Low dose metformin in the treatment of type II non-insulin-dependent diabetes: Clinical and metabolic evaluations

Summary Low doses of metformin (500 mg twice daily) were administered to 20 diabetic patients, combined with the original sulfonylurea treatment which had become ineffective even at full dosage. After 1 and 5 weeks, the effects of the drug on glycemic control, blood intermediate metabolites and monocyte insulin receptors were monitored. Metformin clearly improved glycemic control by reducing both fasting blood glucose from 189.88±21.11 mg/dl to 131.12±16.02 mg/dl after 1 week and to 130.11±13.29 mg/dl after 5 weeks (p<0.025 both after 1 and 5 weeks); the diurnal blood glucose average fell from 235.33±24.11 mg/dl to 174.66±23.45 mg/dl (p<0.0025) after 1 week and to 177.65±21.71 mg/dl (p<0.0005) after 5 weeks. Consequently both blood glycosylated hemoglobin (p=n.s. after 1 week, p<0.025 after 5 weeks) and serum fructosamine (p<0.0025 after both 1 and 5 weeks) also decreased after metformin treatment. No change in plasma insulin and C-peptide levels was reported and no modification in diurnal rhythms of blood lactate, pyruvate, alanine glycerol and β-OH-butyrate was detected at any time during metformin treatment. All the changes documented in the binding values were already complete at the end of the first week: insulin binding to monocytes increased slightly but significantly (p<0.05) and the number of receptors per cell rose (p<0.05) but could not be correlated to any index of glycemic control. These data suggest that the antidiabetic action of metformin is neither related to its lactate-increasing activity nor does it depend upon its inducing an increase in insulin binding values. This metformin-related hypoglycemic effect might be the result, at least in part, of a reduced oxidative phosphorylation without inhibition of hepatic guconeogenesis and/or of decreased hepatic glucose output. Moreover, our data are also consistent with the hypothesis that metformin might affect insulin action at a post-receptor level.     

Lack of a persistent reduction in serum lipid and apoprotein levels in insulin-dependent diabetic patients receiving intensified insulin treatment

Summary Type I insulin-dependent diabetic patients have an increased risk of atherosclerotic vascular disease that may be determined in part by their tendency to develop circulating lipid and lipoprotein abnormalities. The occurrence of such findings in asymptomatic ambulant Type I patients with mild or moderate hyperglycemia might suggest that conventional methods of insulin treatment are as inefficient at normalizing lipid abnormalities as they are in achieving euglycemia. It would then be important to ascertain whether intensive methods of insulin treatment effectively normalized lipid levels. Ten insulin-dependent young adult diabetic patients were studied on a conventional insulin treatment regimen and then at two-monthly intervals for a six-month period during which they were managed by three different intensified insulin treatment regimens. Plasma glucose levels improved substantially (p<0.001) after two months of intensified therapy (106±4 mg/dl) and did not change significantly thereafter for the remaining four months of intensified insulin treatment. Apart from a short-lived decrease in total, LDL and HDL-cholesterol after two months of intensified treatment (baseline total triglyceride 116±13 mg/dl, total cholesterol 174±16 mg/dl, HDL-cholesterol 46±3 mg/dl). There were no persistent changes in serum lipids, lipoprotein cholesterol or in levels of their major apoproteins A-I, A-II and B. These findings support the contention that, despite moderate hyperglycemia, conventional insulin treatment may be adequate to maintain normal lipid levels. In such circumstances achievement of euglycemia by intensified insulin therapy leads to little change in circulating lipid and lipoprotein values.     

