Effect of Dietary Sodium on Insulin Sensitivity in Older,Obese, Sedentary Hypertensives

Increased dietary sodium intake has been associated with an increase in blood pressure as well as a decrease in insulin-mediated glucose disposal in young healthy adults. The purpose of this study was to determine whether dietary sodium intake is associated with changes in oral glucose tolerance, insulin sensitivity, and blood pressure in older, sedentary, overweight hypertensives. Eight older (70.0 ± 1.4 years, mean ± SEM), overweight (40.2 ± 3.1% body fat), mildly hypertensive (151 ± 8/82 ± 2 mm Hg) patients with a fasting plasma glucose < 7.8 mmol/L were studied after 2 weeks on low (3 g/day) and 2 weeks on high (10 g/day) sodium diets. To examine carbohydrate metabolism we performed a 2 h oral glucose tolerance test and a two-dose (240 and 600 pmol/m ²/min) hyperinsulinemic-euglycemic clamp at the end of each sodium diet. High sodium intake was associated with a significantly greater urinary sodium excretion (364 ± 45 mmol/day v 112 ± 21 mmol/day; P < .0001). The increase in dietary sodium from low to high did not result in significant differences in fasting plasma glucose (6.0 ± 0.2 v 5.8 ± 0.1 mmol/L, P = .20) or insulin (72.5 ± 7.8 v 69.9 ± 12.4 pmol/L, P = 0.71) levels or in the glucose (374.0 ± 50.8 v 493.2 ± 45.0 mmol/min/L, P = .12) and insulin (43,783 ± 10,278 v 44,110 ± 12,392 pmol/min/L, P = .96) areas determined during the oral glucose tolerance test. Similarly, there was no effect of dietary sodium on insulin-mediated glucose disposal at low (5.87 ± 1.02 v 5.60 ± 0.94 mg/kg LBM/min, P = .36) or high (12.15 ± 1.49 v 11.91 ± 1.49 mg/kg _LBM/min, P = .64) insulin infusion rates. Our findings suggest that, in insulin resistant hypertensives, increased dietary sodium does not affect either glucose or insulin responses during an oral glucose tolerance test or glucose disposal during a hyperinsulinemic euglycemic clamp.     

Effects of l-arginine on blood pressure and metabolic changes in fructose-hypertensive rats

In the present study, we examined the effects of chronic l-arginine treatment on plasma insulin levels and systolic blood pressure (SBP) in fructose-fed (F) rats. Fructose feeding resulted in hyperinsulinemia and elevated blood pressure when compared with that in controls (plasma insulin, 311.3 ± 11.4 v control 164.4 ± 11.8 pmol/L, P < .05; SBP, 135.4 ± 4.2 v control 105.5 ± 1.3 mm Hg, P < .05). l-arginine treatment of fructose-hypertensive rats prevented the development of hyperinsulinemia and hypertension (plasma insulin, 200.1 ± 7.5 pmol/L; P < .05 compared with that in F rats; SBP, 108.0 ± 0.9 mm Hg; P < .05 compared with F rats). However, treatment with l-arginine did not influence any of these parameters in control rats. Statistical analysis of the data of plasma insulin level and SBP, revealed a significant correlation between these two variables. On the other hand, l-arginine treatment of F rats prevented the increased glucose and insulin concentrations in response to oral glucose challenge. l-arginine treatment also prevented the decrease in insulin sensitivity of F rats. These results indicate that l-arginine treatment is able to prevent fructose-induced hypertension and hyperinsulinemia. Our data also suggest a strong relationship between hyperinsulinemia and hypertension in this hypertensive rat model. Therefore, the antihypertensive effect of l-arginine could be, at least in part, the result of the restoration of plasma insulin levels by its vasodilator ability to increase blood flow to insulin sensitive tissues.     

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.     

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.     

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity

Aims/hypothesis

Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity.

Methods

Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined.

