Insulin Sensitivity Of Glucose Metabolism Research Articles

Effect of Estrogen Replacement Therapy on Insulin Sensitivity of Glucose Metabolism and Preresistance and Resistance Vessel Function in Healthy Postmenopausal Women

Effect of Estrogen Replacement Therapy on Insulin Sensitivity of Glucose Metabolism and Preresistance and Resistance Vessel Function in Healthy Postmenopausal Women

Expression of a Dominant Negative SHP-2 in Transgenic Mice Induces Insulin Resistance

To elucidate the roles of SHP-2, we generated transgenic (Tg) mice expressing a dominant negative mutant lacking protein tyrosine phosphatase domain (DeltaPTP). On examining two lines of Tg mice identified by Southern blot, the transgene product was expressed in skeletal muscle, liver, and adipose tissues, and insulin-induced association of insulin receptor substrate 1 with endogenous SHP-2 was inhibited, confirming that DeltaPTP has a dominant negative property. The intraperitoneal glucose loading test demonstrated an increase in blood glucose levels in Tg mice. Plasma insulin levels in Tg mice after 4 h fasting were 3 times greater with comparable blood glucose levels. To estimate insulin sensitivity by a constant glucose, insulin, and somatostatin infusion, steady state blood glucose levels were higher, suggesting the presence of insulin resistance. Furthermore, we observed the impairment of insulin-stimulated glucose uptake in muscle and adipocytes in the presence of physiological concentrations of insulin. Moreover, tyrosine phosphorylation of insulin receptor substrate-1 and stimulation of phosphatidylinositol 3-kinase and Akt kinase activities by insulin were attenuated in muscle and liver. These results indicate that the inhibition of endogenous SHP-2 function by the overexpression of a dominant negative mutant may lead to impaired insulin sensitivity of glucose metabolism, and thus SHP-2 may function to modulate insulin signaling in target tissues.

Glucose and fatty acid metabolism in type 2 diabetes mellitus: an assessment using low-dose insulin infusion and the hyperinsulinaemic euglycaemic clamp.

To assess whether resistance to the effects of insulin on lipid metabolism in type 2 diabetes mellitus parallels that demonstrated for glucose metabolism. Thirteen patients with type 2 diabetes were studied (mean age 56.2 years, mean body mass index (b.m.i.) 28.7 kg m(-2)). The hyperinsulinaemic euglycaemic clamp (2 mU insulin kg(-1) min(-1)) and a low-dose insulin infusion technique were used in order to assess insulin effects on both glucose and lipid metabolism. Using the low-dose insulin infusion there were significant correlations between measures of insulin sensitivity for glucose metabolism and those for NEFA (r = 0.82, p < 0.01) and glycerol (r = 0.73, p < 0.01). Mean clamp glucose disposal was 33.4 micromol kgb.w.(-1) min(-1). There was no correlation between clamp glucose disposal and insulin sensitivity derived from the low-dose insulin infusion. At low insulin concentrations, insulin's effects on glucose metabolism (mainly suppression of hepatic glucose output) mirror those on inhibition of lipolysis. At the high insulin concentrations seen during the clamp, stimulation of glucose uptake provides a measure of maximal insulin action which does not parallel its physiological effects shown at lower concentrations.

Effects of aging on the insulin actions for the glucose metabolism and renal function in normotensives and essential hypertensives

