Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study

OBJECTIVE: To determine the efficacy of acarbose, compared with placebo, on the metabolic control of NIDDM patients inadequately controlled on maximal doses of conventional oral agents. RESEARCH DESIGN AND METHODS: In this three-center double-blind study, 90 Chinese NIDDM patients with persistent poor glycemic control despite maximal doses of sulfonylurea and metformin were randomly assigned to receive additional treatment with acarbose 100 mg thrice daily or placebo for 24 weeks, after 6 weeks of dietary reinforcement. Efficacy was assessed by changes in HbA1c, fasting and 1-h postprandial plasma glucose and insulin levels, and fasting lipid levels. RESULTS: Acarbose treatment was associated with significantly greater reductions in HbA1c (-0.5 +/- 0.2% vs. placebo 0.1 +/- 0.2% [means +/- SEM], P = 0.038), 1-h postprandial glucose (-2.3 +/- 0.4 mmol/l vs. placebo 0.7 +/- 0.4 mmol/l, P < 0.001) and body weight (-0.54 +/- 0.32 kg vs. placebo 0.42 +/- 0.29 kg, P < 0.05). There was no significant difference between the two groups regarding changes in fasting plasma glucose and lipids or fasting and postprandial insulin levels. Flatulence was the most common side effect (acarbose vs. placebo: 28/45 vs. 11/44, P < 0.05). One patient on acarbose had asymptomatic elevations in serum transaminases that normalized in 4 weeks after acarbose withdrawal. Another patient on acarbose developed severe hypoglycemia; glycemic control was subsequently maintained on half the baseline dosage of sulfonylurea. CONCLUSIONS: In NIDDM patients inadequately controlled on conventional oral agents, acarbose in moderate doses resulted in beneficial effects on glycemic control, especially postprandial glycemia, and mean body weight. Additional use of acarbose can be considered as a useful alternative in such patients if they are reluctant to accept insulin therapy.     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-(2)H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl(b)), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Cl(b)/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 +/- 0.6 vs 0.76 +/- 0.18 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; ISI: 0.40 +/- 0.06 vs 0.13 +/- 0.05 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; Cl600: 333 +/- 47 vs 137 +/- 26 ml x min(-1) x m(-2), p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 +/- 169 vs 606 +/- 123 micromol x min(-1) x m(-2), NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 +/- 15 vs 12 +/- 7 pmol x min x m(-2) x mmol/l(-1), p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.     

1,5-Anhydro-D-glucitol evaluates daily glycemic excursions in well-controlled NIDDM

OBJECTIVE: To evaluate the usefulness of plasma 1,5-anhydro-D-glucitol (1,5-AG) as a possible marker for daily glycemic excursion, we measured plasma 1,5-AG, HbA1c, fasting plasma glucose (FPG) level, and daily excursion of glycemia, from which the M-value (after Schlichtkrull) was calculated as an index of daily glycemic excursion. RESEARCH DESIGN AND METHODS: The subjects were 76 patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) treated with diet therapy only (diet, n = 17), oral hypoglycemic agents (OHA, n = 28), conventional insulin therapy (CIT, n = 16), or multiple insulin injection therapy (MIT, n = 15). RESULTS: HbA1c values were similar among all the groups (diet, 6.9 +/- 0.6; OHA, 7.2 +/- 0.5; CIT, 7.1 +/- 0.6; MIT, 7.2 +/- 0.5%). The MIT group showed a significantly higher 1,5-AG concentration (11.5 +/- 5.3 micrograms/ml), a significantly lower M-value (9.2 +/- 5.2), and little risk of hypoglycemia ( < 4 mmol/l) and hyperglycemia ( > 10 mmol/l) (1.3 +/- 1.1 times/24 h) compared with the CIT group (6.9 +/- 3.3 micrograms/ml, 15.7 +/- 8.9, 2.2 +/- 1.6 times/24 h, respectively). Insulin doses (22.4 +/- 4.5 vs. 22.0 +/- 8.9 U/day), FPG (6.6 +/- 2.2 vs. 7.4 +/- 2.4 mmol/l), and HbA1c concentrations were not significantly different between the CIT and MIT groups. M-values significantly correlated with 1,5-AG concentrations (r = 0.414, P < 0.05), but not with HbA1c concentrations. CONCLUSIONS: The findings suggest that the plasma 1,5-AG concentration can be a useful index of the daily excursion of blood glucose, especially in patients with well-controlled NIDDM.     

Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose

To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.     

Effects of diet composition and ketosis on glycemia during very-low-energy-diet therapy in obese patients with non-insulin-dependent diabetes mellitus

To determine whether high-ketogenic very-low-energy diets (VLEDs) can reduce hepatic glucose output (HGO) and hyperglycemia more effectively than can low-ketogenic VLEDs in obese patients with non-insulin-dependent diabetes mellitus (NIDDM), seven patients were treated with a high-ketogenic VLED for 3 wk and were compared with six patients treated with a low-ketogenic VLED. All patients were then crossed over and treated with the alternate diet for another 3 wk. Basal HGO, fasting ketone bodies, and glycemia, insulin, and C-peptide after fasting and an oral-glucose-tolerance test (OGTT) were measured. Before treatment, prediet weight and fasting, OGTT, and HGO measurements were not different between groups. After dieting, weight loss was not different between the groups. However, fasting and OGTT glycemia were lower during treatment with the high-ketogenic VLED than with the low-ketogenic VLED (treatment effect: P < 0.05, by analysis of variance). Moreover, there was a strong correlation between basal HGO and fasting plasma ketone bodies (r = -0.71 at 3 wk, r = -0.67 at 6 wk; both P < 0.05). In contrast, fasting and OGTT plasma insulin and C-peptide concentrations were not different between treatment groups. These data indicate that in obese patients with NIDDM, high-ketogenic VLEDs have a more clinically favorable effect on glycemia than do low-ketogenic VLEDs.     

Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus

Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets. Mean +/- SD 24-h urinary sodium was 197 +/- 76.0 mmol (replete) and 67 +/- 19.5 mmol (deplete), P = 0.03. Insulin sensitivity was 42.0 +/- 11.3 mumol/kg.min (replete) and 37.0 +/- 11.6 mumol/kg.min (deplete), P = 0.04 (a reduction of 12%). Blood pressure was 130 +/- 21/78 +/- 11 mmHg (replete) and 128 +/- 12/73 +/- 10 mmHg (deplete). Dietary sodium restriction may result in a decrease in peripheral insulin sensitivity in normotensive patients with NIDDM, possibly via an elevation in prevailing angiotensin II concentrations.     

Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus

An initial improvement in glycemic control is often followed by gradual deterioration of glycemia during insulin treatment of patients with noninsulin-dependent diabetes mellitus (NIDDM). We examined the causes of such worsening in a 12-month follow-up analysis of 100 insulin-treated NIDDM patients in the Finnish Multicenter Insulin Therapy Study who were treated with either combination therapy with insulin or insulin alone. In the entire study group, glycemic control averaged 9.7 +/- 0.2% at 0 months and 8.0 +/- 0.1%, 8.0 +/- 0.1%, 8.2 +/- 0.1%, and 8.5 +/- 0.2% at 3, 6, 9, and 12 months (P < 0.001 for each time point vs. 0 months). Glycemic control at 12 months was significantly worse than that at 3 (P < 0.001), 6 (P < 0.001), and 9 months (P < 0.02). Baseline body mass index was the most significant predictor of deterioration in glycemic control. During 1 yr, hemoglobin A1c decreased almost 3-fold more (by 1.7 +/- 0.2%; P < 0.001 vs. 0 months) in patients whose baseline weight was below the mean baseline body mass index of 28.1 kg/m2 (nonobese patients) than in those whose weight exceeded 28.1 kg/m2 (obese patients; 0.5 +/- 0.2%; P = NS vs. 0 months; P < 0.01 vs. obese patients). Glycemic control improved similarly over 1 yr in the nonobese subjects and deteriorated similarly in the obese patients regardless of their treatment regimen. Insulin doses, per body weight, were similar in the nonobese and obese patients. The nonobese patients consistently gained less weight during 12 months of combination therapy with insulin (3.5 +/- 0.6 kg at 12 months) than during insulin therapy alone (5.1 +/- 0.6 kg; P < 0.05). The treatment regimen did not influence weight gain in the obese group, who gained 4.4 +/- 1.0 kg during combination therapy with insulin and 4.5 +/- 1.1 kg during insulin therapy alone. We reached the following conclusions: 1) after an initial good response, glycemic control deteriorates more in obese than in nonobese patients with NIDDM; 2) in obese patients, weight gain per se cannot explain the poor glycemic response to combination or insulin therapy, but it may induce a disproportionately large increase in insulin requirements because of greater insulin resistance in the obese than in the nonobese; 3) in nonobese patients, glycemic control improves equally during 1 yr with combination therapy with insulin and insulin alone, but combination therapy with insulin is associated with less weight gain than treatment with insulin alone; 4) weight gain appears harmful, as it is associated with increases in blood pressure and low density lipoprotein cholesterol.     

