Forearm vascular control during acute hyperglycemia in healthy humans

The vascular endothelium is a site of pathological changes in patients with diabetes mellitus that may be related to severe chronic hyperglycemia. However, it is unclear whether transient hyperglycemia alters vascular function in an otherwise healthy human forearm. To test the hypothesis that acute, moderate hyperglycemia impairs endothelium-dependent forearm vasodilation, we measured vasodilator responses in 25 healthy volunteers (11 F, 14 M) assigned to one of three protocols. In protocol 1, glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance. Protocol 2 involved 6 h of mild hyperglycemia (approximately 7 mmol/l). Protocol 3 involved 6 h of euglycemia. Glucose concentration was maintained with a variable systemic glucose infusion. Insulin concentrations were maintained at approximately 65 pmol/l by means of a somatostatin and "basal" insulin infusion. Glucagon and growth hormone were replaced at basal concentrations. Forearm blood flow (FBF) was calculated from Doppler ultrasound measurements at the brachial artery. In each protocol, FBF dose responses to intrabrachial acetylcholine (ACh) and sodium nitroprusside (NTP) were assessed at baseline and at 60, 180, and 360 min of glucose infusion. Peak endothelium-dependent vasodilator responses to ACh were not diminished by hyperglycemia in any trial. For example, peak responses to ACh during protocol 2 were 307 +/- 47 ml/min at euglycemic baseline and 325 +/- 52, 353 +/- 65, and 370 +/- 70 ml/min during three subsequent hyperglycemic trials (P = 0.46). Peak endothelium-independent responses to NTP infusion were also unaffected. We conclude that acute, moderate hyperglycemia does not cause short-term impairment of endothelial function in the healthy human forearm.     

The influence of insulin on circulating ghrelin

Ghrelin is a novel peptide that acts on the growth hormone (GH) secretagogue receptor in the pituitary and hypothalamus. It may function as a third physiological regulator of GH secretion, along with GH-releasing hormone and somatostatin. In addition to the action of ghrelin on the GH axis, it appears to have a role in the determination of energy homeostasis. Although feeding suppresses ghrelin production and fasting stimulates ghrelin release, the underlying mechanisms controlling this process remain unclear. The purpose of this study was to test the hypotheses, by use of a stepped hyperinsulinemic eu- hypo- hyperglycemic glucose clamp, that either hyperinsulinemia or hypoglycemia may influence ghrelin production. Having been stable in the period before the clamp, ghrelin levels rapidly fell in response to insulin infusion during euglycemia (baseline ghrelin 207 +/- 12 vs. 169 +/- 10 fmol/ml at t = 30 min, P < 0.001). Ghrelin remained suppressed during subsequent periods of hypoglycemia (mean glucose 53 +/- 2 mg/dl) and hyperglycemia (mean glucose 163 +/- 6 mg/dl). Despite suppression of ghrelin, GH showed a significant rise during hypoglycemia (baseline 4.1 +/- 1.3 vs. 28.2 +/- 3.9 microg/l at t = 120 min, P < 0.001). Our data suggest that insulin may suppress circulating ghrelin independently of glucose, although glucose may have an additional effect. We conclude that the GH response seen during hypoglycemia is not regulated by circulating ghrelin.     

The pancreatic glucagon and C-peptide secretion during hyperinsulinemia in euglycemic glucose clamp with or without somatostatin infusion in normal man

6 normal subjects received two times of 2 hr euglycemic glucose clamp studies (insulin infusion rate 40 mU/M2/min) one with and the other without somatostatin (SRIF) infusion (500 microgram/hr). Serum C-peptide and glucagon levels were measured during clamp to study the sensitivity of pancreatic alpha and beta cells to the suppressive effects of exogenous hyperinsulinemia during normoglycemia in normal subjects and to find whether SRIF had any modulative effects on endocrine pancreas secretion at the status of hyperinsulinemia. The results showed that in normal man the degree of suppression of pancreatic glucagon secretion by hyperinsulinemia (approximately 100 uU/ml) during euglycemic glucose clamp without SRIF infusion was less than that of C-peptide with mean value of 62 +/- 4% of basal glucagon remained at the end of clamp study; while only about 30 +/- 2% of basal C-peptide concentrations remained. But during SRIF infused glucose clamp studies (SRIF was infused from 60 to 120 min), 32 +/- 2% of mean basal C-peptide concentrations and 38 +/- 6% of mean basal glucagon concentrations left at the end of 2 hr clamp studies when serum insulin level was about 100 uU/ml. For the glucose infusion rate (M value), it was significantly greater in our normal subjects in response to insulin + SRIF as compared to insulin alone (12.0 + 0.9 vs 8.8 +/- 1.4; P less than 0.01). We concluded: during hyperinsulinemia (100 uU/ml), the sensitivity of pancreatic alpha cells to insulin seems less than that of beta cells in normal man at normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oscillations of circulating plasma insulin concentrations in the rat

