Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone

OBJECTIVE: Acarbose inhibits alpha-glucosidases of the small intestine and thus delays glucose release from complex carbohydrates. Therefore, its efficacy and acceptability as a first-line drug in non-insulin-dependent diabetes mellitus (NIDDM) insufficiently treated with diet alone was tested in a randomized double-blind placebo-controlled study. RESEARCH DESIGN AND METHODS: Ninety-four NIDDM subjects, aged 43-70 yr with average body mass index of 28 kg/m2 and undergoing a pretreatment period of at least 3 mo with diet alone, were treated with 100 mg acarbose three times daily or placebo for 24 wk. The patients were recruited after a 4-wk screening period of dietary reinforcement. The inclusion limits for patients termed diet not satisfactory were fasting blood glucose (FBG) greater than or equal to 7.8 mM and/or postprandial blood glucose (BG) greater than or equal to 10 mM. RESULTS: FBG was lowered in the acarbose group from 9.8 to 8.4 mM and in the placebo group from 10.2 to 9.6 mM after 24 wk (P = 0.007 vs. placebo). The most impressive therapeutic effect was a highly significant reduction of postprandial hyperglycemia for at least 5 h after the test meal (1-h postprandial BG with acarbose 10.4 mM and placebo 13.5 mM at 24 wk, P less than 0.001) accompanied by a significant decrease in HbA1 (acarbose 8.65%, placebo 9.32%, P = 0.003). Whereas C-peptide and fasting serum insulin were not significantly affected by acarbose, postprandial insulin increment was approximately 30% lower after 24 wk compared with placebo. Furthermore, acarbose significantly reduced 1-h postprandial triglyceride levels. After an initial phase of greater than 4 wk (when 76.6% in the acarbose group vs. 28% on placebo complained about flatulence, P less than 0.001), the drug was well accepted. At the end of the study, only 32% showed mild or moderate gastrointestinal sensations. CONCLUSIONS: Extrapolation shows that acarbose is an efficient and acceptable drug for the treatment of NIDDM with poor metabolic control by diet alone. It has beneficial effects on postprandial hyperinsulinemia and postprandial hypertriglyceridemia.     

Benefits and risks with glyburide and glipizide in elderly NIDDM patients.

OBJECTIVE--To compare the efficacy, benefits, and risks of glyburide and glipizide in elderly patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS--Twenty-one elderly outpatients (mean age 70 yr) were treated for 8 wk, after being dose-titrated to achieve a fasting plasma glucose (FPG) concentration of less than 7.8 mM with glyburide or glipizide in a randomized crossover trial. FPG and postprandial plasma glucose, serum C-peptide, and HbA1c levels were measured. In 13 patients, self-monitoring of blood glucose (SMBG) with a memory meter was performed seven times per week. RESULTS--Glipizide (11.9 mg) and glyburide (8.4 mg) produced similar fasting and postprandial plasma glucose and HbA1c concentrations. No significant differences in basal or stimulated C-peptide levels were detected. Despite a few patient reports of hypoglycemia, a high incidence of SMBG readings less than 4.5 mM was attributed to the use of both drugs. CONCLUSIONS--Both treatments proved effective for glycemic control; however, both second-generation sulfonylureas are associated with a significant risk of hypoglycemia in elderly NIDDM patients. The proper use of sulfonylureas in this population should include close surveillance of ambulatory glucose monitoring and intensive and repeated patient education about the risks of hypoglycemia.     

Effects of combination therapy with glyburide and insulin on serum lipid levels in NIDDM patients with secondary sulfonylurea failure.

