Genetics of 21-hydroxylase deficiency: Clinical presentation should guide the investigation.

A young couple applied for preconception counseling because of a case of congenital adrenal hyperplasia in the family. They were concerned about their risk of giving birth to a child with classic congenital adrenal hyperplasia. The case presented here demonstrates the complexity of the genetics of 21-hydroxylase deficiency and the way the clinical presentation should guide the genetic inquiry.

Parathyroid fine-needle aspiration with parathyroid hormone washout as a preoperative localisation of parathyroid adenoma-A retrospective study.

OBJECTIVE: The use of parathyroid lesion aspiration in preoperative adenoma localisation is controversial. Concerns have been raised regarding both immediate safety (hematoma, infection, alterations on a subsequent histologic preparate) and long-term safety (seeding). We aimed to evaluate the short- and long-term safety, and the efficacy, of parathyroid fine-needle aspiration with parathyroid hormone washout as a localisation modality of parathyroid adenoma in patients with primary hyperparathyroidism. DESIGN: A retrospective study. PATIENTS: The sample comprised 29 patients with primary hyperparathyroidism who underwent minimally invasive parathyroidectomy at a tertiary referral centre, following localisation with parathyroid hormone washout. MEASUREMENTS: We reviewed all parathyroid hormone washout procedures performed during 2011-2021. Clinical, biochemical, and imaging information; and cytology, surgery, and pathology reports were extracted from electronic medical records. RESULTS: Parathyroid hormone levels from the needle wash were 2.1-112.5 times the upper limit of the serum norm. Other than mild neck discomfort, no immediate procedure complications were documented. Fibrotic changes and necrosis were reported in two patients, with no effect on the final pathologic diagnosis or surgery course. No long-term complications (seeding, or parathyromatosis) were found. A total of 26 (90%) patients who were operated following a positive parathyroid hormone washout result were normocalcemic at the end of a mean 38.1-month follow-up period. CONCLUSIONS: Parathyroid fine-needle aspiration with parathyroid hormone washout was accurate. Immediate, surgical, or delayed complications were not demonstrated in our series. This approach might be considered for selected patients.

Effect of prandial treatment timing adjustment, based on continuous glucose monitoring, in patients with type 2 diabetes uncontrolled with once-daily basal insulin: A randomized, phase IV study.

AIMS: To evaluate the glycaemic control achieved by prandial once-daily insulin glulisine injection timing adjustment, based on a continuous glucose monitoring sensor, in comparison to once-daily insulin glulisine injection before breakfast in patients with type 2 diabetes who are uncontrolled with once-daily basal insulin glargine. MATERIALS AND METHODS: This was a 24-week open-label, randomized, controlled, multicentre trial. At the end of an 8-week period of basal insulin optimization, patients with HbA1c ≥ 7.5% and FPG < 130 mg/dL were randomized (1:1) to either arm A (no sensor) or arm B (sensor) to receive 16-week intensified prandial glulisine treatment. Patients in arm A received pre-breakfast glulisine, and patients in arm B received glulisine before the meal with the highest glucose elevation based on sensor data. The primary outcome was mean HbA1c at week 24 and secondary outcomes included rates of hypoglycaemic events and insulin dosage. RESULTS: A total of 121 patients were randomized to arm A (n = 61) or arm B (n = 60). There was no difference in mean HbA1c at week 24 between arms A and B (8.5% ± 1.2% vs 8.4% ± 1.0%; P = .66). The prandial insulin glulisine dosage for arm A and arm B was 9.3 and 10.1 units, respectively (P = .39). The frequency of hypoglycaemic events did not differ between study arms (36.1% vs 51.7%; P = .08). CONCLUSION: Using a CGM sensor to identify the meal with the highest glucose excursion and adjusting the timing of prandial insulin treatment did not show any advantage in terms of glycaemic control or safety in our patients.

The effect of continuous subcutaneous recombinant PTH (1-34) infusion during pregnancy on calcium homeostasis - a case report.

OBJECTIVE: We describe calcium homeostasis during pregestation and gestation in a woman with iatrogenic hypoparathyroidism, treated with continuous subcutaneous recombinant parathyroid hormone (PTH) (1-34) infusion. RESULTS: The requirement for PTH did not fluctuate much during pregnancy and was essential for maintaining normal calcium and phosphorus serum levels. CONCLUSIONS: This study documents the insufficiency of PTH-related protein (PTHrP) or other gestation-related hormones to compensate for PTH deficiency in hypoparathyroid women, and the successful utilization of continuous subcutaneous recombinant PTH (1-34) infusion to achieve normal calcium homeostasis during gestation. Clinical trials with PTH replacement in such circumstances are warranted.

