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PubMedDate not supplied

Ultrastructure of lamellar bodies in congenital surfactant deficiency.

Congenital surfactant deficiency (CSD) is a newly identified neonatal lung disorder associated with a variety of molecular defects affecting surfactant synthesis and secretion in alveolar type II cells. The authors present ultrastructural findings of abnormal lamellar bodies in lung biopsies from 4 infants with CSD. All were term infants presenting shortly after birth with severe respiratory failure that was unresponsive to conventional therapy and all died within the first month of life. Lung biopsies were performed between 8 and 25 days of age. Biochemical and molecular studies in 2 unrelated male infants identified SP-B deficiency, one case with 121 ins 2 mutation and the second with a 209 + 4 A > G mutation. Light microscopy in both cases showed features of alveolar proteinosis. Ultrastructurally, alveolar type II cells lacked mature lamellar bodies, and their cytoplasm contained numerous pleomorphic inclusions with membranous and vesicular structures not seen in normal type II cells. The other 2 infants were a pair of siblings in whom molecular studies identified mutations in ABCA3 transporter gene. Light microscopy showed features of acinar dysplasia and desquamative interstitial pneumonitis. TEM studies revealed absence of mature lamellar bodies in type II cells and instead showed a mixture of cytoplasmic electron-dense inclusions with concentric membranes and distinctive electron dense aggregates. The ultrastructural changes in alveolar type II cells correlated well with specific gene defect. In SP-B deficiency, the absence of mature lamellar bodies is consistent with the postulated role for this protein in the formation of lamellar bodies. The lack of mature lamellar bodies in the ABCA3 gene mutations is due to the dysfunction of this endogenous lipid transporter that targets surfactant lipid moieties to the lamellar bodies. The findings demonstrate the importance of TEM studies of lung biopsies from infants with CSD as it is a critical adjunct in the diagnosis of neonatal lung disease and in defining the underlying cellular defects.

ATP-Binding Cassette Transporters↗
PubMed1991

The aetiology of non-insulin-dependent diabetes mellitus: is abnormal suppression of hepatic gluconeogenesis the primary event?

Despite intensive research effort, the aetiology of non-insulin dependent diabetes mellitus remains unknown. In this disorder, hyperglycaemia results from three defects: impaired suppression of hepatic glucose production; reduced peripheral clearance of glucose; and impaired glucose-mediated insulin secretion. It has been proposed that reduced peripheral glucose clearance is the primary or inherited defect and that hyperinsulinaemia secondary to this eventually leads to beta cell exhaustion and impaired insulin secretion. Other authors have proposed that the initial defect is an abnormality in the first phase of insulin secretion. In this paper it is proposed that the primary abnormality is failure of hepatic gluconeogenesis to suppress adequately and that the resulting excess glucose flux results in peripheral insulin resistance and in a defect of glucose-mediated insulin secretion. This hypothesis is supported by recent data showing the glucose per se can induce defects in insulin action and insulin secretion.

Diabetes Mellitus, Type 2↗
PubMed2003

Reelin-immunoreactive neurons, axons, and neuropil in the adult ferret brain: evidence for axonal secretion of reelin in long axonal pathways.

