Effects of long-acting release octreotide on glucose homeostasis in acromegaly patients after trans-sphenoidal surgery.

The present study was aimed to investigate glucose homeostasis and insulin secretion in acromegalic patients during octreotide-long acting release (LAR) therapy and designed as an observational prospective study. 18 acromegalic patients who had undergone trans-sphenoidal surgery with active disease were included. All patients were treated with octreotide-LAR injection for 1 year. These patients received oral glucose tolerance test (OGTT) before, 21 days after, and 1 year after octreotide-LAR treatment. Primary outcomes were changes in glucose levels and insulin secretion during an OGTT. We also determined the differences between subjects with normalized and uncontrolled IGF-1 levels. Of the 18 patients treated with octreotide-LAR for 1 year, 89% achieved fasting GH levels <2.5 µg/l, 85% reached the nadir GH concentration <1 µg/l, and 61% achieved normal age- and sex-matched IGF-1 values. 21 days after one dose of octreotide-LAR injection, insulin response during OGTT significantly decreased, and the Matsuda index increased significantly. One year after octreotide-LAR therapy, most parameters of glucose homeostasis returned to baseline levels. However, insulin response during OGTT at 30 and 60 min, and the insulinogenic index were still significantly decreased. Compared with the IGF-1-normalized group, the IGF-1 uncontrolled group had the same fasting GH and nadir GH levels and a higher insulin AUC and total insulin secretion. During octreotide-LAR treatment, the early-phase insulin response to OGTT is reduced and plasma glucose levels remained normal in most patients. The IGF-1 uncontrolled group had the same fasting GH and nadir GH levels during OGTT, but had better glucose homeostasis.

Improvement of glycaemia control in subjects with type 2 diabetes by self-monitoring of blood glucose: comparison of two management programs adjusting bedtime insulin dosage.

AIM: Self-monitoring of blood glucose (SMBG) is important for patients treated with insulin to detect asymptomatic hypoglycaemia and to guide patients towards reaching blood glucose goal. This study compared two management programs for adjusting bedtime insulin dose: program 1 (performed by study subjects) vs. program 2 (performed by study subjects and reminded by investigators). METHODS: This is a prospective, open-level, 28-week randomized trial in poorly controlled type 2 diabetic subjects. One hundred subjects treated with oral antidiabetic drugs plus bedtime insulin with glycated haemoglobin A(1C) (A1C) >8.0% were screened and received a structure education package in a 4-week run-in period. Seventy-eight subjects were randomized to two treatment programs (adjust insulin dose by themselves with or without investigators' reminder) and reviewed by the investigators at a 4-week interval clinical visit. RESULTS: The mean SMBG decreased significantly in both groups, with a greater decrease observed in program 2 vs. program 1 (from 198.7 +/- 43.1 to 122.6 +/- 21.9 mg/dl vs. from 194.0 +/- 42.7 to 151.6 +/- 37.7 mg/dl, p < 0.001). Bedtime insulin dose increased in both groups with a greater increase in program 2 (from 14.4 +/- 8.7 to 27.4 +/- 12.8 IU vs. from 14.3 +/- 8.3 to 18.4 +/- 6.2 IU, p < 0.001). There was a significant reduction in A1C from 9.54 +/- 1.67% to 7.76 +/- 1.27%, with a greater decrease (p < 0.001) in program 2 (2.17%) than in program 1 (1.40%). There were more subjects in the program 2 group achieving the treating targets: mean SMBG < or =120 mg/dl (46.9 vs. 17.9%) and A1C < or =7.0% (54.5 vs. 32.2%). There was no significant difference in the incidence of hypoglycaemia and body weight changes. CONCLUSIONS: Systematically titrating bedtime insulin dose added to oral therapy, especially combined with health care reminders, can safely improve glycaemic control in type 2 diabetes with poor glycaemic control. This regimen may facilitate safe and effective insulin therapy in routine medical practice and improve achievement of recommended standards of diabetes care.

Growth hormone (GH) replacement reduces total body fat and normalizes insulin sensitivity in GH-deficient adults: a report of one-year clinical experience.