Assessing the risk of having a child with classic 21-hydroxylase deficiency: a new paradigm.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a complicated condition genetically, clinically, and treatment wise. Genetically, there are numerus mutations with different effect on enzyme activity that make genetic diagnosis a challenge. Clinically, there are a wide range of presentations from asymptomatic patients to the severe life-threatening classic CAH. Both an asymptomatic heterozygote and a mildly affected non-classical patient can carry a 'severe' mutation and endow it to their offspring. We present a case of non-classic CAH and discuss the problematic relations between biochemical and genetic diagnosis. By integrating the seemingly contradicting literature, we provide a new simple tool to assess the risk of such patients to give birth to a child with classic CAH.

Salt-Losing 21-Hydroxylase Deficiency Caused by Double Homozygosity for Two "Mild" Mutations.

CONTEXT: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency presents with different severities that correlate with the genotype. The salt-losing phenotype requires 2 alleles with "severe" mutations. CASE DESCRIPTION: We present a case of salt-losing 21-hydroxylase deficiency that was found to be homozygous for 2 "mild" pathogenic variants: V281L and S301Y. Both in silico and heterologous expression functional analysis demonstrated that co-occurrence of these 2 mutations in cis severely impairs the function of the 21-hydroxylase enzyme. CONCLUSIONS: This case has important implications for genetic counseling. Regarding this combination of 2 "mild" variants as having mild phenotypic effects could lead to inappropriate counseling of heterozygote carriers.

Mesopic foveal contrast sensitivity is impaired in diabetic patients without retinopathy.

BACKGROUND: Contrast sensitivity (CS) has been studied extensively to determine its effectiveness as a test for diagnosing early and advanced diabetic retinopathy. Various techniques have been adopted to measure CS, and most of them reported a significant difference between diabetic and normal eyes. Our purpose is to demonstrate differences in foveal CS between diabetic patients without retinopathy and healthy subjects under mesopic and photopic conditions, using a simple, rapid computerized test. METHODS: Seventeen eyes of nine patients with type 2 diabetes without diabetic retinopathy were included. Fourteen eyes of seven non-diabetic patients served as controls. All the patients underwent a careful ophthalmologic examination, including ETDRS chart visual acuity, color photographs, and optical coherence tomography (OCT). Patients with any ocular disease were excluded. All eyes had a visual acuity of 20/25 or better, a normal eye examination and optical coherence tomography (OCT). Photopic and mesopic contrast sensitivity was tested using a computerized psychophysical static method involving four forced-choice procedures. The targets were Gabor patches with spatial frequencies of 3-12 cycles per degree (cpd). The mesopic testing was conducted in a completely darkened room; the monitor was covered with a neutral density filter, allowing luminance of only 0.9 cd/m(2). RESULTS: The average age was similar: 59.1 ± 5.3 years in the diabetic group vs 61.4 ± 3.2 years in the control group. The average duration of diabetes was 16 years (range 6-26). The average visual acuity was 0.04 ± 0.01 logMAR and 0.01 ± 0.01 logMAR in the diabetic and control groups respectively. Photopic foveal CS was similar in both groups. Significantly lower CS was found in diabetic patients under mesopic conditions at a spatial frequency of 3 (p < 0.008). At higher spatial frequencies, the mesopic contrast sensitivity was very low in both groups and without a significant difference. CONCLUSIONS: Mesopic foveal CS is impaired in diabetic patients despite good visual acuity, a normal fundus examination and normal OCT. Early central visual function impairment may occur in diabetic patients before the appearance of retinopathy.

Efficacy of long-term lanreotide treatment in patients with acromegaly.

We investigated the effectiveness of lanreotide for the treatment of active acromegaly in a retrospectively multicenter case series including 53 patients (24 male, 29 female; mean age at diagnosis, 49.5 +/- 13.9 years) with acromegaly treated with lanreotide in nine different centers. Mean tumor diameter was 20 +/- 13 mm; mean basal levels of growth hormone (GH) and insulin-like growth factor I (IGF-I) were 21.3 +/- 26.3 and 579 +/- 177 mug/l, respectively. The primary mode of treatment was surgery in 70% of patients. Twenty-nine patients received only lanreotide (Prolonged Release, Autogel), whereas 24 subjects were also treated with octreotide at another treatment stage. Primary therapy with lanreotide was administered in five patients. Maximal monthly dose of lanreotide Autogel (n = 44) was 60 mg in 45%, 90 mg in 26%, 120 mg in 21% and 180 mg in 8%. During 36 months of lanreotide treatment, mean IGF-I levels decreased from 443 +/- 238 to 276 +/- 147 mug/l (P < 0.001), and mean GH levels, from 5.2 +/- 6.4 to 3.2 +/- 3.0 mug/l (P < 0.001). IGF-I levels normalized in 51% of patients and decreased by >50% towards normal in 32%; the normalization rate was higher in women (65%) than men (33%, P = 0.04). Safe random GH levels (