In previous studies, we found that insulin is secreted in a pulsatile fashion in vitro in isolated rat pancreatic islets. This study evaluated whether similar plasma insulin fluctuations occur in the rat in vivo. Freely moving rats were implanted with a chronic jugular catheter and serial blood samples were obtained 48-72 hrs post surgery. Blood was sampled at 3 min intervals for 60 mins with volume replacement using a red cell preparation. Plasma insulin concentrations were observed to fluctuate around a mean of 10.6 +/- 1.1 uU/ml, with an amplitude of 4.7 +/- 0.5 uU/ml and a period of 13.3 +/- 1 mins (n = 6). This was similar to the cycling observed in isolated islets at similar glucose concentrations. Sampling during the dark phase of the light-dark cycle in the rat was associated with an increase in the mean plasma level, amplitude and period of insulin oscillations compared with values obtained during the light phase (n = 3). These data are the first in vivo demonstration of oscillatory circulating insulin concentrations in the rat and show that the pulsatility in this species is similar to that observed in other mammals including man. We conclude that the chronically catheterised rat is a useful model for the evaluation of oscillating insulin concentrations in vivo, and may provide interesting insights by comparison with in vitro data in the same species.     

Sulfonylurea therapy fails to diminish insulin resistance in type I-diabetic subjects

To assess whether extrapancreatic effects of sulfonylureas in vivo are detectable in the absence of endogenous insulin secretion, insulin sensitivity was determined in six insulin-deficient type 1-diabetic subjects. Peripheral uptake and hepatic production of glucose and lipolysis were measured during hyperinsulinemia using the euglycemic clamp technique and 3-3H-glucose infusions twice, once during a period with glibornuride treatment (50 mg b.i.d.), and once without. Hepatic glucose production decreased in diabetic subjects during hyperinsulinemia (insulin infusion of 20 mU/m2 X min; plasma free insulin levels of 40 +/- 4 mU/l) from 2.9 +/- 0.6 mg/kg min to 0.2 +/- 0.1 mg/kg X min after 120 min, and plasma free fatty acid (FFA) concentrations decreased from 1.33 +/- 0.29 to 0.38 +/- 0.08 mmol/l. Hepatic production, peripheral uptake of glucose and plasma FFA concentrations before and during hyperinsulinemia were not influenced by pretreatment with glibornuride. Compared to 8 non-diabetic subjects, type 1-diabetics demonstrated a diminished effect of hyperinsulinemia on peripheral glucose clearance (2.4 +/- 0.04 vs 4.2 +/- 0.5 ml/kg X min, P less than 0.01), whereas hepatic glucose production and plasma FFA levels were similarly suppressed by insulin. The data indicate that sulfonylurea treatment did not improve the diminished insulin sensitivity of peripheral glucose clearance in type 1-diabetic subjects; insulin action on hepatic glucose production and lipolysis was unimpaired in diabetics and remained uninfluenced by glibornuride. Thus, extrapancreatic effects of sulfonylureas in vivo are dependent on the presence of functioning beta-cells.     

Comparison of local and systemic effects of insulin on myocardial glucose extraction in ischemic heart disease