The effects of GH replacement on body fat composition and insulin sensitivity were assessed in GH-deficient adults. The patients were randomized into a double-blind, placebo-controlled study of human recombinant GH replacement therapy for 6 months (period 1), followed by an open phase of GH for another 6 months (period 2). Anthropometric variables, body fat composition (fat %), and biochemical parameters were measured during the trial. Measurements of in vivo insulin sensitivity were carried out at the commencement of the study and on completion of the trial by modified insulin suppression test. The modified insulin suppression test was performed both in the morning (AM) and in the afternoon (PM) to further evaluate the PM-AM steady-state plasma glucose (SSPG) pattern. We found that the GH-deficient adults had more body fat and were insulin resistant. Significant reduction in fat % and total body fat mass was found in the active arm of period 1 without alteration of body weight. Besides, we demonstrated, for the first time, the GH replacement for 6 months did not alter the insulin sensitivity, but replacement for a longer period (12 months) normalized not only the AM SSPG level but also the PM-AM SSPG pattern. We also found a positive correlation between SSPG (regardless of AM vs. PM) and fat % and total body fat mass. In conclusion, normalization of insulin sensitivity in GH-deficient adults after replacement of GH may be related to the reduction of total body fat.

Exacerbation of insulin resistance and postprandial triglyceride response in newly diagnosed hypertensive patients with hypertriglyceridaemia.

The purpose of the study is to examine the differences in insulin resistance and postprandial triglyceride (TG) response between hypertensive patients with or without hypertriglyceridaemia. The study is a comparative cohort study with matching. Thirty-one newly diagnosed hypertensive patients without any medication were recruited from a health survey. The participants were further divided into two groups: those with fasting TG <2.26 mmol/L, and those with TG between 2.26 and 5.65 mmol/L. Both groups were matched in age, sex, body mass index and waist circumference. Each patient received a 75-g oral glucose tolerance test, an insulin suppression test, and a 1000 kcal high fat mixed meal test. The hypertriglyceridaemic hypertensive patients had significantly higher fasting insulin, 2-h plasma glucose, 2-h insulin, and steady-state plasma glucose (SSPG) (13.16 +/- 1.87 vs 9.76 +/- 3.18 mmol/L). They also had a greater postprandial TG response to the challenge of mixed meal (DeltaAUC 20.76 +/- 10.06 vs 7.97 +/- 3.18 mmol 8 h/L). The postprandial TG response was closely correlated (r = 0.72-0.95, P < 0.0001) with fasting TG in all hypertensive patients. Both fasting TG levels and postprandial TG response were significantly (P < 0.05) correlated with SSPG. In conclusion, the hypertensive patients with hypertriglyceridaemia were more insulin resistant than those without it. Exacerbation of postprandial hypertriglyceridaemia was identified in these patients. The TG response to the challenge of high fat meal was significantly correlated with fasting TG and insulin resistant in them. The results provide a rationale for the alleviation of insulin resistance and hypertriglyceridaemia in these atherosclerosis-prone hypertensive patients.

Acipimox attenuates hypertriglyceridemia in dyslipidemic noninsulin dependent diabetes mellitus patients without perturbation of insulin sensitivity and glycemic control.

Hyperlipidemia, hypertriglyceridemia in particular, is a common feature in patients with noninsulin dependent diabetes mellitus (NIDDM) and may associate with insulin insensitivity. Acipimox, being widely prescribed for treating hypertriglyceridemia, is also used in NIDDM patients for their dyslipidemia. In the present study, we evaluated the effect of acipimox in Chinese NIDDM patients with hypertriglyceridemia. A total of 16 patients enrolled in a double-blind, randomized, placebo-controlled and two-period crossover study. After an 8 week run-in period, patients were randomly assigned into two groups receiving either acipimox (250 mg, twice daily) or placebo treatment. A total of 12 weeks later, these two groups switched their treatment for an additional 12 weeks. Blood samples were collected at the end of the run-in period and then at 4-week intervals in the whole study for lipid profile. A modified insulin suppression test was performed at the ends of the run-in period, 12-week and 24-week treatment to assess changes in insulin sensitivity. Our results showed that acipimox significantly lowered serum total triglyceride while compared to those by placebo. However, no difference was observed in serum non-esterified fatty acid, low-density lipoprotein cholesterol, total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C) and HDL-C/ TC ratio between the two groups. Furthermore, glycemic indices and insulin sensitivity were similar during the base-line, placebo or acipimox periods. Taken together, our data suggest that acipimox significantly lowered TG without perturbation of insulin sensitivity in hypertriglyceridemic NIDDM patients.

