Moderate Hyperinsulinemia Research Articles

Twenty four hour insulin infusion impairs the ability of plasma from healthy subjects and Type 2 diabetic patients to promote cellular cholesterol efflux

Removal of cholesterol from peripheral cells by high density lipoproteins (HDL) is regarded as an important defence mechanism against atherosclerosis development. PLTP is involved in the generation of pre β-HDL that can act as initial acceptors of cellular cholesterol. Exogenous hyperinsulinaemia may not only decrease HDL cholesterol, but also plasma phospholipid transfer protein (PLTP) activity. The effect of 24-h insulin infusion (30 mU/kg/h) on the ability of plasma to promote cholesterol efflux from Fu5AH cells was examined in eight healthy men and eight male Type 2 diabetic patients, matched for HDL cholesterol. Baseline HDL cholesterol and phospholipids, pre β-HDL in incubated plasma, plasma apolipoprotein (apo) AI, PLTP activity and cholesterol efflux to plasma were not different between the groups. In both groups, HDL lipids, as well as plasma apo AI and PLTP activity decreased after 24 h of insulin ( P<0.05 to P<0.01) compared to baseline and recovery, i.e. 1 week after insulin. Pre β-HDL in incubated plasma did not significantly change. Cholesterol efflux to plasma from both groups decreased after insulin ( P<0.05). Using plasma from healthy subjects, cholesterol efflux was correlated positively with HDL cholesterol, HDL phospholipids, pre β-HDL in incubated plasma, plasma apo AI and PLTP activity ( P<0.05 to P<0.001). Using plasma from diabetic patients, cholesterol efflux was not significantly correlated with any of these parameters. In conclusion, 24-h moderate hyperinsulinaemia impairs the ability of plasma to promote cholesterol efflux from Fu5AH cells. It is suggested that, apart from HDL, plasma PLTP activity is a determinant of cholesterol efflux via stimulation of pre β-HDL formation. Cellular cholesterol efflux to plasma from selected Type 2 diabetic patients is maintained, but the interaction of Fu5AH cells with HDL may be altered.

Adipocyte metabolism in adipocyte fatty acid binding protein knockout mice (aP2-/-) after short-term high-fat feeding: functional compensation by the keratinocyte [correction of keritinocyte] fatty acid binding protein.

Mice null for adipocyte fatty acid binding protein (AFABP) compensate by increasing expression of keratinocyte fatty acid binding protein (KFABP) (Hotamisligil et al. Science 274:1377-1379, 1996). In the present study, AFABP knockout (KO) and wild-type (WT) mice became equally obese on a high-fat diet, as judged by fat pad weights, adipocyte size, and body composition analysis. High-fat feeding led to moderate insulin resistance in both WT and AFABP knockout mice, as indicated by an approximately 2-fold increase in plasma insulin. However, in the high fat-fed mice, plasma glucose levels were approximately 15% lower in the AFABP-KO mice. Adipocytes isolated from AFABP-KO and WT mice fed high- or low-fat diets exhibited similar rates of basal and norepinephrine-stimulated lipolysis and insulin-stimulated rates of glucose conversion to fatty acids and glyceride-glycerol. However, basal glucose conversion to fatty acids was higher in adipocytes of AFABP-KO mice. Adipocyte tumor necrosis factor-alpha release was similarly increased by high-fat diet-induced obesity in both WT and AFABP-KO mice. As assessed by Western blot analysis, the level of KFABP protein in AFABP-KOs was approximately 40% of the level of AFABP in WT controls. The binding affinities of KFABP for long-chain fatty acids were 2- to 4-fold higher than those of AFABP, but the relative affinities for different fatty acids were similar. As for AFABP, the rate of fatty acid transfer from KFABP to model phospholipid vesicles was increased with acceptor membrane concentration and by inclusion of acidic phospholipids, indicating a similar mechanism of transfer. We conclude KFABP can functionally compensate for the absence of AFABP, resulting in no major alterations in adipocyte metabolism or fat accumulation in response to short-term feeding of high-fat diets that result in moderate hyperinsulinemia.