Physiological increases in circulating insulin level significantly increase myocardial glucose uptake in vivo. To what extent this represents a direct insulin action on the heart or results indirectly from reduction in circulating concentrations of free fatty acids (FFA) is uncertain. To examine this, we measured myocardial glucose, lactate, and FFA extraction in 10 fasting men (ages 49-76 yr) with stable coronary artery disease during sequential intracoronary (10 mU/min, coronary plasma insulin = 140 +/- 20 microU/ml) and intravenous (100 mU/min, systemic plasma insulin = 168 +/- 26 microU/ml) insulin infusion. Basally, hearts extracted 2 +/- 2% of arterial glucose and extracted 27 +/- 6% of FFA. Coronary insulin infusion increased glucose extraction to 5 +/- 3% (P < 0.01 vs. basal) without changing plasma FFA or heart FFA extraction. Conversion to intravenous infusion lowered plasma FFA by approximately 50% and heart FFA extraction by approximately 75%, increasing heart glucose extraction still further to 8 +/- 3% (P < 0. 01 vs. intracoronary). This suggests the increase in myocardial glucose extraction observed in response to an increment in systemic insulin concentration is mediated equally by a reduction in circulating FFA and by direct insulin action on the heart itself. Coronary insulin infusion increased myocardial lactate extraction as well (from 20 +/- 10% to 29 +/- 9%, P < 0.05), suggesting the local action may include stimulation of a metabolic step distal to glucose transport and glycolysis.     

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles

To determine whether, in the presence of constant insulin concentrations, a change in glucose concentrations results in a reciprocal change in endogenous glucose production (EGP), glucagon ( approximately 130 ng/l) and insulin ( approximately 65 pmol/l) were maintained at constant "basal" concentrations while glucose was clamped at approximately 5.3 mM (euglycemia), approximately 7.0 mM (sustained hyperglycemia; n = 10), or varied to create a "postprandial" profile (profile; n = 11). EGP fell slowly over the 6 h of the euglycemia study. In contrast, an increase in glucose to 7.13 +/- 0.3 mmol/l resulted in prompt and sustained suppression of EGP to 9.65 +/- 1.21 micromol x kg-1 x min-1. On the profile study day, glucose increased to a peak of 11.2 +/- 0.5 mmol/l, and EGP decreased to a nadir of 6.79 +/- 2.54 micromol x kg-1 x min-1 by 60 min. Thereafter, the fall in glucose was accompanied by a reciprocal rise in EGP to rates that did not differ from those observed on the euglycemic study day (11.31 +/- 2.45 vs. 12.11 +/- 3.21 micromol x kg-1 x min-1). Although the pattern of change of glucose differed markedly on the sustained hyperglycemia and profile study days, by design the area above basal did not. This resulted in equivalent suppression of EGP below basal (-1,952 +/- 204 vs. -1,922 +/- 246 mmol. kg-1. 6 h-1). These data demonstrate that, in the presence of a constant basal insulin concentration, changes in glucose within the physiological range rapidly and reciprocally regulate EGP.     

Effect of glucose on plasma glucagon and free fatty acids during prolonged exercise

The effects of glucose ingestion on the changes in blood glucose, FFA, insulin and glucagon levels induced by a prolonged exercise at about 50% of maximal oxygen uptake were investigated. Healthy volunteers were submitted to the following procedures: 1. a control test at rest consisting of the ingestion of 100 g glucose, 2. an exercise test without, or 3. with ingestion of 100 g of glucose. Exercise without glucose induced a progressive decrease in blood glucose and plasma insulin; plasma glucagon rose significantly from the 60th min onward (+45 pg/ml), the maximal increase being recorded during the 4th h of exercise (+135 pg/ml); plasma FFA rose significantly from the 60th min onward and reached their maximal values during the 4th h of exercise (2177 +/- 144 muEq/l, m +/- SE). Exercise with glucose ingestion blunted almost completely the normal insulin response to glucose. Under these conditions, exercise did not increase plasma glucagon before the 210th min; similarly, the exercise-induced increase in plasma FFA was markedly delayed and reduced by about 60%. It is suggested that glucose availability reduces exercise-induced glucagon secretion and, possibly consequently, FFA mobilization.     

Role of Insulin and Free Fatty Acids in the Regulation of ob Gene Expression and Plasma Leptin in Normal Rats

