Type 2 diabetes (T2D) increases the risk for cerebrovascular disease (CVD) and dementia. The underlying molecular mechanisms remain elusive, which hampers the development of treatment or/and effective prevention strategies. Recent studies suggest that dyshomeostasis of amylin, a satiety hormone that forms pancreatic amyloid in patients with T2D, promotes accumulation of amylin in cerebral small blood vessels and interaction with Alzheimer's disease (AD) pathology. Overexpression of human amylin in rodents (rodent amylin does not form amyloid) leads to late-life onset T2D and neurologic deficits. In this Review, we discuss clinical evidence of amylin pathology in CVD and AD and identify critical characteristics of animal models that could help to better understand molecular mechanisms underlying the increased risk of CVD and AD in patients with prediabetes or T2D.
Alzheimer Disease ; Amyloid ; Blood Vessels ; Cerebrovascular Disorders ; Dementia ; Diabetes Complications ; Diabetes Mellitus, Type 2 ; Humans ; Islet Amyloid Polypeptide ; Models, Animal ; Neurologic Manifestations ; Pathology ; Prediabetic State ; Rodentia

Aged ; Diabetes Mellitus, Type 2 ; complications ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; blood ; etiology ; pathology ; Retrospective Studies

OBJECTIVETo investigate the perfusion restoration of type 1 diabetic mouse under the setting of surgically induced hind limb ischemia and the number and function of bone marrow endothelial progenitor cells (EPCs).

METHODSForty mice were randomly divided into two groups: one group was injected with alloxan through tail vein to induce type 1 diabetes mellitus, and another group was set as control group. All mice were surgically induced to hind limb ischemia. Blood flow was monitored with Laser Doppler perfusion imaging for 4 weeks after artery ligation. Ten mice in each group were sacrificed and muscle tissues were harvested for histological detection. The remaining mice were sacrificed 7 days after surgery, bone marrow mesenchymal stem cells were harvested and EPCs were analyzed by flow cytometry and then were collected to culture for functional detection.

RESULTSAll mice received alloxan injection showed typical symptoms of type 1 diabetes mellitus. Restoration of blood flow was significantly slower in type 1 diabetic mice with lower level of vascular density in ischemic muscles than control group (P < 0.001, P < 0.05). The number and function of EPCs (CD34 and vascular endothelial growth factor receptor 2 double positive cells) in type 1 diabetic mice were significantly lower than that in control mice (P < 0.05).

CONCLUSIONSThe spontaneous angiogenesis is attenuated with a decreased number and function of EPCs in the setting of type 1 diabetes mellitus. This may partly explain why diabetic patients with peripheral artery diseases have more aggressive disease and poorer outcome.

Animals ; Antigens, CD34 ; analysis ; Cell Count ; Diabetes Mellitus, Experimental ; complications ; pathology ; Diabetes Mellitus, Type 1 ; complications ; Hindlimb ; blood supply ; Ischemia ; complications ; physiopathology ; Mesenchymal Stromal Cells ; chemistry ; Mice ; Reperfusion ; Vascular Endothelial Growth Factor Receptor-2 ; analysis

The aim of this study was to investigate the relationship between obesity, insulin resistance and atherosclerosis in type 2 diabetes mellitus (T2DM) patients. Total 530 patients with T2DM were included. To evaluate the severity of atherosclerosis, we measured the coronary artery calcification (CAC) score, intima-media thickness (IMT) of the common carotid artery, and the ankle-brachial pressure index (ABPI). Subjects were classified according to body mass index (BMI), a marker of general obesity, and waist-to-hip ratio (WHR), a marker of regional obesity. The insulin sensitivity index (ISI) was measured by the short insulin tolerance test. All subjects were classified into four groups, according to BMI: the under-weight group, the normal-weight (NW) group, the over-weight (OW) group, and the obese (OB) group. WHR and systolic blood pressure, triglycerides (TG), HDL-cholesterol (HDLC), free fatty acids (FFA), fibrinogen, and fasting c-peptide levels were significantly different between BMI groups. TG, HDL-C, FFA, fibrinogen and ISI were significantly different between patients with and without abdominal obesity. In the OW group as well as in the NW group, carotid IMT, ABPI and CAC score were significantly different between patients with and without abdominal obesity. This study indicates that abdominal obesity was associated with atherosclerosis in T2DM patients.
Aged ; Atherosclerosis/complications ; Blood Pressure ; Coronary Vessels/pathology ; Diabetes Complications ; Diabetes Mellitus, Type 2/*genetics ; Female ; Humans ; Insulin Resistance ; Korea ; Male ; Middle Aged ; Obesity/*complications/*genetics ; Triglycerides/metabolism ; Tunica Intima/pathology ; Tunica Media/pathology

