Acute Hyperinsulinemia Research Articles

Acute hyperinsulinemia is associated with increased circulating levels of adrenomedullin in patients with type 2 diabetes mellitus.

To investigate the effect of acute hyperinsulinemia on the plasma levels of adrenomedullin (AM) in patients with type 2 diabetes mellitus. We measured the plasma levels of AM in 18 patients with type 2 diabetes mellitus and in 19 normal subjects before and during a euglycemic hyperinsulinemic clamp study (the goal was for blood sugar levels of 5.24 mmol/l and insulin levels of 1200 pmol/l). Both plasma AM and serum insulin were measured by immunoradiometric assays. Before the glucose clamp study there was no significant difference in the plasma levels of AM between patients with type 2 diabetes mellitus and normal subjects. During the glucose clamp study, the serum levels of insulin significantly increased (from 33.0+/-3.6 to 1344.6+/-67.8 pmol/ml, P<0.001), as did the plasma levels of AM (from 12.8+/-0.7 to 14.2+/-0.9 fmol/ml, P<0.03) only in patients with type 2 diabetes mellitus. There was a significant correlation between the change in circulating levels of insulin and AM (r=0.755, P<0.01). Acute hyperinsulinemia induced a significant increase in the plasma levels of AM in patients with type 2 diabetes mellitus. Increased insulin may regulate circulating levels of AM in patients with type 2 diabetes mellitus.

Erythrocyte membrane ion transport in offspring of hypertensive parents: effect of acute hyperinsulinemia and relation to insulin action.

Some patients with essential hypertension exhibit insulin resistance (IR) and several red blood cell (RBC) ion transport abnormalities. The aims of the study were to assess RBC ion transport acitivities under basal conditions, to test in vivo the effect of acute hyperinsulinemia, and to evaluate the relationship to IR in the offspring of hypertensive parents (n = 12; OHP) and healthy controls (n = 14; C). Activities of the Na+-K+ pump, Na+-K+ cotransport, Na+-Li+ countertransport (SLC), and Na+, Rb+, and Li+ leaks (passive membrane permeability) were measured before and after a hyperinsulinemic (75 microU/mL) euglycemic clamp (HIC) and compared to those found under isoinsulinemic isovolumic conditions in OHP and C. An insulin action was calculated as glucose disposal and insulin sensitivity index (M/I) after HIC. OHP were characterized by lower M/I (0.12+/-0.07 vs. 0.20+/-0.09 mg/kg/min/microU/mL; p < 0.05) and elevated SLC and Li+ and Rb+ leaks (p < 0.05) compared with C. Although acute hyperinsulinemia did not modify significantly any ion transport parameter studied, negative correlation was observed between insulin action and membrane cation leaks. Glucose disposal correlated with an Li+ leak in C (r = -0.736; p < 0.01) and all subjects (r = -0.424; p < 0.05) after HIC and in OHP with an Na+ leak (r = -0.727; p < 0.05) before HIC. In conclusion, OHP displayed higher insulin resistance, enhanced activity of SLC, and augmented Li+ and Rb+ leaks. Acute hyperinsulinemia did not modify any ion transport parameter studied, although negative correlation was observed between insulin action and membrane leaks.

Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat.

Decreased plasma fibrinolysis may contribute to accelerated atherothrombosis in diabetes. To observe whether hyperglycemia and hyperinsulinemia, common findings in type 2 diabetes, acutely affect plasma fibrinolysis in vivo, we evaluated plasma fibrinolysis (lysis of fibrin plates, free PAI-1 activity and t-PA activity) in the rat after a hyperglycemic euinsulinemic clamp (n=8), an euglycemic hyperinsulinemic clamp (n=7) or a saline infusion (n=15). Plasma fibrinolytic activity was sharply reduced after both the hyperglycemic and hyperinsulinemic clamps as compared to the respective controls (mean lysis areas on the fibrin plate, 139+/-21 vs. 323+/-30 mm2, p<0.001; 78+/-27 vs. 312+/-27 mm2 p<0.001, respectively). Plasma PAI-1 activity was greater after both hyperglycemic and hyperinsulinemic clamps as compared to saline infusion (6.6+/-2.6 vs. 1.6+/-0.6 IU/ml, p<0.001; 26+/-4 vs. 1.3+/-0.7 IU/ml, p<0.0001, respectively). Plasma t-PA activity was significantly reduced both after the hyperglycemic (0.36+/-0.15 vs. 2.17+/-0.18 IU/ml in controls, p<0.001) and the hyperinsulinemic (0.3+/-0.1 vs. 2.3+/-0.3 IU/ml in control, p<0.001) clamps. These data show that in vivo both acute hyperglycemia and acute hyperinsulinemia can decrease plasma fibrinolytic potential and that this is due to increased plasma PAI-1 and decreased free t-PA activities.