A comparison of insulin suppression tests performed with somatostatin and octreotide with particular reference to tolerability.

To evaluate the tolerability of insulin suppression test (IST) using octreotide instead of somatostatin, we compared the steady-state plasma glucose (SSPG) values and the safety during and after the test in 17 normal volunteers. The subject received IST twice (with somatostatin or with octreotide) in random order. During the test, all subjects were infused with regular insulin and glucose simultaneously for 180 min. In addition, either somatostatin or octreotide was infused intravenously over the same period of time. Plasma glucose, insulin and C-peptide were measured. The subject response to the test was recorded during and one day after the test by a structured questionnaire. The SSPG and the steady-state plasma insulin (SSPI) values reached during IST were similar, irrespective of the use of somatostatin or octreotide. There was a positive correlation between the SSPG values obtained from both methods (r = 0.67, P = 0.003). However, the mean intra-individual coefficient of variation is 17.9% for SSPG. The SSPG levels, no matter from which method, correlated positively with the 2-h insulin after oral glucose challenge. Most adverse events (especially gastrointestinal discomfort) occurred after the test, and increased much more after using octreotide than somatostatin (P = 0.002 by chi 2 test). In conclusion, the SSPG values measured by IST using octreotide or somatostatin are similar in normal healthy subjects. Yet, the octreotide method has more adverse events after the test.

Using semi-automated oscillometric blood pressure measurement in diabetic patients and their offspring.

To determine whether a semi-automatic oscillometric blood pressure (BP) monitor Dinamap 1846SX (DIN) can replace the standard mercury sphygmomanometer (SMS) for BP measurements in diabetic patients and their offspring, we compared SMS with DIN in 105 diabetic patients and their families. Their mean age was 50.6 (range 24-86) years, of whom 41 had diabetes mellitus (DM), 32 impaired glucose tolerance and 32 non-DM. After resting quietly for 10 min, their right arm BP were measured twice with each device at random and with 1-min intervals between each measurement. Agreement between measurements was tested by plotting the differences between the methods against means and by intraclass correlation coefficient (r(I)). The DIN was also evaluated by the criteria of American Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society (BHS) criteria and clinical criteria of O'Brien. All measurements by DIN [first readings or averaged readings of duplicate measurements of systolic BP (SBP) or diastolic BP (DBP)] satisfied the AAMI criteria and had good agreement with SMS (r(I)=. 951 for SBP and r(I)=.905 for DBP). The first readings of systolic BP measured by DIN vs. SMS failed to satisfy the criteria by O'Brien and reached BHS grade C level. Other measurements passed the limits of O'Brien and reached BHS grade A or B. In conclusion, averaged readings of duplicate BP measurements by DIN are interchangeable with that by SMS in Chinese diabetic patients and their offspring. Only one single DIN measurement is not acceptable for clinical application.

Diurnal variation of insulin sensitivity in NIDDM patients and normal subjects.

