The renal response to exogenous insulin in non-insulin-dependent diabetes mellitus in relation to blood pressure and cardiovascular hormonal status

BACKGROUND: Non-insulin-dependent diabetes mellitus (NIDDM) is characterizedby insulin resistance, hyperinsulinaemia and a high frequencyof hypertension. It has recently been shown that insulin exertsa sodium-retaining effect, which is preserved in NIDDM. We soughtto determine whether insulin affected renal sodium handlingdifferently in hypertensive and normotensive NIDDM patients. METHODS: After a baseline period of 2 h, eight normotensive (N-) NIDDMpatients and eight NIDDM patients with hypertension (H-) underwenta euglycaemic clamp with infusion of two sequential doses ofinsulin (50 and 500 mU/kg/h) or vehicle (time control) during2-h periods each. Fractional clearances of sodium and lithiumwere determined according to standard methods. Fractional lithiumclearance was used to assess segmental tubular sodium handling. RESULTS: Insulin induced similar decrements in fractional sodium excretion(N-NIDDM: 43±5.9 and 57±9.1%, H-NIDDM: 48±16.4and 62±12.5%, low and high insulin dose respectively).Distal tubular sodium absorption increased simultaneously. Afall in fractional proximal sodium reabsorption was observedin N-NIDDM (4.4±2.7 and 29.8±5.1%, low and highinsulin dose respectively), which was attenuated in H-NIDDM(–5.0±7.3 and –2.1±13.9% respectively).The latter appeared to be related to a defective atrial natriureticfactor (ANF) and renal cyclic GMP response. A modest decreasein blood pressure occurred during insulin infusion that wasnot related to changes in ANF or Fe_Li. CONCLUSION: The findings suggest that insulin-induced sodium retention maycontribute to hypertension in NIDDM if the homeostatic responseto offset this effect fails.     

Effect of priming of amino acids on insulin and growth hormone response in the premature infant

Glucose, alpha-amino nitrogen, serum insulin, and HGH were studied in preterm infants during the first 24 hours of life. Glucose infusion (1.25 gm.) resulted in a slight elevation of serum insulin. When this amount of glucose was infused during the last 30 minutes of a two-and-a-half-hour infusion of a mixture of essential amino acids, there was a rapid and striking increase in serum insulin. However, this increase was not associated with a faster glucose disposal rate. The administration of this mixture of amino acids doubled the basal level of alpha-amino nitrogen, and during the first two hours, before glucose infusion, it caused a significant rise of serum insulin and HGH. In both cases glucose caused an increase of HGH secretion that was not significantly different in the two groups of infants.     

Effect of insulin on the exaggerated glucagon response to arginine stimulation in diabetes mellitus.

The effect of insulin on the glucagon response to intravenous arginine was studied in eight juvenile-type and six adult-onset diabetics. In the juvenile-type diabetics, concomitant administration of insulin significantly blunted the glucagon response from a mean maximal rise of 310 +/- 54 pg./ml. to only 184 +/- 39 pg./ml. (p less than 0.01), about the same as in nondiabetics. In the adult-onset patients, however, insulin had no effect, the mean maximal rise being 250 +/- 50 pg./ml. without insulin and 307 +/- 71 pg./ml. with insulin (N.S.). This study demonstrates that in juvenile-type diabetics concomitant administration of supraphysiologic quantities of insulin can reduce the exaggerated glucagon response to intravenous arginine to normal, whereas in the adult-type group, it has no apparent effect.     

