Metabolic effects of IGF-I in diabetic rats

Insulinlike growth factor I (IGF-I) stimulates glucose utilization (GU) in nondiabetic rats. We compared the effects of IGF-I and insulin on glucose metabolism in control (fed plasma glucose 7.7 +/- 0.1 mM, n = 30) and partially (90%) pancreatectomized diabetic (plasma glucose 18.4 +/- 0.8 mM, n = 30) awake unstressed rats. IGF-I was infused at 0.65 or 1.96 nmol.kg-1.min-1 and insulin at 22 or 29 pmol.kg-1.min-1 in combination with [3-3H]glucose while euglycemia was maintained by a variable glucose infusion. In controls, GU during the 0.65- and 1.96-nmol.kg-1.min-1 IGF-I infusions (127 +/- 7 and 168 +/- 4 mumol.kg-1.min-1, respectively) was similar to rates observed during the 22- and 29-pmol.kg-1.min-1 insulin infusions (121 +/- 2 and 156 +/- 5 mumol.kg-1.min-1). Whole-body glycolytic rate (3H2O generation) and muscle glycogen synthetic rate were identical during insulin and IGF-I infusions. In diabetic rats, GU was reduced by 30% versus control rats (P less than 0.01) during both the low-dose (88 +/- 7 vs. 121 +/- 7 mumol.kg-1.min-1) and higher-dose (109 +/- 4 vs. 156 +/- 5 mumol.kg-1.min-1) insulin clamps. The defect in insulin action involved both muscle glycogen synthesis and glycolysis. In diabetic rats, IGF-I elicited rates of GU similar to controls (115 +/- 10 and 164 +/- 12 mumol.kg-1.min-1 during the 0.65- and 1.96-nmol.kg-1.min-1 infusions, respectively) and corrected the intracellular defects in glycogen synthesis and glycolysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of insulin resistance in vivo by amylin and calcitonin gene-related peptide

During hyperinsulinemic glucose-clamp studies, intravenous infusion of calcitonin gene-related peptide (CGRP) in rats antagonized the ability of insulin to stimulate peripheral glucose disposal by 52% (196 +/- 7.2 vs. 105 +/- 10.5 mumol.kg-1.min-1, P less than 0.05) and to inhibit hepatic glucose output by 54% (P less than 0.01). CGRP also inhibited the in vitro effects of insulin to stimulate hexose uptake in cultured BC3H1 myocytes at all insulin concentrations studied. Amylin is a peptide isolated from amyloid deposits in pancreatic islets of type II (non-insulin-dependent) diabetic subjects, is present in normal beta-cells, and bears a striking homology to CGRP. When synthetic human amylin was infused during clamp studies, it inhibited the ability of insulin to stimulate glucose disposal by 56% (96.9 +/- 9.4 vs. 42.4 +/- 5.0 mumol.kg-1.min-1, P less than 0.05) and to suppress hepatic glucose output by 64%. Therefore, amylin and CGRP can cause insulin resistance in vivo and may be implicated in insulin-resistant states such as type II diabetes mellitus.     

Metformin normalizes nonoxidative glucose metabolism in insulin-resistant normoglycemic first-degree relatives of patients with NIDDM.

Many first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are characterized by insulin resistance. Because metformin improves peripheral insulin sensitivity, we examined the acute effect of metformin and placebo on glucose and lipid metabolism in nine insulin-resistant first-degree relatives of NIDDM patients with the euglycemic insulin-clamp technique combined with indirect calorimetry and infusion of [3-3H]glucose. Either placebo or 500 mg metformin was taken in random order twice the day before and once 1 h before the clamp. Nine healthy individuals without family history of diabetes served as control subjects. Basal plasma glucose was normal and did not differ between the metformin and the placebo study (4.8 +/- 0.2 vs. 5.0 +/- 0.2 mM) and neither did basal hepatic glucose production (10.59 +/- 0.54 vs. 10.21 +/- 0.80 mumol.kg-1.min-1). Insulin-stimulated glucose disposal was significantly increased by 25% after metformin compared with placebo (26.67 +/- 2.87 vs. 21.31 +/- 1.73 mumol.kg-1.min-1, P less than 0.05). The enhancement in glucose utilization was primarily due to normalization of nonoxidative glucose disposal (from 8.02 +/- 1.35 to 15.07 +/- 2.69 mumol.kg-1.min-1, P less than 0.01, vs. 15.65 +/- 2.72 mumol.kg-1.min-1 in control subjects). In contrast, glucose oxidation during the clamp was slightly lower after metformin compared with both placebo (11.59 +/- 0.83 vs. 13.30 +/- 1.00 mumol.kg-1.min-1, P = 0.06) and healthy control subjects (15.68 +/- 1.38 mumol.kg-1.min-1, P less than 0.05). We conclude that acutely administered metformin improves peripheral insulin sensitivity in insulin-resistant normoglycemic individuals primarily by stimulating the nonoxidative pathway of glucose metabolism.     

