Changes in insulin sensitivity and clearance in anorexia nervosa

Anorexia nervosa (AN) is a state of self-induced malnutrition characterized by a marked pursuit of thinness and the fear of obesity. Although low fasting blood glucose and insulin have been demonstrated, there is contradictory data on insulin sensitivity and a lack of information about insulin metabolism and its metabolic effects in AN. Insulin sensitivity, kinetics, and metabolic effects were measured using the euglycemic clamp in nine females with AN (age 25.2 +/- 1.9 years and 70.6 +/- 2.2% ideal body weight), and the results compared with seven female normal controls (NC) (age 23.6 +/- 1.0 years and 92.7 +/- 2.5% ideal body weight). Fasting plasma glucose (FPG), immunoreactive insulin (IRI), and C-peptide were significantly lower in AN as compared to NC (84.3 +/- 1.5 v 91.5 +/- 1.7 mg dL-1, 9.3 +/- 1.0 v 13.5 +/- 1.4 microU mL-1, and 0.26 +/- 0.03 v 0.41 +/- 0.02 pmol mL-1) (P less than 0.05). During the glucose clamp, the glucose metabolized (M), the metabolic clearance rate of glucose (MCRg), and the glucose metabolized per unit of insulin (M/I ratio) were all higher in AN as compared to NC (M, 8.7 +/- 1.2 v 6.9 +/- 0.6 mg min-1 kg-1; MCRg, 9.9 +/- 1.5 v 7.4 +/- 0.6 mL min-1 kg-1; M/I ratio, 8.6 +/- 1.6 v 5.0 +/- 0.3 mg min-1 kg-1/microU mL-1 X 100), but only the M/I ratio attained statistical significance (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic response to insulin in control of glucose kinetics in the neonatal lamb

Imprecise control of neonatal glucose homeostasis may be partially due to decreased hepatic response to insulin. In prior kinetic studies the effect of that response could not be determined because the hormonal effects of insulin could not be separated from those of glucagon. Somatostatin (SRIF) suppresses secretion of both and has been used to differentiate the hormonal effects. Eighteen term lambs (age 4.2 +/- 0.3 days and birth weight 4.0 +/- 0.2 kg (M +/- SEM] were infused with 0.9% NaCl at 0.06 mL.kg-1 min-1 plus 100 microCi/kg D[6-3H] glucose by prime plus constant infusion. Ra (production) and Rd (utilization) were measured during infusion of SRIF or SRIF plus replacement insulin (0.2 mU.kg-1 min-1). There was a rise in pl. glucose (98 +/- 10 to 119 +/- 10 mg/dL (P less than .0001)); a fall (46.2%) in pl insulin [13 +/- 2 to 7 +/- 1 microU/mL (P less than .0004); a rise in Ra (7.8 +/- 1.5 to 13.2 +/- 4.1 mg.kg-1 min-1 P less than .047); and a rise in Rd (7.7 +/- 1.4 to 11.3 +/- 3.0 mg.kg-1 min-1 (P less than .047)) in SRIF treated animals compared to nontreated controls. There was no change in plasma glucagon (454 +/- 182 to 255 +/- 141 pg/mL) in SRIF treated animals compared to nontreated controls. All perturbations were eliminated when SRIF plus replacement insulin produced control insulin levels. Insulin suppression in the neonatal period resulted in glucagon being unopposed which produced an elevated rate of glucose production and elevated plasma glucose concentration.     

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)     

Insulin action and hepatic glucose cycling in essential hypertension.