Correlation of sodium-related factors with insulin sensitivity in young, lean, male offspring of hypertensive and normotensive subjects.

Pioneer studies have proposed that multiple metabolic abnormalities, such as insulin resistance, increased Na(+)-H(+) exchanger activity and abnormal intracellular calcium homeostasis, are frequently associated with a subset of essential hypertensive patients with low plasma renin activity (PRA). However, it is unclear whether insulin resistance is related to the low renin status in the very early phase of genetical hypertension. Besides, there is controversy on the subject of the in vivo effect of acute hyperinsulinaemia on sodium-related factors. We investigated the relationship between sodium-related parameters and insulin sensitivity, and the effects of euglycaemic hyperinsulinaemia on cyclic guanosine monophosphate (cGMP) and atrial natriuretic peptide (ANP) levels in 17 young, lean, normotensive male subjects, who displayed extreme predispositions for the development of hypertension. PRA was significantly lower in the positive than in the negative family history group (P < 0.05). Insulin sensitivity (M-value) was correlated with PRA before euglycaemic hyperinsulinaemic clamping (r = 0.577, P < 0.05), and was also inversely correlated with fractional excretion of sodium (FE(Na)) before clamping (r = -0.51, P < 0.05). Euglycaemic hyperinsulinaemia significantly decreased PRA (P < 0.0001) and increased cGMP (P < 0.05) and ANP levels (P < 0.01). In conclusion, insulin sensitivity may be partially determined by PRA levels and FE(Na) before clamping in young, lean, normotensive male subjects. Acute euglycaemic hyperinsulinaemia decreases PRA, and increases cGMP and ANP levels from the fasting condition.

Effect of acute exogenous hyperinsulinaemia on very low density lipoprotein subfraction composition in normal subjects.

Subtle abnormalities of very-low-density lipoprotein (VLDL) composition and distribution seem to be associated with increased cardiovascular risk. The aims of this study were first, to evaluate whether hyperinsulinaemia per se is able to produce VLDL abnormalities and second, whether this occurs through a stimulation of lipolytic enzymes. Eight normal male volunteers, age 36 +/- 7 years (M +/- SD), body mass index (BMI) 26+/-3 kg m-2, underwent a 5-h euglycaemic hyperinsulinaemic clamp (1.2 mU insulin/kg b.w. min-1). Nine sex, age and BMI comparable subjects underwent control experiments (saline infusion). Three VLDL subfractions of decreasing size were isolated by density gradient ultracentrifugation; lipoprotein lipase (LPL) and hepatic lipase (HL) post-heparin plasma activities were determined by the 3H-labelled triolein method. Hyperinsulinaemia ( approximately 65 mU mL-1) produced the expected plasma free fatty acid suppression. Triglyceride levels were reduced in total VLDL (- 27 +/- 32% vs. + 38 +/- 52% after saline, P < 0.05) and in the larger VLDL (- 56 +/- 19 vs. + 34 +/- 38, P < 0.001). Moreover the relative contribution of the larger subfraction was decreased (- 39 +/- 15% vs. - 3 +/- 21%, P < 0.01), while the percentage of smaller particles was increased (+17 +/- 20 vs. - 9 +/- 22, P < 0.05). LPL and HL activities were decreased to the same degree during either insulin or saline infusion. Exogenous hyperinsulinaemia produced lipoprotein abnormalities partially similar to those previously shown in type 1 diabetic patients, indicating that these abnormalities may be secondary to insulin therapy.

Acute hyperinsulinism modulates plasma apolipoprotein B-48 triglyceride-rich lipoproteins in healthy subjects during the postprandial period.

The role of postprandial insulin in the regulation of postprandial lipid metabolism is still poorly understood. The roles of hyperinsulinemia and insulin resistance in the alteration of postprandial lipid metabolism are not clear either. To improve knowledge in this area, we submitted healthy men to acute hyperinsulinemia in two different ways. In the first study, we compared in 10 men the effects of four isolipidic test meals that induce different degrees of hyperinsulinemia on postprandial lipid metabolism. Three different carbohydrate sources were compared according to their glycemic indexes (GIs; 35, 75, and 100 for white kidney bean, spaghetti, and white bread test meals, respectively); the fourth test meal did not contain any carbohydrates. Postprandial plasma insulin levels were proportional to the GIs (maximal plasma insulin concentrations: 113 +/- 16 to 266 +/- 36 pmol/l). We found a strong positive correlation during the 6-h postprandial period between apolipoprotein (apo) B-48 plasma concentration and insulin plasma concentration (r2 = 0.70; P = 0.0001). In a second study, 5 of the 10 subjects again ingested the carbohydrate-free meal, but during a 3-h hyperinsulinemic- (550 +/- 145 pmol/l plasma insulin) euglycemic (5.5 +/- 0.8 mmol/l plasma glucose) clamp. A biphasic response was observed with markedly reduced levels of plasma apoB-48 during insulin infusion, followed by a late accumulation of plasma apoB-48 and triglycerides. Overall, the data obtained showed that portal and peripheral hyperinsulinism delays and exacerbates postprandial accumulation of intestinally derived chylomicrons in plasma and thus is involved in the regulation of apoB-48-triglyceride-rich lipoprotein metabolism, in the absence of insulin-resistance syndrome.