Objective: It is under debate whether free fatty acids (FFAs) play an independent role in the regulation of adipose cell functions. In this study, we evaluated whether leptin secretion induced by FFA is due directly to an increased FFA availability or whether it is mediated by insulin levels. Research Methods and Procedures: To test this hypothesis, we compared the effects of six different experimental designs, with different FFA and insulin levels, on plasma leptin: euglycemic clamp, euglycemic clamp + FFA infusion, FFA infusion alone, FFA + somatostatin infusion, somatostatin infusion alone, and saline infusion. Results: Our results showed that euglycemic clamp, FFA infusion, or both in combination induced a similar increment of circulating leptin (3.31 ± 0.30, 3.40 ± 0.90, and 3.35 ± 0.80 ng/mL, respectively). Moreover, the inhibition of FFA‐induced insulin increase by means of somatostatin infusion completely abolished the rise of leptin in response to FFA (1.05 ± 0.30 vs. 3.40 ± 0.90 ng/mL, p < 0.001). Discussion: In conclusion, our data showed that the effects of high FFA levels on plasma leptin were mediated by the rise of insulin concentration. These data confirm a major role for insulin in the regulation of leptin secretion from rat adipose tissue and support the hypothesis that leptin secretion is coupled to net triglyceride synthesis in adipose tissue.     

Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes.

The role of preserved beta-cell function in preventing ketoacidosis in type I insulin-dependent diabetes was assessed in eight patients with and seven patients without residual beta-cell function as determined from C-peptide concentrations. After 12 hours of insulin fatty-acid, and glycerol concentrations were all significantly higher in patients without beta-cell function than in those with residual secretion. Mean blood glucose concentrations reached 17.2 +/- SE of mean 1.3 mmol/l (310 +/- 23 mg/100 ml) in the first group compared with 8.8 +/- 1.4 mmol/l (159 +/- 25 mg/100 ml) in the second (P less than 0.01), while 3-hydroxybutyrate concentrations rose to 5.5 +/- mmol/l (57 +/- 5 mg/100 ml) and 1.4 +/- 0.3 mmol/l (15 +/- 3 mg/100 ml) in the two groups respectively (P less than 0.01). Individual mean C-peptide concentrations showed a significant inverse correlation with the final blood glucose values (r = -0.91; P less than 0.02). These findings strongly suggest that even minimal residual insulin secretion is important for metabolic wellbeing in diabetes and may prevent the development of severe ketoacidosis when insulin delivery is inadequate.     

Metabolic changes in Brycon cephalus (Teleostei,Characidae) during post-feeding and fasting

Metabolic changes during the transition from post-feeding to fasting were studied in Brycon cephalus, an omnivorous teleost from the Amazon Basin in Brazil. Body weight and somatic indices (liver and digestive tract), glycogen and glucose content in liver and muscle, as well as plasma glucose, free fatty acids (FFA), insulin and glucagon levels of B. cephalus, were measured at 0, 12, 24, 48, 72, 120, 168 and 336 h after the last feeding. At time 0 h (the moment of food administration, 09.00 h) plasma levels of insulin and glucagon were already high, and relatively high values were maintained until 24 h post-feeding. Glycemia was 6.42+/-0.82 mM immediately after food ingestion and 7.53+/-1.12 mM at 12 h. Simultaneously, a postprandial replenishment of liver and muscle glycogen reserves was observed. Subsequently, a sharp decrease of plasma insulin occurred, from 7.19+/-0.83 ng/ml at 24 h of fasting to 5.27+/-0.58 ng/ml at 48 h. This decrease coincided with the drop in liver glucose and liver glycogen, which reached the lowest value at 72 h of fasting (328.56+/-192.13 and 70.33+/-14.13 micromol/g, respectively). Liver glucose increased after 120 h and reached a peak 168 h post-feeding, which suggests that hepatic gluconeogenesis is occurring. Plasma FFA levels were low after 120 and 168 h and increased again at 336 h of fasting. During the transition from post-feeding to fast condition in B. cephalus, the balance between circulating insulin and glucagon quickly adjust its metabolism to the ingestion or deprivation of food.     

The longitudinal effect of inhibiting fatty acid oxidation in diabetic rats fed a high fat diet.