Effects of amino acids on glucose disposal

Free fatty acids are known to inhibit carbohydrate disposal and oxidation. This action may play an important role in the pathophysiology of insulin resistance and non-insulin-dependent diabetes mellitus. To investigate whether amino acids (AAs) have similar actions, we determined the effects of an intravenously infused mixture of 15 AAs on carbohydrate disposal during euglycemic-hyperinsulinemic clamps associated with either basal or high glucagon concentrations in healthy male volunteers. Plasma glucose concentration was clamped at approximately 4.7 mM (coefficient of variation 4.7%). Insulin infusion (7.18 pmol.kg-1.min-1) raised serum insulin concentrations from 36-50 pM to between 300 and 600 pM. AA infusions (0.5 g.kg-1.h-1.4 h) raised plasma alpha-amino N2 concentrations about five- to six-fold. Infusion of AAs, somatostatin (somatotropin release inhibitory factor, SRIF), and high-glucagon replacement (3.0 ng.kg-1.min-1) reduced the rate of exogenous glucose infusion needed to maintain euglycemia from 51.1 +/- 7.2 mumol.kg-1.min-1 (saline + SRIF + high glucagon) to 28.3 +/- 11.1 mumol.kg-1.min-1 and stimulated endogenous glucose production (from 0 to approximately 17 mumol.kg-1.min-1). Thus, glucose disposal (exogenous infusion plus endogenous production of glucose) remained essentially unchanged. During infusion of AAs + SRIF + basal glucagon replacement (0.25 ng.kg-1.min-1), endogenous glucose production remained completely suppressed, and the rates of exogenous glucose infusion did not change (compared with saline + SRIF + basal glucagon replacement). The data showed that 1) hyperaminoacidemia associated with hyperglucagonemia stimulated endogenous glucose production despite hyperinsulinemia, and 2) intravenous infusion of a mixture of 15 AAs had no inhibitory effect on insulin-stimulated total-body glucose disposal.     

Lack of effect of islet amyloid polypeptide in causing insulin resistance in conscious dogs during euglycemic clamp studies

In this study, we administered constant intravenous infusions of human islet amyloid polypeptide (hIAPP) to conscious dogs during euglycemic glucose-clamp studies. The doses of hIAPP used (5 and 50 pmol.kg-1.min-1) raised the circulating IAPP levels approximately 12- and 50-fold above basal levels, respectively. Studies were conducted at two different insulin infusion rates, resulting in steady-state plasma insulin levels of approximately 600 and 2800 pM. According to our results, the hIAPP infusions did not lead to any measurable change in the insulin-stimulated glucose disposal rate at either insulin infusion rate. Additionally, we observed no effect of IAPP on hepatic glucose production. Although we did not observe any effect of hIAPP on any of the aspects of glucose or insulin metabolism measured, we did find a consistent hypocalcemic effect of this peptide at the 50-pmol.kg-1.min-1 infusion rate. Shortly after the onset of hIAPP infusion, serum calcium levels fell by 10-15% and remained at these levels throughout the course of the hIAPP infusion. In summary, 1) infusion of hIAPP at doses of 5 or 50 pmol.kg-1.min-1 in conscious dogs raised the circulating IAPP level 12- to 50-fold above basal; 2) during these infusion studies, no effect of hIAPP was observed on any of the aspects of glucose or insulin homeostasis measured; 3) 50 pmol.kg-1.min-1 hIAPP lead to a prompt reduction in plasma calcium concentrations with intravenous administration.     