Rad GTPase deficiency leads to cardiac hypertrophy.

BACKGROUND: Rad (Ras associated with diabetes) GTPase is the prototypic member of a subfamily of Ras-related small G proteins. The aim of the present study was to define whether Rad plays an important role in mediating cardiac hypertrophy. METHODS AND RESULTS: We document for the first time that levels of Rad mRNA and protein were decreased significantly in human failing hearts (n=10) compared with normal hearts (n=3; P<0.01). Similarly, Rad expression was decreased significantly in cardiac hypertrophy induced by pressure overload and in cultured cardiomyocytes with hypertrophy induced by 10 micromol/L phenylephrine. Gain and loss of Rad function in cardiomyocytes significantly inhibited and increased phenylephrine-induced hypertrophy, respectively. In addition, activation of calcium-calmodulin-dependent kinase II (CaMKII), a strong inducer of cardiac hypertrophy, was significantly inhibited by Rad overexpression. Conversely, downregulation of CaMKIIdelta by RNA interference technology attenuated the phenylephrine-induced hypertrophic response in cardiomyocytes in which Rad was also knocked down. To further elucidate the potential role of Rad in vivo, we generated Rad-deficient mice and demonstrated that they were more susceptible to cardiac hypertrophy associated with increased CaMKII phosphorylation than wild-type littermate controls. CONCLUSIONS: The present data document for the first time that Rad is a novel mediator that inhibits cardiac hypertrophy through the CaMKII pathway. The present study will have significant implications for understanding the mechanisms of cardiac hypertrophy and setting the basis for the development of new strategies for treatment of cardiac hypertrophy.

The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance.

Insulin receptors (IRs) on vascular endothelial cells have been suggested to participate in insulin-regulated glucose homeostasis. To directly address the role of insulin action in endothelial function, we have generated a vascular endothelial cell IR knockout (VENIRKO) mouse using the Cre-loxP system. Cultured endothelium of VENIRKO mice exhibited complete rearrangement of the IR gene and a more than 95% decrease in IR mRNA. VENIRKO mice were born at the expected Mendelian ratio, grew normally, were fertile, and exhibited normal patterns of vasculature in the retina and other tissues. Glucose homeostasis under basal condition was comparable in VENIRKO mice. Both eNOS and endothelin-1 mRNA levels, however, were reduced by approximately 30-60% in endothelial cells, aorta, and heart, while vascular EGF expression was maintained at normal levels. Arterial pressure tended to be lower in VENIRKO mice on both low- and high-salt diets, and on a low-salt diet VENIRKO mice showed insulin resistance. Thus, inactivation of the IR on endothelial cell has no major consequences on vascular development or glucose homeostasis under basal conditions, but alters expression of vasoactive mediators and may play a role in maintaining vascular tone and regulation of insulin sensitivity to dietary salt intake.

Glucose Outcomes with the In-Home Use of a Hybrid Closed-Loop Insulin Delivery System in Adolescents and Adults with Type 1 Diabetes.

