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OBJECTIVE To evaluate the efficacy and long-term safety of linagliptin added to basal insulins in type 2 diabetes inadequately controlled on basal insulin with or without oral agents. RESEARCH DESIGN AND METHODS A total of 1,261 patients (HbA1c ≥7.0% [53 mmol/mol] to ≤10.0% [86 mmol/mol]) on basal insulin alone or combined with metformin and/or pioglitazone were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo for ≥52 weeks. The basal insulin dose was kept unchanged for 24 weeks but could thereafter be titrated according to fasting plasma glucose levels at the investigators’ discretion. The primary end point was the mean change in HbA1c from baseline to week 24. The safety analysis incorporated data up to a maximum of 110 weeks. RESULTS At week 24, HbA1c changed from a baseline of 8.3% (67 mmol/mol) by −0.6% (−6.6 mmol/mol) and by 0.1% (1.1 mmol/mol) with linagliptin and placebo, respectively (treatment difference −0.65% [95% CI −0.74 to −0.55] [−7.1 mmol/mol]; P < 0.0001). Despite the option to uptitrate basal insulin, it was adjusted only slightly upward (week 52, linagliptin 2.6 IU/day, placebo 4.2 IU/day; P < 0.003), resulting in no further HbA1c improvements. Frequencies of hypoglycemia (week 24, linagliptin 22.0%, placebo 23.2%; treatment end, linagliptin 31.4%, placebo 32.9%) and adverse events (linagliptin 78.4%, placebo 81.4%) were similar between groups. Mean body weight remained unchanged (week 52, linagliptin −0.30 kg, placebo −0.04 kg). CONCLUSIONS Linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight.

Regarding the question of how to use insulin in type 2 diabetes, a systematic review conforming to methods of the Cochrane collaboration was published in 2006 (1). This review included studies published in Medline until May 2004. The analysis compared insulin monotherapy with combination therapy with insulin and oral hypoglycemic agent (OHA) in previously insulin-naive patients. With use of the methods detailed in the review (1), 13 randomized controlled trials (RCTs) could be identified and included 1,811 participants with a mean age of 60 years and duration of diabetes of 10 years. The authors concluded that bedtime NPH insulin combined with oral antihyperglycemic agents provides glycemic control comparable with that provided by insulin monotherapy with twice daily insulin or basal/bolus insulin regimens but is associated with less weight gain if metformin is used. However, since May 2004 there has been an exponential increase in the number of patients participating in RCTs comparing basal insulin plus OHA with other insulin regiments with similar OHA (vide infra). Such studies have become possible thanks to the development of rapid- and long-acting insulin analogs and commercial support for studies addressing insulin therapy. This review focuses on comparison of different insulin treatment regimens in both insulin-naive (first objective) and previously insulin-treated (second objective) patients with type 2 diabetes. We wished to examine whether there is an advantage (glycemic control, weight gain, or hypoglycemia) of using premixed and basal-bolus regimens with or without OHA compared with basal insulin and OHA. For the first objective, we used the principles outlined in the previous Cochrane review (1) to compare glycemic control between basal insulin/OHA and other regimens. The latter included regimens with premixed insulin twice daily with or without OHA or regimens using prandial insulin three times daily or multiple insulin injection therapy (basal and prandial three times …

OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P < 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

