Sustained Hyperinsulinemia Research Articles

Inhibition of nitric oxide synthesis accentuates blood pressure elevation in hyperinsulinemic rats.

To examine the role of endogenous nitric oxide (NO) in the pathogenesis of hypertension and insulin resistance in chronic hyperinsulinemic rats. Sustained hyperinsulinemia was achieved by insulin infusion (21.5 pmol/kg per min) via subcutaneous osmotic minipump for 6 weeks. NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg per day) was given orally after 4 weeks of vehicle or insulin infusion. The systolic blood pressure (SBP) was measured under conscious state by an electrosphygmomanometer before and after drug treatments. Insulin infusion alone significantly increased SBP from 134 +/- 3 to 156 +/- 2 mmHg by week 4 and further to 158 +/- 3 mmHg by week 6 of insulin infusion. The insulin-infused rats had markedly decreased insulin sensitivity, as reflected by an elevated steady-state plasma glucose level estimated by the insulin suppression test. There were no significant differences in plasma glucose and triglyceride levels between rats with and without insulin infusion. When hypertension had been established in rats receiving insulin infusion for 4 weeks, superimposed L-NAME on insulin infusion for additional 2 weeks further increased SBP by 18 +/- 2 mmHg (from 157 +/- 2 to 175 +/- 2 mmHg). Plasma levels of NO metabolites (NOx) significantly decreased from 13.7 +/- 1.1 micromol/l during the control period to 6.1 +/- 0.6 micromol/l after 4 weeks of insulin infusion and further reduced to 4.1 +/- 0.5 micromol/l after combined infusion of L-NAME and insulin. L-NAME treatment alone for 2 weeks in control rats significantly increased SBP by 33 +/- 2 mmHg (from 133 +/- 2 to 166 +/- 2 mmHg) and plasma insulin levels, as a consequence of insulin resistance. Despite marked increases in blood pressure due to infusion of insulin alone or in combination with L-NAME, the sodium balance, urinary sodium and water excretions, water intake and body weight gain of insulin/L-NAME-treated rats were not significantly different from rats without insulin infusion. Sustained hyperinsulinemia causes partial impairment of NO production that may contribute to the development of insulin resistance and hypertension. Additional inhibition of NO synthesis by L-NAME accentuates the blood pressure elevation and insulin resistance in hyperinsulinemic rats. Furthermore, a rightward shift of the renal arterial pressure-natriuretic function relationship occurred in this hypertensive model.

Greffe de pancréas et de rein : résultats métaboliques à long terme

Study aim: Pancreas and kidney transplantation (PKTx) is indicated in uremic patients with insulin-dependent diabetes mellitus (IDDM). The aim of this study was to determine its long-term effect on metabolic control in order to establish the real efficacy of this treatment in diabetic patients. Patients and method: Among a total experience of 191 pancreas and kidney transplantations, a metabolic control was performed in 80 patients who underwent PKTx in our center, with both grafts functioning for more than one year. Immunological markers of diabetes mellitus were also evaluated (ICA and GADab) in 50 patients. Results: Basal glycemia and glycosilated hemoglobin (HbA1c) levels throughout follow-up were within the normal range. Hyperinsulinemia was present throughout follow-up till the fourth year. The oral glucose tolerance test (OGTT) was normal in 82,5 % of the patients beyond one year after the graft. Over time, no differences were detected on basal glucose and insulin levels and areas under the curve (AUC) of glycemia and insulinemia. During the evolution, no differences were found in the festing insulin resistance index (FIRI), in spite of increasing body weight. ICA were + in 2 patients before graft and + in 7 after graft (14 %). GADab were + in 10 patients before graft and + in 11 after graft (22 %). Conclusion: Pancreas and kidney transplantation provides without any insulin treatment and diet long-term normalization of glycemic control, assessed by HbA1c and OGTT, despite the existence of sustained hyperinsulinemia. Our results strongly suggest that pancreas and kidney transplantation is the most efficient treatment for uremic patients with insulinodependent diabetes mellitus from a metabolic point of view.