Peripheral insulin resistance is a feature of essential hypertension, but there is little information about hepatic insulin sensitivity. To investigate peripheral and hepatic insulin sensitivity and activity of the hepatic glucose/glucose 6-phosphate (G/G6P) substrate cycle in essential hypertension, euglycemic glucose clamps were performed in eight untreated patients and eight matched controls at insulin infusion rates of 0.2 and 1.0 mU.kg-1.min-1. A simultaneous infusion of (2(3)H)- and (6(3)H)glucose, combined with a selective detritiation procedure, was used to determine glucose turnover, the difference being G/G6P cycle activity. Endogenous hepatic glucose production (EGP) determined with (6(3)H)glucose was similar in hypertensive and control groups in the postabsorptive state (11.0 +/- 0.3 v 10.9 +/- 0.3 mumol.kg-1.min-1) and with the 0.2 mU insulin infusion (4.9 +/- 0.5 v 4.0 +/- 0.8 mumol.kg-1.min-1). With the 1.0 mU insulin infusion, glucose disappearance determined with (6(3)H)glucose was lower in the hypertensive group (21.8 +/- 2.4 v 29.9 +/- 2.4 mumol.kg-1.min-1, P less than .001). G/G6P cycle activity was similar both in the postabsorptive state (2.2 +/- 0.4 v 2.7 +/- 0.4 mumol.kg-1.min-1) and during insulin infusion (0.2 mU, 2.5 +/- 0.3 v 2.9 +/- 0.4; 1.0 mU, 4.7 +/- 0.3 v 5.3 +/- 1.1 mumol.kg-1.min-1 for hypertensive and control groups, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Skeletal muscle is a primary site of insulin resistance in essential hypertension

To determine the contribution of skeletal muscle to the insulin resistance of essential hypertension, insulin-stimulated forearm glucose uptake was quantitated in 12 control (age, 32 +/- 3 years) and 12 hypertensive subjects (age, 36 +/- 2 years) using the forearm perfusion technique. Peripheral insulin levels were raised acutely (approximately 60 microU/mL), while blood glucose concentration was clamped at its basal value (90 mg/dL) by a variable glucose infusion. During insulin stimulation, whole body glucose uptake was lower in hypertensive (4.5 +/- .3 mg.kg-1.min-1) than in normal subjects (5.8 +/- .4 mg.kg-1.min-1, P less than .05). Similarly, the amount of glucose taken up by the forearm was markedly reduced in the hypertensive (5.3 +/- .91 mg.L-1.min-1) compared with the control group (8.7 +/- 1.1 mg.L-1.min-1). No appreciable difference was observed as to forearm blood flow (39 +/- 4 mL.L-1.min-1 and 37 +/- 5 mL.L-1.min-1) in hypertensive patients. These results indicate that skeletal muscle is a major site of insulin resistance in essential hypertension and that this defect is independent of muscle perfusion.     

Direct assessment of splanchnic uptake and metabolic effects of human and porcine insulin

The hepatic vein catheterization technique was used to quantitate the splanchnic uptake and the metabolic effects of biosynthetic human insulin (BHI) and porcine insulin (PI) in normal man. BHI and PI were infused into a peripheral vein (0.9-1.3 mU kg-1 min-1) for 60 min together with SRIH (0.6 mg/h) to inhibit endogenous insulin secretion and glucose to induce moderate hyperglycemia (9-10 mmol/liter). During the infusion period, arterial-hepatic venous difference of plasma C-peptide as well as splanchnic C-peptide output fell by more than 98% indicating virtually complete cessation of endogenous insulin release. Under these conditions, the arterial-hepatic venous differences in plasma insulin concentrations represent a valid and direct measurement of splanchnic insulin uptake. During BHI infusion, arterial insulin levels rose to 82 +/- 11 (SE) microU/ml (range: 33-105 microU/ml). Splanchnic insulin uptake paralleled the rise of arterial insulin, reaching 430 +/- 72 microU kg-1 min-1 at 60 min. No appreciable difference between BHI and PI was demonstrable. A highly significant correlation between arterial insulin concentrations and splanchnic insulin uptake was found (r = 0.816; P less than 0.001). Accordingly, both fractional splanchnic insulin extraction and splanchnic insulin clearance remained unchanged throughout insulin infusion and averaged 70 +/- 4% and 5.3 +/- 2 ml kg-1 min-1, respectively. With BHI infusion, splanchnic glucose balance (-8.5 +/- 0.9 mumol kg-1 min-1, basal) became positive (7.3 +/- 1 mumol kg-1 min-1). In contrast, basal splanchnic lactate uptake was inhibited by BHI and there was lactate production (from 3.4 +/- 0.9 to -1.7 +/- 1.4 mumol kg-1 min-1). Similar changes in splanchnic glucose and lactate metabolism occurred during PI infusion. These studies indicate that: 1) A considerable amount of insulin (70 +/- 4%) is extracted by the splanchnic bed on a single passage, after exogenous administration of either human insulin or PI; 2) over a physiological range of insulin concentrations (33-105 microU/ml) a linear relationship exists between arterial insulin concentrations and splanchnic insulin removal; and 3) BHI and PI do not differ appreciably with respect to their uptake and metabolic effects at the splanchnic level.     

