Improved control of blood pressure and albuminuria among patients with type-2 diabetes in Finnish open care.

Risk of cardiovascular events within the diabetic population has decreased and survival increased with patients living longer and thus facing the development of end-stage renal disease (ESRD). This calls for good care of patient with diabetes with a focus on hypertension. Patient data were collected from 42 Finnish primary care centres. Each was asked to enrol 10-12 consecutive patients with type-2 diabetes between March 2011 and August 2012. Along with the office blood pressure measurements and laboratory tests, the presence of albuminuria was measured and glomerular filtration rate estimated (eGFR). The 2013 ESH criteria for diabetic hypertensive patients (<140/85 mmHg) was reached by 39% of all 625 study patients and 38% of the pharmacologically treated 520 patients. The absence of detectable albumin in urine was significantly associated with the control of systolic blood pressure and achievement of treatment goals. Beta blockers were the most common antihypertensive agents and patients treated with them had lower eGFR compared to those not treated with these agents. The blood pressure of patients was not in full concordance with the present guideline recommendations. However, satisfactory improvement in blood pressure control, reduction of albuminuria and hence ESRD prevention was achieved.

The activation of hepatic and muscle polyamine catabolism improves glucose homeostasis.

The mitochondrial biogenesis and energy expenditure regulator, PGC-1α, has been previously reported to be induced in the white adipose tissue (WAT) and liver of mice overexpressing spermidine/spermine N (1)-acetyltransferase (SSAT). The activation of PGC-1α in these mouse lines leads to increased number of mitochondria, improved glucose homeostasis, reduced WAT mass and elevated basal metabolic rate. The constant activation of polyamine catabolism produces a futile cycle that greatly reduces the ATP pools and induces 5'-AMP-activated protein kinase (AMPK), which in turn activates PGC-1α in WAT. In this study, we have investigated the effects of activated polyamine catabolism on the glucose and energy metabolisms when targeted to specific tissues. For that we used a mouse line overexpressing SSAT under the endogenous SSAT promoter, an inducible SSAT overexpressing mouse model using the metallothionein I promoter (MT-SSAT), and a mouse model with WAT-specific SSAT overexpression (aP2-SSAT). The results demonstrated that WAT-specific SSAT overexpression was sufficient to increase the number of mitochondria, reduce WAT mass and protect the mice from high-fat diet-induced obesity. However, the improvement in the glucose homeostasis is achieved only when polyamine catabolism is enhanced at the same time in the liver and skeletal muscle. Our results suggest that the tissue-specific targeting of activated polyamine catabolism may reveal new possibilities for the development of drugs boosting mitochondrial metabolism and eventually for treatment of obesity and type 2 diabetes.

Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism.

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is an attractive candidate gene for type 2 diabetes, as genes of the oxidative phosphorylation (OXPHOS) pathway are coordinatively downregulated by reduced expression of PGC-1 alpha in skeletal muscle and adipose tissue of patients with type 2 diabetes. Here we demonstrate that transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) had reduced white adipose tissue (WAT) mass, high basal metabolic rate, improved glucose tolerance, high insulin sensitivity, and enhanced expression of the OXPHOS genes, coordinated by increased levels of PGC-1 alpha and 5'-AMP-activated protein kinase (AMPK) in WAT. As accelerated polyamine flux caused by SSAT overexpression depleted the ATP pool in adipocytes of SSAT mice and N(1),N(11)-diethylnorspermine-treated wild-type fetal fibroblasts, we propose that low ATP levels lead to the induction of AMPK, which in turn activates PGC-1 alpha in WAT of SSAT mice. Our hypothesis is supported by the finding that the phenotype of SSAT mice was reversed when the accelerated polyamine flux was reduced by the inhibition of polyamine biosynthesis in WAT. The involvement of polyamine catabolism in the regulation of energy and glucose metabolism may offer a novel target for drug development for obesity and type 2 diabetes.

The effect of moderate exercise training on skeletal muscle myosin heavy chain distribution in chronic heart failure.