Results

Maternal insulin increased from a fasting level of 67?±?25 pmol/l (mean ± SD) to 918?±?492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4?±?0.3 to 7.4?±?1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297?±?99 to 235?±?84 ms (p?=?0.01) and then remained stable until 120 min (235?±?84 vs 251?±?91 ms, p?=?0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r?=?0.68, p?=?0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283?±?79 ms) than those of insulin-sensitive mothers (178?±?46 ms, p?=?0.03).

Conclusions/interpretation

Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.     

Prospective evaluation of insulin resistance and lipid metabolism in women receiving oral contraceptives

OBJECTIVES It has been suggested that normal women receiving oral contraceptives (OC) may develop a series of metabolic side-effects which relate to the risk of cardiovascular disease. These metabolic disturbances include changes in glucose and insulin metabolism, raised serum lipid and lipoprotein concentrations and elevated blood pressure. All these changes indicate that OC might cause insulin resistance. We have prospectively examined the effect of OC on insulin resistance and lipid metabolism including Lp(a) values. PATIENTS The study group comprised 13 normally menstruating Chinese women. DESIGN The study subjects were given a combined triphasic oral contraceptive which was administered on a 21-day on, 7-day off medication cyclic regimen, the first pill being administered on day 5 from the beginning of menses. The metabolic investigations were carried out during luteal phase before OC and again the third week of the third month of OC administration. MEASUREMENTS Metabolic evaluation including insulin secretion and insulin-mediated glucose uptake were evaluated by oral glucose tolerance test and the modification of insulin suppression test. Fasting triglyceride, cholesterol, HDL-cholesterol and Lp(a) concentrations were also measured. RESULTS The plasma glucose and insulin responses during a 75-g oral glucose challenge increased significantly (P<0 05 and P<003, respectively). The steady-state plasma glucose (SSPG) concentrations achieved during constant infusion of glucose, insulin and somatostatin increased significantly after 3 cycles of OC administration (glucose 7–5±08 vs 124±07 mmol/l, P<0001) while the steady-state plasma insulin (SSPI) concentrations were relatively similar (410±14 vs 391 ±7 pmol/l, NS). Plasma triglyceride levels increased significantly (0 81 ±012 vs 1 09±0 19 mmol/l, P<0 03) following OC administration. Fasting plasma cholesterol, HDL cholesterol and calculated LDL cholesterol concentrations did not change as compared with baseline values, nor did the ratio of total cholesterol to HDL cholesterol. The Lp(a) concentrations did not change during the administration of OC (81 ±25 vs 71 ±21 mg/l, NS). CONCLUSIONS These data indicated that intake of OC for 3 cycles induced glucose intolerance, hyperinsulinaemia and insulin resistance in normal menstruating Chinese women. These changes occurred in association with elevated plasma triglyceride concentrations and no alteration in Lp(a) or other lipid values.     

Pioglitazone attenuates basal and postprandial insulin concentrations and blood pressure in the spontaneously hypertensive rat

Subjects with hypertension are hyperinsulinemic and resistant to insulin-stimulated glucose uptake. A similar paradigm is found in the spontaneously hypertensive rat (SHR). These findings suggest the possibility that insulin resistance and hyperinsulinemia may play an important role in blood pressure regulation. Pioglitazone, a thiazolidinedione derivative, sensitizes target tissues to insulin and decreases hyperglycemia and hyperinsulinemia in various insulin-resistant animals. The purpose of this study was to assess the influence of pioglitazone administration on pre- and postprandial glucose and insulin concentrations and determine whether changes in β-cell secretion resulted in any change in blood pressure measurements. Twelve SHR were fed custom diets ad libitum, six with and six without pioglitazone (20 mg/kg chow). Fasting and postprandial glucose levels were unaltered by pioglitazone treatment. Fasting insulin concentrations were similar at week 1, but were significantly lower (P < .01) in the pioglitazone group at weeks 3 (1.89 ± 0.3 v7.94 ± 1.5 ng/mL) and 4 (4.5 ± 1.4 v9.1 ± 0.7 ng/mL), compared with the control group. Pioglitazone also significantly (P < .01) lowered postprandial insulin concentrations after an oral glucose challenge. Systolic, mean, and diastolic blood pressures were significantly lower (P < .01), 177 ± 3 v190 ± 4.7 mm Hg, 162 ± 2.1 v175 ± 5.9 mm Hg, and 156 ± 2.1 v168 ± 6.2 mm Hg, respectively, in the animals receiving pioglitazone versus the control group. Heart rate, body weight, serum cholesterol, and triglyceride levels were comparable between the two groups. In conclusion, pioglitazone significantly decreased fasting and postprandial insulin concentrations and effectively lowered blood pressure in the SHR.     