Alpha-adrenergic agonists stimulate neonatal glucose production less than beta-adrenergic agonists in the lamb

Epinephrine, a catecholamine with both alpha (alpha)- and beta (beta)-adrenergic agonist effects, may produce clinical hyperglycemia in the adult by increasing glucose production and decreasing glucose clearance. However, the relative contribution of alpha v beta adrenergic agonists in control of neonatal glucose kinetics has not been defined. Twenty-three term lambs (weighing 4.4 +/- 0.2 kg, mean +/- SEM, and aged 3.8 +/- 0.4 days) were infused with 0.9% NaCl at 0.6 mL.kg-1 min-1 + 100 microCi/kg D[6-3H]-glucose by prime plus constant infusion for 210 minutes. Ra (rate of production) was measured during infusion of variable doses of epinephrine with or without variable doses of propranolol, a competitive beta-adrenergic antagonist to isolate the alpha-adrenergic agonist effects. All basal kinetic data were comparable. Under conditions of epinephrine infusion, the plasma glucose concentration increased from 95 +/- 10 mg/dL to 129 +/- 18 mg/dL (50 ng.kg-1 min-1 epinephrine; P less than .0001) and from 85 +/- 6 mg/dL to 253 +/- 8 mg/dL (500 ng.kg-1 min-1 epinephrine; P less than .00001) compared with controls (96 +/- 7 mg/dL to 95 +/- 8 mg/dL). When epinephrine and propranolol were infused simultaneously, plasma glucose concentration increased from 95 +/- 10 mg/dL to 122 +/- 12 mg/dL (50 ng.kg-1 min-1 epinephrine + 1.1 micrograms.kg-1 min-1; P less than .0001) and from 78 +/- 9 mg/dL to 134 +/- 12 mg/dL (500 ng.kg-1 min-1 epinephrine + 11 micrograms.kg-1 min-1; P less than .0001) compared with controls (no epinephrine, no propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic and peripheral insulin resistance following streptozotocin-induced insulin deficiency in the dog

Insulin resistance and insulin deficiency are both present in many patients with diabetes mellitus. We tested the hypothesis that insulin resistance can evolve from a primary lesion of the beta-cell secretory function. Insulin-mediated glucose uptake (insulin clamp), endogenous glucose production, and glucose-stimulated insulin secretion (hyperglycemic clamp) were measured in awake dogs before and four to six weeks after streptozotocin-induced diabetes mellitus. Streptozotocin (30 mg/kg) resulted in a significant rise in the mean fasting plasma glucose concentration from 104 +/- 2 mg/100 mL to 200 +/- 34 mg/100 mL, (P less than 0.05), and a slight decrease in the mean fasting plasma insulin concentration (from 21 +/- 2 microU/mL to 15 +/- 2 microU/mL). Under conditions of steady-state hyperglycemia (+75 mg/100 mL hyperglycemic clamp, insulin secretion was reduced by 75% in the streptozotocin-treated dogs (P less than 0.025), and the total amount of glucose metabolized decreased from 13.56 +/- 1.04 to 4.74 +/- 0.70 mg/min X kg (P less than 0.001). In the postabsorptive state, endogenous glucose production was slightly, although not significantly, higher in the diabetic dogs (3.05 +/- 0.46 v 2.51 +/- 0.22 mg/min . kg), while the glucose clearance rate was 35% lower (P less than 0.001). When the plasma insulin concentration was increased to approximately 45 microU/mL (insulin clamp) while holding plasma glucose constant at the respective fasting levels (99 +/- 1 and 186 +/- 30 mg/100 mL), endogenous glucose production was completely suppressed in control dogs but suppressed by only 51% (1.46 +/- 0.37 mg/min . kg, P less than 0.025) in diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin resistance in multiple aspects of intermediary metabolism in myotonic dystrophy

