Physiological hyperinsulinemia caused by acute hyperglycemia minimizes renal sodium loss by direct action on kidneys.

This study used acute, renal artery insulin infusion in conscious rats to test the hypothesis that hyperinsulinemia attenuates glucose-induced natriuresis by a direct renal mechanism. We reported previously that hyperinsulinemia was required to prevent ad libitum eating or an acute glucose bolus from causing excessive renal sodium loss. Rats were instrumented with renal artery, aortic, and femoral vein catheters and Data Sciences International blood pressure telemeters and were housed in metabolic cages. Insulin was clamped chronically at normal levels in two groups [vehicle infused (irV) and insulin infused (irI)] by administering streptozotocin and then infusing insulin intravenously 24 h/day to maintain normal blood glucose. Bolus glucose administration was used as a meal substitute to produce hyperglycemia that was not different between groups, and urinary sodium excretion (UNaV) was measured over the next 4 h. In the irV and control (C) rats, vehicle was infused in the renal artery during that period, whereas insulin was infused in the renal artery of the irI rats. Plasma insulin increased significantly in C rats but not in either of the clamped groups. UNaV in the irV rats, which could not increase circulating insulin levels, was approximately threefold greater than in C rats, similar to our previous report. However, allowing the kidney of irI rats to experience hyperinsulinemia via the renal artery insulin infusion completely prevented this, with no blood pressure differences. These data support our hypothesis that meal-induced increases in plasma insulin are a major component of normal sodium homeostasis, and that this occurs by direct action of insulin on the kidney.

Elevated fasting insulin level significantly increases the risk of microalbuminuria.

BACKGROUND: Microalbuminuria is significantly associated with long-term prognosis in the general population as well as in diabetic patients. It is well known that insulin resistance (IR) can induce microalbuminuria, but an elevated fasting insulin level, which is an early clinical manifestation of IR, as a risk factor for microalbuminuria has not been clarified, so we investigated the association between fasting insulin level and the development of microalbuminuria in a general population. METHODS AND RESULTS: A total of 1,192 non-diabetic Korean men without microalbuminuria in 2005 were followed until 2010. They were categorized into 3 groups according to their fasting insulin levels and monitored for the development of microalbuminuria. The incidence of microalbuminuria was compared among groups, and Cox proportional hazards models were used to calculate the hazard ratios for microalbuminuria according to the fasting insulin levels. During 4,013.0 person-years of follow-up, 51 incident cases of microalbuminuria developed between 2006 and 2010. The incidence of microalbuminuria increased in proportion to the fasting insulin levels (tertile 1: 1.8%, tertile 2: 4.5%, tertile 3: 6.5%, P<0.001). Hazard ratios for microalbuminuria also increased in proportion to the fasting insulin levels [tertile 1: reference, tertile 2: 2.44 (1.01-5.89), tertile 3: 3.30 (1.40-7.78), respectively, P for trend 0.013]. CONCLUSIONS: Elevated fasting insulin level was associated with the future development of microalbuminuria.

Hyperinsulinemia and urinary calcium excretion in calcium stone formers with idiopathic hypercalciuria.

CONTEXT: Calcium stone formers with idiopathic hypercalciuria (IH) are known to exhibit an exaggerated postprandial rise in urine calcium excretion compared with non-stone-forming individuals, and insulin has been proposed to mediate this difference. OBJECTIVE: Our objective was to investigate the impact of hyperinsulinemia on urine calcium excretion in IH compared with non-stone-forming controls. PARTICIPANTS AND SETTING: Ten IH patients and 22 control non-stone-forming subjects (8 lean and 14 overweight and obese) participated at the University of Texas Southwestern Clinical and Translational Research Center. DESIGN: After stabilization on a fixed metabolic diet, subjects underwent a hyperinsulinemic-euglycemic clamp. Fasting 2-hour urine specimens were collected before and during the clamp. MAIN OUTCOME MEASURES: Changes in fractional calcium excretion (F(E)Ca) during the clamp were compared between the 3 groups of subjects (IH, overweight/obese controls, and lean controls). Insulin sensitivity was measured by glucose disposal rate. RESULTS: IH had significantly higher 24-hour urine calcium excretion than controls, and exhibited similar age, body mass index, and insulin sensitivity as overweight/obese controls. The hyperinsulinemic-euglycemic clamp resulted in a significant increase in serum insulin with no significant changes in serum calcium and glucose. This was accompanied by a small increase in F(E)Ca, with no significant differences between the 3 groups. There was no correlation between insulin sensitivity and 24-hour urine calcium or the change in F(E)Ca during the hyperinsulinemic clamp. CONCLUSIONS: The rise in urine calcium associated with euglycemic hyperinsulinemia was small and not statistically different between IH and non-stone-forming controls. Insulin is therefore unlikely to play a significant pathogenetic role in IH.