Hemodynamic responses to obstructive respiratory events during sleep are augmented in women with preeclampsia

Preeclampsia is the most common disease of pregnancy, occurring in up to 10% of the pregnant population. The cause of the disease is as yet undetermined; however, most of the clinical effects are commonly attributed to damage to the endothelial layer, leading to increased pressor activity of all the maternal blood vessels. Therefore, we suspected that if obstructive sleep apnea (OSA) coexisted with preeclampsia in pregnancy, the hemodynamic effects of the OSA would be markedly potentiated. To test this hypothesis, we performed full sleep studies and overnight beat-to-beat blood pressure (BP) monitoring. The control patient group included 10 pregnant women with OSA and no evidence of hypertensive disease either before or during their current pregnancy. The test group included 10 women with preeclampsia and coexisting OSA. The pressor responses to obstructive respiratory events during sleep were enhanced in preeclamptic patients compared with control OSA patients (21 ± 2/12 ± 1 mm Hg and 38 ± 5/25 ± 4 mm Hg above baseline in control OSA and preeclamptic OSA patients, respectively, P = .005/.005). In contrast, there was no difference in heart rate responses between the two groups of subjects (34 ± 5 beats/min and 49 ± 13 beats/min above baseline in control and preeclamptic patient groups, respectively, P = .326). We suggest that the augmented pressor responses in preeclamptic women occur as a result of maternal endothelial damage induced by the preeclampsia disease process. These findings may have important implications in the management of preeclamptic patients.     

The effect of the deterioration of insulin sensitivity onβ-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy

The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on β-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment with biosynthetic GH 2 IU/m²s.c. daily (n=13) or placebo (n=11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study period, body weight decreased 1.6 kg from 94.0 ± 18.7 to 92.4 ± 19.4 kg (mean ± SD) (P<0.05) in the GH-treated group, but remained unchanged in the placebo group. Fat mass decreased from 32.4 ± 9.6 to 28.1 ± 10.5 kg (P<0.001), whereas lean body mass increased from 58.3 ± 11.5 to 61.0 ± 11.7 kg (P<0.01) in the GH-treated group. Treatment with GH for 4 months resulted in a significant increase in fasting blood glucose (before GH 5.0 ± 0.3 and after 5.4 ± 0.6 mmol/l,P<0.05), fasting plasma insulin (before GH 38.4 ± 30.2 and after 55.3 ± 34.7 pmol/l,P<0.02) and fasting proinsulin (before 8.1 ± 6.7 and after 14.6 ± 16.1 pmol/l,P<0.05). The insulin sensitivity index S_I, estimated by Bergmans Minimal Model, decreased significantly [before GH 1.1 ± 0.7 and after 0.4 ± 0.2 10^–4(min × pmol/l),P<0.003]. The non-insulin-dependent glucose uptake (glucose effectiveness S_Gdid not change (before GH 0.017 ± 0.005 and after 0.015 ± 0.006 min^–1, NS). Insulin secretion was enhanced during GH therapy, but insufficiently to match the changes in S_I, resulting in a higher blood glucose level during an OGTT. Blood glucose at 120 min was 5.5 and 6.3 mmol/l before and after GH treatment, respectively (P= 0.07). One patient developed impaired glucose tolerance.Short-term GH replacement therapy in a dose of about 2 IU/m²daily in GHD adults induces a reduction in insulin sensitivity, despite favourable changes in body composition, and an inadequate enhancement of insulin secretion.     

