Vision loss in diabetic retinopathy (DR) is attributable to retinal vascular disorders that result in macular edema and neoangiogenesis. In addition to laser photocoagulation therapy, intraocular injections of antivascular endothelial growth factor drugs have contributed to the treatment of these disease conditions. Nonetheless, the clinical feasibility of intraocular drug administration has raised an increasing demand to develop alternative drugs that can fundamentally ameliorate the retinal vascular dysfunctions in DR. For this purpose, experimental animal models that reproduce human DR would be of clinical benefit. Despite the unavailability of DR models in rats or mice, pharmacological and genetic manipulations without hyperglycemia have successfully recapitulated retinal edema and neoangiogenesis in postnatal mouse retinas, thereby enabling the understanding of the pathophysiology underlying DR. This article highlights the utility of experimental mouse models of retinal vascular abnormalities and discusses cellular and molecular mechanisms responsible for the onset and progression of DR. These approaches will lead to the identification of novel drug targets for the restoration of vascular integrity and regeneration of functional capillaries in DR.
Angiopoietins; Diabetic macular edema; Diabetic retinopathy; Neoangiogenesis; PlexinD1; RhoJ; Sema3E
As with the dramatic increases in childhood obesity over the past decades, the incidence of type 2 diabetes has increased among children and adolescents in the United States. Insulin resistance is a common feature of childhood obesity and increases the risk of type 2 diabetes, metabolic syndrome, and atherogenic lipoprotein profile in obese youth. Although cross-sectional studies report beneficial effects of physical activity or cardiorespiratory fitness on insulin sensitivity, the role of regular exercise alone (e.g., no calorie restriction) as a strategy to reduce the risk of type 2 diabetes is unclear in obese children and adolescents. In this mini review, we examined the independent effects of various exercise on glucose tolerance and insulin sensitivity in obese youth.
Abdominal fat; Childhood obesity; Exercise; Glucose tolerance; Insulin resistance; Resistance exercise
There are many studies on the prevalence, clinical characteristics, and economic burden of diabetes across the past four decades in Korea. Nonetheless, there is a dearth of nationwide study regarding diabetes encompassing all age group. Eight years ago, the Committee on the Epidemiology of Diabetes Mellitus of Korean Diabetes Association collaborated with Health Insurance Review & Assessment Service to evaluate the status of diabetes care and characteristics in diabetic patients in Korea. In 2007, the collaborative task force team published a comprehensive survey titled "Diabetes in Korea 2007." In this review, we reappraise the diabetic epidemics from the joint report and suggest further studies that are needed to be investigated in the future.
Diabetes mellitus, type 2; Epidemiology; Health Insurance Review & Assessment Service; Korea; National survey
Polytopic transmembrane protein, Niemann-Pick C1-Like 1 (NPC1L1) is localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It mediates intestinal cholesterol absorption and prevents extensive loss of cholesterol by transporting biliary cholesterol into hepatocytes. NPC1L1 is a molecular target of ezetimibe, an agent for hypercholesterolemia. Recently, NPC1L1 inhibition has been shown to prevent metabolic disorders such as fatty liver disease, obesity, diabetes, and atherosclerosis. In this review, the identification and characterization of NPC1L1, NPC1L1-dependent cholesterol transport, the relationship with pathogenesis of metabolic disease and its newly introduced function for virus entry are discussed.
Cholesterol; Intestines; Liver, Niemann-Pick C1-Like 1
Studies on factors which may predict the risk of diabetes are scarce. This prospective cohort study was conducted to determine the association between adiponectin and type 2 diabetes among Korean men and women.
A total of 42,845 participants who visited one of seven health examination centers located in Seoul and Gyeonggi province, Republic of Korea between 2004 and 2008 were included in this study. The incidence rates of diabetes were determined through December 2011. To evaluate the effects of adiponectin on type 2 diabetes, the Cox proportional hazard model was used.
