Studies from our laboratory using acute pharmacologic blockade of nitric oxide synthase (NOS) activity have suggested that nitric oxide (NO) has an important role in regulating carbohydrate metabolism. We now report on insulin sensitivity in mice with targeted disruptions in endothelial NOS (eNOS) and neuronal NOS (nNOS) genes compared with their wild-type (WT) counterparts. Mice underwent hyperinsulinemic-euglycemic clamp studies after a 24-h fast, during an insulin infusion of 20 mU · k g -1 · min -1 . Glucose levels were measured at baseline and every 10 min during the clamp. Insulin levels were measured at baseline and at the end of the clamp study. Glucose infusion rates (GIRs) during the last 30 min of the clamp study were in a steady state. Tritiated glucose infusion was used to measure rates of endogenous glucose output (EGO) both at baseline and during steady-state euglycemia. Glucose disposal rates (GDRs) were computed from the GIR and EGO. Fasting and steady-state glucose and insulin levels were comparable in the 3 groups of mice. No differences in fasting EGO were noted between the groups. GIR was significantly reduced (37%, P = 0.001) in the eNOS knockout (KO) mice compared with the WT mice, with values for the nNOS mice being intermediate. EGO was completely suppressed in the nNOS and WT mice during insulin infusion, but not in the eNOS mice. Even so, the eNOS mice displayed significantly reduced whole-body GDRs compared with those of the WT mice ( 8 2 . 6 7 ± 10.77 vs. 103.67 ± 3.47 m g · k g -1 · min -1 , P = 0.03). eNOS KO mice are insulin resistant at the level of the liver and peripheral tissues, whereas the nNOS KO mice are insulin resistant only in the latter. These data indicate that NO plays a role in modulating insulin sensitivity and carbohydrate metabolism and that the eNOS isoform may play a dominant role relative to nNOS. Diabetes 49:XXX-XXX, 2000 N itric oxide (NO) has emerged as an important molecule with diverse biological functions. In the blood vessels, NO mediates endotheliumdependent vasodilation (1-3) in response to diverse stimuli such as shear stress (4-6), insulin (7), acetylcholine (8,9), and bradykinin (3,10). In the central nervous system (CNS) and peripheral nervous tissue, NO is an unusual neurotransmitter (11-13). NO is generated when the amino acid L-arginine is converted to citrulline by the enzyme NO synthase (NOS) (14,15). Three separate genes encode the known isoforms of NOS (16): endothelial NOS (eNOS or NOS III) and neuronal NOS (nNOS or NOS II) catalyze the constitutive production of NO in a calcium-dependent manner predominantly in the blood vessels and neural tissues, respect i v e l y. The third isoform, inducible NOS (iNOS or NOS I) is located in macrophages and catalyzes NO formation in i n flammatory cells.Intravenous administration of N G -m o n o m e t h y l -L-a r g i n i n e (L-NMMA), a competitive inhibitor of all NOS isoforms, acutely induces hypertension and insulin resistance in rats ( 1 7 ) . M o r e r e c e n t l y, we reported that acute pharm...

Background and Purpose-Hyperglycemia may worsen brain injury during acute cerebral infarction. We tested the feasibility and tolerability of aggressive hyperglycemia correction with intravenous insulin compared with usual care during acute cerebral infarction. Methods-We conducted a randomized, multicenter, blinded pilot trial for patients with cerebral infarction within 12 hours after onset, a baseline glucose value Ն8.3 mmol/L (Ն150 mg/dL), and a National Institutes of Health Stroke Scale score of 3 to 22. Patients were randomized 2:1 to aggressive treatment with continuous intravenous insulin or subcutaneous insulin QID as needed (usual care). Target glucose levels were Ͻ7.2 mmol/L (Ͻ130 mg/dL) in the aggressive-treatment group and Ͻ11.1 mmol/L (Ͻ200 mg/dL) in the usual-care group. Glucose was monitored every 1 to 2 hours, and the protocol treatments continued for up to 72 hours. Final clinical outcomes were assessed at 3 months. Results-We randomized 46 patients (31 to aggressive treatment and 15 to usual care). All patients in the aggressivetreatment group and 11 (73%) in the usual-care group had diabetes (Pϭ0.008). Glucose levels were significantly lower in the aggressive-treatment group throughout protocol treatment (