Operation of Randle's cycle in patients with NIDDM

It has been suggested that the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) may be caused by substrate competition between glucose and free fatty acids (FFAs) (Randle's cycle). We measured substrate oxidation and energy metabolism in 10 nonobese untreated NIDDM patients with fasting glucose levels of 7-8 mM with indirect calorimetry in the basal state and during an isoglycemic-hyperinsulinemic (approximately 100 mU/L) clamp without (control) and with a concomitant infusion (approximately 0.35 mmol/min) of Intralipid, a triglyceride emulsion. In the control study, fasting rates of total glucose turnover [( 3-3H]glucose) and glucose and lipid oxidation (9.4 +/- 1.4, 7.3 +/- 1.3, and 3.0 +/- 0.4 mumol.kg-1.min-1, respectively) were comparable with those of nondiabetic individuals. After insulin administration, lipid oxidation was normally suppressed (to 1.3 +/- 0.3 mumol.kg-1.min-1, P less than 0.01), as were the circulating levels of FFA, glycerol, and beta-hydroxybutyrate, whereas glucose oxidation doubled (14.1 +/- 1.8 mumol.kg-1.min-1, P less than 0.01). Because glycemia was clamped at 7.5 mM, endogenous glucose production (EGP) was completely suppressed, and total glucose disposal was stimulated (to 25.7 +/- 5.2 mumol.kg-1.min-1, P less than 0.01 vs. baseline), but glucose clearance (3.6 +/- 0.8 ml.kg-1.min-1) was 30% reduced compared with normal. With concomitant lipid infusion, FFA, glycerol, and beta-hydroxybutyrate all rose during the clamp; correspondingly, lipid oxidation was maintained at fasting rates (3.6 +/- 0.2 mumol.kg-1.min-1, P less than 0.01 vs. control).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prolonged pulsatile hyperinsulinemia in humans. Enhancement of insulin sensitivity

Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemic effect than continuous insulin infusion. We have previously shown that continuous hyperinsulinemia induces insulin insensitivity. This study examines the mechanisms responsible for the greater hypoglycemic effect of pulsatile insulin administration, in particular, whether prolonged pulsatile hyperinsulinemia induces insulin insensitivity. Basally and 1 h after cessation of a 20-h pulsatile infusion of insulin (0.5 mU.kg-1.min-1), eight nondiabetic human subjects were assessed for 1) glucose turnover with [3-3H]glucose, 2) insulin sensitivity by minimal-model analysis of intravenous glucose tolerance tests, and 3) monocyte insulin-receptor binding. The time-averaged plasma insulin levels were 30 +/- 5 mU/L (mean +/- SE) during the infusion, which was similar to the levels achieved in our previous continuous hyperinsulinemia study. However, the average rate of glucose infusion to maintain euglycemia was 55% greater than in the previous study. Hepatic glucose production was -5.2 +/- 1.4 mumol.kg-1.min-1 during the infusion but returned to preinfusion levels 1 h after the infusion was stopped. Insulin sensitivity (Sl) and glucose tolerance (rate of glucose disappearance, Kg) showed changes opposite in direction to our previous continuous hyperinsulinemia study (pre- vs. postinfusion Kg 1.5 +/- 0.1 vs. 1.7 +/- 0.2 min-1 x 10(2), NS; pre- vs. postinfusion Sl 8.4 +/- 2.3 vs. 11.8 +/- 3.7 min-1.mU-1.L x 10(4), P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of impaired muscle glucose clearance to reduced postabsorptive systemic glucose clearance in NIDDM

