11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates cortisol from cortisone within adipose tissue and liver. 11HSD1 inhibitors may enhance insulin sensitivity in type 2 diabetes and be most efficacious in obesity when 11HSD1 is increased in subcutaneous adipose biopsies. We examined the regeneration of cortisol in vivo in obesity, and the effects of the 11HSD1 inhibitor carbenoxolone. We compared six lean and six obese men and performed a randomized, placebo-controlled crossover study of carbenoxolone in obese men. The obese men had no difference in their whole-body rate of regenerating cortisol (measured with 9,11,12,12-[(2)H(4)]cortisol tracer), but had more rapid conversion of [(3)H]cortisone to [(3)H]cortisol in abdominal subcutaneous adipose tissue (measured with microdialysis). During insulin infusion, adipose 11HSD1 activity fell markedly in lean but not in obese men. Carbenoxolone inhibited whole-body cortisol regeneration, but did not significantly inhibit adipose 11HSD1 and had no effects on insulin sensitivity (measured by [(2)H(2)]glucose infusion with or without hyperinsulinemia). Thus, in vivo cortisol generation is increased selectively within adipose tissue in obesity, perhaps reflecting resistance to insulin-mediated downregulation of 11HSD1. However, obese men are less susceptible than lean men to the insulin-sensitizing effects of carbenoxolone. To be useful in obese patients, 11HSD1 inhibitors will need to inhibit the enzyme more effectively in adipose tissue.

DHEA (dehydroepiandrosterone) replacement is not part of the current standard of care in hypoadrenal subjects. Animal studies have shown that DHEA administration prevents diabetes. To determine the physiological effect of DHEA replacement on insulin sensitivity in adrenal-deficient women, we performed a single-center, randomized, double-blind, placebo-controlled, crossover study in 28 hypoadrenal women (mean age 50.2 +/- 2.87 years) who received a single 50-mg dose of DHEA daily or placebo. After 12 weeks, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. DHEA replacement significantly increased DHEA-S (sulfated ester of DHEA), bioavailable testosterone, and androstenedione and reduced sex hormone-binding globulin levels. Fasting plasma insulin and glucagon were lower with DHEA (42 +/- 4.94 vs. 53 +/- 6.58 pmol/l [P = 0.005] and 178 +/- 11.32 vs. 195.04 +/- 15 pmol/l [P = 0.02], respectively). The average amount of glucose needed to maintain similar blood glucose levels while infusing the same insulin dosages was higher during DHEA administration (358 +/- 24.7 vs. 320 +/- 24.6 mg/min; P < 0.05), whereas endogenous glucose production was similar. DHEA also reduced total cholesterol (P < 0.005), triglycerides (P < 0.011), LDL cholesterol (P < 0.05), and HDL cholesterol (P < 0.005). In conclusion, replacement therapy with 50 mg of DHEA for 12 weeks significantly increased insulin sensitivity in hypoadrenal women, thereby suggesting that DHEA replacement could have a potential impact in preventing type 2 diabetes.

Effects of hypoglycemia on cardiac autonomic regulation may contribute to the occurrence of adverse cardiac events. This study assessed the effects of sustained hyperinsulinemic hypoglycemia on cardiovascular autonomic regulation in type 1 diabetic patients and their nondiabetic counterparts. The study consisted of 16 type 1 diabetic patients and 8 age-matched healthy control subjects who underwent euglycemic and hypoglycemic clamp procedures in a random order. Heart rate variability was measured from continuous electrocardiogram recordings by time and frequency domain methods, along with Poincare plot analysis during both a hyperinsulinemic-euglycemic and hypoglycemic clamp at three different glucose levels (4.5-5.5, 3.0-3.5, and 2.0-2.5 mmol/l). Controlled hypoglycemia resulted in an increase of supine heart rate in both the diabetic patients (from 72 +/- 9 to 80 +/- 11 bpm, P < 0.01) and the control subjects (from 59 +/- 5 to 65 +/- 5 bpm, P < 0.05) and progressive reductions of the high-frequency spectral component and beat-to-beat heart rate variability (SD1; P < 0.05 in the diabetic patients and P < 0.01 in control subjects). No significant changes in heart rate variability occurred during the euglycemic clamp. We conclude that hypoglycemia results in a reduction of cardiac vagal outflow in both diabetic and nondiabetic subjects. Altered autonomic regulation may contribute to the occurrence of cardiac events during hypoglycemia.