Our study was performed to determine whether cardiac autonomic neuropathy can predict deterioration of the renal function in normoalbuminuric, normotensive people with type 2 diabetes mellitus (DM). One hundred and fifty-six normoalbuminuric, normotensive people with type 2 DM were included in our retrospective longitudinal study. We categorized normal patterns, early patterns, and definite or severe patterns according to the results of the cardiac autonomic function test. Of 156 patients included, 54 had normal patterns, 75 had early patterns, 25 had definite or severe patterns, and 2 had atypical patterns. During a median follow-up of nine years, glomerular filtration rates (GFR) remained stable in the normal and early pattern groups (mean changes, 4.50% and 0.77%, respectively) but declined in those with definite or severe patterns (mean change, -10.28%; p=0.047). An abnormal heart response to the deep breathing test of the cardiac autonomic function tests was an independent predictor of GFR decline. Our data suggest that cardiac autonomic neuropathy, especially with a definite or severe pattern, might be associated with a subsequent deterioration in renal function in normoalbuminuric, normotensive people with type 2 DM.
Aged ; Blood Pressure ; Diabetes Complications ; Diabetes Mellitus, Type 2/*diagnosis/*pathology ; Female ; Follow-Up Studies ; Glomerular Filtration Rate ; Heart Diseases/*complications ; Heart Rate ; Humans ; Kidney/*pathology ; Kidney Diseases/*therapy ; Male ; Middle Aged ; Nephrology/methods ; Neurodegenerative Diseases/*complications

OBJECTIVETo investigate the possible involvement of erythr opoietin (EPO)/erythropoietin receptor (EPOR) system in neovascularization and vascular regeneration in diabetic retinopathy (DR).

METHODSEPOR positive circulating progenitor cells (CPCs: CD34(+)) and endothelial progenitor cells (EPCs: CD34(+)KDR(+)) were assessed by flow cytometry in type 2 diabetic patients with different stages of DR. The cohort consisted of age- and sex-matched control patients with out diabetes ( n=7),non-proliferative DR (NPDR, n=7),non-proliferative DR (PDR, n=8), and PDR complicated with diabetic nephr opathy (PDR-DN, n=7).

RESULTSThe numbers of EPOR(+) CPCs and EPOR(+) EPCs were reduced remarkably in NPDR compared with the control group (both Pü0.01), whereas rebounded in PDR and PDR-DN groups in varyingdegrees. Similar changes were observed in respect of the proportion of EPOR(+)CPCs in CPCs (NPDR vs. control, Pü0.01) and that of EPOR(+) EPCs in EPCs (NPDR vs. control, Pü0.05).

CONCLUSIONExogenous EPO, mediated via the EPO/EPOR system of EPCs, may alleviate the impaired vascular regeneration in NPDR, whereas it might aggravate retinal neovascularization in PDR due to a rebound of EPOR(+)EPCs associated with ischemia.

Aged ; Cell Count ; Diabetes Mellitus, Type 2 ; complications ; Diabetic Retinopathy ; pathology ; Endothelium, Vascular ; cytology ; Erythropoietin ; blood ; Female ; Humans ; Male ; Middle Aged ; Receptors, Erythropoietin ; analysis ; Stem Cells ; physiology

OBJECTIVETo study the possible association between C-reactive (CRP) and insulin resistance (IR) as well as the pathogenesis of type 2 diabetes macrovascular complication.

