식전 부하의 내당능, 식욕 및 음식 섭취에 대한 효과 연구

학위논문(박사)--서울대학교 대학원 :의과대학 의학과,2020. 2. 조영민.당뇨병과 비만은 대표적인 비감염성 질환으로 전세계적으로 이로 인한 질병부담이 크게 증가하고 있어 이에 대한 효과적인 예방과 치료가 필요하다. 영양요법은 당뇨병과 비만 관리에서 가장 중요한 부분으로 적절하게 수행될 경우 당뇨병과 비만의 발생 위험을 낮추고 치료 효과를 높여 질병의 예후를 개선할 수 있다. 당뇨병과 비만 환자의 식사요법은 기본적으로 적절한 양의 질 좋은 식사를 섭취하는 것이다. 하지만 최근 음식의 양이나 질에 더해 음식을 섭취하는 시기나 순서가 식사요법에 중요하다는 연구 결과들이 보고되고 있다. 이를 이용한 영양요법은 기존의 식습관을 크게 바꾸지 않으면서 혈당과 체중 조절에 이로운 효과를 기대할 수 있어 향후 효과적인 치료 전략이 될 수 있다. 식전 부하란 식사 전 정해진 시간에 소량의 음식이나 영양소를 섭취하는 것을 말한다. 식전 부하의 대사적인 효과는 주로 우유 단백의 일종인 유청 단백에서 보고되었는데 당뇨병 환자를 포함한 다양한 대상군에서 식후 혈당을 낮추고 음식 섭취량을 감소시켰다. 하지만 이 방법이 임상적으로 유의한 효과를 보이기 위해서는 하루 50 g 정도의 단백 섭취가 필요하였다. 이는 약 200 kcal에 해당하는 양으로써 장기간 섭취할 경우 열량 과잉으로 인해 체중 증가 등의 문제가 발생할 수 있다. 이에 본 연구에서는 이러한 단점을 개선하고 식전 부하의 대사 효과는 유지하기 위해 단백질을 10.7 g으로 감량하는 대신 12.7 g의 식이섬유를 첨가한 강화시리얼바를 개발하여 제2형 당뇨병 환자와 정상인에서 식후 혈당, 식욕 및 음식 섭취에 대한 효과를 평가하였다. 강화시리얼바의 식후 혈당 개선 효과는 제2형 당뇨병 환자와 정상 내당능인 사람 각각 15명(총 30명)을 대상으로 평가하였다. 연구는 무작위 배정 개방 교차연구로 진행되었다. 피험자들은 배정 순서에 따라 30분 전에 강화시리얼바를 섭취한 뒤 시험식을 섭취하거나 시험식을 섭취한 뒤 강화시리얼바를 섭취하도록 하였으며, 혼합식 부하검사를 통해 혈당, 인슐린 및 위장관호르몬의 변화를 측정하였다. 연구 결과 강화시리얼바를 식전에 투여하면 강화시리얼바를 식후에 투여한 경우 비해 제2형 당뇨병 환자(14,723 ± 1,310 mg·min/dL vs. 19,642 ± 1,367 mg·min/dL, P = 0.0002)와 정상 내당능인 사람 (3,943 ± 416 mg·min/dL vs. 4,827 ± 520 mg·min/dL, P = 0.0296) 모두 식후 혈당이 유의하게 감소하였다. 제2형 당뇨병 환자의 경우 식후 혈당 감소와 함께 초기 인슐린 분비와 식후 glucagon-like peptide-1 분비가 유의하게 증가하였다. 강화시리얼바의 식욕 및 음식 섭취량에 대한 효과는 건강 자원자를 대상으로 평가하였다. 연구는 무작위 배정 개방 교차연구로 진행되었으며 총 20명이 연구에 참여하였다. 피험자들은 배정 순서에 따라 식전 부하로 강화시리얼바, 일반 시리얼바 또는 물 중 하나를 섭취한 뒤 15분 후 2시간 동안 시험식을 제한 없이 섭취하도록 하였으며, 식욕, 충만감과 함께 혈당, 인슐린 및 위장관호르몬의 변화를 측정하였다. 연구 결과 강화시리얼바의 식전 섭취는 물을 섭취한 경우에 비해 총 열량 섭취를 유의하게 감소시켰다(904.4 ± 534.9 kcal vs. 1,075.0 ± 508.0 kcal, P = 0.016). 또한 강화시얼바는 일반 시리얼바나 물을 섭취한 경우 비해 충만감을 유의하게 증가시켰으며 식후 혈당을 낮추고 glucagon-like peptide-1 분비를 증가시켰다. 두 연구 모두 위장관불편감을 포함해 강화시리얼바 섭취와 관련된 이상 반응은 발생하지 않았다. 결론적으로 강화시리얼바는 제2형 당뇨병 환자와 정상 내당능인 사람에서 위장관호르몬의 변화와 함께 식후 혈당, 식욕 및 음식 섭취를 감소시킴으로써 혈당과 열량 섭취 조절에 이로운 효과를 보여주었다.The unprecedented global epidemic of diabetes mellitus and obesity necessitates more effective prevention and treatment to halt the growing burden of diseases. Nutrition therapy is an essential component of the management of these noncommunicable diseases. Recently, besides meal size and composition, meal timing and the order of eating food have been identified as major determinants of postprandial glycemia and food intake. Thus, the nutritional strategies, such as nutrient preload and manipulation of food order, could be a feasible option for the management of diabetes mellitus and obesity. Nutrient preload, which refers to the intake of a small amount of food before a meal, using whey protein has reduced postprandial hyperglycemia and food intake in individuals with varying degrees of glucose intolerance. In previous studies, a high dose of protein, usually 50 g, was required to achieve clinically meaningful improvements in hyperglycemia. However, long-term caloric surplus by protein preload might promote weight gain and offset its beneficial effects. In this regard, we developed a protein-enriched, dietary fiber-fortified bar (PFB), containing 10.7 