Improvement in Age at Mortality and Changes in Causes of Death in the Population with Diabetes: An Analysis of Data from the Korean National Health Insurance and Statistical Information Service, 2006 to 2018.

BACKGRUOUND: Diabetes is a leading cause of death that is responsible for 1.6 million annual deaths worldwide. However, the life expectancy and age at death of people with diabetes have been a matter of debate. METHODS: The National Health Insurance Service claims database, merged with death records from the National Statistical Information Service in Korea from 2006 to 2018, was analyzed. RESULTS: In total, 1,432,567 deaths were collected. The overall age at death increased by 0.44 and 0.26 year/year in the diabetes and control populations, respectively. The disparity in the mean age at death between the diabetes and control populations narrowed from 5.2 years in 2006 to 3.0 years in 2018 (p<0.001). In a subgroup analysis according to the presence of comorbid diseases, the number and proportion of deaths remained steady in the group with diabetes only, but steadily increased in the groups with diabetes combined with dyslipidemia and/or hypertension. Compared to the control population, the increase in the mean death age was higher in the population with diabetes. This trend was more prominent in the groups with dyslipidemia and/or hypertension than in the diabetes only group. Deaths from vascular disease and diabetes decreased, whereas deaths from cancer and pneumonia increased. The decline in the proportion of deaths from vascular disease was greater in the diabetes groups with hypertension and/or dyslipidemia than in the control population. CONCLUSION: The age at death in the population with diabetes increased more steeply and reached a comparable level to those without diabetes.

Gamma glutamyltransferase and risk of dementia in prediabetes and diabetes.

Diabetes is associated with cognitive impairment and greater risk for dementia, but the role of gamma-glutamyltransferase (γ-GT) in dementia has not been elucidated. We determined incident dementia including Alzheimer's disease and vascular dementia, analyzing data from participants aged 40 years or older in the National Health Insurance Database, collected by the National Health Insurance Service in Korea, from January 2009 to December 2015. During a median follow-up of 7.6 years, 272,657 participants were diagnosed as having dementia. Higher serum γ-GT was associated with increased risk of dementia (HR = 1.22, 95% CI = 1.20-1.24), and had a strong positive association with early onset dementia (HR = 1.32, 95% CI = 1.24-1.40). An additive impact of higher γ-GT on dementia was observed regardless of glycemic status, and prevalent diabetes with the highest γ-GT quartile had a 1.8-fold increased dementia risk (HR = 1.82, 95% CI = 1.78-1.85). This effect of γ-GT concentration in diabetes was more prominent in individuals with vascular dementia (HR = 1.94, 95% CI = 1.84-2.04). In subgroup analysis, young age, male sex, and relatively healthy subjects with a higher γ-GT quartile had more increased dementia risk. In conclusion, γ-GT concentration as well as glycemic status could be a future risk factor for dementia in the general population.

Efficacy and Safety of Voglibose Plus Metformin in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

BACKGROUND: Combination of metformin to reduce the fasting plasma glucose level and an α-glucosidase inhibitor to decrease the postprandial glucose level is expected to generate a complementary effect. We compared the efficacy and safety of a fixed-dose combination of voglibose plus metformin (vogmet) with metformin monotherapy in drug-naïve newly-diagnosed type 2 diabetes mellitus. METHODS: A total of 187 eligible patients aged 20 to 70 years, with a glycosylated hemoglobin (HbA1c) level of 7.0% to 11.0%, were randomized into either vogmet or metformin treatments for 24 weeks. A change in the HbA1c level from baseline was measured at week 24. RESULTS: The reduction in the levels of HbA1c was -1.62%±0.07% in the vogmet group and -1.31%±0.07% in the metformin group (P=0.003), and significantly more vogmet-treated patients achieved the target HbA1c levels of <6.5% (P=0.002) or <7% (P=0.039). Glycemic variability was also significantly improved with vogmet treatment, estimated by M-values (P=0.004). Gastrointestinal adverse events and hypoglycemia (%) were numerically lower in the vogmet-treated group. Moreover, a significant weight loss was observed with vogmet treatment compared with metformin (-1.63 kg vs. -0.86 kg, P=0.039). CONCLUSION: Vogmet is a safe antihyperglycemic agent that controls blood glucose level effectively, yields weight loss, and is superior to metformin in terms of various key glycemic parameters without increasing the risk of hypoglycemia.