The responses of circulating intermediary metabolites to a low-dose incremental insulin infusion (basal, 0.005, 0.01, and 0.05 U.kg-1.h-1) were examined in eight ambulant subjects with the multisystem disorder, myotonic dystrophy. Eight healthy subjects matched for age, gender, and body mass index served as controls. Oral glucose tolerance (75 g) was normal in all subjects. Basal (postabsorptive) hyperinsulinemia was observed in the subjects with myotonic dystrophy (8.4 +/- 2.0 v 2.3 +/- 0.2 mU/L, P less than .01) with increased basal C-peptide levels. Basal blood glycerol (0.09 +/- 0.02 v 0.05 +/- 0.01 mmol/L, P less than .05), lactate (1.14 +/- 0.12 v 0.77 +/- 0.07 mmol/L, P less than .02), and pyruvate (0.08 +/- 0.01 v 0.05 +/- 0.01 mmol/L, P less than .02) were also elevated in these subjects. During the incremental insulin infusion, circulating insulin (F = 8.2, P less than .02) and C-peptide (F = 5.1, P less than .05) levels were significantly higher in the myotonic subjects. Despite the hyperinsulinemia, circulating concentrations of lactate (F = 9.8, P less than .01), pyruvate (7.8, P less than .02), and glycerol (F = 7.5, P less than .02) were also higher in the subjects with myotonic dystrophy, providing prima facie evidence of insulin resistance in the regulation of these metabolites. During the highest insulin rate, isotopically determined metabolic clearance rate of glucose was significantly lower in the myotonic subjects (3.6 +/- 0.4 v 5.5 +/- 0.7 mL.kg-1.min-1, P less than .05), indicating impaired peripheral glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin action is normalized in newly diagnosed type I diabetic patients after three months of insulin treatment

We studied insulin action at submaximal and maximal insulin levels in seven newly diagnosed type I (insulin-dependent) diabetic patients after 2 weeks (t1/2) and after 3 months (t3) of insulin treatment, and in seven control subjects. Insulin action was determined with a sequential euglycemic (5.0 mmol/L) glucose clamp technique using insulin infusion rates of 0.5, 1.0, 2.0, and 5.0 mU.kg-1.min-1 in four periods of two hours each. The final 30 minutes of each infusion period (referred to as steady-state) were taken for the assessment of insulin action. Steady-state insulin levels were similar in the diabetic patients at t1/2 and t3, and in control subjects. During the first and second infusion periods, steady-state glucose infusion rates (SSGIR) were lower at t1/2 than at t3 (12.2 +/- 1.7 v 18.8 +/- 2.4, P less than .05, and 34.3 +/- 3.8 v 47.6 +/- 2.5 mumol.kg-1.min-1, P less than .02, respectively), and were lower at t1/2 compared to controls (12.2 +/- 1.7 v 22.4 +/- 2.3, P less than .01, and 34.3 +/- 3.8 v 47.3 +/- 2.8 mumol.kg-1.min-1, P less than .02). No differences were found during the third and fourth infusion periods between t1/2 and t3, or t1/2 and controls. When these data were used to construct dose-response curves, insulin action was decreased in the diabetic patients at t1/2 at submaximal insulin levels (shift to the right), while insulin responsiveness was unchanged. This finding may be regarded as a still-present manifestation of the metabolic derangement at the onset of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects. Studies at physiologic and supraphysiologic hormone levels

