The role of diminished beta cell reserve and insulin resistance in secondary sulfonylurea failure of type 2 diabetes mellitus.

INTRODUCTION: The correction of hyperglycemia by insulin treatment has been shown to ameliorate beta cell function and insulin sensitivity in SU failure patients, and there also appears to have disparity between tests of beta cell function among these patients. The objectives of this study were to determine beta cell secretory reserve and insulin resistance of secondary SU failure type 2 diabetic patients who had fairly good glycemic control compared with those who were SU responsive and the disparity of beta cell responses to glucose and non-glucose stimuli were examined in these two groups. SUBJECTS AND METHOD: Eight secondary SU failure, insulin-treated and 11 SU responsive type 2 diabetic patients who were matched for age, degree of obesity, duration of diabetes as well as HbAlc were studied. Intravenous glucagon and oral glucose tolerance tests (OGTT) as well as short intravenous insulin tolerance test using arterialized venous blood were randomly performed on separate occasions to assess beta cell secretory reserve and insulin sensitivity, respectively. RESULTS: Basal (0.37+/-0.05 (SEM) vs 0.80+/-0.14 nmol/l; p=0.02) and stimulated c-peptide levels (0.66+0.08 vs 1.16+/-0.14 nmol/l; p=0.007) after glucagon as well as basal (0.46+/-0.06 vs 0.73+/-0.10 nmol/l; p=0.046) and maximal c-peptide responses (1.41+/-0.14 vs 1.97+/-0.14 nmol/l; p=0.021) to glucose stimulation were significantly lower in SU failure than SU responsive patients. However, the incremental changes of c-peptide over basal after glucagon (0.29+/-0.06 vs 0.37+/-0.09 nmol/l) and glucose (AUC: 36.9+/-7.6 vs 47.9+/-4.5 nmol/l/h) were not different between both groups. There were strong positive relationships between basal and stimulated c-peptide responses to glucagon (r=0.818; p=0.002) and glucose (r=0.85; p=0.001) in SU responsive patients but these relationships were not as strong in SU failure patients (r=0.682; p=0.062 and r=0.41; p=NS, respectively). Insulin sensitivity did not differ between the two groups. CONCLUSION: This study demonstrated that decreased basal, but not stimulated, insulin secretion was possibly a major factor associated with secondary SU failure in type 2 diabetic patients. With comparable glycemic control, there was no disparate beta cell responses to glucose and glucagon in patients with or without secondary SU failure.

The oxidative metabolism of estradiol conditions postmenopausal bone density and bone loss.

Because lifelong exposure to estrogen is a strong determinant of bone mass, we asked whether metabolic conversion of estrogen to either inactive or active metabolites would reflect postmenopausal bone mineral density (BMD) and rate of bone loss. Biochemical markers of inactive estrogen metabolites, urinary 2-hydroxyestrogen (2OHE1) and 2-methoxyestrogen (2MeOE1), and active metabolites, urinary 16alpha-hydroxyestrone (16alphaOHE1), estradiol (E2), and estriol (E3), were determined in 71 untreated, healthy postmenopausal women (age, 47-59 years) followed prospectively for 1 year. Urinary 2MeOE1 was correlated negatively with baseline vertebral (anteroposterior [AP] projection, r = -0.23 andp < 0.05; lateral view, r = -0.27 and p < 0.05) and proximal femur bone density measured by dual-energy X-ray absorptiometry (DXA; total, r = -0.38 and p < 0.01; neck, r = -0.28 and p = 0.02; trochanter, r = -0.44 and p < 0.01). BMDs of women in the lowest quartile of urinary 2MeOE1 (< 15 ng/g) were significantly higher than those in the highest quartile at all skeletal sites (p < 0.05). Likewise, women in the lowest quartile of urinary 2OHE1/16alphaOHE1 ratio (< 1.6) did not experience bone loss after 1 year, in contrast to women in the higher quartiles. We propose that the rate of inactivation of estrogens through 2-hydroxylation may contribute to postmenopausal osteoporosis.

Thyroid autoantibodies in Thai type 1 diabetic patients: clinical significance and their relationship with glutamic acid decarboxylase antibodies.

OBJECTIVE: To study the clinical significance of thyroid autoantibodies in Thai patients with type 1 diabetes and their relationship with glutamic acid decarboxylase antibodies (GAD(65)Ab). METHODS: Thyroglobulin antibodies (TG-Ab) and thyroid peroxidase antibodies (TPO-Ab) were measured in 50 Thai type 1 diabetic patients. Forty-four patients also had GAD(65)Ab measured. Serum thyrotropin (TSH) was measured in all patients who had no history of thyroid disease regardless of thyroid antibody status. Clinical data including sex, age at onset and duration of diabetes, family history of diabetes, fasting c-peptide levels as well as frequencies of GAD(65)Ab were compared between patients with and without thyroid antibodies. GAD(65)Ab was also measured in 29 non-diabetic patients with hyperthyroid Graves' disease or Hashimoto thyroiditis as a control group. RESULTS: TG-Ab and TPO-Ab were positive in nine (18%) and 15 (30%) patients, respectively. Eight patients (16%) were positive for both antibodies. Two of 16 patients who were positive for TG-Ab or TPO-Ab had a previous history of hyperthyroidism prior to diabetes onset. Of the remainder, two were newly diagnosed with hyperthyroidism and one was found to have clinical hypothyroidism at the time of the study. None of 34 patients without thyroid antibodies had thyroid dysfunction. Eight patients with positive thyroid antibodies but without clinical thyroid dysfunction and 21 patients without thyroid antibodies were followed for up to 3 years, two patients of the first group developed hypothyroidism, whereas none of the latter developed thyroid dysfunction. The frequency of thyroid dysfunction at the time of initial study was significantly higher in patients with positive thyroid antibodies (3/14 vs. 0/34; P=0.021) and these patients who were initially euthyroid tended to have a higher risk of developing thyroid dysfunction (2/8 vs. 0/21; P=0.069). The frequency of thyroid antibodies was significantly increased in females and in those who had positive GAD(65)Ab. GAD(65)Ab was negative in all of the non-diabetic patients with autoimmune thyroid disease. CONCLUSIONS: About one-fourth of Thai patients with type 1 diabetes without thyroid disease had thyroid antibodies. The frequency of thyroid antibodies was increased in female and in GAD(65)Ab positive patients. The presence of thyroid antibodies is associated with a higher frequency of and may predict a higher risk for thyroid dysfunction in Thai type 1 diabetic patients.