This study was designed to examine the time-course of response to inhibition of fatty acid (FA) oxidation in rats rendered mildly diabetic with streptozotocin and fed a high fat diet (50% of energy derived from fat). Etomoxir, a specific carnitine palmitoyltransferase (CPT-1) inhibitor, was administered subcutaneously (12.5 mg/kg) to inhibit long chain fatty acid oxidation. Diabetic and non-diabetic control rats were maintained on the high fat diet. Following an overnight fast, glucose, free fatty acid (FFA) and triglyceride (TG) concentrations were determined after three days, one week and four weeks of treatment. The effect of Etomoxir treatment in reducing fasting glucose concentrations was not evident until after one week, while fasting FFA and TG concentrations were already reduced after three days treatment. All of these changes were maintained over the four week period (P less than 0.001), resulting in reduced levels of fasting plasma glucose (17.6 +/- 2.4 vs 22.3 +/- 1.9 mmol/l), fasting plasma TG (0.32 +/- 0.07 vs 0.98 +/- 0.14 mmol/l) and fasting serum FFA (1.52 +/- 0.26 vs 3.51 +/- 0.69 mEq/l). In addition, the improvements in glucose and lipid levels were accompanied by restored rates of growth towards that of non-diabetic control rats. These results suggest that the short term inhibition of FA oxidation improves fasting glucose, FFA and TG concentrations in diabetic rats fed a high fat diet.     

Effect of sparteine sulfate on insulin secretion in normal men

This study aimed at evaluating the influence of sparteine sulfate either upon basal plasma glucose and insulin or glucose-induced insulin secretion in normal man. Thirteen overnight fasted volunteers took part in this study; five of them were submitted to sparteine sulfate bolus (15 mg in 10 ml of saline solution) followed by a slow infusion (90 mg/100 ml X 60 min) and eight subjects underwent two different glucose pulses (20 gr. i.v.) in absence or in presence of sparteine, infused as described above. In basal conditions, along with sparteine infusion, plasma glucose showed a progressive and significant decrease (P less than 0.0001) and plasma insulin was significantly higher from min 10 to 120' (P less than 0.0005-0.001). Even during the glucose-induced insulin secretion, in the presence of sparteine infusion, plasma glucose levels were significantly lower while plasma insulin levels were significantly higher when compared to those observed after glucose alone. The acute insulin response (AIR) was 42 +/- 10 microU/ml after glucose alone vs 67 +/- 9 microU/ml after glucose plus sparteine (P less than 0.05). Total insulinemic areas were significantly different being 1410 +/- 190 vs 2250 +/- 310 microU/ml/min (P less than 0.001) during glucose and glucose plus sparteine infusion, respectively. This study thereby, demonstrates that in normal man sparteine sulfate, administrated by intravenous infusion, is able to increase either basal or glucose-induced insulin secretion.     

Intermediate acting insulin given at bedtime: effect on blood glucose concentrations before and after breakfast.

Six C-peptide deficient diabetics receiving twice daily mixtures of short and intermediate acting insulins were selected for study because of persistently raised blood glucose concentrations before and after breakfast. They were investigated to assess the effect of moving their evening injection of intermediate acting insulin to bedtime. The patients'' usual twice daily insulin treatment was optimised and compared with the bedtime regimen during inpatient metabolic studies and an outpatient crossover study. With the conventional injection regimen blood glucose concentration rose sharply from 0500 to reach a fasting mean value of 10 +/- SE 1 . 6 mmol/l (180 +/- 29 mg/100 ml) and 16 . 8 +/- 2 . 2 mmol/l (303 +/- 40 mg/100 ml) after breakfast. By contrast, when the evening dose of intermediate acting insulin was delayed until bedtime the nocturnal rise in blood glucose concentration started later and was significantly lower both fasting (7 . 5 +/- 1 . 1 mmol/l (135 +/- 20 mg/100 ml); p less than 0 . 02) and after breakfast (13 . 2 +/- 1 . 4 mmol/l(238 +/- 25 mg/100 ml); p less than 0 . 02). Fasting blood concentrations of ketone bodies (3-hydroxybutyrate) were also significantly decreased. Plasma free insulin concentrations showed the predicted changes in five of the six patients. Blood glucose profiles collected over four months during the outpatient study confirmed the beneficial effect of giving intermediate acting insulin at bedtime.     