A modified insulin suppression test was adopted to assess the diurnal variation in insulin sensitivity and insulin clearance in 14 non-insulin-dependent diabetes mellitus (NIDDM) patients and eight age-, sex- and weight-matched normal subjects. The modified insulin suppression test was combined with an infusion of regular insulin, 30 mU/min x m2; glucose, 6 mg/kg x min; and somatostatin, 500 micrograms/h, for 120 minutes followed by only a somatostatin infusion for 60 minutes. Blood samplings were performed at appropriate times to obtain data on steady-state plasma insulin (SSPI), steady-state plasma glucose (SSPG as an index of insulin sensitivity), metabolic clearance and the half disappearance time (T1/2) of insulin. Blood specimens were also obtained during SSPI for measurement of erythrocyte insulin receptor binding. Each subject took the insulin suppression test twice. One test was started at 8 am and the other at 4 pm; each test was preceded by 16 hours of fasting. The order of the insulin suppression tests in each subject was randomized and balanced. In normal subjects, the SSPG level was lower in the morning than in the afternoon (118.0 +/- 43.6 vs 150.3 +/- 34.2 mg/dL, p less than 0.05). The NIDDM patients had a higher SSPG in the morning (217.7 +/- 51.4 vs 188.3 +/- 40.6 mg/dL, p less than 0.01). There was no diurnal difference in insulin clearance or the T1/2 in either normal subjects or NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Prehypertension is associated with insulin resistance.

BACKGROUND: Prehypertension, a new category of blood pressure (BP) classification introduced by The Seven Report of the Joint National Commission (JNC-7) on High BP for individuals with systolic BP in the range of 120-139 mmHg or diastolic BP between 80 and 89 mmHg, is a strong predictor for the development of hypertension. Insulin resistance (IR) has been proposed to be a key feature of metabolic abnormalities of hypertension and may precede the elevation of BP. AIM: The purpose of the study is to evaluate whether prehypertension is associated with IR. DESIGN: This is a cross-sectional study. METHODS: Anthropometric and BP measurements were performed in 83 prehypertensive subjects and 192 normotensives. All subjects received a 75-g oral glucose tolerance test (OGTT) for the measurements of IR. RESULTS: The prehypertensive subjects were more obese and had higher levels of fasting triglycerides and 2-h insulin than the normotensives. The subjects with prehypertension were more insulin resistant than the counterparts, indicated by lower insulin sensitivity index, ISI(0,120), values. While there was no difference between the two groups in insulin response of OGTT after adjustments for confounders, the prehypertension group maintained significant between-group differences in glucose response even when the incremental insulin levels were added to covariates for adjustments. DISCUSSION: Our data show that prehypertension is associated with IR. The subjects with prehypertension have clinical characteristics of the IR syndrome. It seems that the prehypertension group cannot handle oral glucose challenge as well as the normotension, probably a consequence of IR in prehypertension.

Congenital muscular dystrophy: report of one case.

A case is reported of a newborn who presented with generalized hypotonia shortly after delivery. Creatine kinase (CK) was highly elevated. Muscle biopsy of the rectus femoris muscle revealed varying sized muscle fibers, displacement by fat and connective tissues, necrosis and regeneration of the muscle fibers. Magnetic resonance imaging (M.R.I.) of the brain showed normal development, compatible with the patient's age. Congenital muscular dystrophy was diagnosed from clinical manifestations, laboratory findings, and the results of muscle biopsy.

Undiagnosed glucose intolerance encountered in clinical practice: reappraisal of the use of the oral glucose tolerance test.

BACKGROUND: In 1997, the Expert Committee of the American Diabetes Association (ADA) revised the diabetes mellitus (DM) diagnostic criteria to facilitate the diagnosis of DM on the basis of fasting plasma glucose (PG). The major purpose of the study is to evaluate if oral glucose tolerance test (OGTT) is still needed after the revision of criteria. METHODS: From September 1994 to March 1995, 247 ambulatory subjects referred by clinicians for 75-g OGTT were recruited for the study. Fasting and 2-h PG and serum insulin concentrations were determined. Additional fasting blood samples were collected for the measurement of HbA1c. We used the receiver operating characteristic (ROC) curve to locate a cut-point of fasting PG corresponding to 2-h PG of 200 mg/dl. RESULTS: The optimal fasting PG level depicted by ROC curve was more than 105 mg/dl, giving 80.6% sensitivity and 85.6% specificity for the diagnosis of DM in clinical setting. If fasting PG > or = 126 mg/dl was employed, the specificity was 98.3% but the sensitivity went down to 42.6%. High rates of glucose intolerance would remain undiagnosed in subjects with fasting PG less than 126 mg/dl (41.6% of them being IGT and 38.6% DM), if the OGTT was exempted from clinical practice. HbA1c more than 6.2% could be a clue to recognize undiagnosed DM, but was unable to separate impaired glucose tolerance (IGT) from non-DM. CONCLUSIONS: In the population studied, undiagnosed glucose intolerance can still be encountered in a large number of subjects with fasting PG less than 126 mg/dl. OGTT is still indispensable in clinical setting for the diagnosis of DM and IGT after the revision of diagnostic criteria.