OBJECTIVE—The purpose of this study was to determine whether type 2 diabetic patients have more liver fat than age-, sex-, and BMI-matched nondiabetic subjects and whether liver enzymes (serum alanine aminotransferase [S-ALT] and serum aspartate aminotransferase) are similarly related to liver fat in type 2 diabetic patients and normal subjects. RESEARCH DESIGN AND METHODS—Seventy type 2 diabetic patients and 70 nondiabetic subjects matched for BMI, age, and sex were studied. Liver fat (1H-magnetic resonance spectroscopy), body composition (magnetic resonance imaging), and biochemical markers of insulin resistance were measured. RESULTS—The type 2 diabetic patients had, on average, 80% more liver fat and 16% more intra-abdominal fat than the nondiabetic subjects. The difference in liver fat between the two groups remained statistically significant when adjusted for intra-abdominal fat (P < 0.05). At any given BMI or waist circumference, the type 2 diabetic patients had more liver fat than the nondiabetic subjects. The difference in liver fat between the groups rose as a function of BMI and waist circumference. Fasting serum insulin (r = 0.55, P < 0.0001), fasting plasma glucose (r = 0.29, P = 0.0006), A1C (r = 0.34, P < 0.0001), fasting serum triglycerides (r = 0.36, P < 0.0001), and fasting serum HDL cholesterol (r = −0.31, P = 0.0002) correlated with liver fat similarly in both groups. The slopes of the relationships between S-ALT and liver fat were significantly different (P = 0.004). Liver fat content did not differ between the groups at low S-ALT concentrations (10–20 units/l) but was 70–200% higher in type 2 diabetic patients compared with control subjects at S-ALT concentrations of 50–200 units/l. CONCLUSIONS—Type 2 diabetic patients have 80% more liver fat than age-, weight-, and sex-matched nondiabetic subjects. S-ALT underestimates liver fat in type 2 diabetic patients.

OBJECTIVE—Insulin is often postponed for years because initiation is time-consuming. We sought to compare initiation of insulin individually and in groups with respect to change in A1C and several other parameters in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A randomized (1:1), multicenter, two-arm, parallel design study with a recruiting period of up to 14 weeks and a 24-week treatment period. Either in groups of 4–8 or individually, using the same personnel and education program, 121 insulin-naive type 2 diabetic patients with an A1C of 7.0–12.0% were randomized to initiate bedtime insulin glargine. The patients visited the treatment center before and at the time of insulin initiation and at 6, 12, and 24 weeks. Patients self-adjusted the insulin dose to achieve a fasting plasma glucose 4.0–5.5 mmol/l. RESULTS—At 24 weeks, mean ± SE A1C had decreased from 8.7 ± 0.2 to 6.9 ± 0.1% in those treated individually and from 8.8 ± 0.2 to 6.8 ± 0.1% in those in groups (not significant [NS]). Insulin doses averaged 62 ± 5 IU and 56 ± 5 IU at 24 weeks (NS), respectively. The frequency of hypoglycemia was similar. The total time (visits and phone calls) spent in initiating insulin in the patients in groups (2.2 ± 0.1 h) was 48% less than in those treated individually (4.2 ± 0.2 h). Diabetes treatment satisfaction improved significantly in both sets of patients. CONCLUSIONS—Similar glycemic control and treatment satisfaction can be achieved by initiating insulin in groups and individually. Starting insulin in groups takes one-half as much time as individual initiation.

OBJECTIVE—To compare the efficacy and safety of adding once-daily basal insulin versus switching to twice-daily premixed insulin in type 2 diabetic patients insufficiently controlled by oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS—In a 24-week, multinational, multicenter, open, parallel group clinical trial, 371 insulin-naïve patients with poor glycemic control (fasting blood glucose [FBG] ≥120 mg/dl, HbA1c 7.5–10.5%) on OADs (sulfonylurea plus metformin) were randomized to once-daily morning insulin glargine plus glimepiride and metformin (glargine plus OAD) or to 30% regular/70% human NPH insulin (70/30) twice daily without OADs. Insulin dosage was titrated to target FBG ≤100 mg/dl (both insulins) and predinner blood glucose ≤100 mg/dl (70/30 only) using a weekly forced-titration algorithm. RESULTS—Mean HbA1c decrease from baseline was significantly more pronounced (−1.64 vs. −1.31%, P = 0.0003), and more patients reached HbA1c ≤7.0% without confirmed nocturnal hypoglycemia (45.5 vs. 28.6%, P = 0.0013) with glargine plus OAD than with 70/30. Similarly, FBG decrease was greater with glargine plus OAD (adjusted mean difference −17 mg/dl [–0.9 mmol/l], P < 0.0001), and more patients reached target FBG ≤100 mg/dl with glargine plus OAD than with 70/30 (31.6 vs. 15.0%, P = 0.0001). Glargine plus OAD patients had fewer confirmed hypoglycemic episodes than 70/30 patients (mean 4.07 vs. 9.87/patient-year, P < 0.0001). CONCLUSIONS—Initiating insulin treatment by adding basal insulin glargine once daily to glimepiride plus metformin treatment was safer and more effective than beginning twice-daily injections of 70/30 and discontinuing OADs in type 2 diabetic patients inadequately controlled with OADs.

