0.05) but was similar with ultralente (20 ± 6 h). NPH and ultralente exhibited a peak concentration and action (at 4.5 ± 0.5 and 10.1 ± 1 h, respectively) followed by waning, whereas glargine had no peak but had a flat concentration/action profile mimicking CSII. Interindividual variability (calculated as differences in SD of plasma insulin concentrations and glucose infusion rates in different treatments) was lower with glargine than with NPH and ultralente (P < 0.05) but was similar with glargine and CSII (NS). In conclusion, NPH and ultralente are both peak insulins. Duration of action of ultralente is greater, but intersubject variability is also greater than that of NPH. Glargine is a peakless insulin, it lasts nearly 24 h, it has lower intersubject variability than NPH and ultralente, and it closely mimics CSII, the gold standard of basal insulin replacement. Diabetes 49:2142-2148, 2000 T he goal of treatment of type 1 diabetes is maintenance of long-term near-normoglycemia to prevent the onset and/or progression of long-term complications (1,2). At present, this goal is feasible with physiological models of insulin replacement (3), provided that patients are appropriately educated about the strategy of intensive insulin therapy (4,5). However, several obstacles, such as day-to-day variability in insulin requirements and slow (6) and variable absorption (7) of insulin from the subcutaneous (SC) site of injection, make it difficult for type 1 diabetic patients to maintain long-term near-normoglycemia.The DNA-recombinant technique has led to synthesis of the short-acting human insulin analogs lispro and aspart, which are absorbed faster than human regular insulin and improve 1-and 2-h postprandial blood glucose levels (8). However, better postprandial blood glucose control with short-acting insulin analogs results in improvement in glycemic control in the long term only by the extent to which replacement of basal insulin is optimized at the same time, either by continuous subcutaneous insulin infusion (CSII) or multiple daily administrations of NPH (8). The latter regimen results in lower HbA 1c (9), with no increase (9) or a decrease in the frequency of hypoglycemia compared with the regimen based on mealtime administration of human regular insulin and bedtime NPH (8). In turn, less frequent hypoglycemia results in better awareness of and counterregulation to hypoglycemia in the long term (10). However, the approach of multiple daily injections of NPH or CSII may be too demanding for the majority of patients worldwide who use mealtime administration of short-acting insulin analogs.An ideal basal insulin candidate is a peakless long-lasting preparation that mimics the flat interprandial insulin secretion of nondiabetic subjects, with reproducible SC absorption. The presently available intermediate-acting (NPH) or long-acting (ultralente) insulin preparations are poor surrogates for the ideal basal insulin, primarily because of their peak-action profile (11,12) and day-to-day variability in SC absorption (7)....

Abstract-The question of serum uric acid as an independent risk factor in subjects with essential hypertension remains controversial. For up to 12 years (mean, 4.0) we followed 1720 subjects with essential hypertension. At entry, all subjects were untreated and all were carefully screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Outcome measures included total cardiovascular events, fatal cardiovascular events, and all-cause mortality. Key Words: uric acid Ⅲ blood pressure Ⅲ cardiovascular disease Ⅲ hypertension, essential Ⅲ blood pressure monitoring Ⅲ hypertrophy, left ventricular S everal cohort studies conducted over the past 5 decades showed a link between serum uric acid (SUA) and subsequent cardiovascular (CV) disease. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] However, in some of these studies such association did not remain significant after adjustment for concomitant risk factors for CV disease 2,4,5,12,15 or it was detected only in women. 6,8,10 Thus, the role of SUA as an independent risk marker remains controversial. 16 An increase in SUA might be simply a marker of obesity, hyperinsulinemia and glucose intolerance, 17,18 hypertension, 5 hyperlipidemia 19 and renal disease. 20,21 The assessment of the independent prognostic value of SUA is clinically relevant in the specific setting of essential hypertension, in which hyperuricemia is frequent 22 and cardiovascular risk stratification is of utmost importance. In a recent cohort study in subjects with hypertension, 14 the association between SUA and future CV events remained significant after adjustment for concomitant diuretic therapy, previous CV events, and other risk factors including office blood pressure (BP). In contrast, pretreatment SUA was not an independent predictor of CV events in the setting of the European Working Party on High Blood Pressure in the Elderly trial. 23 Because of the discrepancy between these findings, we analyzed the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) database to clarify the independent prognostic value of SUA in a large cohort of initially untreated and apparently healthy subjects with essential hypertension. Methods PIUMA StudyThe design of the PIUMA study has been reported previously. 24,25 Office BP had to be Ն140 mm Hg systolic and/or Ն90 mm Hg diastolic on Ն3 visits, and all of the subjects fulfilled the following inclusion criteria: no previous antihypertensive treatment or treat-