The effects of epinephrine on islet hormone secretion in the dog

Summary We investigated the direct effects of physiological levels of epinephrine on the basal and arginine-stimulated secretion of insulin, glucagon, and somatostatin from the in situ pancreas in halothane-anaesthetized dogs. An IV infusion of 20 ng/kg/min of epinephrine increased plasma epinephrine levels to 918±103 pg/ml (P<0.001), and increased the baseline pancreatic output of insulin (P<0.05), glucagon (P<0.05) and somatostatin (P<0.05). The acute insulin response (AIR) to 2.5 g of arginine during this infusion of epinephrine was significantly higher (P<0.05) than in controls as were the acute glucagon response (AGR) (P<0.05) and the acute somatostatin response (ASLIR) (P<0.05). Plasma glucose levels increased slightly and transiently during infusion of epinephrine from 99±2 mg/dl to a maximum of 110±3 mg/dl (P<0.05). An IV infusion of 80 ng/kg/min of epinephrine produced plasma epinephrine levels of 2948±281 pg/ml, and increased the baseline pancreatic output of insulin (P<0.05) and glucagon (P<0.05). In contrast, baseline somatostatin output decreased transiently during this high dose infusion of epinephrine. The AIR and ASLIR to arginine were both significantly lower (P<0.05) than those during the infusion of epinephrine at the low dose. The AGR to arginine remained potentiated (P<0.05). Plasma glucose levels increased from 99±3 mg/dl to 119±4 mg/dl (P<0.01). We conclude that the effect of epinephrine on islet hormone secretion is dependent on the plasma level of epinephrine. At stress levels of 900–1000 pg/ml, both insulin and somatostatin secretion are stimulated; only at near pharmacologic, or extreme stress levels, does epinephrine produce net inhibition.     

Efficacy of liraglutide as a follow-up therapy after resolution of glucotoxicity with intensive insulin therapy

ObjectiveTo assess the utility of liraglutide, a GLP-1 receptor agonist, as additional therapy following resolution of glucotoxicity with insulin therapy.MethodsThe subjects were 13 Japanese patients with short-duration type 2 diabetes mellitus (2.0 ± 2.1 years). At first, treatment with insulin therapy consisted of bolus insulin before each meal and basal insulin at bed time commenced to improve every preprandial glucose levels below 130 mg/dL. Then, insulin therapy was replaced with liraglutide monotherapy in case in which 50% or more self-monitoring of blood glucose (SMBG) tests revealed preprandial glucose levels of less than 130 mg/dL at least for one month. Liraglutide dosing was initiated at 0.3 mg/day and increased in weekly or biweekly increments of 0.3 mg/day, to the maximum permissible dose (in Japan) of 0.9 mg/day. The participants were treated with liraglutide for 24 weeks.ResultsThe average insulin therapy period was 13.2 ± 5.4 weeks, and insulin therapy significantly improved HbA1c values from 12.4% ± 1.6% to 6.8% ± 0.9% (P < 0.05). After improvement of hyperglycemia with insulin therapy and switching to liraglutide monotherapy for 24 weeks, HbA1c values remained constant (6.2% ± 1.0% at week 24) and the rates of hypoglycemic episodes significantly decreased (P < 0.05).ConclusionsThese data suggest that liraglutide is proposed as an alternative follow-up therapy subsequent to eliminate glucotoxicity with insulin therapy.     

Effects of prazosin and propranolol on blood pressure and plasma lipids in patients undergoing chronic hemodialysis

Twenty patients receiving hemodialysis who had mild to moderate hypertension were treated with prazosin or propranolol to control predialysis hypertension. Effective blood pressure control was achieved with prazosin (mean dose 8.3 ± 2.2 mg [± standard error of the mean], n = 10) and propranolol (mean dose 123 ± 39 mg, n = 10). Therapy with prazosin did not significantly affect total plasma triglyceride or total cholesterol levels. The level of high-density lipoprotein (HDL) cholesterol tended to increase, but not significantly. However, the HDL₃ subfraction did increase significantly, from 16.3 ± 1.5 to 20.6 ± 1.5 mg/dl (p = 0.05). Propranolol therapy increased plasma triglyceride levels, primarily of the very low density lipoprotein class. HDL cholesterol levels decreased from 44.2 ± 6.7 to 34.7 ± 4.2 mg/dl (p < 0.03). The reduction in the HDL cholesterol levels was attributable to a decrease in HDL₂ cholesterol levels (from 21.3 ± 3.8 to 16.3 ± 3.0 mg/dl, p < 0.04) and HDL₃ cholesterol levels (from 23.0 ± 3.1 to 19.5 ± 2.1 mg/dl, difference not significant). Thus, both prazosin and propranolol are effective in controlling hypertension in patients undergoing hemodialysis. HDL₃ cholesterol levels increased in patients treated with prazosin, but no other significant changes in the plasma lipids occurred. Patients treated with propranolol had a significant decrease in plasma HDL₂ and HDL₃ cholesterol levels.     

