Obesity is a major cause of insulin resistance and type 2 diabetes. The altered glucose homeostasis is caused by faulty insulin signal transduction, which results in decreased glucose uptake by the muscle, altered lipogenesis, and increased glucose output by the liver. The etiology of this derangement in insulin signaling is related to a chronic inflammatory state, leading to the induction of inducible nitric oxide synthase and release of high levels of nitric oxide and reactive nitrogen species, which together cause posttranslational modifications in the signaling proteins. There are substantial differences in the molecular mechanisms of insulin resistance in muscle versus liver. Hormones and cytokines from adipocytes can enhance or inhibit both glycemic sensing and insulin signaling. The role of the central nervous system in glucose homeostasis also has been well established. Multi-pronged therapies aimed at rectifying obesity induced anomalies in both central nervous system and peripheral tissues may prove to be beneficial. The golden standard method to evaluate the insulin sensitivity is hyperinsulinemic euglycemic clamp.
Diabetes Mellitus, Type 2 ; etiology ; Glucose ; metabolism ; Humans ; Insulin ; metabolism ; Insulin Resistance ; physiology ; Obesity ; complications ; metabolism ; physiopathology

Endothelial dysfunction contributes to cardiovascular diseases that are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders including Type 2 diabetes, obesity, and the metabolic syndrome that are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. PI 3-kinase-dependent insulin signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct non-metabolic branches of insulin signaling pathways regulate secretion of the vasoconstrictor endothelin-1 (ET-1) in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in PI 3-kinase-dependent signaling that in endothelium may cause imbalance between production of NO and secretion of ET-1 leading to decreased blood flow that worsens insulin resistance. Therapeutic interventions in both animal models and human studies demonstrate that improving endothelial function ameliorates insulin resistance while improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In this review, pathophysiological mechanisms that couple endothelial dysfunction with insulin resistance will be discussed with an emphasis on important therapeutic implications for the metabolic syndrome.
Animals ; Diabetes Mellitus, Type 2 ; physiopathology ; Endothelium, Vascular ; physiopathology ; Glucose ; metabolism ; Humans ; Hypertension ; metabolism ; pathology ; Insulin ; metabolism ; Insulin Resistance ; Metabolic Syndrome ; physiopathology ; Nitric Oxide ; metabolism

Blood Glucose ; metabolism ; Diabetes Complications ; prevention & control ; Diabetes Mellitus, Type 1 ; blood ; metabolism ; physiopathology ; Diabetes Mellitus, Type 2 ; blood ; metabolism ; physiopathology ; Dinoprost ; analogs & derivatives ; blood ; Glucose ; metabolism ; Glycated Hemoglobin A ; Humans ; Hypoglycemic Agents ; pharmacology ; Insulin ; pharmacology ; Oxidative Stress

Type 2 diabetes can be treated by gastrointestinal surgery, but the underlying mechanism is unclear. This review summarizes the possible mechanisms which include weight loss, gastrointestinal hormones, foregut hypothesis, hindgut hypothesis, adipocytokines, and inflammatory factors.
Diabetes Mellitus, Type 2 ; metabolism ; physiopathology ; surgery ; Digestive System Surgical Procedures ; Gastric Bypass ; Gastrointestinal Hormones ; metabolism ; Humans ; Weight Loss

Aged ; Blood Glucose ; metabolism ; Diabetes Mellitus, Type 2 ; blood ; physiopathology ; Female ; Glycated Hemoglobin A ; metabolism ; Humans ; Male ; Middle Aged ; Neuropsychological Tests