Effects of hyperglycaemia and hyperinsulinaemia on proximal gastric motor and sensory function in humans.

During acute hyperglycaemia, gastric emptying is delayed and the compliance of the proximal stomach is increased significantly. It is not known whether the effect of hyperglycaemia on proximal gastric motor function in healthy volunteers results from endogenous hyperinsulinaemia. Therefore we studied the effects of acute hyperglycaemia and hyperinsulinaemia on proximal gastric function, measured using an electronic barostat. Eight healthy volunteers were studied on three separate occasions during: (a) normoglycaemia, (b) hyperglycaemic hyperinsulinaemic clamping, and (c) euglycaemic hyperinsulinaemic clamping. Gastric compliance was significantly (P<0.01) increased during hyperglycaemia (44+/-5 ml/mmHg), and also during hyperinsulinaemia (38+/-4 ml/mmHg), compared with during normoglycaemia (31+/-3 ml/mmHg). During pressure distension, sensations of fullness were greater during hyperglycaemia and during hyperinsulinaemia compared with controls. At a set pressure of minimal distension pressure +2 mmHg, the intrabag volume was significantly higher during hyperglycaemia (292+/-36 ml; P<0.05), but not during hyperinsulinaemia (161+/-35 ml), compared with during normoglycaemia (129+/-10 ml). Postprandial relaxation was significantly (P<0.01) decreased during hyperglycaemia (93+/-64 ml) and hyperinsulinaemia (101+/-64 ml) compared with normoglycaemia (224+/-56 ml). Thus not only hyperglycaemia, but also hyperinsulinaemia, influences proximal gastric compliance, postprandial relaxation and symptom perception.

Effects of hyperglycaemia and hyperinsulinaemia on proximal gastric motor and sensory function in humans

During acute hyperglycaemia, gastric emptying is delayed and the compliance of the proximal stomach is increased significantly. It is not known whether the effect of hyperglycaemia on proximal gastric motor function in healthy volunteers results from endogenous hyperinsulinaemia. Therefore we studied the effects of acute hyperglycaemia and hyperinsulinaemia on proximal gastric function, measured using an electronic barostat. Eight healthy volunteers were studied on three separate occasions during: (a) normoglycaemia, (b) hyperglycaemic hyperinsulinaemic clamping, and (c) euglycaemic hyperinsulinaemic clamping. Gastric compliance was significantly (P &lt; 0.01) increased during hyperglycaemia (44±5 ml/mmHg), and also during hyperinsulinaemia (38±4 ml/mmHg), compared with during normoglycaemia (31±3 ml/mmHg). During pressure distension, sensations of fullness were greater during hyperglycaemia and during hyperinsulinaemia compared with controls. At a set pressure of minimal distension pressure +2 mmHg, the intrabag volume was significantly higher during hyperglycaemia (292±36 ml; P &lt; 0.05), but not during hyperinsulinaemia (161±35 ml), compared with during normoglycaemia (129±10 ml). Postprandial relaxation was significantly (P &lt; 0.01) decreased during hyperglycaemia (93±64 ml) and hyperinsulinaemia (101±64 ml) compared with normoglycaemia (224±56 ml). Thus not only hyperglycaemia, but also hyperinsulinaemia, influences proximal gastric compliance, postprandial relaxation and symptom perception.