Reelin is a large secretable protein which, when developmentally defective, causes the reeler brain malformation in mice and a recessive form of lissencephaly with cerebellar hypoplasia in humans. In addition, Reelin is heavily expressed throughout the adult brain, although its function/s there are still poorly understood. To gain insight into which adult neuronal circuits may be under the influence of Reelin, we systematically mapped Reelin-immunoreactive neuronal somata, axons, and neuropil in the brain and brainstem of ferrets. Results show that Reelin immunoreactivity is found in widespread but specific sets of neuronal bodies, axonal tracts, and gray matter neuropil regions. Depending on the region, the immunoreactive neuronal somata correspond to interneurons, projection neurons, or both. Some well-defined axonal projection systems are immunoreactive, whereas most other white matter tracts are unlabeled. The labeled pathways include, among others, the lateral olfactory tract, the entorhinohippocampal (perforant) pathway, the retroflex bundle, and the stria terminalis. Labeled axons in these tracts contain large numbers of discrete, very small, immunoreactive particles, suggestive of secretory vesicles under the light microscope. The neuropil in the terminal arborization fields of these axons is also heavily immunoreactive. Taken together, our observations are consistent with the notion that some neurons may anterogradely transport Reelin along their axons in large membrane-bound secretory vesicles (Derer et al. [2001] J. Comp. Neurol. 440:136-143) and secrete it into their terminal arborization fields, which may be quite distant from the somata synthesizing the protein. These findings have implications for identifying where Reelin acts in adult brain circuits.

Animals↗
PubMed2001

Poliovirus 3A protein limits interleukin-6 (IL-6), IL-8, and beta interferon secretion during viral infection.

During viral infections, the host secretory pathway is crucial for both innate and acquired immune responses. For example, the export of most proinflammatory and antiviral cytokines, which recruit lymphocytes and initiate antiviral defenses, requires traffic through the host secretory pathway. To investigate potential effects of the known inhibition of cellular protein secretion during poliovirus infection on pathogenesis, cytokine secretion from cells infected with wild-type virus and with 3A-2, a mutant virus carrying an insertion in viral protein 3A which renders the virus defective in the inhibition of protein secretion, was tested. We show here that cells infected with 3A-2 mutant virus secrete greater amounts of cytokines interleukin-6 (IL-6), IL-8, and beta interferon than cells infected with wild-type poliovirus. Increased cytokine secretion from the mutant-infected cells can be attributed to the reduced inhibition of host protein secretion, because no significant differences between 3A-2- and wild-type-infected cells were observed in the inhibition of viral growth, host cell translation, or the ability of wild-type- or 3A-2-infected cells to support the transcriptional induction of beta interferon mRNA. We surmise that the wild-type function of 3A in inhibiting ER-to-Golgi traffic is not required for viral replication in tissue culture but, by altering the amount of secreted cytokines, could have substantial effects on pathogenesis within an infected host. The global inhibition of protein secretion by poliovirus may reflect a general mechanism by which pathogens that do not require a functional protein secretory apparatus can reduce the native immune response and inflammation associated with infection.

Amino Acid Sequence↗
PubMed1990

Mechanisms of impaired insulin secretion after chronic excess of parathyroid hormone.

Excess parathyroid hormone (PTH) in presence or absence of chronic renal failure impairs insulin release from pancreatic islets. This abnormality has been attributed to PTH-induced accumulation of Ca in the cytosol of the islets. Direct evidence for the latter phenomenon is lacking. This study examined the effect of chronic administration of PTH to rats with normal renal function on resting cytosolic Ca of the islets and evaluated the mechanisms through which a rise in resting cytosolic Ca may inhibit insulin secretion. After 42 days of PTH administration, glucose-induced insulin secretion was impaired, and this defect was corrected by the use of D-glyceraldehyde as secretagogue for insulin. Resting cytosolic Ca of islets from PTH-treated rats was markedly increased compared with that of islets from normal animals (288 +/- 27.1 vs. 135 +/- 3.7 nM, P less than 0.01), and their content of ATP in the presence of both 2.8 and 16.7 mM D-glucose was reduced (2.8 mM D-glucose, 4.6 +/- 0.17 vs. 6.0 +/- 0.42 pmol/islet, P less than 0.01; and 16.7 mM D-glucose, 6.9 +/- 0.25 vs. 11.1 +/- 0.95 pmol/islet, P less than 0.01). D-Glyceraldehyde increased ATP content in islets of PTH-treated rats from 4.6 +/- 0.17 to 8.8 +/- 0.71 pmol/islet. Glucose uptake by the islets, their insulin content, and both the Vmax and the apparent Km for fructose 6-phosphate of phosphofructokinase 1 (EC 2.7.1.11) in PTH-treated rats were not different from normal. The two major cellular derangements in the islets of PTH-treated rats were a reduction in ATP content and a rise in resting cytosolic Ca.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1985

Very low density lipoproteins in type II diabetes mellitus and risk of atherosclerosis.

