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Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum-resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux., Numerous studies have investigated the biological impact of variations in fasting blood glucose (FBG) levels in humans. Elevated FBG has been shown to be associated with increased risk for the [...]

OBJECTIVE--Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), now known as G6PC2, is a major target of autoreactive T cells implicated in the pathogenesis of type 1 diabetes in both mice and humans. This study aimed to determine whether suppression of G6p2 gene expression might therefore prevent or delay disease progression. RESEARCH DESIGN AND METHODS--[G6pc2.sup.-/-] mice were generated on the NOD/ShiLtJ genetic background, and glycemia was monitored weekly up to 35 weeks of age to determine the onset and incidence of diabetes The antigen specificity of [CD8.sup.+] T cells infiltrating islets from NOD/ShiLtJ [G6pc2.sup.+/+] and [G6pc2.sup.-/-] mice at 12 weeks was determined in parallel. RESULTS--The absence of G6pc2 did not affect the time of onset, incidence, or sex bias of type 1 diabetes in NOD/ShiLtJ mice. Insulitis was prominent in both groups, but whereas NOD/ ShiLtJ [G6pc2.sup.+/+] islets contained [CD8.sup.+] T cells reactive to the G6pc2 NRP peptide, G6pc2 NRP-reactive T cells were absent in NOD/ShiLtJ [G6pc2.sup.-/-]islets. CONCLUSIONS--These results demonstrate that G6pc2 is an important driver for the selection and expansion of islet-reactive [CD8.sup.+] T cells infiltrating NOD/ShiLtJ islets. However, autoreactivity to G6pc2 is not essential for the emergence of autoimmune diabetes. The results remain consistent with previous studies indicating that insulin may be the primary autoimmune target, at least in NOD/ShiLtJ mice. Diabetes 60:2922-2927, 2011, The G6PC gene family is composed of three members, G6PC, G6PC2, and G6PC3 (1), each encoding multispanning membrane proteins located in the endoplasmic reticulum that catalyze the hydrolysis of glucose-6-phosphate [...]

OBJECTIVE--Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. RESEARCH DESIGN AND METHODS--We genotyped 9,532 normal FPG participants (FPG RESULTS--Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: β = 0.075, P = 3.6 x 10-a5; rs573225 = 0.073 P = 3.6 x [10.sup.-34]), in addition to rs560887 (13 = 0.071, P = 1.2 x [10.sup.-31]). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity. CONCLUSIONS--Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out. Diabetes 59:2662-2671, 2010, The glucose-6-phosphatase catalytic subunit gene family comprises three members, G6PC, G6PC2, and G6PC3 (1). G6PC2, also known as the IGRP gene (2-4), is principally expressed in the 13-cells of pancreatic [...]

OBJECTIVE--We explored whether cardiovascular disease (CVD) risk and the effects of fenofibrate differed in subjects with and without metabolic syndrome and according to various features of metabolic syndrome defined by [...]

OBJECTIVE--Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is selectively expressed in islet β-cells and is a major autoantigen in both mouse and human type 1 diabetes. This study describes the use [...]

We have previously reported the discovery of an islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) that is predominantly expressed in islet [beta]-cells. IGRP has recently been identified as a major autoantigen in a mouse model of type 1 diabetes. The analysis of IGRP-chloramphenicol acetyltransferase (CAT) fusion gene expression in transiently transfected islet-derived hamster insulinoma tumor and [beta]TC-3 cells revealed that the promoter region located between -306 and +3 confers high-level reporter gene expression. To determine whether this same promoter region is sufficient to confer islet [beta]-cell-specific gene expression in vivo, it was ligated to a [beta]-galactosidase reporter gene, and transgenic mice expressing the resulting fusion gene were generated. In two independent founder lines, this -306 to +3 promoter region was sufficient to drive [beta]-galactosidase expression in newborn mouse islets, predominantly in [beta]-cells, which was initiated during the expected time in development, around embryonic day 12.5. However, unlike the endogenous IGRP gene, [beta]-galactosidase expression was also detected in the cerebellum. Moreover, [beta]-galactosidase expression was almost completely absent in adult mouse islets, suggesting that cis-acting elements elsewhere in the IGRP gene are required for determining appropriate IGRP tissue-specific expression and for the maintenance of IGRP gene expression in adult mice., Islet-specific glucose-6-phosphatase (G6Pase) catalytic subunit-related protein (IGRP) is a putative enzyme that is specifically expressed in the islets of Langerhans (1-3), where it is localized predominantly in insulin-producing [beta]-cells (4). [...]

Glucose-6-phosphatase (G6Pase) is a multicomponent system located in the endoplasmic reticulum comprising a catalytic subunit and transporters for glucose-6-phosphate, inorganic phosphate, and glucose. We have recently cloned a novel gene [...]