BACKGROUND: The myosin heavy chain (MHC) is altered in chronic heart failure (CHF), but the effect of exercise on MHC expression in CHF patients is not understood. The aim of the present study was to show the effect of aerobic exercise on MHC distribution in patients with CHF. METHODS: Patients (n=17) with stable NYHA class I-III CHF were randomised into training and control groups. For a period of three months, the training group cycled on an ergometric cycle 3 times a week for 30 min, the control group continued as they did previously. Both a baseline and a final 3 month graded maximal exercise test and exercise endurance test with constant submaximal work load were performed. Muscle samples, obtained from vastus lateralis muscle at baseline and after 3 months from the 8 patients in the training group and the 9 in the control group, were analysed for MHC distribution using SDS-polyacrylamide gel electrophoresis. RESULTS: Baseline MHC distributions were similar in both groups and training did not alter the MHC distribution. Exercise duration, at constant submaximal work load, improved from 14.9+/-7.1 to 26.9+/-9.6 min (p<0.01 for the change between the groups). Training did not improve peak oxygen consumption. CONCLUSION: No correlation between the change in exercise capacity and MHC distribution appeared despite the significant improvement of exercise duration.

High prevalence of chronic kidney disease in Finnish patients with type 2 diabetes treated in primary care.

OBJECTIVE: To examine the prevalence of chronic kidney disease (CKD) and related cardiovascular morbidity in a cross-sectional population in patients with type 2 diabetes (T2D) treated in a primary care setting in Finland. RESEARCH DESIGN AND METHODS: Data were collected and recorded from 42 primary care centres, which recruited 629 patients diagnosed with type 2 diabetes (T2D) to this non-interventional study. Data including patient characteristics, kidney function and albuminuria, blood pressure, HbA1c, lipid and lipoprotein levels, and diabetes duration as well as current medication was collected in each patient. RESULTS: In the final study population of 625 patients, the mean age was 67 years (range 29-92 years), BMI 32.8 kg/m(2) (95% CI 32-33), blood pressure 142/80 mmHg (140-143/80-81) and HbA1c 7.1% (7.0-7.2) (53.8 mmol/mol, 53-55) and the median duration of diabetes was 9.2 years ranging from newly diagnosed to 43 years. History of dyslipidemia had in 73.3% of patients, 27.8% had cardiovascular disease and 82.7% had hypertension. The primary endpoint, prevalence of CKD of any grade (1-5) or albuminuria, was 68.6%. Regarding declined renal function, 16.2% of patients had an estimated glomerular filtration rate (eGFR) <60 ml/min/1.72 m(2), classifying as CKD 3-5. Only one patient was within CKD5. Regarding renal damage, albuminuria was present in 24.3% of patients, with microalbuminuria in 17.1% and macroalbuminuria in 7.2%, respectively. Combining the patients with CKD 3-5 and/or the presence of albuminuria, 34.7% seemed to suffer from significant CKD. The proportion of patients with albuminuria increased with a decrease in glomerular filtration rate. Historically, diabetic nephropathy had been diagnosed in 24.3% of the patients. CONCLUSIONS: Nearly 70% of patients with T2D treated in primary care in Finland have some sign of CKD and nearly half of all T2D patients have a significant CKD. However, only half of the latter had it diagnosed and documented in their patient charts, thus highlighting the importance of performing routine screening of nephropathy by measuring both albuminuria and eGFR in patients with T2D. Prevention of this complication with active therapy for risk factors, such as hypertension and dyslipidemia is warranted.

Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy.

