Biomedical subjects

J Proietto

Publications and source records attributed to J Proietto.

At least 55 records · Page 3Linked to original sources

PubMed1995

Abnormal transient rise in hepatic glucose production after oral glucose in non-insulin-dependent diabetic subjects.

A transient rise in hepatic glucose production (HGP) after an oral glucosa load has been reported in some insulin-resistant states such as in obese fa/fa Zucker rats. The aim of this study was to determine whether this rise in HGP also occurs in subjects with established non-insulin-dependent diabetes mellitus (NIDDM). Glucose kinetics were measured basally and during a double-label oral glucose tolerance test (OGTT) in 12 NIDDM subjects and 12 non-diabetic 'control' subjects. Twenty minutes after the glucose load, HGP had increased 73% above basal in the NIDDM subjects (7.29 +/- 0.52 to 12.58 +/- 1.86 mumol/kg/min, P < 0.02). A transient rise in glucagon (12 pg/ml above basal, P < 0.004) occurred at a similar time. In contrast, the control subjects showed no rise in HGP or plasma glucagon. HGP began to suppress 40-50 min after the OGTT in both the NIDDM and control subjects. A 27% increase in the rate of gut-derived glucose absorption was also observed in the NIDDM group, which could be the result of increased gut glucose absorption or decreased first pass extraction of glucose by the liver. Therefore, in agreement with data in animal models of NIDDM, a transient rise in HGP partly contributes to the hyperglycemia observed after an oral glucose load in NIDDM subjects.

Animals↗

PubMed1995

The effects of oophorectomy and female sex steroids on glucose kinetics in the rat.

In order to clarify the roles played by female sex steroids on glucose metabolism, basal glucose kinetics were studied in control sham operated (C), oophorectomised (O), 17-beta-oestradiol treated oophorectomised (1.5 micrograms/day) (E) and progesterone treated oophorectomised (1.5 mg/day) (P) female rats. Hormone (or vehicle only) delivery was via osmotic pumps which were inserted at the time of oophorectomy (or sham operation) 7 days prior to metabolic testing. In fasted anaesthetised rats, hepatic glucose production (HGP), plasma glucose metabolic clearance rate (MCR) and glucose uptake indices (GUI) of selected peripheral tissues were measured using radioactive tracer methodology. Following surgery, the O rats significantly gained and the E rats significantly lost weight compared to the C rats. Plasma insulin and glucose were not different between groups. HGP and MCR were increased by 24-29% (P < 0.005) and 19-28% (P < 0.001), respectively, in the O compared to the C, E and P rats. The GUI of brown adipose tissue was significantly reduced in the P compared to the C rats (3 +/- 1 vs 25 +/- 10 micromol/100 g/min). In conclusion, female sex steroid hormones significantly influence rat body weight, hepatic glucose metabolism and the metabolism of brown adipose tissue.

Animals↗

PubMed1995

Understanding the pathogenesis of type 2 diabetes: can we get off the metabolic merry-go-rounds?

The aetiology of non-insulin-dependent diabetes mellitus (NIDDM) is not known. The concordance of NIDDM in identical twins and differences in the prevalence rate of NIDDM between different racial groups suggest a genetic cause. Hyperglycaemia in established diabetes is caused by a combination of hepatic insulin resistance, impaired peripheral (muscle and fat) glucose uptake and a defect in glucose-mediated insulin secretion. However, it is not known if these defects are all inherited or if one can cause the others. This uncertainty is due to the fact that hyperglycaemia per se can cause defects in insulin action and insulin secretion that resemble those found in NIDDM. Furthermore the elevated free fatty acid (FFA) levels found when NIDDM is associated with obesity are known to cause both peripheral and hepatic insulin resistance. Recently we have demonstrated the mechanism by which elevated FFA levels can cause hepatic insulin resistance. However, we also have evidence that the converse holds in that genetically engineered hepatic insulin resistance in a transgenic rat model leads to obesity. Thus an understanding of the pathogenesis of NIDDM is complicated by the fact that hyperglycaemia and obesity can be both causes and consequences of insulin resistance. To overcome these difficulties, studies in young euglycaemic diabetes-prone subjects have been conducted. Results suggest that there may be different causes for NIDDM in different racial groups.

Animals↗

PubMed1995

Influence of muscle glycogen on glycogenolysis and glucose uptake during exercise in humans.

