Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes

OBJECTIVE: The aim of this study was to test whether vascular reactivity is modified by improving metabolic control and peripheral insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a randomized, double-blind design, we assigned 74 type 2 diabetic patients to rosiglitazone (8 mg/day), metformin (1,500 mg/day), or placebo treatment for 16 weeks and measured insulin sensitivity (euglycemic insulin clamp), ambulatory blood pressure, and forearm blood flow response to 1) intra-arterial acetylcholine (ACh), 2) intra-arterial nitroprusside, 3) the clamp, and 4) blockade of nitric oxide (NO) synthase. RESULTS: Compared with 25 nondiabetic subjects, patients had reduced insulin sensitivity (30 +/- 1 vs. 41 +/- 3 micromol. min(-1). kg fat-free mass(-1); P < 0.001) and reduced maximal response to ACh (586 +/- 42 vs. 883 +/- 81%; P < 0.001). Relative to placebo, 16 weeks of rosiglitazone and metformin similarly reduced fasting glucose (-2.3 +/- 0.5 and -2.3 +/- 0.5 mmol/l) and HbA(1c) (-1.2 +/- 0.3 and -1.6 +/- 0.3%). Insulin sensitivity increased with rosiglitazone (+6 +/- 3 micromol. min(-1). kg fat-free mass(-1); P < 0.01) but not with metformin or placebo. Ambulatory diastolic blood pressure fell consistently (-2 +/- 1 mmHg; P < 0.05) only in the rosiglitazone group. Nitroprusside dose response, clamp-induced vasodilatation, and NO blockade were not affected by either treatment. In contrast, the slope of the ACh dose response improved with rosiglitazone (+40% versus baseline, P < 0.05, +70% versus placebo, P < 0.005) but did not change with either metformin or placebo. This improvement in endothelium-dependent vasodilatation was accompanied by decrements in circulating levels of free fatty acids and tumor necrosis factor-alpha. CONCLUSIONS: At equivalent glycemic control, rosiglitazone, but not metformin, improves endothelium dependent vasodilatation and insulin sensitivity in type 2 diabetes.     

Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin

OBJECTIVE: Nateglinide, a new short-acting D-phenylalanine derivative for treating type 2 diabetes, reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. This study evaluated the pharmacokinetic and pharmacodynamic interactions of nateglinide and metformin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic subjects with the following baseline characteristics were enrolled: age, 56 +/- 13 years; BMI, 28.7 +/- 4.5 kg/m2; HbA1c, 8.4 +/- 1.3%; and fasting plasma glucose 13 +/- 2.8 mmol/l. All subjects had been previously treated with glyburide and were switched to metformin monotherapy for 3 weeks before study start. Subjects then randomly received, in combination with 500 mg metformin, either 120 mg nateglinide or placebo before meals for 1 day, followed by the alternate treatment 7 days later. After 1 week of washout from both drugs, subjects received 1 day of open-label nateglinide treatment. Plasma concentrations of glucose, insulin, nateglinide, and metformin were assessed frequently during inpatient periods. RESULTS: Postmeal plasma glucose levels were significantly lower in subjects treated with nateglinide plus metformin than in those treated with either drug alone (P < 0.001), especially after lunch and dinner. Coadministration of nateglinide and metformin did not affect the pharmacokinetics of either drug. All treatments were safe and well tolerated. CONCLUSIONS: Combination therapy with nateglinide and metformin was more effective than either treatment alone and did not result in any pharmacokinetic interactions. Coadministration of nateglinide and metformin appears to be an excellent option for treating patients with type 2 diabetes not controlled with monotherapy.     

Effect of pinitol treatment on insulin action in subjects with insulin resistance