Increased Insulin Receptor Substrate-1 and Enhanced Skeletal Muscle Insulin Sensitivity in Mice Lacking CCAAT/Enhancer-binding Protein β

CCAAT/enhancer-binding protein beta (C/EBPbeta) controls gene transcription and metabolic processes in a variety of insulin-sensitive tissues; however, its role in regulating insulin responsiveness in vivo has not been investigated. We performed hyperinsulinemic-euglycemic clamps in awake, non-stressed, chronically catheterized adult mice homozygous for a deletion in the gene for C/EBPbeta (C/EBPbeta(-/-)). Fasting plasma insulin, glucose, and free fatty acid (FFA) levels were significantly lower in C/EBPbeta(-/-) mice compared with wild-type (WT) controls. Acute hyperinsulinemia (4 h) suppressed hepatic glucose production, phosphoenolpyruvate carboxykinase mRNA, and plasma FFA to a similar extent in WT and C/EBPbeta(-/-) mice, suggesting that C/EBPbeta deletion does not alter the metabolic and gene regulatory response to insulin in liver and adipose tissue. In contrast, using submaximal (5 milliunits/kg/min) and maximal (20 milliunits/kg/min) insulin infusions, whole-body glucose disposal was 77% (p < 0.01) and 33% (p < 0.05) higher in C/EBPbeta(-/-) mice, respectively, compared with WT mice. Maximal insulin-stimulated 3-O-methylglucose uptake in isolated soleus muscle was 54% greater in C/EBPbeta(-/-) mice (p < 0.05). Furthermore, insulin-stimulated insulin receptor and Akt Ser(473) phosphorylation and phosphatidylinositol 3-kinase activity were 1.6-2.5-fold greater in skeletal muscle from C/EBPbeta(-/-) mice compared with WT mice. The level of insulin receptor substrate-1 protein was increased 2-fold in skeletal muscle from C/EBPbeta(-/-) mice. These results demonstrate that C/EBPbeta deletion decreases plasma FFA levels and increases insulin signal transduction specifically in skeletal muscle, and both contribute to increased whole-body insulin sensitivity.

Insulin Increases Leptin mRNA Expression in Abdominal Subcutaneous Adipose Tissue in Humans

Insulin regulates expression and production of leptin in rodents but whether this is also true in humans remains unclear. To test the effects of acute hyperinsulinemia on expression of leptin mRNA in humans, percutaneous needle biopsies of abdominal subcutaneous adipose tissue were performed at baseline and immediately following a 200-min two-step hyperinsulinemic–euglycemic glucose clamp in 16 Pima Indians (8M/8F). Leptin mRNA was quantified by reverse transcription, PCR amplification and expressed relative to actin mRNA. Leptin mRNA levels were higher in women than men (25.6 ± 1.7 v 16.9 ± 2.1 relative units, P = 0.003) at baseline. Baseline levels were directly related to percentage body fat (r = 0.54, P = 0.03) and fasting plasma glucose concentrations (r = 0.57, P = 0.02) and were negatively correlated to glucose disposal at physiologic insulin concentrations (750 ± 40 pmol/L) during the clamp (r = −0.51, P = 0.04). Acute hyperinsulinemia (final insulin concentration 11560 ± 950 pmol/L) increased leptin mRNA levels in 13 of 16 individuals an average of 13% (21.3 ± 1.7 to 24.2 ± 1.2 relative units, P = 0.01). Changes in leptin mRNA were directly related to glucose disposal rates during physiologic hyperinsulinemia (r = 0.54, P < 0.04). These results suggest that the expression of leptin mRNA is regulated by insulin in humans, as it is in rodents.

Subcutaneous adipose tissue expression of tumour necrosis factor-alpha is not associated with whole body insulin resistance in obese nondiabetic or in type-2 diabetic subjects.

An association with subcutaneous adipose tissue TNFalpha expression and insulin resistance has been suggested in obesity/type-2 diabetes, but this has not been examined directly. In the first part of the study we investigated whether this association is present in 7 lean, 10 obese nondiabetic and 9 type-2 diabetic men. In the second part of the study we examined the relationship between adipose tissue TNFalpha mRNA levels and BMI in 81 nondiabetic subjects spanning a wide range of BMIs. Subcutaneous adipose tissue TNFalpha mRNA levels and insulin sensitivity were determined with quantitative RT-competitive PCR and hyperinsulinaemic clamp, respectively. Subcutaneous adipose tissue TNFalpha mRNA levels were similar in 7 lean and 10 obese nondiabetic and 9 type-2 diabetic men (P = 0.68), and did not change in response to 240-min hyperinsulinaemia. TNFalpha mRNA levels and insulin sensitivity were not correlated. Unexpectedly, no correlation between TNFalpha mRNA and BMI was found. The relationship between adipose tissue TNFalpha mRNA and BMI was examined further in 31 male and 50 female nondiabetic subjects. The subcutaneous adipose tissue TNFalpha mRNA level correlated with BMI in all subjects (rS = 0.32, P < 0.01), and in a subgroup analysis in men (rS = 0.55, P < 0.01) but not in women (rS = - 0.08). The correlation in men was dependent on a fourfold higher TNFalpha mRNA level in 5 morbidly obese men while there was no difference in TNFalpha mRNA levels in lean or obese men. Subcutaneous adipose tissue TNFalpha expression does not correlate with insulin sensitivity in nondiabetic or type-2 diabetic men; is not regulated by acute hyperinsulinaemia; and is increased only in morbidly obese men.