Hepato-splanchnic and systemic hemodynamic effects of sustained euglycemic hyperinsulinemia, in rats

Hepato-splanchnic and systemic hemodynamic effects of sustained euglycemic hyperinsulinemia, in rats

Hepato-splanchnic and systemic hemodynamic effects of sustained euglycemic hyperinsulinemia, in rats

Hepato-splanchnic and systemic hemodynamic effects of sustained euglycemic hyperinsulinemia, in rats

Splanchnic and systemic hemodynamic effects of sustained euglycemic hyperinsulinemia in rats

Splanchnic and systemic hemodynamic effects of sustained euglycemic hyperinsulinemia in rats

Successful pancreas and kidney transplantation: a view of metabolic control

BackgroundPancreas and kidney transplantation (PKTx) has become the treatment of choice in uremic patients with insulin‐dependent diabetes mellitus (IDDM). In these patients, the pancreatic graft provides an endogenous source of insulin. However, the determination of its long‐term effect on metabolic control is crucial in order to establish the real efficacy of this treatment in diabetic patients. In this article, we describe the experience of the University of Barcelona in shortand long‐term metabolic control in PKTx recipients. Subjects and methods. We performed seriated determinations of glycosilated hemoglobin (HbA1c) and oral glucose tolerance tests (OGTT) in 55 patients who underwent PKTX at our center from 1983 to 1996 with both grafts functioning for more than 1 yr (mean follow‐up 4.2±2.3 yr). Basal glucose and insulin levels, areas under the curve (AUC) of glycemia and insulinemia after OGTT were analyzed throughout follow‐up, as well as the fasting insulin resistance index (FIRI).ResultsHbA1c levels throughout follow‐up were within the normal range. The OGTT was normal in 80% of the patients 5 yr after transplantation. Hyperinsulinemia was present throughout follow‐up. Over time, no differences were detected in the AUC of glycemia and insulinemia between controls and patients with PKTx. During the evolution, no differences were found in FIRI, in spite of increasing body weight.ConclusionWhen successful, PKTx provides long‐term normalization. of glycemic control, assessed by HbA1c and OGTT, despite the existence of sustained hyperinsulinemia. Our results strongly suggest that PKTX is the most effective treatment for uremic patients with IDDM from a metabolic point of view.

Sympathetic hyperactivity in Wistar rats with insulin-resistance

In an attempt to know the effect of sustained hyperinsulinemia on sympathetic function, plasma norepinephrine (NE) and glucose levels were measured in Wistar rats with insulin resistance. Both the basal plasma glucose and the plasma NE levels in insulin-resistant rats were markedly higher than that obtained in normal or streptozotocin (STZ)-induced diabetic rats. Treatment with guanethidine and prazosin reversed these sympathetic hyperactive responses in insulin-resistant rats. Moreover, increase of plasma insulin in rats receiving an intraperitoneal glucose challenge test confirmed the mediation of endogenous insulin in this sympathetic hyperactivity. These results suggest an increase of sympathetic activity in insulin-resistant state that may be related to the hypertension-prone associated with diabetes mellitus in clinics.

Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats.

Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.

Insulin secretion and hepatic insulin clearance as determinants of hyperinsulinaemia in normotolerant grossly obese adolescents.