The set point for maternal glucose homeostasis is lowered during late pregnancy in the rat: the role of the islet beta-cell and liver

Summary The aim of this study was to determine the effects of late pregnancy on the ability of insulin to suppress maternal hepatic glucose production in the rat. Unlike in most previous studies, suppression of hepatic glucose production was measured at levels of glycaemia above the relatively hypoglycaemic basal pregnant level. Glucose kinetics were measured using steady-state tracer methodology in chronically catheterised, conscious virgin control and pregnant rats, firstly, during basal and low-dose hyperinsulinaemic euglycaemic clamp conditions and secondly, during a three-step glucose infusion protocol (glucose infusion rates of 0, 60 and 150 μmol · kg⁻¹· min⁻¹). During the clamps, plasma glucose levels were not different (6.1 ± 0.4 vs 6.5 ± 0.3 mmol/l, pregnant vs virgin; N. S.), but plasma insulin levels were higher in the pregnant rats (242 ± 30 vs 154 ± 18 pmol/l, pregnant vs virgin; p < 0.05) most probably due to stimulated endogenous insulin release in this group. Hepatic glucose production was suppressed from basal levels by 41 % in virgin and 90 % in pregnant rats. During the glucose infusion studies, at matched insulin levels (147 ± 10 vs 152 ± 14 pmol/l), but at plasma glucose levels which were much lower in the pregnant rats (5.5 ± 0.2 vs 8.4 ± 0.6 mmol/l, pregnant vs virgin; p < 0.0001), hepatic glucose production was shown to be suppressed by a similar degree in both groups (41 ± 5 vs 51 ± 5 % from basal, pregnant vs virgin; N. S.). Both the plasma insulin and percentage suppression of hepatic glucose production dose responses to plasma glucose were markedly shifted to the left indicating that the plasma glucose set point is lowered in pregnancy. In conclusion, suppression of hepatic glucose production by insulin is not impaired and the set point for plasma glucose homeostasis is lowered during late pregnancy in the rat. [Diabetologia (1996) 39: 785–792] Received: 2 October 1995 and in final revised form: 1 February 1996     

Glucose-alanine relationship in normal human pregnancy

In order to quantify the glucose-alanine relationship in normal human pregnancy, the turnover rates of alanine and the incorporation of alanine carbon into glucose were quantified in 15 pregnant women during the last 4 weeks of gestation following a ten-hour fast. Eight nonpregnant women of similar age group were studied as controls. l-[2,3-¹³C₂]Alanine and d[6,6-²H₂]glucose were infused as tracers. The ¹³C enrichment of alanine, lactate, and glucose and the deuterium enrichment of glucose were measured by gas chromatography-mass spectrometry. In five pregnant and five nonpregnant women, the contribution of alanine carbon to expired CO₂ directly and via glucose was estimated by combining indirect respiratory calorimetry with the tracer infusions. The alanine turnover rates in the pregnant and nonpregnant women were similar (pregnant, 4.43 ± 0.82 μmol/kg × min; nonpregnant, 4.11 ± 1.08 μmol/kg × min, mean ± SD). However, the fraction of alanine incorporated into glucose was significantly lower during pregnancy (23.5 ± 8.3% v 30.8 ± 8.2%, P < .04). In pregnant women, 20% of lactate pool was derived from alanine as compared with 28% in nonpregnant subjects (P < .02). Twenty-four percent of alanine turnover was converted to CO₂ in both pregnant and nonpregnant women. The plasma insulin concentration was increased significantly during pregnancy (P < .05). These data suggest that gluconeogenesis from alanine is attenuated during pregnancy. This decrease in gluconeogenesis is not the result of decreased alanine flux, but due to intrinsic intrahepatic mechanism such as decreased deamination of alanine mediated by the predominant insulin effect or a decreased hepatic uptake of alanine. These unique adaptive responses in human pregnancy result in conservation of maternal nitrogen for new maternal and fetal protein synthesis.     