Cloning and functional expression of a human liver organic cation transporter

OBJECTIVE: The triglyceride-lowering effects of omega-3 fats and HDL cholesterol-raising effects of exercise may be appropriate management for dyslipidemia in NIDDM. However, fish oil may impair glycemic control in NIDDM. The present study examined the effects of moderate aerobic exercise and the incorporation of fish into a low-fat (30% total energy) diet on serum lipids and glycemic control in dyslipidemic NIDDM patients. RESEARCH DESIGN AND METHODS: In a controlled, 8-week intervention, 55 sedentary NIDDM subjects with serum triglycerides > 1.8 mmol/l and/or HDL cholesterol < 1.0 mmol/l were randomly assigned to a low-fat diet (30% daily energy intake) with or without one fish meal daily (3.6 g omega-3/day) and further randomized to a moderate (55-65% VO2max) or light (heart rate < 100 bpm) exercise program. An oral glucose tolerance test (75 g), fasting serum glucose, insulin, lipids, and GHb were measured before and after intervention. Self-monitoring of blood glucose was performed throughout. RESULTS: In the 49 subjects who completed the study, moderate exercise improved aerobic fitness (VO2max) by 12% (from 1.87 to 2.07 l/min, P = 0.0001). Fish consumption reduced triglycerides (0.80 mmol/l, P = 0.03) and HDL3 cholesterol (0.05 mmol/l, P = 0.02) and increased HDL2 cholesterol (0.06 mmol/l, P = 0.01). After adjustment for age, sex, and changes in body weight, fish diets were associated with increases in GHb (0.50%, P = 0.05) and self-monitored glucose (0.57 mmol/l, P = 0.0002), which were prevented by moderate exercise. CONCLUSIONS: A reduced fat diet incorporating one daily fish meal reduces serum triglycerides and increases HDL2 cholesterol in dyslipidemic NIDDM patients. Associated deterioration in glycemic control can be prevented by a concomitant program of moderate exercise.     

Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol x kg(-1) x min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.     

Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group

OBJECTIVE: To compare the efficacy and safety of two daily doses of the new sulfonylurea, glimepiride (Amaryl), each as a once-daily dose or in two divided doses, in patients with NIDDM. RESEARCH DESIGN AND METHODS: Of the previously treated NIDDM patients, 416 entered this multicenter randomized double-blind placebo-controlled fixed-dose study. After a 3-week placebo washout, patients received a 14-week course of placebo or glimepiride 8 mg q.d., 4 mg b.i.d., 16 mg q.d., or 8 mg b.i.d. RESULTS: Fasting plasma glucose (FPG) and HbA1c values were similar at baseline in all treatment groups. The placebo group's FPG value increased from 13.0 mmol/l at baseline to 14.5 mmol/l at the last evaluation endpoint (P < or = 0.001). In contrast, FPG values in the four glimepiride groups decreased from a range of 12.4-12.9 mmol/l at baseline to a range of 8.6-9.8 mmol/l at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change [vs. placebo] from baseline). Two-hour postprandial plasma glucose (PPG) findings were consistent with FPG findings. In the placebo group, the HbA1c value increased from 7.7% at baseline to 9.7% at endpoint (P < or = 0.001), whereas HbA1c values for the glimepiride groups were 7.9-8.1% at baseline and 7.4-7.6% at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change from baseline). There were no meaningful differences in glycemic variables between daily doses of 8 and 16 mg or between once- and twice-daily dosing. Adverse events and laboratory data demonstrate that glimepiride has a favorable safety profile. CONCLUSIONS: Glimepiride is an effective and well-tolerated oral glucose-lowering agent. The results of this study demonstrate maximum effectiveness can be achieved with 8 mg q.d. of glimepiride in NIDDM subjects.     