Rapidly accumulation data suggest a close relation between defects in the metabolism of VLDL in type II diabetic subjects and atherogenesis in these patients. Increased concentrations of VLDL seem to be primarily due to an increased secretion of these particles. In addition, defective clearance of VLDL may be involved (e.g. impaired lipoprotein-lipase activity or an altered apolipoprotein composition of triglyceride-rich particles). VLDL and their degradation products may contribute to cholesteryl ester and triglyceride accumulation in macrophages and may affect the normal cholesterol transfer between the different lipoprotein particles or the revers cholesterol transport from peripheral cells to the liver.

Arteriosclerosis↗
PubMed1992

Expression of K12 keratin in alkali-burned rabbit corneas.

The healing of alkali-injured corneas is characterized by the persistence of polymorphonuclear leukocytes (PMN) in tissues and recurrent corneal epithelial defects. It has been suggested that the proteolytic enzymes secreted by PMN may account in part for the recurrent epithelial defects in the alkali-burned corneas. Cytoplasmic keratins, which form intracellular intermediate filaments, participate in the formation of hemidesmosomes and play a key role in the focal adhesion of epithelial cells to the basement membranes. The K3/K12 keratin pair is a major constituent of differentiated and stratified corneal epithelium. We have recently cloned the cDNA encoding the rabbit K12 keratin. In the present study we examined the expression of K12 keratin during the healing of alkali-burned rabbit corneas by slot-blot and in situ hybridization. Our results indicate that in normal cornea K12 keratin is equally expressed in all cell layers of stratified corneal epithelium and suprabasal layers of limbal epithelium, but not in bulbar conjunctival and other epithelia, i.e., lens, iris, and retinal pigment epithelium. The basal cells of the detached regenerating epithelium of the injured cornea express a very low level of K12 keratin. These observations are consistent with the notion that defective expression of K3/K12 keratins may play a role in the abnormal attachment of the regenerating epithelium to the basement membrane.

Animals↗
PubMed1994

Abnormal leucine-induced insulin secretion in chronic renal failure.

Chronic renal failure (CRF) is associated with a sundry of abnormalities in pancreatic islets including a rise in their cytosolic calcium, reduced ATP content, and impaired glucose-induced insulin secretion. The latter is also stimulated by amino acids (such as leucine), and the cellular processes involved in leucine-induced insulin secretion are different from those responsible for glucose-induced insulin release. The present study examined whether leucine-induced insulin secretion is also impaired in CRF and investigated the cellular derangements for such a potential abnormality. The results showed that leucine-induced insulin secretion is markedly reduced by islets from CRF animals, and this defect was prevented by parathyroidectomy (PTX) of the CRF animals or by their treatment with verapamil, an agent that blocks the action of parathyroid hormone (PTH) on the pancreatic islets. Both leucine uptake and alpha-ketoisocaproic acid-induced insulin secretion by islets from CRF rats are normal; however, both the activation of glutamate dehydrogenase (GLDH) by leucine or by 2-aminobicyclo-[2-2-1]-haptene and the utilization of alpha-ketoglutarate are impaired, and the maximal reaction rate (Vmax) of glutaminase is reduced. These derangements are corrected by PTX of CRF rats or by their treatment with verapamil. The data demonstrate that 1) CRF is associated with impaired leucine-induced insulin secretion, 2) this defect is due to the state of secondary hyperparathyroidism of CRF, and 3) the cellular derangements responsible for this defect involve abnormalities in the metabolism of leucine and derangements in the leucine-GLDH-alpha-ketoglutarate-glutaminase pathway of the islets.

