Diabetes & Metabolism Journal

Original Articles

Clinical Diabetes & Therapeutics
Effectiveness and Safety of Adding Basal Insulin Glargine in Patients with Type 2 Diabetes Mellitus Exhibiting Inadequate Response to Metformin and DPP-4 Inhibitors with or without Sulfonylurea: Yu Mi Kang, Chang Hee Jung, Seung-Hwan Lee, Sang-Wook Kim, Kee-Ho Song, Sin Gon Kim, Jae Hyeon Kim, Young Min Cho, Tae Sun Park, Bon Jeong Ku, Gwanpyo Koh, Dol Mi Kim, Byung-Wan Lee, Joong-Yeol Park; Diabetes Metab J. 2019;43(4):432-446. Published online June 19, 2019; DOI: https://doi.org/10.4093/dmj.2018.0092

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Background

We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM).

Methods

This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia.

Results

The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects (n=33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. −0.9±6.0 kg, P=0.011).

Conclusion

The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs.

Citations

Citations to this article as recorded by

Glycaemic control with add‐on thiazolidinedione or a sodium‐glucose co‐transporter‐2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24‐week, randomized controlled trial
Jaehyun Bae, Ji Hye Huh, Minyoung Lee, Yong‐Ho Lee, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2021; 23(2): 609. CrossRef
Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease
Kyung-Soo Kim, Byung-Wan Lee
Clinical and Molecular Hepatology.2020; 26(4): 430. CrossRef

Relationship of LDL Particle Size to IMT and Insulin Resistance in Non-Diabetic Adult.: Jina Park, Chul Sik Kim, Jong Suk Park, Dol Mi Kim, Min Ho Cho, Jee Hyun Kong, Hai Jin Kim, Jeong Ho Kim, Chul Woo Ahn, Kyung Rae Kim, Bong Soo Cha, Sung Kil Lim, Hyun Chul Lee; Korean Diabetes J. 2005;29(4):333-343. Published online July 1, 2005

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Abstract PDF: BACKGROUND
The aims of this study were to investigate the predictor of the low density lipoprotein(LDL) particle size and the relationship of the LDL particle size to the levels of insulin resistance and the carotid intima-media thickness (IMT) in healthy Koreans. METHODS: The subjects were 47 and 89 clinically healthy males and females, aged between 32 and 70years, without medications that could potentially alter glucose and lipid metabolisms. The mean LDL particle size was determined by polyacrylamide tube gel electrophoresis(Lipoprint(r) LDL, Quantimetrix), the insulin resistance using a short insulin tolerance test kit, and the subclinical atherosclerosis from the carotid intima-media thickness. RESULTS: The LDL particle size was found to be significantly correlated with insulin resistance using a simple Pearson's correlation(r=0.233, P<0.01), but the independent predictors of the LDL particle size, as determined by a multiple stepwise regression analysis, were serum triglyceride(TG), high density lipoprotein(HDL) cholesterol level and age(beta=-0.403, P=< 0.001; beta=0.309, P=0.003; beta=-0.219, P=0.016, respectively). Significant relationships were found between an increasing IMT and the traditional risk factors of atherosclerosis: age, LDL cholesterol, HDL cholesterol, systolic and diastolic blood pressure(r=0.490, P<0.001; r=-0.251, P<0.01; r=0.211, P<0.05; r=0.298, P<0.01; r=0.263, P<0.01, respectively). However, no significant correlation was found between an increasing IMT and the LDL particle size (r=-0.172, P=0.075). CONCLUSION: The best predictors for the LDL particle size were the serum TG level, HDL cholesterol level and age. Insulin resistance was not found to be an independent predictor of the LDL particle size. Small dense LDL was not found to be a predictor of the IMT in healthy Koreans.

Prevalence of Diabetes Mellitus(Fasting Plasma Glucose by the ADA Criteria) and Impaired Fasting Glucose according to Anthropometric Characteristics and Dietary Habits: 1998 National Health and Nutrition Survey.: Chul Sik Kim, Eun Kyong Jeong, Jina Park, Min Ho Cho, Ji Sun Nam, Hai Jin Kim, Jee Hyun Kong, Jong Suk Park, Joo Young Nam, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Chung Mo Nam; Korean Diabetes J. 2005;29(2):151-166. Published online March 1, 2005