New model of atherosclerosis in insulin resistant sand rats: hypercholesterolemia combined with D2 vitamin

To overcome the sand rats’ resistance to cholesterol induced atherosclerosis, animals were given D2 vitamin at 2000 IU/rat per day associated with cholesterol-enriched diet for 45 days, following 45 days of high cholesterol diet alone. At days 0, 45 and 90, plasma parameters, aortic and heart morphology were examined. Other animals receiving a high cholesterol diet alone were used as a control group. Results showed at day 45 severe hypercholesterolemia, elevated plasma LDL and VLDL-cholesterol, oxidized LDL and calcium levels, a rise of lecithin cholesterol acyl transferase activity and moderate hyperinsulinemia. Lesions were characterized by widening of the first interlamellar spaces in the aorta, fibrosis of coronary arterial wall and recent foci of myocardial fibrosis. At day 90, plasma calcium level decreased and oxidized LDL were more enhanced. Insulin resistance development was associated with glucose intolerance and hyperinsulinemia. The D2 vitamin administration induced advanced atherosclerotic lesions in arterial wall, represented by the rupture of elastic lamellae, smooth muscle cell proliferation and lipid-calcic core. The complicated plaque frequently evolved into ulcerations. The ischaemic effects were represented by acute myocardial infarction. D2 vitamin is an atherogenic agent which, when associated with hypercholesterolemia, allows the development of advanced atherosclerotic lesions in sand rat which resembles human plaque.

Twenty-four hours of insulin infusion does not lower plasma lipoprotein(a) in healthy men

The effect of 24-h exogenous hyperinsulinaemia on the plasma level of the atherogenic lipoprotein(a) (Lp(a)) is unknown. We evaluated the responses of plasma cholesterol, triglycerides, apolipoprotein (apo) B and Lp(a) during 24-h insulin infusion (180 pmol/kg/h) in 6 healthy men. Plasma total cholesterol (p < 0.01) and triglycerides (p < 0.05) decreased after 24 h of hyperinsulinaemia. Apo B was unchanged after 8 h (-2.4 +/- 3.0%, n.s.) and decreased by 10.9 +/- 4.8% (p<0.025) after 24 h of insulin. In contrast, Lp(a) did not decrease (+28.4 +/- 18.4%, n.s., and +/- 49.1 +/- 22.0%, n.s., after 8 and 24 h of insulin, respectively). This experiment supports the hypothesis that moderate hyperinsulinaemia has a different effect on the plasma level of triglyceride-rich lipoproteins compared to Lp(a).

In late pregnancy insulin-dependent glucose transport/phosphorylation is selectively impaired and activation of glycogen synthase by insulin facilitated in skeletal muscles of 24-h starved rats.

We investigated the relation between glucose transport/phosphorylation and glycogen synthase activation in individual rat skeletal muscles in response to moderate hyperinsulinaemia in the absence or presence of hyperglycaemia during pregnancy. Rats were studied on day 20 of pregnancy after 24-h starvation, with unmated rats as controls. Insulin and glucose were infused into conscious rats through an indwelling cannula as specified. Glucose transport/phosphorylation was assessed in vivo using 2-deoxy-[1-3H]glucose. Glycogen synthase activity was measured in muscle extracts < or = 10 mmol/l glucose-6-phosphate. In unmated rats, stimulation of glucose transport/phosphorylation occurred in response to euglycaemic-hyperinsulinaemia in all muscles studied but activation of glycogen synthase was not observed. Muscle glucose transport/phosphorylation rates during euglycaemic-hyperinsulinaemia after 24-h starvation were lower in pregnant compared with unmated rats, whereas glycogen synthase activation by insulin occurred in two of three fast-twitch muscles of pregnant rats. When insulin and glucose concentrations were matched between the 24-h starved unmated and pregnant groups through variable glucose infusion (15 min), glycogen synthase activities in fast-twitch muscles did not differ between unmated and pregnant groups. The response of glycogen synthase to hyperglycaemia in slow-twitch muscle was, however, greater in the pregnant group. Glycogen synthase activation in slow-twitch muscle in response to hyperinsulinaemia after 24-h starvation is enhanced in late pregnancy but the response is critically dependent on glycaemia. Pregnancy is, nevertheless, associated with reduced muscle glucose transport/phosphorylation. This disassociation ensures that available glucose is directed towards the fetus rather than the mother under conditions of moderate hyperinsulinaemia, for example during refeeding after starvation.

Chronic free fatty acid infusion in rats results in insulin resistance but no alteration in insulin-responsive glucose transporter levels in skeletal muscle.