BACKGROUND: The safety and effectiveness of the in-home use of a hybrid closed-loop (HCL) system that automatically increases, decreases, and suspends insulin delivery in response to continuous glucose monitoring were investigated. METHODS: Adolescents (n = 30, ages 14-21 years) and adults (n = 94, ages 22-75 years) with type 1 diabetes participated in a multicenter (nine sites in the United States, one site in Israel) pivotal trial. The Medtronic MiniMed® 670G system was used during a 2-week run-in phase without HCL control, or Auto Mode, enabled (Manual Mode) and, thereafter, with Auto Mode enabled during a 3-month study phase. A supervised hotel stay (6 days/5 nights) that included a 24-h frequent blood sample testing with a reference measurement (i-STAT) occurred during the study phase. RESULTS: Adolescents (mean ± standard deviation [SD] 16.5 ± 2.29 years of age and 7.7 ± 4.15 years of diabetes) used the system for a median 75.8% (interquartile range [IQR] 68.0%-88.4%) of the time (2977 patient-days). Adults (mean ± SD 44.6 ± 12.79 years of age and 26.4 ± 12.43 years of diabetes) used the system for a median 88.0% (IQR 77.6%-92.7%) of the time (9412 patient-days). From baseline run-in to the end of study phase, adolescent and adult HbA1c levels decreased from 7.7% ± 0.8% to 7.1% ± 0.6% (P < 0.001) and from 7.3% ± 0.9% to 6.8% ± 0.6% (P < 0.001, Wilcoxon signed-rank test), respectively. The proportion of overall in-target (71-180 mg/dL) sensor glucose (SG) values increased from 60.4% ± 10.9% to 67.2% ± 8.2% (P < 0.001) in adolescents and from 68.8% ± 11.9% to 73.8% ± 8.4% (P < 0.001) in adults. During the hotel stay, the proportion of in-target i-STAT® blood glucose values was 67.4% ± 27.7% compared to SG values of 72.0% ± 11.6% for adolescents and 74.2% ± 17.5% compared to 76.9% ± 8.3% for adults. There were no severe hypoglycemic or diabetic ketoacidosis events in either cohort. CONCLUSIONS: HCL therapy was safe during in-home use by adolescents and adults and the study phase demonstrated increased time in target, and reductions in HbA1c, hyperglycemia and hypoglycemia, compared to baseline. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02463097.

Low-dose recombinant human thyrotropin-aided radioiodine treatment of large, multinodular goiters in elderly patients.

OBJECTIVE: We aimed to assess low-dose recombinant human thyroid-stimulating hormone (rhTSH)-aided, fixed-activity radioiodine therapy of large, multinodular goiters (MNGs) in elderly patients with comorbidities. DESIGN: This was a short-term, observational study. METHODS: We measured 24-h thyroid radioiodine uptake (RAIU) of 2 microCi 131-iodine at baseline and 24 h after intramuscular injection of 0.03 mg rhTSH in 17 patients (aged 60-86 years, 12 women), who subsequently received 30 mCi 131-iodine 24 h after an identical rhTSH injection. TSH and free thyroxine (FT4) were measured at baseline and days 10, 30 and 90 after therapy. Thyroid volume was assessed by computed tomography at baseline and day 180. RESULTS: rhTSH, 0.03 mg, significantly increased mean 24-h thyroid RAIU from 25.8% +/- 10.3% to 43.3% +/- 8.4% (68% relative increase; t(16) = -8.43, P < 0.001). The proportion of patients overtly or subclinically hyperthyroid (TSH < 0.5 mU/l) decreased from 71% (12/17) at baseline to 19% (3/16) at 3 months. Mean serum FT4 peaked at slightly above normal range, 25.9 +/- 7.7 pmol/l (46% over baseline) and was 21% under baseline levels at 3 months. Mean estimated thyroid volume fell 34% from baseline to 6 months (170.0 +/- 112.8 to 113.1 +/- 97.5 ml; P < 0.01). Symptomatic relief, improved well-being, and/or reduction or elimination of antihyperthyroid medication were seen in 76% of patients. Three (18%) patients had transient neck pain or tenderness, or palpitations; one had transient asymptomatic thyroid enlargement; and three (18%) became hypothyroid by 3 months. CONCLUSIONS: Intramuscular rhTSH, 0.03 mg, followed 24 h later by 30 mCi 131-iodine, is a safe, effective and convenient treatment for MNG in elderly patients with comorbidities.

Feedback inhibition of gonadotropins by testosterone in men with hypogonadotropic hypogonadism: comparison to the intact pituitary-testicular axis in primary hypogonadism.

Men with hypogonadotropic hypogonadism (HH) due to hypothalamic-pituitary disease present with low serum testosterone levels combined with undetectable, low, or normal gonadotropin levels. Treatment consists of testosterone replacement to reverse the symptoms of androgen deficiency. The aim of this study was to examine the dynamics and feedback inhibition of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in relation to testosterone in 38 men with HH treated with testosterone. Findings were compared with 11 men with primary hypergonadism (PH). Testosterone replacement led to a suppression of FSH levels from 2.8 IU/L at baseline to 1.1 IU/L and to a suppression of LH levels from 2.3 to 0.8 IU/L. There was a linear correlation between levels of FSH and LH (after natural log transformation for both) and testosterone levels in both the HH and PH groups. However, the differences in intercepts and slopes between the groups were significant. To determine whether nonsuppressed FSH or LH during testosterone replacement reduces the probability of eugonadism, as reflected by normal testosterone levels, gonadotropin levels were measured and categorized as low (<0.5 IU/L), medium (0.5-2 IU/L), and high levels (>2 IU/L). The higher FSH or LH levels were found to significantly decrease the chance for achieving eugonadism. In conclusion, in men with HH due to hypothalamic-pituitary disease or injury, the pituitary-testicular hormonal axis maintains its physiological negative feedback between testosterone and gonadotropins. Thus, gonadotropin levels in men with HH might be useful, together with testosterone concentrations, for assessing the adequacy of androgen replacement.