The effect of the angiotensin-converting enzyme inhibitor, perindopril, on functional and structural parameters of diabetic nephropathy has been compared with triple therapy (hydralzine, reserpine, and hydrochlorothiazide) in normotensive, STZ-induced diabetic [...]

The effects of enalapril (an angiotensin-converting enzyme inhibitor), hydralazine and metoprolol (conventional antihypertensive drugs) on kidney function; the urinary excretion of the blood protein albumin; and the structure of glomeruli (the filtering units of the kidney) were assessed in experimental hypertensive rats with and without diabetes. Spontaneously hypertensive rats (SHR; a special breed of rats with high blood pressure) were made diabetic with the agent streptozocin, which destroys the insulin-secreting beta cells in the pancreas. The antihypertensive drugs were given to the rats in their drinking water. Enalapril and hydralazine plus metoprolol produced similar decreases in blood pressure. The blood levels of creatinine (an indicator of kidney function) increased in untreated diabetic SHR rats after 32 weeks, but not in treated, diabetic and treated, nondiabetic SHR rats. Both drug regimens caused similar decreases in albuminuria (urinary excretion of albumin), thickening of the glomerular basement membrane, and glomerular volume. These findings show that antihypertensive treatment delays the development of albuminuria, glomerular basement thickening, and glomerular overgrowth in SHR rats with and without diabetes. Enalapril did not appear to have additional benefit over the conventional antihypertensive agents in these models of hypertension-related kidney disease. Studies examining the effects of different types of antihypertensive agents on kidney function, albuminuria, and glomerular structure in humans are needed. (Consumer Summary produced by Reliance Medical Information, Inc.)

Tuberculosis (TB), an infectious disease caused by the tubercle bacillus, is characterized by the formation of abnormal growths called tubercles, abscesses, and fiber-like tissue, as well as calcium deposits and tissue deterioration. The infection commonly affects the respiratory system, but may also involve other body organs. Two drug regimens for treating TB were compared. In the six-month regimen, isoniazid, rifampin and pyrazinamide were taken daily for eight weeks, and, then, isoniazid and rifampin were taken daily for four months. In the second therapeutic plan, isoniazid and rifampin were taken daily for nine months. There were 617 patients with TB assigned to the six-month regimen, and 445 TB patients assigned to the nine-month program. The results demonstrate that patients on the six-month regimen improved more rapidly than patients on the nine-month regimen. Both groups had similar rates of adverse drug reactions. Patients on the six-month regimen had better compliance or better tolerance of drug therapy. Both groups had similar relapse rates two years after completing drug therapy. More patients successfully completed the six-month drug regimen than the nine-month drug regimen. The results show that the six-month drug regimen is similar in effectiveness, toxicity, and tolerance to the nine-month regimen for treating TB affecting the lungs. (Consumer Summary produced by Reliance Medical Information, Inc.)

NHS Direct must be better marketed and deal with problems more effectively EDITOR--In their responses to the paper by Munro et al,[1] who found that NHS Direct had no appreciable [...]

Insulin inhibits basal glucose-6-phosphatase catalytic subunit (G6Pase) and insulin-like growth factor binding protein-1 (IGFBP-1) gene transcription through the same inhibitory insulin response sequence (IRS). This IRS has the consensus sequence [...]

Glucose-6-phosphatase is a multi-component system that catalyzes the terminal step in gluconeogenesis and hepatic glycogenolysis. To examine the effect of the cAMP signal transduction pathway on expression of the gene [...]

Transcription Factor FKHR Binds the Insulin Response Sequence Because overexpression of the glucose-6-phosphatase catalytic subunit (G-6-Pase) in both type 1 and type 2 diabetes may contribute to the characteristic increased [...]

In liver and kidney the terminal step in gluconeogenesis is catalyzed by glucose-6-phosphatase. To examine the effect of the cAMP signal transduction pathway on transcription of the gene encoding the [...]

We have recently cloned the gene encoding an islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). The amino acid sequence of IGRP is approximately 50% identical to that of the catalytic subunit [...]

In liver the terminal step in both the gluconeogenic and glycogenolytic pathways, the dephosphorylation of glucose-6-phosphate to glucose, is catalyzed by glucose-6-phosphatase. This enzyme is thought to be a multisubunit [...]

Insulin and phorbol esters stimulate the transcription of multiple genes through the AP- 1 motif. The mechanisms of insulin and phorbol ester action are distinct but both involve the stimulation [...]

Whereas extralymphatic involvement is common in lymphomas associated with HIV infection, there have been few reports of pulmonary lymphoma. In 648 eases of MDS reported in Colorado, 40 have had [...]