Growth hormone and carbohydrate intolerance in cirrhosis

Patients with cirrhosis of the liver often have insulin resistance and elevated circulating growth hormone levels. This study was undertaken (a) to evaluate glucose intolerance, insulin resistance and abnormal growth hormone secretion and (b) to determine if GH suppression improves insulin resistance. Glucose tolerance tests (GTT), intravenous insulin tolerance tests (IVITT), arginine stimulation tests (AST) and glucose clamp studies before and during GH suppression with somatostatin were performed in a group of patients with alcohol-induced liver cirrhosis. During GTT cirrhotic subjects had a 2-hour plasma glucose of 200 +/- 9.8 ng/dl (N = 14) compared to 128 +/- 8.0 ng/dl in normal controls (N = 15), P less than 0.001. Basal GH was elevated in cirrhotic patients and in response to arginine stimulation reached a peak of 17.0 +/- 5.4 ng/ml (N = 7), compared to a peak of 11.3 +/- 1.8 ng/ml in 5 normal controls (P = NS). During IVITT patients with cirrhosis had a glucose nadir of 60.0 +/- 4.0 mg/dl (N = 9), compared to 29.0 +/- 7.0 mg/dl in controls (N = 5), P less than 0.001. Peak GH levels during IVITT were not significantly different in cirrhotics and controls. Glucose utilization rates in 4 patients with cirrhosis of the liver before somatostatin mediated GH suppression was 3.1 +/- 0.5 mg/kg/min and 6.5 +/- 1.5 mg/kg/min during somatostatin infusion, P less than 0.025. We conclude that patients with alcohol induced cirrhosis have sustained GH elevations resulting in insulin resistance which improves after GH suppression.     

Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans

Cortisol's effects on lipid metabolism are controversial and may involve stimulation of both lipolysis and lipogenesis. This study was undertaken to define the role of physiological hypercortisolemia on systemic and regional lipolysis in humans. We investigated seven healthy young male volunteers after an overnight fast on two occasions by means of microdialysis and palmitate turnover in a placebo-controlled manner with a pancreatic pituitary clamp involving inhibition with somatostatin and substitution of growth hormone, glucagon, and insulin at basal levels. Hydrocortisone infusion increased circulating concentrations of cortisol (888 +/- 12 vs. 245 +/- 7 nmol/l). Interstitial glycerol concentrations rose in parallel in abdominal (327 +/- 35 vs. 156 +/- 30 micromol/l; P = 0.05) and femoral (178 +/- 28 vs. 91 +/- 22 micromol/l; P = 0.02) adipose tissue. Systemic [(3)H]palmitate turnover increased (165 +/- 17 vs. 92 +/- 24 micromol/min; P = 0.01). Levels of insulin, glucagon, and growth hormone were comparable. In conclusion, the present study unmistakably shows that cortisol in physiological concentrations is a potent stimulus of lipolysis and that this effect prevails equally in both femoral and abdominal adipose tissue.     

Diminution of hypertriglyceridemia-induced pressor effect under hyperinsulinemic condition in normal and fructose-induced insulin resistant rats

This study aimed to evaluate the effect of hyperinsulinemia on hypertriglyceridemia-induced pressor response in normal and fructose-induced insulin resistant rats. The rats were divided into six groups of eight rats and were fed a fructose-enriched diet (FINs, F(INS+TG)) or a regular chow diet (C, C(TG), C(INS), C(INS+TG)) for 8 wks. The acute experiment was conducted at the end of wk 8 and consisted of a 30-min basal period and followed by a 120-min test period. After the basal period, somatostatin (1.3 microg/kg/ min) combined with regular insulin (0.6 or 4 mU/kg/min) and variable glucose infusion were given to clamp euglycemia and euinsulinemia in C and C(TG) or euglycemia and hyperinsulinemia in CINs, C(INS+TG), F(INS) and F(INS+TG). During test period, lipofundin (a triglyceride emulsion) was infused into CTG, C(INS+TG), F(INS+TG) and saline instead was infused into C, C(INS), FINS. Plasma insulin and triglyceride levels were significantly higher in fructose-fed rats than in normal rats. During the test period, the lipofundin infusion (1.2 ml/kg/hr) increased plasma triglyceride levels by 368 +/- 39, 351 +/- 71 and 489 +/- 38 mg/dl compared with their baseline levels in lipid-infused groups. During the test period, low-dose insulin infusion kept plasma insulin at basal levels in C and C(TG) and high-dose insulin infusion increased plasma insulin levels about 6 times the baseline insulin level in C. Glucose infusion rate (GIR) was significantly higher in rats with high insulin infusion than those with low insulin infusion. The increase in GIR was lower in fructose-fed groups than in control groups under similar hyperinsulinemia. Rats with or without lipofundin infusion did not alter GIR during the test period. The present results demonstrated that hypertriglyceridemia-induced pressor response was diminished under hyperinsulinemic condition in both normal and fructose-induced insulin resistant rats.     