To examine the effects of alterations in preexercise muscle glycogen availability on glycogenolysis and glucose uptake during exercise, 12 active but untrained men [22.8 +/- 1.6 (SE) yr, 71.7 +/- 2.0 kg, peak pulmonary oxygen uptake 3.85 +/- 0.16 l/min] were studied during 40 min of cycle ergometer exercise at 65-70% peak pulmonary oxygen uptake on two separate occasions, at least 1 wk apart. Preexercise muscle glycogen concentrations were manipulated by having the subjects perform glycogen-lowering exercise either 24 or 48 h before a trial, in combination with either high or low dietary carbohydrate intake. In series 1 (n = 7), increasing muscle glycogen from 90.3 +/- 6.0 to 124.7 +/- 10.8 mmol/kg wet wt increased muscle glycogenolysis during exercise (62.7 +/- 7.9 vs. 49.1 +/- 6.6 mmol/kg; P < 0.05). Similarly, in series 2 (n = 5) when muscle glycogen was reduced from 96.2 +/- 6.6 to 53.7 +/- 6.0 mmol/kg, glycogen utilization during exercise was reduced from 51.8 +/- 4.6 to 28.3 +/- 3.8 mmol/kg (P < 0.05). The altered muscle glycogen utilization was associated with alterations in carbohydrate oxidation during exercise, without effect on tracer ([3H]glucose)-determined glucose uptake. These results indicate that preexercise muscle glycogen availability influences muscle glycogenolysis, but not glucose uptake, during exercise.

Adult↗

PubMed1995

Impaired glucose tolerance and increased weight gain in transgenic rats overexpressing a non-insulin-responsive phosphoenolpyruvate carboxykinase gene.

The effects of an overexpressed, non-insulin-responsive gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32), on glucose homeostasis were investigated. Transgenic rats harboring a metallothionein-driven PEPCK gene (lacking the entire PEPCK upstream-regulatory region) expressed transgene PEPCK mRNA in the key gluconeogenic tissues, liver and kidney. Female transgenic rats, studied at 10 weeks of age, showed mild fasting hyperglycemia (6.9 +/- 0.2 vs. 5.9 +/- 0.1 mM P = 0.002 n = 6), hyperinsulinemia (92.2 +/- 4.0 vs. 54.0 +/- 6.6 pM, P = 0.001, n = 6), impaired glucose tolerance and increased weight gain (178.3 +/- 3.2 vs. 153.4 +/- 2.5 g, P = 0.001, n = 16 and n = 13 transgenic and control rats, respectively). Despite hyperinsulinemia at this age, kidneys of transgenic rats maintained a significant 20% elevation of total PEPCK enzyme activity, while total liver PEPCK activity was not reduced. This study suggests that an insulin-resistant step in the gluconeogenic pathway can lead to glucose intolerance and an increase in weight. These rats offer the unique opportunity to study the metabolic consequences of chronic, mild excess glucose supply, as seen in non-insulin-dependent diabetes.

Animals↗

PubMed1994

Isoproterenol inhibits cyclic AMP-mediated but not insulin-mediated translocation of the GLUT4 glucose transporter isoform.

Isoproterenol is a beta adrenergic agonist whose effects have been attributed to the generation of cAMP. Previous studies have shown that it inhibits glucose transport in adipocytes without changing the number of insulin-responsive glucose transporters (GLUT4) on the cell surface. However, we have shown previously that cAMP stimulates translocation of GLUT4 to the cell surface in adipocytes (Kelada et al. J Biol Chem 267, 7021-7025, 1992). We therefore further investigated the mechanisms involved in isoproterenol regulation of glucose transport. Consistent with the effects of dibutyryl cAMP, we found that a low concentration of isoproterenol (10 nM) stimulated glucose transport and the translocation of GLUT4 from the low density microsomal fraction to the plasma membrane. By contrast, a higher concentration of isoproterenol (1 microM) did not stimulate transport or GLUT4 translocation and furthermore inhibited dibutyryl cAMP-stimulated GLUT4 translocation. This inhibitory effect was specific for cAMP since isoproterenol had no effect on insulin-stimulated GLUT4 translocation. We conclude that isoproterenol has a biphasic effect on glucose transport, mediated by acute translocation of GLUT4 at low concentrations and by inhibition of intrinsic activity at high concentration, both of which may be explained by effects of cAMP. It has a further cAMP-independent effect at high concentration to inhibit cAMP-mediated translocation of GLUT4.

Adipocytes↗

PubMed1994

The feto-placental glucose steal phenomenon is a major cause of maternal metabolic adaptation during late pregnancy in the rat.