OBJECTIVE—The intake of antioxidants was studied for its ability to predict type 2 diabetes. RESEARCH DESIGN AND METHODS—A cohort of 2,285 men and 2,019 women 40–69 years of age and free of diabetes at baseline (1967–1972) was studied. Food consumption during the previous year was estimated using a dietary history interview. The intake of vitamin C, four tocopherols, four tocotrienols, and six carotenoids was calculated. During a 23-year follow-up, a total of 164 male and 219 female incident cases occurred. RESULTS—Vitamin E intake was significantly associated with a reduced risk of type 2 diabetes. The relative risk (RR) of type 2 diabetes between the extreme quartiles of the intake was 0.69 (95% CI 0.51–0.94, P for trend = 0.003). Intakes of α-tocopherol, γ-tocopherol, δ-tocopherol, and β-tocotrienol were inversely related to a risk of type 2 diabetes. Among single carotenoids, β-cryptoxanthin intake was significantly associated with a reduced risk of type 2 diabetes (RR 0.58, 95% CI 0.44–0.78, P < 0.001). No association was evident between intake of vitamin C and type 2 diabetes risk. CONCLUSIONS—This study supports the hypothesis that development of type 2 diabetes may be reduced by the intake of antioxidants in the diet.

The U.K. Prospective Diabetes Study (UKPDS) demonstrated that intensive glucose control with insulin or sulfonylureas markedly reduces the risk of microvascular complications (1). For myocardial infarction, the reduction in risk (16% for a 0.9% decrease in HbA1c) was of borderline significance but corresponded closely to epidemiological predictions (14% decrease for a 1% drop in HbA1c) (2). These data demonstrated that neither insulin nor sulfonylureas, despite causing hyperinsulinemia and weight gain, have adverse effects on cardiovascular outcome. Glycemic control deteriorated continuously, however, even in intensively treated patients in the UKPDS (1). In the UKPDS, the worsening of glycemic control has been attributed to the natural course of type 2 diabetes and lack of efficacy of current antihyperglycemic therapies (1). Insulin therapy consisted of a single injection of ultralente or isophane insulin. If the daily dose exceeded 14 U, regular insulin was added and home-glucose monitoring was encouraged (1). Combination therapy regimens with insulin and oral agents were not used. We now know that 14 U of long-acting insulin is insufficient to control fasting glycemia in most type 2 diabetic patients (3). Since 1977, when the UKPDS was started, several studies have tried to define the optimal insulin treatment regimen for type 2 diabetic patients. These studies are the focus of this review and include studies comparing insulin alone to combination therapy with insulin and sulfonylureas (subject to meta-analyses in 1991 and 1992) (4,5) and more recent trials using metformin, glitazones, or acarbose in insulin combination therapy regimens. They do not contain data on cardiovascular end points but only on surrogate markers of risk of micro- and macrovascular complications, mostly data on glycemia, body weight, insulin doses, lipids, and in a few studies, also accurate data on the frequency of hypoglycemias. According to a Medline search (1966–2000), …

OBJECTIVE: The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear. RESEARCH DESIGN AND METHODS: We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. RESULTS: The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. CONCLUSIONS: We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.