Obesity is characterized by variable degrees of hyperinsulinaemia, which has been attributed to either beta-cell hypersecretion or reduced hepatic insulin extraction, or both. To investigate this controversial issue, a 4-h frequently sampled i.v. glucose tolerance test (glucose dose 12.8 g m(-2)) was performed in 13 normotolerant, grossly obese adolescents (10 F/3 M; 13+/-1 y; body mass index 32+/-0.9; pubertal stage 4-5; obesity duration 7.8+/-3 y) and in a comparable group of 8 healthy, normal-weight subjects. Glucose, insulin and C-peptide time-course were analysed by the minimal model technique, which estimates beta-cell secretion, insulin sensitivity (Si), glucose effectiveness (SG) and hepatic insulin extraction (HE). Despite similar fasting and after load glucose patterns (SG similar in the two groups), obese adolescents showed sustained peripheral hyperinsulinaemia (total insulin area under the concentration curve 67.2+/-10.8 vs 19.1+/-1.2 pmol l(-1) in 240 min; p <0.002) and a 71% reduction in Si (2.02+/-0.33 vs 6.95+/-1.03 x 10(4) min(-1) (microU ml(-1)); p < 0.001). Compared with control subjects, the total amounts of prehepatic insulin secretion and posthepatic insulin delivery were also increased significantly in obese adolescents by 30% and 46%, respectively; HE was reduced by 15% during the first 30 min of the test, but recovered within the normal range during the rest of the test. In conclusion, severely obese adolescents are insulin resistant and their hyperinsulinaemia is primarily caused by beta-cell hypersecretion, whereas the reduction in insulin hepatic extraction is a transient metabolic phenomenon.

Seven days of euglycemic hyperinsulinemia induces insulin resistance for glucose metabolism but not hypertension, elevated catecholamine levels, or increased sodium retention in conscious normal rats.

Epidemiological studies have suggested an association among chronic hyperinsulinemia, insulin resistance, and hypertension. However, the causality of this relationship remains uncertain. In this study, chronically catheterized conscious rats were made hyperinsulinemic for 7 days (approximately 90 mU/l, i.e., threefold over basal), while strict euglycemia was maintained (approximately 130 mg/dl, coefficient of variation < 10%) by using a modification of the insulin/glucose clamp technique. Control rats received vehicle infusion. Baseline mean arterial pressure and heart rate were 125 +/- 5 mmHg and 427 +/- 12 beats/min and remained unchanged during the 7-day infusion of insulin (127 +/- 7 mmHg; 401 +/- 12 beats/min) or vehicle (133 +/- 4 mmHg; 411 +/- 10 beats/min). Baseline plasma epinephrine (88 +/- 15 pg/ml), norepinephrine (205 +/- 31 pg/ml), and sodium balance (0.34 +/- 0.09 mmol) remained constant during the 7-day insulin or vehicle infusion. After 7 days of insulin or vehicle infusion, in vivo insulin action was determined in all rats using a 2-h hyperinsulinemic (1 mU/min) euglycemic clamp with [3-3H]glucose infusion to quantitate whole-body glucose uptake, glycolysis, glucose storage (total glucose uptake minus glycolysis), and hepatic glucose production. Compared with vehicle-treated rats, 7 days of sustained hyperinsulinemia resulted in a reduction (P < 0.01) in insulin-mediated glucose uptake, glucose storage, and glycolysis by 39, 62, and 26%, respectively. Hepatic glucose production was normally suppressed after 7 days of hyperinsulinemia. Neither insulin-stimulated glucose uptake nor glucose storage correlated with blood pressure or heart rate. In conclusion, 7 days of euglycemic hyperinsulinemia induces severe insulin resistance with respect to whole-body glucose metabolism but does not increase blood pressure, catecholamine levels, or sodium retention. This indicates that hyperinsulinemia-induced insulin resistance is not associated with the development of hypertension in rats who do not have a genetic predisposition for hypertension. Because hyperinsulinemia was initiated in normal rats under euglycemic conditions, additional (inherited or acquired) factors may be necessary to observe an effect of hyperinsulinemia and/or insulin resistance to increase blood pressure.

