Effects of morbid obesity on insulin clearance and insulin sensitivity in several aspects of metabolism as assessed by low-dose insulin infusion.

Obesity is associated with impaired insulin action in glucose disposal, but not necessarily in other aspects of intermediary metabolism or insulin clearance. Sixteen morbidly obese and 14 normal-weight subjects (body mass index, 51.2 +/- 11.5 v 22.1 +/- 2.2 kg.m-2; mean +/- SD) were studied with sequential, low-dose, incremental insulin infusion with estimation of glucose turnover. In obese patients, basal plasma insulin was higher (10.5 +/- 3.8 v 2.4 +/- 3.0 mU.L-1, P less than .001) and remained elevated throughout infusion (F = 492, P less than .001), as did C-peptide (F = 22.7, P less than .001). Metabolic clearance rate for insulin (MCRI) at the highest infusion rate was similar (1,048 +/- 425 v 1,018 +/- 357 mL.m-2.min-1, NS). Basal hepatic glucose production in obese subjects was less than in normal-weight subjects (270 +/- 108 v 444 +/- 68 mumol.m-2.min-1, P less than .01), as was the basal metabolic clearance rate for glucose (MCRG, 77 +/- 26 v 108 +/- 31 mL.m-2.min-1, P less than .05). Insulin infusion caused blood glucose to decrease less in the obese patients (1.4 +/- 0.5 v 1.9 +/- 0.5 mmol.L-1, P less than .05); hepatic glucose production was appropriately suppressed in them by hyperinsulinemia, but their insulin-mediated glucose disposal was reduced (1.67 [0.79] v 4.45 [2.13] mL.m-2.min-1/mU.L-1, P less than .01). Concentrations of nonesterified fatty acids (NEFA), glycerol, and ketones were elevated throughout the insulin infusions in obese patients, despite the higher insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of weight loss in massive obesity on insulin and C-peptide dynamics: sequential changes in insulin production, clearance, and sensitivity

In massively obese patients hyperinsulinemia and insulin insensitivity usually improve with weight loss. To clarify the mechanism of these reversible abnormalities eight nondiabetic massively obese patients were studied before and at intervals (3 months and 1 yr) after weight loss following gastroplasty. Insulin dynamics were studied during the hyperglycemic clamp (change in glucose, 7 mmol L-1 for 2 h) by measuring the area under the insulin and C-peptide response curves, representing, respectively, systemic insulin response and insulin production. Compared to lean age-matched normal subjects the massively obese patients had the expected fasting hyperinsulinemia and an exaggerated insulin response (P less than 0.05). Within 3 months and after an approximately 20% weight loss, they had a marked reduction in the systemic insulin response but no change in the C-peptide response. Therefore, the reduction in insulin response was due to enhanced hepatic insulin clearance rather than reduced insulin production. Thus, the liver serves a gate-keeping role in regulating the systemic insulin response to a glucose challenge. With additional weight loss of 14% and then weight maintenance, insulin clearance was further increased, and a reduction in insulin production became evident, since the C-peptide response was reduced. Exogenous insulin clearance was measured using the euglycemic clamp technique before and after weight loss. Insulin clearance was initially lower in the massively obese patients compared to that in the normal subjects (P less than 0.05) and increased toward normal with weight loss (P less than 0.05). Similarly, insulin sensitivity, as measured by the ratio of glucose metabolised per U endogenous insulin, normalized with weight loss and weight maintenance. Thus, after significant weight loss followed by weight maintenance at a reduced, but not ideal, level, insulin clearance, production, and sensitivity all reverted to normal. These findings suggest that adipose mass per se may not be exclusively responsible for altered insulin and glucose dynamics in obesity and that additional factors associated with obesity, such as nutrient load, adipose distribution, fat cell size, or fatty acid flux, play a contributing role.     