OBJECTIVE: The American Diabetes Association has recently defined a new category of abnormal glucose homeostasis called "impaired fasting glucose" (IFG), where glucose levels do not meet the criteria of diabetes but are too high to be considered normal. We determined whether endothelial dysfunction is a characteristic of subjects with IFG. RESEARCH DESIGN AND METHODS: In vivo vasodilatory responses to intra-arterial infusions of endothelium-dependent (acetylcholine [ACh]) and -independent (sodium nitroprusside [SNP]) vasoactive agents were determined in 17 IFG subjects (age 63 +/- 1 years, BMI 26.5 +/- 0.8 kg/m2, serum LDL cholesterol 3.5 +/- 0.2 mmol/l) with fasting plasma glucose levels of 117 +/- 1 mg/dl and in 12 subjects with normal fasting plasma glucose concentrations. RESULTS: The blood-flow response to the low dose of ACh was 46% (5.9 +/- 0.7 vs. 10.9 +/- 1.3 ml.dl-1.min-1, IFG vs. normal, P < 0.01) and to the high dose was 31% (9.1 +/- 1.2 vs. 13.2 +/- 1.5 ml.dl-1.min-1, P < 0.05, respectively) lower in the IFG than in the normal subjects. In contrast, blood-flow responses to both low (7.8 +/- 0.5 vs. 9.0 +/- 0.9 ml.dl-1.min-1, IFG vs. normal, NS) and high (11.6 +/- 1.2 vs. 12.3 +/- 1.3 ml.dl-1.min-1, NS, respectively) doses of SNP were comparable. The ratio of endothelium-dependent to -independent blood flow was 40% lower in the IFG (0.75 +/- 0.1) than in the normal (1.24 +/- 0.1, P < 0.001) subjects. Both fasting plasma glucose (r = -0.48, P < 0.01) and glycosylated hemoglobin (r = -0.42, P < 0.05) were inversely correlated with endothelium-dependent vasodilation but not with other parameters, such as weight, blood pressure, or lipids. CONCLUSIONS: We conclude that vascular dysfunction is associated with abnormal, although nondiabetic, glucose homeostasis.

OBJECTIVE: To search for determinants of endothelial dysfunction in type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a comprehensive analysis of cardiovascular risk markers and measured blood flow responses to endothelium-dependent (acetylcholine [ACh] and NG-monomethyl-L-arginine) and -independent (sodium nitroprusside [SNP]) vasoactive agents in 30 nonsmoking men with type 2 diabetes (age 51 +/- 1 years, BMI 27.8 +/- 0.4 kg/m2, HbA1c 7.4 +/- 0.3%) and 12 matched normal control men. RESULTS: ACh-induced vasodilation was 37% lower in type 2 diabetic (6.1 +/- 0.5) than in normal subjects (9.7 +/- 1.5 ml.dl-1.min-1, P < 0.01), while flows during SNP were similar (9.1 +/- 0.6 vs. 9.9 +/- 1.3 ml.dl-1.min-1, NS). The ratio of endothelium-dependent vs. -independent flow (ACh:SNP ratio) was 31% lower in type 2 diabetic (0.70 +/- 0.05) than in normal subjects (1.10 +/- 0.18, P < 0.01). Total (2.2 +/- 0.4 vs. 1.3 +/- 0.2 mmol/l, P < 0.05), VLDL, and intermediate-density lipoprotein triglycerides were significantly higher, and the mean LDL particle diameter was significantly smaller in type 2 diabetic than in normal subjects. The lag times for LDL oxidation by Cu2+ in vitro were similar in patients with type 2 diabetes (183 +/- 7) and in normal subjects (183 +/- 9 min, NS). Measured and calculated (sum of concentration of individual antioxidants in serum) total peroxyl radical-trapping capacities (TRAPs) were comparable between the groups. In the patients with type 2 diabetes, LDL size was significantly correlated with endothelium-dependent vasodilation (r = 0.43, P < 0.05), serum triglycerides (r = -0.75, P < 0.001), and the lag time for LDL oxidation in vitro (r = 0.38, P < 0.05). HbA1c was inversely correlated with the lag time for LDL oxidation in vitro (r = -0.41, P < 0.05) and TRAP. CONCLUSIONS: In summary, patients with type 2 diabetes exhibited impaired endothelium-dependent vasodilation in vivo, elevated serum triglycerides, decreased LDL size, and normal antioxidant capacity. Of these parameters, LDL size was significantly correlated with endothelial function.

