Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects

Raised levels of free fatty acids (FFA) compete with glucose for utilization by insulin-sensitive tissues, and, therefore, they may induce insulin resistance in the normal subject. The influence of experimental elevations in FFA levels on glucose metabolism in native insulin-resistant states is not known. We studied seven women with moderate obesity (63% above their ideal body weight) but normal glucose tolerance with the use of the insulin clamp technique with or without an infusion of Intralipid + heparin. Upon raising plasma insulin levels to approximately 60 microU/mL while maintaining euglycemia, whole body glucose utilization (3H-3-glucose) rose similarly without (from 66 +/- 7 to 113 +/- 11 mg/min m2, P less than .02) or with (from 70 +/- 7 to 137 +/- 19 mg/min m2, P less than .02) concomitant lipid infusion. In contrast, endogenous glucose production was considerably (73%) suppressed (from 66 +/- 7 to 15 +/- 8 mg/min m2, P less than .001) during the clamp without lipid, but declined only marginally (from 70 +/- 7 to 48 +/- 7 mg/min m2, NS) with lipid administration. The difference between the control and the lipid study was highly significant (P less than .02), and amounted to an average of 3.8 g of relative glucose overproduction during the second hour of the clamp. Blood levels of lactate rose by 34 +/- 15% (.1 greater than P greater than .05) in the control study but only by 17 +/- 10% (NS) during lipid infusion. Blood pyruvate concentrations fell in both sets of experiments (by approximately 45% at the end of the study) with similar time courses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance

Summary Recent evidence suggests that the post-prandial hyperglycaemia in impaired glucose tolerance is primarily due to impaired suppression of basal hepatic glucose output. This in turn appears to be secondary to decreased first phase insulin secretion, although decreased hepatic insulin sensitivity, which is a feature of non-insulin-dependent diabetes mellitus, might also play a role. Eight mildly overweight subjects with impaired glucose tolerance and eight closely matched control subjects with normal glucose tolerance underwent an intravenous glucose tolerance test to assess first phase insulin secretion. Insulin sensitivity was examined by a 150-min hyperinsulinaemic-euglycaemic clamp. Somatostatin was infused from 150 min to suppress endogenous insulin secretion, and glucagon and insulin were replaced by constant infusion. Glucose with added dideuterated glucose (labelled infusion technique) was infused to maintain euglycaemia. First phase insulin secretion ( 0–10 min insulin area ÷ 0–10 min glucose area) was significantly decreased in the subjects with impaired glucose tolerance (median [range]: 1.2 [0.2–19.4] vs 9.1 [2.6–14.5] mU·mmol^–1; p<0.01). During the clamp, circulating insulin (93±8 [mean±SEM] and 81±10 mU·l^–1) and glucagon (54±4 and 44±6 ng·l^–1) levels were comparable. Total glucose disposal was decreased in subjects with impaired glucose tolerance (2.78±0.27 vs 4.47±0.53 mg·kg^–1·min^–1; p<0.02), and was primarily due to decreased non-oxidative glucose disposal. However, hepatic glucose output rates were comparable during the clamp (0.38±0.10 and 0.30±0.18 mg·kg^–1·min^–1). Therefore, the main defects in subjects with impaired glucose tolerance are decreased first phase insulin secretion and peripheral non-oxidative glucose disposal, but hepatic glucose output shows normal responsiveness to insulin.Abbreviations FPIS First phase insulin secretion - PG plasma glucose - NIDDM non-insulin-dependent diabetes mellitus - IGT impaired glucose tolerance - HGO hepatic glucose output - IVGTT intravenous glucose tolerance test - OGTT oral glucose tolerance test     