Inhibition of Thromboxane Synthesis Attenuates Insulin Hypertension in Rats

Chronic insulin infusion in rats increases mean arterial pressure (MAP) and reduces glomerular filtration rate (GFR), but the mechanisms for these actions are not known. This study tested whether thromboxane synthesis inhibition (TSI) would attenuate the renal and blood pressure responses to sustained hyperinsulinemia. Male Sprague-Dawley rats were instrumented with arterial and venous catheters, and MAP was measured 24 h/day. After 4 days of baseline measurements, endogenous synthesis of thromboxane was suppressed in 7 rats by infusing the thromboxane synthetase inhibitor, U63557A, intravenously (30 μg/kg/min) for the remainder of the experiment; 7 other rats received vehicle. Baseline MAP was not significantly different between vehicle and TSI rats (96 ± 1 v 99 ± 1 mm Hg). After 3 days of U63557A or vehicle, a 5-day control period was started, followed by a 7-day infusion of insulin (1.5 mU/kg/min, intravenously). Glucose (22 mg/kg/min, intravenously) was infused along with insulin to prevent hypoglycemia. In the control period, MAP was not different between vehicle and TSI rats (99 ± 2 v 100 ± 1 mm Hg), but MAP increased throughout the 7-day infusion period only in the vehicle rats with an average increase in blood pressure of 7 ± 2 mm Hg. In the control period, GFR was lower in vehicle rats compared with TSI rats (2.5 ± 0.1 v 3.1 ± 0.2 mL/min, P = .06), and the decrease to 81% ± 4% and 91% ± 6% of control, respectively, during insulin was significant only in the vehicle rats. All variables returned toward control during a 6-day recovery period. These results suggest that full expression of hypertension and renal vasoconstriction during hyperinsulinemia in rats is dependent on a normal ability to synthesize thromboxane.

Diabetic nephropathy. Its relationship to hypertension and means of pharmacological intervention.

Hypertension and diabetes mellitus are common chronic conditions which frequently coexist. Diabetic nephropathy is a major cause of elevated blood pressure in patients with insulin-dependent diabetes mellitus (IDDM). Diabetic nephropathy, arterial sclerosis, obesity and association of essential hypertension can be the causes of hypertension in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ambulatory blood pressure monitoring has revealed that the nocturnal fall of blood pressure is blunted in patients with diabetic nephropathy. A blunted diurnal blood pressure variation is seen in microalbuminuric diabetic patients and even in some normoalbuminuric patients. Accumulating data suggest that normalisation of blood pressure in hypertensive IDDM patients is most important to minimise the loss of kidney function. Angiotensin converting enzyme (ACE) inhibitors have been reported to be effective in postponing the development of nephropathy and in slowing its progression. Whether only ACE inhibitors have such beneficial renal effects on diabetic nephropathy is under discussion. While many studies have suggested that insulin resistance and hyperinsulinaemia are related to an elevated blood pressure in hypertensive patients, there does not seem to be enough evidence to prove that insulin per se can raise blood pressure in humans. Neither an insulin infusion within a physiological range nor sustained hyperinsulinaemia and insulin resistance (e.g. patients with insulinoma, cystic ovary syndrome) have been associated with an elevated blood pressure. Insulin resistance in some hypertensive patients may be a consequence of a decreased blood flow due to an increased peripheral resistance. Preliminary evidence suggests that low birth weight or impaired fetal growth is related to hypertension and NIDDM. Familial clustering of diabetic nephropathy suggests the contribution of genetic susceptibility and/or environmental inheritance. The frequent association of nephropathy with hypertension has led to research on the genes related to hypertension (ACE, angiotensinogen). Nevertheless, to date no reliable and clinically useful genetic marker has been found. Attempts to correct the metabolic abnormalities derived from diabetes are a new topic in the treatment of diabetic nephropathy. The effects of HMG CoA reductase inhibitors (antihypercholesterolaemic drugs), aldose reductase inhibitors (inhibitors of the polyol pathway) and glycation inhibitors (inhibitors of formation of advanced glycosylation end-products) on diabetic nephropathy have been evaluated in animal studies and in some clinical trials. Thus far, results with HMG CoA reductase and aldose reductase inhibitors have been somewhat conflicting. The potential therapeutic role of glycation inhibition in the treatment of diabetes deserves further study.