Animals↗
PubMed2003

Expression of interleukin-6 and its effects on growth of HP75 human pituitary tumor cells.

The role of IL-6 in the pathogenesis of pituitary adenomas is unclear, as tumor biology is difficult to study in primary culture. We have shown here that the human pituitary cell line HP75 synthesizes IL-6 mRNA and expresses and secretes IL-6 (6167 +/- 56 pg/ml/72 h for 30,000 cells). IL-6 receptor (IL-6R) mRNA was identified by in situ hybridization and RT-PCR. Exogenous IL-6 in low dose (1 ng/ml) stimulated, whereas higher doses (100 ng/ml) inhibited, growth. This diverse effect occurs in other cell types as a result of receptor down-regulation. Cell growth was inhibited by IL-6-blocking antibody (76 +/- 6.5% inhibition; P < 0.0001). This demonstrates that IL-6 is an important growth regulator in HP75 cells, having an autocrine growth stimulatory effect under basal conditions. IL-1alpha and dibutyryl cAMP stimulated and dexamethasone inhibited IL-6 secretion; however, bacterial lipopolysaccharide, forskolin, and cholera toxin had no effect. This implies that there is a defect in the control of IL-6 secretion. Soluble IL-6R was not detected, but soluble gp130 receptor was present in the conditioned medium. Stimulation of cleavage of soluble IL-6R from the membrane-bound IL-6R could not be induced by phorbol ester or dexamethasone. Whether IL-6 has a similar effect in human pituitary adenomas requires further investigation.

Adenoma↗
PubMed1992

Platelet storage pool deficiency, leukemia, and myelodysplastic syndromes.

Abnormalities in platelet dense granules, small intracellular organelles containing ATP, ADP, calcium, serotonin, and pyrophosphate, have frequently been reported in patients with leukemia and myeloproliferative disorders, particularly acute and chronic myelogenous leukemia. Recent studies of a family which includes several members with an autosomal dominant dense granule deficiency condition show an association between the presence of this form of dense granule deficiency and the development of acute myelogenous leukemia. Studies in two additional patients, one with the Monosomy 7 syndrome and the second with a myelodysplastic syndrome, revealed a defect in platelet dense granules. This defect appears to be due to an abnormality in the formation of these granules rather than the presence of empty vesicular structures or decreased contents due to activation associated secretion. The results suggest that the defect in platelet dense granules associated with leukemia or myelodysplastic syndromes may result from a chromosome alteration in the megakaryocyte cell line leading to decreased formation of dense granules. Studies in the family with an inherited bleeding disorder suggest that a gene coding for a protein important for the formation of dense granules is located adjacent to a gene which, when abnormal, may predispose to the development of leukemia.

Adult↗
PubMed1993

Reduced inhibin and elevated gonadotropin levels in early pubertal boys with testicular defects.

In the prepubertal quiescent period, the control of gonadotropin secretion is assumed to be mediated by neuroendocrine inhibitory mechanisms, whereas little or no effect is thought to be mediated by the gonad. However, in pubertal-aged children with primary gonadal failure, gonadotropins increase to supranormal levels, suggesting that gonadal factors become more important in the control of gonadotropin secretion at that age. These gonadal factors have been poorly characterized so far. To clarify the relationship of inhibin and testosterone to the control of gonadotropin secretion during sexual maturation, we examined serum inhibin, testosterone, LH, and FSH concentrations in 10 boys with testicular defects and in nine healthy boys, in prepuberty and in early puberty. Serum was obtained at 15-min intervals for at least 6 h during the night. Prepubertal-aged boys with testicular defects had only slightly higher FSH levels than healthy boys, and their LH and inhibin levels were no different. In contrast, pubertal-aged boys with testicular defects had higher LH and FSH levels and lower inhibin levels than healthy boys. In prepubertal-aged boys, no correlation was found between individual mean inhibin level and mean FSH or LH level. In contrast, in pubertal-aged boys, an inverse nonlinear relationship between mean inhibin level and mean FSH and LH level was seen. The inverse value for inhibin correlated with FSH (r = 0.74, p < 0.01) and with LH (r = 0.81, p < 0.01). In conclusion, our results suggest that inhibin is a factor involved in the control of gonadotropin secretion in boys, at least in the pubertal period.