Hyperinsulinemia is closely related to low urinary clearance of D-chiro-inositol in men with a wide range of insulin sensitivity.

We have previously shown that women with polycystic ovary syndrome (PCOS) have increased urinary clearance of D-chiro-inositol (uCl(DCI)), which was positively associated with hyperinsulinemia. The objective of this study was thus to determine if such relationship also exists in men with a large range of insulin sensitivity and levels. A cross-sectional study was performed on 11 brothers of women with PCOS and 21 control men. In this study, brothers served as a model of insulin resistance. We assessed uCl(DCI), urinary clearance of myo-inositol, and insulin levels with a standard 75-g oral glucose tolerance test, a 2-hour euglycemic-hyperinsulinemic clamp, and a 24-hour urine collection. Our results showed in all men together that low uCl(DCI) was strongly associated (P < .001) with hyperinsulinemia, for which uCl(DCI) was a significant predictor independent of other classic factors. Brothers were heavier than controls (P = .02), with increased glucose-stimulated glucose (P < .001) and insulin levels (P < .001) and reduced insulin sensitivity (P = .001). In this group, plasma DCI was increased by 3-fold (P = .02), with a 3-fold decrease in the uCl(DCI) to urinary clearance of myo-inositol ratio, which was almost significant (P = .07). Low uCl(DCI) is strongly associated with hyperinsulinemia in all men, and brothers of PCOS women who are more insulin resistant display increased plasma DCI and borderline decreased uCl(DCI). Thus, compensatory hyperinsulinemia might suppress renal clearance of DCI to increase plasma DCI levels and partially compensate for insulin resistance by improving DCI availability in men. The apparent discrepancy with PCOS women might be explained by higher insulin levels in men as compared with women and requires confirmation.

Effect of venous drainage site on insulin action after simultaneous pancreas-kidney transplantation.

BACKGROUND: The aim of the present study was to determine the influence of the venous drainage site on insulin homeostasis in simultaneous pancreas-kidney (SPK) transplant recipients. METHODS: The study included 12 SPK patients with portal venous drainage (P) and 11 SPK patients with systemic venous drainage (S) of pancreas allograft. All of the participants presented similar characteristics. The euglycemic hyperinsulinemic clamp was performed using a 0.4-mU/kg/min insulin infusion. An infusion of [6,6-(2)H2] glucose was used to determine glucose turnover at the basal state and during the clamp to determine liver and peripheral tissue sensitivity to insulin. RESULTS: Minor changes in glycemia and insulinemia were shown: fasting plasma glucose was significantly higher in the SPK-P group and insulinemia was higher in the SPK-S group. Hepatic glucose production was similar in both groups. During the clamp, insulin levels were higher in SPK-S recipients, but hepatic glucose production was suppressed in both groups. Glucose use was lower in SPK-S recipients than in SPK-P recipients, 3.32 +/-1.41 mg/kg/min and 4.70 +/-1.64 mg/kg/min, respectively (P<0.02). Basal and under-clamp free fatty acid levels were similar. In addition, no significant difference in cholesterol and low-density lipoprotein levels was shown, whereas high-density lipoprotein levels were higher in the SPK-S group; triglycerides during fasting and under clamp were significantly higher in the SPK-P group. CONCLUSIONS: In both groups, neither hepatic nor peripheral insulin resistance was detected. In SPK-S recipients, the authors have showed only a lower insulin clearance and a slight decreased peripheral responsiveness to insulin without modifications of lipid status.