Chronic hyperinsulinernia inhibits platelet-activating factor (PAF) biosynthesis in the rat kidney

A number of risk factors for cardiovascular disease, including hypertension, are associated with the insulin resistance syndrome. The hallmark of this syndrome is an impairment in insulin action which provokes a compensatory increase in pancreatic β-cell insulin secretion leading to chronic hyperinsulinemia. Indirect studies show that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine, PAF), a potent antihypertensive lipid produced by the kidney, may be decreased by hyperinsulinemia. The present study was designed to evaluate the effect of chronic hyperinsulinemia on renal PAF metabolism, arterial blood pressure and whole body insulin sensitivity. Chronic catheterized, unstressed rats were infused with saline or insulin plus glucose to create a chronic condition of sustained euglycemic (∼ 130 mg/dl) hyperinsulinemia (∼ 90 mU/1, or 3-fold over basal levels). PAF is a metabolically unstable compound being susceptible to rapid degradation to the biologically inactive lyso-PAF, a metabolite which also serves as a precursor for PAF synthesis. PAF synthesis and counter-regulatory prostaglandins may be derived from the same arachidonate precursor. The enzymes which catalyze these reactions were measured in plasma and in the subcellular fractions of the kidneys. Compared to saline-treated rats, sustained physiologic hyperinsulinemia for 7 days: (i) decreased insulin-mediated glucose disposal by 30%; (ii) caused an increased plasma PAF:acetylhydrolase, which degrades PAF to lyso-PAF, without any change in cytosolic PA F: acetyl hydrolase activity; and (iii) completely inhibited microsomal lyso-PAF:acetyl CoA acetyltransferase activity which catalyzes the conversion of lyso-PAF back to bioactive PAF. The increased catabolism of PAF in plasma, combined with decreased renal PAF biosynthesis, would be expected to decrease circulating PAF levels, leading to a rise in blood pressure. However, blood pressure remained unchanged. The sustained hyperinsulinemia stimulated plasma membrane CoA-independent transacylase activity, which is responsible for the mobilization of arachidonates into lyso-PAF, to form 1-alkylarachidonoyl-glycerophosphocholine. The latter is the stored precursor for the synthesis of PAF and vasodilatory prostaglandins, which may have offset the effect of decreased PAF. We hypothesize that hyperinsulinemia may alter the blood pressure only if the balance between the synthesis /catabolism of PAF and vasodilatory Prostaglandins is disrupted.

Glucose and Insulin Response to Inhaled Beta-adrenergic and Parenteral Corticosteroid Therapy for Status Asthmaticus. † 1786

Current inpatient management of status asthmaticus employs continuous inhaled beta-adrenergics and high dose parenteral corticosteroids, both of which cause hyperglycemia. To determine the effects of asthma management on glucose homeostasis, we measured the glucose and insulin responses in patients that were admitted from the emergency room to the asthma care unit. Serial glucose and insulin samples were drawn at time 0, 1, 6, 12, 24, 36, and 48hrs. Methylprednisolone(8mg/kg/day with maximum of 240mg/day) was given intravenously every six hours beginning at time zero. Patients were weaned from therapy as tolerated. Ten subjects(ages 2-15yrs) completed the study. Seven patients were on continuos albuterol for at least 85% of the time. Three patients were weaned to q3-4hr nebs by the end of the 48 hour study period. One obese patient was found to have significant insulin resistance and is excluded from the below analysis. Paired t-test analysis was performed compared to initial concentrations; data from 24,36, and 48hrs was grouped together; and all insulin concentrations were log transformed for analysis. At time 0, the mean glucose was 135±25.4mg/dL. Peak glucose was reached at 6hrs with mean of 254±74.8mg/dL(p 0.10). The mean initial insulin was 43.6μ U/ml. The insulin peak was at 12hrs and broader than that of glucose with a value of 138μ U/ml(p<0.01). Insulin secretion leveled off above baseline values by 24hrs., with the mean insulin concentrations 24-48 hrs being 83μU/ml(p<0.001). The marked hyperglycemia observed during high dose methylprednisolone administration resolved by 24 hours. The mild hyperglycemia observed at 24-48 hours is accompanied by increased insulin secretion. In only 1 of our 10 patients was this clinically significant. The combination of continuous inhaled beta-agonists and high dose glucocorticoids, as employed in present management of status asthmaticus is a significant stress to normal glucose homeostasis. However, the majority of children appear to tolerate this challenge with only a brief period of significant hyperglycemia but sustained hyperinsulinemia.