A circadian rhythm-related MTNR1B genetic variant (rs10830963) modulate body weight change and insulin resistance after 9 months of a high protein/low carbohydrate vs a standard hypocaloric diet

Background & aimsThe risk allele (G) of rs10830963 in the melatonin receptor 1 B (MTNR1B) gene presents an association with biochemical parameters and obesity. We study the effect of this SNP on insulin resistance and weight loss secondary to two hypocaloric diets.Methods270 obese subjects were randomly allocated during 9 months (Diet HP: a high protein/low carbohydrate vs. Diet S: a standard severe hypocaloric diets). Anthropometric parameters, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile and adipocytokines levels were measured. Genotype of MTNR1B gene polymorphism (rs10830963) was evaluated.ResultsAll adiposity parameters, systolic blood pressure and leptin levels decreased in all subjects after both diets. This improvement of adiposity parameters was higher in non-G allele carriers than G allele carriers. After weight loss with Diet HP, (CC vs. CG + GG at 9 months); total cholesterol (delta: −9.9 ± 2.4 mg/dl vs. −4.8 ± 2.2 mg/dl:p < 0.05), LDL-cholesterol (delta: −8.3 ± 1.9 mg/dl vs. −5.1 ± 2.2 mg/dl: p < 0.05), insulin (delta: −4.7 ± 0.8 UI/L vs. −0.9 ± 1.0 UI/L: p < 0.05), triglycerides (delta: −17.7 ± 3.9 mg/dl vs. −6.1 ± 2.8 mg/dl: p < 0.05) and HOMA IR (delta: −0.8 ± 0.2 units vs. −0.2 ± 0.1 units: p < 0.05) improved only in no G allele carriers. After weight loss with Diet S in non G allele carriers, insulin levels (delta (CC vs. CG + GG): −3.4 ± 0.6 UI/L vs. −1.2 ± 0.4 UI/L: p < 0.05), triglycerides (delta: −29.2 ± 3.4 mg/dl vs. −8.2 ± 3.8 mg/dl: p < 0.05), HOMA-IR (delta (CC vs. CG + GG): −1.1 ± 0.2 units vs. −0.1 ± 0.1 units: p < 0.05), total cholesterol (delta: −15.9 ± 7.4 mg/dl vs. −5.8 ± 2.9 mg/dl:ns) and LDL-cholesterol (delta: −13.7 ± 5.9 mg/dl vs. −6.0 ± 2.9 mg/dl: ns) decreased, too.Conclusionsour study detected a relationship of rs10830963 variant of MTNR1B gene with adiposity changes, cholesterol changes and insulin resistance modification induced by two different hypocaloric during 9 months.     