It has been suggested that hyperinsulinemia compensating insulin resistance in glucose metabolism may be a pathogenic factor in essential hypertension. On the other hand, age-associated increases in the prevalence of glucose intolerance and hypertension are also well established. The aim of this study is to clarify the influence of aging on insulin sensitivity in glucose metabolism and on renal sodium handling under hyperinsulinemia, which may relate to high blood pressure in insulin-resistant subjects. Fifty-two normotensive subjects and 61 patients with essential hypertension were evaluated in this study. The subjects of these groups were divided into young (<40 years old) and middle-elderly (≥40 years old): young normotensives (Y-NT, n = 22); middle-elderly normotensives (ME- NT, n = 30); young hypertensives (Y-HT, n = 9); and middle-elderly hypertensives (ME-HT, n = 52). Using the euglycemic hyperinsulinemic glucose clamp, insulin sensitivity was assessed as M value. Just before the start and the termination of the glucose clamp, creatinine clearance (Ccr) and urinary excretion of sodium (U NaV) were measured. In addition, renal plasma flow assessed as para-aminohippuric acid clearance was also measured at the same time in several subjects; 8 Y-NT, 8 ME-NT, 3 Y-HT, and 10 ME-HT. The M value was significantly lower in ME-NT, Y-HT, and ME-HT, compared to Y-NT, although blood sugar and immunoreactive insulin levels were similar in all four groups. In normotensive subjects, there was a significant, negative correlation between age and M value. However, this correlation was not observed in hypertensive patients. U NaV decreased in ME-NT, Y-HT, and ME-HT, but not in Y-NT under hyperinsulinemia by the glucose clamp, whereas Ccr showed no significant change in any group. In all subjects, the change of U NaV (ΔU NaV) correlated significantly and positively with the M value. Renal plasma flow significantly increased under hyperinsulinemia by the glucose clamp in only Y-HT, but not in the other groups. There was a significant, positive correlation between ΔU NaV and the change of renal plasma flow under hyperinsulinemia by the glucose clamp. These results suggested that both the impairments of the insulin sensitivity and insulin-induced vasodilation at the renal artery with aging may partially contribute to age-related elevation of blood pressure through renal sodium retention by compensating hyperinsulinemia. On the other hand, it seems reasonable to assume that these abnormalities, which can contribute to high blood pressure in essential hypertension, already may exist at lower ages in essential hypertensive patients.

Induction of insulin resistance by cholinergic blockade with atropine in the cat.

1. Insulin sensitivity was quantified using a modified euglycaemic technique after hepatic cholinergic blockade with atropine and compared with that after surgical denervation. 2. Intraportal administration of atropine produced dose-dependent inhibition of insulin sensitivity in glucose metabolism. ED50 of atropine was 0.99 mg kg-1 (1 mg = 1.5 microM) with maximum inhibition of 40.3 +/- 11.6%. 3. Atropine (3 mg kg-1) reduced insulin sensitivity by a similar amount (33.6 +/- 3.4%) to that produced by hepatic surgical denervation (37.8 +/- 9.8%). Doses greater than 3 mg kg-1 failed to further alter the insulin resistance produced by surgical denervation or atropine (3 mg kg-1) administration, suggesting that activation of hepatic parasympathetic nerves is necessary to fully express the insulin effect. 4. Atropine reduced insulin sensitivity without changes in plasma concentrations of glucagon or insulin. The temporal response to insulin in this euglycaemic study was not changed after atropine administration or after surgical hepatic denervation. 5. It is suggested that hepatic parasympathetic nerves show a synergistic effect with insulin. Disease states that result in hepatic parasympathetic neuropathy would be expected to produce an insulin resistant liver. 6. The modified euglycaemic clamp method for assessing insulin responses was shown to be reproducible up to four times in the same animal and was sufficiently sensitive and quantitative to be able to generate a dose-response curve in each animal for atropine-induced insulin resistance.

Decreasing triglyceride by gemfibrozil therapy does not affect the glucoregulatory or antilipolytic effect of insulin in nondiabetic subjects with mild hypertriglyceridemia

We studied the effects of gemfibrozil on glucose and fatty acid metabolism in subjects with mild endogenous hypertriglyceridemia. Twenty subjects (serum triglycerides, 3.2 ± 1.4 mmol/L; age, 52 ± 7 years; body mass index, 27.8 ± 1.8 kg/m 2) were randomly allocated to receive either placebo or gemfibrozil 1,200 mg daily for 12 weeks in a double-blind study. Gemfibrozil decreased serum total and very—low-density lipoprotein (VLDL) triglycerides by 53% and 57%, respectively, and serum apolipoprotein (apo) B concentration by 21%. Gemfibrozil had no effect on the diurnal concentration of free fatty acids (FFA). Neither did gemfibrozil change diurnal blood glucose or serum insulin concentrations. The endogenous glucose production rate remained unchanged in both groups during the treatment period, and was similarly suppressed by hyperinsulinemia. The rate of insulin-induced whole-body glucose disposal increased similarly both before (basal 10.8 ± 1.8, low-dose insulin 10.5 ± 2.1, and high-dose insulin 20.9 ± 11.9 μmol · kg −1 · min −1) and after (11.1 ± 1.7, 10.7 ± 1.2, and 18.6 ± 7.9, respectively) gemfibrozil treatment. Rates of oxidative and nonoxidative glucose metabolism remained unchanged during gemfibrozil treatment. Basal pretreatment and posttreatment FFA turnover rates were similar in both study groups, as were the rates of substrate oxidation. In summary, gemfibrozil proved to be an effective serum triglyceride-lowering agent in patients with mild hypertriglyceridemia, but had no effect on the insulin sensitivity of glucose metabolism or of antilipolysis. These data support the idea that triglycerides per se do not cause insulin resistance, and that the triglyceride-lowering effect of gemfibrozil is not mediated via antilipolytic action.