Computer simulation of factors involved in the down-regulation of hormonal effects

Down-regulation of hormonal effects is in the presented simulation related to the number of functional receptors and quantity of available hormonal stimulation. The former is in the model substituted with the quantity of stimulation able to produce a full down-regulation ( Hs 100) of target cells. The halftime ( t 1/2) of the hormonal effect recovery means the interval before the second hormonal stimulation can elicit half of the initial hormonal effect. Recovered hormonal effects are calculated after periods of two, three, four and five t 1/2. The interval among hormonal stimulations varied from 1/2 to 5/2 of t 1/2. Shorter than t 1/2 intervals showed profound down-regulation even at weak hormonal stimulations (> 20% of Hs 100). Stable levels of hormonal effects after frequent hormonal stimulations are found only in cases of very weak stimulations (< 10% of Hs 100). Intervals equalling t 1/2 among weak stimulations (< 20% Hs 100) produced stable hormonal effects. Further prolongation among repeated stimulations improved stability of hormonal effects and even strong stimulations (> 60% of Hs 100) were followed with only temporary profound down-regulation. Hormone-binding receptors unable to activate target cells are in the model described as defective. Probability for the target cell to be stimulated is in the model defined as P. Relative quantity of hormonal stimulation per target cell needed to achieve certain P is calculated for cells bearing different proportions of defective receptors. Activation following weak hormone stimulations is highly probable (> 90%) for cells bearing less than 30% of defective receptors. With the proportion of defective receptors over 60%, the activation probability after weak hormone stimulations is reduced (< 66%). Down-regulation can be considered as a modulator of hormonal effects. In prediabetic patients, intense stimulation of pancreatic insulin secretion by frequent or increased ingestion of carbohydrates might lead to sustained hyperinsulinemia. A substantial portion of the target tissue would become down-regulated with increased number of defective insulin receptors. Poor glucose utilization in the down-regulated tissue with resultant hyperglycemia would further stimulate insulin secretion until failure. Reduced tissue transportability of large hormone molecules, such as hGH, or proinsulin, can make their effects more pronounced in the perivascular space. Circulating hormone binding proteins or the basal membrane thickening in small vessels can further decrease the hormonal effects on more remote cells. Physical activity in IDDM patients increases insulin effect. Possible explanation is that increased muscle perfursion is making more insulin available to the less down-regulated skeletal muscle cells.

Effect of systemic glucagon administration on ACTH secretion in anaesthetized rats.