Failure of insulin infusion during euglycemia to influence endogenous basal insulin secretion

Despite some evidence of self-regulation of insulin secretion, it is unclear whether endogenous insulin influences insulin secretion independently of blood glucose. The aim of the present study was to examine this question in humans. Seven healthy fasting men were given two-hour porcine insulin infusions (40 mU/min) with and without maintenance of euglycemia (glucose clamp). Intravenous glucose required to maintain basal blood glucose levels (4.2 ± 0.1 mmole/liter) during insulin infusion was 34.3 ± 3.0 gm with a mean rate of 273 ± 29 mg/min in the second hour of insulin infusion. During the glucose clamp, mean C-peptide levels were not significantly altered from fasting levels of 1.91 ± 0.24 ng/ml, but when blood glucose levels fell by approximately 1 mmole/liter, C-peptide fell to 0.37 ± 0.07 ng/ml. Plateau insulin levels were significantly higher during euglycemia than during mild hypoglycemia (53.2 ± 5.6 mU/liter versus 38.5 ± 3.6 mU/liter, P < 0.01). Plasma nonesterified fatty acids were suppressed equally in the two studies. However, a rise in plasma glucagon seen during mild hypoglycemia was absent when euglycemia was maintained. We conclude that insulin self-regulation (either direct or neurally mediated) is not physiologically important in the basal state in normal humans and that the blood glucose-insulin feedback loop dominates in the short-term control of basal insulin secretion.     

Improved exercise ejection fraction with long-term prazosin therapy in patients with heart failure

To study the effect of prazosin therapy on left ventricular function in patients with chronic stable heart failure, first pass radionuclide angiography at rest and during exercise was performed in 15 patients before the administration of prazosin and after seven to 12 weeks of prazosin therapy. There was no significant change in resting ejection fraction before and during prazosin therapy (36 ± 14 per cent versus 37 ± 14 per cent) (mean ± standard deviation). However, exercise ejection fraction increased from 34 ± 14 per cent to 42 ± 17 per cent (p < 0.01). The difference in ejection fraction from rest to exercise (ejection fraction response) changed significantly from ?2 ± 6 per cent before prazosin therapy to +5 ± 7 per cent during prazosin therapy (p < 0.01). Exercise duration increased from 368 ± 82 seconds to 476 ± 82 seconds (p < 0.01). Total work capacity measured in kilojoules increased from 12.6 ± 8.3 to 18.6 ± 10.4 (p < 0.01). The improved ejection fraction response during prazosin therapy correlated with the improved work capacity (r = 0.69, p < 0.01) and exercise duration (p = 0.59, p < 0.05). This improvement occurred despite a significant weight gain with prazosin from 72.2 ± 20.8 kg to 73.5 ± 20.8 kg (p < 0.01).These data suggest that long-term prazosin therapy is effective in the treatment of heart failure. However, the beneficial effects of prazosin, an alpha₁ blocking agent, may be evident only during exercise.     

The Effect of Spironolactone on Lipid,Glucose and Uric Acid Levels in Blood during Long-Term Administration to Hypertensives

Spironolactone, an aldosterone antagonist, was given in a daily dose of 100 mg to 15 patients with primary hypertension for one year. Fasting levels of lipids, uric acid, glucose, insulin, potassium and growth hormone were measured before and after 6 and 12 months of treatment. Total cholesterol, LDL cholesterol, glucose, potassium and growth hormone were unchanged, HDL cholesterol fell from (mean±SD) 1.5±0.6 to 1.1 ±0.3 mmol/l (p<0.05) after 6 months of treatment and remained lowered (1.0 ±0.3 mmol/l) (p<0.01) after 12 months of treatment. There was a transient fall after 6 months of treatment in triglycerides from 2.4±1.5 to 2.0±1.1 mmol/l (p < 0.05), uric acid from 380±73 to 342±58 μmol/l (p<0.05) and an increase in insulin from 16±9.5 to 28.6±26.8 mU/l (p<0.05). The blood glucose curves above fasting levels after glucose loading were unchanged during spironolactone treatment, whereas the area under the net insulin curve was higher after 6 months of treatment (163±103 mU · h/l) than before treatment (105±71 mU·h/l), indicating a small and transient insulin resistance. Thus, spironolactone impaired the glucose tolerance transiently and gave small and almost transient changes in fasting serum lipid and uric acid levels.     

