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Glycometabolic state at hospital admission is an important risk marker for long-term mortality in patients with acute myocardial infarction, whether or not they have known diabetes mellitus. Our aim was to ascertain the prevalence of impaired glucose metabolism in patients without diagnosed diabetes but with myocardial infarction, and to assess whether such abnormalities can be identified in the early course of a myocardial infarction. We did a prospective study, in which we enrolled 181 consecutive patients admitted to the coronary care units of two hospitals in Sweden with acute myocardial infarction, no diagnosis of diabetes, and a blood glucose concentration of less than 11·1 mmol/L. We recorded glucose concentrations during the hospital stay, and did standardised oral glucose tolerance tests with 75 g of glucose at discharge and again 3 months later. The mean age of our cohort was 63.5 years (SD 9) and the mean blood glucose concentration at admission was 6·5 mmol/L (1·4). The mean 2-h postload blood glucose concentration was 9.2 mmol/L (2·9) at hospital discharge, and 9·0 mmol/L (3.0) 3 months later. 58 of 164 (35%, 95% CI 28–43) and 58 of 144 (40%, 32–48) individuals had impaired glucose tolerance at discharge and after 3 months, respectively, and 51 of 164 (31%, 24–38) and 36 of 144 (25%, 18–32) had previously undiagnosed diabetes mellitus. Independent predictors of abnormal glucose tolerance at 3 months were concentrations of HbA1c at admission (p=0·024) and fasting blood glucose concentrations on day 4 (p=0·044). Previously undiagnosed diabetes and impaired glucose tolerance are common in patients with an acute myocardial infarction. These abnormalities can be detected early in the postinfarction period. Our results suggest that fasting and postchallenge hyperglycaemia in the early phase of an acute myocardial infarction could be used as early markers of high-risk individuals.

Diminished responsiveness to hypoglycemia contributes to defective counterregulation in diabetes. Pancreatic and/or circulating somatostatin are elevated in diabetes, which may inhibit counterregulatory hormone release during hypoglycemia. Thus, a selective somatostatin receptor type 2 antagonist (SSTR2a) should improve hormone counterregulation to hypoglycemia. Nondiabetic (N) and streptozotocin-induced diabetic (D) rats underwent 4-h infusion of saline or SSTR2a with insulin-induced hypoglycemia clamped at 2.5 ± 0.5 mmol/L. To evaluate the effect of the SSTR2a in the absence of hypoglycemia, rats underwent a 4-h infusion of saline (Ctrl:N, Ctrl:D) or SSTR2a (Ctrl:D+SSTR2a) only. The attenuated glucagon response to hypoglycemia in D (P < 0.0002) was fully restored by SSTR2a (P < 0.0001). Furthermore, the attenuated corticosterone response in D (P < 0.002) was also enhanced by SSTR2a (P < 0.05). In the absence of hypoglycemia, SSTR2a did not alter basal blood glucose levels. D exhibited 62% more pancreatic somatostatin than N after hypoglycemia. In N rats, SSTR2a did not augment the glucagon or corticosterone response to hypoglycemia. Thus, somatostatin may contribute to impaired glucagon responsiveness to hypoglycemia in diabetes. We demonstrate that SSTR2 antagonism enhances hypoglycemia-stimulated glucagon and corticosterone release in D but not in N rats. SSTR2 antagonism does not affect basal glycemia in D rats.

Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes Nicolas Musi 1 , Michael F. Hirshman 1 , Jonas Nygren 2 , Monika Svanfeldt 3 , Peter Bavenholm 4 5 , Olav Rooyackers 6 , Gaochao Zhou 7 , Joanne M. Williamson 7 , Olle Ljunqvist 2 3 , Suad Efendic 8 9 , David E. Moller 7 , Anders Thorell 2 and Laurie J. Goodyear 1 1 Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 2 Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden 3 Department of Surgery, Huddinge University Hospital, Huddinge, Sweden 4 Division of Medicine, Karolinska Hospital and Institute, Stockholm, Sweden 5 Department of Emergency and Cardiovascular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden 6 Department of Anesthesiology and Intensive Care, Huddinge University Hospital, Huddinge, Sweden 7 Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey 8 Division of Molecular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden 9 Department of Endocrinology, Karolinska Hospital and Institute, Stockholm, Sweden Abstract Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK α2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK α2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK α2. Footnotes Address correspondence and reprint requests to Laurie J. Goodyear, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: laurie.goodyear{at}joslin.harvard.edu . Received for publication 1 February 2002 and accepted in revised form 12 April 2002. ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMPK, AMP-activated protein kinase; PCr, phosphocreatine. DIABETES

[This corrects the article DOI: 10.1371/journal.pone.0057458.].