The effect of glucagon on ACTH secretion was studied in anaesthetized rats injected with either saline (0.1 ml i.m.) or glucagon (0.02 mg/kg i.m.). For the first 90 min after glucagon injection, plasma ACTH fell by 50% from the basal value of 23 +/- 4 pmol/l (mean +/- S.E.M.) to 11 +/- 2 (P = 0.011), after which an abrupt return to baseline occurred (120 min value: 26 +/- 2 pmol/l). In saline injected rats, the baseline ACTH value was not significantly different from either the 90 min value or the 120 min value (27 +/- 3 vs 21 +/- 4 and 24 +/- 3 pmol/l respectively; P > 0.10). Plasma glucose after glucagon peaked at 11.6 +/- 1.1 mmol/l by 15 min but subsequently fell rapidly, attaining the baseline by 60 min. Insulin levels increased sharply after glucagon, from 381 +/- 78 pmol/l to 3172 +/- 668 pmol/l at 15 min, and plateaued at approximately 1000 pmol/l thereafter. No changes in glucose or insulin were seen in saline injected rats. The magnitude of suppression of ACTH after glucagon was not affected either by sustained hyperinsulinaemia (congruent to 1400 pmol/l), induced with continuous glucose infusion to maintain plasma glucose > 12 mmol/l, or by pretreatment with the long-acting somatostatin analogue octreotide (50 micrograms/kg s.c.). However, the return to baseline between 100 and 120 min was prevented both by hyperinsulinaemia induced with sustained hyperglycaemia, and by octreotide. It is postulated that glucagon may inhibit ACTH secretion either by a direct effect on the hypothalamus or indirectly through insulin, which is known to stimulate endogenous somatostatin release.

Albumin and Amino Acid Levels as Markers of Adequacy in Continuous Ambulatory Peritoneal Dialysis

Similar to previous findings in HD patients, a markedly decreased serum albumin level has been found to be a strong predictor of morbidity and mortality in CAPD patients. However, a slight decrease in serum albumin levels (to about 30 g/L if measured with nephelometry or the bromcresol purple method) does not always seem to reflect impaired nutritional status or to be associated with an increased morbidity or mortality in CAPD patients. A low serum albumin level among CAPD patients is related to dialysate albumin loss, comorbidity, age, and a low dietary protein intake. The possible relation between the dialysis dose (as assessed by small solute clearances) and serum albumin levels among CAPD patients is much less established and needs further study, although serum albumin tends to increase in prospective studies of increased peritoneal dialysis dose. Although the plasma levels of amino acids seem to be lower in CAPD patients compared to HD patients, this does not reflect the intracellular amino acid pattern in muscle which is less abnormal in CAPD patients, possibly because of the sustained hyperinsulinemia during CAPD, resulting in an increased intracellular to extracellular gradient. It is at present not established to what extent the amino acid abnormalities are related to the dialysis dose. Malnourished and hypoalbuminemic CAPD patients should be recommended to increase the protein intake, and if this is not effective, the dialysis dose should be increased. Furthermore, the use of amino acid-based peritoneal dialysis solutions is a promising new tool for the treatment of malnourished CAPD patients and may become an important component of CAPD therapy in the future. On the other hand, if the nutritional status deteriorates in spite of these efforts, the patient should be transferred to hemodialysis if possible.

The link between insulin resistance and hypertension. Effects of antihypertensive and antihyperlipidaemic drugs on insulin sensitivity.

Insulin resistance is generally interpreted as the physiological state under which insulin causes a reduced glucose-lowering effect. Hyperinsulinaemia is considered to be a result of insulin resistance. Many recent studies have suggested that hyperinsulinaemia and/or insulin resistance is associated with an elevated blood pressure, whereas several other studies have found a modest or no association. Many factors (e.g. adiposity, age, ethnic difference) have been suggested to confound the insulin-blood pressure relationship. Insulin is thought to raise blood pressure by a few possible mechanisms (e.g. stimulating sympathetic nervous system activity, enhancing renal tubular sodium reabsorption). On the other hand, insulin has also been reported to possess a vasodilatory property. Neither an insulin infusion within a physiological range nor continuously sustained hyperinsulinaemia in patients with insulinoma are associated with elevated blood pressure. Therefore, the relationship between insulin and blood pressure is still under discussion. Among the antihypertensive drugs, angiotensin converting enzyme (ACE) inhibitors seem to have marginal effects of improving insulin sensitivity, but whether this effect would lead to a better prognosis for diabetic patients remains to be proven. Lipid lowering drugs appear to show no benefit in lowering blood glucose.