Improvement of insulin sensitivity for glucose metabolism with the long-acting Ca-channel blocker amlodipine in essential hypertensive subjects

To clarify whether the long-acting calcium-channel blocker amlodipine restores insulin insensitivity in essential hypertension, insulin sensitivity tests were performed at the physiological steady-state insulin level (45 to 55 μU/mL) before and after amlodipine (2.5 to 7.5 mg/d) administration for 2 to 4 months in borderline and mild essential hypertensive subjects. Instead of somatostatin, Sandostatin (Sandoz, Basel, Switzerland) was used for the determination of steady-state plasma glucose (SSPG) in the same way as previously described. SSPG, which was initially high (212.9 ± 18.0 mg/dL, mean ± SE), was significantly reduced to 169.8 ± 14.7 after amlodipine treatment. Responses of ketone bodies during the test at 30 minutes, which reflect the insulin effect on lipolysis in adipose tissue and hepatic fatty acid oxidation, also improved after amlodipine treatment. Norepinephrine, noted to be mildly elevated after amlodipine treatment, decreased during the sensitivity test at 2 hours probably due to the sedative effect, without any change in the fractional extraction of Na. This indicates that the physiological level of insulin does not activate sympathetic nerve activity or stimulate Na reabsorption. The long-acting calcium-channel blocker amlodipine has significantly improved the initially decreased insulin sensitivity for glucose metabolism at least partially in borderline or mild essential hypertension.

The effect of enalapril with and without hydrochlorothiazide on insulin sensitivity and other metabolic abnormalities of hypertensive patients with NIDDM

The effect of 20 mg of enalapril with and without 12.5 mg of hydrochlorothiazide on glucose metabolism insulin sensitivity and lipids was evaluated in hypertensive non-insulin-dependent diabetes. Ten mild to moderate hypertensive patients with non-insulin-dependent diabetes mellitus were treated for 8 weeks with 20 mg enalapril once a day, and then divided into two groups of 5 patients each for a second 8 weeks of treatment with enalapril alone or in combination with hydrochlorothiazide, 12.5 mg once a day. Blood pressure, fasting plasma glucose, lipids and insulin, glycosylated hemoglobin, and insulin sensitivity were measured at baseline and after 8 and 16 weeks. Results were analyzed by the ANOVA test for repeated measures and all values are given as mean +/- SD. Diastolic blood pressure decreased significantly after the first and second period of enalapril and after the combination of enalapril and hydrochlorothiazide. Glycosylated hemoglobin dropped significantly after the first and second period of enalapril monotherapy. Plasma triglycerides and fasting plasma insulin decreased significantly after the 16 weeks of enalapril. Insulin-mediated glucose uptake increased significantly after 8 and 16 weeks of monotherapy with enalapril. No significant difference was observed in any of the metabolic characteristics, including insulin sensitivity, between the values after 8 weeks of enalapril alone and the final values of the enalapril-treated and the enalapril/hydrochlorothiazide-treated groups. It is concluded that enalapril improves some of the metabolic parameters, including insulin sensitivity, of hypertensive diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Sensitivity in Post-Obese Women

