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PubMed2002

PPAR activators inhibit endothelial cell migration by targeting Akt.

Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose metabolism and exert several vascular effects that may provide a dual benefit of these receptors on metabolic disorders and atherosclerotic vascular disease. Endothelial cell migration is a key event in the pathogenesis of atherosclerosis. We therefore investigated the effects of lipid-lowering PPARalpha-activators (fenofibrate, WY14643) and antidiabetic PPARgamma-activators (troglitazone, ciglitazone) on this endothelial cell function. Both PPARalpha- and PPARgamma-activators significantly inhibited VEGF-induced migration of human umbilical vein endothelial cells (EC) in a concentration-dependent manner. Chemotactic signaling in EC is known to require activation of two signaling pathways: the phosphatidylinositol-3-kinase (PI3K)-->Akt- and the ERK1/2 mitogen-activated protein kinase (ERK MAPK) pathway. Using the pharmacological PI3K-inhibitor wortmannin and the ERK MAPK-pathway inhibitor PD98059, we observed a complete inhibition of VEGF-induced EC migration. VEGF-induced Akt phosphorylation was significantly inhibited by both PPARalpha- and gamma-activators. In contrast, VEGF-stimulated ERK MAPK-activation was not affected by any of the PPAR-activators, indicating that they inhibit migration either downstream of ERK MAPK or independent from this pathway. These results provide first evidence for the antimigratory effects of PPAR-activators in EC. By inhibiting EC migration PPAR-activators may protect the vasculature from pathological alterations associated with metabolic disorders.

Apoptosis↗
PubMed2002

Effects of peroxisome proliferator-activated receptor agonists on LPS-induced neuronal death in mixed cortical neurons: associated with iNOS and COX-2.

In neurodegenerative disease, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been regarded as beneficial. The NSAID, an inhibitor of cyclooxygenase (COX), has been also suggested as a ligand of the peroxisome proliferator-activated receptor (PPAR). In cortical neuron-glial co-cultures, we examined the effect of PPAR agonists on lipopolysaccharide(LPS)-induced neuronal death, which has been known to be NO-dependent. LPS induced iNOS expression and the release of nitric oxide in microglia, and COX-2 expression in neurons. PPAR-gamma agonists such as 15d-PGJ(2), ciglitazone and troglitazone prevented LPS-induced neuronal death and abolished LPS-induced NO and PGE(2) release, however PPAR-alpha agonists such as clofibrate and WY14,643 did not produce the same results. PPAR-gamma agonists also reduced LPS-induced iNOS and COX-2 expression, which suggested by interfering with the NF-kappaB signal pathway.

Animals↗
PubMed1999

Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative.

JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxaz olidinedione, is an isoxazolidinedione derivative which is structurally distinct from thiazolidinediones such as pioglitazone and troglitazone. We investigated the effects of JTT-501 on insulin-sensitizing activity and in rodent diabetic models. JTT-501 enhanced insulin-stimulated cell differentiation of 3T3-L1 fibroblasts with an EC50 value of 110 nM. Furthermore, JTT-501 activated peroxisome proliferator-activated (PPA) gamma and alpha receptors with the EC5-fold values of 0.28 and 5.4 microM, respectively. In the non-insulin-dependent diabetes mellitus model KK-Ay mice, JTT-501 improved hyperglycemia, hyperinsulinemia and hypertriglyceridemia, and enhanced insulin-stimulated glucose oxidation in adipose tissues. JTT-501 was also effective in the non-insulin-dependent diabetes mellitus model Zucker diabetic fatty (ZDF) rats but not in the insulin-dependent diabetes mellitus model streptozotocin-induced diabetic mice. These observations suggest that JTT-501 enhances insulin sensitivity in peripheral tissues and improves hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in non-insulin dependent diabetes mellitus models. In particular, the triglyceride-lowering activity of JTT-501 is a unique characteristic compared to the thiazolidinediones. Therefore, JTT-501 may be a promising antidiabetic agent for treating non-insulin-dependent diabetes mellitus patients with insulin resistance.

3T3 Cells↗
PubMed2000

Peroxisome proliferator-activated receptors are expressed in mouse bone marrow-derived mast cells.