OBJECTIVE: To compare the long-term effect of combined treatment with insulin and glyburide versus insulin alone on serum lipid levels in non-insulin-dependent diabetic (NIDDM) patients with secondary failure to sulfonylurea therapy. RESEARCH DESIGN AND METHODS: The study was a randomized double-blind placebo-controlled parallel trial with a duration of 325 days. The study was conducted at a referral-based endocrinology clinic. Subjects were a sequential sample of 20 patients with NIDDM with failure to respond to glyburide treatment after at least 1 yr of adequate glucose control with this therapy. The patients were randomized to treatment with insulin and glyburide (IG) or insulin and placebo (IP). Insulin was given twice daily to all patients as a mixture of NPH and regular insulins in dosages aiming at optimal glucose control. Glyburide or placebo was taken before breakfast (7 mg) and dinner (3.5 mg). RESULTS: Mean HbA1c decreased from 11.1% (range 9.8-12.9%) before insulin to 9.1% (range 6.8-11.4%) on day 325 (P less than 0.001) in IG patients and from 10.3% (range 8.4-13.3%) to 9.0% (range 6.3-11.8%) (P less than 0.05) in IP patients. In both groups, there was an increase in high-density lipoprotein cholesterol of approximately 20% lasting throughout the study (P less than 0.01). During the first 83 days of the study, there was a decrease in serum cholesterol (P less than 0.01) and serum triglycerides (P less than 0.05) in both groups. All changes in lipid variables were comparable in magnitude and duration in both treatment with insulin and glyburide in NIDDM patients with secondary sulfonylurea failure improves lipid metabolism to a similar degree as insulin therapy alone.     

Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM.

OBJECTIVE: To study the effects of CS-045, a newly developed thiazolidine analogue, on glucose tolerance and insulin response to oral glucose load in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Nineteen NIDDM patients (mean +/- SD age 48.9 +/- 9.4 yr) whose previous glycemic control on diet and/or sulfonylurea (SU) therapy was judged stable but unsatisfactory (greater than 7.8 mM) were selected for this study. CS-045 (400 mg/day p.o.) was given alone or together with the previous SU drugs for 12 wk. A 75-g oral glucose tolerance test (OGTT) was performed before and after CS-045 treatment. Results: The following results were found after CS-045 treatment. 1) Fasting plasma glucose (FPG) and HbA1c decreased (n = 19, FPG, 11.0 +/- 2.4 vs. 8.4 +/- 2.7 mM [before vs. after], P less than 0.001; HbA1c, 8.0 +/- 1.1 vs. 7.4 +/- 1.3%, P less than 0.005), and glucose tolerance markedly improved. 2) Fasting insulin (immunoreactive insulin [IRI]) and insulin response during OGTT decreased (n = 19, fasting IRI, 77.4 +/- 49.8 vs. 56.5 +/- 24.6 pM [before vs. after], P less than 0.05; area under the curve of IRI, 540.3 +/- 350.5 vs. 426.4 +/- 216.3 pM.h, P less than 0.05). CONCLUSIONS: CS-045 is effective in improving glucose tolerance without stimulation of insulin secretion in NIDDM, suggesting an effect in improving insulin sensitivity.     

Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study.

OBJECTIVE--To determine coronary heart disease (CHD) incidence among dyslipidemic subjects with non-insulin-dependent diabetes mellitus (NIDDM) and to assess the effect of lipid-modifying treatment on serum and lipoprotein lipids and the CHD incidence in these patients. RESEARCH DESIGN AND METHODS--Of the 4081 men participating in the Helsinki Heart Study, a coronary primary prevention trial with gemfibrozil in middle-aged men with high non-high-density lipoprotein (HDL) cholesterol (greater than 5.2 mM; 200 mg/dL), 135 had NIDDM at entry. The incidence of definite myocardial infarction and cardiac death and changes in serum and lipoprotein lipids were determined during the 5-yr trial in the NIDDM patients and compared with those observed in nondiabetic trial participants. RESULTS--Compared with nondiabetic subjects, NIDDM patients had lower HDL cholesterol (P less than 0.001), higher triglyceride concentration (P less than 0.0001), and greater body mass index (P less than 0.001), there were more hypertensive patients (P less than 0.001) among them. The incidence of myocardial infarction and cardiac death was significantly higher among diabetic than nondiabetic participants (7.4 vs. 3.3%, respectively, P less than 0.02). CHD incidence in the gemfibrozil-treated diabetic men (n = 59) was 3.4% compared with 10.5% in the placebo group (NS). In multivariate analysis, diabetes (P less than 0.05), age (P less than 0.0001), smoking (P less than 0.0001), low HDL cholesterol (P less than 0.05), and high low-density lipoprotein cholesterol (P less than 0.005) were independently related to CHD incidence. Gemfibrozil-induced serum and lipoprotein lipid changes in diabetic patients were similar to those observed in nondiabetic subjects. CONCLUSIONS--Compared with similarly dyslipidemic nondiabetic subjects, patients with NIDDM are at markedly increased risk of CHD. This elevated risk can be somewhat reduced by gemfibrozil.     