1. Both increased and decreased sensitivity to insulin has been proposed to precede the development of obesity. Therefore, insulin sensitivity was measured during a 2 h hyperinsulinaemia (100 m-units min-1 m-2) euglycaemic (4.5 mmol/l) glucose clamp combined with indirect calorimetry in nine weight-stable post-obese women and in nine matched control women preceded by 12 h fasting after 48 h on a standardized diet. 2. Both glucose disposal rate (post-obese women, 9.5 +/- 2.2 mg min-1 kg-1, control women, 11.2 +/- 1.4 mg min-1 kg-1, not significant) and glucose oxidation (3.6 +/- 0.5 mg min-1 kg-1 versus 4.0 +/- 0.7 mg min-1 kg-1, not significant) were similar in the two groups during the last 30 min of the clamp. Lipid oxidation also decreased similarly during the clamp in the post-obese women (from 30.4 +/- 12 to 2.0 +/- 7 J min-1 kg-1) and in the control women (from 33.6 +/- 11 to 5.4 +/- 8 J min-1 kg-1, not significant). Basal plasma concentrations of free fatty acids were similar, but at the end of the clamp free fatty acids were lower in the post-obese women than in the control women (139 +/- 19 and 276 +/- 48 mumol/l, P = 0.02). 3. We conclude that the insulin sensitivity of glucose metabolism is unaltered in the post-obese state. The study, however, points to an increased antilipolytic insulin action in post-obese subjects, which may favour fat storage and lower lipid oxidation rate postprandially.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in insulin clearance and hepatic blood flow during the night do not contribute to the 'dawn phenomenon' in type 1 diabetes.

To assess mechanisms leading to the 'dawn phenomenon' in type 1 diabetes mellitus, overnight insulin clearance, hepatic blood flow and insulin sensitivity of glucose metabolism were determined in 9 type 1 diabetic subjects treated with continuous subcutaneous insulin infusions. Glucose clamp studies were performed twice, once after midnight (from 24.00 to 02.00 h), and once in the early morning (from 06.00 to 08.00 h) during insulin infusion at 15 mU/m2/min. Insulin clearance was 482 +/- 57 ml/m2/min during the first, and 528 +/- 56 ml/m2/min during the second clamp (nonsignificant). Hepatic plasma flow assessed by measuring indocyanine green clearance was 984 +/- 115 and 1,040 +/- 163 ml/min, after the first and after the second clamp, respectively (nonsignificant). Glucose uptake during the two clamps was not significantly different. Since hepatic blood flow is known to influence insulin clearance and hepatic glucose metabolism, the data demonstrate that overnight changes in hepatic blood flow and insulin clearance do not contribute to the previously described early morning increase in insulin requirements in type 1 diabetic subjects (dawn phenomenon).

Effects of insulin and norepinephrine on glucose transport and metabolism in rat brown adipocytes. Potentiation by insulin of norepinephrine-induced glucose oxidation.

Glucose is an important fuel for rat brown adipose tissue in vivo and its utilization is highly sensitive to insulin. In this study, the different glucose metabolic pathways and their regulation by insulin and norepinephrine were examined in isolated rat brown adipocytes, using [6-14C]glucose as a tracer. Glucose utilization was stimulated for insulin concentrations in the range of 40-1000 microU/ml. Furthermore, the addition of adenosine deaminase (200 mU/ml) or adenosine (10 microM) did not alter insulin sensitivity of glucose metabolism. The major effect of insulin (1 mU/ml) was a respective 7-fold and 5-fold stimulation of lipogenesis and lactate synthesis, whereas glucose oxidation remained very low. The 5-fold stimulation of total glucose metabolism by 1 mU/ml of insulin was accompanied by an 8-fold increase in glucose transport. In the presence of norepinephrine (8 microM), total glucose metabolism was increased 2-fold. This was linked to a 7-fold increase of glucose oxidation, whereas lipogenesis was greatly inhibited (by 72%). In addition, norepinephrine alone did not modify glucose transport. The addition of insulin to adipocytes incubated with norepinephrine, induced a potentiation of glucose oxidation, while lipogenesis remained very low. In conclusion, in the presence of insulin and norepinephrine glucose is a oxidative substrate for brown adipose tissue. However the quantitative importance of glucose as oxidative fuel remains to be determined.

Insulin sensitivity of glucose metabolism in obese rat soleus muscle strips

Insulin sensitivity of glucose metabolism in obese rat soleus muscle strips

Glucose utilization rates and insulin sensitivity in vivo in tissues of virgin and pregnant rats.