To examine the mechanism by which moderate weight reduction improves basal and insulin-stimulated rates of glucose metabolism in patients with type 2 diabetes, we used (1)H magnetic resonance spectroscopy to assess intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) content in conjunction with hyperinsulinemic-euglycemic clamps using [6,6-(2)H(2)]glucose to assess rates of glucose production and insulin-stimulated peripheral glucose uptake. Eight obese patients with type 2 diabetes were studied before and after weight stabilization on a moderately hypocaloric very-low-fat diet (3%). The diabetic patients were markedly insulin resistant in both liver and muscle compared with the lean control subjects. These changes were associated with marked increases in IHL (12.2 +/- 3.4 vs. 0.6 +/- 0.1%; P = 0.02) and IMCL (2.0 +/- 0.3 vs. 1.2 +/- 0.1%; P = 0.02) compared with the control subjects. A weight loss of only approximately 8 kg resulted in normalization of fasting plasma glucose concentrations (8.8 +/- 0.5 vs. 6.4 +/- 0.3 mmol/l; P < 0.0005), rates of basal glucose production (193 +/- 7 vs. 153 +/- 10 mg/min; P < 0.0005), and the percentage suppression of hepatic glucose production during the clamp (29 +/- 22 vs. 99 +/- 3%; P = 0.003). These improvements in basal and insulin-stimulated hepatic glucose metabolism were associated with an 81 +/- 4% reduction in IHL (P = 0.0009) but no significant change in insulin-stimulated peripheral glucose uptake or IMCL (2.0 +/- 0.3 vs. 1.9 +/- 0.3%; P = 0.21). In conclusion, these data support the hypothesis that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled type 2 diabetes by mobilizing a relatively small pool of IHL, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism.

Lifestyle modification reduces the risk of developing type 2 diabetes and may have its effect through improving insulin sensitivity, beta-cell function, or both. To determine whether diet and exercise improve insulin sensitivity and/or beta-cell function and to evaluate these effects over time, we quantified insulin sensitivity and the acute insulin response to glucose (AIRg) in 62 Japanese Americans (age 56.5 +/- 1.3 years; mean +/- SE) with impaired glucose tolerance (IGT) who were randomized to the American Heart Association (AHA) Step 2 diet plus endurance exercise (n = 30) versus the AHA Step 1 diet plus stretching (n = 32) for 24 months. beta-Cell function (disposition index [DI]) was calculated as S(i) x AIRg, where S(i) is the insulin sensitivity index. The incremental area under the curve for glucose (incAUCg) was calculated from a 75-g oral glucose tolerance test. Intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas were measured by computed tomography. At 24 months, the Step 2/endurance group had lower weight (63.1 +/- 2.4 vs. 71.3 +/- 2.9 kg; P = 0.004) and IAF (75.0 +/- 7.9 vs. 112.7 +/- 10.4 cm(2); P = 0.03) and SCF (196.5 +/- 18.0 vs. 227.7 +/- 19.9 cm(2); P < 0.001) areas, greater S(i) (4.7 +/- 0.5 vs. 3.3 +/- 0.3 x 10(-5) min . pmol(-1) . l(-1); P = 0.01), and a trend toward lower AIRg (294.9 +/- 50.0 vs. 305.4 +/- 30.0 pmol/l; P = 0.06) and incAUCg (8,217.3 +/- 350.7 vs. 8,902.0 +/- 367.2 mg . dl(-1) . 2 h(-1); P = 0.08) compared with the Step 1/stretching group after adjusting for baseline values. There was no difference in the DI (P = 0.7) between the groups. S(i) was associated with changes in weight (r = -0.426, P = 0.001) and IAF (r = -0.395, P = 0.003) and SCF (r = -0.341, P = 0.01) areas. Thus, the lifestyle modifications decreased weight and central adiposity and improved insulin sensitivity in Japanese Americans with IGT. However, such changes did not improve beta-cell function, suggesting that this degree of lifestyle modifications may be limited in preventing type 2 diabetes over the long term.