OBJECTIVE The question of whether to use insulin in the evening or in the morning during combination therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM) is controversial. We compared the acute effects of 12-h nocturnal or daytime insulin infusions on the 24-h glucose profile in 20 patients with NIDDM. RESEARCH DESIGN AND METHODS NIDDM patients were 56 ± 2 (mean ± SE) years of age and had a body mass index of 29.6 ±1.1 kg/m2; fasting plasma glucose concentration of 12.2 ± 0.5 mM; and fasting C-peptide concentration of 0.9 ± 0.2 nM. Each patient was studied twice. On one occasion, the patient received a 12-h intravenous infusion of insulin (mean 1.5 ± 0.1 1U/h) during the day, and on the other occasion an identical dose of insulin was infused during the night. Blood glucose, insulin, c-peptide, and free fatty acid concentrations were determined for 24 h. RESULTS The mean 24-h free insulin concentrations were similar in both studies (150 ± 12 vs. 162 ± 12 pM, daytime versus nocturnal insulin infusion). The mean 24-h free fatty acid concentration was 18% lower in the nocturnal than in the daytime (309 ± 30 vs. 376 ± 30 μM, P < 0.001) insulin infusion study. The mean 24-h C-peptide concentration was less suppressed if insulin was infused overnight than during the day (1.3 ± 0.2 vs. 1.1 ± 0.2 nM, P < 0.01). The mean 24-h plasma glucose concentrations were identical in both studies (11.1 ±0.6 vs. 11.4 ± 0.7 mM, daytime versus nocturnal insulin infusion). We also searched for factors predicting the decrease in the blood glucose concentration during the nocturnal insulin infusion. The best predictors were a high initial blood glucose concentration at 2200 and a low fasting C-peptide concentration. These factors explained, independent of each other, 50% of the rate of decrease in the plasma glucose concentration. CONCLUSIONS Despite better suppression of lipolysis and less suppression of endogenous insulin secretion by nocturnal than daytime insulinization, the hypoglycemic effect of these two treatments is similar.

OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P < 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

Insulin is often postponed for years because initiation is time-consuming. We sought to compare initiation of insulin individually and in groups with respect to change in A1C and several other parameters in type 2 diabetic patients.A randomized (1:1), multicenter, two-arm, parallel design study with a recruiting period of up to 14 weeks and a 24-week treatment period. Either in groups of 4-8 or individually, using the same personnel and education program, 121 insulin-naive type 2 diabetic patients with an A1C of 7.0-12.0% were randomized to initiate bedtime insulin glargine. The patients visited the treatment center before and at the time of insulin initiation and at 6, 12, and 24 weeks. Patients self-adjusted the insulin dose to achieve a fasting plasma glucose 4.0-5.5 mmol/l.At 24 weeks, mean +/- SE A1C had decreased from 8.7 +/- 0.2 to 6.9 +/- 0.1% in those treated individually and from 8.8 +/- 0.2 to 6.8 +/- 0.1% in those in groups (not significant [NS]). Insulin doses averaged 62 +/- 5 IU and 56 +/- 5 IU at 24 weeks (NS), respectively. The frequency of hypoglycemia was similar. The total time (visits and phone calls) spent in initiating insulin in the patients in groups (2.2 +/- 0.1 h) was 48% less than in those treated individually (4.2 +/- 0.2 h). Diabetes treatment satisfaction improved significantly in both sets of patients.Similar glycemic control and treatment satisfaction can be achieved by initiating insulin in groups and individually. Starting insulin in groups takes one-half as much time as individual initiation.

OBJECTIVE—Effects of weight loss on vascular function are unknown. We compared, in the face of similar weight loss over 3–6 months, effects of orlistat (120 mg t.i.d., n = 23) and placebo (n = 24) on in vivo endothelial function in a high-risk group of obese (BMI 32.1 ± 0.4 kg/m2) premenopausal nondiabetic women with a history of gestational diabetes. RESEARCH DESIGN AND METHODS—Forearm blood flow responses to intra-arterial infusions of acetylcholine (ACh) and sodium nitroprusside (SNP), body composition, and serum lipids were determined before and after weight loss. RESULTS—Weight loss averaged 7.3 ± 0.2 kg (8.3 ± 0.1%) and 7.4 ± 0.2 kg (8.2 ± 0.1%) of initial body weight in the orlistat and placebo groups, respectively. Forearm and body compositions changed similarly in both groups. Responses to ACh increased by 41% to the low dose (5.9 ± 0.6 vs. 8.3 ± 0.3 for flow in the experimental/control arm, P < 0.01) and by 33% to the high dose (7.6 ± 0.8 vs. 10.1 ± 0.6, P < 0.001) in the orlistat group, but they remained unchanged in the placebo group. The blood flow responses to SNP did not differ significantly between the groups. LDL cholesterol decreased significantly in the orlistat group from 3.5 ± 0.2 to 3.0 ± 0.1 mmol/l (P < 0.01) but remained unchanged in the placebo group. Within the orlistat group, the decrease in LDL cholesterol correlated significantly with the improvement in the blood flow response to ACh (r = −0.44, P < 0.05). CONCLUSIONS—Orlistat but not moderate (8%) weight loss per se improves endothelial function in women with previous gestational diabetes. This improvement is associated with a lowering of LDL cholesterol by orlistat.