Glomerular morphology by light microscopy in non-insulin-dependent diabetes mellitus. Lack of glomerular hypertrophy

We quantitated glomerular structure by light microscopy in 19 subjects with non-insulin-dependent diabetes mellitus (NIDDM) and studied the possible connection between morphology and urinary albumin concentration. Autopsy material was collected retrospectively from diabetic subjects in whom urinary albumin concentration had been measured within 1.5 yr. Nineteen consecutive sex- and age-matched nondiabetic subjects were controls. A quantitative study of a random sample of glomeruli was performed blindly on periodic acid-Schiff (PAS)-stained sections. The main parameters obtained were 1) mean volume of open glomeruli, 2) frequency of glomerular occlusion, and 3) volume fraction of red-stained material (PAS-positive substance) in open glomeruli [Vv(R/G)]. There was no increase in glomerular volume in these NIDDM subjects, contrary to the glomerular hypertrophy found early as well as late in insulin-dependent diabetes mellitus. An increase in Vv(R/G) was found in diabetic subjects, demonstrating the presence of glomerulopathy as it is diagnosed by light microscopy. The frequency of glomerular occlusion was not significantly different between the groups. A high urinary albumin concentration did not necessarily reflect more advanced glomerulopathy.     

Post-transplant renal artery stenosis: the hemodynamic response to revascularization.

BACKGROUND: Percutaneous transluminal angioplasty and stenting are relatively noninvasive approaches to treat post-transplant renal artery stenosis. However, the real impact of this procedure on renal function recovery has never been quantitated precisely to date. METHODS: In eight consecutive renal transplant patients with renal graft artery stenosis, blood pressure, body weight, and anatomical, functional, and Doppler ultrasound parameters were evaluated before and one month after renal artery transluminal angioplasty and stenting. On both occasions, glomerular filtration rate and renal plasma flow were evaluated by inulin and paraaminohippuric acid renal clearances, and glomerular size-selective function was evaluated by the fractional clearances of neutral dextran macromolecules. RESULTS: The correction of renal artery stenosis, by normalizing renal vascular resistances, fully restored kidney perfusion and decreased arterial blood pressure, relieved water and sodium retention, restored an almost laminar arterial blood flow, and normalized vascular shear stress without appreciable effects on glomerular barrier size-selective function and proteinuria. Preangioplasty and postangioplasty renal resistive indices and peak systolic blood velocity estimated by Doppler ultrasounds were significantly correlated with the effective renal plasma flow and the blood velocity calculated at the site of stenosis. All patients were discharged without sequelae one or two days after angioplasty. CONCLUSIONS: Percutaneous transluminal angioplasty and stenting are safe and effective procedures to normalize the functional changes sustained by hemodynamically significant artery stenosis after renal transplantation. Doppler ultrasound scanning is a reliable and reproducible technique to monitor the renal functional response to vascular reperfusion.     

Loss of insulin response to ingested amino acids after jejunoileal bypass surgery for morbid obesity

Amino acid tolerance tests were performed before and after jejunoileal bypass surgery for morbid obesity to determine whether an enteric factor(s) originating in the bypassed jejunum and/or ileum potentiates the insulin response to oral nitrogen loading. Preoperatively a 30-gm. mixture of amino acids given orally evoked a larger peak insulin than an intravenous load yielding comparable plasma amino acid elevations (82 +/- 17 muU./ml versus 38 +/- 8 muU./ml., p less than 0.05). Four months after operation, basal insulin concentrations were 46 per cent (p less than 0.001) of preoperative values. After surgery the response to intravenous amino acids was preserved when expressed as percentage increase above basal. In contrast, the peak increment and the percentage increase in insulin secretion after 30-gm. oral amino acid loading was significantly blunted (p less than 0.005). A smaller amino acid load (16.5 gm.) was given preoperatively to duplicate the plasma amino acid elevations seen postoperatively with the 30-gm. mixture given by mouth. The insulin response postoperatively was still significantly lower (167 +/- 33 per cent versus 98 +/- 16 per cent, p less than 0.05). After various explanations for the diminished postoperative insulin release following oral amino acid ingestion are considered, the results are best explained by the loss of an enteric insulinotrophic factor(s) normally released by the bypassed portions of jejunum or ileum in response to ingested protein.     