The aim of this study was to determine the extent to which a feto-placental glucose steal phenomenon contributes to the process of maternal metabolic adaptation to late pregnancy. Glucose metabolism was studied in virgin control, pregnant rats and virgin rats with a phlorizin-induced model of the feto-placental glucose steal phenomenon. Whole body glucose kinetics and glucose uptake into individual tissues were measured in anaesthetised rats basally and during hyperinsulinaemic euglycaemic clamps. The basal glucose metabolism of the pregnant rats was closely mimicked by the phlorizin-treated rats. Basal plasma glucose was 39% and 38% lower (p < 0.0001 for both); hepatic glucose production was 21% and 26% higher (p < 0.05 for both); and plasma glucose clearance was 109% and 104% higher (p < 0.0001 for both) in the pregnant and phlorizin-treated rats, respectively, compared to the control rats. Basal glucose uptake into peripheral tissues was lower in both the pregnant and phlorizin-treated compared to the control rats, being most evident in heart (p < 0.01 for both) and brown adipose tissue (p < 0.001 for both). In the clamp studies, impairment of glucose uptake into skeletal muscle was observed in both the pregnant and phlorizin-treated rats compared to the control rats. In conclusion, the feto-placental glucose steal phenomenon is a major contributing factor to postabsorptive glucose metabolism in late pregnancy. This phenomenon also contributes to the impairment of maternal insulin-stimulated peripheral glucose uptake.

Adaptation, Physiological↗

PubMed1994

Effects of dexfenfluramine on glucose turnover in non-insulin-dependent diabetes mellitus.

Dexfenfluramine, a serotonin agonist with effects on the central nervous system (CNS), lowers blood glucose in patients with non-insulin-dependent mellitus (NIDDM). Previous studies using the hyperinsulinemic clamp have shown that dexfenfluramine improves insulin action on both stimulation of glucose uptake and inhibition of hepatic glucose production (HGP). Since the central nervous system can influence glucose tolerance in ways that may not be detected using a clamp procedure, we investigated the effects of dexfenfluramine on glucose kinetics during an oral glucose tolerance test (OGTT) in patients with NIDDM. Glucose kinetics were measured basally and during an OGTT using a double isotope technique and the modified one-pool model of the glucose system. After a 4-week run-in period, studies were performed before, after two 15 mg doses, and then after 4 weeks on 15 mg twice daily in 10 subjects with NIDDM. Fasting-plasma glucose was significantly lower after 4 weeks on dexfenfluramine (P < 0.01) as was plasma glucose at both 1 and 2 h during the OGTT (P < 0.05). The lower plasma glucose was associated with a reduction in HGP both basally (P < 0.01) and during the 1st hour of the OGTT (P < 0.05). There was no change in peripheral glucose uptake. Plasma insulin levels were unaltered, but plasma glucagon was lower after 1 month of treatment. We conclude that dexfenfluramine improves fasting-blood glucose and oral glucose tolerance predominantly by reducing hepatic glucose production.

Adult↗

PubMed1994

Animal models of obesity--theories of aetiology.

The multiplicity of proposed mechanisms for obesity is confusing and many questions remain to be answered. A review of all the proposed mechanisms for obesity suggests that they can be placed in two groups (Table 3). The first centres on the role of the hypothalamus in the regulation of body weight. With further knowledge it may be possible to find unifying mechanisms originating in the brain for the set-point theory, the autonomic nervous system imbalance hypothesis, the thermogenesis, hyperphagia and the hyperinsulinaemia hypotheses and the gestational undernutrition hypothesis. This group of mechanisms suggests that obesity is due to altered function of central regulatory mechanisms and that the various related hypotheses are merely looking at different aspects of the same problem. The second centres on abnormalities intrinsic to the adipocyte and could link the fat cell and perinatal overnutrition theories. This group of theories suggests that an abnormality at the fat cell level, either genetic or acquired, can result in the excessive accumulation of fat. The two groups are not contradictory. The ability to develop obesity as a result of a fat cell abnormality does not negate the existence of regulatory central mechanisms since there is a finite capacity for these mechanisms to operate.

Adipocytes↗

PubMed1994

Glucose kinetics during exercise in trained men.