Hybrid Closed-Loop Insulin Delivery in Type 1 Diabetes During Supervised Outpatient Conditions.

BACKGROUND: Efficacy and safety of the Medtronic Hybrid Closed-Loop (HCL) system were tested in subjects with type 1 diabetes in a supervised outpatient setting. METHODS: The HCL system is a prototype research platform that includes a sensor-augmented insulin pump in communication with a control algorithm housed on an Android-based cellular device. Nine subjects with type 1 diabetes (5 female, mean age 53.3 years, mean A1C 7.2%) underwent 9 studies totaling 571 hours of closed-loop control using either default or personalized parameters. The system required meal announcements with estimates of carbohydrate (CHO) intake that were based on metabolic kitchen quantification (MK), dietician estimates (D), or subject estimates (Control). Postprandial glycemia was compared for MK, D, and Control meals. RESULTS: The overall sensor glucose mean was 145 ± 43, the overall percentage time in the range 70-180 mg/dL was 80%, the overall percentage time <70 mg/dL was 0.79%. Compared to intervals of default parameter use (225 hours), intervals of personalized parameter use (346 hours), sensor glucose mean was 158 ± 49 and 137 ± 37 mg/dL (P < .001), respectively, and included more time in range (87% vs 68%) and less time below range (0.54% vs 1.18%). Most subjects underestimated the CHO content of meals, but postprandial glycemia was not significantly different between MK and matched Control meals (P = .16) or between D and matched Control meals (P = .76). There were no episodes of severe hypoglycemia. CONCLUSIONS: The HCL system was efficacious and safe during this study. Personally adapted HCL parameters were associated with more time in range and less time below range than default parameters. Accurate estimates of meal CHO did not contribute to improved postprandial glycemia.

Regulatory T-cells in Graves' orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin.

BACKGROUND AND AIM: Graves' orbitopathy (GO) is characterized by orbital T cell infiltration and local release of proinflammatory cytokines. We aimed to evaluate the involvement of baseline regulatory T (Treg) cells and rabbit anti-T lymphocyte globulin (rATG)-induced Treg cells in GO. DESIGN: Peripheral blood mononuclear cells (PBMCs) from seven patients with Graves' disease (GD) without eye manifestations, 29 patients with GO, and 15 healthy controls were incubated with rATG, washed, and analyzed for expression of Treg cell markers and for ability to suppress mixed lymphocyte reaction. RESULTS: Elevation of CD4 to CD8 ratio and enhanced secretion of IL-6, IL-10, and TNFα were detected in PBMCs of GO patients compared with controls (both P < 0.01). Despite this abnormality, the frequencies of CD4(+)CD25(+)FoxP3(+) of GO and control PBMCs were similar and remained unchanged after 24 h incubation with control rabbit IgG (rIgG). Incubation with polyclonal rATG increased the frequency of PBMCs of GO patients, expressing Treg cell markers (CD25, FoxP3, and the IL-7 receptor CD127(low/-)) by 2.5-8 fold over corresponding rIgG-incubated cells (P < 0.05). FoxP3/CD4 rATG-induced Treg cell marker expressed more intensively on GO peripheral blood leukocytes (PBLs) than on GD (P < 0.01) or normal (P < 0.05) PBLs, yet its expression on normal PBLs was stronger than on GD PBLs (P < 0.05). GO rATG-incubated PBMCs, but not rIgG-incubated PBMCs, suppressed (P < 0.05) proliferation of autologous responder cells stimulated with allogeneic irradiated cells in mixed lymphocyte reaction. Such rATG-induced suppressive activity was not detected in GD. CONCLUSION: This study is the first to show that PBMCs of patients with GO substantially increase Treg cells in both frequency and potency after in vitro incubation with rATG.

Glucose homeostasis abnormalities in cardiac intensive care unit patients.