An increasing body of evidence now links estrogenic signalling with the metabolic syndrome (MS). Despite the beneficial estrogenic effects in reversing some of the MS symptoms, the underlying mechanisms remain largely undiscovered. We have previously shown that total estrogen receptor alpha (ERα) knockout (KO) mice exhibit hepatic insulin resistance. To determine whether liver-selective ablation of ERα recapitulates metabolic phenotypes of ERKO mice we generated a liver-selective ERαKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERα selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERα action may not be the responsible factor for the previously identified hepatic insulin resistance in ERαKO mice.

Inhibition of Dipeptidyl Peptidase IV Improves Metabolic Control Over a 4-Week Study Period in Type 2 Diabetes Bo Ahrén , MD, PHD 1 2 , Erik Simonsson , MD 1 , Hillevi Larsson , MD, PHD 1 , Mona Landin-Olsson , MD, PHD 2 , Hlin Torgeirsson , MD 2 , Per-Anders Jansson , MD, PHD 3 , Madeléne Sandqvist , MD 3 , Peter Båvenholm , MD, PHD 4 , Suad Efendic , MD, PHD 4 , Jan W. Eriksson , MD, PHD 5 , Sheila Dickinson , MSC 6 and David Holmes , MD 6 1 Department of Medicine, Lund University, Malmö, Sweden 2 Department of Medicine, Lund University, Lund, Sweden 3 Department of Medicine, Göteborg University, Göteborg, Sweden 4 Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden 5 Department of Medicine, Umeå University, Umeå, Sweden 6 Novartis, Basel, Switzerland Abstract OBJECTIVE —Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1–degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study. RESEARCH DESIGN AND METHODS —A total of 93 patients (61 men and 32 women), aged 64 ± 9 years (means ± SD) and with BMI 27.3 ± 2.7 kg/m 2 , entered the study. Fasting blood glucose was 8.5 ± 1.5 mmol/l, and HbA 1c was 7.4 ± 0.7%. Before and after treatment with NVP DPP728 at 100 mg × 3 ( n = 31) or 150 mg × 5 ( n = 32) or placebo ( n = 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESULTS —Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P < 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups ( P = 0.017 and P = 0.023). Although not an efficacy parameter foreseen in the study protocol, HbA 1c was reduced to 6.9 ± 0.7% in the combined active treatment groups ( P < 0.001). Laboratory safety and tolerability was good in all groups. CONCLUSIONS —We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease. DDP IV, dipeptidyl peptidase IV FPG, fasting plasma glucose GIP, gastric inhibitory polypeptide GLP-1, glucagon-like peptide-1 NVP DPP728, 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine Footnotes Address correspondence and reprint requests to Dr. Bo Ahrén, Department of Medicine, Lund University, B11 BMC, S-221 84 Lund, Sweden. E-mail: bo.ahren{at}med.lu.se . Received for publication 15 August 2001 and accepted in revised form 5 February 2002. Bo Ahrén, Peter Båvenholm, Suad Efendic, Per-Anders Jansson, Madeléne Sandqvist, and Erik Simonsson have received grant support and Jan W. Eriksson has received consulting fees from Novartis, Basel, Switzerland. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Single Nucleotide Polymorphisms in the Proximal Promoter Region of the Adiponectin ( APM1 ) Gene Are Associated With Type 2 Diabetes in Swedish Caucasians Harvest F. Gu 1 , Adili Abulaiti 1 , Claes-Göran Östenson 1 , Keith Humphreys 2 , Claes Wahlestedt 3 , Anthony J. Brookes 3 and Suad Efendic 1 1 Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden 2 Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden 3 Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden Address correspondence and reprint requests to Harvest F. Gu, Department of Molecular Medicine, Karolinska Hospital, Stockholm, 171 76 Sweden. E-mail: harvest.gu{at}molmed.ki.se Abstract Adiponectin ( APM1 ) is an adipocyte-derived peptide. The APM1 gene is located on chromosome 3q27 and linked to type 2 diabetes. In patients with type 2 diabetes, the adiponectin level in plasma is decreased in comparison to healthy subjects. To identify genetic defects of the APM1 gene that contribute to the development of type 2 diabetes, we genotyped 13 single nucleotide polymorphisms (SNPs) in 106 patients with type 2 diabetes, 325 patients with impaired glucose tolerance (IGT), and 497 nondiabetic control subjects in Swedish Caucasians by using dynamic allele-specific hybridization (DASH). We found that SNPs −11426(A/G) and −11377(G/C) in the proximal promoter region had significant differences of allele frequencies between type 2 diabetic patients and nondiabetic control subjects ( P = 0.02 and P = 0.04, respectively). SNP-11426(A/G) was significantly associated with fasting plasma glucose in type 2 diabetic patients ( P = 0.02) and in IGT subjects ( P = 0.04), while the patients carrying CC and CG genotypes for SNP-11377(G/C) had a higher BMI than the patients with the GG genotype ( P = 0.03). Haplotype analysis of 13 SNPs in the APM1 gene showed that estimates of haplotype frequencies in Swedish Caucasians are similar to those estimated in French Caucasians. However, no significant association of haplotypes with type 2 diabetes and IGT was detected in our study. The present study provides additional evidence that SNPs in the proximal promoter region of the APM1 gene contribute to the development of type 2 diabetes. DASH, dynamic allele-specific hybridization HOMA, homeostasis model assessment HOMA-IR, HOMA index for insulin resistance IGT, impaired glucose tolerance SNP, single nucleotide polymorphism UTR, untranslated region Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Les Laboratoires Servier. Accepted May 27, 2003. Received March 10, 2003. DIABETES

Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats Kenan Cejvan 1 , David H. Coy 2 and Suad Efendic 1 1 Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital and Institute, Stockholm, Sweden 2 Peptide Research Laboratories, Department of Medicine, Tulane Health Sciences Center, New Orleans, Louisiana Abstract Exogenously administered somatostatin (SST) inhibits secretion of insulin and glucagon. Furthermore, it is hypothesized that islet SST regulates glucagon secretion by a local action. A number of studies utilizing SST antibodies have been performed to test this hypothesis, and their results have been conflicting. Five subtypes of SST receptor (SSTR1–5) mediate the effect of SST on target cells. In rodents, SST inhibits the release of glucagon, but not that of insulin, via SSTR2. A novel SSTR2-selective antagonist, DC-41-33, was synthesized recently. We have investigated the effects of this antagonist on arginine-stimulated glucagon and insulin release in batch incubations of isolated rat islets, perifused isolated rat islets, and isolated perfused rat pancreas. In batch incubations at 3.3 mmol/l glucose, DC-41-33 increased glucagon release in a dose-dependent manner. At the maximum dose tested (2 μmol/l), DC-41-33 enhanced the glucagon response by 4.3- to 5-fold. Similarly, this compound increased arginine-induced glucagon release in perifused islets at 3.3 mmol/l glucose (2.8-fold) and perfused pancreas at 3.3 and 5.5 mmol/l glucose (2.5- and 2.3-fold, respectively). In the two latter experimental systems, DC-41-33 had no significant effect on insulin release. In conclusion, our results strongly support the hypothesis that islet SST inhibits glucagon secretion via a local action. Footnotes Address correspondence and reprint requests to Kenan Cejvan, Endocrine & Diabetes Unit, Department of Molecular Medicine, Karolinska Hospital, L6:02, S-171 76 Stockholm, Sweden. E-mail: kenan.cejvan{at}molmed.ki.se . Received for publication 19 April 2002 and accepted in revised form 14 February 2003. KRBB, Krebs-Ringer bicarbonate buffer; SST, somatostatin; SSTR, SST receptor. DIABETES