of protein and 12.7 of dietary fiber, to maintain the metabolic benefits of nutrient preload while decreasing the potential risk of high-dose protein. In the present study, we investigated the effects of the PFB preload on glucose tolerance, appetite, and food intake. The first study evaluated the effect of premeal PFB on postprandial glucose excursions in 15 individuals with type 2 diabetes and 15 individuals with normal glucose tolerance (NGT). This study was a randomized, open-label, crossover study. The participants consumed the PFB at −30 minutes before (premeal) or immediately after (postmeal) a test meal. Plasma levels of glucose, insulin, and gut hormones were measured during a mixed meal tolerance test. The premeal PFB significantly reduced postprandial hyperglycemia compared with the postmeal PFB in individuals with type 2 diabetes (14,723 ± 1,310 mg·min/dL vs. 19,642 ± 1,367 mg·min/dL, P = 0.0002) and NGT (3,943 ± 416 mg·min/dL vs. 4,827 ± 520 mg·min/dL, P = 0.0296). In individuals with type 2 diabetes, the premeal PFB significantly increased early insulin secretion and enhanced postprandial GLP-1 secretion compared with the postmeal PFB. All participants completed the study with no adverse event. The second study evaluated the effect of PFB preload on appetite and food intake in 20 healthy individuals. This study was a randomized, open-label, crossover, and exploratory study. After consuming a PFB, usual cereal bar, or water preload at −15 minutes before a test meal in a randomized order, the participants had an ad libitum test meal for 120 minutes. The amount of food intake, appetite, fullness, and plasma levels of glucose, insulin, and gut hormones were measured. The PFB preload significantly reduced the total energy intake compared with the water preload (904.4 ± 534.9 kcal vs. 1,075.0 ± 508.0 kcal, P = 0.016). In addition, the PFB preload significantly increased fullness, lowered postprandial glucose levels, and enhanced GLP-1 secretion compared with the other two preloads. All participants completed the study with no adverse event. In conclusion, premeal consumption of the PFB improved postprandial glucose excursions in individuals with type 2 diabetes and NGT and reduced appetite and food intake in healthy individuals with changes in gut hormones, which might be beneficial to the management of diabetes mellitus and obesity.Introduction 1 1. The importance of nutrition therapy in postprandial glycemic control 1 2. Evidence of the effect of nutrient preload on glycemic control 3 3. Evidence of the effect of the order of eating food on glycemic control 6 Hypothesis of the Study 9 Chapter 1. Postprandial glucose-lowering effect of premeal consumption of protein-enriched, dietary fiber-fortified bar in individuals with type 2 diabetes and normal glucose tolerance 10 Introduction 11 Methods 13 Results 20 Discussion 33 Chapter 2. Effect of premeal consumption of protein-enriched, dietary fiber-fortified bar on the total energy intake in healthy individuals 38 Introduction 39 Methods 40 Results 44 Discussion 65 Summary and Conclusion 70 Acknowledgement 71 References 72 국문 초록 90Docto