Suppression of basal, but not of glucose-stimulated insulin secretion by human insulin in healthy and obese hyperinsulinemic subjects

To evaluate the suppressive effect of biosynthetic human insulin (BHI; 2.5 U/m2 . h) on basal and glucose-stimulated insulin secretion in healthy and obese hyperinsulinemic subjects, the plasma C-peptide response was measured during maintenance of euglycemia and hyperglycemia by means of the glucose clamp technique. In five healthy subjects in whom arterial insulin concentration was increased to 94 +/- 8 microU/mL, but euglycemia was maintained at the fasting level. C-peptide concentration fell from 1.3 +/- 1.0 ng/mL by 21 +/- 8% (P less than 0.05). When hyperglycemia of 7 mmol/L above basal was induced by a variable glucose infusion, the C-peptide response was similar in the control (5.0 +/- 0.6 ng/mL) and BHI experiments (4.7 +/- 0.6 ng/mL) and was paralleled by an identical increase in plasma insulin above the prevailing insulin concentration. In seven obese patients plasma C-peptide fell from 3.5 +/- 0.4 to 2.8 +/- 0.5 ng/mL (P less than 0.05) when BHI was infused at the same rate of euglycemia maintained as in the lean subjects. As in healthy subjects, however, the plasma C-peptide response to the hyperglycemic stimulus (8.7 +/- 0.9 ng/mL) was not altered by BHI (7.9 +/- 0.8 ng/mL). Glucose utilization as determined by the glucose infusion rate necessary to maintain the desired glucose level was reduced by half in the obese patients compared with that of normal subjects. From these data we conclude that in healthy as well as obese hyperinsulinemic subjects, insulin at concentrations capable of suppressing its basal secretion fails to suppress its glucose-stimulated secretion.     

Reversal of steroid-induced insulin resistance by a nicotinic-acid derivative in man.

A recent report suggested that the glucose-free fatty acid (FFA) cycle may contribute to steroid-induced insulin resistance in rats, and that glucose tolerance could be restored to normal when FFA levels were lowered with nicotinic acid. To test this hypothesis in man, we measured insulin sensitivity (by euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) before and after short-term administration of a nicotinic-acid derivative (Acipimox) in 10 steroid-treated, kidney transplant patients with insulin resistance. Thirty-five healthy subjects served as controls. Six of them received Acipimox. Total body glucose metabolism was reduced in steroid-treated patients compared with control subjects (41.7 +/- 3.3 v 50.0 +/- 2.2 mumol/kg lean body mass [LBM].min, P less than .05). The reduction in insulin-stimulated glucose uptake was mainly due to an impairment in nonoxidative glucose metabolism (primarily glucose storage as glycogen) (18.3 +/- 2.8 v 27.2 +/- 2.2 mumol/kg LBM.min, P less than .01). Acipimox lowered basal FFA concentrations (from 672 +/- 63 to 114 +/- 11 mumol/L, P less than .05) and the rate of lipid oxidation measured in the basal state (1.5 +/- 0.2 to 0.6 +/- 0.1 mumol/kg LBM.min, P less than .01) and during the clamp (0.7 +/- 0.2 to 0.03 +/- 0.2 mumol/kg LBM.min, P less than .05). In addition, Acipimox administration normalized total glucose disposal (to 54.4 +/- 4.4 mumol/kg LBM.min), mainly due to enhanced nonoxidative glucose metabolism (to 28.9 +/- 3.9 mumol/kg LBM.min) in steroid-treated patients (both P less than .05 v before Acipimox).(ABSTRACT TRUNCATED AT 250 WORDS)     

Type I diabetes is characterized by insulin resistance not only with regard to glucose, but also to lipid and amino acid metabolism