OBJECTIVE: To determine the expressions of multiple genes in the subcutaneous adipose tissue of HIV-positive, highly active antiretroviral therapy (HAART)-treated patients with and without lipodystrophy. DESIGN AND METHODS: Real-time polymerase chain reaction was used to measure gene expressions in this cross-sectional study. RESULTS: The messenger RNA concentrations of adipose transcription factors (peroxisome proliferator-activated receptor (PPAR) gamma and delta and sterol regulatory element binding protein 1c) were all significantly lower in the lipodystrophic than the non-lipodystrophic group. The mRNA concentration of PPAR-gamma co-activator 1 (PGC-1), which regulates mitochondrial biogenesis, was lower in the lipodystrophic than the non-lipodystrophic group. The mRNA expression of lipoprotein lipase, acyl coenzyme A synthase and glucose transport protein 4 were significantly lower in the lipodystrophic than the non-lipodystrophic group, but the mRNA concentrations of fatty acid transport and binding proteins were similar in both groups. The mRNA concentrations of IL-6 and CD45 (a common leukocyte marker) were significantly higher in the lipodystrophic than the non-lipodystrophic group. CONCLUSION: Multiple alterations characterize gene expression in the subcutaneous adipose tissue of patients with HAART-associated lipodystrophy compared with HIV-positive, HAART-treated patients without lipodystrophy. The low expression of transcription factors inhibits adipocyte differentiation. The low expression of PGC-1 may contribute to mitochondrial defects. In addition, IL-6 and CD45 expressions are increased, the latter implying an excessive number of cells of leukocyte origin in lipodystrophic adipose tissue. Mitochondrial injury and an excess of proinflammatory cytokines may lead to increased apoptosis. All these changes may contribute to the loss of subcutaneous fat in HAART-associated lipodystrophy.

Fasting plasma glucose variability as a marker of nocturnal hypoglycemia in diabetes: evidence from the PREDICTIVE study.

The relationship between fasting glucose (FG) variability and nocturnal hypoglycemia was assessed using longitudinal data from PREDICTIVE, the large-scale observational study of insulin detemir. An HbA(1c)-corrected correlation was found between these endpoints, suggesting FG variability can serve as a useful marker for this risk in clinical practice.

Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: involvement in diabetic teratogenesis.

BACKGROUND: Oxidative stress is critical to the teratogenic effects of diabetic pregnancy, yet the specific biochemical pathways responsible for oxidative stress have not been fully elucidated. The hexosamine pathway is activated in many tissues during diabetes and could contribute to oxidative stress by inhibiting the pentose shunt pathway, thereby diminishing production of the cellular antioxidant, reduced glutathione (GSH). METHODS: To test the hypothesis that activation of the hexosamine pathway might contribute to the teratogenic effects of diabetic pregnancy, pregnant mice were injected with glucose, to induce hyperglycemia, or glucosamine, to directly activate the hexosamine pathway. Embryo tissue fragments were also cultured in physiological glucose, high glucose, or physiological glucose plus glucosamine, to test effects on oxidative stress and embryo gene expression. RESULTS: Glucosamine increased hexosamine synthesis and inhibited pentose shunt activity. There was a trend for transient hyperglycemia to have the same effects, but they did not reach statistical significance. However, both glucose and glucosamine significantly decreased GSH, and increased oxidative stress, as indicated by 2',7'-dichloro-dihydrofluorescein fluorescence. Glucose and glucosamine inhibited expression of Pax-3, a gene required for neural tube closure both in vivo and in vitro, and increased neural tube defects (NTDs) in vivo; these effects were prevented by GSH ethyl ester. High glucose and glucosamine inhibited Pax-3 expression by embryo culture, but culture in glutamine-free media to block the hexosamine pathway prevented the inhibition of Pax-3 expression by high glucose. CONCLUSIONS: Activation of the hexosamine pathway causes oxidative stress through depletion of GSH and consequent disruption of embryo gene expression. Activation of this pathway may contribute to diabetic teratogenesis.

Elevated fasting insulin concentrations associate with impaired insulin signaling in skeletal muscle of healthy subjects independent of obesity.