We examined the expression of peroxisome proliferator-activated receptors (PPARs) and the role of PPARs in cytokine production in mouse bone marrow-derived mast cells (mBMMCs). mBMMCs expressed PPARbeta strongly and gamma slightly, but not alpha. Activation of mBMMCs with antigen or calcium ionophore resulted in the increased expression of PPARgamma mRNA specifically. 15-Deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)) and troglitazone, all PPARgamma ligands, attenuated the antigen-induced cytokine production by mBMMCs. Carbaprostacyclin, a PPARbeta ligand, also inhibited cytokine production, whereas PPARalpha ligands did not. These results suggest that PPARbeta and gamma might be included in the negative regulation of mast cell activation.

Animals↗
PubMed1999

Up-regulation of uncoupling protein 3 by thyroid hormone, peroxisome proliferator-activated receptor ligands and 9-cis retinoic acid in L6 myotubes.

Uncoupling protein 3 (UCP3), expressed abundantly in the skeletal muscle, is one of the carrier proteins dissipating the transmitochondrial electrochemical gradient as heat, and thereby has been implicated in the regulation of energy metabolism. We have investigated UCP3 mRNA expression in the widely used L6 myocyte cell line by Northern blot analysis. UCP3 mRNA was not detected in L6 myoblasts, but appeared after their differentiation to myotubes. The UCP3 mRNA level was increased when L6 myotubes were treated with increasing concentrations of triiodothyronine (T3), oleic acid, alpha-bromopalmitate and carbacyclin, a non-selective ligand of peroxisome proliferator-activated receptors (PPARs), whereas it was not influenced when treated with selective ligands of PPARalpha (WY 14¿ omitted¿643) and PPARgamma (troglitazone). A ligand of retinoid X receptor (RXR), 9-cis retinoic acid, was also effective by itself and in combination with carbacyclin in stimulating UCP3 mRNA expression. The mRNA analysis of individual PPAR isoforms revealed that L6 cell expressed a significant level of PPARdelta but undetectable levels of PPARalpha and PPARgamma. These results suggest that UCP3 expression in myocytes is differentiation-dependent and regulated by the T3 receptor, RXR and PPARdelta.

Alitretinoin↗
PubMed2001

Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides.

Insulin resistance has been highlighted as a common causal factor for glucose intolerance, hypertension and dyslipidemia, all of which are cardiovascular risk factors. A new class of antidiabetic agents, thiazolidinediones (TZDs), has been developed and demonstrated to improve insulin sensitivity. TZDs are high affinity ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), the crucial transcription factor for adipocytes. Recent studies showed that PPARgamma is also expressed in monocytes/macrophages and is suggested to be involved in atherosclerosis. We could detect PPARgamma gene transcript in several cultured endothelial cells (human aortic endothelial cells (HAoECs), human coronary artery endothelial cells (HCAECs), human umbilical vein endothelial cells (HUVECs) and bovine carotid artery endothelial cells (BAECs)) as well as human coronary arteries we examined. Since endothelial dysfunction is critical for atherosclerosis, we investigated the effects of TZDs, troglitazone (TRO) and pioglitazone (PIO), on endothelial cell growth and secretion of C-type natriuretic peptide (CNP), which we demonstrated as a novel endothelium-derived relaxing peptide, and endothelin (ET), a potent vasoconstrictor, using HAoECs, HCAECs, HUVECs and BAECs. When all these cultured endothelial cells were daily treated with TRO and PIO for 5 days, both TRO and PIO (10(-8)M) significantly stimulated (3)H-thymidine incorporation of all these endothelial cells. In contrast, higher dose of TRO and PIO (10(-5)M) significantly suppressed DNA synthesis. TRO and PIO also exerted the compatible effect on the increase of cell numbers. TRO and PIO significantly enhanced CNP secretion from BAECs. In contrast, ET secretion from BAECs was suppressed by both TRO and PIO in a dose-dependent manner. The results of the present study suggest that TZDs modulate endothelial functions, including regulation of endothelial cell growth and secretion of endothelium-derived vasoactive substances, which affect vascular tone and remodeling in the process of atherosclerosis.

Animals↗
PubMed2003

Contrasting effects of nateglinide and rosiglitazone on insulin secretion and phospholipase C activation.