We examined the effects of high-dosage vitamin E treatment over a 12-month period on the vascular reactivity of micro- and macrocirculation and left ventricular function in diabetic patients. Subjects (n = 89) were randomized to vitamin E (1,800 IU daily) or placebo and were followed for 12 months. High-resolution ultrasound images were used to measure the flow-mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (NID; endothelium independent) of the brachial artery. Laser Doppler perfusion imaging was used to measure vascular reactivity in the forearm skin. Left ventricular function was evaluated using transthoracic echocardiogram. At the end of the 6-month period, a worsening in endothelium-dependent skin vasodilation (P = 0.02) and rise in endothelin levels (P = 0.01) were found in the vitamin E compared with the placebo group. At the end of the 12-month period, a worsening was observed in NID (P = 0.02) and a marginal worsening was seen in systolic blood pressure (P = 0.04) and FMD (P = 0.04) in the vitamin E compared with the placebo group. In addition C-reactive protein levels decreased marginally in the vitamin E compared with the placebo group (P = 0.05). No changes were observed in left ventricular function. We concluded that long-term treatment with 1,800 IU of vitamin E has no beneficial effects on endothelial or left ventricular function in diabetic patients. Because vitamin E-treated patients had a worsening in some vascular reactivity measurements when compared with control subjects, the use of high dosages of vitamin E cannot be recommended.

Clinical trials have demonstrated that lifestyle changes can prevent type 2 diabetes, but the importance of leisure-time physical activity (LTPA) is still unclear. We carried out post hoc analyses on the role of LTPA in preventing type 2 diabetes in 487 men and women with impaired glucose tolerance who had completed 12-month LTPA questionnaires. The subjects were participants in the Finnish Diabetes Prevention Study, a randomized controlled trial of lifestyle changes including diet, weight loss, and LTPA. There were 107 new cases of diabetes during the 4.1-year follow-up period. Individuals who increased moderate-to-vigorous LTPA or strenuous, structured LTPA the most were 63-65% less likely to develop diabetes. Adjustment for changes in diet and body weight during the study attenuated the association somewhat (upper versus lower third: moderate-to-vigorous LTPA, relative risk 0.51, 95% CI 0.26-0.97; strenuous, structured LTPA, 0.63, 0.35-1.13). Low-intensity and lifestyle LTPA and walking also conferred benefits, consistent with the finding that the change in total LTPA (upper versus lower third: 0.34, 0.19-0.62) was the most strongly associated with incident diabetes. Thus increasing physical activity may substantially reduce the incidence of type 2 diabetes in high-risk individuals.

A number of patients with type 2 diabetes are GAD antibody positive. A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind clinical trial in recently diagnosed drug-naive patients with type 2 diabetes that allows for the evaluation of GAD positivity in the context of anthropometric and biochemical characteristics. Of the 4,134 subjects enrolled in ADOPT for whom GAD status was obtained, 174 (4.2%) were GAD positive, with the prevalence of GAD antibodies being similar in North America (4.7%) and Europe (3.7%). Although BMI and age were similar, GAD-positive patients had a lower fasting insulin level, compatible with them being more insulin sensitive. The lower fasting insulin concentration was accompanied by a decreased early insulin response to oral glucose. However, when this insulin response was corrected for the degree of insulin sensitivity, GAD-positive and -negative patients had similar beta-cell function. Consistent with the difference in insulin sensitivity, GAD-positive patients had higher HDL cholesterol and lower triglyceride levels. In the GAD-positive individuals, the prevalence of the metabolic syndrome as defined by NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) was also lower (74.1 vs. 83.7%, P = 0.0009). These phenotypic differences may underlie a potential difference in the natural history of hyperglycemia and its clinical outcomes.

Insulin acts in the central nervous system to reduce food intake and body weight and is considered a major adiposity signal. After intranasal administration, insulin enters the cerebrospinal fluid compartment and alters brain functions in the absence of substantial absorption into the blood stream. Here we report the effects of 8 weeks of intranasal administration of insulin (4 x 40 IU/day) or placebo to two groups of healthy human subjects (12 men and 8 women in each group). The insulin-treated men lost 1.28 kg body wt and 1.38 kg of body fat, and their waist circumference decreased by 1.63 cm. Plasma leptin levels dropped by an average of 27%. In contrast, the insulin-treated women did not lose body fat and gained 1.04 kg body wt due to a rise in extracellular water. Our results provide a strong, first confirmation in humans that insulin acts as a negative feedback signal in the regulation of adiposity and point to a differential sensitivity to the catabolic effects of insulin based on sex.