Proteinuria is Associated with Carotid Artery Atherosclerosis in Non-Albuminuric Type 2 Diabetes: A Cross-Sectional Study

The association of specific urinary proteins other than albumin with cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) has been shown. In this respect, CV outcomes may differ in non-albuminuric T2D patients who were considered as a low risk group, according to the presence of proteinuria. We investigated the association between proteinuria and atherosclerosis assessed by carotid artery intima-media thickness (CIMT) in non-albuminuric T2D patients. 2047 T2D patients whose urine albumin-to-creatinine ratio was below 30 mg/g were recruited and classified into a non-proteinuria (NP, uPCR < 150 mg/g, n = 1865) group and a non-albuminuric proteinuria (NAP, uPCR ≥ 150 mg/g, n = 182) group. CIMT was compared between the two groups and logistic regression analysis was conducted to verify whether proteinuria could predict deteriorated CIMT status. In this cross-sectional study, mean CIMT of the NAP group were significantly thicker than those of the NP group (0.73 ± 0.16 vs. 0.70 ± 0.14, p = 0.016). The presence of proteinuria is associated with deteriorated CIMT after the adjustment for conventional risk factors (odds ratio, 2.342; 95% confidence interval, 1.082-5.070, p = 0.030) in regression analysis. We postulated that the measurement of urinary protein in conjunction with albumin might be helpful for predicting atherosclerosis, especially for non-albuminuric patients.ope

The Effect of Thyroid Stimulating Antibody on the Bone Remodeling in Graves' Disease

학위논문 (석사)-- 서울대학교 대학원 : 의학과 분자유전체의학 전공, 2013. 2. 문민경.Background: Thyroid hormone is known as a main contributor to bone loss in hyperthyroidism. However, recent studies reported that thyroid stimulating hormone (TSH) acts directly on the bone through TSH receptor (TSHR), independent of the effects of thyroid hormone. As serum thyroid stimulating antibody (TSAb) binds to TSHR in Graves disease, serum TSAb may produce a direct effect on bone metabolism. Aim of the study: We conducted this study to identify the effects of serum TSAb on bone metabolism in patients with Graves disease. Materials and Methods: In patients with newly diagnosed Graves disease, the association between serum TSAb levels and biochemical parameters of bone metabolism are evaluated. To identify the effect of TSAb on osteoblasts, we examined alkaline phosphatase (ALP) activity assay and the expression of osteoblastogenic genes in murine mesenchymal C3H10T1/2 cells. Results: One hundred and thirty nine patients were included in the study. Patients with serum TSAb were 127men were 25, premenopausal women 83, and postmenopausal women 19. Patients with serum thyroid blocking antibody (TBAb) were 12all females. In patients with serum TSAb, the levels of serum triiodothyronine (T3), free T4 (FT4), TSAb, and parathyroid hormone was significantly correlated with the levels of serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), and C-terminal telopeptide of type Ⅰ collagen (CTx). After multivariate regression analysis, serum TSAb was an independent variable for serum OC in men (P=0.019) and for serum BAP and OC in premenopausal women (P=0.043 and P=0.043). Treatment with TSH and TSAb did not show significant changes in ALP activity assay and the expression of BAP, OC and CTx in murine C3H10T1/2 cells Conclusion: The levels of serum TSAb were associated with biochemical parameters of osteoblastogenesis and bone coupling in patients with Graves disease, independent of the effects of T3 and FT4. Serum TSAb might have a protective role in osteoporosis in men and premenopausal women with Graves disease.Abstract Contents List of Tables List of Figures Introduction Materials and Methods Results Discussion References Abstract (Korean)Maste

Differential Effects of Thiazolidinediones and Dipeptidyl Peptidase-4 Inhibitors on Insulin Resistance and β-Cell Function in Type 2 Diabetes Mellitus: A Propensity Score-Matched Analysis