The reduced postabsorptive rates of systemic glucose clearance in non-insulin-dependent diabetes mellitus (NIDDM) are thought to be the consequence of insulin resistance in peripheral tissues. Although the peripheral tissues involved have not been identified, it is generally assumed to be primarily muscle, the major site of insulin-mediated glucose disposal. To test this hypothesis, we measured postabsorptive systemic and forearm glucose utilization and clearance in 15 volunteers with NIDDM and 15 age- and weight-matched nondiabetic volunteers. Although systemic glucose utilization was increased in NIDDM subjects (14.5 +/- 0.5 vs. 11.2 +/- 0.2 mumol.kg-1.min-1, P less than 0.001), systemic glucose clearance was reduced 1.40 +/- 0.06 vs. 2.13 +/- 0.05 ml.kg-1.min-1, P less than 0.01). Although forearm glucose utilization was increased in NIDDM subjects (0.663 +/- 0.058 vs. 0.411 +/- 0.019 mumol.dl-1.min-1, P less than 0.001), forearm glucose dl-1 clearance was reduced (0.628 +/- 0.044 vs. 0.774 +/- 0.037 ml.L-1.min-1, P less than 0.01). However, extrapolation of forearm data to total-body muscle indicated that impaired clearance reduced muscle glucose disposal by only 61 +/- 21 mumol/min, whereas impaired systemic clearance reduced systemic glucose disposal by 662 +/- 82 mumol/min. Thus, impaired muscle glucose clearance accounted for less than 10% of the reduced systemic glucose clearance in NIDDM subjects. Therefore, we conclude that muscle insulin resistance plays only a minor role in the reduced systemic glucose clearance found in NIDDM in the postabsorptive state and propose that reduced brain glucose clearance is largely responsible.     

Adenosine reversal of in vivo hepatic responsiveness to insulin

Modulation by adenosine of hepatic responsiveness to insulin was investigated in vivo in 10 healthy mongrel dogs of both sexes by determining net hepatic glucose output (NHGO) in response to insulin during the presence or absence of exogenous adenosine infusion. In addition, two separate series of experiments were performed to study the effect of adenosine (n = 7) or glucagon (n = 5) on NHGO. Basal NHGO, quantitated via the Fick principle, was significantly decreased by insulin infusion (4 U/min; 4.8 +/- 0.6 vs. -1.7 +/- 2.6 mg.kg-1.min-1, P less than 0.05). The addition of an intrahepatic arterial infusion of adenosine (10 mumol/min) during insulin infusion caused glucose output to return to basal levels (insulin, -1.7 +/- 2.6 mg.kg-1.min-1; insulin + adenosine, 3.8 +/- 1.6 mg.kg-1.min-1, P less than 0.05). The addition of intrahepatic arterial saline (control) during insulin infusion had no effect on insulin's action (insulin, -1.0 +/- 1.9 mg.kg-1.min-1; insulin + saline, -1.2 +/- 1.6 mg.kg-1.min-1, P greater than 0.05). Hepatic glucose, lactate, and oxygen deliveries were not affected during either insulin or insulin plus adenosine infusion. Intrahepatic arterial infusion of adenosine alone had no effect on NHGO, whereas intrahepatic arterial infusion of glucagon alone stimulated glucose output approximately fivefold (basal, 2.7 +/- 0.4 mg.kg-1.min-1; glucagon, 15.5 +/- 1.2 mg.kg-1.min-1, P less than 0.01). These results show that adenosine completely reversed the inhibition by insulin of NHGO. These data suggest that adenosine may act as a modulator of insulin action on the liver.     

Effects of acute and chronic counterregulatory hormone infusions on glucose tolerance and insulin sensitivity in diabetic dogs.

The effects of elevated EPI and CORT levels on KG, SI, and SG were studied in dogs with alloxan-induced diabetes. Conscious dogs received SAL, EPI 20 ng.kg-1.min-1 for 30 min (short EPI) or 72 h (long EPI), or CORT 200 micrograms.kg-1.min-1 for 60 min (short CORT) or 72 h (long CORT) before assessment of glucose metabolism by rapid sampling for glucose and insulin levels after 300 mg/kg i.v. glucose and exogenous insulin infusion designed to simulate the normal secretory pattern. With EPI infusion, KG fell acutely from 2.9 +/- 0.4 to 2.0 +/- 0.2%/min (SAL vs. short EPI, P < 0.05), but rose to 3.4 +/- 0.4%/min during long EPI. Minimal-model analysis of the glucose response with the insulin data as input showed that SI decreased acutely from 4.7 +/- 1.8 to 2.5 +/- 0.6 x 10(-5) min-1/pM (SAL vs. short EPI, P < 0.05), but rose to 4.5 +/- 2.5 x 10(-5) min-1/pM during long EPI. The effects of EPI on SG paralleled the results for KG and SI, with acute decline from 3.9 +/- 0.4 to 2.1 +/- 0.4 x 10(-2) min-1 (SAL vs. short EPI, P < 0.05) and recovery to 3.3 +/- 0.3 x 10(-2) min-1 during long EPI. During CORT infusion, KG tended to fall (SAL 2.9 +/- 0.4 vs. short CORT 2.5 +/- 0.5 vs. long CORT 2.2 +/- 0.5%/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients.