Addition of glucagon-like peptide-1 receptor agonist therapy to insulin in C-peptide-positive patients with type 1 diabetes

We aimed to test the hypothesis that addition of glucagon-like peptide-1 receptor agonists (GLP-1RAs) to insulin in C-peptide-positive patients with type 1 diabetes (T1D) will result in a reduction in glycated haemoglobin (HbA1c) with reduced insulin requirements and a rise in C-peptide concentrations. We conducted a retrospective analysis of 11 normal-weight patients with T1D consecutively treated with a GLP-1RA in addition to insulin. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, and C-peptide concentrations prior to and 12 ± 1 weeks after GLP-1RA therapy. At the end of 12 ± 1 weeks of GLP-1RA therapy, HbA1c fell from 10.74 ± 0.96% (95 ± 10.5 mmol/mol) to 7.4 ± 0.58% (58 ± 6.3mmol/mol) (P < 0.01), body weight fell from 71 ± 2.0 to 69 ± 2 kg (P = 0.06), and total insulin dose was reduced by 64% from 33 ± 6 to 11 ± 5 units (P < 0.01). Five out of 10 patients did not require any insulin. C-peptide concentrations increased significantly from 0.43 ± 0.09 ng/ml (0.14 ± 0.02 nmol/L) to 1.42 ± 0.42ng/ml (0.47 ± 0.13 nmol/L) (P = 0.01). Addition of GLP-1RA therapy to insulin in normal-weight patients with T1D led to a reduction in HbA1c with reduced insulin requirements, a 3.5-fold increase in C-peptide concentrations and freedom from insulin therapy in 50% of patients who tolerated the GLP-1RA therapy over a period of 12 ± 1 weeks.     

Effects of long term sulfonylurea therapy on plasma insulin and fasting lipid levels.

Insulin secretion was studied before and after the control of hyperglycemia in fourteen maturity onset male non-obese diabetics. Optimum control of hyperglycemia was achieved by the addition of the sulfonylurea chlorpropamide to dietary treatment. One patient was a primary treatment failure, but nine out of thirteen had excellent control of hyperglycemia. A standardized oral glucose tolerance test (GTT) was performed before and after eight months of individualized therapy with the sulfonylurea. The GTT was repeated with each patient taking his usual dose of chlorpropamide 90 min prior to the administrationo f the glucose load. In the baseline test glucose levels rose from 135.6 +/- 9.9 mg/dl to a peak level of 268.8 +/- 17.7 mg/dl at 120 min. After control of hyperglycemia glucose levels were significantly lower at 0, 30 and 60 min, and rose from 106.8 +/- 8.5 mg/dl to a maximum of 224.5 +/- 17.3 mg/dl at 120 min. Plasma insulin response was unchanged. Fasting serum cholesterol, triglyceride and total lipid levels changed only minimally during therapy. It is concluded that lowered serum glucose levels after long term treatment with chlorpropamide occured while plasma insulin response to glucose was no greater than before treatment. These findings may be explained by an extrapancreatic effect of the drug or by an indirect result of chlorpropamide induced insulin release which occured earlier in the course of therapy.     

Safe and effective treatment of diabetes mellitus associated with chronic liver diseases with an alpha-glucosidase inhibitor, acarbose