Of the 40,005 participants, 959 developed type 2 diabetes during a 6-year follow-up. After the adjustment for age, body mass index (BMI), and waist circumference, the risks for type 2 diabetes in participants with normoglycemia had a 1.70-fold (95% confidence interval [CI], 1.21 to 2.38) increase in men and a 1.83-fold (95% CI, 1.17 to 2.86) increase in women with the lowest tertile of adiponectin when compared to the highest tertile of adiponectin. For participants with impaired fasting glucose (IFG), the risk for type 2 diabetes had a 1.46-fold (95% CI, 1.17 to 1.83) increase in men and a 2.52-fold (95% CI, 1.57 to 4.06) increase in women with the lowest tertile of adiponectin. Except for female participants with normoglycemia, all the risks remained significant after the adjustment for fasting glucose and other confounding variables. Surprisingly, BMI and waist circumference were not predictors of type 2 diabetes in men or women with IFG after adjustment for fasting glucose and other confounders.
A strong association between adiponectin and diabetes was observed. The use of adiponectin as a predictor of type 2 diabetes is considered to be useful.
Adiponectin; Cohort studies; Diabetes mellitus; Impaired fasting glucose
We investigated the relationship between endothelial dysfunction and diabetic retinopathy (DR) in patients with type 2 diabetes.
We used a cross-sectional design to examine 167 patients with type 2 diabetes mellitus. All patients underwent biochemical and ophthalmological examination. We assessed endothelial dysfunction by a flow-mediated vasodilation method of the brachial artery. Changes in vasodilation (flow-mediated vasodilatation, %FMD) were expressed as percent change over baseline values.
The mean±standard deviation of patient age was 54.1±8.6 years. The %FMD was significantly lower in patients with DR than without DR. The prevalence of retinopathy decreased across increasing tertiles of %FMD. After adjusting for patients' age, sex, diabetes duration, use of insulin, use of antihypertensive, antiplatelet, and lipid lowering medications, systolic blood pressure, fasting plasma glucose, 2-hour plasma glucose, glycated hemoglobin, and urinary albumin excretion, participants with a reduced %FMD were more likely to have DR (odds ratio, 11.819; 95% confidence interval, 2.201 to 63.461; P=0.004, comparing the lowest and highest tertiles of %FMD).
Endothelial dysfunction was associated with DR, which was most apparent when the endothelial dysfunction was severe. Our study provides insights into the possible mechanism of the influence of endothelial dysfunction on the development of DR.
Diabetes mellitus, type 2; Diabetic retinopathy; Endothelial dysfunction; Flow-mediated vasodilation
Estrogen plays a fundamental role in the pathogenesis of type 2 diabetes mellitus (T2DM). Very few studies have shown the association between estrogen receptor α (ERα), PvuII and XbaI gene polymorphisms with T2DM in both men and women. We evaluated the hypothesis that PvuII and XbaI polymorphisms of ERα gene may be associated with T2DM in adult.
From spring of 2010 to the fall of 2011, a case-control study was performed at clinical centers of Jahrom University of Medical Sciences. We included 174 patients with T2DM including men and women and 174 age, sex, and body mass index frequency-matched health controls. We analyzed the PvuII and XbaI polymorphisms of ERα by using the polymerase chain reaction-based restriction fragment length polymorphism method.
No significant differences between demographic characteristics of control and patients groups were observed. Allele frequencies of both PvuII and XbaI polymorphisms were significantly different between patients and control subjects (P=0.014 vs. P=0.002, respectively). When the group was separated into women and men, logistic regression analysis of genotype distribution of PvuII (pp vs. Pp+PP) in both sexes revealed that there was no significant association of PvuII genotype with men (odds ratio [OR], 1.67; confidence interval [CI], 0.86 to 3.28; P=0.89) and women (OR, 0.96; CI, 0.53 to 1.74; P=0.12).
PvuII and XbaI polymorphisms in ERα are related with T2DM in the inpatient population.
Diabetes mellitus, type 2; Estrogen receptor alpha; Genetic; Humans; PvuII; XbaI
Nonalcoholic fatty liver disease (NAFLD) is closely correlated with abnormal accumulation of visceral fat, but the role of skeletal muscle remains unclear. The aim of this study was to elucidate the role of skeletal muscle in development of NAFLD.
Among 11,116 subjects (6,242 males), we examined the effects of skeletal muscle mass and visceral fat area (VFA, by bioelectric impedance analysis) on NAFLD using by the fatty liver index (FLI).