Pre-sarcopenia is associated with renal hyperfiltration independent of obesity or insulin resistance: Nationwide Surveys (KNHANES 2008-2011).

Renal hyperfiltration is closely linked to cardiometabolic disorders, and it may increase the mortality risk of the general population. Despite the well-established association between cardiometabolic diseases and sarcopenia, the relationship between renal hyperfiltration and sarcopenia has not yet been assessed.This population-based, cross-sectional study used a nationally representative sample of 13,800 adults from the 2008 to 2011 Korea National Health and Nutrition Examination Survey. Renal hyperfiltration was defined as the age- and sex-specific glomerular filtration rate above the 90th percentile in subjects with normal kidney function (>60 mL/min/1.73 m). Appendicular skeletal muscle (ASM), measured by dual-energy x-ray absorptiometry, was used to assess pre-sarcopenia, which the international consensus defines as both ASM per se and ASM that was adjusted for the body mass index and the height.A total of 1402 (10.2%) participants were classified as having renal hyperfiltration. The prevalence of pre-sarcopenia ranged from 11.6% to 33.0%, by definition. Individuals with pre-sarcopenia had higher risks of renal hyperfiltration compared to those without pre-sarcopenia (10.9% vs 17.4%, P < .001; odds ratio [OR] = 1.71, 95% confidential interval [CI] = 1.48-1.99, P < .001). Multiple logistic regression analyses also demonstrated this independent association between pre-sarcopenia and renal hyperfiltration, following adjustment for confounding factors such as insulin resistance and obesity (OR = 1.84, 95% CI = 1.57-2.15, P < .001).In the general population of healthy individuals, pre-sarcopenia might be associated with renal hyperfiltration independent of obesity or insulin resistance.

Effects of Omega-3 Fatty Acid Supplementation on Diabetic Nephropathy Progression in Patients with Diabetes and Hypertriglyceridemia.

Beneficial effects of omega-3 fatty acid (O3FA) supplementation in a wide range of disease condition have been well studied. However, there is limited information regarding the effects of O3FAs on chronic kidney disease (CKD), especially in diabetic nephropathy (DN) with hypertriglyceridemia. We investigate whether O3FA supplementation could help maintain renal function in patients with diabetes and hypertriglyceridemia. Total 344 type 2 diabetic patients with a history of O3FA supplementation for managing hypertriglyceridemia were included. Reduction in urine albumin to creatinine ratio (ACR) and glomerular filtrate rate (GFR) were examined. Subgroup analyses were stratified according to the daily O3FA doses. Serum total cholesterol, triglyceride, and urine ACR significantly reduced after O3FA supplementation. Overall, 172 (50.0%) patients did not experience renal function loss, and 125 (36.3%) patients had a GFR with a positive slope. The patients treated with O3FAs at 4g/day showed greater maintenance in renal function than those treated with lower dosages (p < 0.001). This dose dependent effect remains significant after adjustment for multiple variables. O3FA supplementation in diabetic patients with hypertriglyceridemia shows benefits of reducing albuminuria and maintaining renal function. The effects are dependent on the dose of daily O3FA supplementation.

Serum cholesterol concentration and prevalence, awareness, treatment, and control of high low-density lipoprotein cholesterol in the Korea National Health and Nutrition Examination Surveys 2008-2010: Beyond the Tip of the Iceberg.