Urinary alpha-ketoglutarate is elevated in patients with hyperinsulinism-hyperammonemia syndrome.

BACKGROUND: Congenital hyperinsulinism (CHI) is the most frequent cause of recurrent episodes of hypoglycemia in infancy and results from different underlying genetic defects. The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from dominant germ line mutations within the glutamate dehydrogenase gene (GLUD1, OMIM *138130). Diagnosis of this entity is of clinical importance since invasive diagnostic procedures which are performed to identify focal pancreatic lesions are not necessary in HHS. Therefore, we investigated whether urinary concentration of alpha-ketoglutarate (alpha-KG) is elevated in patients with hyperinsulinism. METHODS: Excretion of alpha-KG was measured by gas-chromatography/mass spectrometry (GC/MS) in eight patients with an activating GLUD1 mutation and 90 controls. RESULTS: Urinary alpha-KG was significantly elevated in seven of eight patients when compared to controls. Hyperammonemia was found in six of the eight patients with HHS. No relation was found between the underlying GLUD1 mutation and the level of urinary alpha-KG as well as the presence or absence of hyperammonemia. CONCLUSION: Urinary alpha-KG is elevated in most patients with HHS and should be included in the work-up of patients with hyperinsulinism.

Microalbuminuria is associated with the insulin resistance syndrome independent of hypertension and type 2 diabetes in the Korean population.

To investigate whether microalbuminuria is associated with the insulin resistance syndrome independent of hypertension and type 2 diabetes, we studied the association between microalbuminuria and features of insulin resistance syndrome in Korean general population. We selected 1006 subjects by a random cluster sampling among residents aged >40 years living in the Chung-Up district, a rural area of South Korea. Subjects were stratified by oral glucose tolerance status [normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus], and by the presence or absence of hypertension. Urinary albumin excretion rate (UAER) was determined using timed overnight urine collection. Various cardiovascular risk factors including anthropometric indices, serum lipid, true insulin and proinsulin concentrations were also measured. The prevalence of microalbuminuria (UAER between 20 and 200 microg/min) increased as the glucose tolerance worsened (6.0% in NGT, 11.8% in IGT, and 21.8% in diabetes; chi(2) trend=25.9, P<0.001). Subjects with microalbuminuria had a higher body mass index (BMI), waist-to-hip circumference ratio (WHR), systolic and diastolic blood pressure (BP), fasting and 2 h plasma glucose, fasting plasma insulin and proinsulin levels, and lower HDL-cholesterol level than subjects without microalbuminuria. In multiple regression analysis, BMI, diastolic BP, 2 h plasma glucose, and fasting plasma insulin levels were found to be independent factors associated with UAER. Multiple logistic regression analysis showed that not only diabetes mellitus and hypertension, but also fasting hyperinsulinemia and waist-to-hip ratio were independent factors associated with the presence of microalbuminuria. When the normotensive, non-diabetic subjects were analyzed separately, fasting hyperinsulinemia and impaired glucose tolerance remained independent variables associated with the presence of microalbuminuria. These results show that microalbuminuria in the Korean general population is associated with hyperinsulinemia and central obesity, and suggest that microalbuminuria is a feature of the insulin resistance syndrome independent of hypertension or type 2 diabetes.

[Urate affection of kidneys and metabolic disturbances in hypertensive patients]. / Uratnoe porazhenie pochek i metabolicheskie sdvigi u patsientov s arterial'noi gipertoniei.