BACKGROUND: Insulin signaling is impaired in the skeletal muscle of obese subjects but whether defects in skeletal muscle insulin signaling also characterize insulin resistance of non-obese individuals is unknown. The detection of insulin signaling defects in muscle biopsies is hampered by the variation of the contaminating non-muscle elements such as blood, connective tissue, fat, and blood vessel structures. Freeze-drying and macroscopic purification of the muscle fibers prior to the analysis might offer a possibility to minimize the analytical variation due to these contaminants. METHODS: In the present study we first determined whether insulin signaling could be reliably assessed in freeze-dried muscle specimens, which are free of non-muscle contaminants, and then applied this method to the study of insulin signaling in weight-matched insulin-sensitive and insulin-resistant non-diabetic men. RESULTS: In rat muscle, increases in tyrosine phosphorylation of insulin receptor (IR) and activity of the insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity by insulin were similar or higher in freeze-dried and purified muscle than wet muscle. Prior to freeze-drying and purification, biopsies of human vastus lateralis muscle contained between 1% and 40% non-muscle contaminants (11+/-3%, mean+/-SEM, n=19). In freeze-dried biopsies of human vastus lateralis muscle taken before and after 30 min of hyperinsulinemia (serum free insulin 61+/-1 mU/l) in 13 non-diabetic men, insulin increased IR tyrosine phosphorylation 1.4-fold (p<0.05) and IRS-1-associated PI 3-kinase activity 1.7-fold (p<0.005). Insulin-stimulated PI 3-kinase activity was significantly inversely correlated with the fasting serum insulin concentration (r=-0.57, p<0.05). When divided according to the median fasting serum insulin concentration, the men with high fasting insulin [HI, n=7, age 44+/-3 years, body mass index (BMI) 25+/-1 kg/m(2)] as compared to the men with low fasting insulin [LI, n=6, age 45+/-3 years (NS), BMI 24+/-1 kg/m(2) (NS)] had lower rates of whole-body glucose uptake (3.4+/-0.4 vs 5.5+/-0.3 mg/kg min, p<0.005), higher fasting plasma glucose concentrations (5.9+/-0.2 vs 5.2+/-0.1 mmol/l, p<0.05), higher fasting serum triglycerides (1.4+/-0.2 vs 0.9+/-0.1 mmol/l, p<0.05) and lower high-density lipoprotein (HDL) cholesterol concentrations (1.3+/-0.1 vs 1.7+/-0.1 mmol/l, p<0.05). Insulin-stimulated IR tyrosine phosphorylation (p<0.05) and IRS-1-associated PI 3-kinase activity (p<0.05) were significantly lower in the HI than the LI group. CONCLUSIONS: Taken together these data demonstrate that early insulin signaling events can be reliably assessed in freeze-dried human skeletal muscle, and that in vivo insulin resistance and its accompanying features are associated with defects in early insulin signaling events in human skeletal muscle independent of body weight.

Effects of rosiglitazone on gene expression in subcutaneous adipose tissue in highly active antiretroviral therapy-associated lipodystrophy.

Highly active antiretroviral therapy (HAART) has improved the prognosis of human immunodeficiency virus (HIV)-infected patients but is associated with severe adverse events, such as lipodystrophy and insulin resistance. Rosiglitazone did not increase subcutaneous fat in patients with HAART-associated lipodystrophy (HAL) in a randomized, double-blind, placebo-controlled trial, although it attenuated insulin resistance and decreased liver fat content. The aim of this study was to examine effects of rosiglitazone on gene expression in subcutaneous adipose tissue in 30 patients with HAL. The mRNA concentrations in subcutaneous adipose tissue were measured using real-time PCR. Twenty-four-week treatment with rosiglitazone (8 mg/day) compared with placebo significantly increased the expression of adiponectin, peroxisome proliferator-activated receptor-gamma (PPARgamma), and PPARgamma coactivator 1 and decreased IL-6 expression. Expression of other genes involved in lipogenesis, fatty acid metabolism, or glucose transport, such as acyl-CoA synthase, adipocyte lipid-binding protein, CD45, fatty acid transport protein-1 and -4, GLUT1, GLUT4, keratinocyte lipid-binding protein, lipoprotein lipase, PPARdelta, and sterol regulatory element-binding protein-1c, remained unchanged. Rosiglitazone also significantly increased serum adiponectin concentration. The change in serum adiponectin concentration was inversely correlated with the change in fasting serum insulin concentration and liver fat content. In conclusion, rosiglitazone induced significant changes in gene expression in subcutaneous adipose tissue and ameliorated insulin resistance in patients with HAL. Increased expression of adiponectin might have mediated most of the favorable insulin-sensitizing effects of rosiglitazone in these patients.