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.     

Simultaneous insulinlike growth factor I and insulin resistance in obese Zucker rats.

It has recently been shown that the ability of insulinlike growth factor I (IGF-I) to stimulate glucose uptake and to lower circulating amino acid levels is retained in insulin-resistant diabetic BB rats. To examine in vivo effects of IGF-I in obese Zucker rats (another model of insulin resistance) 6 obese and 6 lean rats received euglycemic IGF-I infusions (0.65 nmol.kg-1.min-1). IGF-I-stimulated glucose uptake in obese rats was 50% lower than lean control rats (45.0 +/- 2.8 vs. 92.2 +/- 6.1 mumol.kg-1.min-1, respectively), even though the rise in circulating IGF-I levels was greater in the obese group during IGF-I infusion. In addition, branched chain amino acid concentrations that declined by 45% in lean controls were not suppressed significantly in obese rats (392 +/- 33 basal vs. 327 +/- 29 microM at 90 min). Equivalent results were observed during euglycemic insulin clamps (12 pmol.kg-1.min-1) in 7 obese and 11 lean rats. These studies demonstrate that obese Zucker rats are resistant to the effects of IGF-I and insulin on glucose and amino acid metabolism.     

Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis

The effect of low-dose insulin treatment (5-10 U/h) on hepatic glucose production (HGP) and peripheral glucose disposal was determined in 5 insulin-dependent diabetes mellitus (IDDM) subjects who were admitted with diabetic ketoacidosis (DKA; plasma glucose 598 +/- 50 mg/dl, blood pH 7.20 +/- 0.06, plasma bicarbonate 12 +/- 2 meq/L). Basal hepatic glucose production (4.3 +/- 0.5 mg.kg-1.min-1) in the DKA patients was 1.5- to 2-fold greater (P less than .01) than in controls (2.1 +/- 0.1 mg.kg-1.min-1) and nonketotic IDDM subjects (2.9 +/- 0.3 mg.kg-1.min-1), whereas tissue glucose disposal was significantly reduced (1.7 +/- 0.1 vs. 2.1 +/- 0.1 mg.kg-1.min-1, P less than .05). After the institution of insulin therapy (1 mU.kg-1.min-1), the plasma glucose concentration fell at the rate of 60 +/- 5 mg.dl-1.h-1 to reach a value of 220 +/- 10 mg/dl, which was maintained constant for 2 h (insulin-clamp technique). Blood pH (7.21 +/- 0.06 to 7.35 +/- 0.05) and plasma bicarbonate (12 +/- 3 to 18 +/- 2 meq/L) both increased during insulin therapy (P less than .01). The decline in plasma glucose concentration during insulin therapy primarily resulted from a suppression of HGP (from 4.3 +/- 0.5 to 1.7 +/- 0.2 mg.kg-1.min-1, P less than .01) and to a lesser extent from the stimulation of tissue glucose disposal (1.7 +/- 0.2 to 2.6 +/- 0.3 mg.kg-1.min-1, P less than .01). At this time, urine glucose excretion decreased from 2.6 +/- 0.2 to 0.6 +/- 0.1 mg.kg-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of IGF-I and insulin on glucoregulation and fat metabolism in depancreatized dogs