Peripheral hormone levels in healthy subjects during controlled fasting

The effect of one week of controlled fasting (31 of fluid containing 50 g of carbohydrate/day) upon the serum levels of hormones, sex hormone binding globulin, and albumin was studied in healthy subjects. Fasting caused decreased levels of prolactin and T3, no changes in the levels of TSH, FSH, LH, dehydroepiandrosterone, 4-androstene-3, 17-dione, total oestrone, and total testosterone, and increased levels of cortisol, dehydroepiandrosterone sulphate and albumin. A significant positive correlation was found between albumin and dehydroepiandrosterone sulphate. Fasting rapidly increased the levels of sex hormone binding globulin and decreased the percentage of free testosterone and the calculated free testosterone level in both sexes. A decreased metabolic clearance of certain steroids (cortisol, dehydroepiandrosterone sulphate) owing to an increased protein binding may be one of the endocrine consequences of fasting. An increased protein binding of testosterone may be outweighed by a decreased gonadal production, thus resulting in an unchanged total testosterone level. The increased sex hormone binding globulin level could not be explained by changes in gonadal and thyroid hormones.     

Peripheral sensitivity to insulin in aged subjects

Insulin sensitivity has been studied in ten young patients (22 years old means) and in eleven elderly patients (72 years old means). They were free of family diabetes history, glucose intolerance, hypertriglyceridemia, hepatic or renal failure or factor of insulin resistance such as infectious diseases. A two hours hyperinsulinic euglycemic clamp was done with an artificial pancreas (Biostator GCIIS Miles). The ten young patients and the eleven old patients had a stable hyperinsulinic level (93.3 +/- 5 uu/ml and 90 +/- 8 uu/ml) they respectively required 8.08 +/- 0.73 and 5.5 +/- 2.5 mg/kg/min of glucose. Metabolic clearance of insulin does not seem altered with aging. For a same hyperinsulinic level the glucose requirement is less in old patients. So there is an apparent insulin resistance in aging.     

The effect of somatostatin on plasma insulin and growth hormone levels in basal conditions and after glucagon in normal and acromegalic subjects

Summary The effect of low-dose somatostatin (2.5 μg/min i.v.) on blood sugar, insulin and GH levels (basal and after i.v. 1 mg glucagon) was studied in 7 normal and 10 acromegalic subjects. No changes in basal values were noted in normal subjects, whereas the insulin response to glucagon was partly inhibited and the glucose response enhanced. Basal blood glucose was likewise unaltered in the acromegalics. There was, however, a significant, though unrelated, fall in both insulin and GH. The insulin response to glucagon was inhibited to a greater degree than in normal subjects. It is clear, therefore, that somatostatin can inhibit the insulin response to glucagon, as well as that to the other stimuli for which data are given in the literature. Acromegalic subjects appear to be more sensitive to inhibition of insulin secretion by somatostatin, though no relation between this and the drug’s parallel inhibition of GH secretion can be shown.     

Elevated insulin levels contribute to the reduced growth hormone (GH) response to GH-releasing hormone in obese subjects.

We have recently presented experimental evidence indicating that insulin has a physiologic inhibitory effect on growth hormone (GH) release in healthy humans. The aim of the present study was to determine whether in obesity, which is characterized by hyperinsulinemia and blunted GH release, insulin contributes to the GH defect. To this aim, we used a simplified experimental protocol previously used in healthy humans to isolate the effect of insulin by removing the interference of free fatty acids (FFAs), which are known to block GH release. Six obese subjects (four men and two women; age, 30.8 +/- 5.2 years; body mass index, 36.8 +/- 2.8 kg/m2 [mean +/- SE]) and six normal subjects (four men and two women; age, 25.8 +/- 1.9 years; body mass index, 22.7 +/- 1.1 kg/m2) received intravenous (i.v.) GH-releasing hormone (GHRH) 0.6 microg/kg under three experimental conditions: (1) i.v. 0.9% NaCl infusion and oral placebo, (2) i.v. 0.9% NaCl infusion and oral acipimox, an antilipolytic agent able to reduce FFA levels (250 mg at 6 and 2 hours before GHRH), and (3) euglycemic-hyperinsulinemic clamp (insulin infusion rate, 0.4 mU x kg(-1) x min(-1)). As expected, after placebo, the GH response to GHRH was lower for obese subjects versus normals (488 +/- 139 v 1,755 +/- 412 microg/L x 120 min, P < .05). Acipimox markedly reduced FFA levels and produced a mild reduction of insulin levels; under these conditions, the GH response to GHRH was increased in both groups, remaining lower in obese versus normal subjects (1,842 +/- 360 v 4,871 +/- 1,286 microg/L x 120 min, P < .05). In both groups, insulin infusion yielded insulin levels usually observed under postprandial conditions and reduced circulating FFA to the levels observed after acipimox administration. Again, the GH response to GHRH was lower for obese subjects versus normals (380 +/- 40 v 1,075 +/- 206 microg/L x 120 min, P < .05), and in both groups, it was significantly lower than the corresponding response after acipimox. In obese subjects, as previously reported in normals, the GH response to GHRH was inversely correlated with the mean serum insulin (r = -.70, P < .01). In conclusion, our data indicate that in the obese, as in normal subjects, the GH response to GHRH is a function of insulin levels. The finding that after both the acipimox treatment and the insulin clamp the obese still show higher insulin levels and a lower GH response to GHRH than normal subjects suggests that hyperinsulinemia is a major determinant of the reduced GH release associated with obesity.     