When stimulated with 6 mmol/L glucose, a minimal, transient insulin secretory response was observed from perifused rat islets. The inclusion of 5 micromol/L nateglinide significantly amplified release. Elevating glucose to 8 or 10 mmol/L resulted in an increasing insulin secretory response that was again markedly potentiated by the further inclusion of nateglinide. The calcium channel antagonist, nitrendipine, abolished secretion to 8 mmol/L glucose plus nateglinide. Unlike nateglinide, rosiglitazone (5 micromol/L), troglitazone (1 to 10 micromol/L), or darglitazone (10 micromol/L), 3 peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, were without any acute stimulatory effect on insulin release in the simultaneous presence of 6 to 10 mmol/L glucose. Glucose (8 to 10 mmol/L) significantly increased inositol phosphate accumulation. Nateglinide amplified this response. Nitrendipine reduced inositol phosphate (IP) accumulation in response to the combination of 8 mmol/L glucose plus 5 micromol/L nateglinide. Rosiglitazone had no effect on IP accumulation. These results confirm the efficacy of nateglinide as a potent glucose-dependent insulin secretagogue that exerts its stimulatory effect, at least in part, through the activation of phospholipase C (PLC). No acute potentiating effect of rosiglitazone on either insulin secretion or IP accumulation could be detected in isolated rat islets.

Androstadienes↗
PubMed1999

15-Deoxy-delta(12,14) prostaglandin J2: a putative endogenous promoter of adipogenesis suppresses the ob gene.

Leptin is considered a key factor in the regulation of appetite and energy expenditure, but little is known about the control of its synthesis and release. Thiazolidinediones (TZDs) have recently been shown to downregulate leptin expression, and it has been speculated that downregulation of the ob gene occurs through activation of the transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma). However, there are no studies using an endogenous PPARgamma ligand. We examined the effect of 15-deoxy-delta(12,14) prostaglandin J2 (15d-PGJ2), a putative natural ligand of PPARgamma, on ob gene expression in fully differentiated 3T3-L1 adipocytes and compared its effect with that of two other PPARgamma activators, the TZD troglitazone (Trog) and indomethacin (Indo). 15d-PGJ2, Trog, and Indo all inhibited leptin expression at concentrations at which they activate PPARgamma. The inhibition of leptin expression of PPARgamma activators was surprising, since PPARgamma is known to induce adipogenesis during which the ob gene is expressed. To address the possibility that PPARgamma plays different roles before and after the induction of adipogenesis, we examined the effects of the three PPARgamma ligands on the expression of leptin and the glucose transporter protein GLUT4, both of which are expressed during differentiation of 3T3-L1 preadipocytes to adipocytes. In the absence of PPARgamma ligands, leptin and GLUT4 synthesis increased from day 3 to day 9 or 10 during differentiation. However, in the presence of any of the three PPARgamma ligands, GLUT4 expression was unaffected, while ob gene expression was inhibited. We hypothesize that PPARgamma may be essential for induction of adipocyte differentiation but then needs to be inactivated to allow expression of the ob gene.

Adipose Tissue↗
PubMed2001

Gonadotropins at menopause: the influence of obesity, insulin resistance, and estrogens.

UNLABELLED: Obese, postmenopausal women have lower FSH levels. To determine whether this is due to higher estrogen exposure, we compared feedback gonadotropin sensitivity and its relation to insulin resistance in four groups of obese and lean, postmenopausal women. Group one was treated with 400 mg troglitazone (TG) daily for two weeks; 150 clomiphene citrate (CC) was added daily for the second week. Group two received 150 mg CC daily for a week. Group three received 1000 mg metformin (MET) daily for two weeks, with 120 mg raloxifene (RAL) added during the second week. Group four received 120 mg RAL for a week. Before and after each period, a serum pool was obtained from samples taken every minute during a 10 ml interval. The women recruited for this study were categorized as obese or lean based on BMI >/= 29 or BMI < 29, respectively. Obese, menopausal women had lower FSH (45.5 IU/l) and LH (16.2 IU/l) values than those of lean (64.1 IU/l and 23.0 IU/l), but the obese menopausal women had higher leptin, DHEAS, glucose, insulin, and HOMA-IR levels. Log [FSH] was associated with BMI (r = -0.53, P < 0.000001) and number of pregnancies (r = -0.37, P = 0.0009). TG treatment did not change HOMA-IR or gonadotropin levels, but DHEAS and androstenedione levels decreased significantly. CC alone or together with TG, diminished FSH (-7.9 and -9.2) and LH (-2.5 and -3.6) concentrations, with a greater reduction in lean women. MET reduced glucose and the HOMA-IR index without affecting gonadotropin or steroid levels. CONCLUSIONS: obese, menopausal women have lower FSH levels due to greater estrogen exposure, by mechanisms unrelated to insulin resistance.