This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol. kg(-1). min(-1)) or placebo during a 270-min stepwise hyperinsulinemic-hypoglycemic clamp (insulin infusion 0.8 mU. kg(-1). min(-1)). Plasma glucose was clamped sequentially at 5.0 (0-120 min), 4.0 (120-180 min), 3.2 (180-240 min), and 2.7 mmol/l (240-270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to approximately 3.2 mmol/l. The time to achieve plasma glucose >/=4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were approximately 3.5-fold higher than in the placebo arm (353 +/- 29 vs. 100 +/- 29 pmol/min [least-square means +/- SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (</=4 mmol/l) in both groups. Glucagon was suppressed in the exenatide arm during euglycemia and higher than placebo during hypoglycemia. Plasma glucose recovery time was equivalent for both treatments. The areas under the concentration-time curve from 270 to 360 min for cortisol, epinephrine, norepinephrine, and growth hormone were similar between treatment arms. There were no differences in adverse events. In the presence of exenatide, there was a preserved, glucose-dependent insulin secretory response and counterregulatory response during hypoglycemia.

There has been interest in the effect of various types and amounts of dietary carbohydrates and proteins on blood glucose. On the basis of our previous data, we designed a high-protein/low-carbohydrate, weight-maintaining, nonketogenic diet. Its effect on glucose control in people with untreated type 2 diabetes was determined. We refer to this as a low-biologically-available-glucose (LoBAG) diet. Eight men were studied using a randomized 5-week crossover design with a 5-week washout period. The carbohydrate:protein:fat ratio of the control diet was 55:15:30. The test diet ratio was 20:30:50. Plasma and urinary beta-hydroxybutyrate were similar on both diets. The mean 24-h integrated serum glucose at the end of the control and LoBAG diets was 198 and 126 mg/dl, respectively. The percentage of glycohemoglobin was 9.8 +/- 0.5 and 7.6 +/- 0.3, respectively. It was still decreasing at the end of the LoBAG diet. Thus, the final calculated glycohemoglobin was estimated to be approximately 6.3-5.4%. Serum insulin was decreased, and plasma glucagon was increased. Serum cholesterol was unchanged. Thus, a LoBAG diet ingested for 5 weeks dramatically reduced the circulating glucose concentration in people with untreated type 2 diabetes. Potentially, this could be a patient-empowering way to ameliorate hyperglycemia without pharmacological intervention. The long-term effects of such a diet remain to be determined.

Our objective was to study whether young first-degree relatives of patients with type 2 diabetes (FDRs) have altered insulin secretion and insulin clearance in response to gastric inhibitory polypeptide (GIP) in combination with glucose and arginine. A hyperglycemic clamp (11.1 mmol/l for 115 min), followed by addition of GIP (2 pmol. kg(-1). min(-1), 60-115 min) and an arginine bolus and infusion (10 mg. kg(-1). min(-1), 90-115 min), was conducted on 14 healthy volunteers and 13 FDRs. Both groups had normal glucose tolerance. FDRs were more insulin resistant (HOMA(IR)) under basal conditions (P = 0.003). FDRs demonstrated significant global impairment in insulin secretion capacity, which was not specific for one of the secretagogues. Insulin clearance was significantly reduced in the group of FDRs under basal conditions and in response to GIP, but there was no general defect in insulin clearance in response to glucose and arginine. The HOMA(IR) correlated negatively (P < 0.01) with insulin clearance under basal conditions (r = -0.96) and under GIP infusion (r = -0.56). We propose that impairment in insulin secretion capacity and decreased insulin sensitivity is compensated for several mechanisms, one of which includes a GIP-dependent reduction of the insulin clearance that will increase peripheral insulin levels to maintain normoglycemia.