Resistance to the metabolic effects of insulin has been reported with regard to glucose disposal in type I diabetic patients (IDDM) even when they were euglycemic. Our aim was to study glucose, lipid, and amino acid metabolism during glucose clamping at multiple levels of insulin in 10 normal (N) and 6 IDDM patients. Blood glucose was maintained constant (4.7 mmol/liter) at three insulin plateaus (160 min each) [42 +/- 6 (SD) 89 +/- 11, and 1255 +/- 185 microU/ml in N and 36 +/- 4, 80 +/- 13, and 1249 +/- 107 microU/liter in IDDM]. Mean glucose disposal was 34 +/- 11, 69 +/- 10, and 84 +/- 22 mumol kg-1 min-1 in N and 16 +/- 5, 40 +/- 18, and 65 +/- 27 in IDDM, respectively. Baseline concentrations of blood lactate, pyruvate, alanine, and branched chain amino acids were 560 +/- 130, 36 +/- 9, 212 +/- 44, and 451 +/- 19 mumol/liter, in N and 793 +/- 179 (P less than 0.05), 45 +/- 14, 195 +/- 50, and 439 +/- 33 in IDDM, respectively. The maximum percent change of lactate during the euglycemic clamp was +147 +/- 23% in N and +75 +/- 15% (P less than 0.05) in IDDM; that of branched chain amino acids was -61 +/- 5% in N and -48 +/- 7% (P less than 0.01) in IDDM. Baseline concentrations of glycerol, FFA, and adipate were 44 +/- 15, 449 +/- 152, and 8 - 8 mumol/liter in N and 39 +/- 14, 473 +/- 44, and 41 +/- 14 (P less than 0.01) in IDDM. The maximum percent change of glycerol during the euglycemic clamp was -50 +/- 8% in N and -16 +/- 8% (P less than 0.01) in IDDM, that of FFA -98 +/- 3% in N and -70 +/- 4% in IDDM (P less than 0.05). No significant differences were found between N and IDDM with regard to blood concentrations of ketone bodies, citrate, ketoglutarate, and hydroxymethylglutaryl coenzyme A both before and during the euglycemic clamp. The lactate percent increase was significantly correlated to glucose disposal rate (P less than 0.001). The lactate turnover rate increased during the euglycemic clamp and was lower in IDDM than in N. We conclude that during euglycemic-multiple insulin clamp studies the greater lactate increase suggests that the flux of glycolysis is higher in N than in IDDM, tricarboxylic acid concentrations are comparable in N and IDDM, and FFA, glycerol, and branched chain amino acid decreases were less in IDDM than in N, suggesting that IDDM patients are resistant to insulin with regard to lipid and protein metabolism. The higher adipate basal values demonstrate enhanced omega-oxidation in IDDM.     

Lack of insulin inhibition on insulin secretion in non-diabetic morbidly obese patients.

OBJECTIVE: Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance. SUBJECTS: Twelve obese patients, normotolerant to glucose (8 F/4 M, body mass index (BMI)=54.8+/-2.5 kg/m(2), 39 y) and 16 lean control subjects (10 F/6 M, BMI=22.0+/-0.5 kg/m(2), 31 y). DESIGN AND MEASUREMENTS: An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280 pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry. RESULTS: The obese subjects were insulin resistant (M=19.8+/-1.6 vs 48.7+/-2.6 micromol/min kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425+/-131 pmol/l vs lean 550+/-63 pmol/l; P<0.0001) decreased less during the clamp in the obese groups (-16.9+/-6.9% vs -43.0+/-5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation. CONCLUSION: We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.     

Effects of ketone bodies on basal and insulin-stimulated glucose utilization in man

Using the euglycemic clamp technique, we investigated the effects of high ketone body levels on basal and insulin-stimulated glucose utilization in normal subjects. Infusion of sodium acetoacetate in the postabsorptive state raised ketone body levels from 150 +/- 20 (+/- SE) mumol/liter to more than 1 mmol/liter. Endogenous glucose production declined from 2.71 +/- 0.20 mg kg-1 min-1 to 1.75 + 0.26 (P less than 0.01) and glucose utilization from 2.71 +/- 0.20 to 1.98 +/- 0.17 mg kg-1 min-1 (P less than 0.01), while blood glucose was maintained at the initial level by the infusion of glucose. There were no changes in plasma glucagon, insulin, or C-peptide. Plasma nonesterified fatty acids (P less than 0.01) and blood glycerol (P less than 0.01) and alanine (P less than 0.05) decreased, while blood lactate increased (P less than 0.01). Infusion of sodium bicarbonate had no effect on glucose kinetics. The decreases in glucose utilization and endogenous glucose production during the infusion of acetoacetate were not modified when the fall of plasma nonesterified fatty acids was prevented by iv heparin injection. During control euglycemic hyperinsulinemic clamps (1 and 10 mU kg-1 min-1 insulin infusion), endogenous glucose production was suppressed at the lowest insulin infusion rate; glucose utilization increased first to 7.32 +/- 0.96 mg kg-1 min-1 and then to 16.5 +/- 1.27 mg kg-1 min-1. During euglycemic hyperinsulinemic clamps with simultaneous sodium acetoacetate infusion, similar insulin levels were attained; endogenous glucose production was also suppressed at the lowest insulin infusion rate, and insulin-stimulated glucose utilization rates (7.93 +/- 1.70 and 15.80 +/- 1.30 mg kg-1 min-1) were not modified. In conclusion, acetoacetate infusion decreased basal, but not insulin-stimulated, glucose utilization. The increase in lactate during acetoacetate infusion in the postabsorptive state suggests that ketone body acted by decreasing pyruvate oxidation.     

