Associations of Circulating Osteoglycin With Bone Parameters and Metabolic Markers in Patients With Diabetes.

Objective: Circulating osteoglycin may facilitate the crosstalk between bone and pancreas to empower adaptation of bone mass to whole body energy balance. We aimed to examine whether osteoglycin is associated with bone and metabolic parameters and if osteoglycin levels differ between patients with type 1 and 2 diabetes (T1D and T2D). Design and methods: A cross-sectional study of 190 patients with diabetes mellitus and stable hemoglobin A1c (HbA1c) (97 T1D and 93 T2D) was conducted. S-osteoglycin was analyzed by ELISA. Unpaired t-tests were performed to test differences between patients with T1D and T2D and linear regression analyses were performed to investigate associations between osteoglycin, glycemic markers, bone turnover markers and characteristics. Results: S-osteoglycin did not differ between patients with T1D and T2D (p=0.10). No associations were present between osteoglycin and age, gender, microvascular complications, HbA1c, or plasma glucose in T1D or T2D patients (p>0.05 for all). S-osteoglycin was not associated with levels of bone turnover markers (C-terminal cross-linked telopeptide of type-I collagen (CTX), P-procollagen type 1 amino terminal propeptide (P1NP), P-osteocalcin (OC), P-sclerostin, S-osteoprotegerin (OPG) or S-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL)) in neither T1D or T2D patients (p>0.05 for all). Conclusion: Osteoglycin levels were similar in T1D and T2D patients. Osteoglycin did not correlate with glucose, HbA1c or any other biochemical marker of bone turnover. Thus, we did not find evidence supporting the existence of an osteoglycin-bone-pancreas axis. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01870557.

Increased retention of LDL from type 1 diabetic patients in atherosclerosis-prone areas of the murine arterial wall.

BACKGROUND AND AIMS: Type 1 diabetes accelerates the development of atherosclerotic cardiovascular diseases. Retention of low-density lipoprotein (LDL) in the arterial wall is a causal step in atherogenesis, but it is unknown whether diabetes alters the propensity of LDL for retention. The present study investigated whether LDL from type 1 diabetic and healthy non-diabetic subjects differed in their ability to bind to the arterial wall in a type 1 diabetic mouse model. METHODS: Fluorescently-labeled LDL obtained from type 1 diabetic patients or healthy controls was injected into mice with type 1 diabetes. The amount of retained LDL in the atherosclerosis-prone inner curvature of the aortic arch was quantified by fluorescence microscopy. Healthy control LDL was in vitro glycated, analyzed for protein glycation by LC-MS/MS, and tested for retention propensity. RESULTS: Retention of LDL from type 1 diabetic patients was 4.35-fold higher compared to LDL from nondiabetic subjects. Nuclear magnetic resonance (NMR) spectroscopy analysis of LDL revealed no differences in the concentration of the atherogenic small dense LDL between type 1 diabetic and non-diabetic subjects. In vitro glycation of LDL from a non-diabetic subject increased retention compared to non-glycated LDL. LC-MS/MS revealed four new glycated spots in the protein sequence of ApoB of in vitro glycated LDL. CONCLUSIONS: LDL from type 1 diabetic patients showed increased retention at atherosclerosis-prone sites in the arterial wall of diabetic mice. Glycation of LDL is one modification that may increase retention, but other, yet unknown, mechanisms are also likely to contribute.

Risk of cardiovascular disease: the effects of diabetes and anti-diabetic drugs - a nested case-control study.

AIMS: Type 2 diabetes (DM) increases the risk of cardiovascular disease. We investigated the effects of antidiabetic drugs on the composite endpoint (CE) of ischemic heart disease, heart failure or stroke in DM patients. METHODS: We conducted a nested case-control study. Cases were DM patients who subsequently suffered from CE; controls were DM patients with no history of CE after DM diagnosis. Using the Danish National Hospital Discharge Register, we included DM patients with information on date of DM diagnosis, date of CE, and comorbidities. From the Central Region of Jutland, Denmark, medication use and biochemical parameters were collected. Logistic regression analyses were conducted and mutually adjusted for comorbidities, pharmaceutical use, and biochemical parameters. RESULTS: 10,073 DM patients were included (65,550person-years). 1947 suffered from a subsequent CE. CE prior to DM diagnosis (OR=20.18, 95% CI: 16.88-24.12), neuropathy (OR=1.39, 95% CI: 1.05-1.85) and peripheral artery disease (OR=1.31, 95% CI: 1.02-1.69) increased the risk of CE. Biguanides (OR=0.62 95% CI; 0.54-0.71) and liraglutide (OR=0.48 95% CI; 0.38-0.62) significantly decreased the risk of CE as did statin treatment (OR=0.63, 95% CI: 0.54-0.72). DPP-4 inhibitors, insulin and ß-cell stimulating agents had neutral effect. When results were adjusted for biochemical risk markers (1103 patients, 7271person-years, 189 cases), biguanides (OR=0.54, 95% CI: 0.34-0.87) and liraglutide (OR=0.32, 95% CI: 0.14-0.70) treatment retained a significant risk reduction. The effect of liraglutide was dose and duration dependent (p<0.05). CONCLUSION: We have shown an association between the use of biguanides and liraglutide and a reduced risk of CE in DM patients.