Impact of associated conditions on glycemic control of NIDDM patients.

OBJECTIVE--To assess the impact of associated conditions (obesity, dyslipidemia, and hypertension) on the glycemic control of non-insulin-dependent diabetes mellitus (NIDDM) patients under home-life conditions. RESEARCH DESIGN AND METHODS--We analyzed the metabolic data of 271 NIDDM patients (89% Mexican American) screened in a population-based survey (the San Antonio Heart Study). RESULTS--Obesity was present in 77% of the patients, hypertension in 23%, hypertriglyceridemia (serum triglycerides greater than 2.9 mM) in 23%, and hypercholesterolemia (serum total cholesterol greater than 6.5 mM) in 14%. Forty percent of the patients had two or more comorbid conditions. With the use of a multiple linear regression model, which was adjusted for age, sex, ethnicity, distribution of body fat (waist-hip ratio), plasma insulin, and treatment (of both diabetes and hypertension), we found that the presence of higher serum triglyceride concentrations was associated with significantly higher plasma glucose levels both in the fasting state (1.4 mM, P less than 0.001) and 2 h after an oral glucose load (1.2 mM, P = 0.003). The presence of obesity, hypertension, or high serum cholesterol levels was not associated with significant changes in glycemic control. When the entire group was stratified by diabetes treatment (untreated n = 89, diet n = 75, oral agents n = 82, insulin n = 25) and after adjusting for age, sex, ethnicity, and waist-hip ratio, only fasting and 2-h plasma glucose and insulin concentrations were significantly different across treatment groups, with diet and oral agents being associated with higher fasting (P less than 0.001) and postglucose (P less than 0.005) plasma glucose levels and lower plasma insulin concentrations (P less than 0.005) compared with newly diagnosed patients. Neither serum lipids nor blood pressure differed across treatment. CONCLUSIONS--In NIDDM patients under home-life conditions, higher serum triglycerides are associated with higher fasting and postglucose hyperglycemia regardless of antidiabetic treatment. The presence of obesity, hypertension, or high serum cholesterol levels is not associated with significant changes in glycemic control.     

Improvement in in vitro insulin action after one month of insulin therapy in obese noninsulin-dependent diabetics. Measurements of glucose transport and metabolism, insulin binding, and lipolysis in isolated adipocytes

It has been previously reported that maximum insulin-stimulated glucose transport and utilization were both decreased, while basal lipolysis was increased in adipocytes from obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). To determine whether these values can be returned towards those obtained in equally obese subjects with normal glucose tolerance, these measures of adipocyte metabolism were quantified in 10 NIDDM subjects before and after control of hyperglycemia with insulin. The results demonstrate that maximum insulin-stimulated glucose transport (P less than 0.02) and glucose incorporation into triglyceride (P less than 0.01) and CO2 (P less than 0.05) (at 5.5 mM glucose) increased and basal lipolysis decreased (P less than 0.05) after 4 wk of insulin treatment. In contrast, glucose incorporation into lactate and other glycolytic metabolites (at 5.5 mM glucose), and sensitivity of glucose transport to insulin, did not improve with insulin therapy. The latter occurred despite an increase in insulin binding (P less than 0.01). Finally, the improvement in maximal insulin-stimulated glucose transport correlated with the fall in fasting hyperglycemia (r = 0.77, P less than 0.01). These findings demonstrate that several of the abnormalities of carbohydrate and lipid metabolism recently noted to be present in adipocytes from patients with NIDDM can be shown to significantly improve with insulin treatment.     

Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine

OBJECTIVE: To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulin-induced glucose disposal. RESEARCH DESIGN AND METHODS: A randomized double-blind placebo-controlled crossover trial with 1-wk treatment periods (2 x 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-3H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U.kg-1.h-1) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U.kg-1.h-1) insulin delivery rates. RESULTS: In the nondiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (-1.2 +/- 0.5 kg, P less than 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 +/- 0.8 vs. 9.4 +/- 1.1 mM, P less than 0.005) and plasma free fatty acid concentrations (1150 +/- 227 vs. 1640 +/- 184 microM, P less than 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after d-fenfluramine (average increase of glucose MCR 35 +/- 12%, P less than 0.02). CONCLUSIONS: Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance.     

Patterns of glucose and lipid abnormalities in black NIDDM subjects.

OBJECTIVE: We had previously shown two variants among black non-insulin-dependent diabetic (NIDDM) subjects in a normoglycemic remission: one with insulin resistance and the other with normal insulin sensitivity. This study examined whether these two variants exist in the ordinary hyperglycemic black NIDDM population. Research Design and Methods: Fifty-two black NIDDM subjects were assessed for insulin-stimulated glucose disposal (euglycemic clamp), glycemic control (fasting plasma glucose and HbA1c), and fasting lipid profiles. RESULTS: The distribution of glucose disposal in 30 black NIDDM subjects (body mass index; BMI less than 30 kg/m2) was bimodal, which indicated two populations. Eighteen of 30 subjects (BMI 26.4 +/- 0.5 kg/m2) had insulin resistance (glucose disposal 3.21 +/- 0.24 mg.kg-1.min-1). Twelve of 30 subjects (BMI 24.83 +/- 1.1 kg/m2) had normal insulin sensitivity (glucose disposal 7.19 +/- 0.46 mg.kg-1.min-1). Twenty-one of the remaining 22 subjects (BMI 33.4 +/- 0.7 kg/m2) were insulin resistant (glucose disposal 2.88 +/- 0.21 mg.kg-1.min-1). Fasting serum triglyceride levels were lowest in the insulin-sensitive population (0.91 +/- 0.07 mM) and different from the insulin-resistant population, BMI less than 30 and greater than 30 kg/m2, (1.20 +/- 0.10 mM, P less than 0.05 and 1.42 +/- 0.17 mM, P less than 0.025, respectively). Fasting serum low-density lipoprotein cholesterol levels were not significantly different among the groups, although it did increase with insulin resistance and increasing obesity. Total serum cholesterol levels and glycemic control were similar for all three groups. Serum high-density lipoprotein cholesterol levels were higher in women compared with men. CONCLUSIONS: In the hyperglycemic black NIDDM population, two variants exist: one with insulin resistance and one with normal insulin sensitivity. This insulin-sensitive variant represents 40% of subjects with a BMI less than 30 kg/m2. Moreover, the insulin-sensitive group has a lower risk profile for cardiovascular disease.     

In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus.

To assess possible cellular mechanisms of in vitro resistance in noninsulin-dependent diabetes mellitus (NIDDM), maximum insulin-stimulated glucose transport and utilization and insulin binding were measured in adipocytes isolated from weight-matched normal glycemic subjects and patients with NIDDM. Glucose transport rate was determined by measuring the amount of [U-14C]-D-glucose taken up by incubating adipocytes at trace concentrations of glucose (300 nM), and glucose metabolism by estimating the amount of lactate, CO2, triglyceride, and total glucose carbons retained in the cells following incubating at 5.5 mM glucose. Insulin binding was measured at 50, 100, and 200 pM [mono125I-tyrosinyl A14]insulin. Both maximum insulin-stimulated glucose transport and utilization in adipocytes from diabetic subjects were 40% (P less than 0.01) and 32% (P less than 0.05) lower, respectively, than values obtained for subjects with normal glucose tolerance. In addition, the maximum capacity of glucose transport was correlated with the maximum capacity of glucose utilization (r = 0.81, P less than 0.001). Furthermore, fasting plasma glucose concentrations of diabetic subjects were negatively correlated with both maximum insulin-stimulated glucose transport (r = -0.56, P less than 0.05) and glucose utilization (r = -0.67, P less than 0.05). Since basal glucose transport in adipocytes from diabetic subjects was also 33% lower than in adipocytes from normal subjects, there was no change in the relative ability of insulin to stimulate glucose transport. However, there was a 64% decrease in the sensitivity of the glucose transport system to insulin (P less than 0.05), unrelated to concomitant changes in insulin binding. These results demonstrate that both maximal insulin-stimulated glucose transport and utilization, and the sensitivity of the glucose transport system to insulin, was decreased in adipocytes isolated from subjects with NIDDM. These in vitro defects were associated with impaired glucose metabolism in vivo, consistent with the view that the metabolic alterations observed at the cellular level may contribute to the in vivo insulin resistance of NIDDM.     