The major objective was to explore the effect of early hyperbaric oxygen (HBO) therapy on the tissue structure, apoptosis, and metalloproteinases of kidney cells in Goto-Kakizaki (GK) rats with type 2 diabetes mellitus. GK rats (n = 24) were divided randomly and evenly into model, metformin hydrochloride (MH), and hyperbaric oxygen (HBO) groups, while healthy Wistar rats (n = 8) were used as normal control group. The healthy rats in the normal control group and the GK rats in the model group were both intragastrically administered with purified water (5 mL/kg) once per day. Meanwhile, the rats in the MH group received intragastric administration of MH (250 mg/kg) once daily, while the rats in the HBO group inhaled pure oxygen under a constant pressure (0.15 MPa) for 30 min. After 3 weeks of treatment, the body weight of each rat was measured, and the blood samples were collected from tails. Subsequently, the kidneys of all rats were excised for weighing mass and further examination. For each renal sample, the sections were firstly embedded with paraffin and sliced to prepare histopathologic sections stained using HE, PAS and Masson, respectively, for subsequent observation with optical microscopy. Later, the apoptosis of kidney cells was examined using the TUNEL method by computing the apoptotic index. Furthermore, the histopathologic sections were also examined using the immunohistochemistry approach with Caspase-3, MMP-2, and TIMP-2 antibodies, respectively. At the same time, the plasma concentration of TGF-β1 of the rats in each group was detected using ELISA method. These resultant data showed that the pathological changes of the HBO group were less than those of the model group with respect to increased glomerular volume density of mesangial cells, broadening mesangial matrix and thickening basement membrane as well as swelling renal tubular epithelial cells. The index of cell apoptosis and Caspase-3 expression in the HBO group showed no significant differences (P > 0.05) compared with those in the normal control and MH groups respectively, but demonstrated significant decrease compared with that in the model group (P < 0.01). Meanwhile, the MMP-2 and TIMP-2 expressions of the HBO group were stronger than those in the model and MH groups, but weaker than those in the normal control group (P < 0.05). Although the plasma concentration of TGF-β1 in HBO, MH and model groups was greater than that in the normal control group, no significant statistical difference was distinguished among these four groups (P > 0.05). These results indicate that the HBO treatment can inhibit the apoptosis and Caspase-3 expression of renal cells of GK rats, adjust the activity of MMP-2 and its inhibitors, and reduce the accumulation of extracellular matrix. This implies that the HBO treatment might protect renal tissues, thus delaying occurrence and retaining development of diabetic nephropathy.
Animals ; Apoptosis ; Caspase 3 ; metabolism ; Diabetes Mellitus, Experimental ; physiopathology ; Diabetes Mellitus, Type 2 ; physiopathology ; Diabetic Nephropathies ; therapy ; Hyperbaric Oxygenation ; Kidney ; cytology ; Matrix Metalloproteinase 2 ; metabolism ; Oxygen ; administration & dosage ; Rats ; Rats, Wistar ; Tissue Inhibitor of Metalloproteinase-2 ; metabolism ; Transforming Growth Factor beta1

OBJECTIVE: To compare the flow-mediated dilatation (FMD) among the newly diagnosed impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2DM), and the normal controls (NC) and to analyze relevant factors under different glucose levels. METHODS: The study included IGT (n=34), DM1 (n=52), DM2 (n=33) and NC (n=25). Levels of fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG), fasting insulin (FINS), 2-hour postprandial insulin (PINS), triglyceride (TG), total cholesterol (TC), and hemoglobin A1C (HbA1C) were determined in all participants. High resolution ultrasound examining FMD was performed to measure vascular endothelial function subsequently. RESULTS: There was statistically significant difference between IGT, DM, HG and NC group in FMD (P=0.008). Partial correlation analysis found that a significant negative correlation existed between FMD and homeostasis model assessment-index (HOMA-IRI), difference of plasma glucose (DPG), FPG and PPG (P<0.01), and a negative correlation between FMD and HbA1C (P<0.05). Setting FMD as dependent variable to conduct multiple linear stepwise regression, in IGT group it was the waist/hip ratio (WHR) and HOMA-IRI that entered the regression equation; in DM1 group it was HOMA-IRI, PPG and DPG that entered the regression equation; in DM2 group it was FPG and HOMA-beta that entered the regression equation. CONCLUSION There exists a flow-mediated vasodilatation dysfunction in patients of newly diagnosed IGT and T2DM. Effect of relevant factors on FMD differs with different glucose levels.
Adult ; Blood Glucose ; metabolism ; Case-Control Studies ; Diabetes Mellitus, Type 2 ; blood ; physiopathology ; Endothelium, Vascular ; physiopathology ; Female ; Glucose Intolerance ; blood ; physiopathology ; Humans ; Male ; Middle Aged

OBJECTIVETo observe the dynamic expression of calcium-sensing receptor(CaSR) in myocardium of diabetic rats.