Insulin resistance is a characteristic feature of primary hypertension independent of obesity

The relationship between abnormalities in carbohydrate metabolism and hypertension was studied in 143 newly detected hypertensive patients (59% obese) of both sexes (90 males, 53 females) and compared with 51 normotensive controls. Insulin-mediated glucose disposal assessed with the euglycemic insulin clamp technique was significantly decreased in both non-obese (7.2 +/- 2.1 mg/kg/min; P less than .05) and obese hypertensives (5.1 +/- 2.1 mg/kg/min; P less than .01) compared with the controls (8.4 +/- 1.8 mg/kg/min). The decrease in insulin sensitivity and increase in basal insulin as well as a decreased rate of glucose disposal after an intravenous glucose tolerance test (IVGTT) were verified also after statistical adjustment for sex, age, body mass index, and waist-hip ratio. The insulin index (ratio between peak and basal insulin) during IVGTT was significantly decreased in the hypertensive patients (P less than .001). After the statistical adjustment for the factors mentioned the following lipid abnormalities were still significant: total cholesterol (6.25 +/- 1.12 mmol/L non-obese; 6.06 +/- 1.20 mmol/L obese; 5.41 +/- 1.02 mmol/L controls), triglycerides (1.70 +/- 0.74 mmol/L nonobese; 2.26 +/- 1.13 mmol/L obese; 1.24 +/- 0.53 mmol/L controls) and free fatty acids (0.57 +/- 0.20 mmol/L nonobese; 0.59 +/- 0.20 mmol/L obese; 0.48 +/- 0.15 mmol/L controls). This study shows that after correction for a series of probable confounding variables, hypertension emerges as part of a syndrome characterized by major abnormalities of carbohydrate, insulin, and lipid metabolism, which independently or in concert may act as important risk factors for cardiovascular disease.     

Physiologic hyperinsulinemia stimulates lactate extraction by heart muscle in the conscious dog

The effect of physiologic hyperinsulinemia on the net balance of lactate, glucose, and free fatty acids across the heart was studied in eight normal postabsorptive conscious dogs. After obtaining basal measurements of myocardial substrate balance, arterial plasma insulin was increased from 8 +/- 1 to 68 +/- 14 microU/mL while blood glucose was maintained constant (64 +/- 1 mg/dL) using the hyperinsulinemic euglycemic clamp. Myocardial lactate uptake increased nearly fourfold, from 5.8 +/- 1.8 to 22.4 +/- 2.9 mumol/min (P less than .005). Despite a small increase in arterial lactate concentration from 0.46 +/- 0.08 to 0.79 +/- 0.11 mmol/L (P less than .02), the lactate extraction fraction increased from 23% +/- 7% to 54% +/- 2% (P less than .001) indicating an increased efficiency of lactate extraction. Euglycemic hyperinsulinemia led to a comparable increase in myocardial glucose uptake (6.7 +/- 2.3 to 18.2 +/- 3.7 mumol/min, P less than .05). Arterial free fatty acid concentrations fell from 1.06 +/- 0.13 to 0.35 +/- 0.06 mmol/L (P less than .001) with a concomitant decline in the myocardial uptake of free fatty acids from 18.5 +/- 5.3 to 5.8 +/- 2.9 mumol/min (P less than .05). These results indicate that physiologic hyperinsulinemia increases lactate as well as glucose uptake in normal heart muscle.     

Hyperglycemia per se can reduce plasma free fatty acid and glycerol levels in the acutely insulin-deficient dog

To evaluate the in vivo effect of hyperglycemia per se on plasma free fatty acid (FFA) and glycerol concentrations, euglycemic and hyperglycemic clamp studies were performed in six overnight fasted dogs in the state of insulin deficiency produced by somatostatin (SRIF) infusion. The mean blood glucose concentrations during the steady-state (the second hour of each study) averaged 4.65 +/- 0.10 mmol/L in euglycemic clamp and 14.11 +/- 0.10 mmol/L in hyperglycemic clamp. During the SRIF infusion, plasma FFA concentrations increased from 0.32 +/- 0.05 mumol/mL at the basal state to 0.76 +/- 0.04 mumol/mL at the steady-state in euglycemic clamp and from 0.26 +/- 0.04 mumol/mL to 0.43 +/- 0.02 mumol/mL in hyperglycemic clamp. Plasma glycerol concentrations increased from the basal value of 0.07 +/- 0.01 mumol/mL to 0.15 +/- 0.01 mumol/mL during the steady-state in euglycemic clamp and from 0.06 +/- 0.01 mumol/mL to 0.08 +/- 0.01 mumol/mL in hyperglycemic clamp. The steady-state concentrations of plasma FFA and glycerol in hyperglycemic clamp were significantly lower than those in euglycemic clamp (P less than .001; respectively). These results suggest that hyperglycemia per se might decrease plasma FFA and glycerol concentrations at least in part by decreasing lipolysis in the acutely insulin-deficient dog.     