AIM: To detect urate renal affection and correlations between purine metabolism, hyperinsulinemia, obesity, dyslipidemia in patients with arterial hypertension (AH). MATERIALS AND METHODS: 78 patients with mild, moderate and severe hypertension have undergone 24-h monitoring of arterial pressure and microalbuminuria test. RESULTS: Hyperuricemia was diagnosed in 21 of 78, hyperuricosuria in 27 patients. 13 patients had combination of hyperinsulinemia with obesity, dyslipidemia, arterial hypertension. Renal symptoms occurred in almost half of the patients with hyperuricemia. Disturbed 24-h rhythm and variability of arterial pressure were encountered more frequently in patients with hyperuricemia and hyperinsulinemia than in patients with normal purin metabolism and no other metabolic shifts. CONCLUSION: Renal abnormalities were found more frequently in hypertensive patients with hyperuricemia and those free of urate disturbances and metabolic changes. A positive correlation exists between body mass index and insulinemia (r = 0.58, p < 0.01), body mass index and uricemia (r = 0.37, p < 0.01), insulinemia and uricemia (r = 0.32, p < 0.01).

Hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia.

UNLABELLED: Two cases of hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia in unrelated infants of 7 days and 4 months of age are reported. Blood ammonia levels were 100-300 micromol/l (normal values <40 micromol/l). The hyperammonaemia was asymptomatic and not associated with any of the abnormalities of amino acids or organic acids observed in urea cycle enzyme defects. Orotic aciduria was normal. The hyperammonaemia was not influenced by the levels of blood glucose nor by subtotal pancreatectomy. On admission blood glucose was ca. 1.2 mmol/l (21.6 mg/dl) corresponding to blood insulin levels of 35 and 22 mU/l respectively in both infants. Continuous intravenous glucose perfusion was necessary to prevent hypoglycaemia. Furthermore 2-oxoglutaric acid in urine was increased in the second infant to 3.15 mg/mg creatinine (normal 0.41+/-0.12). This may point to mutations in the glutamate dehydrogenase gene. CONCLUSION: 2-Oxoglutaric aciduria may be an important clue to the diagnose in this syndrome.

Effect of hyperinsulinaemia on renal function and nitrate/nitrite excretion in healthy subjects.

1. In addition to its metabolic actions, insulin acts as a vasodilator in certain vascular beds, such as skeletal muscle. It has been shown that this effect is mediated by endothelium-derived nitric oxide (NO). Unlike in the skeletal muscle, insulin-NO interactions in the kidney, another major site of insulin action, have been less studied. The aim of the present study was to explore the role of NO in renal effects of hyperinsulinaemia in healthy subjects. 2. Changes in renal function and urinary nitrate/nitrite (NO2-/NO3-; Griess method) levels as a marker of renal production of NO were assessed during euglycaemic hyperinsulinaemic clamp and compared with normoinsulinaemic isovolaemic conditions (administration of the same amount of insulin/glucose-free vehicle) in 10 healthy male volunteers. 3. Hyperinsulinaemia was associated with a decrease in renal excretion of stable metabolites of NO (mean (+/- SEM) 0.56 +/- 0.12 vs 0.38 +/- 0.05 mumol/min, respectively; P < 0.05). In contrast, administration of the same volume of insulin-free vehicle resulted in elevation of urinary NO2-/NO3- (P < 0.05). The changes in renal sodium handling followed a similar pattern as changes in the renal excretion of NO2-/NO3- with a significantly different response to hyperinsulinaemia when compared with normoinsulinaemia (F = 12.2; P < 0.001). The mean arterial pressure, blood levels of low-density lipoprotein-cholesterol and free fatty acids, possible factors influencing renal and systemic NO production, remained constant throughout both experiments. 4. These results suggest that hyperinsulinaemia is associated, in healthy males, with a decrease in renal generation of NO. In contrast, mild volume expansion with insulin-free vehicle resulted in increased excretion of NO metabolites. This insulin-induced attenuation of renal NO synthesis may contribute to the anti-natriuretic actions of insulin.

[Excretion of uric aid, sodium, and potassium in preeclampsia patients and its behavior in acute hyperglycemia-hyperinsulinemia]. / Excreción de ácido úrico, sodio y potasio en la paciente con preeclampsia y su comportamiento ante un estado agudo de hiperglucemia-hiperinsulinemia.