The effects of equipotent glucose-lowering doses of insulinlike growth factor I (IGF-I) and insulin on tracer-determined glucose kinetics and several metabolites were compared in 14 experiments (7 in each group) in fasted, totally depancreatized dogs. This model prevented variations in insulin secretion induced by IGF-I and permitted evaluation of the effects of IGF-I on extrapancreatic glucagon. Steady-state moderate hyperglycemia (9.9 +/- 0.2 mM) was maintained by a subbasal intraportal infusion of insulin (1.29 +/- 0.17 pmol.kg-1.min-1). This was continued throughout the experiment, allowing evaluation of IGF-I effects on insulin clearance. Human recombinant IGF-I or insulin was given intravenously as a primed infusion for 90 min, followed by a 50-min recovery period. The dose of IGF-I was a 2.6-nmol/kg bolus plus 57.4 pmol.kg-1.min-1. The insulin dose required to induce the same plasma glucose decline as IGF-I (44 +/- 6 vs. 43 +/- 5%, NS) was 9-12 times lower (0.06-nmol/kg bolus + 6.4 +/- 0.6 pmol.kg-1.min-1). However, the mechanism of this decline differed with IGF-I and insulin; glucose production was much less suppressed (25 +/- 9 vs. 42 +/- 11%, P less than 0.001) and glucose utilization was more stimulated (68 +/- 18 vs. 38 +/- 19%, P less than 0.05) with IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of insulin resistance to catabolic effect of prednisone on leucine metabolism in humans

To determine the role insulin resistance may play in the catabolic effect of high-dose prednisone therapy, healthy volunteers were studied on four occasions with the hormone-clamp technique at two insulin infusion rates. Subjects were studied after 5 days of prednisone (60 mg/day) or no steroid treatment and were infused with somatostatin, glucagon, growth hormone, [3H]glucose, [14C]leucine, and insulin (0.1 or 0.2 mU.kg-1.min-1). At each rate of insulin infusion, the rate of leucine oxidation was increased (P less than .001) after steroid treatment. Leucine flux, an indicator of whole-body proteolysis, was similar in the presence or absence of steroid treatment (2.26 +/- 0.08 vs. 2.13 +/- 0.04 mumol.kg-1.min-1, respectively) at the lower rate of insulin infusion but was higher during steroid treatment (2.18 +/- 0.06 vs. 1.84 +/- 0.13 mumol.kg-1.min-1) at the 0.2-mU.kg-1.min-1 insulin infusion. Steroid pretreatment had no significant effect on the nonoxidative rates of leucine disappearance. These data provide strong evidence that the protein wasting associated with glucocorticosteroid therapy is in part the result of steroid-induced resistance to the antiproteolytic effect of insulin and an increase in the oxidation (and thus wasting) of one essential amino acid, leucine.     

Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients

Glycemic control and glucose metabolism were examined in 5 patients with insulin-dependent diabetes mellitus (IDDM) and 8 insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients before and after 2 mo of therapy with glyburide (20 mg/day). Glycemic control was assessed by daily insulin requirement, 24-h plasma glucose profile, glucosuria, and glycosylated hemoglobin. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, and insulin sensitivity was determined by a two-step euglycemic insulin clamp (1 and 10 mU X kg-1. X min-1) performed with indirect calorimetry and [3-3H]glucose. In the IDDM patients, the addition of glyburide produced no change in daily insulin dose (54 +/- 8 vs. 53 +/- 7 U/day), mean 24-h glucose level (177 +/- 20 vs. 174 +/- 29 mg/dl), glucosuria (20 +/- 6 vs. 35 +/- 12 g/day) or glycosylated hemoglobin (10.1 +/- 1.0 vs. 9.5 +/- 0.7%). Furthermore, there was no improvement in basal hepatic glucose production (2.1 +/- 0.2 vs. 2.4 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by low- and high-dose insulin infusion, or in any measure of total, oxidative, or nonoxidative glucose metabolism in the basal state or during insulin infusion. C-peptide levels were undetectable (less than 0.01 pmol/ml) in the basal state and after glucagon infusion and remained undetectable after glyburide therapy. In contrast to the IDDM patients, the insulin-treated NIDDM subjects exhibited significant reductions in daily insulin requirement (72 +/- 6 vs. 58 +/- 9 U/day), mean 24-h plasma glucose concentration (153 +/- 10 vs. 131 +/- 5 mg/dl), glucosuria (14 +/- 5 vs. 4 +/- 1 g/day), and glycosylated hemoglobin (10.3 +/- 0.7 vs. 8.0 +/- 0.4%) after glyburide treatment (all P less than or equal to .05). However, there was no change in basal hepatic glucose production (1.7 +/- 0.1 vs. 1.7 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by insulin, or insulin sensitivity during the two-step insulin-clamp study. Both basal (0.14 +/- 0.05 vs. 0.32 +/- 0.05 pmol/ml, P less than .05) and glucagon-stimulated (0.24 +/- 0.07 vs. 0.44 +/- 0.09 pmol/ml) C-peptide levels rose after 2 mo of glyburide therapy and both were correlated with the decrease in insulin requirement (basal: r = .65, P = .08; glucagon stimulated: r = .93, P less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)     