To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU.kg-1.min-1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU.kg-1.min-1) sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16, 22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates [( 3(-3)H]glucose) in uraemic patients compared with controls (P less than 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 +/- 1.0 versus 1.4 +/- 0.3 (mean +/- 1 SD), -0.3 +/- 0.7 versus 0.7 +/- 0.3, and -1.1 +/- 0.7 versus 0.2 +/- 0.6 mg.kg-1.min-1; P less than 0.05, P less than 0.01 and P less than 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 +/- 0.3 versus 2.2 +/- 0.6 mg.kg-1.min-1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above approximately equal to 30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng.kg-1.min-1, respectively, for 210 min concomitant with somatostatin (125 micrograms/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 +/- 0.8 versus 4.8 +/- 1.0 mg.kg-1.min-1; P less than 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.     

Effects of food restriction and insulin treatment on (Ca2+ + Mg2+)-ATPase response to insulin in kidney basolateral membranes of noninsulin-dependent diabetic rats

Insulin increases (Ca2+ + Mg2+)-ATPase activity in cell membranes of normal rats but fails to do so in membranes of non-insulin-dependent diabetic (NIDD) rats. The loss of regulatory effect of the hormone on the enzyme might contribute to the insulin resistance observed in the NIDD animals. To further test this hypothesis, the effects of insulin treatment and acute food restriction on the ability of insulin to regulate the ATPase activity in kidney basolateral membranes (BLM) of NIDD rats were studied. Although insulin levels in NIDD and control rats were similar, plasma glucose was higher in the NIDD rats (18.3 +/- 1.5 v 19.3 +/- 1.7 microU/mL and 236 +/- 32 v 145 +/- 3 mg/dL, respectively). Insulin treatment (2 U/100 g), which increased plasma insulin in the NIDD rats (47.8 +/- 11.5 microU/mL; P less than .05), did not decrease their glucose (221 +/- 25 mg/dL). Higher insulin dose (4 U/100 g) decreased glucose level in the NIDD rats (73 +/- 3 mg/dL; P less than .001) but increased their plasma insulin 10-fold (202.5 +/- 52.5 microU/mL). Acute food restriction decreased glucose levels in the NIDD rats to levels seen in controls (135 +/- 3 mg/dL), while their insulin decreased by half (8.5 +/- 1.0 microU/mL; P less than .05). Basal (Ca2+ + Mg2+)-ATPase activity in BLM of all diabetic rats was higher than in controls (P less than .05). None of the treatments reversed this defect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased glucose oxidation during short-term starvation

Prolonged fasting (for days or weeks) decreases glucose production and oxidation. The effects of short-term starvation (ie, less than 24 hours) on glucose metabolism are not known. To evaluate this issue, glucose oxidation and glucose turnover were measured after 16-hour and subsequently after 22-hour fasting. Glucose oxidation was calculated by indirect calorimetry in 12 healthy men (age 22 to 44 years); glucose turnover was measured by primed, continuous infusion of 3-3H-glucose in eight of these 12 volunteers. After 16-hour fasting net glucose oxidation was 0.59 +/- 0.17 mg x kg-1 x min-1 and glucose tissue uptake 2.34 +/- 0.12 mg x kg-1 x min-1. No correlation was found between net glucose oxidation and glucose tissue uptake. Prolonging fasting with an additional 6 hours resulted in decreases of respiratory quotient (0.77 +/- 0.01 v 0.72 +/- 0.01) (P less than .005), plasma glucose concentration (4.7 +/- 0.1 v 4.6 +/- 0.1 mmol/L) (P less than .05), glucose tissue uptake (2.10 +/- 0.12 mg x kg-1 x min-1) (P less than .05), net glucose oxidation (0.09 +/- 0.04 mg x kg-1 x min-1) (P less than .005), and plasma insulin concentration (8 +/- 1 v6 +/- 1 mU/L) (P less than .005). Net glucose oxidation expressed as a percentage of glucose tissue uptake decreased from 22% +/- 8% to 2% +/- 1% (P less than .05). There was no net glucose oxidation in seven of 12 controls after 22-hour fasting.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased response to catecholamines in the newborn: effect on glucose kinetics in the lamb