Effect of insulin on renal sodium and uric acid handling in essential hypertension

In normal subjects, insulin decreases the urinary excretion of sodium, potassium, and uric acid. We tested whether these renal effects of insulin are altered in insulin resistant hypertension. In 37 patients with essential hypertension, we measured the changes in urinary excretion of sodium, potassium, and uric acid in response to physiological euglycemic hyperinsulinemia (by using the insulin clamp technique at an insulin infusion rate of 6 pmol/min/kg). Glucose disposal rate averaged 26.6 ± 1.5 μmol/min/kg, ie, 20% lower than in normotensive controls (33.1 ± 2.1 μmol/min/kg, P = .015). In the basal state, fasting plasma uric acid concentrations were higher in men than women (P < .001), were positively related to body mass index (r = 0.38, P = .02), waist/hip ratio (r = 0.35, P < .05), and serum triglyceride levels (r = 0.59, P = .0001), and negatively related to HDL cholesterol concentrations (r = −0.59, P = .0001) and glucose disposal rate (r = 0.42, P < .01). Uric acid clearance, on the other hand, was inversely related to body mass index (r = 0.41, P = .01), plasma uric acid (r = 0.65, P < .0001) and triglyceride concentrations (r = 0.39, P < .02), and directly related to HDL cholesterol levels (r = 0.52, P < .001). During insulin infusion, blood pressure, plasma uric acid and sodium concentration, and creatinine clearance did not change. In contrast, hyperinsulinemia caused a significant decrease in the urinary excretion of uric acid (2.67 ± 0.12 to 1.86 ± .14 μmol/min/1.73 m², P = .0001), sodium (184 ± 12 to 137 ± 14 μmol/min/1.73 m², P = .0001), and potassium (81 ± 7 to 48 ± 4 μmol/min/1.73 m², P = .0001). Both in absolute terms (clearance and fractional excretion rates) and percentagewise, these changes were similar to those found in normotensive subjects. Insulin-induced changes in urate excretion were coupled (r = 0.55, P < .0001) to the respective changes in sodium excretion. In hypertensive patients, higher uric acid levels and lower renal urate clearance rates cluster with insulin resistance and dyslipidemia. Despite insulin resistance of glucose metabolism, acute physiological hyperinsulinemia causes normal antinatriuresis, antikaliuresis, and antiuricosuria in these patients.     

Effect of amlodipine on hemodynamic and endocrine responses to mental stress

Little is known about the effects of antihypertensive drugs on hemodynamic responses to mental stress. We studied 24 patients with mild-to-moderate hypertension in a double-blind random-sequence crossover study comparing placebo with amlodipine titrated up from 5 to 10 mg daily. After 1 month of treatment, the subjects performed 20 min of a frustrating cognitive task. At baseline before task, amlodipine significantly reduced systolic pressure (128.9 ± 8.2 mm Hg v 140.3 ± 10.7 mm Hg, P < .001), diastolic pressure (81.7 ± 7.7 mm Hg v 90 ± 7.5 mm Hg, P < .001), and total peripheral resistance (37.5 ± 15 v 45.6 ± 23.7 mm Hg/L/min, P < .05), while elevating baseline norepinephrine levels (2286 ± 731 pmol/L v 1788 ± 546 pmol/L, P < .001).Blood pressure during the stress task was significantly less with amlodipine than with placebo (systolic 142.3 ± 12.3 mm Hg v 150.9 ± 14.6 mm Hg, P < .001; diastolic 87.9 ± 8.4 mm Hg v 97.7 ± 9.3 mm Hg, P < .001), whereas norepinephrine was significantly higher (2754 ± 1007 pmol/L v 1970 ± 740 pmol/L, P < .001).There were no significant differences in cardiac output, plasma lipids or lipoproteins, or markers of platelet activation. Heart rate increased significantly during stress, but there was no significant difference between amlodipine and placebo either at baseline or during stress. Our conclusion is that amlodipine reduces blood pressure at baseline and during mental stress, but raises basal and stress-related plasma catecholamines. This finding may have implications for the recent controversy over the safety of calcium channel antagonists, and suggests the potential relevance of combining amlodipine with adrenergic blockers.     