Of the total subjects (9,565 total, 5,293 males) included, 1,848 were classified as having NALFD (FLI ≥60). Body mass index, lipid profile, fasting plasma glucose, hemoglobin A1c, prevalence of type 2 diabetes (DM), hypertension (HTN), and metabolic syndrome were higher in males than females, but FLI showed no significant difference. The low FLI group showed the lowest VFA and highest skeletal muscle mass of all the groups. Skeletal muscle to visceral fat ratio (SVR) and skeletal muscle index had inverse correlations with FLI, when adjusted for age and gender. In multivariate regression analysis, SVR was negatively associated with FLI. Among SVR quartiles, the highest quartile showed very low risk of NAFLD when adjusted for age, gender, lipid profile, DM, HTN, and high sensitivity C-reactive protein from the lowest quartiles (odds ratio, 0.037; 95% confidence interval, 0.029 to 0.049).
Skeletal muscle mass was inversely associated with visceral fat area, and higher skeletal muscle mass may have a beneficial effect in preventing NAFLD. These results suggest that further studies are needed to ameliorate or slow the progression of sarcopenia.
Fatty liver index; Intra-abdominal fat; Muscle, skeletal; Non-alcoholic fatty liver disease
There are controversial reports about the effect of granulocyte colony-stimulating factor (G-CSF) in peripheral nerve protection. Therefore, the present study aimed to investigate the effect of G-CSF on peripheral nerves in streptozotocin (STZ) induced diabetic rats. After STZ or vehicle injection, rats were divided into five groups (n=6) as follows: normal+vehicle, normal+G-CSF (50 µg/kg for 5 days), diabetes mellitus (DM)+vehicle, DM+G-CSF (50 µg/kg for 5 days), and DM+G-CSF extension (50 µg/kg for 5 days and followed by two injections per week up to 24 weeks). Our results showed that the current perception threshold was not significantly different among experimental groups. G-CSF treatment inhibited the loss of cutaneous nerves and gastric mucosal small nerve fibers in morphometric comparison, but statistical significance was not observed. The present results demonstrated that G-CSF has no harmful but minimal beneficial effects with respect to peripheral nerve preservation in diabetic rats.
Diabetes mellitus; Granulocyte colony-stimulating factor; Peripheral nerves
To assess the feasibility and results of screening diabetes mellitus (DM) patients for tuberculosis (TB) and TB patients for DM within the routine health care setting. Prospective observational study carried out within the Diabetes Centre and Pulmonary Medicine Department from February 2012 to September 2012. The screening for active TB in DM and DM in TB patients is followed as per the guidelines of the Revised National Tuberculosis Control Programme and national programmes in India. Total of 307 patients diagnosed with TB during the study period. Among the TB patients 9.77% were smokers, 19.54% were known cases diabetes, and 15.96% were newly diagnosed cases of diabetes. Total of 4,118 diabetes patients were screened for TB in which 111 patients found to have TB. The strengths of this study are that we implemented screening within the routine health system. It is feasible to screen DM patients for TB resulting in high rates of TB detection.
Diabetes mellitus; India; Prevalence; Tuberculosis
Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic β-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.
ABC transporter; Insulin secretion; KATP channels; Kir6.2; Neonatal diabetes; Pancreatic β-cell; Sulphonylurea receptor; Sulphonylureas
Obesity is a state of chronic low-grade systemic inflammation. This chronic inflammation is deeply involved in insulin resistance, which is the underlying condition of type 2 diabetes and metabolic syndrome. A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been recognition of the critical role of adipose tissue macrophages (ATMs). Chemokines are small proteins that direct the trafficking of immune cells to sites of inflammation. In addition, chemokines activate the production and secretion of inflammatory cytokines through specific G protein-coupled receptors. ATM accumulation through C-C motif chemokine receptor 2 and its ligand monocyte chemoattractant protein-1 is considered pivotal in the development of insulin resistance. However, chemokine systems appear to exhibit a high degree of functional redundancy. Currently, more than 50 chemokines and 18 chemokine receptors exhibiting various physiological and pathological properties have been discovered. Therefore, additional, unidentified chemokine/chemokine receptor pathways that may play significant roles in ATM recruitment and insulin sensitivity remain to be fully identified. This review focuses on some of the latest findings on chemokine systems linking obesity to inflammation and subsequent development of insulin resistance.
Adipokines; Adipose tissue macrophage; C-C motif chemokine receptor 2; C-C motif chemokine receptor 5; Chemokine CCL2; Chemokines; Diabetes mellitus, type 2; Inflammation; Insulin resistance; Macrophage polarization
The aim of this study was an in vitro investigation of the effect of high glucose concentration on adipogenesis, as prolonged hyperglycemia alters adipocyte differentiation.