OBJECTIVE: Endogenous low-molecular-weight glycans containing pinitol (3-O-methyl-D-chiro-inositol) and D-chiro-inositol are thought to mediate certain actions of insulin. We tested the hypothesis that oral administration of soybean-derived pinitol would improve insulin sensitivity in obese subjects (BMI = 36.6 kg/m2) with diet-treated type 2 diabetes or glucose intolerance (HbA1c = 6.8%). RESEARCH DESIGN AND METHODS: There were 22 subjects randomized to receive either pinitol 20 mg x kg(-1) x day(-1) (n = 12) or placebo (n = 10) in a 28-day double-blinded trial. RESULTS: No toxicity due to the pinitol was observed during the study The sensitivity of glucose and lipid metabolism to insulin were assessed by measurement of whole-body glucose, palmitate, and glycerol kinetics during basal conditions and a hyperinsulinemic-euglycemic clamp. Metabolic measurements were made at baseline and again at the end of the study Final plasma levels of pinitol were 48-fold (1.06 +/- 0.15 vs. 0.02 +/- 0.01 micromol/l, P < 0.0001) and D-chiro-inositol levels 14-fold (0.56 +/- 0.08 vs. 0.04 +/- 0.02 micromol/l, P < 0.0001) greater in the pinitol group compared with placebo. CONCLUSIONS: Four weeks of pinitol treatment did not alter baseline glucose production, insulin-mediated glucose disposal, or rates of appearance of free fatty acids and glycerol in plasma. We conclude that plasma levels of both pinitol and D-chiro-inositol are very responsive to pinitol ingestion, but insulin sensitivity does not increase after pinitol treatment in individuals with obesity and mild type 2 diabetes.     

Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year

OBJECTIVE: To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related beta-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a 12-week core study, placebo (n = 51) or vildagliptin (n = 56; 50 mg OD) was added to metformin treatment (1.5-3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated. RESULTS: In subjects completing 52 weeks with participation in all meal tests (n = 57), HbA(1c) (A1C) decreased in the vildagliptin/metformin group (VM group, n = 31) but increased in the placebo/metformin group (PM group, n = 26; between-group difference -1.0 +/- 0.2%; P < 0.001; baseline of all subjects combined 7.7 +/- 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference -0.9 +/- 0.3 mmol/l, P = 0.016; baseline 9.8 +/- 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0- to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference +0.011 +/- 0.03 pmol/l 30 min/mmol/l, P = 0.018; baseline 0.036 +/- 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference +27 +/- 4 ml x min(-1) x m(-2), P = 0.036; baseline 246 +/- 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference +3.2 +/- 1.0, P = 0.040; baseline 9.1 +/- 0.5). The change in adaptation index correlated to the change in A1C (r = -0.39, P = 0.004). CONCLUSIONS: This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves beta-cell function along with improved postmeal insulin sensitivity.     

Effects of metformin and rosiglitazone monotherapy on insulin-mediated hepatic glucose uptake and their relation to visceral fat in type 2 diabetes

OBJECTIVE: Impaired insulin-mediated hepatic glucose uptake (HGU) has been implicated in the hyperglycemia of type 2 diabetes. We examined the effects of metformin (2 g/day) and rosiglitazone (8 mg/day) monotherapy on HGU and its relation to subcutaneous fat, visceral fat (VF), and whole-body insulin-mediated glucose metabolism in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Glucose uptake was measured before and after 26 weeks of treatment using positron emission tomography with [(18)F]2-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia; fat depots were quantified by magnetic resonance imaging. RESULTS: Fasting plasma glucose levels were significantly decreased after either rosiglitazone (-0.9 +/- 0.5 mmol/l) or metformin treatment (-1.1 +/- 0.5 mmol/l) in comparison with placebo; only metformin was associated with weight loss (P < 0.02 vs. placebo). When controlling for the latter, the placebo-subtracted change in whole-body glucose uptake averaged -1 +/- 4 micromol x min(-1) x kg(-1) in metformin-treated patients (NS) and +9 +/- 3 micromol x min(-1) x kg(-1) in rosiglitazone-treated patients (P = 0.01). Both rosiglitazone and metformin treatment were associated with an increase in HGU; versus placebo, the change reached statistical significance when controlling for sex (placebo-subtracted values = +0.008 +/- 0.004 micromol x min(-1) x kg(-1) x pmol/l(-1), P < 0.03, for metformin; and +0.007 +/- 0.004, P < 0.07, for rosiglitazone). After treatment with either drug, insulin-mediated VF glucose uptake (VFGU) was higher than with placebo. In the whole dataset, changes in HGU were negatively related to changes in HbA(1c) (r = 0.43, P = 0.01) and positively associated with changes in VFGU (r = 0.48, P < 0.01). CONCLUSIONS: We conclude that both metformin and rosiglitazone monotherapy increase HGU in type 2 diabetes; direct drug actions, better glycemic control, and enhanced VF insulin sensitivity are likely determinants of this phenomenon.     

Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial

OBJECTIVE: Mealtime amylin replacement with the human amylin analog pramlintide, as an adjunct to mealtime insulin replacement, reduces postprandial glucose excursions in patients with type 2 diabetes. The aim of the present study was to assess the long-term efficacy and safety of pramlintide in this patient population. RESEARCH DESIGN AND METHODS: In a 52-week, double-blind, placebo-controlled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 +/- 10 years, diabetes duration 12 +/- 7 years, BMI 34.0 +/- 7.0 kg/m(2), HbA(1c) 9.1 +/- 1.2%, mean +/- SD) treated with insulin (alone or in combination with sulfonylureas and/or metformin) were randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 micro g TID, 90 microg BID, or 120 microg BID). RESULTS: Treatment with pramlintide 120 micro g BID led to a sustained reduction from baseline in HbA(1c) (-0.68 and -0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P < 0.05). The proportion of patients achieving an HbA(1c) <8% was approximately twofold greater with pramlintide (120 microg BID) than with placebo (46 vs. 28%, P < 0.05). The glycemic improvement with pramlintide 120 micro g BID was accompanied by a mean weight loss (-1.4 kg vs. +0.7 kg with placebo at week 52, P < 0.05) and occurred without an overall increase in the severe hypoglycemia event rate. The most common adverse event associated with pramlintide use was transient, mild-to-moderate nausea. CONCLUSIONS: Mealtime amylin replacement with pramlintide 120 microg BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes.     

Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes

OBJECTIVE: To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment. RESEARCH DESIGN AND METHODS: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n=51) or LAF237 (50 mg once daily, n=56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52. RESULTS: In patients randomized to LAF237, baseline HbA1c averaged 7.7 +/- 0.1% and decreased at week 12 (Delta=-0.6 +/- 0.1%), whereas HbA1c did not change from a baseline of 7.9 +/- 0.1% in patients given placebo (between-group difference in DeltaHbA1c=-0.7 +/- 0.1%, P <0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 +/- 0.4 mmol/l (P <0.0001) and 1.2 +/- 0.4 mmol/l (P=0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 +/- 0.6 mmol/l (P=0.0001), 40 +/- 16 pmol/l (P=0.0153), and -1.1 +/- 0.5 mmol/l (P=0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n=42) but increased in participants given placebo (n=29). The between-group difference in DeltaHbA1c after 1 year was -1.1 +/- 0.2% (P <0.0001). CONCLUSIONS: Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes.     

Treatment of type 2 diabetes in childhood using a very-low-calorie diet

OBJECTIVE: Pharmacologic agents currently approved for use in children with type 2 diabetes (metformin and insulin) are less than optimal for some patients. We evaluated the use of a ketogenic, very-low-calorie diet (VLCD) in the treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a chart review of 20 children (mean age 14.5 +/- 0.4 years) who consumed a ketogenic VLCD in the treatment of type 2 diabetes. Several response variables (BMI, blood pressure, HbA(1c), blood glucose, and treatment regimens) were examined before, during, and up to 2 years after the diet and compared with a matched diabetic control group. RESULTS: Before starting the diet, 11 of 20 patients were treated with insulin and 6 with metformin. Mean daily blood glucose values fell from 8.9 +/- 1.1 to 5.5 +/- 0.38 mmol/l (P < 0.0001) in the first 3 days of the VLCD, allowing insulin and oral agents to be discontinued in all but one subject. BMI fell from 43.5 +/- 1.8 to 39.3 +/- 1.8 kg/m(2) (P < 0.0001) and HbA(1c) dropped from 8.8 +/- 0.6 to 7.4 +/- 0.6% (P < 0.005) as the diet was continued for a mean of 60 +/- 8 days (range 4-130 days), and none required resumption of antidiabetic medications. Sustained decreases in BMI and insulin requirements were observed in patients remaining on the VLCD for at least 6 weeks when compared with those of the control group. CONCLUSIONS: The ketogenic VLCD is an effective short-term, and possibly long-term, therapy for pediatric patients with type 2 diabetes. Blood glucose control and BMI improve, allowing the discontinuation of exogenous insulin and other antidiabetic agents. This diet, although strict, has potential as an alternative to pharmacologic therapies for this emerging subset of diabetic individuals.     

Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes

OBJECTIVE: This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS: A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m(2) and HbA(1c) of 8.2 +/- 1.1%. After 4 weeks of placebo, subjects self-administered 5 microg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 microg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy. RESULTS: At week 30, HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg), -0.40 +/- 0.11% (5 microg), and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 microg), 32% (5 microg), and 13% (placebo) achieved HbA(1c) < or =7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg], -1.6 +/- 0.4 kg [5 microg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia. CONCLUSIONS: Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.     

Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes

OBJECTIVE: To investigate the dose-response effects of pioglitazone on glycemic control, insulin sensitivity, and insulin secretion in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 58 diet-treated patients with type 2 diabetes (aged 54 +/- 1 years; 34 men and 24 women; BMI 31.5 +/- 0.6 kg/m(2)) were randomly assigned to receive placebo (n=11) or 7.5 mg (n=13), 15 mg (n=12), 30 mg (n=11), or 45 mg (n=11) of pioglitazone per day for 26 weeks. Before and after 26 weeks, subjects underwent a 75-g oral glucose tolerance test (OGTT). RESULTS: Patients treated with 7.5 or 15 mg/day of pioglitazone had no change in fasting plasma glucose (FPG) and fasting plasma insulin (FPI) concentrations or in plasma glucose (PG) and insulin concentrations during the OGTT. Patients treated with 30 and 45 mg/day of pioglitazone, respectively, had significant decreases from placebo in HbA1c (delta=-2.0 and -2.9%), FPG (delta=-66 and -97 mg/dl), and mean PG during OGTT (delta=-84 and -107 mg/dl). Fasting plasma insulin decreased significantly in the 45-mg/day pioglitazone group, but the mean plasma insulin during the OGTT did not change. The insulinogenic index (delta area under the curve [AUC] insulin/deltaAUC glucose) during the OGTT increased significantly in the 30- and 45-mg/day pioglitazone groups (0.13 +/- 0.03 to 0.27 +/- 0.05, P < 0.05). From the OGTT, we previously have derived a composite whole-body insulin sensitivity index (ISI) that correlates well with that measured directly with the insulin clamp technique. Whole-body ISI [ISI=10,000/(square-root (FPG x FPI) x (PG x PI)) where PG and PI equal mean plasma glucose and insulin concentrations during OGTT] increased significantly in patients treated with 30 mg (1.8 +/- 0.3 to 2.5 +/- 0.3, P < 0.05) or 45 mg (1.6 +/- 0.2 to 2.7 +/- 0.6, P < 0.05) per day of pioglitazone. In the basal state, the hepatic ISI [k/(FPG x FPI)[k/(FPG x FPI)], which agrees closely with that measured directly with tritiated glucose, increased in patients treated with 30 mg (0.13 +/- 0.02 to 0.21 +/- 0.03, P < 0.05) and 45 mg (0.11 +/- 0.02 to 0.24 +/- 0.06, P < 0.05) per day of pioglitazone. Significant correlations between the dose of pioglitazone and the changes in HbA1c (r=-0.58), FPG (r=-0.47), mean PG during the OGTT (r=-0.46), insulinogenic index (r=0.34), hepatic ISI (r=0.44), and whole-body ISI (r=0.36) were observed. CONCLUSIONS: Pioglitazone improves glycemic control through the dose-dependent enhancement of beta-cell function and improved whole-body and hepatic insulin sensitivity.     

Effect of acarbose on insulin sensitivity in elderly patients with diabetes

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on insulin release and insulin sensitivity in elderly patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Elderly patients with type 2 diabetes were randomly treated in a double-blind fashion with placebo (n = 23) or acarbose (n = 22) for 12 months. Before and after randomization, subjects underwent a meal tolerance test and a hyperglycemic glucose clamp study designed to measure insulin release and sensitivity. RESULTS: After 12 months of therapy there was a significant difference in the change in fasting plasma glucose levels (0.2 +/- 0.3 vs. -0.5 +/- 0.2 mmol/l, placebo vs. acarbose group, respectively; P < 0.05) and in incremental postprandial glucose values (-0.4 +/- 0.6 vs. -3.5 +/- 0.6 mmol/l, placebo vs. acarbose group, P < 0.001) between groups. There was a significant difference in the change in HbA(1c) values in response to treatment (0.4 +/- 0.2 vs. -0.4 +/- 0.1%, placebo vs. acarbose group, P < 0.01). The change in fasting insulin in response to treatment (-2 +/- 2 vs. -13 +/- 4 pmol/l, placebo vs. acarbose group, P < 0.05) and incremental postprandial insulin responses (-89 +/- 26 vs. -271 +/- 59 pmol/l, placebo vs. acarbose group, P < 0.01) was also significantly different between groups. During the hyperglycemic clamps, glucose and insulin values were similar in both groups before and after therapy However, there was a significant difference in the change in insulin sensitivity in response to treatment between the placebo and the acarbose groups (0.001 +/- 0.001 vs. 0.004 +/- 0.001 mg/kg x min(-1) [pmol/l](-1), respectively, P < 0.05) CONCLUSIONS: Acarbose increases insulin sensitivity but not insulin release in elderly patients with diabetes.     

Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: A 1-year randomized controlled trial

OBJECTIVE; Weight loss improves glycemic control, lipid profiles, and blood pressure in patients with type 2 diabetes. However, successful long-term weight loss is difficult for these patients, particularly those treated with insulin. The aim of this study was to assess the effect of orlistat, a gastrointestinal lipase inhibitor, on weight loss, glycemic control, and cardiovascular risk factors in overweight or obese insulin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS: This study was a 1-year multicenter, randomized, double-blind, placebo-controlled trial of orlistat (120 mg three times a day) or placebo combined with a reduced-calorie diet in overweight or obese adults (BMI 28-40 kg/m(2)) with type 2 diabetes treated with insulin alone or combined with oral agents, but with suboptimal metabolic control (HbA(1c) 7.5-12.0%). Outcome measurements included changes in body weight, glycemic control, blood pressure, and serum lipids. RESULTS; After 1 year, the orlistat group lost significantly more weight (-3.89 +/- 0.3% of baseline body weight, means +/- SE) than the placebo group (-1.27 +/- 0.3%, P < 0.001). Orlistat treatment, compared with placebo, produced greater decreases in HbA(1c) (-0.62 +/- 0.08 vs. -0.27 +/- 0.08%, P = 0.002), fasting serum glucose (-1.63 +/- 0.3 vs. -1.08 +/- 0.3 mmol/l, P = 0.02), and the required doses of insulin and other diabetic medications. Orlistat also produced greater improvements than placebo in serum total cholesterol (P = 0.0002) and LDL cholesterol concentrations (P = 0.001) and LDL/HDL ratio (P = 0.01). CONCLUSIONS; Orlistat therapy produces clinically significant weight loss, with improvements in glycemic control and cardiovascular disease risk factors, in overweight or obese patients with type 2 diabetes who have suboptimal metabolic control with insulin therapy.     

Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) is an insulinotropic gut hormone that, when given exogenously, may be a useful agent in the treatment of type 2 diabetes. We conducted a 3-month trial to determine the efficacy and safety of GLP-1 in elderly diabetic patients. RESEARCH DESIGN AND METHODS: A total of 16 patients with type 2 diabetes who were being treated with oral hypoglycemic agents were enrolled. Eight patients (aged 75 +/- 2 years, BMI 27 +/- 1 kg/m(2)) remained on usual glucose-lowering therapy and eight patients (aged 73 +/- 1 years, BMI 27 +/- 1 kg/m(2)), after discontinuing hypoglycemic medications, received GLP-1 delivered by continuous subcutaneous infusion for 12 weeks. The maximum dose was 120 pmol x kg(-1). h(-1). Patients recorded their capillary blood glucose (CBG) levels (four times per day, 3 days per week) and whenever they perceived hypoglycemic symptoms. The primary end points were HbA(1c) and CBG determinations. Additionally, changes in beta-cell sensitivity to glucose, peripheral tissue sensitivity to insulin, and changes in plasma ghrelin levels were examined. RESULTS: HbA(1c) levels (7.1%) and body weight were equally maintained in both groups. The usual treatment group had a total of 87 CBG measurements of 相似文献   

Combined metformin and insulin therapy for patients with type 2 diabetes mellitus