OBJECTIVE—To determine whether large arteries are resistant to insulin. RESEARCH DESIGN AND METHODS—Insulin normally acutely decreases central systolic pressure by decreasing wave reflection in vivo. This effect occurs before any changes in peripheral vascular resistance or heart rate under normoglycemic conditions. We determined whether the ability of insulin to decrease central aortic pressure is altered in uncomplicated type 2 diabetes. The study subjects consisted of 16 type 2 diabetic patients (age 54 ± 2 years, BMI 29 ± 1 kg/m2) and 19 matched nondiabetic individuals (51 ± 2 years, 29 ± 1 kg/m2) studied under normoglycemic-hyperinsulinemic conditions. Central aortic pressure waveforms were synthesized from those recorded in the periphery using applanation tonometry and a validated reverse transfer function to construct the central aortic pressure waveform every 30 min. This method allowed determination of aortic augmentation (the pressure difference between the first and second central systolic pressure waves) and the augmentation index (augmentation divided by pulse pressure). RESULTS—Whole-body insulin sensitivity was 31% lower (P < 0.05) in the type 2 diabetic patients than in the normal subjects. Basally, before the insulin infusion, augmentation averaged 8.9 ± 1.3 and 11.1 ± 1.2 mmHg (NS) and the augmentation index averaged 23.1 ± 2.1 and 27.5 ± 2.1% (NS) in the normal subjects and diabetic patients, respectively. After 30 min of hyperinsulinemia, augmentation decreased significantly to 6.1 ± 1.1 mmHg (P < 0.001) in the normal subjects but remained unchanged at 9.1 ± 1.1 mmHg (NS) in type 2 diabetic patients. At 30 min, the augmentation index had decreased significantly (30 ± 7% decrease) to 17.9 ± 2.6% in the normal subjects but remained at 24.4 ± 2.4% in the diabetic patients (13 ± 4% decrease, P < 0.05 for change vs. normal subjects). Central systolic pressure decreased significantly by 30 min in the normal subjects but only after 120 min in the type 2 diabetic patients. There were no significant changes in heart rate, pulse pressure, or forearm blood flow during the first 120 min of the insulin infusion. CONCLUSIONS—Insulin resistance in type 2 diabetes involves a delay in the ability of insulin to decrease central aortic pressure. This defect could predispose these patients to develop systolic hypertension.