NIDDM in the elderly

OBJECTIVE: We conducted this study to assess the metabolic alterations in elderly patients with NIDDM. RESEARCH DESIGN AND METHODS: Healthy, lean (n = 15; age, 73 +/- 1 years; BMI, 23.8 +/- 0.5 kg/m2), and obese (n = 10; age, 71 +/- 1 years; BMI, 28.9 +/- 1.2 kg/m2) control subjects and lean (n = 10; age, 75 +/- 2 years; BMI, 24.0 +/- 0.5 kg/m2) and obese (n = 23; age, 73 +/- 1 years; BMI, 29.9 +/- 0.7 kg/m2) NIDDM patients underwent a 3-h glucose tolerance test, a 2-h hyperglycemic glucose clamp study, and a 3-h euglycemic glucose clamp study with tritiated glucose methodology to measure glucose production and disposal rates. RESULTS: Waist-to-hip ratio (WHR) was greater in both lean and obese NIDDM patients than in control subjects. Insulin responses during the oral glucose tolerance test were similar in obese subjects (control subjects: 417 +/- 64 pmol/l; NIDDM patients: 392 +/- 47 pmol/l) but were reduced in lean NIDDM patients (control subjects: 374 +/- 34 pmol/l; NIDDM patients: 217 +/- 20 pmol/l, P < 0.01). Lean and obese NIDDM patients had absent first-phase insulin responses during the hyperglycemic clamp. Second-phase insulin responses were reduced in lean (P < 0.01 vs. control subjects by analysis of variance) but not obese NIDDM patients. Hepatic glucose output was not increased in lean or obese NIDDM patients. Steady-state (150-180 min) glucose disposal rates were 16% less in lean NIDDM patients (control subjects: 8.93 +/- 0.37 mg.kg LBM (lean body mass)-1.min-1; NIDDM patients: 7.50 +/- 0.28 mg.kg LBM-1.min-1, P < 0.05) and 37% less in obese NIDDM patients (control subjects: 8.17 +/- 0.38 mg.kg LBM-1.min-1; NIDDM patients: 5.03 +/- 0.36 mg.kg LBM-1.min-1, P < 0.001). CONCLUSIONS: Lean elderly NIDDM patients have a profound impairment in glucose-induced insulin release but mild resistance to insulin-mediated glucose disposal. Obese elderly NIDDM patients have adequate circulating insulin, but marked resistance to insulin-mediated glucose disposal. Hepatic glucose output is not increased in elderly NIDDM patients.     

Small weight loss on long-term acarbose therapy with no change in dietary pattern or nutrient intake of individuals with non-insulin-dependent diabetes

OBJECTIVES: To see if the long-term treatment of non-insulin dependent diabetes (NIDDM) with the alpha-glucosidase inhibitor acarbose affects food intake and body weight. DESIGN: Randomized, double-blind, placebo-controlled, parallel design clinical trial of 12 months duration. SUBJECTS: Subjects with NIDDM in four treatment strata: 77 on diet alone, 83 also treated with metformin, 103 also treated with sulfonylurea and 91 also treated with insulin. MEASUREMENTS: Two 3 day diet records were obtained before randomization to acarbose or placebo therapy, and additional 3 day diet records were obtained at 3, 6, 9 and 12 months after randomization. Body weight was also measured at these times. RESULTS: Of the 354 subjects randomized, 279 (79%) completed at least 9 months of therapy and, of these, 263 (94%) provided at least one diet record during the baseline period and two diet records during the treatment period. After one year, subjects on acarbose had lost 0.46 +/- 0.28 kg, which differed significantly from the 0.33 +/- 0.25 kg weight gain on placebo (P = 0.027). The difference in weight change between acarbose and placebo did not differ significantly in the different treatment strata. Being in the study had significant effects on diet, including a reduction in energy intake from 1760-1700 Kcal/d (P < 0.05), a reduction in simple sugars intake from 18.5-17.4% of energy (P < 0.001), and reductions in the number of different foods consumed (33-30, P < 0.001) and the number of meals eaten per day (4.7-4.3, P < 0.001). However, compared to placebo treatment, acarbose had no effect on energy intake, nutrient intakes, or dietary patterns. CONCLUSIONS: In subjects with NIDDM on weight-maintaining diets, long-term acarbose therapy results in a small weight loss, but has no effect on energy or nutrient intakes. The weight loss induced by acarbose may be due partly to reduced doses of concomitant oral agents and insulin and partly to energy loss due to increased colonic fermentation.     

Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment

Insulin resistance is characterized principally by impaired insulin-mediated glucose uptake which provokes a compensatory increase in pancreatic beta-cell secretory activity. For a time this may produce well-controlled plasma glucose levels but as the insulin resistance worsens the augmented insulin production becomes inadequate to keep plasma glucose at euglycemia leading to the development of non-insulin dependent diabetes mellitus (NIDDM), accompanied by hyperinsulinemia and hyperglycemia. A number of metabolic defects are associated with NIDDM including obesity, hypercoagulability, cardiovascular disease risk factors such as hypertension and dyslipidemia and these constitute the insulin resistance syndrome. The identity of the biochemical factor that might link all these defects is not yet known. We have hypothesized that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) may be such a link. In this study, we measured plasma acetylhydrolase (EC.1.1.48), which degrades PAF to the inactive metabolise lyso-PAF, as a surrogate for PAF activity in three groups of hypercholesterolemic subjects: lean controls (n = 9), non-diabetic obese (n = 6) and NIDDM subjects (n = 6). The ages and body mass indices of the subjects were 46 +/- 3.1 and 24.2 +/- 2.2 for the lean controls, 52 +/- 2.5 and 28.7 +/- 0.9 for the NIDDM subjects and 60 +/- 2 and 27.6 +/- 2.1 for the obese, non-diabetic subjects (mean +/- S.E.M.). The measurements were made before and after therapy with the cholesterol-lowering drug lovastatin, a 3-hydroxy 3 methylglutaryl (HMG) coenzyme. A reductase inhibitor (40 mg/day) for 3 months. Fasting plasma glucose (FPG) levels were 91 +/- 11, 96 +/- 3 and 146 +/- 11 mg/dl, for the lean, obese and NIDDM subjects, respectively, before therapy began. Lovastatin did not affect FPG in any of the three subject groups. Before treatment, the fasting plasma insulin (FPI) levels were 6.1 +/- 0.92, 10.83 +/- 2.03 and 14.68 +/- 3.64 mU/l for the lean, non-diabetic obese and NIDDM subjects, respectively. After lovastatin therapy only the obese group exhibited a significant change in FPI (15.35 +/- 2.47 mU/l) (P < 0.05). Total cholesterol levels were similar in all three groups both before and after lovastatin therapy but within each group lovastatin therapy significantly reduced the total cholesterol by 32, 29 and 34% in the lean, obese and NIDDM subject groups respectively (P < 0.0001). Lovastatin therapy reduced LDL-cholesterol levels by 40, 32 and 46% in the lean, obese and NIDDM subjects, respectively, but produced no significant effect on HDL or triglyceride levels. Before therapy, the plasma acetylyhydrolase activities were 104 +/- 7, 164 +/- 7 and 179 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Lovastatin therapy reduced plasma acetylhydrolase levels to 70 +/- 7, 87 +/- 6 and 86 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Plasma acetylhydrolase activity was predominantly (> 80%) associated with LDL cholesterol both before and after lovastatin treatment. Also, plasma acetylhydrolase activity significantly correlated with fasting plasma insulin levels before lovastatin therapy but not after. Taken together, this study clearly implicates PAF metabolism in three defects associated with the insulin resistance syndrome: hypercholesterolemia, obesity and NIDDM. Additionally, we conclude that chronic hyperinsulinemia may play a significant role in the production of plasma acetylhydrolase.     