A novel mechanism of glipizide sulfonylurea action: decreased metabolic clearance rate of insulin

To examine whether sulfonylureas inhibit the metabolic clearance rate (MCR) of insulin, 19 healthy young subjects participated in two experiments. In the first protocol (n=10), a 3-h oral glucose load was performed with and without 2 mg of glipizide given 30 min before glucose ingestion. The total insulin response was 60% greater with than without glipizide (5.9±0.6 vs 3.7±0.5 μU/ml;P<0.001). However, the total C-peptide responses were virtually identical (4.7±0.5 vs 4.8±0.4 nmol/l) in both studies. In the second protocol (n=9), the MCR of insulin was measured during 4-h euglycemic insulin clamps performed with and without glipizide. In the study with glipizide, the subjects ingested 5 mg of glipizide at 120 min. The steady-state plasma insulin concentration during the 4th h, i.e., 1–2 h after glipizide ingestion, was significantly higher than during the 2nd h, i.e., before glipizide ingestion (99±22 vs 78±17 μU/ml;P<0.01). In addition, glucose uptake during the 4th h was greater (8.0±1.6 vs 6.4±1.5 mg/kg·min) and the MCR of insulin was reduced (503±126 vs 621±176 ml/m²·min;P<0.01). We conclude that glipizide augments plasma insulin levels both by enhancing its secretion and by decreasing the MCR of insulin.     

Troglitazone,an insulin sensitizer,increases forearm blood flow in humans

To test whether troglitazone, a thiazolidinedione insulin sensitizer, increases the peripheral blood flow, the changes in forearm blood flow (FBF) were evaluated by venous occlusion plethysmography in 11 lean healthy male volunteers (age range, 24 to 39 years) after a single oral dose of 200 mg of troglitazone. Forearm vascular resistance (FVR) was calculated from FBF and blood pressure. Two hours after the dose, FBF increased from 3.66 ± 0.31 to 4.81 ± 0.57 mL/100 mL/min (P < .01), and FVR decreased from 24.7 ± 2.2 to 20.2 ± 2.2 units (P < .01), whereas both these values did not change during the control recordings obtained without troglitazone. Blood pressure, blood glucose levels, and serum immunoreactive insulin levels did not change significantly during the observation period. Serum concentrations of nitrate ions decreased from 27.0 ± 3.5 mmol/L to 23.1 ± 2.7 mmol/L (P < .01) after the administration. These results suggest that troglitazone increases muscular blood flow through vasodilation induced by a mechanism other than the correction of hyperinsulinemia or the increase in nitric oxide. The present study provides the first evidence that troglitazone dilates the vasculature in humans.     

No Effect of Beta-adrenergic Blockade on Hypoglycaemic Effect of Glucagon-like Peptide-1 (GLP-1) in Normal Subjects

GLP-1 administration decreases blood glucose levels in normal subjects and non-insulin-dependent diabetes mellitus patients and is therefore proposed as a treatment for diabetic hyperglycaemia. The glucose lowering effect of GLP-1 is glucose dependent and therefore self-limiting, but it is not known to which extent counterregulatory mechanisms participate in this. GLP-1 was infused i.v. into 8 healthy subjects after an overnight fast at a rate of 100 pmol kg₋₁ h₋₁ for 1 h with and without beta-adrenoceptor blockade (i.v. bolus of 5 mg propranolol followed by a continuous infusion of 0.08 mg min₋₁). In a control experiment, saline and propranolol were infused. Hepatic glucose production was measured and blood was analysed for plasma glucose, insulin, glucagon, catecholamines, and radioactivity. Plasma GLP-1 levels were similar on the two GLP-1 infusion days and resulted in: (1) a significant decrease in plasma glucose from 5.2 ± 0.2 to 4.1 ± 0.1 mmol l₋₁ with GLP-1/propranolol infusion, and from 5.2 ± 0.1 to 4.0 ± 0.1 mmol l₋₁ with GLP-1/saline infusion (NS); (2) a corresponding significant increase in plasma insulin from 58.0 ± 6.3 to 144.5 ± 22.3 pmol l₋₁ and from 61.7 ± 6.4 to 148.2 ± 34.0 pmol l₋₁, respectively (NS); (3) a significant decrease in plasma glucagon from 11.7 ± 1.6 to 6.5 ± 1.5 pmol l₋₁ and from 10.4 ± 1.6 to 4.6 ± 1.0 pmol l₋₁, respectively; (4) a significant decrease in the rate of glucose appearance which was not significantly different on the two GLP-1 infusion days; and (5) an increase in catecholamine levels in the GLP-1/saline experiment and also in the beta-blockade experiments. We conclude that adrenergic counterregulation plays an insignificant role in curtailing GLP-1's glucose lowering effect.     