METHODSThirty male Wistar rats were randomly divided into 3 groups including control, diabetic-4 week and diabetic-8 week groups(n = 10). The type 2 diabetes mellitus models were established by intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat and high-sugar diet for one month. The cardiac morphology was observed by electron microscope. Western blot analyzed the expression of CaSR, phospholamban (PLN), a calcium handling regulator, and Ca+-ATPase(SERCA) in cardiac tissues.

RESULTSCompared with control group, the expressions of CaSR and SERCA were decreased, while the expression of PLN was significantly increased in a time-dependent manner in diabetic groups. Meanwhile diabetic rats displayed abnormal cardiac structure.

CONCLUSIONThese results indicate that the CaSR expression of myocardium is reduced in the progression of DCM, and its potential mechanism may be related to the imnaired intracellular calcium homeostasis.

Animals ; Calcium-Binding Proteins ; metabolism ; Diabetes Mellitus, Experimental ; complications ; Diabetes Mellitus, Type 2 ; Diabetic Cardiomyopathies ; metabolism ; physiopathology ; Disease Progression ; Heart ; physiopathology ; Male ; Myocardium ; metabolism ; pathology ; Rats ; Rats, Wistar ; Receptors, Calcium-Sensing ; metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; metabolism ; Streptozocin

PURPOSE: We previously reported that insulin resistance, low high-density lipoprotein (HDL) cholesterol, and glycaemic exposure Index are independently associated with peripheral neuropathy in Korean patients with type 2 diabetes mellitus. We followed the patients who participated in that study in 2006 for another 6 years to determine the relationship between insulin resistance and neuropathy. MATERIALS AND METHODS: This study involved 48 of the original 86 Korean patients with type 2 diabetes mellitus who were referred to the Neurology clinic for the assessment of diabetic neuropathy from January 2006 to December 2006. These 48 patients received management for glycaemic control and prevention of diabetic complications in the outpatient clinic up to 2012. We reviewed blood test results and the nerve conduction study findings of these patients, taken over a 6-year period. RESULTS: Low HDL cholesterol and high triglycerides significantly influenced the development of diabetic neuropathy. Kitt value (1/insulin resistance) in the previous study affected the occurrence of neuropathy, despite adequate glycaemic control with HbA1c <7%. Insulin resistance affected the development of diabetic neuropathy after 6 years: insulin resistance in 2006 showed a positive correlation with a change in sural sensory nerve action potential in 2012. CONCLUSION: Diabetic neuropathy can be affected by previous insulin resistance despite regular glycaemic control. Dyslipidaemia should be controlled in patients who show high insulin resistance because HDL cholesterol and triglycerides are strongly correlated with later development of diabetic neuropathy.
Adult ; Diabetes Mellitus, Type 2/*metabolism/*physiopathology ; Diabetic Neuropathies/*metabolism/*physiopathology ; Female ; Humans ; Insulin Resistance/*physiology ; Logistic Models ; Male ; Middle Aged

β-cell failure coupled with insulin resistance plays a key role in the development of type 2 diabetes mellitus (T2DM). Changed adipokines in circulating level form a remarkable link between obesity and both β-cell failure and insulin resistance. Some adipokines have beneficial effects,whereas others have detrimental properties. The overall contribution of adipokines to β-cell failure mainly depends on the interactions among adipokines. This article reviews the role of individual adipokines such as leptin,adiponectin,and resistin in the function,proliferation,death,and failure of β-cells. Future studies focusing on the combined effects of adipokines on β-cells failure may provide new insights in the treatment of T2DM.
Adipokines ; metabolism ; Adiponectin ; metabolism ; Diabetes Mellitus, Type 2 ; physiopathology ; Humans ; Insulin Resistance ; Insulin-Secreting Cells ; pathology ; Leptin ; metabolism ; Obesity ; Resistin ; metabolism