Epinephrine, a catecholamine with both alpha (alpha) and beta (beta) adrenergic effects, may produce hyperglycemia in adults by increasing glucose production and decreasing glucose clearance. To document the degree of sensitivity and characterize maturation of neonatal glucose control, glucose kinetics were measured in 14 term newborn lambs (weight 4.5 +/- 0.3 kg [mean +/- SEM] and aged 4.1 +/- 0.4 days). Following infusion of 0.9% NaCl at 0.06 mg.kg-1 min-1 plus 100 microCi/kg D[6-3H] glucose by prime plus constant infusion, rate of production (Ra) and glucose clearance were measured during administration of epinephrine. The responses in the newborns were compared with those in six adult sheep. Under conditions of epinephrine infusion, the plasma glucose concentration in the newborn lambs increased to 129 +/- 18 mg/dL (50 ng.kg-1 min-1 epinephrine), P less than .0001, and 253 +/- 8 mg/dL (500 ng.kg-1 min-1 epinephrine), P less than .0001, compared with 95 +/- 8 mg/dL (controls, no epinephrine). Comparable values for Ra were 6.5 +/- 1.6 mg.kg-1 min-1 (50 ng.kg-1 min-1 epinephrine), P = NS, and 18.5 +/- 3.0 mg.kg-1 min-1 (500 ng.kg-1 min-1 epinephrine), P less than .0001, compared with 5.3 +/- 0.5 mg.kg-1 min-1 (controls, no epinephrine).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of massive obesity on insulin sensitivity and insulin clearance and the metabolic response to insulin as assessed by the euglycemic clamp technique

Insulin sensitivity was studied in nine nondiabetic massively obese patients (one male and eight females ages 39.0 +/- 2.7 years, body mass index 47.1 +/- 1) by the euglycemic clamp technique (40 microU/m2/min) and compared to seven lean control subjects (three males and three females, ages 34.8 +/- 2.5 years, body mass index 23 +/- 1.1). Fasting plasma glucose, immunoreactive insulin, and C-peptide concentrations were higher in the massively obese patients than in the controls (P less than 0.025). Following exogenous insulin infusion, immunoreactive glucagon and C-peptide concentrations decreased similarly in the massively obese patients and controls, indicating normal sensitivity of the alpha and beta cell to insulin. Glucose uptake (M) expressed either as mg X min-1 of fat free mass was significantly reduced in the massively obese patients compared to the controls (P less than 0.001). Similarly, the M/I ratio (glucose uptake per unit of insulin) was significantly reduced in the massively obese patients (P less than 0.001). Free fatty acids and glycerol concentrations measured in the fasting state were significantly elevated in the massively obese patients (free fatty acids 678 +/- 51 v 467 +/- 55 mumol/L, P less than 0.05; glycerol 97 +/- 9 v 59 +/- 11 mumol/L, P less than 0.02). The effects of insulin on antilipolysis was assessed by measuring the reductions in free fatty acids and glycerol concentration during the glucose clamp study. Although the absolute levels remained higher in the massively obese patients, inhibition of lipolysis was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin-dependent metabolism of branched-chain amino acids in obesity