We describe the clinical course and pleural fluid findings in patients with AIDS-associated pleural KS and survival analysis of cases from the Colorado registry with and without pleuropulmonary KS. Twenty-one [...]

Byline: Richard P O'Brien Author Affiliation: Emergency Department Moses Taylor Hospital Scranton, Pennsylvania

To the Editor: We read with interest the article by Singer et al (1) which reported elevated serum angiotensin converting enzyme (ACE) levels in patients with AIDS and Pneumocystis carinii [...]

In liver and kidney, the terminal step in the gluconeogenic pathway is catalyzed by glucose-6-phosphatase (G-6-Pase). This enzyme is actually a multicomponent system, the catalytic subunit of which was recently [...]

A pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP) was cloned using a subtractive cDNA expression cloning procedure from mouse insulinoma tissue. Two alternatively spliced variants that differed by the presence or absence [...]

News briefs on sports are presented. Saint Louis University basketball coach Rick Majerus has taken a leave of absence for health reasons. Los Angeles Dodgers sportscaster Vin Scully announced he would return for the 2013 season. Minor league baseball player Justin Toole played all nine positions in the field during one game.

Profiles Magic Johnson and developments in his life and health since his announcement, on November 7, 1991, that he was HIV-positive. Activities such as a world tour with the Magic Johnson All-Stars, development of a syndicated television talk show and adoption of a second child with his wife, Cookie; Cookie's announcement that Johnson was healed, due to a reduction in his viral load; Cautions against this optimism from virologist David Ho, who treats Johnson with prototease inhibitors.

Relates that 1993 world bicycling champion Lance Armstrong has developed testicular cancer. The spreading of the disease; The removal of the Texan's malignant testicle and use of chemotherapy; Speculation on Armstrong's possible use of performance-enhancing drugs as the cause.

Announces the decision to let Nicholas Knapp play basketball for the Northwestern Wildcats despite his heart condition in the 1996 season. Judge James B. Zagel's citing of the federal Rehabilitation Act; Knapp's history with his heart condition and playing.

Profiles University of Florida basketball player Eddie Shannon, who will play the 1998-1999 season with only one eye after he had his right eye removed in October of 1998. Why Shannon's eye was removed; How the loss of one eye is expected to impact Shannon's ability to play basketball; Comments from Shannon, who has been compensating for vision loss in the damaged eye since he was in seventh grade.

Relates how American International College linebacker Dave Zanin was rescued by three labrador retrievers after a hunting accident in Massachusetts. Circumstances; The dogs' response; Details of the rescue.

Focuses on Dan Kendra, who would have been the starting quarterback for the Florida State Seminoles football team in the 1998 season, if he had not torn the anterior cruciate ligament in his right knee during an intrasquad scrimmage in April of 1998. What the injury means for Kendra's hopes of playing professional football; Other injuries which Kendra has faced.

Focuses on Washington Wizards' Gheorghe Muresan and his movie debut in `My Giant.' The author's review of the movie and Muresan's acting abilities; How Muresan will not play a single minute in the 1998 season because of a stretched tendon in his right-ankle; Whether Muresan will ever be able to play basketball again.

Reports that Pete Sampras, the world's top-ranked tennis player for the last five years, may never play in another Davis Cup again. Injuries he endured at the 1997 Davis Cup; The Davis Cup not generating much excitement back in the United States; Comments from Sampras.

Focuses on hunter heart attacks. How hunting can cause scores of heart attacks in hunters overexcited by the sighting or shooting of a deer; Case of Roger Pawlovich; Comments from Susan Haapaniemi, an exercise physiologist at William Beaumont Hospital in Michigan on the strenuous nature of hunting; How hunting can be addictive.

An interview is presented with college basketball player Nerlens Noel of the University of Kentucky. Noel says his rehabilitation from anterior cruciate ligament (ACL) surgery is ahead of schedule. He defends his decision to declare himself eligible for the 2013 National Basketball Association (NBA) draft. Noel says he was a childhood fan of the Boston Celtics team in the NBA.

Reports that Nashville Predators defenseman Jan Vopat has developed an allergic reaction to something in his uniform and pads. Details of attempts by doctors to heal the rash; Why sweating makes the rash worse; Comments of coach Barry Trotz; How Vopat has continued to practice while on injured reserve.

Focuses on former Buffalo Bills football coach Marv Levy as of July 1999. Diagnosis of prostate cancer; His contact with Len Dawson, a former quarterback for the Kansas City Chiefs and a prostate cancer survivor; Importance of the conversations about cancer; His role in helping others with cancer; Comments from Levy.

Focuses on tennis player Rod Laver as of April 5, 1999. His recovery from a stroke in July 1998; His appearance at the Lipton Championships in Key Biscayne, Florida in 1999; Effects of his stroke; Comments from Laver.