BACKGROUND: The mortality rate from cardiovascular disease (CVD) among young adults has declined less than that in the older population, raising concerns about the increasing prevalence of obesity-related conditions including hypercholesterolemia in the younger population. We investigated the age-standardized mean levels of serum cholesterols and the prevalence, awareness, treatment and control rates of hyper-low-density lipoprotein (LDL)-cholesterolemia based on age. METHODS AND RESULTS: Nationally representative samples of 19 489 subjects aged ≥20 years were analyzed from the Korea National Health and Nutrition Examination Surveys 2008-2010. Hyper-LDL-cholesterolemia was individually evaluated by the 2004 National Cholesterol Education Program Adult Treatment Panel III guidelines. Age-standardized mean levels of total cholesterol, high-density lipoprotein-cholesterol, LDL-cholesterol, and triglycerides were 186.8, 48.0, 112.9, and 136.0 mg/dL, respectively. Age-standardized prevalence of hyper-LDL-cholesterolemia was 23.2% (men, 25.5%; women, 21.8%). Among subjects with hyper-LDL-cholesterolemia, awareness and treatment rates were significantly lower in younger adults (<50 years) compared to older adults ≥50 years (awareness, 8.0% versus 21.5%; treatment, 5.1% versus 18.5%, all Ps<0.001), indicating significant discrepancies in awareness and treatment rates of hypercholesterolemia between younger and older adults. Among subjects aware of their hyper-LDL-cholesterolemia, younger adults were more likely to have controlled LDL-cholesterol than the elderly (82.1% versus 67.5%, P<0.001). CONCLUSIONS: Compared to the elderly, significant proportions of young and middle-aged adults are unaware of their hypercholesterolemia and are not treated with proper lipid-lowering medications. Early screening, education, and proper management should be stressed in national public healthcare policies to reduce the increasing burden of CVD in the younger population with undiagnosed hypercholesterolemia.

Decreased expression of hepatic low-density lipoprotein receptor-related protein 1 in hypothyroidism: a novel mechanism of atherogenic dyslipidemia in hypothyroidism.

BACKGROUND: The atherogenic effects of hypothyroidism on lipid metabolism could result, in part, from the reduced clearance of remnant lipoproteins. In this study, we investigated the expression of hepatic low-density lipoprotein receptor-related protein 1 (LRP1), a receptor for remnant lipoproteins, in hypothyroidism and the effect of 3,3',5-triiodo-L-thyronine (T3) treatment on hepatic LRP1 expression. METHODS: C57BL/6 mice were fed a normal diet (control group) or a low-iodine diet supplemented with 0.15% propylthiouracil (PTU/LI group) for 4 weeks. Mice in the PTU/LI group were injected intraperitoneally with T3 (0, 30, and 150 µg/kg of body weight) for 7 days. HepG2 cells were incubated in fetal bovine serum or charcoal-stripped fetal bovine serum with various concentrations of T3. The expression and function of LRP1 in liver samples and cells were analyzed. RESULTS: Hypothyroidism was successfully induced in PTU/LI mice. Hepatic LRP1 protein expression was lower in the PTU/LI group than in the control group. T3 treatment upregulated hepatic LRP1 protein expression in PTU/LI mice. LRP1 expression in HepG2 cells was reduced after incubation in the medium containing charcoal-stripped fetal bovine serum, which mimics hypothyroidism in vitro, and was recovered by T3 treatment. The protein expression of LRP1 in HepG2 cells was increased by T3 treatment in a dose-dependent manner up to 2.0 nM T3. However, LRP1 mRNA transcription was not affected by hypothyroidism conditions or T3 treatment, either in liver samples or in HepG2 cells. T3 treatment on HepG2 cells increased cellular uptake of lipid-conjugated apolipoprotein E through LRP1. CONCLUSIONS: Our data demonstrate that hepatic LRP1 expression and function decrease in hypothyroidism and are regulated by the thyroid hormone. These results suggest that in hypothyroidism, decreased expression of hepatic LRP1 may be associated with reduced clearance of circulating remnant lipoproteins.

Korean red ginseng (Panax ginseng) improves insulin sensitivity in high fat fed Sprague-Dawley rats.