The effect of hyperglycemia, hyperinsulinemia, and route of glucose administration on glucose oxidation and glucose storage

The separate effects of hyperinsulinemia, hyperglycemia, and the route of glucose administration on total glucose metabolism, glucose oxidation, and glucose storage were examined in 19 healthy young volunteers by employing the glucose clamp technique in combination with indirect calorimetry. Following 2 hr of euglycemic hyperinsulinemia (plasma insulin ～97μU/ml) created by intravenous insulin/glucose infusion, total glucose metabolism (6.08 ± 0.56 mg/kg. min), glucose oxidation ($\text{2.63 ± 0.26 mg}\text{0.26 mg kg · min}$), and glucose storage (3.46 ± 0.42 mg/kg · min) all increased 2 to 3-fold over basal rates. When additional hyperinsulinemia (163 ± 19 μU/ml) was created while maintaining euglycemia, total glucose metabolism (8.87 ± 0.69) and glucose storage (6.06 ± 0.51) both increased significantly (p < 0.005 and 0.02, respectively), but the rise in glucose oxidation (2.96 ± 0.17) was small and insignificant. During combined hyperglycemia (214 mg/dl) and hyperinsulinemia (217 μU/ml), total glucose metabolism (16.21 ± 0.58 mg/kg · min) and glucose storage (13.05 ± 0.57 mg/kg · min) both increased significantly (p < 0.001) compared to the euglycemic hyperinsulinemic conditions but glucose oxidation (3.04 ± 0.16 mg/kg · min) failed to increase further. These results indicate that the body's ability to oxidize glucose becomes saturated within the physiologic range of plasma insulin and glucose concentrations. With further increases in plasma glucose and insulin levels, the increase in glucose metabolism is primarily accounted for by an increase in glucose storage. The route of glucose administration, oral versus intravenous, had no effect on glucose oxidation. Under conditions of prolonged (6 hrs) euglycemic hyperinsulinemia, glucose oxidation was not significantly different whether the glucose was given intravenously (3.14 ± 0.11 mg/kg · min) or orally (3.63 ± 0.17). Similarly, under comparable conditios of hyperglycemic hyperinsulinemia, glucose oxidation was not different in subjects receiving intravenous (3.60 ± 0.28 mg/kg · min) and oral (4.03 ± 0.13) glucose. However, under conditions of hyperglycemic hyperinsulinemia both total body glucose metabolism (22.91 ± 0.42 versus 19.66 ± 1.10 mg/kg · min, p < 0.02) and glucose storage (18.76 ± 0.47 versus 15.95 ± 1.17, p < 0.02) were significantly greater during oral versus intravenous glucose. The site of the increased glucose storage observed with oral glucose could not be located since hepatic and femoral venous catheterization was not performed.     

Is Insulin Resistance in the Spontaneously Hypertensive Rat Related to Changes in Protein Kinase C in Skeletal Muscle?

The mechanism of insulin resistance in the spontaneously hypertensive rat (SHR) has not been clearly identified, but protein kinase C (PKC) has been implicated as a mechanism of insulin resistance in obesity and diabetes mellitus and in a diet-induced (fructose-fed) model of insulin resistance and hypertension. This study compared PKC enzyme activity (cytosol and particulate fractions) and expression of the muscle-specific isoform, PKC-θ (Western blotting), in red (soleus) and white (tensor fascia latae) hindlimb muscles from SHR (n = 12) and WKY (n = 12) rats. SHRs were hypertensive and insulin resistant, as shown by higher insulin (188 ± 34 v 169 ± 22 pmol/L), triglycerides (1.65 ± 0.07 v 1.38 ± 0.06 mmol/L), and nonesterified fatty acids (0.99 ± 0.05 v 0.78 ± 0.04 mmol/L) concentrations. PKC activity was significantly greater in the membrane fraction, compared with the cytosol, but there were no significant differences either in PKC activity or subcellular distribution, or expression of PKC-θ, between the two strains. Thus, insulin resistance in the SHR (in contrast to the fructose-fed dietary model of insulin resistance and hypertension) is not related to changes in PKC signaling or expression of PKC-θ in skeletal muscle.     