Adolescent↗
PubMed2005

The transcription factor Stat3 is dispensable for pancreatic beta-cell development and function.

The transcription factor Stat3 is activated by multiple cytokines, including leptin and those signaling through the gp130 receptor. In two independent studies, mice in which the Stat3 gene was inactivated using a RIP-Cre transgene led to glucose intolerance, defects in early-phase insulin secretion, and mild obesity [S. Gorogawa, Y. Fujitani, H. Kaneto, Y. Hazama, H. Watada, Y. Miyamoto, K. Takeda, S. Akira, M. Magnuson, Y. Yamasaki, Y. Kajimoto, M. Hori, Insulin secretory defects and impaired islet architecture in pancreatic beta-cell-specific STAT3 knockout mice, Biochem. Biophys. Res. Commun. 319 (2004) 1159; Y. Cui, L. Huang, F. Elefteriou, G. Yang, J. Shelton, J. Giles, O. Oz, T. Pourbahrami, C. Lu, J. Richardson, G. Karsenty, C. Li, Essential role of STAT3 in body weight and glucose homeostasis, Mol. Cell. Biol. 24 (2004) 258]. However, since the RIP-Cre transgene is also expressed in the hypothalamus, and thereby Stat3 was deleted from neurons expressing the leptin receptor, it was not clear as to which of the metabolic defects were due to the loss of Stat3 from beta-cells or the hypothalamus. We have addressed this issue through the inactivation of Stat3 from pancreatic beta-cells using a Pdx1-Cre transgene. Complete loss of Stat3 was observed in islets from mice, which carry two floxed Stat3 alleles and the Pdx1-Cre transgene. However, these mice did not develop glucose intolerance or obesity over a period of 6 months, demonstrating that Stat3 is dispensable for the generation and physiology of beta-cells. Similarly, mice that express only the Pdx1-Cre transgene display a normal physiology. In contrast, mice that expressed only the RIP-Cre transgene developed glucose intolerance as early as 6 weeks of age. The finding that RIP-Cre transgenic mice in a C57B/6 dominated background develop glucose intolerance is important as this line has been used in several studies.

Animals↗
PubMed2001

Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance.

Patients with TSH-secreting pituitary tumors (TSHomas) have high serum TSH levels despite elevated thyroid hormone levels. The mechanism for this defect in the negative regulation of TSH secretion is not known. We performed RT-PCR to detect mutations in TRbeta from a surgically resected TSHoma. Analyses of the RT-PCR products revealed a 135-bp deletion within the sixth exon that encodes the ligand-binding domain of TRbeta2. This deletion was caused by alternative splicing of TRbeta2 mRNA, as near-consensus splice sequences were found at the junction site and no deletion or mutations were detected in the tumoral genomic DNA. This TRbeta variant (TRbeta2spl) lacked thyroid hormone binding and had impaired T3-dependent negative regulation of both TSHbeta and glycoprotein hormone alpha-subunit genes in cotransfection studies. Furthermore, TRbeta2spl showed dominant negative activity against the wild-type TRbeta2. These findings strongly suggest that aberrant alternative splicing of TRbeta2 mRNA generated an abnormal TR protein that accounted for the defective negative regulation of TSH in the TSHoma. This is the first example of aberrant alternative splicing of a nuclear hormone receptor causing hormonal dysregulation. This novel posttranscriptional mechanism for generating abnormal receptors may occur in other hormone-resistant states or tumors in which no receptor mutation is detected in genomic DNA.