The utility of conventional dipsticks for urinary protein for screening of microalbuminuria in diabetic patients.

The demonstration that microalbuminuria is predictive of overt diabetic nephropathy has created a demand for the routine measurement of urinary albumin in diabetic patients. We assessed the sensitivity, specificity, positive and negative predictive values of the conventional dipsticks for urinary protein (Ames Multistix, Bayer Diagnostic, Australia) as the screening test for microalbuminuria in diabetic patients compared with Micral-Test II (Boehringer Mannheim, Germany). Radioimmunoassay for albumin was taken as standard for comparison. With the urinary albumin concentration of 20 mg/L as a discriminating level of microalbuminuria, Micral-Test II had a sensitivity of 98.8 per cent and a specificity of 68.6 per cent whereas Ames Multistix had lower sensitivity but higher specificity. If urinary albumin concentration of 60 mg/L was used instead as a discriminating level of microalbuminuria, none of Ames Multistix by visual reading and only 5 of 32 (15.6%) of those by reflectance photometer had false negative results. By visual reading, the sensitivity of Ames Multistix was increased from 68.1 to 100 per cent with the drop in specificity from 85.7 to 50.2 per cent. On the other hand, the sensitivity was increased from 37.4 to 84.4 per cent but the specificity was maintained if reflectance photometer was used. In conclusion, Ames Multistix was less sensitive than Micral-Test II in detection of urinary albumin concentration above 20 mg/L. At higher urinary albumin concentration above 60 mg/L which indicates a clinically significant microalbuminuria, the sensitivity of Ames Multistix was increased to 100 per cent. Ames Multistix which is much less expensive than Micral-Test II, can be used as the screening test for significant microalbuminuria in clinical practice particularly in cases having financial problems.

Postprandial plasma glucose: a good index of glycemic control in type 2 diabetic patients having near-normal fasting glucose levels.

To investigate the effect of postprandial plasma glucose (PG) concentrations on HbA1c levels in type 2 diabetic patients, we evaluated the relationship between HbA1c levels and postprandial PG concentrations after a meal tolerance test in 35 type 2 diabetic patients who had fasting PG concentrations persistently < 7.8 mmol/l and stable HbA1c levels. Two-hour postprandial PG concentrations were found to be more strongly correlated (r = 0.51) with HbA1c levels than 1-h postprandial PG (r = 0.35) and fasting PG (r = 0.46) concentrations. Patients whose HbA1c levels were high (HbA1c > or = 7%) had significantly higher 2-h postprandial PG concentrations and areas under the glucose curve than those whose HbA1c levels were lower (8.12+/-1.10 (SD) vs 6.70+/-2.22 mmol l(-1), P = 0.004 and 17.43+/-1.92 vs 15.58+/-3.26 mmol h(-1) l(-1), P = 0.02, respectively). Although fasting PG concentrations of patients with higher HbA1c levels were slightly higher, they did not differ significantly from those with lower HbA1c levels (6.21+/-0.89 vs 5.73+/-0.68 mmol l(-1)). Age, duration of diabetes, body mass index, serum C-peptide, both fasting and postprandial, did not differ between these two groups. This study suggests that postprandial hyperglycemia, particularly 2-h postprandial PG concentrations, is associated with high HbA1c levels in type 2 diabetic patients whose fasting PG levels were within normal or near-normal levels.

Effect of pravastatin in treatment of hypercholesterolemia in non-insulin-dependent diabetes patients.

To evaluate the efficacy of pravastatin in treatment of hypercholesterolemia in non-insulin-dependent diabetes patients, a 6-month trial of once daily 10 mg-pravastatin was studied in 30 patients with fairly, well controlled non-insulin-dependent diabetes mellitus. For 27 patients who completed the study, serum total cholesterol and low-density lipoprotein cholesterol were significantly lower 16.7 +/- 2.3 and 20.2 +/- 3.3% from 286.7 +/- 5.9 and 198.6 +/- 7.2 mg/dl at before to 232.6 +/- 7.9 and 147.8 +/- 6.4 mg/dl at 4th week and 237.8 +/- 6.4 and 155.0 +/- 5.8 mg/dl at 24th week after treatment with pravastatin, respectively (P < 0.00001). Serum triglyceride level was decreased from 194.7 +/- 16.8 mg/dl to 175.0 +/- 16.8 mg/dl at 4th week and 176.6 +/- 14.1 mg/dl at 24th week and serum high-density lipoprotein cholesterol level was slightly increased from 45.4 +/- 2.8 mg/dl to 48.2 +/- 2.5 mg/dl at 4th week and 47.5 +/- 2.6 mg/dl at 24th week of pravastatin treatment, respectively (P > 0.05). There was no serious adverse effect except acute hepatitis in one patient who recovered spontaneously after drug withdrawal. Once daily 10 mg-pravastatin in effective in the treatment of hypercholesterolemia in patients with non-insulin-dependent diabetes mellitus.