Chromans↗
PubMed2001

Lessons from the glitazones: a story of drug development.

Troglitazone, the first in the thiazolidinedione class of oral hypoglycaemic agents, was launched in the USA in March, 1997. It reached Europe later that year, only to be withdrawn within weeks on the grounds of liver toxicity. Meanwhile it went on to generate sales of over $2 billion in the USA, and caused at least 90 cases of liver failure (70 resulting in death or transplantation) before it was withdrawn in March, 2000. Rosiglitazone and pioglitazone reached the US market in 1999 as first-line agents to be used alone or in combination with other drugs, but in Europe the same dossiers were used one year later to apply for a limited licence as second-line agents restricted to oral combination therapy. How should we use the glitazones? And how did they achieve blockbuster status without any clear evidence of advantage over existing therapy?

Adverse Drug Reaction Reporting Systems↗
PubMed2001

Diabetic KKAy mice exhibit increased hepatic PPARgamma1 gene expression and develop hepatic steatosis upon chronic treatment with antidiabetic thiazolidinediones.

BACKGROUND/AIMS: Peroxisome proliferator-activated receptor-gamma, which is involved in the regulation of lipid homeostasis, is upregulated in the liver of obese and diabetic mice, but the biological consequences of this induction are largely unknown. This study was aimed at further characterizing this upregulation and exploring the downstream biological effects of specific activators on hepatic lipid metabolism. METHODS: Hepatic expression of peroxisome proliferator-activated receptor-gamma1 and gamma2 mRNA and protein was analyzed by real-time polymerase chain reaction and Western immunoblotting in KKAy mice and ob/ob mice. KKAy mice were treated with thiazolidinediones, and hepatic triglyceride content and lipid distribution were analyzed biochemically and by histopathology. RESULTS: KKAy mice exhibited a marked increase in hepatic peroxisome proliferator-activated receptor-gamma1 mRNA and protein levels, whereas the gamma2 isoform was upregulated in ob/ob mice. Treatment of KKAy mice with troglitazone or rosiglitazone resulted in severe microvesicular periacinar steatosis, whereas lean control mice did not develop any pathological liver changes. Hepatic triglyceride levels, however, were not altered by the treatment. CONCLUSIONS: In mice with obesity-associated upregulated hepatic peroxisome proliferator-activated receptor-gamma expression, thiazolidinediones may produce hepatic steatosis. Under pathophysiological conditions, such as non-insulin-dependent diabetes, the liver may thus become sensitized towards peroxisome proliferator-activated receptor-gamma-activating drugs.

Animals↗
PubMedDate not supplied

Novel phthalazinone and benzoxazinone containing thiazolidinediones as antidiabetic and hypolipidemic agents.

We report here the synthesis of a series of 5-[4-[2-[substituted phthalazinones-2(or 4)yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and 5-[4-[2-[2,3-benzoxazine-4-one-2-yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and their plasma glucose and plasma triglyceride lowering activity in db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. In vitro and in vivo pharmacological studies showed that the phthalazinone analogue has better activity. PHT46 (compound 5a), the best compound in this series, showed better in vitro PPARgamma transactivation potential than troglitazone and pioglitazone. In insulin resistant db/db mice, PHT46 showed better plasma glucose and triglyceride lowering activity than the standard drugs. Pharmacokinetic study in Wistar rats showed good systemic exposure of PHT46. Subchronic toxicity study in Wistar rats did not show any treatment-related adverse effect.

Animals↗
PubMed1999

[Current status of the treatment of type 2 diabetes mellitus. The revival of insulin-resistance drugs].