Pioglitazone increases the insulin sensitivity of peripheral tissues and may provide an alternative first-line treatment for type 2 diabetes. This study compared metabolic control in drug-naive type 2 diabetes patients given either pioglitazone or metformin. Eleven hundred and ninety-nine patients with poorly controlled type 2 diabetes mellitus [glycosylated hemoglobin (HbA1c), 7.5-11%; normal, 4.3-6.1%] were randomized to receive either pioglitazone (< or =45 mg/d) or metformin (< or =850 mg, three times daily). HbA1c, fasting plasma glucose (FPG), insulin levels, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, triglycerides, free fatty acids, and urinary albumin/creatinine ratio were measured. Mean HbA1c decreased in both treatment groups from baseline to wk 52 (-1.4% and -1.5%). Significantly greater mean reductions in FPG were observed in the pioglitazone group (-45.0 mg/dl; -2.5 mmol/liter) than in the metformin (-39.6 mg/dl; -2.2 mmol/liter) group (P = 0.016). Favorable changes in triglycerides and HDL-C were more pronounced with pioglitazone. Although low density lipoprotein cholesterol and TC levels increased with pioglitazone, TC/HDL-C ratios decreased similarly with both treatments. The urinary albumin/creatinine ratio was reduced by 19% with pioglitazone treatment, but remained unchanged with metformin therapy (-1%; P = 0.002). There was an increase in body weight of 1.9 kg in the pioglitazone group and a decrease of 2.5 kg in the metformin group. The overall frequency of adverse events was similar between treatment groups, but adverse event profiles were different between treatment groups. HbA1c reduction is similar after pioglitazone and metformin monotherapies, but differences in FPG, plasma lipids, and adverse effects between the two compounds may influence decision-making in individual prescribers.

OBJECTIVE -The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes.RESEARCH DESIGN AND METHODS -In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n ϭ 319) or metformin 850 mg (n ϭ 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA 1c at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured.RESULTS -HbA 1c was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm Ϫ1.3 IU/ml; metformin arm Ϫ0.8 IU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (Ϫ16 vs. Ϫ9%; P ϭ 0.008) and increased HDL cholesterol (14 vs. 8%; P Ͻ 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P Ͻ 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P ϭ 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group.CONCLUSIONS -Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes.

To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 +/- 0.05 to 0.045 +/- 0.03 episodes/patient-day) and an increase in HbA1c (5.8 +/- 0.3 to 6.9 +/- 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.

OBJECTIVE—There is enough evidence that physical activity is an effective therapeutic tool in the management of type 2 diabetes. The present study was designed to validate a counseling strategy that could be used by physicians in their daily outpatient practice to promote the adoption and maintenance of physical activity by type 2 diabetic subjects. RESEARCH DESIGN AND METHODS—The long-term (2-year) efficacy of the behavioral approach (n = 182) was compared with usual care treatment (n = 158) in two matched, randomized groups of patients with type 2 diabetes who had been referred to our Outpatient Diabetes Center. The outcome of the intervention was consistent patient achievement of an energy expenditure of &gt;10 metabolic equivalents (METs)-h/week through voluntary physical activity. RESULTS—After 2 years, 69% of the patients in the intervention group (27.1 ± 2.0 METs × h/week) and 18% of the control group (4.1 ± 0.8 METs × h/week) achieved the target (P &lt; 0.001) with significant (P &lt; 0.001) improvements in BMI (intervention group 28.9 ± 0.2 versus control group 30.4 ± 0.3 kg/m2) and HbA1c (intervention group 7.0 ± 0.1 versus control group 7.6 ± 0.1%). CONCLUSIONS—This randomized, controlled study shows that physicians can motivate most patients with type 2 diabetes to exercise long-term and emphasizes the value of individual behavioral approaches in daily practice.

To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (less than 1 mo); 11 with 2.6 +/- 0.3 (mean +/- SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 +/- 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 X min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80-130 ng/m2 X min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = -0.943; P less than 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.

Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.