Leucine metabolism in IDDM. Role of insulin and substrate availability

The effect of insulin on plasma amino acid concentrations and leucine metabolism was examined in 18 healthy nondiabetic young volunteers and in 7 subjects with insulin-dependent diabetes mellitus (IDDM) with the euglycemic insulin-clamp technique (40 mU.m-2.min-1) in combination with [1-14C]leucine. All diabetic subjects were studied while in poor metabolic control (fasting glucose 13.3 +/- 1.1 mM; HbA1c 10.8 +/- 0.2%) and again after 2 mo of intensified insulin therapy (fasting glucose 7.2 +/- 0.5 mM; HbA1c 8.0 +/- 0.2%). Insulin-mediated total-body glucose uptake in poorly controlled diabetic subjects (3.6 +/- 0.5 mg.kg-1.min-1) was significantly reduced compared with control subjects (7.5 +/- 0.2 mg.kg-1.min-1; P less than .001) and improved slightly after insulin therapy (4.8 +/- 0.3 mg.kg-1.min-1; P less than .05), although it still remained significantly lower than in control subjects (P less than .01). During the insulin-clamp study performed in subjects with poorly controlled IDDM, endogenous leucine flux (ELF), leucine oxidation (LO), and nonoxidative leucine disposal (NOLD) all decreased (50.1 +/- 2.0 to 26.4 +/- 0.4; 9.2 +/- 0.4 to 6.0 +/- 0.3; 40.9 +/- 2.0 to 20.4 +/- 2.0 mumol.m-2.min-1, respectively) to the same extent as in control subjects. After 2 mo of intensified insulin therapy, the effect of acute hyperinsulinemia on ELF, LO, and NOLD was comparable to that of control subjects, whereas insulin-stimulated glucose metabolism was still impaired. To examine the effect of substrate availability on leucine turnover, well-regulated IDDM and control subjects underwent a repeat insulin-clamp study combined with a balanced amino acid infusion designed to increase circulating plasma amino acid levels approximately twofold. Under these conditions, NOLD was equally enhanced above baseline in both control and IDDM subjects (P less than .01), whereas ELF was inhibited to a greater extent (P less than .01) than during the insulin clamp performed without amino acid infusion (control vs. diabetic subjects, NS). In conclusion, insulin-mediated glucose metabolism is severely impaired in subjects with both poorly controlled and well-controlled IDDM, whereas the effect of acute insulin infusion on leucine turnover is normal, and combined hyperaminoacidemia/hyperinsulinemia stimulated NOLD to a similar extent in both IDDM and control subjects.     

Enhanced peripheral and splanchnic insulin sensitivity in NIDDM men after single bout of exercise