Renal handling of insulin and C-peptide in patients with non-insulin-dependent diabetes mellitus

The kidney is responsible for a considerable part of the clearanceof insulin and C-peptide. Two routes are thought to be involvedin the renal extraction of insulin and C-peptide from the circulation:(1) glomerular filtration, and (2) uptake by tubular cells fromperitubular capillaries. The aim of the present study was toinvestigate these processes in non-insulin-dependent diabetesmellitus (NIDDM). For this purpose we measured the renal extractionof inulin, insulin, and C-peptide in 12 NIDDM patients and 16control subjects during elective heart catheterization. In addition,a 24-h urine sample was obtained from all subjects to assessthe fractional clearance of the peptides. The total renal extraction of both insulin and C-peptide exceededthe amount that was extracted by filtration, confirming thesupposition that both peptides are cleared by an additionalmechanism, most probably peritubular uptake. The peritubularuptake of insulin in the NIDDM group was not significantly differentfrom that in the control subjects, whereas the insulin extractionover the legs was significantly lower in NIDDM than in the controls.The peritubular uptake of C-peptide was significantly lowerin NIDDM, while the fractional clearance of C-peptide was significantlyhigher. The latter indicates that the reabsorption of C-peptidefrom the luminal side of the tubular cell is impaired in diabetesmellitus. It is therefore concluded that urinary C-peptide excretionis not a reliable index for insulin production in NIDDM. Furthermore,the discrepancy between the effect of NIDDM on the peritubularuptake of insulin and C-peptide suggests that peritubular uptakeof low-molecular-weight proteins is a selective process.     

Effect of experimental diabetes on insulin binding by renal basolateral membranes

Removal of insulin from the peritubular vessels involves binding of insulin to specific receptors in the basolateral membranes (BLM); this is followed by phosphorylation of the receptor which may mediate the actions of the hormone. In most tissues receptor number is regulated by plasma insulin levels and is increased in insulinopenic diabetics. To determine whether cortical BLM insulin receptors are similarly regulated, we studied insulin binding to receptors in BLM from normal control rats and rats with streptozotocin diabetes of varying severity. Specific binding of insulin did not differ between control and modestly insulinopenic diabetics but was increased significantly in the severely insulinopenic diabetics. Insulin treatment returned binding to normal. Scatchard analysis suggested an increase in the binding capacity of the severe diabetic BLM rather than an increase in affinity for insulin. This latter was confirmed by competitive experiments in which similar displacement curves were obtained with control and diabetic membranes. Insulin removed by glomerular filtration binds to specific receptors in the luminal membranes but unlike BLM receptors, phosphorylation of these luminal receptors has not been observed. To determine whether luminal and BLM receptors differ structurally, binding sites in both membranes were affinity labelled with 125I-insulin and the cross linking agent, disuccinimidyl suberate, and subjected to SDS-polyacrylamide gel electrophoresis in the presence of a reducing agent. Autoradiograms revealed that the major specifically labelled subunit in both membranes is a 135,000 Mr species which is more abundant in the BLM. We conclude that insulin receptors in cortical BLM respond to severe insulinopenic diabetes as do receptors in most other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal

The effects of rigorous insulin treatment on insulin action (insulin clamp) and secretion (plasma insulin response to glucose) were studied in 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Improvements were documented in fasting (P less than 0.0001) and postprandial (P less than 0.0001) plasma glucose concentrations, insulin secretion after oral glucose (P less than 0.001), and insulin action (P less than 0.005) after 30 days of therapy. Mean integrated plasma insulin response to glucose increased 2.5-fold after insulin therapy, but this improvement varied considerably from patient to patient. Insulin action also increased with insulin treatment and the resulting values were no longer significantly different from a weight- and age-matched group of subjects with normal glucose tolerance. However, there was considerable patient-to-patient variation in the degree to which insulin action was enhanced. The insulin-induced improvements in glucose tolerance persisted for at least 2 wk after insulin withdrawal, and were associated with continued increased insulin secretion and insulin action. In conclusion, control of hyperglycemia for 1 mo led to improvements in both insulin secretion and action in a series of obese patients with NIDDM that persisted for at least 2 wk after cessation of therapy.     

Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a deficiency in early prandial insulin secretion. To determine the contribution of this early deficiency to prandial hyperglycemia, exogenous intravenous insulin (1.8 U over 30 min) was delivered to eight NIDDM subjects in a profile designed to simulate the normal initial rise in insulin levels. The same dose of insulin was also administered 1) in the same profile but delayed by 30 min and 2) as a constant infusion over 180 min. Augmentation of the early insulin response caused a 33 +/- 4% reduction in the glycemic response to a mixed meal (P less than .005); the peak blood glucose increment above baseline was reduced by 1.4 mM (P less than .005) to an increment identical to nondiabetic subjects (3.3 +/- 0.3 vs. 3.2 +/- 0.2 mM), and blood glucose levels were still 0.9 mM lower after 180 min (P less than .05). In contrast, the delayed profile or constant infusion did not significantly alter the glycemic response to the meal. Early insulin augmentation resulted in elevated peripheral insulin levels initially (peak level 81 +/- 11 mU/L), but subsequent insulin and C-peptide levels were lower than in the control study (at 180 min after the meal, 22 +/- 5 vs. 33 +/- 8 mU/L, P less than .05, and 4.0 +/- 0.5 vs. 5.3 +/- 0.6 micrograms/L, P less than .02, respectively). Early insulin delivery caused free-fatty acid (FFA) levels to fall at a faster rate after the meal and also attenuated the initial rise in glucagon levels typical of NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired insulin biosynthetic capacity in a rat model for non-insulin-dependent diabetes. Studies with dexamethasone

These studies of a rat model for non-insulin-dependent diabetes mellitus (NIDDM) were performed to determine whether hyperglycemia occurs when capacity to synthesize insulin is exceeded. The neonatal streptozocin (STZ)-treated rat has acute hyperglycemia with marked destruction of pancreatic beta-cells, followed by gradual regeneration to 50-70% normal beta-cell number. At age 4 wk, fed serum glucose concentration is only mildly elevated relative to controls. With age, the rats become progressively hyperglycemic, and by 12 wk they have marked impairment of glucose-stimulated insulin release. In these studies, dexamethasone (0.125 mg/kg/day for 4 days) was administered to control and to STZ-treated animals to produce insulin resistance. The relationship between insulin biosynthesis and serum glucose concentrations was assessed. In control rats, response to dexamethasone was similar at both 4 and 12 wk. Serum glucose levels and pancreatic insulin concentration remained unchanged. Both insulin biosynthetic rates (as measured by 3H-leucine incorporation into proinsulin) and proinsulin mRNA levels increased twofold. STZ-treated rats at age 4 wk demonstrated mild hyperglycemia. Dexamethasone injection resulted in an increase in insulin biosynthesis and proinsulin mRNA in these animals, while serum glucose did not increase. STZ-treated rats at 12 wk showed more profound hyperglycemia (serum glucose 315 +/- 38 mg/dl versus control, 187 +/- 12 mg/dl). A marked rise in serum glucose (to 519 +/- 42 mg/dl) was observed after 4 days of dexamethasone injection. Pancreatic insulin content became severely depleted relative to saline-injected, STZ-treated animals, and there was no response of levels of proinsulin mRNA.     

Impaired renal hemodynamic but conserved natriuretic response to dopamine in patients with renal disease

Renal hemodynamics and sodium excretion were determined before and during infusion of dopamine in doses ranging from 0.25 to 8 micrograms/kg/min in healthy volunteers (n = 15) and in patients with renal disease and moderately impaired renal function (n = 21, baseline glomerular filtration rate 34-85 ml/min). While in normal volunteers dopamine resulted in marked renal vasodilation (maximal fall in filtration fraction 24%), in patients with moderately impaired renal function, the renal vasodilatory response to dopamine was impaired (maximal fall in FF 13%) and was found to depend on baseline glomerular filtration rate. Infusion of dopamine in doses of 2 micrograms/kg/min and higher resulted in an increase in urinary sodium excretion, which was comparable for healthy volunteers and patients with renal disease. We conclude that dopamine results in a predominantly efferent glomerular vasodilation and, therefore, may be salutary in lowering intraglomerular hypertension. However, in patients with renal disease the renal hemodynamic response to dopamine infusion is impaired compared to healthy volunteers, while the natriuretic response is maintained.     