The relief of insulin resistance is one of the two therapeutic targets of the treatment of type 2 diabetes. Insulin-sensitizers are therefore complemental with other oral diabetic drugs. The treatment of insulin resistance was for a long time limited to dietary and exercise programmes, a biguanide, metformine, and benfluorex, a phenylethylamine derivative; the mechanisms of action of both drugs are now better understood and their indications more precisely targeted. A new therapeutic class, the thiazolidinediones (troglitazone, rosiglitazone, pioglitazone) has recently completed the family of insulin-sensitizing agents. These drugs, which should be soon available in France, act by a different way than metformin, which has been recently identified as the peroxisomes proliferator-activated receptor. The role of antilipolytic agents, which might increase glucose uptake by reducing free fatty acid production and oxidation is under evaluation, as well as the potential benefit of orlistat, an inhibitor of lipid digestion which has been proved effective, in addition to hypocaloric diet, in the management of obese patients.

Administration, Oral↗
PubMed2003

DR1-like element in human topoisomerase IIalpha gene involved in enhancement of etoposide-induced apoptosis by PPARgamma ligand.

OBJECTIVE: The nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) ligands may enhance the etoposide-induced apoptosis by modulating the topoisomerase (Topo) IIalpha expression through binding to direct repeat 1 (DR1)-like element. METHODS: To investigate the effect of etoposide-induced apoptosis by PPARgamma ligands, leukemia cell lines were treated with troglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) in the presence of etoposide and studied about various biological responses. RESULTS: We found the enhancement of etoposide-induced apoptosis by PPARgamma ligands in several leukemia cell lines, which was dependent on the expression of PPARgamma and specific for TopoIIalpha inhibitor. We also observed the increased expression of TopoIIalpha protein by 15d-PGJ2 in Jurkat and HUVEC cells, which might lead to the increased sensitivity to etoposide. Furthermore, we demonstrated that 15d-PGJ2 enhanced the promoter activity of human TopoIIalpha promoter construct with a DR1-like site by sevenfold when expressed with PPARgamma and RXRalpha. The mutation of DR1-like site decreased the promoter activity, although the direct binding between DR1-like site and PPARgamma/RXRalpha heterodimer was not demonstrated. CONCLUSIONS: We conclude that the induction of TopoIIalpha expression by PPARgamma ligands via DR1-like site is an important mechanism for the enhancement of etoposide-induced apoptosis and a DR1-like site in TopoIIalpha promoter is involved in transcriptional regulation dependent on PPARgamma ligands and PPARgamma/RXRalpha heterodimer.

Antigens, Neoplasm↗
PubMed2001

Combined treatment with specific ligands for PPARgamma:RXR nuclear receptor system markedly inhibits the expression of cytochrome P450arom in human granulosa cancer cells.

Our previous study demonstrated that PPARgamma specific ligand troglitazone (TGZ) or RXR specific ligand LG100268 (LG) alone decreased the aromatase activity in cultured human ovarian granulosa cells from pre-ovulatory follicles, and combined treatment caused an even greater reduction in this activity. Since similar manners of effects of TGZ or/and LG on the aromatase activity in human ovarian granulosa cancer cell line were observed, we performed the detailed analysis of the mechanisms of these effects using this cell line. The changes in the aromatase activity were associated with comparable changes in the P450arom mRNA levels based on a RNase protection assay. A nuclear run-on assay indicated the P450arom transcript to decrease by 40 and 66% at 24 and 48 h, respectively, after TGZ plus LG treatment. An RNA stability analysis showed the half-life of P450arom mRNA to decrease from 13 to 9 h after the TGZ plus LG treatment. The inhibitory effect of TGZ plus LG on the aromatase activity and P450arom mRNA may not be mediated by the cAMP-PKA pathway that is usually implicated in the regulation of aromatase activity in granulosa cells: because (1) the aromatase activity stimulated by forskolin was not inhibited by TGZ plus LG; (2) the specific PKA inhibitor H89 could not block the inhibitory effect of TGZ plus LG on the aromatase activity; and (3) the luciferase activity of P450arom promoter II did not decrease by the addition of TGZ and LG in transfected cells either at a basic state or in the states stimulated by forskolin or PGE2, respectively. Taken together, these results indicate that TGZ plus LG inhibited the aromatase activity and also decreased the P450arom mRNA level in granulosa cancer cells, and the loss of P450arom mRNA expression was considered to be due to both the decreased transcription and rapid degradation of its RNA.

Aromatase↗
PubMed1998

Complementary measures for promoting insulin sensitivity in skeletal muscle.