Circulating insulin is thought to provide a major feedback signal for the hypothalamic regulation of energy homeostasis and food intake, although this signaling appears to be slowed by a time-consuming blood-to-brain transport. Here we show, by recording direct current potentials, a rapid onset of the effects of circulating insulin on human brain activity. Recordings were obtained from 27 men who were intravenously injected with insulin (0.1 mU/kg body wt as bolus) and placebo. In a euglycemic condition, hypoglycemia was prevented, while in the hypoglycemic condition, plasma glucose reached a postinjection nadir of 43 mg/dl. Insulin injection induced a marked negative direct current (DC) potential shift starting within 7 min in all subjects. With euglycemic conditions, the DC potential at 10-60 min postinsulin injection averaged -621.3 microV (compared with preinjection baseline). Hypoglycemia reduced this potential to an average of -331.2 microV. While insulin per se did not affect oscillatory electroencephalographic activity, hypoglycemia peaking 25 min after insulin injection was accompanied by an immediate increase in theta activity. The rapid emergence of the DC potential shift, reflecting gross ionic changes in brain tissues, indicates that systemic insulin can serve as an immediate feedback signal in the control of hypothalamic and higher brain functions.

Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 +/- 3 years, fasting plasma glucose 152 +/- 9 mg/dl, BMI 30.6 +/- 0.8 kg/m2) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA1c, insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 +/- 4 vs. 82 +/- 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 +/- 3 vs. 7 +/- 1%, 0 vs. 16 weeks, P = 0.003) but not by metformin (13 +/- 3 to 14 +/- 3%, NS). Rosiglitazone (16 +/- 2 vs. 20 +/- 1 ml.kg(-1).min(-1), P = 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r = -0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.

Little is known about common factors (e.g., macronutrients and energy supply) regulating the protein secretory function of adipose tissue. We therefore compared the effects of randomly assigned 10-week hypoenergetic (-600 kcal/day) diets with moderate-fat/moderate-carbohydrate or low-fat/high-carbohydrate content on circulating levels and production of proteins (using radioimmunoassays and enzyme-linked immunosorbent assays) from subcutaneous adipose tissue in 40 obese but otherwise healthy women. Similar results were obtained by the two diets. Body weight decreased by approximately 7.5%. The secretion rate of leptin decreased by approximately 40%, as did that of tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6 and -8 decreased by 25-30%, whereas the secretion of plasminogen activator inhibitor 1 (PAI-1) and adiponectin did not show any changes. Regarding mRNA expression (by real-time PCR), only that of leptin and IL-6 decreased significantly. Circulating levels of leptin and PAI-1 decreased by 30 and 40%, respectively, but there were only minor changes in circulating TNF-alpha, IL-6, or adiponectin. In conclusion, moderate caloric restriction but not macronutrient composition influences the production and secretion of adipose tissue-derived proteins during weight reduction, leptin being the most sensitive and adiponectin and PAI-1 the least sensitive.

The mechanisms that mediate the tightly controlled production and clearance of glucose during muscular work are unclear, and it has been suggested that an unidentified "work factor" exists that influences the contraction-induced increase in endogenous glucose production (EGP). The cytokine interleukin (IL)-6 is released from skeletal muscle during contraction. Here we show that IL-6 contributes to the contraction-induced increase in EGP. Six men performed 2 h of bicycle exercise on three separate occasions, at a relatively high intensity (HI) or at a low intensity with (LO + IL-6) or without (LO) an infusion of recombinant human IL-6 that matched the circulating concentration of IL-6 seen in HI exercise. The stable isotope 6,6 (2)H(2) glucose was infused to calculate EGP (rate of glucose appearance [R(a)]), whole-body glucose disposal (rate of glucose disappearance [R(d)]), and metabolic clearance rate (MCR) of glucose. Glucose R(a), R(d), and MCR were higher (P < 0.05) at HI than at LO. Throughout exercise at LO + IL-6, glucose R(a) and R(d) were higher (P < 0.05) than LO, even though the exercise intensity was identical. In addition, MCR was higher (P < 0.05) at LO + IL-6 than at LO at 90 min. Insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were identical when comparing LO + IL-6 with LO. These data suggest that IL-6 influences glucose homeostasis during exercise. Our results provide potential new insights into factors that mediate glucose production and disposal and implicates IL-6 in the so-called "work factor."

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.9 +/- 0.6%; BMI, 31.9 +/- 1.5 kg/m(2)). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-(3)H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 +/- 0.1 vs. P- = 1.7 +/- 0.3 mg. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). min(-1); P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.