Insulin action during late pregnancy in the conscious dog

Our aim was to assess the magnitude of peripheral insulin resistance and whether changes in hepatic insulin action were evident in a canine model of late (3rd trimester) pregnancy. A 3-h hyperinsulinemic (5 mU.kg(-1).min(-1)) euglycemic clamp was conducted using conscious, 18-h-fasted pregnant (P; n = 6) and nonpregnant (NP; n = 6) female dogs in which catheters for intraportal insulin infusion and assessment of hepatic substrate balances were implanted approximately 17 days before experimentation. Arterial plasma insulin rose from 11 +/- 2 to 192 +/- 24 and 4 +/- 2 to 178 +/- 5 microU/ml in the 3rd h in NP and P, respectively. Glucagon fell equivalently in both groups. Basal net hepatic glucose output was lower in NP (1.9 +/- 0.1 vs. 2.4 +/- 0.2 mg.kg(-1).min(-1), P < 0.05). Hyperinsulinemia completely suppressed hepatic glucose release in both groups (-0.4 +/- 0.2 and -0.1 +/- 0.2 mg.kg(-1).min(-1) in NP and P, respectively). More exogenous glucose was required to maintain euglycemia in NP (15.2 +/- 1.3 vs. 11.5 +/- 1.1 mg.kg(-1).min(-1), P < 0.05). Nonesterified fatty acids fell similarly in both groups. Net hepatic gluconeogenic amino acid uptake with high insulin did not differ in NP and P. Peripheral insulin action is markedly impaired in this canine model of pregnancy, whereas hepatic glucose production is completely suppressed by high circulating insulin levels.     

Hormonal studies in a patient with PP-producing tumors

Five years after the removal of pure pancreatic polypeptide (PP) producing tumors, concentrations of circulating levels of PP, insulin, glucagon, and growth hormone in the basal state, after insulin-induced hypoglycemia, and after a protein-rich meal were determined in a patient with previous truncal vagotomy and Billroth II gastrectomy. Basal plasma levels of PP ranged between 2180 and 2660 pg/ml suggesting persistence or recurrence of PP producing tumors. Concentrations of the other hormones were within normal values. After insulin injection (0.1 U/Kg) levels of PP and glucagon were not modified while those of GH rose from 3.2 to 22.6 ng/ml. After a protein meal (450 gms. of cooked ground beef meat) a sharp rise of plasma PP was observed to a peak of 11310 pg/ml at 10 min. Moreover, plasma levels of immunoreactive insulin also showed an equally prompt rise to a peak of 532 microU/ml while plasma glucagon rose simultaneously to 448 pg/ml. The cause of the abnormal PP, insulin and glucagon responses could not be ascertained but we postulate that they are derived from pancreatic tumors of mixed cell type.     

Cutaneous vascular function during acute hyperglycemia in healthy young adults.

Although it is well established that severe chronic hyperglycemia is associated with microvascular disease, it is not known whether transient hyperglycemia similar to that observed with impaired glucose tolerance or early Type 2 diabetes contributes to this pathology by altering microvascular function. To test the hypothesis that acute hyperglycemia decreases microvascular vasodilator responsiveness in human skin, we measured the cutaneous vasodilator response to local warming. This response can be divided into two phases, an initial peak that relies predominantly on local sensory nerves and a second slower phase that is largely dependent on endothelial nitric oxide. We reasoned that a change in one or both phases would indicate a change in the corresponding mechanism(s) with hyperglycemia. Twenty-eight healthy volunteers (14 women, 14 men) were randomly divided into three groups, corresponding to 6 h of euglycemia (n = 8), 6 h when glucose was clamped at approximately 7 mmol/l (n = 10), or 6 h when glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance (n = 10). Insulin concentrations in all instances were maintained at approximately 65 pmol/l by means of continuous infusions of somatostatin and insulin. Glucagon and growth hormone were also continuously infused to maintain their basal concentrations. Despite substantial differences in both the level and pattern of glucose concentrations, neither maximum cutaneous vasodilation nor the pattern of the vasodilator response to local warming differed over the 6 h of study. We conclude that acute hyperglycemia similar to levels commonly observed in people with either early Type 2 diabetes or impaired glucose tolerance does not alter the vasodilator response to local warming of the skin in humans.