In vivo studies have shown that insulin resistance in late pregnancy results from a decreased sensitivity of liver and peripheral tissues. In the present study, measurements of the rates of glucose utilization by skeletal muscles (soleus, extensor digitorum longus, epitrochlearis, and diaphragm), white adipose tissue, and brain of virgin and 19-day pregnant rats were performed in the basal condition and during a euglycemic, hyperinsulinemic (400 microU/ml) clamp to quantify the partition of glucose utilization and to identify the tissues other than liver responsible for insulin resistance. Fetal and placental glucose utilization rates were also measured in pregnant rats. The fetal glucose utilization rate (22 mg/min/kg) was very high and was not stimulated by physiologic maternal hyperinsulinemia. By contrast, the placental glucose utilization rate (29 mg/min/kg) was increased by 30% during hyperinsulinemia. The glucose utilization rate of the conceptus represented 23% of the maternal glucose utilization rate in the basal state. Glucose utilization rates in the basal condition were not statistically altered by pregnancy in brain, skeletal muscles, and white adipose tissue. During hyperinsulinemia (400 microU/ml), glucose utilization rates in extensor digitorum longus, epitrochlearis, and white adipose tissue were 30-70% lower in pregnant than in virgin rats. Insulin sensitivity of glucose metabolism in all the tissues tested other than brain was 50% lower in pregnant than in virgin rats. We conclude that skeletal muscles and, to a smaller extent, adipose tissue are involved in the insulin resistance of late pregnancy.

Effect of lactation on insulin sensitivity of glucose metabolism in rat adipocytes

During lactation glucose metabolism in paraovarian adipocytes is characterized by a 40 and 80% decrease of glucose incorporation into CO 2 and fatty acids in the presence of insulin. In contrast with the stimulation by insulin of glucose incorporation into lactate, glycerol remains unchanged. As a result, insulin sensitivity of total glucose metabolism (oxidation and lipid synthesis) is not altered in adipocytes from lactating rats.

INSULIN DOES NOT STIMULATE GLYCOGEN AND LIPID SYNTHESIS IN ISOLATED FETAL RAT HEPATOCYTES

We have previously reported differential maturation of insulin sensitivity for glucose metabolism and amino acid uptake in fetal rat hepatocytes. Compared to the adult, insulin binding to liver plasma membrane is double in the fetus (32 ± 0.3 vs. 18 ± 2.4% per 50 μgm membrane protein, p < 0.01) due to a 3 fold increase in receptor number per unit cell surface area. To study further the role of insulin in fetal metabolism, we examined two established insulin-mediated events in freshly isolated rat hepatocytes: glycogen synthase activity and 14C-acetate incorporation into lipid. Viability of both adult (A) and 21 day fetal (F) hepatocytes was documented throughout the experiments. The glucose-6-phosphate dependent form of glycogen synthase (D) was 2.5 fold higher in F (p < 0.01), while the independent form (I) was 50% lower in F compared to A when expressed per mg protein (p< 0.01) . In A, insulin at 10 and 100 ng/ml stimulated both the D and I forms (p < 0.05); %I increased with insulin (p < 0.05). No such augmentations occured in F. At concentrations varying from 0-30 mM, the incorporation of acetate into lipid was higher in A; at a fixed medium acetate (5mM), insulin at 100 ng/ml stimulated acetate incorporation in A (p < 0.025) but not in F. Thus whereas both insulin-mediated events are demonstrable in A they are not present in F despite higher insulin receptor numbers per cell surface area. These results further suggest a dissociation between insulin receptor binding and insulin mediated glucose or lipid metabolism in isolated fetal rat hepatocytes.