Glucose intolerance and diabetes mellitus are both prevalent in patients with chronic liver diseases. We examined the efficacy and systemic safety of therapy with an alpha-glucosidase inhibitor, acarbose, in diabetes mellitus associated with chronic liver diseases. Twenty patients with chronic hepatitis or liver cirrhosis and overt diabetes mellitus received acarbose (taken orally) for 8 weeks. The initial dosage of acarbose was 50mg three times daily, taken before meals; this was increased to 100mg three times daily after 2 weeks. The mean fasting plasma glucose level was 173.7±18.6mg/dl (mean±SE) at entry, and was significantly decreased to 132.9±7.5mg/dl (P<0.05) after 8 weeks of acarbose treatment. The improved glycemic control was reflected by a significant decrease in glycosylated hemoglobin (HbA1c) from 7.2±0.3% at entry to 6.3±0.2% (P<0.05) after 8 weeks. Serum levels of both aspartate and alanine aminotransferases fluctuated during acarbose treatment, probably due to the natural course of chronic liver diseases, but the mean values had decreased after 8 weeks of treatment. Plasma ammonia levels increased, from 61.3±10.7μg/dl to 71.1±9.6μg/dl after 8 weeks of acarbose treatment but the increase was not significant. Clinically significant elevation of plasma ammonia concentration was seen in 2 cirrhotic patients (121 and 124μg/dl); this was asymptomatic and gradually returned to the normal range despite continuous acarbose treatment in one patient, and was reversed after the withdrawal of acarbose with the concomitant administration of lactulose in the other patient. No other blood tests results, including albumin, cholinesterase, and prothrombin time, or lipid profile and nutritional status, in terms of rapid turnover proteins, prealbumin, retinol binding protein, and transferrin, were altered throughout the study period. These results indicate that diabetes mellitus associated with chronic liver diseases may be safely and effectively treated with acarbose. However, clinicians must be aware of the possibility of hyperammonemia when they prescribe acarbose for patients with diabetes mellitus and advanced liver cirrhosis.     

ADRENOCORTICAL FUNCTION IN CHILDREN WITH PRECOCIOUS SEXUAL DEVELOPMENT DURING TREATMENT WITH CYPROTERONE ACETATE

Adrenal function was studied in thirty-two children with precocious sexual development who were being treated with cyproterone acetate (CPA) at doses ranging from 68 to 175 mg. m2. day for periods lasting from 2 to 79 months. In eighteen children the adrenocortical function evaluation was made before and during CPA treatment. In these eighteen patients, the mean basal plasma cortisol level during the morning hours was 11.2 +/- 4.6 micrograms/dl (m +/- SD) before treatment and fell significantly to 7.2 +/- 4.1 micrograms/dl (P less than 0.02) during therapy. In fifteen patients tested during insulin hypoglycaemia the cortisol peak fell from 21.6 +/- 5.5 micrograms/dl before treatment to 16.7 +/- 6.8 micrograms/dl (P less than 0.05) during CPA therapy. There was a significant inverse correlation between this peak and the dose of CPA but no correlation was found between the cortisol response and duration of treatment. In eight of twenty patients tested, urinary free cortisol levels were undetectable during treatment. No change in basal plasma ACTH levels were demonstrated using standard radioimmunoassay techniques. In the patient receiving the highest dose of CPA and showing complete suppression of the adrenal axis, prolonged stimulation with ACTH-Depot demonstrated a responsive adrenal gland. Addition of a replacement dose of cortisol to the CPA treatment led to the rapid development of the typical signs of Cushing's syndrome. It was concluded that despite the evidence of adrenal suppression by CPA, cortisol supplementation is not necessary and may not even be contraindicated.     

Intensive insulin therapy combined with metformin in obese type 2 diabetec patients

Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 ± 3.9 kg/m²) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 ± 0.4 to 7.6 ± 0.3%) and metformin (from 8.5 ± 0.4 to 7.4 ± 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 ± 0.7 to 9.5 ± 0.7 mM) and metformin (from 10.3 ± 0.5 to 9.5 ± 0.6 mM, p = 0.44 vs. placebo) Total exogenous insulin requirements decreased from 53 ± 10 to 35 ± 7 units during metformin treatment (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 ± 18 to 211 ± 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patient improves glycemia but no hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, ∼30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selective obese patients with type 2 diabetes already on intensive insulin therapy. Received: 4 May 1999 / Accepted in revised form: 22 December 1999     

Efficacy of combined use of miglitol in Type 2 diabetes patients receiving insulin therapy-placebo-controlled double-blind comparative study