Work Stress and Low Sense of Coherence Is Associated With Type 2 Diabetes in Middle-Aged Swedish Women Emilie E. Agardh , RN, MPH 1 , Anders Ahlbom , PHD 2 3 , Tomas Andersson , BSC 3 , Suad Efendic , MD, PHD 1 , Valdemar Grill , MD, PHD 1 , Johan Hallqvist , MD, PHD 4 , Anders Norman , MD 4 and Claes-Göran Östenson , MD, PHD 1 1 Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Institutet, Stockholm, Sweden 2 Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 3 Department of Epidemiology, Stockholm Center of Public Health, Stockholm, Sweden 4 Department of Public Health Science, Division of Social Medicine, Karolinska Institutet, Stockholm, Sweden Abstract OBJECTIVE —The risk of type 2 diabetes is suggested to be increased for individuals exposed to stress. We analyzed the association of work stress by high demands, low decision latitude, and job strain (combination of high demands and low decision latitude) with type 2 diabetes. We also studied low sense of coherence (SOC) (a factor for successful coping with stressors) in association with type 2 diabetes. Finally, we investigated the combination of SOC and demands or SOC and decision latitude in association with the disease. RESEARCH DESIGN AND METHODS —This cross-sectional study recruited 4,821 healthy Swedish women (aged 35–56 years) residing in five municipalities in the Stockholm area. An oral glucose tolerance test identified 52 women with type 2 diabetes. Relative risks (RRs) with 95% CIs were estimated in a logistic multiple regression analysis. RESULTS —No association was found between high demands and type 2 diabetes (RR 1.1 [CI 0.5–2.2]). Low decision latitude was associated with type 2 diabetes with a RR of 2.2 (1.0–4.8). The RR of type 2 diabetes with low SOC was 3.7 (1.2–11.2). The combination of low SOC and low decision latitude was associated with type 2 diabetes with a RR of 2.6 (1.2–5.7). Homeostasis model assessment revealed an association of 4.2 (1.2–15.0) between low SOC and insulin resistance. CONCLUSIONS —This study provided new evidence that stress factors such as low decision latitude at work and low SOC were associated with type 2 diabetes in middle-aged Swedish women. FHD, family history of diabetes HOMA, homeostasis model assessment HPA, hypothalamo-pituitary-adrenal IGT, impaired glucose tolerance OGTT, oral glucose tolerance test RR, relative risk SOC, sense of coherence WHR, waist-to-hip ratio Footnotes Address correspondence and reprint requests to Emilie Agardh, RN, MPH, Diabetes Prevention Unit, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: emilie.agardh{at}ks.se . Received for publication 26 September 2002 and accepted in revised form 25 November 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE

OBJECTIVE:--The effect of exercise training and acarbose on glycemic control, insulin sensitivity, and phenotype was investigated in mild type 2 diabetes. RESEARCH DESIGN AND METHODS--Sixty-two men and women with type 2 diabetes were randomized to 12 weeks of structured exercise training with or without acarbose treatment or to acarbose alone. Glycemic control was determined by HbA₁c (A1C), insulin sensitivity (M value) by euglycemic-hyperinsulinemic clamp, and regional fat distribution by computerized tomography and dual X-ray absorptiometry. Physical fitness was determined as maximal oxygen uptake (VO₂max). All investigations were performed before and after the intervention. RESULTS:--Forty-eight subjects completed the study. Exercise improved M value by 92% (P = 0.017) and decreased total and truncal fat (P = 0.002, 0.001) and systolic blood pressure (P = 0.01) but had no significant effect on VO₂max or A1C level. The combination of exercise and acarbose significantly decreased fasting plasma glucose, A1C, lipids, and diastolic blood pressure and increased VO₂max, whereas effects on M value and body composition were comparable with that of exercise alone. Acarbose alone had no significant effect on either M value or A1C but decreased systolic (P = 0.001) and diastolic blood pressure (P = 0.001) and fasting proinsulin level (P = 0.009). Multiple regression analysis showed that addition of acarbose to exercise improved glycemic control. CONCLUSIONS:--In subjects with mild type 2 diabetes, exercise training improved insulin sensitivity but had no effect on glycemic control. The addition of acarbose to exercise, however, was associated with significant improvement of glycemic control and possibly cardiovascular risk factors.