INTRODUCTION: Comparisons of the glycemic durability between thiazolidinediones (TZDs) and dipeptidyl peptidase-4 (DPP-4) inhibitors remain insufficient. This study aimed to find clues for the differences in glycemic durability between TZDs and DPP-4 inhibitors by comparing the insulin resistance and β-cell function among patients using these agents. METHODS: A total of 241 patients with type 2 diabetes mellitus (T2DM) treated with either pioglitazone (a TZD) or DPP-4 inhibitors as combination therapy with metformin for at least 1 year were analyzed. A propensity score based on the patients' baseline characteristics and glycated hemoglobin (HbA1c) was used to match them. Indices for insulin resistance and secretory function of β-cells, namely the homeostasis model assessment of insulin resistance (HOMA-IR) or β-cells (HOMA-β), were calculated and compared. Multiple regression analysis was performed to find the independent variables correlated with β-cell function or insulin resistance. RESULTS: Evaluation of the data from 168 matched patients with T2DM showed that TZD users had significantly better insulin sensitivity compared with DPP-4 inhibitor users (HOMA-IR 2.3 ± 1.9 vs. 3.5 ± 3.2, p = 0.003). Conversely, DPP-4 inhibitor users secreted more insulin than TZD users (HOMA-β 45.7 ± 31.6 vs. 61.4 ± 49.5, p = 0.016). Multiple linear regression analysis showed that these agents were independently associated with both insulin resistance and β-cell function. CONCLUSION: TZD users showed significantly better insulin sensitivity, whereas DPP-4 inhibitor users secreted more insulin from β-cells under similar glycemic control.ope

Effects of Dipeptidyl Peptidase-4 Inhibitors on Hyperglycemia and Blood Cyclosporine Levels in Renal Transplant Patients with Diabetes: A Pilot Study

BACKGROUND: The use of dipeptidyl peptidase-4 (DPP-4) inhibitors is increasing among renal transplant patients with diabetes. However, the glucose-lowering efficacies of various DPP-4 inhibitors and their effects on blood cyclosporine levels have not been fully investigated. We compared the glucose-lowering efficacies of DPP 4 inhibitors and evaluate their effects on the blood levels of cyclosporine in renal transplant recipients with diabetes. METHODS: Sixty-five renal allograft recipients who received treatment with DPP-4 inhibitors (vildagliptin, sitagliptin, or linagliptin) following kidney transplant were enrolled. The glucose-lowering efficacies of the DPP-4 inhibitors were compared according to the changes in the hemoglobin A1c (HbA1c) levels after 3 months of treatment. Changes in the trough levels of the cyclosporine were also assessed 2 months after treatment with each DPP-4 inhibitor. RESULTS: HbA1c significantly decreased in the linagliptin group in comparison with other DPP-4 inhibitors (vildagliptin -0.38%±1.03%, sitagliptin -0.53%±0.95%, and linagliptin -1.40±1.34; P=0.016). Cyclosporine trough levels were significantly increased in the sitagliptin group compared with vildagliptin group (30.62±81.70 ng/mL vs. -24.22±53.54 ng/mL, P=0.036). Cyclosporine trough levels were minimally changed in patients with linagliptin. CONCLUSION: Linagliptin demonstrates superior glucose-lowering efficacy and minimal effect on cyclosporine trough levels in comparison with other DPP-4 inhibitors in kidney transplant patients with diabetes.ope

Comparison of Renal Effects of Ezetimibe-Statin Combination Versus Statin Monotherapy: A Propensity-Score-Matched Analysis

Neither lowering of blood lipid levels nor treatment with statins definitively improves renal outcomes. Ezetimibe, a non-statin antilipidemic agent, is known to not only decrease blood lipid levels but also reduce inflammatory response and activate autophagy. We evaluated the effect of adding ezetimibe to a statin on renal outcome compared with statin monotherapy by analyzing longitudinal data of 4537 patients treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) for more than 180 days. A propensity-score-based process was used to match baseline characteristics, medical history, and estimated glomerular filtration rate (eGFR) between S + E and S groups. Changes in serum creatinine and incidence of renal events, defined as doubling of serum creatinine to ≥1.5 mg/dL or occurrence of end-stage renal disease after the first day of treatment initiation, were compared between the groups. Among 3104 well-matched patients with a median follow-up of 4.2 years, the S + E group showed a significantly lower risk of renal events than the S group (hazard ratio 0.58; 95% CI 0.35-0.95, P = 0.032). In addition, the S + E group tended to preserve renal function compared with the S group throughout follow-up, as assessed by serum creatinine changes (P-values for time-group interactions <0.001). These data support the beneficial effects on renal function when combining ezetimibe with a statin.ope