To investigate the mechanism by which free fatty acids (FFA) affect glucose uptake, we studied the effect of chronic elevation (24 h) of plasma FFA in rats on whole body glucose disposal and glucose utilization index (GUI) in the basal state and under a euglycemic hyperinsulinemic clamp in relation to the amount of insulin-responsive glucose transporter (IRGT, i.e., GLUTU) protein in different muscles (oxidative and glycolytic) and adipose tissue. Infusion of intralipid in the basal state led to a approximately 40% increase in whole body glucose uptake and a approximately 250% increase in GUI in adipose tissue as compared to control rats. There was no change in the amount of IRGT protein in any of the muscle types whereas in fat depots it was either unchanged or decreased. Under moderate of supraphysiological hyperinsulinemia, increment of whole body glucose disposal was significantly lower in intralipid perfused rats when compared to controls (approximately 110 microU/mL: 0.7 +/- 0.1 vs. 1.3 +/- 0.1 mg/min, P < 0.02; approximately 1000 microU/mL: 3.0 +/- 0.2 vs. 3.9 +/- 0.4 mg/min, P < 0.02). Under moderate hyperinsulinemia stimulation, GUI was significantly reduced in different muscles and adipose tissue as compared to controls. We conclude that peripheral insulin resistance which occurs after elevation of plasma FFA levels does not seem to be explained by changes in the amount of IRGT protein in either oxidative or glycolytic skeletal muscle. Thus fatty acid infusion appears to be associated with a defect in IRGT translocation to the plasma membrane, fusion with the membrane, or intrinsic activity.

Therapeutic effect of benfluorex in type II diabetic patients on diet regimen alone

A randomized double-blind study of benfluorex (150 mg × 3 daily) versus placebo was conducted over 3 months in 32 type II diabetic patients (24 men and 8 women, aged 52 ± 8.4 years) with mild stable obesity [body-mass index (BMI) 27 ± 1.6 kg/m 2], moderate fasting hyperglycemia (fasting blood glucose 9 ± 0.5 mmol/L, HbA 1c 6.7 ± 0.9%) and moderate hyperinsulinemia (18.6 ± 3.0 μU/mL) when on treatment with diet alone. After a 1-month placebo run-in period, subjects were randomized to benfluorex or placebo three tablets daily. Inclusion parameters and end-of-study measures were body weight, BMI, fasting blood glucose, glycemic profile, HbA 1c, fasting insulinemia, basal and stimulated C-peptide, and an insulin tolerance test (0.1 U/kg). The groups were homogeneous at baseline, except for glycemic profile (higher postprandial glycemia in the group randomized to benfluorex). At the end of the study, the groups did not differ in body weight or BMI; however, HbA 1c decreased more with benfluorex (6.0 ± 1.0% versus 6.8 ± 0.9%, p = 0.024), as did the mean glycemic profile (7.8 ± 1.4 versus 8.5 ± 1.7 mmol/L, p < 0.001), including a particular decrease in postprandial glycemia. The decreases in fasting blood glucose and insulinemia appeared larger with benfluorex (7.7 ± 1.3 versus 8.4 ± 1.6 mmol/L and 13.5 ± 4.5 versus 16.1 ± 5.1 μU/mL, respectively), but were not statistically significant. The increase in the insulin sensitivity index (K itt) was greater with benfluorex (+0.54 ± 1.4 versus +0.25 ± 1.3%/mn), but the difference was not statistically significant. The same was observed for the stimulated C-peptide. In type II diabetics with mild obesity and hyperglycemia previously managed with diet alone, benfluorex has significant long-term effect on HbA 1c and mean daily blood glucose, and tends to lower insulinemia.

A 3-basepair in-frame deletion (delta Leu999) in exon 17 of the insulin receptor gene in a family with insulin resistance.

We studied a woman with acanthosis nigricans and insulin resistance. The patient's Epstein-Barr virus-transformed lymphocytes revealed slightly decreased insulin binding and markedly decreased insulin-stimulated autophosphorylation of the insulin receptor. The nucleotide sequence analysis of the patient's genomic DNA revealed a 3-basepair in-frame deletion in one allele, resulting in the loss of leucine at position 999 of the insulin receptor (delta Leu999). The messenger ribonucleic acid transcripts from the mutant allele in the patient's lymphocytes were not decreased. Insulin-stimulated autophosphorylation of the insulin receptor from cells expressing delta Leu999 mutant insulin receptor complementary DNA was markedly decreased. The proband, her mother, elder brother, and younger brother, who were heterozygous for this mutation, showed moderate or marked hyperinsulinemia during oral glucose tolerance tests. Although fasting glucose levels were normal and fasting insulin values were preserved in all subjects with the mutation for the 8-yr period of observation, a tendency of progressive increase in postload glucose levels was observed. These results suggest that the delta Leu999 mutation, which reduces tyrosine kinase activity, was responsible for insulin resistance and contributed to postload hyperglycemia.