Lack of effect of simvastatin on insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia: results from a double-blind, randomized, placebo-controlled crossover study.

AIMS: To evaluate the effects of simvastatin on serum lipids and insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia. METHODS: A double-blind, randomized, placebo-controlled and two-period crossover study. After a 2-month run-in, 19 eligible Type 2 diabetic patients with hypercholesterolaemia were randomized to receive either simvastatin or placebo for 3 months, exchanging their treatment thereafter for another 3 months. Blood samples were taken in month 0 and at monthly intervals to measure serum lipids and indices of glycaemic control. An euglycaemic insulin clamp was performed in months 0, 3 and 6 to assess change of insulin sensitivity. The amount of glucose infused during 90-120 min of the clamp (M), and the mean values of serum insulin during 90-120 min (I) were measured. The M and M/I ratio were used to represent the in vivo insulin sensitivity of the subject. RESULTS: Simvastatin significantly reduced serum total cholesterol (TC) by 23+/-18% and low density lipoprotein-cholesterol (LDL-C) by 30+/-26%. It did not alter glycaemic control. The M-values and M/I ratios were similar in both groups in each period and no drug effect on insulin sensitivity could be identified. CONCLUSIONS: Simvastatin significantly reduced the serum TC and LDL-C levels without alteration of insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia.

Surrogate estimates of insulin sensitivity in Chinese diabetic patients and their offspring.

AIMS: To evaluate the relationship between surrogate measures of insulin sensitivity and results from euglycaemic insulin clamp in Chinese diabetic patients and their offspring. METHODS: The study included 59 volunteers from 20 diabetic families. Each participant completed a 75-g oral glucose tolerance test (OGTT) and a euglycaemic insulin clamp. We tested the correlation of surrogate measures of insulin sensitivity with M-values and M/I ratios (the amount of glucose infused during 90-120 min of the clamp was defined as M, and the mean values of plasma insulin during 90-120 min as I) from the euglycaemic insulin clamp. These measures included fasting insulin (FPI), insulin at 120 min of OGTT, insulin area under the curve of OGTT, fasting glucose-to-insulin ratio, homeostasis model assessment for insulin sensitivity (HOMA-IR and HOMA %S) and the Matsuda-DeFronzo index from OGTT. RESULTS: The Matsuda-DeFronzo index closely correlated to M-value and M/I in 21 diabetic, 38 non-diabetic individuals and the 59 participants overall (with M-value, r = 0.68, 0.84 and 0.84; with M/I, r = 0.71, 0.72 and 0.75, respectively, all P < 0.001). Without OGTT, HOMA %S was a good surrogate index for diabetic (correlated to M-value and M/I, r = 0.71 and 0.68, P = 0.001) and for non-diabetic subjects (to M-value, r = 0.73; to M/I, r = 0.55, both P < 0.001). FPI was as good as HOMA %S and Matsuda-DeFronzo index. CONCLUSIONS: The Matsuda-DeFronzo index, HOMA %S and FPI are good surrogate estimates of insulin sensitivity in Chinese diabetic subjects and their offspring.

Insulin sensitivity in normotensive offspring of hypertensive parents.