The effect of euglycemic hyperinsulinism on branched-chain amino acids (BCAA; valine, isoleucine and leucine) was evaluated in five obese subjects and five controls. A continuous intravenous insulin infusion raised plasma insulin to a steady-state level. An artificial endocrine pancrease that infused glucose was used to sustain euglycemia. Basal and steady-state insulin levels were significantly higher in the obese subjects than in the controls. The amount of glucose infused to maintain euglycemia and its ratio to steady-state insulin levels was significantly lower in the obese subjects, suggesting an impaired insulin action on glucose metabolism. Basal BCAA levels were similar in the two groups of subjects. During insulin infusion the decremental areas of BCAA below basal levels were significantly lower in the obese patients (63 +/- 5 nmol/mL X min v 143 +/- 8 nmol/mL X min, P less than 0.001), as was the ratio of the decremental areas of BCAA to the incremental areas of insulin (1.11 +/- 0.05 nmol/microU v 3.30 +/- 0.24 nmol/microU, P less than 0.001). Our data suggest that insulin resistance in obesity reduces hormonal effects on glucose as well as on BCAA metabolism.     

Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women.

A novel lipodystrophy syndrome (characterized by insulin resistance, hypertriglyceridemia, and fat redistribution) has recently been described in human immunodeficiency virus (HIV)-infected patients. However, investigation of the lipodystrophy syndrome has generally been limited to men; and a comprehensive evaluation of insulin, lipids, and regional body composition has not been performed in the expanding population of HIV-infected women. In this study, we assessed fasting insulin, lipid levels, virologic parameters, and regional body composition, using dual-energy x-ray absorptiometry, in a cohort of 75 HIV-infected women (age, 25-46 yr), in comparison with 30 healthy weight-matched premenopausal control subjects. HIV-infected women demonstrated significant truncal adiposity (38.5 +/- 0.9 vs. 34.9 +/- 1.3%, P < 0.05) hyperinsulinemia (15.9 +/- 1.5 vs. 7.5 +/- 0.6 microU/mL, P < 0.001) and an increased insulin-to-glucose ratio (0.2 +/- 0.02 vs. 0.1 +/- 0.03, P < 0.001), compared with control subjects. Insulin and the insulin-to-glucose ratio were increased, even among HIV-infected patients with low body weight (<90% of ideal body weight) (insulin, 13.3 +/- 2.8 microU/mL, P < 0.01 vs. control; insulin/glucose, 0.2 +/- 0.04, P < 0.01 vs. control). Insulin and the insulin-to-glucose ratio were most significantly elevated among patients with increased truncal adiposity (insulin, 28.2 +/- 3.2 microU/mL, P < 0.001 vs. control; insulin/ glucose, 0.32 +/- 0.04, P < 0.001 vs. control). In contrast, no differences in insulin were seen in relation to protease inhibitor (PI) use. Similarly, HIV-infected women also demonstrated significant hypertriglyceridemia (144 +/- 15 vs. 66 +/- 23 mg/dL, P < 0.01 vs. controls), which was present even among low-weight patients (148 +/- 32 mg/dL, P < 0.001 vs. control) but was not related to truncal adiposity or PI usage. These data demonstrate significant hyperinsulinemia and truncal adiposity in HIV-infected women. Our data suggest that these metabolic abnormalities occur at baseline in HIV-infected women, independent of PI use. However, these data do not rule out a direct effect of PI therapy on fat metabolism or indirect effects of PI therapy to further worsen glucose and lipid homeostasis in association with weight gain and disease recovery.     

The physiologic action of insulin on glucose uptake and its relevance to the interpretation of the metabolic clearance rate of glucose