Patients with type 1 diabetes lack vasoconstrictor response in skin microcirculation during insulin-induced hypoglycemia.

Disturbed hemodynamic reactions to insulin-induced hypoglycemia have been documented in diabetic patients and considered related to hyperinsulinemia and impairment of autonomic nervous functions. In the present study we investigated the effect on skin microcirculation of insulin-induced hypoglycemia obtained during moderate hyperinsulinemia, in 7 men with type 1 diabetes and in 8 healthy age- and sex-matched controls. The patients had all normal cardiovascular reflexes as assessed by respiratory sinus arrhythmia and Valsalva ratio. The skin microcirculation of the left fourth finger nailfold was investigated by laser Doppler fluxmetry, and the skin temperature within the same area was measured by a thermistor. Hypoglycemia was induced by a constant insulin infusion of Actrapid Human, 0.034 U kg-1 h-1 during 120 min. Plasma adrenaline, noradrenaline and pancreatic polypeptide increased significantly in both groups during hypoglycemia and the insulin levels never exceeded 50 mUl-1. A close to identical arterial hypoglycemia was obtained in the two groups 60 min after onset of insulin infusion. During hypoglycemia the control subjects revealed a significant decrease in laser Doppler flux (p < 0.025), while it was unchanged in the diabetic patients. Simultaneously, the skin temperature decreased (p < 0.05) in the controls, but was unchanged in the diabetic patients. The present study indicates that type 1 diabetic patients with normal cardiovascular reflexes have an abolished vasoconstrictor response in skin microcirculation of fingers during insulin-induced hypoglycemia, despite the fact that neurogenic and neuroglucopenic symptoms developed in these patients during hypoglycemia.

Clinical implications of hyperinsulinaemia in women.

In the polycystic ovary syndrome, hyperinsulinaemia is commonly found in women with hirsutism, oligomenorrhoea and acanthosis nigricans and this subset of patients possess adverse risk factors for coronary artery disease, particularly reduced HDL2 concentrations. Conversely, raised serum insulin concentrations are not common in women with PCOS in whom raised serum LH concentrations or regular menstrual cycles are present. We postulate that both direct ovarian and indirect actions of insulin (through changes in IGFI-I, IGFBP-I and SHBG concentrations) play important roles in determining androgen concentrations in women. Many intriguing questions follow from this link between the control of nutrition and reproduction and many old observations required re-examination in this new light. Vital to our understanding in this field will be the cause of moderate hyperinsulinaemia, the action of insulin on the normal ovary, and the importance of adverse surrogate risk factors for heart disease in hyperinsulinaemic women.

A pet scan analysis of skeletal muscle blood flow changes during moderate hyperinsulinemia

A pet scan analysis of skeletal muscle blood flow changes during moderate hyperinsulinemia

Reappraisal of the role of insulin on sodium handling by the kidney: effect of intrarenal insulin infusion in the dog

Since several studies suggest that increased insulin levels may induce antinatriuresis, the present work was undertaken to determine whether a physiological increase in insulin levels in blood perfusing the kidney may exert direct effect on kidney function, and more specifically on sodium reabsorption. To this end, insulin was infused directly into one renal artery of 10 anaesthetized dogs at the rate of 4 mU min-1 for a period of 90 min. The contralateral kidney was infused with saline alone, to provide reference values. Insulin level in the renal vein of the insulin-infused kidney went up from 1.4 +/- 0.9 before to 30.6 +/- 7.1 microU ml-1 after 90 min of insulin perfusion. There was no significant effect on renal plasma flow, glomerular filtration rate and renal uptake of substrates or oxygen between ipsi- and contralateral kidney. The fractional excretion of sodium was likewise unaffected, since it averaged at the end of insulin infusion 0.41 +/- 0.11% vs. 0.50 +/- 0.14% for the contralateral saline infused kidney. Even if one may assume that the baseline low insulin concentrations promote tubular sodium reabsorption, the results of the present study suggest that a moderate hyperinsulinaemia is without any additional effect on renal sodium handling.