Differential effects of oral glucose-mediated versus intravenous hyperinsulinemia on circulating androgen levels in women

To determine whether transient endogenous or continuous exogenous hyperinsulinemia produced different changes in circulating gonadal steroid levels because insulin is a putative regulator of gonadal steroid secretion in polycystic ovarian syndrome (PCOS). An oral glucose tolerance test (OGTT) and a 2-hour euglycemic clamp (+100 microU/mL [718 pmol/L] steady-state insulin levels) were performed in obese patients with PCOS (n = 7) in nonobese patients with PCOS (n = 5), and in age- and weight-matched ovulating normal women (obese normal n = 7, nonobese normal n = 6). Despite increased insulin levels, the levels of T and androstenedione (A) decreased in three of the four groups during the OGTT (nonobese normal women showed a slight increase in T during the OGTT). In contrast, the continuous 2-hour insulin infusion resulted in increased androgen levels. When all four groups were pooled, the difference in the changes in A levels between the two tests was significant, and the difference in T levels between the two tests approached significance. Transient physiological hyperinsulinemia produced by an oral glucose load was associated with a decrease rather than an increase in circulating androgen levels. The effects on circulating androgen levels of oral glucose-mediated increases in insulin levels were significantly different from those of a continuous intravenous insulin infusion. Sustained hyperinsulinemia produced by exogenous insulin infusion appeared to be required to increase androgen levels in women; transient physiological increases in insulin levels after an oral glucose load were insufficient to produce hyperandrogenism. Postmeal hyperinsulinemia does not contribute to hyperandrogenism in women.

Glucose modulation of the disposal of an acute potassium load in patients with end-stage renal disease

purpose: Extrarenal potassium disposal plays an important role in the tolerance of an acute potassium load and is particularly critical in patients with renal failure. Insulin is known to stimulate this disposal by enhancing potassium uptake into the cells. Since dietary potassium is generally ingested in combination with carbohydrates, the predictable stimulation of endogenous insulin release may blunt the expected increase in plasma potassium. The goal of the current study was to evaluate the effect of oral glucose on the disposition of an acute oral potassium load in hemodialysis patients and in normal controls.patients and methods: Eight hemodialysis patients and eight normal control subjects were studied after an overnight fast. Each subject received an oral load of potassium chloride elixir (0.25 mmol/kg). Plasma potassium was measured at baseline and at 30-minute intervals for 3 hours. On a separate study day, the subjects underwent the identical protocol, with the addition of 50 g of oral glucose to the potassium load to stimulate endogenous insulin release. The identical two experimental protocols were repeated in each subject during concomitant β blockade with propranolol.results: The maximal increase in plasma potassium after the potassium load was significantly greater in the hemodialysis patients than in the controls (0.93 ± 0.08 versus 0.52 ± 0.04 mmol/L, p < 0.001). Concomitant oral glucose markedly blunted the maximal rise in potassium levels in both experimental groups (0.40 ± 0.09 and 0.22 ± 0.07 mmol/L, respectively, p < 0.005 versus potassium alone). With concomitant β blockade, the maximal increase in plasma potassium after the potassium load was significantly greater in the hemodialysis patients than in the controls (1.11 ± 0.12 versus 0.72 ± 0.09 mmol/L, p = 0.02). Concomitant oral glucose again markedly blunted the maximal increase in potassium in both experimental groups (0.72 ± 0.09 and 0.39 ± 0.06 mmol/L, respectively, p < 0.01 versus potassium alone). The potassium load in the absence of glucose did not produce changes in plasma insulin concentration in either experimental group. The potassium load in combination with oral glucose load produced more sustained hyperinsulinemia in the dialysis patients than in the control subjects.conclusions: Exogenous glucose, by stimulating endogenous secretion of insulin, enhances extrarenal disposal of a potassium load. This protective effect of exogenous glucose against hyperkalemia is independent of adrenergic stimulation. The beneficial effect of exogenous glucose defends against the development of severe hyperkalemia after dietary potassium ingestion, and is critically important in hemodialysis patients, due to their negligible renal potassium excretion.