METHODSSerum CRP was measured by ultrasensitive immuoturbidimetric, which was determined on type 2 diabetes (T2DM) with or without macrovascular complication (70 and 60 cases respectively) and on normal controls (90 cases). IR was estimated by homeostasis model assessment (HOMA-IR).

RESULTSResults showed that the concentration of CRP was higher in T2DM with or without macrovascular complications than that in the healthy subjects (P < 0.01), while it was higher in diabetic patients with macrovascular complications than that in diabetic patients without macrovascular complications (P < 0.01). In diabetic patients with macrovascular complications, person correlation analysis indicated that there existed positive correlations between CRP and FINS, HOMA-IR, triglyceride (TG) while stepwise linear regression showed that usCRP and HOMA-IR, TG having linear correlation.

CONCLUSIONCRP seemed to play a role in the initiation and progression of atherosclerosis in type 2 diabetes, possibly was by the way of IR.

C-Reactive Protein ; metabolism ; Case-Control Studies ; Diabetes Complications ; blood ; metabolism ; pathology ; Diabetes Mellitus, Type 2 ; complications ; metabolism ; physiopathology ; Female ; Homeostasis ; Homocysteine ; blood ; Humans ; Inflammation Mediators ; metabolism ; Insulin Resistance ; Linear Models ; Male ; Middle Aged

We aimed to explore the associations of dietary patterns with blood lipid profiles and obesity in adults with type 2 diabetes. The data were obtained from the Forth Korean National Health and Nutrition Examination Survey, 2007-2008. Adults 30 yr or older, from which had both biochemical and dietary data were obtained. Among them, 680 subjects were defined as having diabetes based on criteria of fasting glucose > or = 126 mg/dL, anti-diabetic treatment, or previously diagnosed diabetes. Dietary data from a 24-hr recall were used to derive dietary patterns by factor analysis. Four dietary patterns by factor analysis were identified: 'Bread & Meat & Alcohol', 'Noodles & Seafood', 'Rice & Vegetables', and 'Korean Healthy' patterns. Serum cholesterol levels in the highest quartile of the 'Bread & Meat & Alcohol' pattern were significantly higher compared with those in the lowest quartile. In addition, total cholesterol and triglyceride levels in the highest quartile of the 'Korean Healthy' pattern were significantly lower after adjusting for potential confounders. Dietary patterns of adults with diabetes were found to be associated with blood lipid profiles. 'Korean Healthy' pattern including whole grains, legumes, vegetables, and fruits could thus improve lipid profiles among those with type 2 diabetes.
Adult ; Aged ; Cholesterol/blood ; Demography ; Diabetes Mellitus, Type 2/*blood/complications/pathology ; *Diet ; Female ; Food Habits ; Humans ; Lipids/*blood ; Male ; Middle Aged ; Nutrition Surveys ; Obesity/complications ; Republic of Korea ; Triglycerides/blood

OBJECTIVETo study the clinicopathological features of diabetic microangiopathy in liver and diabetic hepatosclerosis (DHS) of elderly male with type 2 diabetes mellitus (T2DM).

METHODSOne hundred and twenty autopsy cases with T2DM (diabetic group) and contemporary 48 cases, non-diabetic and glucose tolerance abnormal, matched by gender and age (control group) were selected in the study. Cases with the cirrhosis and fibrosis of liver caused by other foregone etiological factors were excluded. The histopathological changes of microangiopathy in liver, hepatic portal areas and hepatic sinusoid were investigated by HE staining, histochemical and immunohistochemical stain methods. The clinical data of diagnostic DHS cases were analyzed.