Effects of growth hormone on fuel utilization and muscle glycogen synthase activity in normal humans

To examine the insulin antagonistic effects of growth hormone (GH), seven healthy subjects underwent, in random order, two 5-h euglycemic clamp studies with moderate hyperinsulinemia. A GH infusion (45 ng.kg-1.min-1) was given throughout one of the studies. GH inhibited the insulin-stimulated glucose disposal by 27% from 4.4 +/- 0.7 to 3.3 +/- 0.4 mg.kg-1.min-1 (P less than 0.02) and raised the nonprotein energy expenditures (NPEE) from 18.7 +/- 0.5 to 20.5 +/- 0.3 kcal.kg-1.24 h-1 (P less than 0.03). Lipid oxidation contributed 71.7 +/- 5.6% of NPEE during the GH infusion as compared with 48.7 +/- 5.2% during the control clamp (P less than 0.02). In skeletal muscle biopsies, insulin binding to wheat germ agglutinin-purified insulin receptors and insulin receptor kinase activity were unaffected by GH infusion. Glycogen synthase activation by insulin was inhibited by 41% during the GH clamp (fractional velocity 14.1 +/- 2.5 vs. 8.3 +/- 1.4%, P less than 0.03). In conclusion, GH 1) increases energy expenditures and inhibits glucose oxidation in favor of an increased lipid oxidation, and 2) inhibits insulin-mediated activation of the glycogen synthase in skeletal muscle biopsies by a mechanism distal to insulin receptor binding and kinase activity.

An ultrastructural study on the pancreatic islet B cells in diabetic herbivorous voles

An ultrastructural study was performed on the pancreatic islet cells of normal herbivorous voles and of voles in which diet-induced diabetes had been induced by feeding a low-fibre, high-concentrate diet. Examination of the pancreatic islet cells revealed degranulation and a well-developed Golgi apparatus and rough endoplasmic reticulum in the B cells of the slightly diabetic voles showing moderate hyperglycaemia and hyperinsulinaemia, and markedly degenerative B cells with almost complete absence of secretory granules in the severely diabetic voles showing marked hyperglycaemia and hypoinsulinaemia. These results indicate that the pancreatic B cells had become hyperfunctional so that insulin secretion was increased in the slightly diabetic voles; thereafter the B cells degenerated rapidly and the voles fell into insulin deficiency.

Effect of prolonged hyperinsulinaemia on adipocyte insulin binding and action in normal man

Prolonged moderate insulinaemia over 20 h in normal humans produces a significant reduction of in vivo insulin action. To examine the effects in man of such moderate hyperinsulinaemia on in vitro glucose metabolism, insulin-receptor binding, glucose transport and incorporation of glucose into lipid were determined in adipocytes isolated from paired gluteal fat biopsies, taken from six normal human volunteers before and 1 h after 20 h of exogenous hyperinsulinaemia (plasma insulin 38 ± 3 mU/l). Specific binding of insulin to isolated adipocytes was not altered (6.7 ± 0.7 versus 7.6 ± 1.5% per 10 5 cells). Basal glucose transport of 3- O-[ 14C]methylglucose in the absence of insulin was reduced after hyperinsulinaemia (5.2 ± 1.1 versus post 4.3 ± 1.3 pmol/7 s per 10 5 cells, 0.1 < P > 0.05; or expressed as percent of maximal response: 60 ± 5 versus post 49 ±1%, P< 0.05), but maximal transport (9.2 ± 1.5 versus post 8.7 ± 1.5 pmol/7 s per 10 5 cells and ED 50 (89 ± 17 versus 67 ± 15 pmol/l) were unchanged. Conversion of glucose into lipid, using 3- d-[ 3H]glucose, was unchanged basally, at maximal response or ED 50 of the dose response curve. In conclusion, moderate 20 h in vivo hyperinsulinaemia in normal humans induces only a small change in basal vitro adipocyte glucose transport, and no change in insulin-receptor binding or in vitro incorporation of glucose into lipid. These data suggest that the adipocyte does not contribute to the impaired insulin action produced by in vivo moderate hyperinsulinaemia in man.

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus.

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.

Insulin as a factor of increased androgen production in women with obesity and polycystic ovaries.