Alterations in glucose metabolism in the elderly patient with diabetes

OBJECTIVE: To determine the alterations in glucose metabolism in elderly patients with NIDDM. RESEARCH DESIGN AND METHODS: We studied 9 healthy elderly control subjects (73 +/- 1 yr of age; body mass index 25.7 +/- 0.4 kg/m2) and 9 untreated elderly NIDDM patients (72 +/- 2 yr of age; BMI 25.9 +/- 0.5 kg/m2). Each subject underwent a 3-h oral glucose tolerance test (40 g/m2); a 2-h hyperglycemic glucose clamp study (glucose 5.4 mM above basal); and a 4-h euglycemic insulin clamp (40 mM.m2.min-1). Tritiated glucose methodology was used to measure glucose production and disposal rates during the euglycemic clamp. RESULTS: Patients with NIDDM had a higher fasting glucose (9.3 +/- 0.3 vs. 5.1 +/- 0.1 mM in control subjects vs. NIDDM patients, respectively, P < 0.001) and a greater area under the curve for glucose during the OGTT (16.0 +/- 0.6 vs. 6.7 +/- 0.3 mM in control subjects vs. NIDDM patients, respectively, P < 0.01) than the healthy control subjects. During the hyperglycemic clamp, patients with NIDDM had an absent first-phase insulin response (112 +/- 6 vs. 250 +/- 31 pM in control subjects vs. NIDDM patients, respectively, P < 0.01), and a blunted second-phase insulin response (159 +/- 11 vs. 337 +/- 46 pM in control subjects vs. NIDDM patients, respectively, P < 0.01). Before the euglycemic clamp, fasting insulin (99 +/- 5 vs. 111 +/- 10 pM in control subjects vs. NIDDM patients, respectively) and hepatic glucose production (11.8 +/- 0.7 vs. 11.5 +/- 0.5 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively) were similar. Steady-state (180-240 min) glucose disposal rates during the euglycemic clamp were slightly, but not significantly, higher in the normal control subjects (36.5 +/- 1.1 vs. 33.1 +/- 1.9 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively, NS). CONCLUSIONS: We conclude that NIDDM in nonobese elderly subjects is characterized by a marked impairment in insulin release. This may be attributable to the toxic effects of chronic hyperglycemia on the beta-cell. When compared with age-matched control subjects, the NIDDM patients showed no increase in fasting insulin or hepatic glucose production, and insulin resistance was mild.     

Formulation and in vitro and in vivo availability of diclofenac sodium enteric-coated beads

OBJECTIVE: The beneficial effects of weight loss with a very-low-calorie diet (VLCD) on cardiovascular risk factors have been reported at the end of energy restriction. As the effects, especially on blood pressure, may not remain constant during weight maintenance, we studied the longer-term effects of weight loss on 24h ambulatory blood pressure (ABP), lipids, glucose and insulin. DESIGN: Prospective study of a 17-week weight loss programme containing an eight-week VLCD period and follow-up visit at one-year. SUBJECTS: Twenty-nine moderately obese, normotensive or mildly hypertensive women. The mean +/- s.d. body mass index (BMI) was 36.0 +/- 2.6 kg/m2 and mean age 40.3 +/- 8.3 y. RESULTS: In the last week of the VLCD, the mean (s.d.) weight loss was 12.4 +/- 3.3 kg (P < 0.001), at the end of the programme 15.1 +/- 4.4 kg (P < 0.001 vs baseline), and at one-year follow-up 10.7 +/- 7.6 kg (P < 0.001 vs baseline). Mean 24 h ABP decreased 8.0/4.6 mmHg (P < 0.001 for both) on the last week of the VLCD, at the end of the programme, the systolic ABP decrease was 4.7 mmHg (P < 0.01 vs baseline) and diastolic 2.1 mmHg (not statistically significant (NS) vs baseline). At one-year follow-up, the mean systolic ABP decrease was 4.1 mmHg (P < 0.01 vs baseline) and mean diastolic 3.0 mmHg (P < 0.05 vs baseline). Sodium excretion decreased 55 mmol/24 h in the last VLCD week (P < 0.01) and returned to baseline after that. At the one-year follow-up, beneficial changes, compared with baseline, were observed in mean serum glucose (-0.28 mmol/l, P < 0.05), triglyceride (-0.35 mmol/l, P < 0.01) and HDL cholesterol (+0.16 mmol/l, P < 0.001). CONCLUSIONS: This weight loss programme with a VLCD enabled obese subjects to lose weight and decrease cardiovascular risks. Despite some regain in weight during follow-up, the beneficial effects were overall maintained over the year. Sodium intake tended to increase during follow-up. Information on sodium restriction should be included in weight loss programmes.     

Dietary protein restriction alters glucose but not protein metabolism in non-insulin-dependent diabetes mellitus