OBJECTIVE—To examine whether and how improvement of glycemic control by long-term insulin therapy decreases endothelial activation as measured by serum levels of the soluble adhesion molecules sE-selectin and vascular cell adhesion molecule (VCAM-1) and whether the drug used to lower blood glucose in addition to insulin influences such a response.RESEARCH DESIGN AND METHODS—Circulating adhesion molecules were measured before and after 3 and 12 months of therapy in 81 patients with type 2 diabetes and 41 subjects without diabetes. The patients were treated with bedtime administration of NPH insulin combined with either glibenclamide (n = 19), metformin (n = 17), glibenclamide and metformin (n = 17), or morning administration of NPH insulin (n = 23).RESULTS—Before insulin therapy, serum sE-selectin level was 71% higher in the patients with type 2 diabetes (77 ± 4 ng/ml) than in the normal subjects (45 ± 3 ng/ml, P < 0.001), whereas levels of sVCAM-1 were comparable (420 ± 25 vs. 400 ± 11 ng/ml, respectively). Glycemic control in all patients improved as judged from a decrease in HbA1c from 9.7 ± 0.2 to 7.6 ± 0.1% (P < 0.001). sE-selectin decreased to 67 ± 4 ng/ml by 3 months (P < 0.001 vs. 0 months) and then remained unchanged until 12 months (70 ± 4 ng/ml, P < 0.001 vs. 0 months). sVCAM-1 levels at 12 months was similar to those at 0 months (416 ± 25 ng/ml). The change in glycemic control, measured by HbA1c, but not in other parameters, was correlated with the change of sE-selectin (r = 0.41, P < 0.001) within the patients with type 2 diabetes. The decreases in sE-selectin were not different between the various treatment groups.CONCLUSIONS—We conclude that improvement in glycemic control by administration of insulin alone or insulin combined with either glibenclamide, metformin, or both agents induces a sustained decrease in sE-selectin, the magnitude of which seems to be dependent on the degree of improvement in glycemia. These data suggest that sE-selectin might provide a marker of effects of treatment of chronic hyperglycemia on endothelial activation.

OBJECTIVE: Frequency domain analysis of heart rate variability (HRV) is used to assess cardiovascular autonomic function. There are no prospective data on the sensitivity of its various components to glycemia or other diabetes-related risk factors compared with conventional tests and with other complications of diabetes. RESEARCH DESIGN AND METHODS: In 1985, possible risk factors of future complications were determined in 115 children with type 1 diabetes. In 1996, the presence of complications (HRV analysis, conventional tests of autonomic function, urinary albumin excretion rate [UAER], and retinopathy) were assessed in 83 of these patients (age 32 +/- 1 years, duration of diabetes 22 +/- 1 years). RESULTS: Poor glycemic control (measured as lifetime glycemic exposure or HbA1c in 1985) was the most important independent predictor of decreases in all measures of absolute power of HRV (total power [TP] and very low frequency, low frequency [LF], and high frequency [HF] power) and square root of the mean square of R-R interval differences but not of changes of normalized measures or ratios (normalized HF and LF LF/HF). Other significant independent predictors of autonomic dysfunction were late age of onset of diabetes, female sex, and high BMI. To examine the sensitivity of the various tests to glycemia, the patients were divided into tertiles based on lifetime glycemic exposure (A1c months). Glycemic exposure in the tertiles averaged 194 +/- 25 A1c months (20 years of HbA1c 0.8% above normal), 556 +/- 19 A1c months(20 years of HbA1c 2.3% above normal), and 963 +/- 30 A1c months (20 years of HbA1c 4% above normal). Tests of complications that were significantly abnormal in patients already in the lowest tertile and were correlated with glycemia were TP and severity of retinopathy. Of conventional tests, only the ratio of length of R-R intervals during expiration to inspiration (E/I ratio) was significantly related to glycemic exposure, but it required high glycemic exposure (20 years of HbA1c 4% above normal) to be abnormal. UAER was significantly increased only in the highest tertile of glycemic exposure. CONCLUSIONS: TP and retinopathy score were much more sensitive to antecedent glycemia than conventional tests of autonomic function or UAER and were significantly abnormal in patients exposed to approximately 20 years' duration of an HbA1c 0.8% above normal.

OBJECTIVE: Available basal insulin formulations do not provide a constant and reliable 24-h insulin supply. We compared the efficacy and safety of glargine (a long-acting insulin analog) and NPH insulins in insulin-naive type 2 diabetic patients treated with oral antidiabetic agents. RESEARCH DESIGN AND METHODS: There were 426 type 2 diabetic patients (age 59 +/- 9 years, BMI 28.9 +/- 4.3 kg/m2, mean +/- SD) with poor glycemic control on oral antidiabetic agents randomized to treatment for 1 year with bedtime insulin glargine or bedtime NPH insulin. Oral agents were continued unchanged. The fasting blood glucose (FBG) target was 6.7 mmol/l (120 mg/dl). RESULTS: Average glycemic control improved similarly with both insulins (HbA(1c), [reference range

OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.