Lipolysis and gluconeogenesis from glycerol are increased in patients with noninsulin-dependent diabetes mellitus.

The rate of lipolysis (glycerol Ra), gluconeogenesis from glycerol, and its contribution to overall hepatic glucose production (glucose Ra) were determined in 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) [body mass index (BMI) 27.2 +/- 1.0 kg/m2, fasting plasma glucose 10.3 +/- 1.2 mmol/L], and in 6 matched control subjects (BMI 27.3 +/- 1.1 kg/m2, fasting plasma glucose 5.3 +/- 0.3 mmol/L) using infusions of [3-3H]glucose (0-600 min) and [U-14C]glycerol (360-600 min). Glycerol Ra was increased in the patients with NIDDM (120 +/- 16 mumol/m2.min) compared to the normal subjects (84 +/- 9 mumol/m2.min, P less than 0.05). Gluconeogenesis from glycerol was 1.7-fold higher in the patients (96 +/- 16 mumol/m2.min) than in the normal subjects (56 +/- 10 mumol/m2.min, P less than 0.05), and explained 9 +/- 1% and 7 +/- 1% (NS) of total glucose Ra in patients with NIDDM and normal subjects, respectively. To determine whether these abnormalities are more pronounced in overweight patients with NIDDM, glucose and glycerol Ra were also determined in 5 obese patients with NIDDM (BMI 36.4 +/- 1.0 kg/m2, fasting plasma glucose 11.3 +/- 1.3 mmol/L). Glycerol Ra (154 +/- 26 mumol/m2.min) was again higher than in the normal subjects (P less than 0.05) but not different from that in the less obese patients with NIDDM. The rate of gluconeogenesis from glycerol (159 +/- 20 mumol/m2.min) was significantly higher in the obese than in the less obese patients with NIDDM (P less than 0.05) but its contribution to total glucose Ra (10 +/- 1%) was similar to that in the less obese patients with NIDDM. When all data were analyzed together, gluconeogenesis from glycerol (r = 0.57, P less than 0.01) but not lipolysis (r = 0.02, NS) correlated with the percentage of lipolysis diverted toward gluconeogenesis suggesting that the rate of gluconeogenesis from glycerol is regulated by intrahepatic mechanisms rather than by glycerol availability. Neither the rate of lipolysis nor the rate of glycerol gluconeogenesis correlated with BMI, serum triglyceride, or insulin concentrations. We conclude that gluconeogenesis from glycerol is increased in patients with NIDDM. This increase appears to be the consequence of both accelerated lipolysis and increased intrahepatic conversion of glycerol to glucose.     

Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(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.     

Hyperinsulinemia in the physiologic range is not superior to short-term fasting in suppressing insulin secretion in obese men

The negative-feedback control exerted by plasma insulin on beta-cell insulin release in normal-weight and obese subjects is still a matter of debate. Subjects submitted to a euglycemic insulin clamp undergo a suppression of insulin secretion that is due to both the infused insulin and the 2- to 3-hour fast during the procedure. We elected to elucidate the role of physiologic hyperinsulinemia per se in the insulin negative autofeedback in obese men. Ten men with massive uncomplicated obesity (age, 18 to 37 years; body mass index [BMI], 41 +/- 1.15 kg/m2) and 6 normal-weight healthy men (age, 22 to 30 years; BMI, 22 +/- 0.28 kg/m2) underwent 2 studies in random order: (1) a euglycemic-hyperinsulinemic glucose clamp with an insulin infusion rate of 1 mU/kg/min and (2) a control study with saline infusion. Serum C-peptide concentrations were significantly higher in obese versus control subjects at baseline (2.54 +/- 0.178 v 1.63 +/- 0.256 ng/mL, P < .05). Exogenous insulin infusion significantly suppressed serum C-peptide at steady state ([SS] last 30 minutes of insulin or saline infusion) in controls (mean of the last 4 measurements from 120 minutes to 150 minutes, 0.86 +/- 0.306 ng/mL, P < .05 vbaseline) but not in obese patients (2.03 +/- 0.26 ng/mL, nonsignificant [NS] v baseline). During the saline infusion studies, C-peptide levels slightly and similarly declined over time in both groups (2.71 +/- 0.350 at baseline v 2.31 +/- 0.300 ng/mL at SS in obese patients, NS, and 1.96 +/- 0.189 v 1.62 +/- 0.150 ng/mL in controls, NS). This study shows that in obese men hyperinsulinemia within the postprandial range is not superior to a 2.5-hour fast for the suppression of beta-cell activity, suggesting an impairment of the insulin negative autofeedback in this clinical condition.     