OBJECTIVE: This study was undertaken to assess the effects of combined treatment with insulin and metformin in patients with type 2 diabetes mellitus in whom dietary measures, weight control, and oral antihyperglycemic therapy had failed. BACKGROUND: Insulin resistance in peripheral tissues, increased hepatic gluconeogenesis, and impaired insulin secretion are the underlying factors in the development of type 2 diabetes. Metformin is a biguanide antihyperglycemic agent that increases peripheral insulin sensitivity, reduces hepatic gluconeogenesis, and decreases intestinal glucose absorption. METHODS: Thirty-one patients (24 women, 7 men; mean age, 61.8 years; mean body mass index [BMI], 28.0 kg/m2) were enrolled in this randomized, double-blind, 2-way, crossover, placebo-controlled study. Patients with type 2 diabetes who were treated previously with insulin or oral hypoglycemic agents and who had a glycosylated hemoglobin (HbA1c) level >9% or a fasting blood glucose level >8 mmol/L were included. Patients who were being treated with oral agents were switched to insulin therapy and required to maintain stable blood glucose control for 2 months prior to randomization. Patients received insulin plus either metformin 1,700 mg/d or placebo for 5 months, followed by a 2-month washout period, and were then crossed over to the other treatment arm for 5 months of additional treatment (total treatment period: 12 months). RESULTS: Thirty patients completed the study; 1 patient withdrew early because of hypoglycemia. Compared with placebo, metformin produced significant reductions from overall baseline in mean daily insulin dose requirement (-8.69 units (17.2%], P < 0.001), HbA1c level (-0.74 [9.9%], P = 0.005), serum fructosamine level (-44.40 micromol/L, P = 0.026), 24-hour blood glucose profile (P = 0.008), and total cholesterol level (-0.42 mmol/L, P = 0.005). No treatment effects were observed on body weight, blood pressure, serum high-density lipoprotein cholesterol levels, or serum triglyceride levels. There was no correlation between BMI and reduction in HbA1C. No major side effects were reported. CONCLUSIONS: Combination therapy with metformin and insulin improves glycemic control and reduces insulin requirements. with no major side effects, in patients with type 2 diabetes and may improve the risk profile in this patient population.     

Youth type 2 diabetes: insulin resistance, beta-cell failure, or both?

OBJECTIVE: This study evaluates insulin sensitivity, pancreatic beta-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA(1c) to insulin sensitivity and BCF. RESEARCH DESIGN AND METHODS: The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU . m(-2) . min(-1)) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-(2)H(2)]glucose. RESULTS: Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 +/- 1.1 vs. 12.3 +/- 0.5 micromol . kg(-1) . min(-1); P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 +/- 0.1 vs. 2.0 +/- 0.2 micromol . kg(-1) . min(-1) per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 +/- 24.6 vs. 220.2 +/- 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 +/- 42.0 vs. 1,365.0 +/- 111.0 pmol/l; SPIS: 652.2 +/- 88.8 vs. 1,376.4 +/- 88.8 pmol/l; P < 0.001 for both). The glucose disposition index (GDI = insulin sensitivity x FPIS) was approximately 86% lower in type 2 diabetic patients than in obese control subjects. HbA(1c) correlated with FPIS (r = -0.61, P = 0.025) with no relationship to insulin sensitivity. CONCLUSIONS: Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA(1c) may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of beta-cell failure and means of retarding and/or preventing it.     

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.     

Initiating insulin therapy in type 2 Diabetes: a comparison of biphasic and basal insulin analogs

OBJECTIVE: Safety and efficacy of biphasic insulin aspart 70/30 (BIAsp 70/30, prebreakfast and presupper) were compared with once-daily insulin glargine in type 2 diabetic subjects inadequately controlled on oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS: This 28-week parallel-group study randomized 233 insulin-naive patients with HbA(1c) values >/=8.0% on >1,000 mg/day metformin alone or in combination with other OADs. Metformin was adjusted up to 2,550 mg/day before insulin therapy was initiated with 5-6 units BIAsp 70/30 twice daily or 10-12 units glargine at bedtime and titrated to target blood glucose (80-110 mg/dl) by algorithm-directed titration. RESULTS: A total of 209 subjects completed the study. At study end, the mean HbA(1c) value was lower in the BIAsp 70/30 group than in the glargine group (6.91 +/- 1.17 vs. 7.41 +/- 1.24%, P < 0.01). The HbA(1c) reduction was greater in the BIAsp 70/30 group than in the glargine group (-2.79 +/- 0.11 vs. -2.36 +/- 0.11%, respectively; P < 0.01), especially for subjects with baseline HbA(1c) >8.5% (-3.13 +/- 1.63 vs. -2.60 +/- 1.50%, respectively; P < 0.05). More BIAsp 70/30-treated subjects reached target HbA(1c) values than glargine-treated subjects (HbA(1c) 8.5%.     

Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.

OBJECTIVE: To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period. RESULTS: In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). CONCLUSIONS: Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.     