Effect of diabetes and aminoguanidine therapy on renal advanced glycation end-product binding

BACKGROUND: Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic nephropathy, and aminoguanidine (AG) has been shown to decrease the accumulation of AGEs in the diabetic kidney. METHODS: This study investigates changes in AGE binding associated with diabetes in the rat kidney using in vitro and in vivo autoradiographic techniques. Male Sprague-Dawley rats were randomized into control and diabetic groups with and without AG treatment and were sacrificed after three weeks. Frozen kidney sections (20 microm) were incubated with [125I]-AGE-RNase or [125I]-AGE-BSA. To localize the AGE binding site, in vivo autoradiography was performed by injection of 15 microCi of [125I]-AGE-BSA into the abdominal aorta of the rat. RESULTS: Low-affinity binding sites specific for AGEs in the renal cortex (IC50 = 0.28 microm) were detected by in vitro autoradiography. There was a significant increase in [125I]-AGE binding in the diabetic kidney, which was prevented by AG treatment. Emulsion autoradiography revealed that binding was localized primarily to proximal tubules in the renal cortex. Renal AGE levels, as assessed by fluorescence or by radioimmunoassay, were increased after three weeks of diabetes. This increase was attenuated by AG therapy. CONCLUSIONS: AGE binding sites are present within the proximal tubules of the kidney and appear to be modulated by endogenous AGE levels. It remains to be determined if these binding sites represent receptors involved in clearance of AGEs or are linked to pathogenic pathways that lead to the development of diabetic nephropathy.     

Gastric secretory response to intravenous amino acids in eviscerated dogs

Eight dogs, four with intact vagi and four with vagotomy, were studied to see if the gastric secretory effect of intravenously administered L-amino acids is mediated by a gastrointestinal (GI) hormone or hormones. Intravenous infusion of amino acids produced a significant secretory response in denervated and in innervated stomachs. When the known sites of formation of GI hormones were removed by resection of antrum, duodenum, pancreas, jejunum, ileum, and colon, the gastric stimulatory effect of amino acids was not changed significantly in denervated stomachs but was greatly increased in innervated stomachs. We conclude that amino acids have a direct effect on parietal cell secretion that is not dependent on the intermediary release of a stimulatory hormone, and that evisceration enhances this effect in dogs with intact vagi.     

Role of nitric oxide in the renal hemodynamic response to unilateral nephrectomy

Reduction of renal mass by unilateral nephrectomy results in an immediate increase in renal blood flow (RBF) to the remnant kidney, followed by compensatory renal hypertrophy. Whether the increase in RBF after unilateral nephrectomy is mediated by nitric oxide (NO) was tested. It was found that immediately after nephrectomy, blood flow to the remaining kidney increased by 8% (P < 0.01), and inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) blocked the increase in RBF. In addition, 2 d after nephrectomy, there was a 49% increase in RBF (corrected per gram of kidney weight), a 25% increase at 7 and 14 d, and a 16% increase after 28 d. Acute inhibition of NO synthesis with L-NAME in uninephrectomized rats caused a greater decrease in RBF on days 2 and 7 compared with controls, whereas by 14 and 28 d, the response to L-NAME was similar to controls. Urinary excretion of cyclic guanosine monophosphate, a marker for renal NO production, increased 2.5-fold by 2 d after uninephrectomy (P < 0.005) and remained at this level through 28 d. Pretreating rats chronically with a subpressor dose of L-NAME beginning 2 d before nephrectomy blocked the increase in RBF seen at 2 and 7 d and retarded the renal hypertrophy that should have developed by 7 d. It is concluded that after unilateral nephrectomy, immediate and sustained increases in RBF are mediated at least in part by NO. The hypertrophic response to unilateral nephrectomy may be partially initiated by the signal of hemodynamic changes.