Fenfluramine increases insulin action in patients with NIDDM

These studies examined the effect of fenfluramine on insulin action and insulin secretion in healthy subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). In the first study, a double-blind crossover design was used in healthy subjects to compare the effect of short-term fenfluramine therapy (60 mg orally for 3 days) with placebo. Insulin secretion and whole-body insulin sensitivity (determined by frequently sampled intravenous glucose tolerance tests with analysis by the minimal-model method) were unchanged by fenfluramine. In the second study, involving patients with NIDDM inadequately controlled on submaximal to maximal doses of oral hypoglycemic agents, a double-blind crossover strategy was used to compare baseline studies (conducted after a run-in period) with fenfluramine (60 mg orally) or placebo for 4 wk. There was a significant fall in fasting blood glucose after therapy with fenfluramine compared with the baseline study period (13.0 +/- 1.2 vs. 8.4 +/- 0.89 mM, mean +/- SE, P less than .01) with no significant fall in fasting serum insulin (20 +/- 2 vs. 24 +/- 3 microU/ml) or C-peptide (1.3 +/- 0.2 vs. 1.3 +/- 0.1 nM). During euglycemic-hyperinsulinemic (1 mU.kg-1.min-1) clamp studies there was a significant increase in insulin action from 12.7 +/- 2.3 to 17.3 +/- 1.8 min-1.10(3) microU.ml-1 (P less than .05), although clamp insulin levels were lower after fenfluramine treatment (136 +/- 14 vs. 96 +/- 9 microU/ml, P less than .02), reflecting an enhanced metabolic clearance rate for insulin (12.7 +/- 1.5 vs. 20.1 +/- 2.1 ml.kg-1.min-1, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Does residual insulin secretion (assessed by C-peptide concentration) affect lipid and lipoprotein levels in insulin-dependent diabetes mellitus?

1. Residual endogenous insulin secretion can be assessed by the circulating C-peptide concentration and is present in up to 15% of subjects with established insulin-dependent diabetes mellitus (IDDM). Its role in lipid metabolism in IDDM is not clearly defined. We examined the relationships between serum lipid and lipoprotein concentrations and the response of circulating C-peptide to a test meal in 205 subjects with IDDM. 2. Lipid and lipoprotein levels and glycaemic control did not differ significantly between patients with undetectable, low or high C-peptide responses. 3. High density lipoprotein (HDL) cholesterol and its subfractions were inversely related to concentrations of serum triacylglycerols (P less than 0.01-0.001), but not to C-peptide or glycated haemoglobin (HbA1) levels. Levels of HbA1 and triacylglycerols were correlated with one another (P less than 0.01). Analysis of variance revealed that differences in gender and triacylglycerol concentrations were the most important determinants of HDL and HDL2 cholesterol levels. C-peptide only exerted a weak effect on HDL2 cholesterol levels and no significant predictors of HDL3 cholesterol were found. 4. It is concluded that endogenous insulin secretion (assessed by C-peptide concentration) is relatively unimportant in modifying HDL metabolism in IDDM and that associated clinical features, in particular ambient hypertriglyceridaemia, are of greater importance.     