Effects of physiologic and supraphysiologic hyperglycemia on early and late-phase insulin secretion in chronically dialyzed uremic patients

To test secretory capacity of the beta-cell to a glucose stimulus in uremic patients on chronic dialysis, three hyperglycemic clamps (plasma glucose increments: 1, 4.5 and 11 mmol/l) were performed in 8 uremic and 8 healthy subjects. Early-phase insulin and C-peptide responses (delta I and delta C) during the initial 6 min were consistently exaggerated at all three steps in uremic patients compared with controls (delta I. 16 +/- 4 vs 4 +/- 2, 41 +/- 11 vs 15 +/- 4 and 60 +/- 12 vs 24 +/- 5 mU/l; delta C. 0.39 +/- 0.13 vs 0.07 +/- 0.02, 0.40 +/- 0.13 vs 0.16 +/- 0.02 and 0.73 +/- 0.15 vs 0.29 +/- 0.04 nmol/l, p less than 0.05 in all cases). Similarly, late-phase insulin secretion defined as the insulin increment between 90 and 120 min after initiation of the glucose challenge was enhanced in uremic patients at the two highest glycemic steps (44 +/- 10 vs 16 +/- 2 and 123 +/- 29 vs 44 +/- 5 mU/l, both p less than 0.01). The raised late-phase insulin response allowed comparable glucose disposal in the two groups (uremic patients: 9.2 +/- 1.0 and 15.5 +/- 1.6 mg.kg-1.min-1. Controls: 9.0 +/- 1.3 and 19.9 +/- 2.4 mg.kg-1.min-1). The slopes of potentiation, i.e. the slopes of the regression lines expressing the relationship between changes in insulin increments and changes in glucose, were markedly steeper in uremic patients (0.45 +/- 0.09 and 0.66 +/- 0.20, early and late-phase respectively) than in controls (0.20 +/- 0.06 and 0.25 +/- 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible roles of insulin,glucagon, growth hormone and free fatty acids in the pathogenesis of insulin resistance of subjects with chronic liver diseases

Summary In the present investigation, insulin sensitivity and fasting levels of insulin, C-peptide, glucagon, growth hormone and free fatty acids were estimated and correlated in a population of individuals suffering from liver cirrhosis or chronic hepatitis. Insulin sensitivity, assessed by glucose disappearance rate after intravenous bolus injection of insulin, was reduced but not significantly different from controls in subjects with chronic persistent hepatitis, while it was significantly reduced in individuals suffering from chronic active hepatitis or liver cirrhosis. Insulin, glucagon, growth hormone, and free fatty acid fasting levels were higher than in healthy subjects in individuals with liver cirrhosis or chronic active hepatitis but not in subjects with chronic persistent hepatitis. C-peptide concentrations did not differ from controls in subjects with liver disease. Significant negative correlations occurred between coefficients of insulin sensitivity and fasting concentrations of insulin, glucagon, growth hormone and free fatty acids, but not with fasting levels of C-peptide. Positive relationships were present between fasting levels of free fatty acids and both glucagon and growth hormone concentrations. These results show that, unlike subjects with liver cirrhosis and chronic active hepatitis, individuals suffering from chronic persistent hepatitis do not differ from healthy subjects in insulin sensitivity and fasting levels of insulin, glucagon, growth hormone, and free fatty acids. Moreover, they suggest that both hyperinsulinemia and high concentrations of counterregulatory substances might play a role in the pathogenesis of insulin resistance in subjects suffering from chronic liver disease. Supported by grants from the Ministry of Public Education and grant No. 83/02132.04 from the National Research Council (C.N.R.), Rome.     