OBJECTIVES: To investigate the insulin sensitivity in normotensive offspring of hypertensive parents. SUBJECTS: Fifteen young normotensive offspring of hypertensive parents were paired with 15 controls matched for age, sex and body mass index. METHODS: The insulin sensitivity was investigated by 75 g oral glucose tolerance test (OGTT) and modified insulin suppression test. A high-fat mixed meal was administered to observe the changes of TG levels. RESULTS: The plasma glucose and serum insulin responses to oral glucose challenge were comparable between both groups. High-fat mixed meal made no difference in the plasma glucose, serum triglyceride or insulin between the 2 groups. With the modified insulin suppression test, the steady-state plasma glucose levels (SSPG) were higher in the offspring of parents with essential hypertension (138+/-43 mg/dl) than in the control group (95+/-26 mg/dl). The diastolic blood pressure and heart rate of the offspring of hypertensive parents are also higher than the control group. CONCLUSIONS: Insulin resistance exists in young normotensive offspring of hypertensive parents, and the impairment of insulin-mediated glucose uptake in these subjects develop before any alteration of fasting and postprandial triglyceride.

Abnormal cardiovascular reflex tests are predictors of mortality in Type 2 diabetes mellitus.

AIMS: To determine whether diabetic autonomic neuropathy is an important factor contributing to mortality in Type 2 diabetes mellitus. METHODS: Between 1989 and 1993, 431 men and 181 women with Type 2 diabetes were given diabetic autonomic neuropathy cardiovascular reflex (CVR) tests. These subjects were followed for the subsequent 5--9 years to assess mortality rates. RESULTS: The prevalence rate of abnormal CVR tests was 46.1% in patients with the history of diabetes less than 5 years and up to 69.4% when the history of diabetes exceeded 20 years. During the follow-up period from 1 January 1989 to 31 December 1997 (mean 7.7 years), a total of 135 participants died. The 8-year survival rate for patients with abnormal CVR tests was 63.6% in males and 76.4% in females, compared with 80.9 and 93.3% for patients with normal CVR tests. The results were grouped as: group 1, normal CVR tests without postural hypotension (PHT); group 2, normal CVR tests with PHT; group 3, abnormal CVR tests without PHT; and group 4, abnormal CVR tests with PHT. The 8-year survival rate was 85.4% in group 1, 80.9% in group 2, 74.5% in group 3 and 61.1% in group 4. CONCLUSION: Type 2 diabetic patients with abnormal CVR tests may have increased mortality, and those combined with postural hypotension have higher mortality than those without. Abnormal CVR tests may be important predictors of mortality in Type 2 diabetes mellitus.

Waist circumference predicts insulin resistance in offspring of diabetic patients.

The purpose of the study was to identify a good abdominal obesity index for insulin resistance in offspring of diabetic patients. A total of 74 non-diabetic subjects (male =36; female =38) were recruited from a diabetic family study. The waist circumference (W), waist-hip ratio (WHR) and conicity index were used as the abdominal obesity indices. The body mass index (BMI) and indices obtained from bioelectric impedance analysis (BIA) (body fat percentage, fat mass and fat mass index) were used as overall obesity indices. Fasting plasma insulin (FPI), homeostasis model assessment for insulin resistance (HOMA-IR) and Matsuda-Defronzo index from oral glucose tolerance test were chosen as the insulin sensitivity indices. We correlated obesity indices with insulin resistance indices with age and family adjusted. W was closely correlated in both sexes of subjects with Matsuda-DeFronzo index (male, r=-0.661,p<0.001; female, r=-0.419,p=0.026), FPI (male, r=0.614,p=0.001; female, r=0.503,p=0.006) and HOMA-IR (male, r=0.609,p=0.001; female, r=0.472,p=0.011). WHR and its log transformation predicted insulin resistance only in males. BMI as an overall obesity index was in good correlation with Matsuda-DeFronzo index (male, r=-0.646,p<0.001; female, r=-0.469,p=0.012), FPI (male, r=0.711,p<0.001; female, r=0.464,p=0.013) and HOMA-IR (male, r=0.708,p<0.001; female, r=0.469,p=0.012). Overall obesity indices from BIA were similar to BMI to predict insulin resistance. In conclusion, W is a good abdominal obesity predictor of insulin resistance in offspring of diabetic patients in Taiwan.