RESULTS(1) Microangiopathy was observed in 54.2% (65/120) cases of diabetic group. Histological features: microangiopathy was found in interlobular arteries (especially in arteriole, the lumen diameter < 100 µm), which included endothelial denudation, eosinophilic material deposition in the tunica intima of artery, and eccentric intimal thickening. The smooth muscle fibers of tunica media were hyperplastic or atrophy. Fibroplasia and collagen deposition were found in the tunica adventitia of artery. Arterial lumina showed stenosis and occlusion. Microangiopathy was seen in 16.7% (8/48) cases of the control group. There was statistically significant difference between the two groups (χ(2) = 19.622, P < 0.01). (2) The fibrosis and sclerosis of portal areas were detected in 55.8% (67/120) cases of T2DM group. Hyaline collagen fiber tissues was deposited around interlobular arteries, interlobular veins and interlobular bile ducts, resulting in enlargement of the portal area and the secondary atrophy and disappearance of portal triad. The fibrosis and sclerosis of portal areas were detected in 22.9% (11/48) cases of the control group. There was a statistically significant difference between the two groups (χ(2) = 14.936, P < 0.01). (3) The pathological features of 14.2% (17/120) cases were consistent with the diagnosis of DHS. The fibrous tissue extended from fibrosis or sclerosis of portal areas, or eosinophilic material deposition in the hepatic sinusoid in non-zonal pattern. The results of histochemical staining showed collagen fiber deposition in hepatic sinusoid. Stainings for Collagen IV, SMA, CD34 were found in the hepatic sinusoid. The sclerosis of hepatic sinusoid was not detected in any case in the control group.Overall, 13/17 and 11/17 DHS cases had liver microangiopathy and portal areas sclerosis respectively. Diabetic nephropathy was seen in 10 of 17 DHS cases. Among the 17 cases, 7 cases showed ALP elevation, of which there were 3 cases with ALT and AST mild elevation.

CONCLUSIONSDiabetic microangiopathy is common in the liver of elderly men with T2DM. And DHS is associated with diabetic microangiopathy. Fibrosis and sclerosis of portal areas may be the early or concomitant changes of DHS on histological ground. DHS is one of the complications of T2DM.

Actins ; metabolism ; Aged ; Aged, 80 and over ; Alanine Transaminase ; blood ; Alkaline Phosphatase ; blood ; Antigens, CD34 ; metabolism ; Aspartate Aminotransferases ; blood ; Collagen Type IV ; metabolism ; Diabetes Mellitus, Type 2 ; complications ; Diabetic Angiopathies ; blood ; etiology ; metabolism ; pathology ; Diabetic Nephropathies ; complications ; pathology ; Humans ; Liver ; blood supply ; pathology ; Liver Cirrhosis ; complications ; Male ; Middle Aged ; Sclerosis

The aim of this study was to evaluate the association of plasma fibroblast growth factor (FGF)-21 with angiographically significant coronary artery disease (CAD) in patients with type 2 diabetes mellitus. Serum FGF-21 was measured in 120 patients undergoing coronary angiography. Patients were divided into 4 groups based on the presence/absence of type 2 diabetes mellitus and of significant CAD. The atherosclerotic burden was obtained by two angiographic scores: Gensini score (GS) and Extent score (ES). FGF-21 levels were higher in type 2 diabetes mellitus than in non-diabetic patients (P = 0.014). FGF-21 levels were significantly correlated with GS (r = 0.358, P < 0.001) and ES (r = 0.324, P < 0.001) in univariate analysis with all patients. After adjusting for several confounding factors, both GS and ES were associated with FGF-21 in all patients (r = 0.271, P = 0.014; r = 0.217, P = 0.041, respectively). However, FGF-21 lost significant correlation with both GS and ES with type 2 diabetes mellitus in the final model. The patients with type 2 diabetes mellitus and CAD feature had elevated FGF-21 levels. Despite of a limited role in diabetic patients, FGF-21 levels are independently associated with angiographic severity and extent of CAD.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Coronary Angiography ; Coronary Artery Disease/complications/*diagnosis/pathology ; Diabetes Mellitus, Type 2/complications/*diagnosis ; Female ; Fibroblast Growth Factors/*blood ; Humans ; Male ; Middle Aged ; Regression Analysis ; Severity of Illness Index ; Young Adult