Combination therapy with an α-glucosidase inhibitor and insulin is commonly performed for type 2 diabetes mellitus. We conducted a placebo-controlled double-blind comparative study to investigate the efficacy of combination therapy with miglitol and insulin. The patients with T2DM on insulin therapy were randomly assigned to either a miglitol treatment group (Group M) or a placebo group (Group P) and treated for 12 weeks. Meal tolerance tests were conducted at the observation period, week 0 and week 12 of the treatment period. Mean values of decrease in 1-h- and 2-h postprandial plasma glucose level were significantly larger in Group M than in Group P (60.3 ± 70.1 mg/dl vs. −5.1 ± 68.2 mg/dl (P < 0.001)), as was HbA1c as well (0.36 ± 0.66% vs. −0.03 ± 0.56% (P < 0.001)). Adverse events included abdominal distension and flatulence, which were significantly more frequent in Group M. The frequency of nocturnal hypoglycemia events tended to be reduced in Group M. Combined use of insulin and miglitol is useful for postprandial glucose regulation and improves glycemic control.     

Feasibility of maintaining normal glucose profiles in insulin-dependent pregnant diabetic women

This study was designed to test the feasibility of a patient-monitored glucose determination program to establish and maintain normal blood glucose levels. Ten pregnant women, who were insulin-dependent diabetics prior to becoming pregnant and who were in their eighth week or less of pregnancy, were offered the program. All 10 accepted and continued the program for the duration of their pregnancy. Normal plasma glucose (60 to 140; x? = 80 mg/dl) levels were achieved after one week of the program and were maintained throughout the pregnancy as documented by 5 to 8 blood glucose determinations a day. The hemoglobin A_1c level, which was elevated in all 10 patients at the start (9.4 ± 1.6 per cent) of the program, fell into the normal range (2 to 5.0 per cent) five weeks after glucose values became normal. Serum estradiol (0.8 ± 0.6 ng/ml), serum prolactin (10 ± 9 ng/ml) and serum human chorionic gonadotropin (5,500 ± 1,700 ng/ml), although all abnormal at the start of the program, became normal after glucose control was achieved (program weeks 4, 5 and 6, respectively). The infants showed no signs of macrosomnia (2,988 ± 959 g), hypoglycemia, hyperbilirubinemia, hypocalcemia, erythremia or respiratory distress. Therefore, a program to maintain normal blood glucose levels during a diabetic patient's pregnancy is not only possible but may also improve the pregnancy and the outcome.     

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 ≤120 mg/dl (46.9 vs. 17.9%) and A1C ≤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.     

Consequences of delayed pump infusion line change in patients with type 1 diabetes mellitus treated with continuous subcutaneous insulin infusion

ObjectiveTo systematically investigate the effect of lack of adherence to the recommended change in insulin pump infusion line use beyond 48 h and determine whether the type of insulin made a difference.Research design and methodsThis was a double-blind, randomized, crossover trial with 20 patients with diabetes mellitus I using insulins aspart and lispro without a line change for up to 100 h. Using retrospective continuous glucose monitoring, we analyzed the average glucose over the day. Changes in serum 1,5-anhydroglucitol, carboxymethyllysine, and free 15-F_2t isoprostane were also studied.ResultsFrom Day 2 to Day 5 of the pump line use, the daily average glucose level increased from 122.7 to 163.9 mg/dl (P<.05), fasting glucose from 120.3 to 154.5 mg/dl (P<.05), postprandial glucose from 114.6 to 172.1 mg/dl (P<.05), and the daily maximum glucose from 207.7 to 242.8 dl (P<.05 for the trend). Time period that the glucose was >180 mg/dl increased from 14.5% to 38.3% (P<.05). Loss of control occurred despite increase in total daily insulin dose from 48.5±11.8 to 55.3±17.9 U (P=.05). There was no difference in loss of control between insulin types, and biomarkers measured did not change significantly.ConclusionsThe insulin pump infusion should be changed every 48 h in patients using continuous subcutaneous insulin infusion (CSII), to avoid loss of glycemic control. In the short-term, this loss of glycemic control has no impact on oxidative stress and glycation.     