The aim of this randomized double-blind study was to compare the within-subject variability of the glucose-lowering effect of a novel insulin analog, insulin detemir, with that of insulin glargine and NPH insulin in people with type 1 diabetes. Fifty-four subjects (32 males and 22 females, age 38 +/- 10 years [mean +/- SD], BMI 24 +/- 2 kg/m(2), HbA(1c) 7.5 +/- 1.2%, diabetes duration 18 +/- 9 years) participated in this parallel group comparison. Each subject received four single subcutaneous doses of 0.4 units/kg of either insulin detemir (n = 18), insulin glargine (n = 16), or human NPH insulin (n = 17) under euglycemic glucose clamp conditions (target blood glucose concentration 5.5 mmol/l) on four identical study days. The pharmacodynamic (glucose infusion rates [GIRs]) and pharmacokinetic (serum concentrations of insulin detemir, human insulin, and insulin glargine) properties of the basal insulin preparations were recorded for 24 h postdosing. Insulin detemir was associated with significantly less within-subject variability than both NPH insulin and insulin glargine, as assessed by the coefficient of variation (CV) for the pharmacodynamic end points studied [GIR-AUC((0-12 h)) 27% (detemir) vs. 59% (NPH) vs. 46% (glargine); GIR-AUC((0-24 h)) 27 vs. 68 vs. 48%; GIR(max) 23 vs. 46 vs. 36%; P < 0.001 for all comparisons]. Insulin detemir also provided less within-subject variability in the pharmacokinetic end points: maximal concentration (C(max)) 18 vs. 24 vs. 34%; INS-AUC((0- infinity )) 14 vs. 28 vs. 33%. The results suggest that insulin detemir has a significantly more predictable glucose-lowering effect than both NPH insulin and insulin glargine.

Modeling analysis of glucose, insulin, and C-peptide following a meal has been proposed as a means to estimate insulin sensitivity (S(i)) and beta-cell function from a single test. We compared the model-derived meal indexes with analogous indexes obtained from an intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp (HGC) in 17 nondiabetic subjects (14 men, 3 women, aged 50 +/- 2 years [mean +/- SE], BMI 25.0 +/- 0.7 kg/m(2)). S(i) estimated from the meal was correlated with S(i) estimated from the IVGTT and the HGC (r = 0.59 and 0.76, respectively; P < 0.01 for both) but was approximately 2.3 and 1.4 times higher (P < 0.05 for both). The meal-derived estimate of the beta-cell's response to a steady-state change in glucose (static secretion index) was correlated with the HGC second-phase insulin response (r = 0.69; P = 0.002), but the estimated rate-of-change component (dynamic secretion index) was not correlated with first-phase insulin release from either the HGC or IVGTT. Indexes of beta-cell function obtained from the meal were significantly higher than those obtained from the HGC. In conclusion, insulin sensitivity and beta-cell indexes derived from a meal are not analogous to those from the clamp or IVGTT. Further work is needed before these indexes can be routinely used in clinical and epidemiological studies.

The Adult Treatment Panel III (ATP III) has published criteria for diagnosing the metabolic syndrome, a cluster of closely related abnormalities related to insulin resistance that increase cardiovascular disease risk. The present analysis was performed to evaluate the ability of these criteria to identify insulin-resistant individuals. The population consisted of 443 healthy volunteers, with measurements of BMI, blood pressure, fasting plasma glucose, triglycerides, HDL cholesterol concentrations, and steady-state plasma glucose (SSPG) concentration. Insulin resistance was defined as being in the top tertile of SSPG concentrations. Of the population, 20% satisfied ATP III criteria for the metabolic syndrome. Although insulin resistance and the presence of the metabolic syndrome were significantly associated (P < 0.001), the sensitivity and positive predictive value equaled 46% (69 of 149) and 76% (69 of 91), respectively. Being overweight, with high triglycerides, low HDL cholesterol, or elevated blood pressure, most often resulted in a diagnosis of the metabolic syndrome. Thus, the ATP III criteria do not provide a sensitive approach to identifying insulin-resistant individuals. The individual components vary both in terms of their utility in making a diagnosis of the metabolic syndrome and their relationship to insulin resistance, with the obesity and lipid criteria being most useful.