Glucose uptake (Ru) is dependent upon the concentrations of both glucose and insulin. The metabolic clearance rate of glucose (MCRG), has been used as an in vivo measure of insulin action, because it was said to be independent of the prevailing glucose concentration. The validity of this assumption has recently been challenged. In this study, the effect of insulin concentration on the rate of glucose uptake (Ru) and on the MCRG was studied during euglycemia (5.1 +/- 0.3 mmol/L) and moderate hyperglycemia (10.4 +/- 0.5 mmol/L) in 17 experiments on nine normal ambulant volunteers. Stable plasma insulin levels were maintained with fixed infusion rates of insulin (0-300 mU/kg/h) and somatostatin (7.5 micrograms/min). At low insulin concentrations (less than 5 microU/mL) the increase in glucose uptake in response to hyperglycemia was small (5.3 +/- 2.3 mumol/kg/min). In contrast, with insulin levels more than 25 microU/mL, there was a steep rise in glucose uptake with hyperglycemia (55 +/- 3 mumol/kg/min; range: 44-74 mumol/kg/min). The metabolic clearance rate of glucose fell by an average of 32% with hyperglycemia in the studies at the lowest insulin levels (2.2 +/- 0.6 v 1.5 +/- 0.1 mL/kg/min; 0.15 greater than P greater than 0.1). There was no change in the MCRG in the subjects studied at higher insulin levels. It is concluded that (1) low concentrations of insulin are essential for the increase in glucose disposal during hyperglycemia; and (2) provided insulin levels are more than 25 microU/mL and plasma glucose less than 11 mmol/L, MCRG is independent of the plasma glucose concentration and is therefore a valid measure of insulin-mediated glucose uptake.     

Epinephrine directly antagonizes insulin-mediated activation of glucose uptake and inhibition of free fatty acid release in forearm tissues.

To determine whether the anti-insulin effect of epinephrine is due to a direct antagonism on target tissues or is mediated by indirect mechanisms (systemic substrate and/or hormone changes), insulin and epinephrine were infused intrabrachially in five normal volunteers using the forearm perfusion technique. Insulin (2.5 mU/min) was infused alone for 90 minutes and in combination with epinephrine (25 ng/min) for an additional 90 minutes, so as to increase the local concentrations of these hormones to physiological levels (60 to 75 microU/mL and 200 to 250 pg/mL for insulin and epinephrine, respectively). Systemic plasma glucose and free fatty acids (FFA) concentrations remained stable at their basal values during local hormone infusion. Forearm glucose uptake (FGU) increased in response to insulin alone from 0.8 +/- 0.2 mg.L-1.min-1 to 4.3 +/- 0.8. Addition of epinephrine completely abolished the insulin effect on FGU, which returned to its preinfusion value (0.7 +/- 0.2). Forearm lactate release was slightly increased by insulin alone, but rose markedly on addition of epinephrine (from 5.2 +/- 0.8 mumol.L-1.min-1 to 17 +/- 2; P less than .02). During infusion of insulin alone, forearm FFA release (FFR) decreased significantly from the postabsorptive value of 1.76 +/- 0.25 mumol.L-1.min-1 to 1.05 +/- 0.11 (P less than .01). Epinephrine addition reverted insulin suppression of FFR, which returned to values slightly above baseline (2.06 +/- 0.47 mumol.L-1.min-1; P less than .05 v insulin alone). The data demonstrate that epinephrine is able to antagonize directly insulin action on forearm tissues with respect to both stimulation of glucose uptake and inhibition of FFA mobilization.     

Glucose tolerance and hormonal responses in heroin addicts. A possible role for endogenous opiates in the pathogenesis of non-insulin-dependent diabetes

Plasma glucose, insulin, glucagon, and growth hormone responses to intravenous glucose stimulation were investigated in 15 heroin-dependent men and in 15 control subjects matched for age, sex, and weight. Although the fasting concentrations of insulin, glucagon, and GH were significantly higher in the heroin addicts, they had markedly reduced plasma insulin responses to intravenous glucose (acute insulin response, calculated as the mean change in insulin levels over 3 to 10 minutes: 10 +/- 5 microU/mL in the addicts v 44 +/- 9 microU/mL in the controls, P less than 0.001) and glucose utilization rates in the diabetic range (KG: 0.96 +/- 0.09%/min in the addicts v 1.65 +/- 0.10%/min in the controls, P less than 0.01). These results show that chronic heroin administration produces a state of fasting hyperinsulinemia even in the absence of obesity, glucose intolerance, and a marked reduction of the first phase of insulin secretion. A possible role for endogenous opiates in the pathogenesis of non-insulin-dependent diabetes is hypothesized.