To evaluate the possible role of moderate hyperinsulinemia on abnormal androgen secretion, we examined 4 age and weight-matched groups of obese subjects: 2 groups of women with normal menses whose fasting insulin (IRI) levels were less than or equal to 20 microU/ml (OB-I) or greater than or equal to 40 microU/ml (OB-I) and 2 groups of women with polycystic ovaries who were similarly grouped. All subjects underwent an oral glucose tolerance test, blood sex hormone determination and multiple LH determinations. Compared to OB, OB-PCO women showed significantly higher values of LH, androgen and estrogen concentrations. OB-I and OB-II showed similar hormonal patterns. On the contrary, OB-PCO-II presented significantly (p less than 0.05) higher androstenedione concentrations (348.7 +/- 129.9 ng/dl) (m +/- SD) than OB-PCO-I women (237.0 +/- 73.7 ng/dl). These differences were evident despite similar plasma LH concentrations. In conclusion, these results suggest that insulin may be a factor amplifying LH-dependent androgen secretion in hyperandrogenized women with obesity and PCO.

Reduction of glycogen stores in a rat model of chronic hyperinsulinism

To assess a suitable model for the study of the mechanisms of development of insulin resistance in vivo, liver and muscle glycogen levels (as a metabolic index of tissue insulin sensitivity) were investigated in rats with functioning islet cell adenomas induced by streptozotocin and nicotinamide. These rats have basal moderate hyperinsulinemia and hypoglycemia and show a remarkable increase in insulin secretion after glucose administration. Plasma glucagon concentrations are normal. Nevertheless, in tumor-bearing rats, a reduction of tissue glycogen stores occurs, related to plasma glucose concentrations, and liver glycogen fails to increase even after a glucose load. The lack of excess fat in tumor-bearing rats also suggests a certain insulin insensitivity of the adipose tissue and distinguishes this model of chronic hyperinsulinism from other reported models, such as genetically obese animals.

The influence of progressive hyperinsulinemia on duodenal calcium absorption in the rat

Using an in situ loop technique, we studied the influence of moderate hyperinsulinemia on the bidirectional fluxes [lumen-to-plasma (LP), plasma-to-lumen (PL)] and on the net absorption of calcium (Ca) in the duodenum of the rat. Under hyperinsulinemic euglycemic clamp conditions, three different steady-state plasma insulin levels (66 ± 16, 187 ± 13, 263 ± 24 μU/mL) were maintained by intravenous (IV) infusion of either 20, 40, or 60 mU/h of insulin. LP flux and net Ca absorption (CaA) increased significantly under all, while the PL flux was not changed by any of the three insulin doses. Under 40 and 60 mU/h of IV insulin, the individual plasma insulin levels and LP fluxes were positively and significantly correlated, suggesting a dose-dependent action of insulin on duodenal CaA. No significant changes were seen in plasma somatostatinlike immunoreactivity (SLI), parathyroid hormone (PTH), and serum Ca, while serum inorganic phosphate (Pi) and 1,25(OH) 2 vitamin D levels fell with increasing doses of IV insulin. It is concluded for the rat that (1) physiologic degrees of hyperinsulinemia enhance duodenal CaA by an as yet unknown mechanism, (2) this action seems to be independent of PTH and, (3) the role of 1,25(OH) 2 vitamin D in this context is poorly understood.

Net substrates balance across hindlimb in conscious rabbit during late pregnancy.

The present work performed in rabbits was designed to investigate whether changes in skeletal muscle metabolism could contribute to glucose homeostasis during late pregnancy a time at which there is a large glucose demand of the gravid uterus. We therefore studied the net substrate balance of glucose, lactate, free fatty acids, and ketone bodies across the hindlimb of pregnant animals (days 24 and 30) and virgin animals. Our data show that on day 24 the basal rate of glucose uptake is similar to that observed in virgin rabbits, but it decreases by approximately 60% on day 30 despite comparable levels of blood glucose and plasma insulin at both gestational ages. A moderate hyperglycemia (20% above basal level) and hyperinsulinemia (2- to 3-fold above basal level) sustained for 80 min failed to increase glucose uptake except in virgin animals. Estimates of the contribution of substrates to oxidative metabolism indicate that free fatty acids could represent the major fuel in all groups, whereas glucose would be of minor importance especially at term. It is concluded that in pregnancy a) under normoglycemia there is a reduced insulin effect on glucose uptake and b) under moderate hyperglycemia and hyperinsulinemia the insulin resistance results from an impaired stimulation of glucose uptake. Sparing glucose from the skeletal muscle, the mother can direct more glucose toward the uterus without marked increase in her production rate.