Cardiovascular biomarker midregional proatrial natriuretic peptide during and after preeclamptic pregnancies

Preeclampsia is associated with increased risk of cardiovascular disease. Midregional proatrial natriuretic peptide (MR-proANP), a precursor of the atrial natriuretic peptide, is a biomarker for cardiovascular disease. We obtained plasma from 184 pregnant women in gestational weeks 24 to 42 (normotensive pregnancies: n=77, preeclampsia: n=107), from 25 of these women at 5 to 8 years after index pregnancy (normotensive pregnancies: n=11, preeclampsia: n=14), and from 49 normotensive, nonpregnant women and analyzed them by immunoassay for MR-proANP. To investigate potential sources, placental and decidual atrial natriuretic peptide mRNA expression levels were analyzed by quantitative real-time PCR in 21 normotensive and 23 preeclamptic pregnancies, as well as in human heart and kidney samples. For further confirmation, we measured circulating MR-proANP and performed expression studies in a transgenic rat model for preeclampsia. MR-proANP was significantly elevated in maternal plasma in preeclampsia compared with normotensive pregnancies (135 versus 56 pmol/L; P<0.001). However, 5 to 8 years after pregnancy, there was no difference (formerly preeclamptic women versus formerly normotensive in pregnancy: 53 versus 49 pmol/L; P=0.5). Our preeclamptic rat model confirmed the acute MR-proANP differences between preeclamptic and normotensive pregnancies (10.9±1.9 versus 4.3±0.3 pmol/L; P=0.05). Atrial natriuretic peptide expression was high in the heart but negligible in the uteroplacental unit in both normotensive humans and rats, whereas expression in maternal and fetal hearts in the preeclamptic rats was significantly increased, compared with controls. MR-proANP is a serviceable biomarker in preeclampsia, both in humans and a rat model, probably reflecting cardiovascular hemodynamic stress.     

Plasma OLC is elevated in mild experimental uremia but is not associated with hypertension

Background:Little is known about the renal handling of endogenous ouabain-like compound (OLC). The aim of this study was to determine the normal renal clearance of OLC and the effect of mild experimental uremia on plasma OLC and its clearance.Methods:Male Wistar rats were studied 8 weeks after subtotal (5/6th) nephrectomy (n = 8) and compared with a control sham-operated group (n = 8).Results:Plasma creatinine and OLC were higher in uremic animals compared with controls (creatinine 76 ± 5.6 μmol/L v 45 ± 9.6 μmol/L, respectively, P < .00005; OLC 195 ± 62 pmol/L v 121 ± 62 pmol/L, P < .02). Creatinine clearance and OLC clearance were lower in uremic animals compared with controls (creatinine 1.06 ± 0.12 mL/min v 1.58 ± 0.32 mL/min, respectively, P < .002; OLC 23.6 ± 10.4 μL/min v 33.2 ± 11.4 μL/min, P < .05). There were no significant differences (all P > .05) between the uremic and control groups in the fractional clearance of OLC (uremic 2.3% ± 1.0% v control 2.2% ± 1.0%), OLC excretion rate (uremic 6.2 ± 2.4 pmol/24 h v control 5.0 ± 1.1 pmol/24 h) or in the mean systolic blood pressure (BP) (uremic 132 ± 13 mm Hg v control 126 ± 3 mm Hg). The amount of OLC excreted per unit of functioning nephron mass was 78% higher in uremic animals than in controls. The rate of tubular absorption varied linearly with filtered load, did not differ between groups, and showed no evidence of saturation.Conclusions:The kidneys are an important excretion route for plasma OLC and moderate but significant increases may occur without inducing hypertension in the short term. The low fractional clearance of OLC is most likely due to tubular absorption and/or catabolism.