Ascochlorin誘導体, AS-6, の血糖低下作用ならびに脂肪組織におけるinsulin効果増強作用

Ascochlorin had been isolated by the present authors from a fungus, Ascochyta visiae. This is a hydrophobic sesquiterpenoid and therefore a more polar 4-0-hydroxycarbonyl methylascochlorin (AS-6) was developed for convenience in pharmacological studies.The hypoglycemic effect of AS-6 was studied in normoinsulinemic, hypoinsulinemic and hyperinsulinemic animal models. AS-6 was given mixed with the commercial diet (CE-2, Nihon CLEA CO., ) for one or 10 weeks to ddY mice, genetically obese Zucker fatty rats and genetically obese diabetic mice C57BL/ksj dbm (dbm-mice). AS-6 was orally given to streptozotocin diabetic rats (STZ-rats) for 14 days by gastric intubation. Serum glucose and triglyceride were determined and compared with each control. AS-6 treatment significantly reduced serum glucose and triglyceride in all experimental animals. In particular, serum glucose in dbm-mice was decreased after one week of AS-6 treatment by 23.2% compared to the dbm control and after 10 weeks by 44.0%. AS-6 showed a lowering of serum immunoreactive insulin (IRI) in normal and dbm-mice. This fact suggests that AS-6 accerelates glucose utilization without stimulating pancreatic insulin release.The mechanism of AS-6 was studied using epididymal fat pads from STZ rats. The tissue slices derived from AS-6 treated STZ rats significantly increased conversion of 14C-glucose to CO2 and total lipids compared to the STZ control which deteriolated to remarkably below normal.Adippocytes from AS-6 treated rats bound significantly more insulin at 1, 10, 100μU/ml insulin concentration than those of the controls and significantly increased 2-deoxyglucose uptake.There is attenuated insulin sensitivity of glucose metabolism in adipocytes from STZ control, however, AS-6 treatment improved insulin sensitivity of glucose metabolism.

Insulin receptor binding to fat and blood cells and insulin action in fat cells from insulin-dependent diabetics.

Insulin binding to fat and blood cells and the effect of insulin on glucose transport, glucose oxidation, lipogenesis, and lipolysis in fat cells were measured in 23 conventionally treated insulin-dependent diabetics (IDDs) with a mean duration of diabetes for 10 yr. In the fasting state diabetics had increased plasma levels of free insulin (P &amp;lt; 0.001) accompanied by a 38% reduction of insulin binding to fat cells (P &amp;lt; 0.001), whereas insulin binding to monocytes and erythrocytes was normal. The concentrations of insulin causing halfmaximal effect on glucose transport and antilipolysis in adipocytes were both higher in diabetics than in normals (P &amp;lt; 0.001), suggesting impaired sensitivity to insulin that may be the functional consequence of the adipocyte insulin receptor defect. The basal rates and the maximal responses to insulin of glucose transport and lipolysis were both within the limits of normals, indicating the absence of postreceptor abnormalities in these effector systems. In contrast, both glucose oxidation and lipogenesis in fat cells from diabetics had normal sensitivity to insulin. This finding was very surprising and suggests possible postreceptor modulation o the insulin sensitivity of glucose metabolism in insulin-treated diabetics counterbalancing the effects of decreased insulin receptor binding. Moreover, both the basal rates for glucose oxidation and lipogenesis and the absolute response of glucose oxidation and lipogenesis rates to maximal insulin stimulation were significantly reduced in fat cells from diabetics indicating postreceptor impairments of glucose metabolism. In conclusion: In long-term-treated IDDs in usual metabolic control and with fasting, peripheral hyperinsulinemia insulin binding to circulating blood cells was normal. In contrast, a peripheral, fixed tissue, as fat cells, exhibited decreased insulin bindingwith impaired insulin sensitivity of some pathways (glucose transport and antilipolysis) and postreceptor impairments of other pathways (lipogenesis and glucose oxidation).

Insulin resistance in adipocytes from fed and fasted obese rats: dissociation of two insulin actions.

Adipocytes from 26-week-old Zucker rats (greater than 600 g) and controls of the same strain and age (greater than 400 g) served as models of insulin resistance and obesity. Adipocytes from fatty rats demonstrated insulin resistance of glucose metabolism and resistance to the antilipolytic effect of insulin which was not improved by fasting. Adipocytes from fatty rats were also resistant to the lipolytic action of norepinephrine. Control rats displayed insulin resistance of glucose metabolism and resistance to the antilipolytic effect of insulin. However, fasting for 6.5 days restored the antilipolytic action of insulin without affecting the insulin sensitivity of glucose metabolism. This dissociation of the responsiveness of insulin actions by fasting indicates that there may be at least two mechanisms of insulin resistance in the same cell.