Adenoma↗
PubMed2003

Missplicing resulting from a short deletion in the reelin gene causes reeler-like neuronal disorders in the mutant shaking rat Kawasaki.

The shaking rat Kawasaki (SRK) is an autosomal recessive mutant that exhibits reeler-like abnormal locomotor behaviors. The murine reeler mutants arise from several mutations in the specific gene called reelin, which result in defects of Reelin expression or secretion in the cerebral cortex and other regions of CNS. To address the issue of whether the SRK mutation also arises from a mutation in reelin, we analyzed the reelin gene in SRK. Northern analysis of reelin mRNA from normal rats showed that rat reelin was expressed as a approximately 12-kb transcript in both the cerebrum and the cerebellum, whereas reelin expression was markedly reduced in the SRK brains. In situ hybridization analysis showed that reelin mRNA in the SRK brains was expressed in Cajal-Retzius cells in the marginal zone of the cerebral cortex and outer granular cells in the cerebellar cortex in similar manners to normal controls, but its expression was considerably reduced. On Western blotting and immunohistochemical analyses using antibodies specific for the Reelin protein, no immunoproduct was recognized in the cerebral and cerebellar cortices. From the cDNA sequences, we found a 64-base heterologous sequence in SRK reelin, which contains a termination codon in the reading frame. Furthermore, genomic DNA analysis revealed that a 10-base deletion, which contains a predicted splice donor site, occurred in the SRK genomic reelin gene, resulting in "read through" into the following intron in SRK. Thus, the SRK mutation is another type of mutation that lacks expression of the functional Reelin protein and, therefore, causes the reeler phenotype.

Animals↗
PubMed1993

PrlA suppressor mutations cluster in regions corresponding to three distinct topological domains.

The SecY protein of Escherichia coli and its homologues in other organisms, are integral components of the cellular protein translocation machinery. Suppressor mutations that alter SecY (the prlA alleles) broaden the specificity of this machinery and allow secretion of precursor proteins with defective signal sequences. Twenty-five prlA alleles have been characterized. These suppressor mutations were found to cluster in regions corresponding to three distinct topological domains of SecY. Based on the nature and position of the prlA mutations, we propose that transmembrane domain 7 of SecY functions in signal sequence recognition. Results suggest that this interaction may involve a right-handed supercoil of alpha-helices. Suppressor mutations that alter this domain appear to prevent signal sequence recognition, and this novel mechanism of suppression suggests a proofreading function for SecY. We propose that suppressor mutations that alter a second domain of SecY, transmembrane helix 10, also affect this proof-reading function, but indirectly. Based on the synthetic phenotypes exhibited by double mutants, we propose that these mutations strengthen the interaction with another component of the translocation machinery, SecE. Suppressor mutations were also found to cluster in a region corresponding to an amino-terminal periplasmic domain. Possible explanations for this unexpected finding are discussed.

Alleles↗
PubMed1990

Second-trimester levels of maternal serum unconjugated oestriol and human chorionic gonadotropin in pregnancies affected by fetal anencephaly and open spina bifida.

Unconjugated oestriol (uE3) and human chorionic gonadotropin (hCG) levels were determined in second-trimester maternal serum (MS) samples from 21 pregnancies associated with fetal anencephaly and 15 pregnancies associated with fetal open spina bifida. Each measurement was expressed as a multiple of the median (MoM) for unaffected pregnancies for each completed week of gestation. In pregnancies associated with anencephaly, the median value for MSuE3 was very low (0.17 MoM, range less than 0.12-0.33 MoM), suggesting a functional defect in the fetal adrenal prior to 20 weeks' gestation; the median value for MShCG was also low (0.73 MoM), although not to the same extent as for MSuE3. A biological explanation for the hCG result is not apparent. In pregnancies associated with open spina bifida, the MSuE3 and MShCG values were unremarkable, consistent with a lack of involvement of these open fetal defects in the synthesis and secretion of uE3 and hCG.