Insulin resistance of skeletal muscle is fundamental to both syndrome X and its frequent sequel, type II diabetes. In these disorders, excessive exposure of muscle to free fatty acids (FFAs) and their metabolic derivatives appears to play a prominent role in the induction of insulin resistance. Recent evidence suggests that activation of novel isoforms of protein kinase C (PKC) by diacylglycerol may mediate at least part of the adverse impact of FFAs on muscle insulin sensitivity. Vitamin E and fish oil omega-3s, by promoting the activity of diacylglycerol kinase and inhibiting that of phosphatidate phosphohydrolase, should reduce diacylglycerol levels, thus accounting for their documented favorable impact on insulin sensitivity. Thiazolidinediones such as troglitazone, on the other hand, appear to intervene in the signaling pathway whereby PKC down-regulates insulin function. The insulin-sensitizing activity of chromium picolinate may be attributable, at least in part, to increased expression of insulin receptors. In combination with lifestyle modifications which reduce FFA exposure--weight loss, very-low-fat eating, excessive training--these measures can be expected to work in a complementary way to promote increased numbers of insulin receptors that are more functionally competent. As these measures appear to be safe and well-tolerated, they may have utility for the prevention of diabetes as well as its therapy. When they do not prove sufficient to achieve optimal glycemic control, excessive hepatic glucose output and impaired cell response to glucose can be addressed with metformin and sulfonylureas, respectively. The prospects for a rational medical management of type II diabetes, obviating the need for injectible insulin, have never been brighter.

Adipocytes↗
PubMed2000

Aging and the neuroendocrine regulation of reproduction and body weight.

Aging in men is associated with a decline in trophic factors such as testosterone (T), alterations in body composition and impaired energy and body weight regulation. We performed studies to investigate the mechanisms underlying age-related changes in the neuroendocrine control of testis function, body composition, food intake and body weight in the Brown Norway (BN) rat. We found that similar to aging men, male BN rats demonstrate both primary and secondary testicular failure with aging without confounding age-related tumors, hormonal changes and systemic illnesses. With aging, these animals have blunted circadian variations in luteinizing hormone (LH) and T, and decreased hypothalamic gonadotropin-releasing hormone (GnRH) synthetic capacity with preserved pituitary gonadotropin responses to GnRH. We found that aging male BN rats have increased peripheral and visceral adiposity associated with increased insulin and leptin levels, and decreased relative lean body mass and muscle mass. We found that these rats exhibit reduced food intake and body weight gain associated with decreased hypothalamic neuropeptide Y (NPY) gene expression in the arcuate nucleus (ARC), both during ad-libitum feeding and after a 72-h fast. Recently, we found that old male BN rats treated chronically with troglitazone, an insulin sensitizer, lowered high insulin and leptin levels, decreased body fat, and corrected the blunted food intake and body weight gain response to fasting without affecting basal ARC NPY gene expression. These findings suggested that hyperinsulinemia and/or hyperleptinemia associated with aging may contribute to the age-related impairment in energy and weight regulation. Our studies suggest that the aging male BN rat is an excellent model to investigate the mechanisms underlying the age-associated changes in the neuroendocrine control of body composition, energy intake and body weight.

Aging↗
PubMed2000

Recent advances in the pharmacologic management of diabetes mellitus.

The importance of glucose control in reducing the complications of diabetes mellitus has been clearly demonstrated. The emergency physician routinely is expected to treat a wide range of problems related to this disease, including making the initial diagnosis of type 2 and occasionally type 1 diabetes. Also common are patients with poorly controlled diabetes. The recent introduction of new classes of agents to lower blood glucose, especially in type 2 diabetes, should improve the control in this category of patient and reduce the complication rate. Some of these agents, such as troglitazone, have potentially fatal complications and require careful monitoring. Emergency physicians should be aware of the common complications of these drugs because patients can present to the ED with them. Hypoglycemia, a common cause of 911 calls and emergency visits, is not a side effect of either metformin or acarbose. Insulin lispro has improved postprandial glycemic control for type 1 and some insulin-requiring type 2 diabetics. Hypoglycemia is less of a risk with insulin lispro, and quality of life is better with this rapidly acting insulin. Newer methods of insulin delivery, such as continuous subcutaneous infusion, have greatly improved glucose control, given greater freedom to patients, and reduced the risks of hypoglycemia.

Acarbose↗