We determined whether a customary diet high or low in protein (1) influences postabsorptive amino acid catabolism, nitrogen (N) balance, and hepatic glucose output (HGO) in normal subjects or patients with non-insulin-dependent diabetes mellitus (NIDDM) or (2) alters blood glucose levels in NIDDM. Eight normal young adults and five obese middle-aged persons with NIDDM consumed low-protein (0.8 g/kg lean body mass [LBM]) or high-protein (3.0 g/kg LBM) diets at maintenance energy for consecutive 7-day periods. Fasting and average blood glucose and N balance were measured daily. The level of dietary protein had no effect on the basal plasma leucine rate of appearance (Ra) or urinary 3-methylhistidine excretion in either subject group. Basal leucine oxidation (and by inference, whole-body amino acid catabolism) was reduced on the low-protein diet but basal HGO was not, and although exogenous glucose effectively suppressed HGO, it did not reduce leucine oxidation with either diet. After adaptation to the low-protein diet, N balance in both the normal and NIDDM subjects was close to zero. The low-protein diet reduced the fasting and daily blood glucose of the diabetic subjects by approximately 2 mmol/L (P < .05). We conclude that physiologic variation in dietary protein does not affect basal whole-body protein turnover or HGO in either normal young adults or obese middle-aged NIDDM subjects. However, protein restriction to the level of the average daily requirement significantly reduces postabsorptive and average daily blood glucose concentrations in persons with NIDDM.     

Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.     

Weight change and glycemic control in a population-based sample of adults with older-onset diabetes

BACKGROUND: Numerous clinic-based studies have observed improved glycemic control with even moderate weight reductions, for periods up to 1 year, in obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Similar benefits of weight loss have not been well documented in free-living populations, particularly in older persons with NIDDM of long duration. METHODS: Relations between weight change and glycosylated hemoglobin were evaluated in a population-based sample of persons with older-onset diabetes. Persons participating in baseline (1980-1982, n = 1370) and two follow-up examinations (1984-1986, n = 987; 1990-1992, n = 550) were included. Mean glycosylated hemoglobin levels among those losing, gaining, or remaining within 5 kg were compared in all subjects combined and stratified by insulin use, using ordinary least-squares regression to adjust for confounding variables. RESULTS: Subjects who lost weight had higher mean glycosylated hemoglobin compared to those who gained weight (baseline to second exam only). This pattern remained in those not using insulin. Weight change was not related to glycosylated hemoglobin in persons using insulin. CONCLUSIONS: Associations suggest that in older persons not using insulin, moderate weight loss over periods of 4-6 years has little beneficial impact on glycosylated hemoglobin. Weight loss may be reflecting disease processes that also result in poor glycemic control. Intentional weight loss achieved over a shorter time period and maintained through the later years in older diabetic persons remains to be evaluated.     

Effects of nonesterified fatty acids on glucose metabolism after glucose ingestion

Impaired suppression of plasma nonesterified fatty acids (NEFAs) after glucose ingestion may contribute to glucose intolerance, but the mechanisms are unclear. Evidence that insulin inhibits hepatic glucose output (HGO), in part by suppressing plasma NEFA levels, suggests that impaired suppression of plasma NEFA after glucose ingestion would impair HGO suppression and increase the systemic delivery of glucose. To test this hypothesis, we studied glucose kinetics (constant intravenous [3-3H]glucose [0.4 microCi/min], oral [1-14C]glucose [100 microCi]), whole-body substrate oxidation, and leg glucose uptake in eight normal subjects (age, 39 +/- 9 years [mean +/- SD]; BMI, 24 +/- 2 kg/m2) in response to 75 g oral glucose on two occasions. In one study, plasma NEFAs were prevented from falling by infusion of 20% Liposyn (45 ml/h) and heparin (750 U/h). Plasma glucose rose more rapidly during lipid infusion (P < 0.05), and mean levels tended to be higher after 120 min (6.45 +/- 0.41 vs. 5.81 +/- 0.25 SE, 0.1 < P < 0.05, NS); peak glucose levels were similar. Total glucose appearance (Ra) was higher during lipid infusion due to a higher HGO (28.4 +/- 1.0 vs. 21.2 +/- 1.5 g over 4 h, P < 0.005). Total glucose disposal (Rd) was also higher (88 +/- 2 vs. 81 +/- 3 g in 4 h, P < 0.05). Plasma insulin rose more rapidly after glucose ingestion with lipid infusion, and leg glucose uptake was 33% higher (P < 0.05) during the 1st hour. During lipid infusion, subjects oxidized less glucose (47 +/- 3 vs. 55 +/- 2 g, P < 0.05) and more fat (7.1 +/- 0.8 vs. 3.9 +/- 0.9 g, P < 0.02). In summary, 1) impaired suppression of NEFAs after oral glucose impairs insulin's ability to suppress HGO, and 2) in normal subjects the greater insulin response compensates for the increased systemic glucose delivery by increasing peripheral glucose Rd.     

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.