Six trained men were studied to examine the relative increases in hepatic glucose output and peripheral glucose uptake during 40 min of exercise at 75% VO2max. Rates of appearance (Ra) and disappearance (Rd) were measured using a primed, continuous intravenous infusion of D-[3-3H]glucose. Plasma glucose increased (P < 0.05) from 4.8 +/- 0.2 mmol l-1 at rest to 6.2 +/- 0.5 mmol l-1 after 40 min of exercise. Both Ra and Rd increased (P < 0.05) during exercise, however, during the early phase of exercise, Ra exceeded Rd (P < 0.05). Ra peaked at 42.0 +/- 3.2 mumol kg-1 min-1 after approximately 15 min of exercise. In contrast, the highest Rd of 33.9 +/- 4.3 mumol kg-1 min-1 was measured at the end of exercise. In additional experiments, five men were studied during 40 min of exercise at 70-75% VO2max, 2 h after ingestion of the non-selective beta-adrenergic antagonist timolol or a placebo capsule. Subjects were unable to complete the exercise bout following timolol, fatiguing after 28.0 +/- 4.0 min (P < 0.05). The increase in blood glucose from 4.3 +/- 0.1 to 4.7 +/- 0.3 mmol l-1 (P < 0.05) following 20 min of exercise under control conditions was completely abolished by prior timolol ingestion (4.2 +/- 0.2 to 4.1 +/- 0.2 mmol l-1). These results demonstrate that during exercise at 75% VO2max in trained men, hepatic glucose output is not always closely matched to peripheral muscle glucose uptake and may be subject to feed-forward regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Effect of detraining on GLUT-4 protein in human skeletal muscle.

The present study was undertaken to examine the effect of 10 days of detraining levels of GLUT-4 protein expression and citrate synthase (CS) activity in the vastus lateralis of trained men. During the course of normal training, seven endurance-trained (T) men and eight age- and weight-matched active but untrained (UT) men underwent an oral glucose tolerance test (OGTT) after an overnight fast. Muscle samples were obtained from the vastus lateralis by needle biopsy for measurement of GLUT-4 protein and CS activity. The tests were repeated on six of the T subjects after 10 days of detraining (DT men). The area under the insulin response curve during OGTT was lower in T men than in DT and UT men (22.4 +/- 2.8, 32.1 +/- 5.9, and 39.9 +/- 4.7 x 10(-3) pmol.l-1.min-1, respectively; P < 0.05). There were no differences between groups in the glucose responses to OGTT. GLUT-4 protein levels and CS activity were higher in T men than in DT and UT men (GLUT-4: 4.37 +/- 0.40, 2.92 +/- 0.53, and 1.71 +/- 0.22 arbitrary standard units and CS: 47.12 +/- 4.75, 33.63 +/- 3.98, and 24.51 +/- 2.97 mumol.min-1.g-1, respectively; both P < 0.05). Muscle GLUT-4 protein content was correlated with CS activity in all three groups (r = 0.64, 0.68, and 0.96 for UT, T, and DT men, respectively). These results suggest that muscle GLUT-4 protein content and oxidative capacity undergo parallel adaptations after detraining in previously well-trained men.

Adult↗

PubMed1994

Effect of carbohydrate ingestion on glucose kinetics during exercise.

Six well-trained men (peak pulmonary oxygen uptake = 5.03 +/- 0.11 l/min) were studied during 2 h of exercise at 69 +/- 1% peak pulmonary oxygen uptake to examine the effect of carbohydrate (CHO) ingestion on glucose kinetics. Subjects ingested 250 ml of either a 10% glucose solution containing 6-[3H]glucose (CHO) or a sweet placebo every 15 min during exercise. Glucose kinetics were assessed by 6,6-[2H]glucose infusion corrected for gut-derived glucose in CHO. Plasma glucose was higher (P < 0.05) in CHO from 20 min. Total glucose appearance was higher in CHO due to glucose delivery from the gut (68 +/- 7 g), since hepatic glucose production was reduced by 51% (29 +/- 5 vs. 59 +/- 5 g). Glucose uptake was higher in CHO (96 +/- 7 vs. 60 +/- 6 g) with the ingested glucose supplying 67 +/- 4 g and, with the assumption that it was fully oxidized, accounted for 14 +/- 1% of total energy expenditure. In conclusion, CHO ingestion during prolonged exercise results in suppression of hepatic glucose production and increased glucose uptake. These effects appear to be mediated mainly by increased plasma glucose and insulin levels.

Administration, Oral↗

PubMed1994

Skeletal muscle GLUT-4 and glucose uptake during exercise in humans.