Growth hormone response to growth hormone-releasing hormone in normal and uraemic children. Comparison with hypoglycaemia following insulin administration

The uraemic syndrome is characterized by several endocrinological disturbances. This study was undertaken in order to evaluate the GH response to growth hormone-releasing hormone (GRH) in children with chronic renal failure (CRF) and to compare the results with those observed after insulin hypoglycaemia. Twenty-two children with CRF, 10 undergoing continuous ambulatory peritoneal dialysis (CAPD) and 12 on conservative treatment (CT), age ranges 2-15 years, were studied and the data were compared with those from 14 children with normal renal function and normal hormonal behaviour, affected by short stature (NC), and those form 13 healthy adult volunteers (NA). The GRH test (l micrograms/kg body weight, iv) was carried out in 8 CAPD, 8 CT, 9 NC and 10 NA subjects. The blood samples were taken every 30 min for 3 h in CAPD and CT and for 2 h in NC and NA starting at 09.00 h. The following hormones were measured: GH, LH, FSH, Prl, TSH and cortisol (F). The insulin test (0.1 U/kg body weight, iv) was carried out in 5 CAPD, 5 CT, 10 NC and 9 NA on blood samples taken every 30 min for 2 h, measuring GH and glycaemia. No adverse effects were observed after the infusion of GRH. GRH administration induced a prompt response in all subjects, but GH plasma levels were significantly higher in uraemic children than in adults (peak value of 43.5 +/- 8.2, 45.0 +/- 8.4, 27.8 +/- 6.0; 13.5 +/- 2.6 micrograms/ml in CAPD, CT, NC and NA, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral and hepatic insulin antagonism in hyperthyroidism

Eight hyperthyroid and eight normal subjects underwent 2-h oral glucose tolerance tests (OGTT) and euglycemic clamp studies to assess the presence of peripheral and hepatic insulin antagonism in hyperthyroidism. Although the mean total glucose area during the OGTT was similar in the hyperthyroid patients and normal subjects [16.4 +/- 0.8 (+/- SE) vs. 15.8 +/- 0.7 mmol/L.h], the mean insulin area was significantly elevated in the hyperthyroid group (1413 +/- 136 vs. 1004 +/- 122 pmol/L.h; P less than 0.05). Basal hepatic glucose production was measured during the second hour of a primed [3-3H]glucose infusion. A two-insulin dose euglycemic clamp study with [3-3H]glucose and somatostatin (500 micrograms/h) was carried out during the next 6 h. The insulin infusion rate was 0.05 mU/kg.min during the third, fourth, and fifth hours and 0.60 mU/kg.min during the sixth, seventh, and eighth hours. Hepatic glucose production and glucose utilization were measured during the final 0.5 h of each clamp period. Serum C-peptide concentrations were measured in the initial sample and in the last sample of each clamp period. The mean equilibrium serum insulin concentrations were similar in both groups during the final 0.5 h of the low (90 +/- 8 vs. 79 +/- 6 pmol/L) and high (367 +/- 11 vs. 367 +/- 15 pmol/L) insulin infusion rates. Basal serum C-peptide levels were significantly increased in the hyperthyroid patients (596 +/- 17 vs. 487 +/- 43 pmol/L; P less than 0.05) but were suppressed equally in both groups at the end of both clamp periods. The MCRs of insulin were similar in the hyperthyroid and normal subjects during the low (6.7 +/- 1.1 vs. 5.6 +/- 0.5 mL/kg.min) and high (11.9 +/- 0.4 vs. 12.1 +/- 0.5 mL/kg.mm) insulin infusion rates. Glucose production was significantly increased in the hyperthyroid patients during the basal state (17.6 +/- 0.9 vs. 11.5 +/- 0.5 mumol/kg.min; P less than 0.001) and remained elevated during the final 0.5 h of the low (12.1 +/- 1.1 vs. 5.9 +/- 1.7; P less than 0.01) and high (3.2 +/- 1.2 vs. 0.5 +/- 0.3; P less than 0.05) insulin infusion rates. Peripheral insulin action, assessed by Bergman's sensitivity index, was significantly decreased in the hyperthyroid patients (7.4 +/- 2.2 vs. 15.6 +/- 2.1 L/kg min-1/pmol/L; P less than 0.02). In conclusion, hyperthyroidism is characterized by 1) hyperinsulinemia after oral glucose loading, 2) increased basal hepatic glucose production, 3) impairment of insulin-mediated suppression of hepatic glucose production, and 4) antagonism to insulin-stimulated peripheral glucose utilization.     

