating monocytes, was superimposable in patients and controls. Serum islet-cell antibodies were not found in any of the patients. In conclusion, disorders of beta cell function may be observed in CF patients even when glucose tolerance is within the normal range. Such abnormalities are not associated with changes in peripheral sensitivity to insulin and do not seem to depend on specific autoimmune events.     

Long-term mild jogging increases insulin action despite no influence on body mass index or VO2 max

Physical training has been shown to improve glucose tolerance and insulin sensitivity. In the present study, insulin action was determined using the euglycemic clamp technique in six untrained nonobese subjects before, during, and after long-term mild regular jogging. After 1 yr of jogging, steady-state plasma insulin levels (I) decreased significantly, and the metabolic clearance rate of insulin was increased by 87%, although insulin infusion rate during the clamp was constant for each individual. The amount of glucose infused (glucose metabolism, M) tended to increase from 6.16 +/- 0.94 to 8.15 +/- 1.94 mg.kg-1.min-1 after regular jogging for 1 yr, although that was not statistically significant. However, M/I increases significantly from 0.060 +/- 0.012 to 0.184 +/- 0.056 (P less than 0.05) after 1 yr. The concentrations of plasma free fatty acids during the hyperinsulinemic clamp decreased more significantly after 1 yr of jogging (P less than 0.05). The concentrations of plasma glycerol decreased gradually before and after long-term regular jogging, showing only a 50-60% reduction in 120 min. Therefore, long-term mild regular jogging, which did not influence either body mass index or maximal O2 uptake, appears to improve insulin action in both carbohydrate and lipid metabolism and to increase the metabolic clearance rate of insulin.     

Kupffer cells play a major role in insulin-mediated hepatic glucose uptake in vivo.

The effect of insulin on the in vivo glucose utilization by different hepatic cells was investigated using the euglycemic, hyperinsulinemic clamp, combined with the 2-deoxyglucose tracer technique. Rats were infused with insulin at a rate of 2.8 or 9.0 mU/min/kg for 220 min, resulting in plasma concentrations of the hormone of about 80 microU/ml and 340 microU/ml, respectively. Glucose use by the whole liver was elevated by more than 200% following insulin. However, glucose uptake by the parenchymal cells was only elevated by 50-60%. By contrast nonparenchymal cells were more responsive to insulin. Glucose uptake by endothelial cells was increased 100% and Kupffer cells displayed the most marked response to insulin showing a 3- to 6-fold increase in glucose uptake. These data indicate that the sinusoidal nonparenchymal cells are the major sites of the insulin-mediated increased glucose utilization by the liver.     

Insulin secretion and glucose uptake in hypomagnesemic sheep fed a low magnesium, high potassium diet

Hyperglycemic and euglycemic clamp experiments were conducted to evaluate insulin secretion and glucose uptake in the hypomagnesemic sheep fed a low magnesium (Mg), high potassium (K) diet. Five mature sheep were fed a semipurified diet containing 0.24% Mg and 0.56% K (control diet) and five were fed 0.04% Mg and 3.78% K (low Mg/high K diet) for at least 2 weeks. In the hyperglycemic clamp experiment, plasma glucose concentrations were raised and maintained at a hyperglycemic steady-state (approximately 130 mg/100 ml) by variable rates of glucose infusion during the experimental period (120 minutes). The insulin response in the sheep fed the low Mg/high K diet (31.0 microU/ml) were significantly (P < 0.01) lower than those (111.7 microU/ml) of the sheep fed the control diet. In the euglycemic clamp experiment, insulin was infused at rates of 5, 10, 15, or 20 mU/kg/min, each followed by variable rates of glucose infusion to maintain a euglycemic steady-state (basal fasting levels). Hypomagnesemic sheep fed the low Mg/high K diet had significantly (P < 0.01) lower mean glucose disposal (3.72 mg/kg/min) across the insulin infusion rates compared with those of the sheep fed the control diet (5.37 mg/kg/min). These results suggest that glucose-induced insulin secretion and insulin-induced glucose uptake would be depressed in hypomagnesemic sheep and are caused by feeding the low Mg/high K diet.