Effects of nebivolol therapy on endothelial functions in cardiac syndrome X

Endothelial dysfunction is major pathophysiologic mechanism in cardiac syndrome X (CSX), which causes a decrease in plasma nitrite oxide (NO) levels. It was demonstrated that nebivolol improves endothelial function and increases NO release. Despite this pathophysiologic relation, the effect of nebivolol therapy on endothelial function in patients with CSX is unknown. The aim of this study is to evaluate the effect of nebivolol on patients in CSX. Thirty-eight patients who were diagnosed with CSX were prospectively enrolled in the study. The treatment group consisted of 20 patients and the control group consisted of 18 patients. An oral 5-mg dose of nebivolol was given daily and maintained for 4 weeks in the treatment group. Ultrasonographic parameters (brachial artery flow-mediated dilatation [FMD], brachial artery lumen diameters) and inflammatory markers (high-sensitivity C-reactive protein [hsCRP], von Willebrand factor [vWf], and fibrinogen) were measured at baseline and end of the 4 weeks. Brachial baseline lumen diameter, brachial lumen diameter after reactive hyperemia, and FMD were 4.61 ± 0.49 mm, 4.87 ± 0.53 mm, and 5.6% ± 2.3% at baseline. After the nebivolol therapy, there was a significant increase in both brachial artery baseline lumen diameter and lumen diameter after reactive hyperemia (P < 0.001 and P = 0.002). However, there was no significant change in FMD (5.6% ± 2.2% vs 5.3% ± 2.1%, P not significant). Levels of hsCRP, vWf, and fibrinogen were significantly decreased (hsCRP: 3.4 ± 0.49 mg/dl vs 2.97 ± 0.74 mg/dl, P = 0.001; vWf: 107 ± 62 vs 86 ± 58, P = 0.004; fibrinogen: 341 ± 89 mg/dl vs 299 ± 87 mg/ dl, P = 0.01) in the treatment group. Nebivolol therapy may have a favorable effect on endothelial function in CSX. Further studies are needed to confirm the clinical significance of nebivolol therapy in CSX.     

The effect of gemfibrozil on lipid profile and glucose metabolism in hypertriglyceridaemic well-controlled non-insulin-dependent diabetic patients

We assessed the efficacy of gemfibrozil therapy on lipid profile and glucose metabolism in a large cohort of (type 2) non-insulin-dependent diabetic patients. We enrolled 217 type 2 diabetic patients with plasma triglyceride concentrations equal to or above 2 mmol/l: 110 were randomized to gemfibrozil (600 mg twice daily) and 107 to placebo treatment in a double blind fashion. Each treatment was followed for 20 weeks. To assess postprandial glucose metabolism and insulin secretion, at time 0 and 20 weeks, a standard meal containing 12.5 g of proteins, 40.1 g of carbohydrate, 10 g of lipids was given. No differences in demographic characteristics were observed between patients randomized either to gemfibrozil or to placebo therapy. No differences were observed in total cholesterol and LDL-cholesterol concentration changes between the baseline observations and week 20 of both treatments. At variance, both treatments significantly increased HDL cholesterol. Gemfibrozil treatment significantly decreased plasma triglyceride concentration from 316±84 to 214±82 mg/dl (P < 0.001), whereas with placebo triglyceride levels increased from 318 + 93 to 380 + 217 mg/dl. No changes were observed in non-esterified fatty acid concentrations or in fasting plasma glucose concentrations, in HbA_1C values, insulin and C-peptide concentrations. Gemfibrozil treatment: 1) significantly reduces circulating triglyceride concentration; 2) does not significantly affect cholesterol concentration; 3) does not worsen glucose metabolism. Received: 13 July 1998 / Accepted in revised form: 24 February 1999