Plasma insulin and glucagon levels in protein-malnourished rats

The plasma concentrations of insulin and glucagon were measured in an experimental rat model for protein malnutrition. Plasma insulin levels were markedly reduced, while plasma glucagon levels were comparable to adequately fed age controls.     

Peripheral resistance to thyroid hormone in an infant

Peripheral resistance to thyroid hormone, a syndrome characterized by elevated serum total and free thyroid hormone levels and abnormal TSH suppression without manifestations of hyperthyroidism, was studied in a clinically euthyroid 6-month-old infant. Initial serum concentrations of T4, T3, and TSH were 22.1 micrograms/dl, 334 ng/dl, and 7.6 microunits/ml, respectively; infusion of synthetic TRH increased the serum TSH to 47.4 microunits/ml, an exaggerated response. Pituitary insensitivity to T3 was investigated by measuring these parameters in response to consecutive 7-day courses of increasing doses of T3. Four times the calculated replacement dose of T3 (40 micrograms/day) was required to normalize the serum T4 and the serum TSH response to TRH. After administration of 80 micrograms/day T3, the serum TSH response to TRH was virtually abolished, but no clinical signs of thyroid hormone excess were observed. High doses of T4 blunted the serum TSH response to TRH in a manner similar to T3. Prednisone also decreased the TSH response to TRH but had no effect on serum thyroid hormone concentrations. In an attempt to determine the mechanism of thyroid hormone resistance, specific nuclear T3 binding was compared in cultured skin fibroblasts from the patient and a normal infant. Normal fibroblast nuclei had a single binding site with a Ka of 3.1 X 10(9) M-1. In contrast, the Scatchard plot of the patient's T3 binding was curvilinear, compatible with a high affinity site that had a Ka (4.2 X 10(9) M-1) similar to that of the normal fibroblasts and a second low affinity site (Ka = 2.7 X 10(8) M-1). Supraphysiological concentrations of T3 elicited a dose-related increase in fibroblast glucose consumption, which was similar in cells from both the patient and from a normal infant. In conclusion, pituitary and peripheral resistance to thyroid hormone has been demonstrated in this infant, but despite the abnormality of nuclear T3 binding, the cellular mechanisms remain unclear.     

Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects

Data from studies in animal models indicate that certain lipid metabolites, particularly diacylglycerol, ceramide, and acylcarnitine, disrupt insulin action. We evaluated the relationship between the presence of these metabolites in the liver (assessed by mass spectrometry) and hepatic insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp with stable isotope tracer infusion) in 16 obese adults (body mass index, 48 ± 9 kg/m2). There was a negative correlation between insulin-mediated suppression of hepatic glucose production and intrahepatic diacylglycerol (r = -0.609; P = .012), but not with intrahepatic ceramide or acylcarnitine. These data indicate that intrahepatic diacylglycerol is an important mediator of hepatic insulin resistance in obese people with nonalcoholic fatty liver disease.     

Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects

BACKGROUND AND AIMS: Abdominal fat accumulation (visceral/hepatic) has been associated with hepatic insulin resistance (IR) in obesity and type 2 diabetes (T2DM). We examined the relationship between visceral/hepatic fat accumulation and hepatic IR/accelerated gluconeogenesis (GNG). METHODS: In 14 normal glucose tolerant (NGT) (body mass index [BMI] = 25 +/- 1 kg/m(2)) and 43 T2DM (24 nonobese, BMI = 26 +/- 1; 19 obese, BMI = 32 +/- 1 kg/m(2)) subjects, we measured endogenous (hepatic) glucose production (3-(3)H-glucose) and GNG ((2)H(2)O) in the basal state and during 240 pmol/m(2)/min euglycemic-hyperinsulinemic clamp, and liver (LF) subcutaneous (SAT)/visceral (VAT) fat content by magnetic resonance spectroscopy/magnetic resonance imaging. RESULTS: LF was increased in lean T2DM compared with lean NGT (18% +/- 3% vs 9% +/- 2%, P < .03), but was similar in lean T2DM and obese T2DM (18% +/- 3% vs 22% +/- 3%; P = NS). Both VAT and SAT increased progressively from lean NGT to lean T2DM to obese T2DM. T2DM had increased basal endogenous glucose production (EGP) (NGT, 15.1 +/- 0.5; lean T2DM, 16.3 +/- 0.4; obese T2DM, 17.2 +/- 0.6 micromol/min/kg(ffm); P = .02) and basal GNG flux (NGT, 8.6 +/- 0.4; lean T2DM, 9.6 +/- 0.4; obese T2DM, 11.1 +/- 0.6 micromol/min/kg(ffm); P = .02). Basal hepatic IR index (EGP x fasting plasma insulin) was increased in T2DM (NGT, 816 +/- 54; lean T2DM, 1252 +/- 164; obese T2DM, 1810 +/- 210; P = .007). In T2DM, after accounting for age, sex, and BMI, both LF and VAT, but not SAT, were correlated significantly (P < .05) with basal hepatic IR and residual EGP during insulin clamp. Basal percentage of GNG and GNG flux were correlated positively with VAT (P < .05), but not with LF. LF, but not VAT, was correlated with fasting insulin, insulin-stimulated glucose disposal, and impaired FFA suppression by insulin (all P < .05). CONCLUSIONS: Abdominal adiposity significantly affects both lipid (FFA) and glucose metabolism. Excess VAT primarily increases GNG flux. Both VAT and LF are associated with hepatic IR.     

Effect of furosemide on insulin and glucagon responses to arginine in normal subjects

Summary This study aimed at evaluating the influence of furosemide upon insulin and glucagon responses to arginine in healthy subjects. For this purpose, six normal subjects received two consecutive arginine pulses (3 g), 60 min apart, before and after the administration of furosemide (40 mg, IV). The acute insulin response (mean change from 3–10 min) to the second arginine pulse was significantly inhibited by furosemide (mean increase: 14.8 ±3.0 U/ml versus 11.7±2.5 U/ml, p<0.01). By contrast, the acute glucagon response was significantly increased (mean increase: 77±18 pg/ml versus 105±21 pg/ml, p<0.01). No significant changes in plasma glucose levels occurred. In control experiments, in which saline rather than furosemide was administered, the acute insulin and glucagon response to the first arginine pulse did not differ from that observed with the second pulse. The effect of furosemide on insulin and glucagon secretion might be mediated through enhanced release of endogenous prostaglandin E.     