3T3-L1 preadipocytes differentiated in the presence of varying concentrations of glucose (25, 45, 65, 85, and 105 mM) were assessed for adipogenesis using AdipoRed (Lonza) assay. Cell viability and proliferation were measured using MTT reduction and [3H] thymidine incorporation assay. The extent of glucose uptake and glycogen synthesis were measured using radiolabelled 2-deoxy-D-[1-3H] glucose and [14C]-UDP-glucose. The gene level expression was evaluated using reverse transcription-polymerase chain reaction and protein expression was studied using Western blot analysis.
Glucose at 105 mM concentration was observed to inhibit adipogenesis through inhibition of CCAAT-enhancer-binding proteins, sterol regulatory element-binding protein, peroxisome proliferator-activated receptor and adiponectin. High concentration of glucose induced stress by increasing levels of toll-like receptor 4, nuclear factor κB and tumor necrosis factor α thereby generating activated preadipocytes. These cells entered the state of hyperplasia through inhibition of p27 and proliferation was found to increase through activation of protein kinase B via phosphoinositide 3 kinase dependent pathway. This condition inhibited insulin signaling through decrease in insulin receptor β. Although the glucose transporter 4 (GLUT4) protein remained unaltered with the glycogen synthesis inhibited, the cells were found to exhibit an increase in glucose uptake via GLUT1.
Adipogenesis in the presence of 105 mM glucose leads to an uncontrolled proliferation of activated preadipocytes providing an insight towards understanding obesity.
3T3-L1 adipocytes; High glucose concentration; Hyperplasia; Obesity; p27
A1chieve® was a noninterventional study evaluating the clinical safety and efficacy of biphasic insulin aspart 30, insulin detemir, and insulin aspart.
Korean type 2 diabetes patients who have not been treated with the study insulin or have started it within 4 weeks before enrollment were eligible for the study. The patient selection and the choice of regimen were at the discretion of the physician. The safety and efficacy information was collected from the subjects at baseline, week 12, and week 24. The number of serious adverse drug reactions (SADRs) was the primary endpoint. The changes of clinical diabetic markers at week 12 and/or at week 24 compared to baseline were the secondary endpoints.
Out of 4,058 exposed patients, 3,003 completed the study. During the study period, three SADRs were reported in three patients (0.1%). No major hypoglycemic episodes were observed and the rate of minor hypoglycemic episodes marginally decreased during 24 weeks (from 2.77 to 2.42 events per patient-year). The overall quality of life score improved (from 66.7±15.9 to 72.5±13.5) while the mean body weight was slightly increased (0.6±3.0 kg). The 24-week reductions in glycated hemoglobin, fasting plasma glucose and postprandial plasma glucose were 1.6%±2.2%, 2.5±4.7 mmol/L, and 4.0±6.4 mmol/L, respectively.
The studied regimens showed improvements in glycemic control with low incidence of SADRs, including no incidence of major hypoglycemic episodes in Korean patients with type 2 diabetes.
Diabetes mellitus, type 2; Insulin; Republic of Korea; Safety; Treatment outcome
To evaluate the effects of severe hypoglycemia without hypokalemia on the electrocardiogram in patients with type 2 diabetes in real-life conditions.
Electrocardiograms of adult type 2 diabetic patients during the episodes of severe hypoglycemia and the recovered stage were obtained and analysed between October 1, 2011 and May 31, 2012. Patients who maintained the normal serum sodium and potassium levels during the episodes of severe hypoglycemia were only selected as the subjects of this study. Severe hypoglycemia was defined, in this study, as the condition requiring active medical assistance such as administering carbohydrate when serum glucose level was less than 60 mg/dL.
Nine type 2 diabetes patients (seven men, two women) were included in the study. The mean subject age was 73.2±7.7 years. The mean hemoglobin A1c level was 6.07%±1.19%. The median duration of diabetes was 10 years (range, 3.5 to 30 years). Corrected QT (QTc) intervals were significantly increased during the episodes of severe hypoglycemia compared to the recovered stage (447.6±18.2 ms vs. 417.2±30.6 ms; P<0.05). However, the morphology and the amplitude of the T waves were not changed and ST-segment elevation and/or depression were not found during the episodes of severe hypoglycemia.