The aim of this study was to characterize the abnormalities in glucose homeostasis in intensive care unit patients following an acute coronary event. The study population included all non-diabetic patients ages 20-80 years that were admitted to a coronary intensive unit. Glucose, insulin and C-peptide levels during an oral glucose tolerance test (OGTT) were measured during the acute admission. From January to September 2003, 277 patients were admitted to the coronary unit. Of these, 127 patients underwent an OGTT. Of these, only 29 patients (23%) exhibited normal glucose metabolism. The remainder had type 2 diabetes (32%), impaired glucose tolerance (37%) or isolated impaired fasting glucose (8%, 100-125 mg/dl). Based on homeostasis model assessment (HOMA) calculations, diabetic patients had impaired beta-cell function and patients with elevated fasting glucose levels were insulin resistant. Beta-cell dysfunction during the acute stress seems to contribute to the glucose abnormalities. Most patients who experience an acute coronary event demonstrate abnormal glucose metabolism. Post glucose-load abnormalities are more common than abnormal fasting glucose level in this situation. It is postulated that the acute stress of a coronary event may contribute to the dysglycemia.

Comparison of myocardial reperfusion in patients with fasting blood glucose < or =100, 101 to 125, and >125 mg/dl and ST-elevation myocardial infarction with percutaneous coronary intervention.

Diabetes and impaired fasting glucose (FG) were associated with worse outcomes in patients with acute myocardial infarction (MI). Because the underlying mechanism is not entirely clear, 376 consecutive patients with ST-elevation MI who underwent primary percutaneous coronary intervention (PPCI) were investigated. Patients were divided into 3 groups based on FG < or =100, FG of 101 to 125, and FG >125 mg/dl or previously diagnosed diabetes mellitus (DM) and studied for electrocardiographic signs of myocardial reperfusion (both spontaneous and after PPCI) and clinical outcomes. Clinical reperfusion was less likely with increasing FG: FG < or =100 mg/dl, 26%; FG of 101 to 125, 19%; and FG >125 and/or DM, 16% (p for trend = 0.03). Accordingly, angiographic TIMI grade 3 flow on initial angiography was 22% for FG < or =100 mg/dl, 13% for FG of 101 to 125, and 14% for FG >125 and/or DM (p for trend = 0.05). Despite similar TIMI flow after PPCI, early ST-segment resolution (> or =70%) was noted in 76%, 63%, and 60% in patients with FG < or =100 mg/dl, FG of 101 to 125, and FG >125 and/or DM, respectively (p for trend <0.01). Peak creatine phosphokinase (CPK) increased gradually, whereas left ventricular ejection fraction decreased with increased FG. Worse outcomes were observed with increasingly higher FG for heart failure (9%, 23%, and 26%; p for trend <0.01), cardiogenic shock (5%, 7%, and 13%; p for trend = 0.02), in-hospital mortality (1%, 2%, and 6%; p for trend = 0.01), and long-term mortality (2.5%, 4.5%, and 12%; p for trend <0.01) for patients with FG < or =100 mg/dl, FG of 101 to 125, and FG >125 and/or DM, respectively. In conclusion, increased FG and previously diagnosed DM were associated with less spontaneous reperfusion and less myocardial reperfusion after PPCI, resulting in worse clinical outcomes.

Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level.

Rad is a low molecular weight GTPase that is overexpressed in skeletal muscle of some patients with type 2 diabetes mellitus and/or obesity. Overexpression of Rad in adipocytes and muscle cells in culture results in diminished insulin-stimulated glucose uptake. To further elucidate the potential role of Rad in vivo, we have generated transgenic (tg) mice that overexpress Rad in muscle using the muscle creatine kinase (MCK) promoter-enhancer. Rad tg mice have a 6- to 12-fold increase in Rad expression in muscle as compared to wild-type littermates. Rad tg mice grow normally and have normal glucose tolerance and insulin sensitivity, but have reduced plasma triglyceride levels. On a high-fat diet, Rad tg mice develop more severe glucose intolerance than the wild-type mice; this is due to increased insulin resistance in muscle, as exemplified by a rightward shift in the dose-response curve for insulin stimulated 2-deoxyglucose uptake. There is also a unexpected further reduction of the plasma triglyceride levels that is associated with increased levels of lipoprotein lipase in the Rad tg mice. These results demonstrate a potential synergistic interaction between increased expression of Rad and high-fat diet in creation of insulin resistance and altered lipid metabolism present in type 2 diabetes.