Obesity and insulin resistance in humans: a dose-response study

Insulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) were examined in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls. In 10 obese and eight control subjects, insulin was infused at six rates to increase plasma insulin concentration by approximately 10, 20, 40, 80, 2,000, and 20,000 microU/mL. Throughout the physiologic range of plasma insulin concentrations, both the increase in total body glucose uptake and the suppression of hepatic glucose production (HGP) were significantly impaired in the obese group (P less than .001 to .01). At the two highest plasma insulin concentrations, inhibition of HGP and the stimulation of glucose disposal were similar in both the obese and control groups. Insulin secretion during the hyperglycemic (+/- 125 mg/dL) clamp was twofold greater in obese subjects than in controls (P less than .01) and was inversely related to the rate of glucose uptake during the insulin clamp (r = -.438, P less than .05), but was still unable to normalize glucose disposal (P less than .05). In conclusion, our results indicate that insulin resistance is a common accompaniment of obesity and can be overcome at supraphysiological insulin concentrations. Both in the basal state and following a hyperglycemic stimulus obese people display hyperinsulinemia, which correlates with the degree of insulin resistance. However, endogenous hyperinsulinemia fails to fully compensate for the insulin resistance.     

B cell secretion and insulin sensitivity in hypertensive and normotensive obese subjects

To test the hypothesis that in obesity hypertension is associated with more pronounced hyperinsulinaemia and insulin resistance we compared plasma insulin levels and insulin sensitivity in a group of 6 obese subjects with untreated hypertension and in a group of 6 obese subjects with normal blood pressure. The two groups were similar for sex, age, body mass index and glucose tolerance. Six nonobese subjects served as controls. The study consisted of a 2-h hyperglycaemic clamp (steady-state plasma glucose = 11 mmol/l) and a 15-min insulin tolerance test (0.1 U/kg body wt). During hyperglycaemic clamp, insulin and C-peptide plasma levels were similar in normotensive and hypertensive obese subjects: the area under the plasma insulin curve was 36,000 +/- 3000 pmol/l X 120 min in the former and 34,000 +/- 1000 pmol/l X 120 min in the latter; the area under the plasma C-peptide curve was 298,000 +/- 26,000 pmol/l X 120 min in the former and 246,000 +/- 26,000 pmol/l X 120 min in the latter (P = n.s.). The ratio M/I between the amount of glucose metabolized (M) and the mean plasma insulin levels (I) during hyperglycaemic clamp was similar in the two groups: 0.59 +/- 0.09 in normotensive and 0.58 +/- 0.08 mg/min X m2 per pmol/l in hypertensive obese subjects (P = n.s.). Also the rate coefficient of glucose disappearance from plasma (K(itt)) after i.v. insulin injection was similar in the two groups (4.08 +/- 0.51 vs. 3.87 +/- 0.53 per cent/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Substrate metabolism during modest hyperinsulinemia in response to isolated hyperketonemia in insulin-dependent diabetic subjects