Sodium Glucose Cotransporter-2 Inhibitors as an Add-on Therapy to Metformin Plus Dipeptidyl Peptidase-4 Inhibitor in Patients with Type 2 Diabetes

Purpose: To date, no study has compared the effects of adding sodium glucose cotransporter-2 (SGLT-2) inhibitors to the combination of metformin plus dipeptidyl peptidase-4 (DPP-4) inhibitors to the effects of adding other conventional anti-diabetic drugs (ADDs) to the dual therapy. We aimed to compare the effect of adding SGLT-2 inhibitors with that of adding sulfonylurea (SU) in type 2 diabetes (T2D) patients inadequately controlled with metformin plus DPP-4 inhibitors. Materials and methods: This study was designed to evaluate the non-inferiority of SGLT-2 inhibitor to SU as an add-on therapy to the dual combination of metformin plus DPP-4 inhibitors. A total of 292 T2D patients who started SU or SGLT-2 inhibitors as an add-on therapy to metformin plus DPP-4 inhibitors due to uncontrolled hyperglycemia, defined as glycated hemoglobin (HbA1c) ≥7%, were recruited. After propensity score matching, 90 pairs of patients remained, and 12-week changes in HbA1c levels were reviewed to assess glycemic effectiveness. Data from these patients were analyzed retrospectively. Results: After 12 weeks of triple therapy, both groups showed significant changes in HbA1c levels, with a mean of -0.9% in each group. The inter-group difference was 0.01% [95% confidence interval (CI): -0.26-0.27], and the upper limit of the 95% CI was within the limit for non-inferiority (0.40%). There were no inter-group differences in the changes of liver enzyme levels and kidney function. Conclusion: Adding SGLT-2 inhibitors is not inferior to adding SU as a third-line ADD to metformin plus DPP-4 inhibitor combination therapy.ope

Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism. Methods: Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks. Results: The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue. Conclusion: SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.ope

Increased Sclerostin Level after Further Ablation of Remnant Estrogen by Aromatase Inhibitors

BACKGROUND: Sclerostin is a secreted Wnt inhibitor produced almost exclusively by osteocytes, which inhibits bone formation. Aromatase inhibitors (AIs), which reduce the conversion of steroids to estrogen, are used to treat endocrine-responsive breast cancer. As AIs lower estrogen levels, they increase bone turnover and lower bone mass. We analyzed changes in serum sclerostin levels in Korean women with breast cancer who were treated with an AI. METHODS: We included postmenopausal women with endocrine-responsive breast cancer (n=90; mean age, 57.7 years) treated with an AI, and compared them to healthy premenopausal women (n=36; mean age, 28.0 years). The subjects were randomly assigned to take either 5 mg alendronate with 0.5 μg calcitriol (n=46), or placebo (n=44) for 6 months. RESULTS: Postmenopausal women with breast cancer had significantly higher sclerostin levels compared to those in premenopausal women (27.8±13.6 pmol/L vs. 23.1±4.8 pmol/L, P0.05). CONCLUSION: Serum sclerostin levels increased with absolute deficiency of residual estrogens in postmenopausal women with endocrine-responsive breast cancer who underwent AI therapy with concurrent bone loss.ope

A Case of Autoantibody-Positive Ketosis-Prone Diabetes Mellitus

Ketosis-prone diabetes mellitus (KPD), which is an atypical type of diabetic mellitus with severe β cell dysfunction, is accompanied by ketosis or ketoacidosis without specific preceding factors at diagnosis. KPD shows mixed features of type 1 and type 2 diabetes. In some cases, the recovery of the function of β cells during intensified diabetic management enabled the termination of insulin therapy. The Aβ classification system classifies KPD patients into four distinct subgroups depending upon the presence or absence of β cell autoimmunity and β cell functional reserve and has been recognized as an important tool to predict clinical outcomes. In Korea, several cases of KPD with absence of β cell autoimmunity have been reported. A 60-year-old man presenting with DKA (diabetic ketoacidosis) as the first manifestation of diabetes, was shown to have β cell autoimmunity. A significant improvement in glycemic control was shown as a result of aggressive diabetic management; shortly after an acute episode of DKA, the recovery of β cell functional reserve was confirmed. This result allowed discontinuation of insulin therapy and maintenance of euglycemic status without antidiabetic medication.ope