Acute hyperinsulinemia and very-low-density and low-density lipoprotein subfractions in obese subjects

The influence of hyperinsulinemia on concentrations of lipoprotein subfractions in obese, nondiabetic persons has not been clarified. We analyzed VLDL and LDL subfractions before and after a euglycemic, hyperinsulinemic clamp. Lipoprotein subfractions were isolated from plasma samples obtained in the basal state and after a 4-h clamp from obese patients, obese patients with type 2 diabetes, and nonobese control subjects. Hyperinsulinemia tended to reduce concentrations (&xmacr;: 20%) of large, triacylglycerol-rich VLDL(1) in obese patients but had a minor effect on VLDL(2) and VLDL(3). Placing obese patients into insulin-sensitive and insulin-resistant subgroups revealed distinct effects of the degree of insulin sensitivity on VLDL. VLDL(1) concentrations decreased by a mean of 38% (P < 0.05) in insulin-sensitive patients after the clamp, similar to but less marked than the decrease observed in control subjects (&xmacr;: 62%; P < 0.01). VLDL(1) concentrations did not change significantly after the clamp in insulin-resistant patients (and patients with type 2 diabetes), whereas VLDL(3) concentrations decreased in both groups, in contrast with the changes seen in the insulin-sensitive patients and control subjects. Acute hyperinsulinemia modified the LDL subfraction profile toward a greater prevalence of small, dense LDLs in insulin-resistant patients and patients with type 2 diabetes. Insulin resistance appears to be the primary determinant of the modifications to VLDL subfraction concentrations. Our results suggest a continuum of impaired insulin action on VLDL, ranging from that in healthy persons to that in patients with type 2 diabetes, in which obese patients occupy a transition state. Insulin resistance may also play a role in detrimental modifications to the LDL profile by allowing the development of hypertriglyceridemia.

Effects of hyperinsulinemia on sympathetic responses to mental stress

In a recent study, we could not find evidence to support the hypothesis that insulin activates the sympathetic nervous system (SNS) during a hyperinsulinemic glucose clamp procedure. Mental stress tests (MST), however, may be used to detect differences in blood pressure and SNS activity that are not present during baseline or resting conditions. In this study, we aimed to investigate the effects of hyperinsulinemia during glucose clamp on blood pressure and sympathetic responses to mental stress. Borderline hypertensive but otherwise healthy 21-year-old men (n = 18) underwent 5 min of mental arithmetic stress testing (MST-1) before and at the end of 120 min of isoglycemic hyperinsulinemic glucose clamp (MST-2) with infusion rates of glucose and insulin kept constant. Insulin concentration increased from 119 ± 10 pmol/L to 752 ± 65 pmol/L. We observed highly significant increases in blood pressure and heart rate in response to MST, but neither insulin nor saline solution infusions affected these responses. During MST-1, norepinephrine increased by 461 ± 165 pmol/L (mean ± SEM) and epinephrine by 218 ± 76 pmol/L. During MST-2 the changes were 372 ± 112 pmol/L and 187 ± 60 pmol/L, respectively. The norepinephrine ( P = .8) and epinephrine ( P = .7) responses were unchanged by insulin. Thus, there were similar increases in blood pressure, heart rate, and plasma catecholamine concentrations in arterialized venous blood in response to MST despite the infusion of insulin. A possible time effect was excluded by including a saline solution control group (n = 7) that showed almost identical results. Our results suggest that acute hyperinsulinemia during isoglycemic glucose clamp does not interfere with cardiovascular or sympathetic responses to mental stress.

Characterization of an early decline in baseline plasma glucose concentration after acute insulin elevation during euglycemic hyperinsulinemic clamp in patients with type 2 diabetes mellitus.

To investigate the contribution of the liver to whole-body insulin resistance in patients with type 2 diabetes mellitus, we analyzed the early decline (slope "a") in the baseline plasma glucose level following acute hyperinsulinemia in the initial phase of a euglycemic hyperinsulinemic clamp study, rather than using an isotope-dilution method. Slope "a" was comparable among groups of diabetic and non-diabetic subjects, and did not correlate well with glucose infusion rate (GIR), an index of peripheral (primarily skeletal muscle) insulin resistance. In contrast, slope "a" was significantly lower in obese (BMI > 25) type 2 diabetic patients compared with their non-obese counterparts, consistent with the general belief that obesity is a condition of insulin resistance in liver as well as in peripheral tissues. A subset of six insulin-resistant (nearly zero GIR) type 2 diabetic patients (pubertal adolescents) demonstrated a markedly blunted slope "a". Their insulin resistance (GIR) substantially recovered concomitant with an increase in slope "a" after pretreatment with somatostatin analogue in two cases studied, suggesting possible suppression of hepatic glucose production through lowering of plasma glucagon concentrations. Furthermore, slope "a" correlated significantly (r = -0.480, p<0.0001) with HOMA index (FPG x FIRI), the latter being recently regarded as an index of hepatic insulin resistance. These data showed that slope "a" obtained from euglycemic hyperinsulinemic clamp may be a clinically useful index of hepatic insulin resistance rather than an index of peripheral insulin resistance.