Anencephaly↗
PubMed1986

Defects in prostaglandin synthesis and metabolism in ulcer disease.

Ulcers occur because of an imbalance between mucosal protective resistance and damaging luminal factors, allowing the latter to predominate. The primary injurious elements are acid and peptic activity. Bile reflux, drugs, and gastroduodenal stasis may alter the luminal milieu and act together with acid-peptic activity to produce injury, weaken mucosal resistance, or both. Since prostaglandins modulate several key mucosal protective mechanisms, and since some exogenous prostaglandins and their derivatives accelerate peptic ulcer healing, it seems plausible that prostaglandin deficiency may contribute to the development of peptic ulcers. At the present time, however, evidence for this postulate is mostly indirect and can be summarized as follows: (1) Defects of mucosal protective mechanisms modulated by prostaglandins have been found in different forms of ulcer disease. Such defects include impaired duodenal bicarbonate secretion, deficient secretion or accelerated degradation of mucus, and reduced mucosal cell proliferation. (2) Drugs that inhibit cyclooxygenase, the key enzyme in tissue prostaglandin synthesis, have ulcerogenic activity. Presumably, in this situation, reduced prostaglandin production renders the mucosa more vulnerable to the action of acid and pepsin, or reduces the capability of the mucosa to repair itself. (3) Decreased mucosal prostaglandin synthesis or prostaglandin content has been found in patients with ulcer disease. Several studies have provided quantitative evidence of disturbed prostaglandin metabolism in some forms of ulcer disease. These studies are of high interest, but they need to be interpreted with caution given the present scientific debate regarding the physiological role of different prostanoids, as well as uncertainty as to the specific cellular source of prostaglandins in gastroduodenal mucosa.

Animals↗
PubMed2003

[Progress in the prevention of type 2 diabetes].

Type 2 diabetes mellitus is a major health problem associated with excess morbidity and mortality. Defects in the action and/or secretion of insulin are the two major abnormalities leading to development of glucose intolerance. Any intervention in the impaired glucose tolerance phase that reduces resistance to insulin or protects the beta-cells, or both, should prevent or delay progression to diabetes. The natural history of type 2 diabetes includes a preceding period of impaired glucose tolerance (IGT)/impaired fasting glucose (IFG) which provides an opportunity for targeted intervention within large communities. As the prevalence of this metabolic disorder is rapidly increasing and current treatment fails to stabilise the disease in most patients, prevention should be considered as a key objective in the near future. Lifestyle intervention studies have consistently shown that quite modest changes can reduce the progression from IGT to diabetes by 50-60%. The Diabetes Prevention Program (DPP) randomised trial has shown that a combined program of weight loss, improvement of diet and increase of physical exercise lowers the risk for development of type 2 diabetes by 58% compared with placebo. It may, however, not be possible to translate these successful findings to larger cohorts or maintain the lifestyle changes longer term. This has lead to consideration of pharmacotherapy. Benefits have been found for metformin, acarbose and troglitazone. Treatment with metformin was less effective than lifestyle modifications, resulting in an average reduction of risk for development of type 2 diabetes by 31% compared with placebo. Similarly, acarbose in the STOP-NIDDM trial reduced the risk of developing type 2 diabetes in patients with IGT by 25%. Remarkably, cardiovascular event rates, in particular myocardial infarction, were significantly reduced when acarbose was used instead of placebo in subjects with glucose intolerance. The ACE inhibitors captopril (CAPPP) or ramipril (HOPE) and the Angiotensin-II receptor antagonist losartan (LIFE) have been shown to reduce the appearance of diabetes by one third when given to patients with hypertension. Since many hypertensive patients are insulin-resistant and have an increased risk in developing type 2 diabetes, the protective effect of these classes of antihypertensive drugs might be explained by their antiinsulin-resistance effects.

Acarbose↗