Double-blind evaluation of efficacy and tolerability of metformin in NIDDM

OBJECTIVE: To test the efficacy and tolerability of metformin. RESEARCH DESIGN AND METHODS: An 8-mo double-blind placebo-controlled parallel-group trial was performed at University hospital diabetic clinics on 60 patients with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone. Metformin was administered and built up to a maximum dosage of 1 g three times daily. RESULTS: Mean HbA1 fell from 11.7 +/- 0.4 to 10.3 +/- 0.4% (means +/- SE) on metformin but rose from 11.8 +/- 0.4 to 13.3 +/- 0.4% on placebo (P less than 0.001). Final mean fasting blood glucose was 5.1 mM lower with metformin than placebo (P less than 0.001). No other biochemical variable differed significantly, and weight did not change. A favorable glycemic response was not restricted to the obese. The mean final dosage of metformin was 1.7 +/- 0.1 g and was well tolerated. CONCLUSIONS: Metformin achieved a 23% lower mean HbA1 than placebo without weight gain or significant unwanted effects.     

Antihypertensive therapy with Ca2+. Antagonist verapamil and/or ACE inhibitor enalapril in NIDDM patients.

OBJECTIVE: To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. RESULTS: Verapamil or enalapril alone normalized blood pressure to less than 90 mmHg diastolic in 30 patients; verapamil decreased mean +/- SE blood pressure from 159/98 +/- 3/1 to 146/87 +/- 3/2 mmHg (n = 18, P less than 0.001) and enalapril from 166/99 +/- 5/2 to 146/86 +/- 3/1 mmHg (n = 12, P less than 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 +/- 4/2 to 152/90 +/- 4/2 mmHg (P less than 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. CONCLUSIONS: In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.     

Effects of four orally administered analogues of prostaglandin E1 and E2 on glucose tolerance and on the secretion of pancreatic and gastrointestinal hormones in man

Oral glucose tolerance tests (75 g, 300 ml) were performed in 12 healthy volunteers, with prior administration of placebo, misoprostol (400 micrograms), rioprostil (300 micrograms), enprostil (70 micrograms), or nocloprost (200 micrograms), in a double-blind, randomized manner. None of the drugs significantly affected glucose tolerance, although with misoprostal some volunteers displayed an impaired glucose tolerance. Nocloprost was without effect on gastric inhibitory polypeptide (GIP) and did not influence insulin or C-peptide concentrations. Misoprostol and rioprostil reduced integrated incremental responses of GIP by 57% (P less than or equal to 0.001) and 45% (P less than or equal to 0.01), respectively, and both gave rise to an initial (approximately 10 min) delay of insulin and C-peptide responses, without a significant overall reduction in integrated incremental responses. Enprostil almost totally inhibited the GIP response (by 94%; P less than or equal to 0.001), delayed initial insulin and C-peptide responses, but reduced the integrated incremental C-peptide response (which corresponds to the overall release of insulin) by only 14% (P less than or equal to 0.05). Enprostil more substantially reduced the integrated incremental response of insulin by 36% (P less than or equal to 0.01), and also reduced the ratio of insulin and C-peptide incremental responses (P less than or equal to 0.001). In conclusion, prostaglandin E analogues which caused a reduction in GIP responses, and thereby disrupting the enteroinsular axis to varying degrees, delayed the time-course of insulin secretion without a significant impact on glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Para-aminosalicylic acid as a lipid-lowering agent.

The capacity of para-aminosalicylic acid (PAS) to lower initially high serum lipoprotein lipid concentrations was tested in a double-blind crossover study. Thirty patients who were on a lipid-lowering diet were treated with PAS (6 gm daily) for 4 wk. There was an average reduction of the serum triglyceride concentration of 28% (p less than 0.001) and of 12% of the serum cholesterol concentration (p less than 0.001) corresponding to a reduction of very low density lipoprotein (VLDL) triglycerides of 40% (p less than 0.001) and low density lipoprotein (LDL) cholesterol of 6% (p less than 0.05). In hypercholesterolemic patients, the LDL cholesterol reduction was 14% (p less than 0.001). In patients with hypertriglyceridemia type IV, the mean reduction of the VLDL triglyceride concentration was 47% (p less than 0.01), corresponding to a serum triglyceride reduction by 37% (p less than 0.01). In spite of the decrease of VLDL concentration, there was an unexpected reduction of the lipoprotein lipase activity in adipose tissue of 16% (p less than 0.02). The glucose tolerance and the serum insulin concentrations at fasting and after glucose injection were not changed.     