Plasma homocysteine concentrations and insulin sensitivity in hypertensive subjects

Hyperhomocysteinemia is associated with several cardiovascular disease risk factors including endothelial dysfunction and abnormalities of clotting functions, which are also common features of insulin resistance syndrome observed in hypertensive patients. Recent study has shown that acute hyperinsulinemia can lower plasma homocysteine concentrations in nondiabetic but not in type 2 diabetic individuals, indicating that insulin may regulate homocysteine metabolism. To investigate the relationships between plasma homocysteine concentration and insulin sensitivity, we studied 90 Chinese hypertensive patients and a group of control subjects (n = 86) matched for age, gender, and body mass index. Fasting plasma homocysteine levels, plasma lipoprotein concentrations, plasma glucose, and insulin responses to oral glucose tolerance tests (OGTT) were determined. The results showed that fasting plasma homocysteine concentrations were significantly higher in subjects with hypertension than in those with normotension (mean ± SEM, 8.1 ± 0.6 v 6.8 ± 0.2 μmol/L; P < .05). Fasting plasma homocysteine levels correlated significantly with insulin secretion in response to OGTT even after adjustment for body mass index ( P < .05) in hypertensive patients but not in normotensive individuals. However, fasting plasma homocysteine concentrations showed no correlations with steady-state plasma glucose concentration, a measurement of insulin sensitivity, during an insulin suppression test in groups of hypertensive (n = 42) and normotensive (n = 37) subjects. When the steady-state plasma glucose concentrations were divided into three tertiles, fasting plasma homocysteine concentrations showed no difference across these three groups in either hypertensive patients (8.6 ± 0.5 v 7.2 ± 0.5 v 8.4 ± 0.6 μmol/L; P = .148) or normotensive subjects (6.3 ± 0.4 v 8.0 ± 0.8 v 7.0 ± 0.8 μmol/L; P = .199). In conclusion, hypertensive Chinese subjects had higher fasting plasma homocysteine concentrations and a higher degree of insulin resistance when compared to a group of age-, gender-, and body mass index-matched normotensive individuals. Fasting plasma homocysteine levels were associated with insulin response to OGTT in hypertensives but not in normotensives. No correlation was observed between the degree of insulin resistance and plasma homocysteine levels in either the hypertensive or the normotensive group. The role of insulin in homocysteine metabolism deserves further investigation.

Insulin decreases plasma cholesteryl ester transfer but not cholesterol esterification in healthy subjects as well as in normotriglyceridaemic patients with type 2 diabetes.

Plasma cholesterol esterification (EST) and subsequent cholesteryl ester transfer (CET) from high-density lipoproteins (HDLs) towards apolipoprotein (apo) B-containing lipoproteins are key steps in HDL metabolism. The effects of exogenous hyperinsulinaemia on plasma CET and EST, measured with isotope methods, were evaluated in 10 male normotriglyceridaemic (plasma triglycerides <2.0 mmol L-1) patients with type 2 diabetes and 10 individually matched healthy subjects during a two-step hyperinsulinaemic euglycaemic clamp over 6-7 h. No between-group differences in baseline plasma lipid parameters were observed, but the HDL cholesteryl ester content was lower (P < 0.02) and the HDL triglyceride content was higher (P < 0.05) in diabetic patients. Baseline CET and EST were similar in the groups. In both groups, hyperinsulinaemia decreased plasma triglycerides (P < 0.01) and the HDL triglyceride content (P < 0.01) compared with saline infusion in healthy subjects, whereas the HDL cholesteryl ester content increased (P < 0.05 vs. saline infusion) in diabetic patients. CET was similarly decreased by hyperinsulinaemia in both groups (P < 0.01 vs. saline infusion). In contrast, the change in EST in either group was not different from that during saline administration. In the combined group, baseline CET was positively correlated with plasma triglycerides (Rs = 0.68, P < 0.01). The HDL cholesteryl ester content was negatively (Rs = -0.48, P < 0.05) and the HDL triglyceride content was positively (Rs = 0.64, P < 0.01) correlated with CET. Insulin infusion decreases plasma CET in conjunction with a fall in triglycerides but does not decrease cholesterol esterification in healthy and type 2 diabetic subjects, indicating that acute hyperinsulinaemia has a different effect on these processes involved in HDL metabolism. Despite unaltered fasting plasma CET, HDL core lipid composition was abnormal in diabetic patients, suggesting that additional mechanisms may contribute to changes in HDL metabolism in diabetes mellitus.

Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects.

Sympathetic activation has been considered as a link between insulin resistance, hyperinsulinemia, and hypertension. However, little is known about the association between insulin sensitivity and autonomic regulation or about the effect of acute hyperinsulinemia on cardiac sympathovagal balance. The aim of this study was to investigate heart rate variability (HRV) during the euglycemic-hyperinsulinemic clamp in nondiabetic offspring of patients with type 2 diabetes. We studied 35 nondiabetic offspring of patients with type 2 diabetes and 19 control subjects. Probands were chosen from a 10-year follow-up study of patients with well-characterized type 2 diabetes according to their fasting C-peptide level (selected from both ends of the distribution) and from control subjects to form three groups: 1) a group including subjects who were offspring of type 2 diabetic patients with low C-peptide levels (deficient insulin secretion group [IS group], n = 17), 2) a group including subjects who were offspring of type 2 diabetic patients with high C-peptide levels (insulin-resistant group [IR group], n = 18), and 3) a control group without a history of type 2 diabetes in first-degree relatives (n = 19). HRV was assessed at baseline and at the steady state during the euglycemic-hyperinsulinemic clamp. Rates of whole-body glucose uptake (M value) were lower in the IR group than in the IS group and the control group (41+/-3 vs. 54+/-2 vs. 60+/-4 micromol x kg(-1) x min(-1), P < 0.01 and P < 0.01, respectively). In all groups, heart rate increased significantly during hyperinsulinemia. In the IR group, insulin infusion increased total power of HRV [from 7.70+/-0.15 to 8.05+/-0.15 ln(ms2), P < 0.01] and the low frequency-to-high frequency ratio (from 0.62+/-0.14 to 1.14+/-0.18, P < 0.01) and decreased power of the high frequency spectral component (from 5.73+/-0.17 to 5.43+/-0.16 ln(ms2), P < 0.05), whereas in other groups, changes in HRV were not significant. We conclude that the HRV response to acute hyperinsulinemia in the offspring of type 2 diabetic probands was likely to be modulated by the type 2 diabetic phenotype of the parent. In insulin-resistant subjects, autonomic dysfunction may be an earlier defect than hitherto acknowledged.

Failure of acute hyperinsulinemia to alter blood pressure is not due to baroreceptor feedback

It is well documented that acute insulin administration stimulates the sympathetic nervous system in both humans and animals. Despite marked sympathetic activation during acute hyperinsulinemia, blood pressure is generally not increased because it is overridden by the vasodilator action of insulin. The maintenance of blood pressure in the face of sympathetic activation is unknown. A possible mechanism includes feedback regulation by the baroreceptor reflex arc. In normotensive states, hyperinsulinemic-induced sympathetic activation may tend to elevate blood pressure, but this change is rapidly sensed by the baroreceptors in the carotid arteries (and aortic arch), and a counterbalancing increase in vasodilation could return blood pressure to normal. Thus, it can be speculated that, in the event of diminished baroreceptor sensitivity and suppressed vasodilator actions of insulin, common abnormalities in hypertension, acute insulin infusion would be expected to increase blood pressure. We undertook the present study to determine whether the baroreceptor reflex arc modulated the blood pressure response to acute hyperinsulinemia. To this end, six normotensive dogs underwent saline or insulin infusions before and after deactivation of the carotid and aortic baroreceptors. Baroreceptor dysfunction was documented after denervation in all cases by an abnormal response to phenylephrine injections. Before denervation, insulin infusions caused a slight but nonsignificant rise in mean arterial pressure (MAP; 110 ± 5 to 120 ± 5 mm Hg; P = 0.13). Baroreceptor denervation caused a marked variability in blood pressure. However, basal mean arterial pressure was not significantly altered. Neither saline nor insulin infusions (105 ± 10 v 105 ± 8 mm Hg, basal v steady state) caused a significant change in MAP in denervated dogs. Likewise, insulin and saline did not change heart rates significantly in intact or denervated animals. Furthermore, glucose metabolism was similar in both groups of animals. This study demonstrates that the baroreceptor reflex arc does not mediate the blood pressure response to acute hyperinsulinemia.