We studied glucose metabolism in non-insulin-dependent diabetic (NIDDM) men with and without glycogen-depleting cycle exercise 12 h beforehand and have compared the results to our previous data in lean and obese subjects. Rates of total glucose utilization, glucose oxidation, nonoxidative glucose disposal (NOGD), glucose metabolic clearance rate (MCR), and endogenous glucose production (EGP) were determined with a "two-level" insulin-clamp technique (100-min infusions at 40 and 400 mU X m-2 X min-1) combined with indirect calorimetry and D-3-[3H]glucose infusion. Muscle biopsy specimens from vastus lateralis were analyzed for glycogen content and glycogen synthase activity before and after insulin infusions. After exercise, NIDDM subjects had muscle glycogen concentrations comparable with those of lean and obese subjects. The activation of glycogen synthase both by prior exercise and insulin infusion was similar to lean controls. After exercise, total glucose disposal was significantly increased during the 40-mU X m-2 X min-1 infusion (P less than .05), but the increase observed during the 400-mU X m-2 X min-1 infusion was not significant. These increases after exercise were the result of significantly higher NOGD during both levels of insulin infusion. The MCR of glucose during both insulin infusions was reduced in NIDDM compared with lean subjects but was very similar to that in obese nondiabetics. Basal EGP was significantly reduced on the morning after exercise (4.03 +/- 0.27 vs. 3.21 +/- 0.21 mg x kg-1 fat-free mass x min-1) (P less than .05) and associated with significant reductions of fasting plasma glucose (197 +/- 12 vs. 164 +/- 9 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulinomimetic properties of trace elements and characterization of their in vivo mode of action

Lithium and vanadate have insulinomimetic actions in vitro. In this study, we examined the in vivo effects of lithium and vanadate on glucose metabolism in diabetic (90% partial pancreatectomy) rats. Four groups of chronically catheterized rats were studied: control, diabetic, diabetic treated with lithium (plasma concn 1.0 +/- 0.1 meq/L) and vanadate (0.05 mg/ml in drinking water), and diabetic treated with lithium, vanadate, zinc, and magnesium. Postmeal plasma glucose was increased in diabetic versus control rats (18.7 vs. 7.7 mM, P less than 0.01) and was normalized by addition of lithium and vanadate (8 mM) or lithium, vanadate, zinc, and magnesium (7.4 mM). Euglycemic insulin-clamp studies were performed 2 wk posttreatment; insulin-mediated glucose uptake was reduced in diabetic compared with control rats (142 +/- 4 vs. 200 +/- 5 mumol.kg-1.min-1, P less than 0.01), returned to normal with lithium and vanadate (206 +/- 6 mumol.kg-1.min-1), or increased to supranormal levels with lithium, vanadate, zinc, and magnesium (238 +/- 6 mumol.kg-1.min-1). During the insulin clamp, muscle glycogenic rate was severely impaired in diabetic versus control rats (18 vs. 70 mumol.kg-1.min-1) and was normalized by lithium and vanadate (91 mumol.kg-1.min-1) or lithium, vanadate, zinc, and magnesium (93 mumol.kg-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans

To compare the dose-response characteristics for suppression of lipolysis and suppression of glucose production by insulin, 13 normal nonobese individuals were infused with insulin at rates of 0.1, 0.2, 0.4, 0.8, and 1.6 mU X kg-1 X min-1 while normoglycemia was maintained with the glucose clamp technique. Glucose appearance and glycerol appearance (taken as index of lipolysis) were measured isotopically with simultaneous infusions of 3-[3H]glucose and U-[14C]glycerol. Baseline glucose and glycerol rates of appearance were 14 +/- 0.5 and 1.7 +/- 0.2 mumol X kg-1 X min-1, respectively. Approximately 3% of plasma glucose originated from glycerol, and this accounted for approximately 50% of glycerol disposal. During the insulin infusions, arterial insulin (basal, 9.8 +/- 0.6 microU/ml) increased to 14 +/- 0.5, 20 +/- 0.5, 31 +/- 1, 58 +/- 2, and 104 +/- 6 microU/ml; calculated portal venous insulin (basal, 24 +/- 2 microU/ml) increased to 26 +/- 1, 32 +/- 3, 70 +/- 4, and 115 +/- 6 microU/ml. The rate of glucose appearance was suppressed 100%, whereas the rate of appearance of glycerol was maximally suppressed only 85%. Nevertheless, the insulin concentration that produced half-maximal suppression of glucose appearance was twice as great as that required for half-maximal suppression of glycerol appearance (26 +/- 2 vs. 13 +/- 2 microU/ml, P less than .001). Insulin decreased both the absolute rate of glycerol conversion to plasma glucose and the percent of glycerol disposal appearing in plasma glucose (both P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)