To assess the metabolic effects of moderate hyperketonemia, six young male type 1 diabetic patients received a 200-minute intravenous (IV) infusion of (1) 0.9 mmol 3-hydroxybutyrate (3-OHB)/kg/h, and (2) saline. To ensure comparable metabolic conditions, a low-dose hyperinsulinemic euglycemic glucose clamp was performed from 5 hours before and throughout 3-OHB/saline infusions. The forearm technique was employed to estimate substrate fluxes in muscle. Infusion of 3-OHB caused: (1) increases (P less than .05) in circulating levels of 3-OHB (from 112 +/- 73 mumol/L to 825 +/- 111 mumol/L) and forearm arteriovenous differences of 3-OHB (from 19 +/- 10 mumol/L to 145 +/- 46 mumol/L), as well as an eightfold increase of plasma acetoacetate. (2) Decreased (P less than .05) levels of nonesterified fatty acids (NEFA; from 466 +/- 85 mumol/L to 201 +/- 14 mumol/L) and glycerol (from 39 +/- 7 mumol/L to 11 +/- 4 mumol/L) and decreased (P less than .05) arteriovenous differences of glycerol (from -16 +/- 8 mumol/L to -3 +/- 2 mumol/L). (3) Increased (P less than .05) levels of serum growth hormone (GH; from 4.1 +/- 1.5 micrograms/L to 15.9 +/- 8.0 micrograms/L). No change was recorded in circulating concentrations of free insulin, glucagon, glucose, lactate, or alanine. Nor were arteriovenous balances of these intermediary metabolites, isotopically determined glucose turnover or amounts of exogenously administered glucose affected. In conclusion, in type 1 diabetic man, the main regulatory effect of isolated hyperketonemia appears to be a direct negative feedback inhibition of lipolysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Total and individual free fatty acid concentrations in liver cirrhosis

The finding of high plasma free fatty acid (FFA) levels in cirrhotic patients has been attributed either to decreased hepatic clearance or to enhanced fat mobilization. To better clarify these hypotheses, total and individual FFA and glycerol levels were determined in 21 cirrhotic patients with different degrees of hepatocellular damage (evaluated by liver function tests), portal hypertension (evaluated by endoscopy and clinical signs), and nutritional status (evaluated by anthropometric and biohumoral parameters) and in 10 age- and sex-matched healthy subjects. Glucose tolerance and insulin and glucagon levels were determined in all individuals. Well-nourished and malnourished patients were identified within the cirrhotic group. Plasma FFA and glycerol concentrations were well correlated (r = 0.47, P less than 0.05), levels being significantly higher in cirrhotic individuals than in controls (746.6 +/- 46.29 SE v 359.22 +/- 40.82 mumol/L, P less than 0.001 for plasma FFA; 150.1 +/- 3.12 v 82.5 +/- 9.2 mumol/L, P less than 0.01 for glycerol). Plasma FFA and glycerol showed no correlation with the liver function test results or portal hypertension parameters. Interestingly, plasma levels of FFA and glycerol were influenced by the nutritional status, significantly higher FFA levels being observed in the well-nourished than in the malnourished patients (842.5 +/- 47.5 v 563.4 +/- 78 mumol/L, P less than 0.005). Furthermore, a positive correlation was found between plasma glycerol level and percentage of triceps skinfold (r = 0.45, P less than 0.05). No correlation was found between plasma levels of FFA or glycerol and glucose tolerance, insulin and glucagon.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolic response to the euglycemic insulin clamp in type I diabetes and normal humans

The euglycemic insulin clamp has been utilized extensively to measure in vivo tissue sensitivity to insulin under various circumstances. Insulin sensitivity is determined from the amount of glucose metabolized under steady state conditions. To assess the effect of abnormalities in other insulin responsive metabolic pathways on glucose metabolism and thus insulin sensitivity as measured by the glucose clamp, the concentration of lactate, pyruvate, 3-hydroxybutyrate, glycerol, alanine, and free fatty acids were measured at baseline and during a two-hour euglycemic clamp in 13 nonobese subjects with type I diabetes. The observed responses were compared to 11 normal controls. Insulin sensitivity as measured by M (glucose metabolized), MCRg (metabolic clearance of glucose), and M/I ratio (glucose metabolized per unit insulin) were all significantly decreased in the diabetic subjects (P less than 0.005). Free fatty acids (FFA) and 3-hydroxybutyrate were significantly elevated at baseline in the diabetic subjects (P less than 0.05) and decreased significantly at 60 and 120 minutes in both groups. Baseline blood pyruvate and lactate concentrations were similar in the control and diabetic subjects. Pyruvate increased significantly at 60 minutes in both groups (P less than 0.05) and returned to baseline in the control subjects but remained elevated at 120 minutes in the diabetic subjects (P less than 0.001). Lactate increased similarly in both groups and remained elevated at 60 and 120 minutes. In summary, insulin sensitivity as assessed by the euglycemic insulin clamp is decreased in type I diabetes. However, specific differences in the concentration of several other metabolites both at baseline and in response to hyperinsulinemia were also identified in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)