Failure of acute hyperinsulinemia to alter blood pressure is not due to baroreceptor feedback

It is well documented that acute insulin administration stimulates the sympathetic nervous system in both humans and animals. Despite marked sympathetic activation during acute hyperinsulinemia, blood pressure is generally not increased because it is overridden by the vasodilator action of insulin. The maintenance of blood pressure in the face of sympathetic activation is unknown. A possible mechanism includes feedback regulation by the baroreceptor reflex arc. In normotensive states, hyperinsulinemic-induced sympathetic activation may tend to elevate blood pressure, but this change is rapidly sensed by the baroreceptors in the carotid arteries (and aortic arch), and a counterbalancing increase in vasodilation could return blood pressure to normal. Thus, it can be speculated that, in the event of diminished baroreceptor sensitivity and suppressed vasodilator actions of insulin, common abnormalities in hypertension, acute insulin infusion would be expected to increase blood pressure. We undertook the present study to determine whether the baroreceptor reflex arc modulated the blood pressure response to acute hyperinsulinemia. To this end, six normotensive dogs underwent saline or insulin infusions before and after deactivation of the carotid and aortic baroreceptors. Baroreceptor dysfunction was documented after denervation in all cases by an abnormal response to phenylephrine injections. Before denervation, insulin infusions caused a slight but nonsignificant rise in mean arterial pressure (MAP; 110 ± 5 to 120 ± 5 mm Hg; P = 0.13). Baroreceptor denervation caused a marked variability in blood pressure. However, basal mean arterial pressure was not significantly altered. Neither saline nor insulin infusions (105 ± 10 v 105 ± 8 mm Hg, basal v steady state) caused a significant change in MAP in denervated dogs. Likewise, insulin and saline did not change heart rates significantly in intact or denervated animals. Furthermore, glucose metabolism was similar in both groups of animals. This study demonstrates that the baroreceptor reflex arc does not mediate the blood pressure response to acute hyperinsulinemia. Am J Hypertens 1999;12:405–413 © 1999 American Journal of Hypertension, Ltd.

Effects of Meal-Induced Acute Hyperinsulinaemia on the Leptin System in Normal and Type 1 Diabetic Subjects during Pregnancy and Post-Partum

Conference Abstract| February 01 1999 Effects of Meal-Induced Acute Hyperinsulinaemia on the Leptin System in Normal and Type 1 Diabetic Subjects during Pregnancy and Post-Partum K Lewandowski; K Lewandowski 1Department of Biological Sciences, University of Warwick, Coventry CV 4 7AL and Medizinische Hochschule, Hannover, Germany (H.R. and B.G.) Search for other works by this author on: This Site PubMed Google Scholar D Dunlop; D Dunlop 1Department of Biological Sciences, University of Warwick, Coventry CV 4 7AL and Medizinische Hochschule, Hannover, Germany (H.R. and B.G.) Search for other works by this author on: This Site PubMed Google Scholar C O'Callaghan; C O'Callaghan 1Department of Biological Sciences, University of Warwick, Coventry CV 4 7AL and Medizinische Hochschule, Hannover, Germany (H.R. and B.G.) Search for other works by this author on: This Site PubMed Google Scholar R Horn; R Horn 1Department of Biological Sciences, University of Warwick, Coventry CV 4 7AL and Medizinische Hochschule, Hannover, Germany (H.R. and B.G.) Search for other works by this author on: This Site PubMed Google Scholar G Medley; G Medley 1Department of Biological Sciences, University of Warwick, Coventry CV 4 7AL and Medizinische Hochschule, Hannover, Germany (H.R. and B.G.) Search for other works by this author on: This Site PubMed Google Scholar G Brabant; G Brabant 1Department of Biological Sciences, University of Warwick, Coventry CV 4 7AL and Medizinische Hochschule, Hannover, Germany (H.R. and B.G.) Search for other works by this author on: This Site PubMed Google Scholar P O'Hare P O'Hare 1Department of Biological Sciences, University of Warwick, Coventry CV 4 7AL and Medizinische Hochschule, Hannover, Germany (H.R. and B.G.) Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1999) 96 (s40): 7P. https://doi.org/10.1042/cs096007Pb Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation K Lewandowski, D Dunlop, C O'Callaghan, R Horn, G Medley, G Brabant, P O'Hare; Effects of Meal-Induced Acute Hyperinsulinaemia on the Leptin System in Normal and Type 1 Diabetic Subjects during Pregnancy and Post-Partum. Clin Sci (Lond) 1 February 1999; 96 (s40): 7P. doi: https://doi.org/10.1042/cs096007Pb Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1999 The Biochemical Society and the Medical Research Society1999 Article PDF first page preview Close Modal You do not currently have access to this content.