The aim of the present research was to compare the uric acid, sodium and potassium excretions among patients with mild preeclampsia and normotensive pregnancy and to determine their behavior towards an acute physiologic state of hyperglycemia-hyperinsulinemia. It was carried out a cuasi-experimental study with parallel group in 25 patients with mild preeclampsia and in 25 patients with normotensive pregnancy all of them in the third trimester of gestation. The intervention consisted in administering an oral load of 50 grams of glucose in order to achieve a physiologic state of hyperglycemia-hyperinsulinemia. The seric levels of glucose, insulin, creatine, uric acid, sodium and potassium were measured, as well as the last four in urine before the oral load (with at least 6 hours fasting) and 60 minutes after the load, besides that, the urinary excretions of solutes were calculated with standard formulas. The urinary excretions of uric acid, sodium and potassium in fasting, and so after the oral glucose load were lower in the group of preeclampsia patients than in the normotensive gestation group. Upon analyzing the influence of a physiologic state of hyperglycemia-hyperinsulinemia, after the oral glucose load on determined solutes and their urinary excretion, we found that there was a significant decrease in the seric potassium level, without modifying its urinary excretion, as much as in the preeclampsia group as in the normotensive group. The seric uric acid and sodium levels diminished in the preeclampsia group and in normotensive group respectively, without modifying their urinary excretion. In conclusion, in the current study the urinary excretion of sodium, potassium and uric acid were lower in the preeclampsia patients than the women with normotensive pregnancy and a physiologic state of hyperglycemia-hyperinsulinemia didn't modify these excretions.

Prolonged elimination of tolbutamide in a premature newborn with hyperinsulinaemic hypoglycaemia.

So far, gestational diabetes treated with tolbutamide has never been associated with severe hypoglycaemia in the newborn when the mother's diabetes was well controlled. We report a case of a premature neonate, gestational age 34 weeks, with severe and long-standing hypoglycaemia from birth. The mother had well-controlled gestational diabetes, treated with tolbutamide from the 24th week of gestation until delivery. The neonate had inappropriately high levels of serum proinsulin, insulin and C-peptide relative to blood glucose concentrations. From day 19 after birth, the levels were normalized. Serum tolbutamide was 140.6 micromol/l (38 microg/ml) at 3 h after birth. Zero-order kinetics were seen during the first 90 postnatal hours. The half-life of serum tolbutamide decreased from 46 to 6 h. It is suggested that tolbutamide, when given to the mother until delivery, may cause severe and prolonged hyperinsulinaemic hypoglycaemia in premature neonates. The initially prolonged tolbutamide half-lives and zero-order kinetics suggest immaturity of hepatic elimination during the first 2 days of postnatal life.

Hyperinsulinemia as a determinant of microalbuminuria in essential hypertension.

OBJECTIVE: To analyze the relationship between insulinemia and urinary albumin excretion in a group of nonobese, young adult hypertensive patients, who had never been treated with antihypertensive drugs. PATIENTS AND METHODS: Forty-nine patients who fulfilled the inclusion criteria were included. Twenty-four-hour ambulatory blood pressure monitorings, urinary albumin excretion (UAE) measurements, and an oral glucose-tolerance test measuring glucose and insulin, were performed, and left ventricular mass was measured by echocardiography. Hypertensive patients were classified as normoalbuminuric when their UAE was < 30 mg/24 h (40 patients; mean UAE 13.4 +/- 7.0 mg/24 h), and as microalbuminuric when their UAE was 30-300 mg/24 h (nine patients; mean UAE 90.5 +/- 86.6 mg/24 h). RESULTS: In comparison with that of the normoalbuminuric group, the fasting plasma glucose concentration for the microalbuminuric group was only slightly higher (100 +/- 9 versus 95 +/- 8 mg/dl, NS). In contrast, the fasting insulin concentration in the microalbuminuric group was significantly higher than that observed in the normoalbuminuric group (25.2 +/- 6.7 versus 16.6 +/- 5.2 microU/ml, P<0.0001). During the oral glucose-tolerance test, the area under the curve (AUC) for glucose (317 +/- 41 versus 253 +/- 53 mg/dl x 2/h, P<0.001) and the AUC for insulin (253 +/- 171 versus 124 +/- 43 microU/ml x 2/h, P<0.001) were significantly higher in the microalbuminuric group than were those AUC observed in the normoalbuminuric group. After adjustments for age, sex, body mass index and average 24 h ambulatory mean blood pressure were made, the fasting insulin level was associated independently with an increase in UAE in a multiple regression model with base 10 logarithm of the UAE as the dependent variable. Variations in fasting insulin level alone accounted for 33% of the UAE variance. In contrast, the 24 h ambulatory mean blood pressure, rather than the insulin level, was the strongest predictor of the left ventricular mass index. CONCLUSIONS: Mild hypertensive patients with microalbuminuria were hyperinsulinemic in the absence of obesity, and their insulin level was the main determinant of microalbuminuria in these patients. Microalbuminuria in essential hypertension seems to identify patients with a cluster of cardiovascular risk factors and a bad risk profile. Thus, assessment of microalbuminuria may be useful in the stratification of risk in essential hypertension.