WITHDRAWN: Low-density lipoprotein cholesterol is associated with fracture risk in diabetes patients - a nested case-control study.

AIM: Diabetes Mellitus is associated with an increased risk of fractures, which is not explained fully by bone mineral density and common risk factors. The aim of this study is to investigate the association of medication and biochemical markers on the risk of fracture in a diabetes population. METHODS: Nested case-control study based on Danish diabetes patients from The Danish National Hospital Discharge Registry. The cases of the study were diabetes patients with a fracture (n= 24,349) and controls were diabetes patients with no fracture (n=132,349). A total of 2,816 diabetes patients were available for an analysis of patient characteristics, co-morbidities, biochemical parameters and drug usage. RESULTS: Patient age at the time of diabetes diagnosis, a diagnosis of previous fracture, an alcohol related diagnosis, total cholesterol level, and the usage of antidepressants, antiepileptics and insulin all increased the odds of fracture. Low-density lipoprotein cholesterol (LDL) levels decreased the odds of fracture, where the level of 3.04-5.96 mmol/l was optimal with regard to fracture risk. CONCLUSION: LDL may add to the understanding of fractures in diabetes patients and it may be added to current fracture risk models in diabetes patients.

Energy restriction prevents the development of type 2 diabetes in Zucker diabetic fatty rats: coordinated patterns of gene expression for energy metabolism in insulin-sensitive tissues and pancreatic islets determined by oligonucleotide microarray analysis.

Energy restriction (ER) causes metabolic improvement in the prediabetic and diabetic state. Little information exists on the mechanism of action of ER, for example, on the changes at the transcriptional gene level in insulin-sensitive tissues. To gain further insight, we have investigated changes in gene expressions in skeletal muscle, liver, fat, and pancreatic islets after ER in male Zucker diabetic fatty rats. Eighteen Zucker diabetic fatty rats were divided at the age of 7 weeks into a control group (ad libitum diet) and an ER group (30% ER compared with the control group). Blood glucose, weight, and food intake were measured weekly. After 5 weeks, blood samples, and skeletal muscle, liver, visceral fat (epididymal fat pads), and islets tissue were collected. Gene expression was quantified with high-density oligonucleotide, microarray GeneChip technology. ER ameliorated the development of hyperglycemia, increased the levels of plasma insulin, and reduced plasma total cholesterol and the glucagon-insulin ratio (P < .05). In skeletal muscle, the expression of 55 genes increased and 245 decreased involving genes related to glucose metabolism (eg, phosphorylase kinase, pyruvate dehydrogenase kinase 4), lipid metabolism (eg, carnitine palmitoyltransferase 1, fatty acid transporter), and signaling pathways (eg, mitogen-activated protein kinases, protein kinase C). In the liver, the expression of 123 genes increased and 103 decreased involving genes related primarily to lipid metabolism. In pancreatic islets, the expression of 110 genes increased and that of 127 decreased, whereas in visceral fat, the expression of 279 genes increased and that of 528 decreased. ER counteracts the development of diabetes and causes changes in the expression of multiple genes involved in glucose and lipid metabolism in skeletal muscle, liver, and pancreatic islets, which may play an important role for the prevention of diabetes.

Prevention of hyperglycemia in Zucker diabetic fatty rats by exercise training: effects on gene expression in insulin-sensitive tissues determined by high-density oligonucleotide microarray analysis.

Exercise training (ET) causes metabolic improvement in the prediabetic and diabetic states. However, only little information exists on the changes to ET at the transcriptional level in insulin-sensitive tissues. We have investigated the gene expression changes in skeletal muscle, liver, fat, and pancreatic islets after ET in male Zucker diabetic fatty (ZDF) rats. Eighteen ZDF rats (7 weeks old) were divided in a control and ET group. Exercise was performed using a motorized treadmill (20 m/min 1 hour daily for 6 days a week). Blood glucose, weight, and food intake were measured weekly. After 5 weeks, blood samples, soleus muscle, liver, visceral fat (epididymal fat pads), and islet tissue were collected. Gene expression was quantified with Affymetrix RG-U34A array (16 chips). Exercise training ameliorates the development of hyperglycemia and reduces plasma free fatty acid and the level of glucagon-insulin ratio (P < .05). In skeletal muscle, the expression of 302 genes increased, whereas that of 119 genes decreased. These changes involved genes related to skeletal muscle plasticity, Ca(2+) signals, energy metabolism (eg, glucose transporter 1, phosphorylase kinase), and other signaling pathways as well as genes with unknown functions (expressed sequence tags). In the liver, expression of 148 genes increased, whereas that of 199 genes decreased. These were primarily genes involved in lipogenesis and detoxification. Genes coding for transcription factors were changed in parallel in skeletal muscle and liver tissue. Training did not markedly influence the gene expression in islets. In conclusion, ET changes the expression of multiple genes in the soleus muscle and liver tissue and counteracts the development of diabetes, indicating that ET-induced changes in gene transcription may play an important role en the prevention of diabetes.