Comparison of combined therapies in treatment of secondary failure to glyburide.

OBJECTIVE--To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS--A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment. RESULTS--Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients. CONCLUSIONS--The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.     

No glycemic benefit from guar administration in NIDDM

A randomized crossover study of 5-g guar minitablets against placebo, given three times per day with main meals for 8 wk, was done in 29 non-insulin-dependent diabetes mellitus (NIDDM) patients who had near-normal fasting plasma glucose concentrations on treatment with diet alone, additional sulfonylurea, or ultralente insulin. Guar did not reduce the excessive postprandial glycemic excursion, glycosylated hemoglobin values, basal plasma glucose concentrations, basal or incremental plasma C-peptide values, or body weight. There were few side effects with either guar or placebo therapy. Mean low-density lipoprotein cholesterol levels were significantly reduced (P less than .001) by guar administration (116 +/- 23 vs. 104 +/- 19 mg/dl). Guar additives did not improve the excessive postprandial glycemia found in NIDDM patients in whom near-normal fasting plasma glucose levels had been obtained.     

Hypertriglyceridemia in different degrees of glucose intolerance in a Finnish population-based study.

OBJECTIVE--To determine the prevalence of hypertriglyceridemia and the mean serum triglyceride concentrations in different degrees of glucose tolerance--non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). In addition, we analyzed the correlates of serum triglyceride concentration to explain why it is more prevalent in diabetic subjects. RESEARCH DESIGN AND METHODS--This study was a cross-sectional survey of 4000 people aged 45-64 yr randomly drawn from the population register of the Finnish population of the provinces of North Karelia and Kuopio in eastern Finland and Turku/Loimaa area in southwestern Finland and stratified by four 10-yr age- and sex groups. The final material comprised 96 subjects with NIDDM, 102 subjects with IGT, and 323 subjects with normal glucose tolerance classified on the basis of two 2-h oral glucose tolerance tests. The prevalence of hypertriglyceridemia by the glucose tolerance status and the variation in serum triglycerides associated with selected life-style and biochemical factors were executed as the main outcome measures. RESULTS--The prevalence of hypertriglyceridemia (greater than or equal to 2.3 mM) was 47.6% (95% confidence interval [CI] 32.5-62.7%) in NIDDM men, 21.9% (95% CI 7.6-36.2%) in IGT men, and 15.4% (95% CI 9.3-21.5%) in NGT. In women, hypertriglyceridemia was found in 51.9% (95% CI 38.6-65.2%) among those with NIDDM, 25.7% (95% CI 15.5-35.9%) among those with IGT, and 10.7% (95% CI 6.3-15.1%) in women with NGT. After adjusting for body mass index (BMI) and age, the difference in the prevalence of hypertriglyceridemia between the glucose tolerance groups remained significant in both men (P = 0.008) and women (P = 0.0001). High serum total cholesterol, high BMI, high waist-hip ratio, and low high-density lipoprotein (HDL) cholesterol were significantly associated with high serum triglycerides in all glucose tolerance groups. No synergistic effect between these parameters and glucose tolerance status was found. In multiple linear regression analyses, fasting plasma insulin, diabetes status, and serum uric acid were significant predictors of serum triglyceride concentration after taking into account age, BMI, and HDL and total cholesterol. The association between BMI and serum triglycerides in the regression analysis was significant only when plasma insulin was not included in the model. CONCLUSIONS--Hypertriglyceridemia is common in subjects with NIDDM and IGT and is often associated with low HDL cholesterol, high total cholesterol, hyperinsulinemia, and elevated serum uric acid concentration.