Many studies have documented that ginseng has antidiabetic and antiobesity effects, but the mechanism of the effects has not been elucidated. The aim of this study was to determine the effect of Korean red ginseng (KRG, Panax ginseng) and investigate the mechanism of antidiabetic and antiobesity effects in obese insulin resistant animal models. Sprague-Dawley (SD) rats were divided into three groups: a control group (group I) fed a normal diet, another group (group II) fed only high fat diet (HFD) and a third group (group III) fed HFD with KRG (200 mg/kg, oral) for 18 weeks. The body weight, food intake, adipose tissues, liver, kidney, pancreas, adiponectin, and leptin were measured. Blood glucose, insulin tolerance test, and hyperinsulinemic euglycemic clamp test were investigated. A significant weight reduction, especially fat mass reduction, was observed in the KRG treated group. Increased insulin sensitivity was found in the KRG treated group. We observed increased insulin signalling, increased phosphorylation of IR, IRS-1, Akt, and membranous GLUT4 in muscle by Western blotting assay. In conclusion, KRG may have antidiabetic and antiobesity effects due to partly increased insulin sensitivity by increased adipokine and partly enhanced insulin signalling.

Dietary monounsaturated fatty acids but not saturated fatty acids preserve the insulin signaling pathway via IRS-1/PI3K in rat skeletal muscle.

Saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) show different effects on the development of insulin resistance. In this study, we compared the effect of dietary SFA and MUFA on the insulin signaling pathway in the skeletal muscle of a type 2 diabetic animal model. Twenty-nine-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were randomly divided into three groups and fed one of the following diets for 3 weeks; a normal chow diet, an SFA (lard oil) enriched or a MUFA (olive oil) enriched high-fat diet. The vastus lateralis muscle was used for analyses. Insulin tolerance test showed improved insulin sensitivity in rats fed the MUFA diet, as compared to those fed the SFA diet (p < 0.001). The SFA diet reduced IRS-1 expression and phosphorylated PI3K levels in skeletal muscle, as compared with a chow diet (p < 0.001, respectively). On the contrary, muscle IRS-2 expression and phosphorylated ERK1/2 was significantly increased in rats fed the SFA diet (p < 0.001, respectively). Membrane translocation of glucose transporter type 4 decreased in the skeletal muscle of rats fed the SFA diet, as compared to those fed a chow diet (p < 0.001). These changes in insulin signaling pathway in skeletal muscle were not observed in rats fed the MUFA diet. In conclusion, the beneficial effect of dietary MUFA on insulin sensitivity is associated with a conserved IRS-1/PI3K insulin signaling pathway which was altered by dietary SFA.

Korean red ginseng (Panax ginseng) improves insulin sensitivity and attenuates the development of diabetes in Otsuka Long-Evans Tokushima fatty rats.

Ginseng has been reported to ameliorate hyperglycemia in experimental and clinical studies; however, its mechanism of action remains unclear. In this study, we investigated the metabolic effects and putative molecular mechanisms of Korean red ginseng (KRG, Panax ginseng) in animal models for type 2 diabetes mellitus (T2DM) and peripheral insulin-responsive cell lines. Korean red ginseng was administered orally at a dose of 200 mg/(kg d) to Otsuka Long-Evans Tokushima fatty rats for 40 weeks. Initially, chronic administration of KRG reduced weight gain and visceral fat mass in the early period without altering food intake. The KRG-treated Otsuka Long-Evans Tokushima fatty rats showed improved insulin sensitivity and significantly preserved glucose tolerance compared with untreated control animals up to 50 weeks of age, implying that KRG attenuated the development of overt diabetes. KRG promoted fatty acid oxidation by the activation of adenosine monophosphate-activated protein kinase (AMPK) and phosphorylation of acetyl-coenzyme A carboxylase in skeletal muscle and cultured C2C12 muscle cells. Increased expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, nuclear respiratory factor-1, cytochrome c, cytochrome c oxidase-4, and glucose transporter 4 by KRG treatment indicates that activated AMPK also enhanced mitochondrial biogenesis and glucose utilization in skeletal muscle. Although these findings suggest that KRG is likely to have beneficial effects on the amelioration of insulin resistance and the prevention of T2DM through the activation of AMPK, further clinical studies are required to evaluate the use of KRG as a supplementary agent for T2DM.

Therapeutic effect of magnesium lithospermate B on neointimal formation after balloon-induced vascular injury.