In this study, QTc interval prolongation during the episodes of severe hypoglycemia was observed without hypokalemia. Therefore, the distinct alterations in cardiac repolarization during the episodes of severe hypoglycemia may not be associated with hypokalemia.
Diabetes mellitus, type 2; Electrocardiography; QT interval; Severe hypoglycemia
The increasing prevalence of type 2 diabetes mellitus (T2DM) is associated with the rapid spread of obesity. Obesity induces insulin resistance, resulting in β-cell dysfunction and thus T2DM. Green tea extract (GTE) has been known to prevent obesity and T2DM, but this effect is still being debated. Our previous results suggested that circulating green tea gallated catechins (GCs) hinders postprandial blood glucose lowering, regardless of reducing glucose and cholesterol absorption when GCs are present in the intestinal lumen. This study aimed to compare the effect of GTE with that of GTE coadministered with poly-γ-glutamic acid (γ-PGA), which is likely to inhibit the intestinal absorption of GCs.
The db/db mice and age-matched nondiabetic mice were provided with normal chow diet containing GTE (1%), γ-PGA (0.1%), or GTE+γ-PGA (1%:0.1%) for 4 weeks.
In nondiabetic mice, none of the drugs showed any effects after 4 weeks. In db/db mice, however, weight gain and body fat gain were significantly reduced in the GTE+γ-PGA group compared to nondrug-treated db/db control mice without the corresponding changes in food intake and appetite. Glucose intolerance was also ameliorated in the GTE+γ-PGA group. Histopathological analyses showed that GTE+γ-PGA-treated db/db mice had a significantly reduced incidence of fatty liver and decreased pancreatic islet size. Neither GTE nor γ-PGA treatment showed any significant results.
These results suggest that GTE+γ-PGA treatment than GTE or γ-PGA alone may be a useful tool for preventing both obesity and obesity-induced T2DM.
db/db mice; Diabetes mellitus, type 2; Gallated catechins; Glucose intolerance; Obesity; Poly-γ-glutamic acid
Beyond statin therapy for reducing low density lipoprotein cholesterol (LDL-C), additional therapeutic strategies are required to achieve more optimal reduction in cardiovascular risk among diabetic patients with dyslipidemia. To evaluate the effects and the safety of combined treatment with omega-3 fatty acids and statin in dyslipidemic patients with type 2 diabetes, we conducted a randomized, open-label study in Korea. Patients with persistent hypertriglyceridemia (≥200 mg/dL) while taking statin for at least 6 weeks were eligible. Fifty-one patients were randomized to receive either omega-3 fatty acid 4, 2 g, or no drug for 8 weeks while continuing statin therapy. After 8 weeks of treatment, the mean percentage change of low density lipoprotein (LDL) particle size and triglyceride (TG) level was greater in patients who were prescribed 4 g of omega-3 fatty acid with statin than in patients receiving statin monotherapy (2.8%±3.1% vs. 2.3%±3.6%, P=0.024; -41.0%±24.1% vs. -24.2%±31.9%, P=0.049). Coadministration of omega-3 fatty acids with statin increased LDL particle size and decreased TG level in dyslipidemic patients with type 2 diabetes. The therapy was well tolerated without significant adverse effects.
Diabetes mellitus, type 2; Dyslipidemia; Fatty acids, omega-3; Hypertriglyceridemia; Low density lipoprotein particle
AMPK is an evolutionary conserved sensor of cellular energy status that is activated during exercise. Pharmacological activation of AMPK promotes glucose uptake, fatty acid oxidation, mitochondrial biogenesis, and insulin sensitivity; processes that are reduced in obesity and contribute to the development of insulin resistance. AMPK deficient mouse models have been used to provide direct genetic evidence either supporting or refuting a role for AMPK in regulating these processes. Exercise promotes glucose uptake by an insulin dependent mechanism involving AMPK. Exercise is important for improving insulin sensitivity; however, it is not known if AMPK is required for these improvements. Understanding how these metabolic processes are regulated is important for the development of new strategies that target obesity-induced insulin resistance. This review will discuss the involvement of AMPK in regulating skeletal muscle metabolism (glucose uptake, glycogen synthesis, and insulin sensitivity).
AMPK; Exercise; Glucose uptake; Insulin resistance; Obesity