Hyperglucagonism and glucagon resistance in cirrhosis. Paradoxical effect of propranolol on plasma glucagon levels

Propranolol, a non-selective beta-blocker, is known to decrease glucagon release in normal subjects. The present study was aimed at investigating the effects of propranolol on the hyperglucagonism commonly observed in patients with cirrhosis. Eight cirrhotic patients and 6 matched healthy controls were studied. The plasma concentrations of glucagon, insulin, c-peptide and glucose were measured in basal conditions and after stimulating glucagon secretion by an i.v. infusion of arginine (0.4 g/kg/30 min). The study was repeated 24 h later after inducing beta-blockade by the i.v. infusion of propranolol (10 mg). In baseline conditions, patients with cirrhosis, despite normal levels of insulin and glucose, had a marked hyperglucagonism (654 +/- 303 pg/ml vs. 269 +/- 90 in controls, P less than 0.01). Prior to propranolol, arginine infusion caused greater glucagon release in cirrhotics (71 +/- 31 ng.h.ml-1) than in controls (33 +/- 17 ng.h.ml-1, P less than 0.02), but despite a similar insulin secretion (assessed from c-peptide), blood glucose did not increase. After propranolol, glucagon secretion decreased as expected in controls (29 +/- 12 ng.h.ml-1, P less than 0.05) but experienced a paradoxical increase in cirrhotics (113 +/- 64 ng.h.ml-1, P less than 0.05). Again, despite the marked increase in glucagon release, there was no increase in glucose production, providing further evidence of the glucagon resistance that accompanies hyperglucagonism in cirrhosis. Our results suggest that hyperglucagonism with glucagon resistance might be the initial disturbance in carbohydrate metabolism in patients with cirrhosis. Contrary to what could be expected, propranolol does not correct but further accentuates this disturbance.     

Evaluation of insulin resistance during inhibition of endogenous insulin and glucagon secretion by somatostatin in non-obese subjects with impaired glucose tolerance

Summary Insulin resistance was studied in seven non-obese male subjects with impaired glucose tolerance and four healthy, age and body-weight matched male control subjects by means of a continuous intravenous infusion of somatostatin, glucose and insulin over 150 min. Glucose tolerance was evaluated by means of a 2-h glucose infusion test. Endogenous insulin (C-peptide), growth hormone, and glucagon secretion were suppressed by somatostatin in both groups. Steady-state plasma insulin and glucose levels were achieved between 90–135 min. Since similar steady-state levels of exogenous insulin were achieved, the resulting steady-state plasma glucose level provided a direct estimate of the ability of insulin to dispose of the infused glucose. The glucose levels were higher in subjects with impaired glucose tolerance with values of 14.6 ± 1.8 mmol/1 compared with 5.1 ± 1.2 mmol/1 in control subjects (p < 0.01), thus indicating insulin resistance. There was a direct correlation between the steady-state plasma glucose level and glucose tolerance suggesting that the degree of glucose intolerance is proportional to the degree of insulin resistance. These results revealed that decreased insulin sensitivity is found in non-obese subjects with impaired glucose tolerance.     

The effect of glucose on the growth hormone response to glucagon and propranolol-glucagon in normal subjects.

The mean (+/- SE) peak level of serum growth hormone (GH) after intramuscular injection of glucagon in ten normal adult men was 15.1 +/- 2.1 ng/ml; glucose infusion suppressed the mean peak GH to 9.6 +/- 3.7 ug/ml (p less than 0.05). Pretreatment of eight of these subjects with propranolol caused a modest increase in the mean peak GH after glucagon (19.4 +/- 2.8 ng/ml) but did not improve the mean peak GH after glucagon when glucose was infused (8.7 +/- 2.8 ng/ml). Individual analysis of the peak GH showed that glucose infusion did not uniformly suppress the peak GH after glucagon; in seven subjects the peak GH was suppressed but in three it was not. Conclusions: (1) The GH response after glucagon is usually due to a fall in serum glucose after the initial rise in serum glucose induced by glucagon. (2) Nevertheless, since glucose does not consistently inhibit the GH response after glucagon, a second mechanism probably exists by which glucagon stimulates GH secretion. (3) Glucose completely suppresses the propranolol-induced increase in the GH response to glucagon; an adrenergic mechanism may be involved in the control of GH secretion by glucose.