Effects of L-arginine infusion on renal hemodynamics and sodium excretion during hypo-, normo-, and hyperinsulinemia, as studied in dogs.

The response of renal hemodynamics and sodium excretion (NaU) to an infusion of L-arginine, in the presence (experiment I) or absence (experiment II) of endogenous insulin secretion and during a sustained hyperinsulinemic euglycemic state (experiment III), was studied in 10 age-matched beagle dogs. The experiments were preceded by a standard oral glucose tolerance test (OGTT), performed 1 week before experiment I. One week resting periods were allowed between experiments I, II, and III. No differences in renal hemodynamics and NaU were observed between basal (experiment I) and insulin secretion suppressed states (experiment II). L-Arginine infusion increased renal plasma flow (RPF), glomerular filtration rate (GFR), and NaU to a similar extent in both experiments. The hyperinsulinemic-euglycemic state (experiment III) induced a decrease in renal hemodynamics and NaU. In this situation, the infusion of L-arginine increased NaU, but was unable to increase RPF and GFR. Our data suggest that a sustained hyperinsulinemic state can interact with the physiological vasoactive mechanisms involved in the regulation of renal vasculature. These results may be pertinent to human disease, especially in pathological conditions in which insulin resistance is present.

Insulin increases renal magnesium excretion: a possible cause of magnesium depletion in hyperinsulinaemic states.

The effects of insulin upon renal magnesium excretion were examined. Urinary magnesium excretion rates were measured in seven healthy volunteers (three men, four women) before and during a euglycaemic, hyperinsulinaemic clamp. Insulin was infused at 120 pmol m-2 min-1 and at 240 pmol m-2 min-1. Compared to baseline, the renal magnesium excretion increased 30% during the infusion of insulin at a rate of 120 pmol m-2 min-1. During infusion of insulin, 240 pmol m-2 min-1, renal magnesium excretion increased 50% compared to baseline. There were no changes in either glomerular filtration rates, plasma magnesium, urinary volume or general changes in the renal handling of divalent ions as judged by an unchanged urinary excretion rate of calcium (0% during infusion of insulin, 120 pmol m-2 min-1, and 8% increase during infusion of 240 pmol m-2 min-1 (NS). During the 120 pmol m-2 min-1 insulin infusion rate, plasma insulin rose from 46.1 pmol I-1 to 158.8 pmol I-1 and during the 240 pmol m-2 min-1 insulin infusion rate, mean plasma insulin concentration was 361.4 pmol I-1. Thus, physiological concentrations of insulin induce a specific increase in the renal excretion of magnesium. This might partly explain the magnesium depletion observed in various hyperinsulinaemic states, diabetes mellitus, atherosclerosis, hypertension, and obesity.

Effects of hypercortisolemia or hyperinsulinemia on neurochemical indices of catecholamine release and synthesis in conscious rats.