Repaglinide versus metformin in combination with bedtime NPH insulin in patients with type 2 diabetes established on insulin/metformin combination therapy

OBJECTIVE: To compare the effect on glycemic control and weight gain of repaglinide versus metformin combined with bedtime NPH insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 80 subjects treated with 850 or 1,000 mg t.i.d. metformin combined with bedtime NPH insulin were randomized to 13 weeks of open-label treatment with 4 mg t.i.d. repaglinide (n = 39) or metformin (dose unchanged) (n = 41). Insulin dose was titrated at the clinician's discretion, aiming for a fasting blood glucose (FBG) < or =6.0 mmol/l. RESULTS: Baseline age, diabetes duration, insulin requirement, weight, BMI, FBG, and HbA(1c) (Diabetes Control and Complications Trial-aligned assay, normal range 4.6-6.2%) were similar. Glycemic control improved (nonsignificantly) with insulin/metformin by (mean) 0.4%, from 8.4 to 8.1% (P = 0.09) but deteriorated with insulin/repaglinide by (mean) 0.4%, from 8.1 to 8.6% (P = 0.03; P = 0.005 between groups). Weight gain was less with insulin/metformin: 0.9 +/- 0.4 kg (means +/- SE) (P = 0.01) versus 2.7 +/- 0.4 kg (P < 0.0001) (P = 0.002 between groups). The Diabetes Treatment Satisfaction Questionnaire score (potential range 0 [minimum] to 36 [maximum]) increased from 32.4 +/- 0.8 to 34.1 +/- 0.5 (P = 0.01) with insulin/metformin but decreased from 32.5 +/- 0.9 to 29.1 +/- 1.3 (P < 0.002) with insulin/repaglinide. CONCLUSIONS: Combined with bedtime NPH insulin, metformin provides superior glycemic control to repaglinide with less weight gain and improved diabetes treatment satisfaction.     

Efficacy of Ipomoea batatas (Caiapo) on diabetes control in type 2 diabetic subjects treated with diet

OBJECTIVE: To investigate the tolerability, efficacy, and mode of action of Caiapo, an extract of white sweet potatoes, on metabolic control in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 61 type 2 diabetic patients treated by diet were given 4 g Caiapo (n = 30; mean age 55.2 +/- 2.1 years; BMI 28.0 +/- 0.4 kg/m(2)) or placebo (n = 31; mean age 55.6 +/- 1.5 years; BMI 27.6 +/- 0.3 kg/m(2)) once daily for 12 weeks. Each subject underwent a 75-g oral glucose tolerance test (OGTT) at baseline and after 1, 2, and 3 months to assess 2-h glucose levels. Additionally, fasting blood glucose, HbA(1c), total cholesterol, and triglyceride levels were measured. RESULTS: After treatment with Caiapo, HbA(1c) decreased significantly (P < 0.001) from 7.21 +/- 0.15 to 6.68 +/- 0.14%, whereas it remained unchanged (P = 0.23) in subjects given placebo (7.04 +/- 0.17 vs. 7.10 +/- 0.19%). Fasting blood glucose levels decreased (P < 0.001) in the Caiapo group (143.7 +/- 1.9 vs. 128.5 +/- 1.7 mg/dl) and did not change in the placebo group (144.3 +/- 1.9 vs. 138.2 +/- 2.1 mg/dl; P = 0.052). A decrease in body weight was observed in both the placebo group (P = 0.0027) and in the Caiapo group (P < 0.0001), probably due to a better- controlled lifestyle. In the Caiapo group, body weight was related to the improvement in glucose control (r = 0.618; P < 0.0002). Two-hour glucose levels were significantly (P < 0.001) decreased in the Caiapo group (193.3 +/- 10.4 vs. 162.8 +/- 8.2 mg/dl) compared with the placebo group (191.7 +/- 9.2 vs. 181.0 +/- 7.1 mg/dl). Mean cholesterol at the end of the treatment was significantly lower in the Caiapo group (214.6 +/- 11.2 mg/dl) than in the placebo group (248.7 +/- 11.2 mg/dl; P < 0.05). No significant changes in triglyceride levels or blood pressure were observed, and Caiapo was well tolerated without significant adverse effects. CONCLUSIONS: This study confirms the beneficial effects of Caiapo on plasma glucose as well as cholesterol levels in patients with type 2 diabetes. For the first time, the long-term efficacy of Caiapo on glucose control was demonstrated by the observed decrease in HbA(1c). Thus, the neutraceutical Caiapo seems to be a useful agent in the treatment of type 2 diabetes.