The present study examined the relationship between total skeletal muscle GLUT-4 protein level and glucose uptake during exercise. Eight active non-endurance-trained men cycled at 72 +/- 1% peak pulmonary oxygen consumption for 40 min, with rates of glucose appearance and disappearance (Rd) determined by utilizing a primed continuous infusion of [3-3H]glucose commencing 2 h before exercise. Muscle glycogen content and utilization, citrate synthase activity, and total GLUT-4 protein were measured on muscle biopsy samples obtained from the vastus lateralis. A direct relationship existed between preexercise muscle glycogen content and glycogen utilization during exercise (r = 0.76, P < 0.05). Citrate synthase activity and glucose Rd at the end of exercise averaged 21.9 +/- 3.0 mumol.min-1.g-1 and 27.3 +/- 2.5 mumol.kg-1.min-1, respectively. There was a direct correlation between citrate synthase activity and GLUT-4 protein (r = 0.78, P < 0.05); however, at the end of exercise, glucose Rd was inversely related to both GLUT-4 (r = -0.89, P < 0.01) and citrate synthase activity (r = -0.72, P < 0.05). Plasma insulin, which decreased during exercise, was not related to glucose Rd. In conclusion, glucose uptake during 40 min of exercise at 72% peak pulmonary oxygen consumption was inversely related to the total muscle GLUT-4 protein level. This suggests that factors other than the total GLUT-4 protein level are important in the regulation of glucose uptake during exercise.

Adult↗

PubMed1994

Early decrease in GLUT4 protein levels in brown adipose tissue of New Zealand obese mice.

The aim of this study was to determine if the previously described insulin resistance in the New Zealand Obese (NZO) mouse is associated with a decrease in GLUT4 protein and if such changes occur early in the evolution of the syndrome. GLUT4 levels were measured in whole membranes isolated from a variety of tissues in 4 and 20-week-old NZO and control NZC mice by Western blotting using a specific antibody to the C terminal end of the protein. At 20 weeks of age, GLUT4 levels were lower in the NZO mice in brown and white adipose tissue, heart, diaphragm, red and white quadriceps, and red and white gastrocnemius, but not in soleus muscle. At 4 weeks of age, GLUT4 levels were 52% lower in BAT (3309 +/- 1006 vs 6951 +/- 1870 cpm P = 0.039) but were not lower in WAT, heart or red quadriceps. It is concluded that adult NZO mice have a decrease in GLUT4 levels in most insulin-sensitive tissues and that in BAT, this occurs at an early age.

Adipose Tissue↗

PubMed1993

Carbohydrate fermentation decreases hepatic glucose output in healthy subjects.

Fermentation of undigested carbohydrate produces short-chain fatty acids (SCFA), some of which have been shown to reduce hepatic glucose production (HGP) in animals. The aim of this study was to examine whether carbohydrate fermentation decreases HGP in man. Ten healthy subjects consumed 90-g carbohydrate portions of either brown rice or barley for dinner in random order 1 week apart. The following morning, glucose kinetics were measured basally and during an oral glucose tolerance test (OGTT). HGP was calculated as the difference between the total rate of glucose appearance (calculated from % enrichment of 6,6 dideuterated glucose [6,6 D2 glucose]) and the rate of appearance of gut-derived glucose (calculated from 6-3H glucose in the glucose drink). To detect fermentation, breath H2 content was measured by end-expiratory sampling of alveolar air. Significantly more breath H2 was produced after barley consumption (24 +/- 4 v 4 +/- 1 ppm, P < .001), indicating that barley contains more fermentable carbohydrate than rice. Glucose tolerance improved after the barley meal, with the peak OGTT plasma glucose concentration being 0.7 mmol/L lower than that after the rice meal (7.7 +/- 0.4 v 8.4 +/- 0.3 mmol/L, P < .05). This was primarily due to a 30% reduction in HGP (area under the curve, 909 +/- 116 v 1,295 +/- 157 mumol/kg; P < .01). No difference in the rates of glucose disappearance or gut glucose absorption was observed. However, serum free fatty acid (FFA) concentrations were significantly reduced the morning after the barley meal. In summary, carbohydrate fermentation enhances the suppression of HGP and FFA levels by oral glucose in man.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Impaired suppression of gluconeogenesis induced by overexpression of a noninsulin-responsive phosphoenolpyruvate carboxykinase gene.