Glucocorticoids and insulin (INS) complexly affect sympathoneural and adrenomedullary outflows. This study assessed effects of chronic hypercortisolemia and effects of INS independent of INS-induced hypoglycemia on neurochemical indices of different aspects of catecholaminergic function in conscious rats. Since L-DOPA is the precursor of the endogenous catecholamines and the immediate product of the rate-limiting enzymatic step in catecholamine biosynthesis, alterations in rates of appearance (spillover) of L-DOPA in arterial plasma may reflect alterations in catecholamine synthesis. The study therefore included examination of whether cortisol (CORT) or INS affects L-DOPA spillover or renal excretion of dopamine (DA) derived from plasma L-DOPA. Arterial plasma levels and urinary excretion rates of endogenous catechols and radiolabelled L-DOPA and DA were measured during systemic intravenous infusions of [3H]L-DOPA. CORT was administered via a subcutaneous minipump reservoir for one week prior to [3H]L-DOPA infusion, and INS was infused with glucose to examine effects of hyperinsulinemia independently of hypoglycemia. CORT decreased plasma levels and urinary excretion of norepinephrine (NE). INS did not. Neither CORT nor INS affected levels of other catechols, L-DOPA spillover, or the rate of urinary excretion of [3H]DA for a given plasma level of [3H]L-DOPA. The results suggest that CORT inhibits sympathetically-mediated NE release without altering overall rates of catecholamine turnover or synthesis in sympathetic nerves in vivo and that INS effects on catecholaminergic function depend entirely on INS-induced hypoglycemia.

Chiroinositol deficiency and insulin resistance. I. Urinary excretion rate of chiroinositol is directly associated with insulin resistance in spontaneously diabetic rhesus monkeys.

Previously, we demonstrated that nondiabetic insulin-resistant monkeys had reduced covalent insulin activation of muscle glycogen synthase (GS) compared to normal monkeys and that covalent insulin activation of adipose tissue GS was absent in these monkeys. Covalent insulin activation of muscle and adipose tissue GS in monkeys with impaired glucose tolerance and noninsulin-dependent diabetes (NIDDM) was also absent. As in humans, monkeys with NIDDM have a lower urinary excretion rate of chiroinositol (CI), a component of a putative mediator of insulin action, compared to normal monkeys. To determine whether the urinary excretion rate of CI was related to insulin resistance, which develops naturally in many obese rhesus monkeys, we examined the relationships between 24-h urinary CI excretion rate and 1) whole body insulin-mediated glucose disposal rates (M) and insulin-mediated changes in 2) the skeletal muscle GS activity ratio (sm delta GSAR), 3) the skeletal muscle glycogen phosphorylase activity ratio, and 4) the adipose tissue GS activity ratio (at delta GSAR) in 27 monkeys ranging from normal (n = 12) to insulin resistant (n = 8) to overtly diabetic (n = 7). The urinary CI excretion rate was significantly correlated with M (r = 0.47; P < 0.02), sm delta GSAR (r = 0.38; P < 0.05), skeletal muscle glycogen phosphorylase activity ratio (r = -0.49; P < 0.01), and at delta GSAR (r = 0.46; P < 0.02). The urinary CI excretion rate was also correlated with glucose tolerance (r = 0.39; P < 0.05). There was a wide range of urinary CI excretion rates (0.42-5.17 mumol/day) in monkeys with normal fasting plasma glucose concentrations. However, of the 7 diabetic monkeys, 6 had a urinary CI excretion rate below 2.0 mumol/day, and in the subgroup of 16 monkeys with a urinary CI excretion rate less than 2.0 mumol/day, the associations of urinary CI with M rate (r = 0.65; P < 0.005), glucose tolerance (r = 0.63; P < 0.01), and sm delta GSAR (r = 0.73; P < 0.001) increased in strength and significance. We propose that the urinary CI excretion rate may be 1) a biochemical indicator of both in vivo and in vitro insulin resistance and 2) a noninvasive diagnostic tool with potential for the identification of those individuals at risk for NIDDM and other related diseases with insulin resistance.

Blood pressure response to hyperinsulinemia in salt-sensitive and salt-resistant rats.

We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 0.3% NaCl diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137 +/- 3 mm Hg versus 119 +/- 3 mm Hg, p < 0.05; plasma norepinephrine, 0.40 +/- 0.02 ng/ml versus 0.27 +/- 0.01 ng/ml, p < 0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an alpha-blocker (bunazosin, 10 mg/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCl), insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model.