Vascular smooth muscle cell (VSMC) proliferation and migration in response to platelet-derived growth factor (PDGF) play an important role in the development of atherosclerosis and restenosis. Recent evidence indicates that PDGF increases intracellular levels of reactive oxygen species in VSMCs and that both PDGF-induced VSMC proliferation and migration are reactive oxygen species-dependent. Danshen is a representative oriental medicine used for the treatment of vascular disease. Previously, we reported that magnesium lithospermate B, an active component of Danshen, is a potent antioxidant. Thus we investigated the therapeutic potential of magnesium lithospermate B in neointimal formation after carotid artery injury in rats along with its effects on the PDGF signaling pathway for stimulating VSMC proliferation and migration in vitro. PDGF is dimeric glycoprotein composed of two A or two B chains. In this study, we used PDGF-BB, which is one of the isoforms of PDGF (i.e., PDGF-AA, PDGF-BB, and PDGF-AB). Our results demonstrated that magnesium lithospermate B directly scavenged reactive oxygen species in a xanthine/xanthine oxidase system and reduced PDGF-BB-induced intracellular reactive oxygen species generation in VSMCs. In a rat carotid artery balloon injury model, magnesium lithospermate B treatment (10 mg/kg/day, i.p) showed a significant effect on the prevention of neointimal formation compared with vehicle treatment. In cultured VSMCs, magnesium lithospermate B significantly attenuated PDGF-BB-induced cell proliferation and migration as measured by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide (MTT) assay and transwell migration assays, respectively. Further, magnesium lithospermate B inhibited PDGF-BB-induced phosphorylation of phospatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways by scavenging reactive oxygen species. Together, these data indicated that magnesium lithospermate B, a potent reactive oxygen species scavenger, prevented both injury-induced neointimal formation in vivo and PDGF-BB-induced VSMC proliferation and migration in vitro, suggesting that magnesium lithospermate B may be a promising agent to prevent atherosclerosis and restenosis following angioplasty.

Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732.

The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732's peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long-Evans Tokushima Otsuka and Otsuka Long-Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114.8 +/- 13.4 g vs 170.7 +/- 20.6 g, 7.9 +/- 0.5% decrease vs 0.3 +/- 2.2% decrease; in treated OLETF rat versus control OLETF rat, P < 0.01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.

Delayed treatment with lithospermate B attenuates experimental diabetic renal injury.

Extracellular matrix (ECM) accumulation in the glomerular mesangium is a characteristic feature of diabetic nephropathy. While transforming growth factor-beta1 (TGF-beta1) is the final mediator of ECM accumulation, reactive oxygen species (ROS) and protein kinase C (PKC) are the upstream signaling molecules that mediate hyperglycemia-induced ECM expansion. Magnesium lithospermate B (LAB) is an active component isolated from Salvia miltiorrhizae with known renoprotective properties due to its antioxidative effects. Thus, the present study examined the effects of LAB on renal injury in streptozotocin-induced diabetic rats (STZR) and on the activation of mesangial cells cultured under high glucose conditions. Ten micrtograms of LAB/kg per day was started 8 wk after streptozotocin injection and continued for a period of 8 wk. It significantly suppressed renal malondialdehyde (MDA), microalbuminuria, glomerular hypertrophy, mesangial expansion, and the upregulation of renal TGF-beta1, fibronectin, and collagen in STZR without significantly affecting plasma glucose. Both 30 mM of glucose and 100 uM of H(2)O(2) significantly increased TGF-beta1 and fibronectin protein secretion by mesangial cells. LAB at 10 micro g/ml inhibited high glucose- and H(2)O(2)-induced TGF-beta1 and fibronectin secretion. LAB also inhibited glucose-induced intracellular ROS generation and PKC activation in mesangial cells, but it did not directly inhibit PKC activity at dosages that inhibited ROS generation. The in vitro data of this study show that LAB inhibits ROS generation leading to PKC activation and TGF-beta1 and fibronectin upregulation in mesangial cells cultured under high glucose conditions. Moreover, delayed treatment with LAB was found to significantly suppress the progression of renal injury in STZR. LAB may become a new therapeutic agent for the treatment of diabetic nephropathy.