OBJECTIVE -Whereas new diagnostic criteria based on a fasting plasma glucose (FPG) of Ͼ126 mg/dl (7.8 mmol/l) have improved the detection of diabetes, multiple reports indicate that many people with diabetes diagnosed by 2-h oral glucose tolerance test (OGTT) glucose measurements of Ն11.1 mmol/l (200 mg/dl) would remain undiagnosed based on this FPG criteria. Thus, improved methods to detect diabetes are particularly needed for high-risk individuals. We evaluated whether the combination of FPG and HbA 1c measurements enhanced detection of diabetes in those individuals at risk for diabetes with nondiagnostic or minimally elevated FPG. RESEARCH DESIGN AND METHODS -We analyzed FPG, OGTT, and HbA 1c data from 244 subjects screened for participation in the Early Diabetes Intervention Program (EDIP).RESULTS -Of 244 high-risk subjects studied by FPG measurements and OGTT, 24% of the individuals with FPG levels of 5.5-6.0 mmol/l (100 -109 mg/dl) had OGTT-diagnosed diabetes, and nearly 50% of the individuals with FPG levels of 6.1-6.9 mmol/l (110 -125 mg/dl) had OGTT-diagnosed diabetes. In the subjects with OGTT-diagnosed diabetes and FPG levels between 5.5 and 8.0 mmol/l, detection of an elevated HbA 1c (Ͼ6.1% or mean ϩ 2 SDs) led to a substantial improvement in diagnostic sensitivity over the FPG threshold of 7.0 mmol/l (61 vs. 45%, respectively, P ϭ 0.002). Concordant FPG levels Ն7.0 mmol/l (currently recommended for diagnosis) occurred in only 19% of our cohort with type 2 diabetes. CONCLUSIONS -Diagnostic criteria based on FPG criteria are relatively insensitive in the detection of early type 2 diabetes in at-risk subjects. HbA 1c measurement improves the sensitivity of screening in high-risk individuals. Diabetes Care 24:465-471, 2001

Blood pressure (BP) in children may increase more during puberty. Using a cohort of children where BP and body size had been closely monitored, we compared the rates of change in BP during the 3-yr period before puberty, during puberty ( approximately 4.5-yr period), and the 3-yr period after puberty. Because there was no specific staging information with respect to puberty, we used pubertal growth (PG) as a surrogate of puberty. The latter was determined from serial measurements of height. All subjects (n = 151) were followed from before the period of PG to the period after PG; none were related. An age-dependent increase in systolic BP in the pre-PG period was similar regardless of sex or race. During PG, systolic BP in males increased three to six times faster than in the pre-PG period. In females, systolic BP increased less than in males during PG but still increased two to four times faster than in the pre-PG period. The increase in males was significantly greater than in females (P < 0.001). Post-PG changes in BP were similar to changes in pre-PG BP. In summary, PG was associated with profound increases in systolic BP. There were noticeably greater increments in males than in females consistent with the emergence of the well known sexual dimorphism in BP.

Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C zeta (PKC zeta) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC zeta with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.

UTI is common and may impose a substantial direct medical cost burden among patients with type 2 diabetes.

Systemic inhibition of nitric oxide synthase (NOS) with N Gmonomethyl-L -arginine ( L -NMMA) causes acute insulin resistance (IR), but the mechanism is unknown. We tested whether L -NMMA-induced IR occurs via NOS blockade in the central nervous system (CNS). Six groups of SpragueDawley rats were studied after chronic implantation of an intracerebroventricular (ICV) catheter into the lateral ventricle and catheters into the carotid artery and jugular vein. Animals were studied after overnight food deprivation, awake, unrestrained, and unstressed; all ICV infusion of L -NMMA or D -NMMA (control) were performed with artificial cerebrospinal fluid. ICV administration of L -NMMA resulted in a 30% rise in the basal glucose level after 2 h, while ICV D -NMMA had no effect on glucose levels. Insulin, epinephrine, and norepinephrine levels were unchanged from baseline in both groups. Tracer ( 3 H-3-glucose)-determined glucose disposal rates during 2 h euglycemic hyperinsulinemic (300 U/ml) clamps performed after ICV administration of L -NMMA were reduced by 22% compared with D -NMMA. Insulin secretory responses to a hyperglycemic clamp and to a superimposed arginine bolus were reduced by 28% in L -NMMA-infused rats compared with D -NMMA. In conclusion, ICV administration of L -NMMA causes hyperglycemia via the induction of defects in insulin secretion and insulin action, thus recapitulating abnormalities observed in type 2 diabetes. The data suggest the novel concept that central NOS-dependent pathways may control peripheral insulin action and secretion. This control is not likely to be mediated via adrenergic mechanisms and could occur via nonadrenergic, noncholinergic nitrergic neural and/or endocrine pathways. These data support previously published data suggesting that CNS mechanisms may be involved in the pathogenesis of some forms of insulin resistance and type 2 diabetes independent of adiposity. ( J. Clin. Invest.

Subjects with T2DM were more likely to experience a UTI and recurrent UTIs than subjects without T2DM during follow-up.