Despite detailed knowledge of the regulation of individual steps in the gluconeogenic pathway, the relative importance of each step to the overall control of gluconeogenesis by insulin is not known. The aim of this study was to determine the role of phosphoenolpyruvate carboxykinase (PEPCK) in the regulation of gluconeogenesis by insulin. Clones of the rat hepatoma cell line H4IIE-C3 were produced, overexpressing a PEPCK gene, driven by a promoter not responsive to insulin. In these cells basal gluconeogenesis from 2-[14C]pyruvate was increased 2.1-fold compared to controls (4.63 +/- 0.49 nmol/10(5) cells vs. 2.21 +/- 0.24 nmol/10(5) cells after 3 h, P < 0.05, n = 5). Increased gluconeogenesis was associated with an increase in basal PEPCK mRNA levels (1.9-fold) and enzyme activity (2.8-fold). Insulin (10(-7) M) suppressed basal gluconeogenesis, PEPCK mRNA levels, and enzyme activity in control cells, but no detectable decrease was observed in PEPCK-transfected cells. These experiments provide direct evidence in intact cells that PEPCK is the rate-limiting enzyme in gluconeogenesis from pyruvate and show that insulin's action to inhibit gluconeogenesis is predominantly on the inhibition of PEPCK transcription.

Animals↗

PubMed1993

Impaired regulation of hepatic fructose-1,6-bisphosphatase in the New Zealand obese mouse model of NIDDM.

The New Zealand obese mouse, a model of NIDDM, is characterized by hyperglycemia, hyperinsulinemia, and hepatic and peripheral insulin resistance. The aim of this study was to investigate the biochemical basis of hepatic insulin resistance in NZO mice. Glycolytic and gluconeogenic enzyme activities were measured in fed and overnight fasted 19- to 20-wk-old NZO and control New Zealand chocolate mice. The NZO mice were twice as heavy as the NZC mice. The activity of the glycolytic enzymes glucokinase and pyruvate kinase was higher, whereas that of the gluconeogenic enzymes PEPCK and glucose-6-phosphatase was lower in fed and fasted NZO mice. These enzyme changes are consistent with a normal response to the hyperinsulinemia in NZO mice. In contrast, the activity of the third regulated gluconeogenic enzyme, fructose-1,6-bisphosphatase, was similar in fed and fasted NZO and NZC mice despite the higher insulin and glucose levels in the NZO mouse. This enzyme is primarily regulated by the powerful inhibitor fructose-2,6-bisphosphate. The levels of this metabolite were measured and found to be increased in both the fed and fasted states in the NZO mouse, suggesting that the activity of the bifunctional enzyme that regulates the level of inhibitor (6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase) is normally regulated in the NZO mouse. We conclude that most insulin-responsive gluconeogenic and glycolytic enzymes are normally regulated in the NZO mouse, but an abnormality in the regulation of fructose-1,6-bisphosphatase may contribute to the increase hepatic glucose production in these mice.

Animals↗

PubMed1993

Low-dose acarbose improves glycemic control in NIDDM patients without changes in insulin sensitivity.

OBJECTIVE: To examine the impact on metabolic control in NIDDM patients of the alpha-glucosidase inhibitor, acarbose, when administered at a low dose in powdered form. RESEARCH DESIGN AND METHODS: Six subjects were recruited for a double-blind cross-over trial using 25 mg powdered acarbose and a placebo 3 times a day with meals for 3 mo. In addition to parameters of diabetes control and body weight, glucose turnover and insulin sensitivity were measured with the hyperinsulinemic/euglycemic clamp technique combined with tracer kinetics. RESULTS: None of the subjects showed significant changes in FPG levels or body weight either on the 3-mo course of acarbose or placebo. HbA1c fell significantly from 10.6 +/- 1.0 to 9.4 +/- 1.3% (P = 0.05) during treatment with acarbose but failed to change on placebo (10.1 +/- 1.0 to 11.1 +/- 2.0%; P = 0.36). Basal HGP and glucose utilization were unchanged during either of the treatment periods, and hyperinsulinemia produced a similar degree of suppression of HGP before and after each treatment. At a physiological concentration, insulin failed to stimulate glucose clearance in these diabetic patients, and no improvement was seen with acarbose treatment. No changes in plasma lipids or lipoprotein profiles were demonstrated after 3 mo on acarbose. In acute studies, it was shown that administration of acarbose at a dose of 25 mg powder per meal significantly decreased the postprandial glycemic excursion. CONCLUSIONS: When administered in the powdered form at the low dose of 25 mg 3 times/day with meals over 3 mo, acarbose was well tolerated by the NIDDM patients and was without side effects. It improved glycemic control by reducing postprandial hyperglycemia, but had no effect on glucose turnover, insulin sensitivity, or lipid profile.

Acarbose↗