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Abstract PDF: BACKGROUND
The study is based on the National Health and Nutrition Examination Survey in Korea(1998). With these data, we want to predict the prevalence of diabetes mellitus(DM) and impaired fasting glucose(IFG), By investigating anthropometric characteristics and dietary intake habits, we also wanted to analyze any significant correlation between those factors and the prevalences of DM and IFG. METHODS: The study group was comprised of 8,166 people, a representative group of Koreans, who had undergone a health check-up and food intake survey among the total 39,331 members of 12,189 families who were surveyed. RESULTS: The final results are as the follows. 1) The peak prevalence of DM was 15.92% among women in their sixties and 18.21% among men in their fifties, and that of IFG was found to be 16.27% of women in their seventies and 14.09% of men in their sixties. 2) When analyzing the eating habits and the prevalences of DM and IFG, we found that women with more glucose intake had a lesser risk of DM, but this was of no statistical significance. 3) In men, age, total cholesterol, triglyceride(TG), and hypertension(HTN) were revealed as meaningful factors and in women, age, TG, and HTN were revealed as meaningful factors. As to the IFG, in females, age and TG were meaningful factors, and in males, age, TG, the waist/hip ratio (WHR), and body mass index (BMI) were meaningful factors. CONCLUSION: Although this study could not demonstrate meaningful correlation between diet habits and DM, the prevalence of IFG and the recent increase in the prevalence of DM in Koreans, owing to alterations in their diet habits, demands further organized group study for a better understanding of their relationship

Case Report

A Case of Severe Prolonged Hypoglycemia Caused by Combined Ramipril and Amiloride Treatment in a Nondiabetic Woman.: Min Ho Cho, Dol Mi Kim, Chul Sik Kim, Joug Suk Park, Joo Young Nam, Jin Hyuck Chang, Jina Park, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(6):554-557. Published online December 1, 2004

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Abstract PDF: The relationship between angiotensin converting enzyme inhibition and hypoglycemia remains controversial. An 82-year-old, nondiabetic woman who had taken ramipril 5 mg with amiloride 5 mg for two months was admitted to the hospital because of her altered mentality. Her plasma glucose was 1.5 mmol/L and she regained her consciousness after normalization of the plasma glucose. The recurrent attacks of hypoglycemia ended when she stopped taking ramipril. Her hypoglycemia was thought to result from the combined deficiency of catecholamines and cortisol that was induced by a deficiency of angiotensin II. The glucagoninsensitivity was thought to result from a chronic elevation of bradykinin due to the ACE inhibitor, and the relative hyperinsulinemia was though to be cased by the amiloride.

Original Articles

Apolipoprotein E Genetic Polymorphism and Diabetic Microangiopathy in Type 2 Diabetic Patients.: Jong Suk Park, Joo Young Nam, Chul Sik Kim, Dol Mi Kim, Min Ho Cho, Jina Park, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(6):511-520. Published online December 1, 2004

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Abstract PDF: BACKGROUND
The pathophysiological causes for the development and progression of diabetic microangiopathy are not well known, but the apo E genetic polymorphism has been proposed to be involved in the disease's development and progression. The aim of this study was to investigate the association between the apo E genetic polymorphism and diabetic microangiopathy in Korean type 2 diabetic patients. METHODS: One hundred eighteen patients with type 2 diabetes who had a duration of diabetes longer than 8 years were divided into the three apo E groups (the E2, E3 and E4 groups). The plasma levels of lipids were measured. The frequency of diabetic nephropathy, retinopathy and neuropathy were compared among the three apo E genotype groups. RESULTS: The frequency of overt nephropathy was significantly greater for the apo E2 patients with diabetes (46.7%) than for the apo E3 (16.7%) or apo E4 patients (10.5%). Logistical regression analysis showed that the odds ratio of the apo E2 and apo E4 genotypes for the presence of overt nephropathy were 4.779 (P < 0.01) and 0.643 (P = 0.583), respectively. Plasma TG levels were significantly greater for the apo E2 patients. This study did not find any association between diabetic retinopathy, neuropathy and apo E polymorphism. CONCLUSION: Apo E2 is a positive risk factor for diabetic nephropathy in Korean type 2 diabetic patients. TG may have an important role in diabetic nephropathy.

The Degree of Atherosclerosis and the Metabolic Characteristics according to the Abdominal Obesity in Type 2 Diabetic Patients.: Chul Sik Kim, Jong Suk Park, Joo Young Nam, Jina Park, Min Ho Cho, Ji Sun Nam, Dol Mi Kim, Soo Jee Yoon, Jae Hyun Nam, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(5):377-391. Published online October 1, 2004

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Abstract PDF: BACKGROUND
Many of the maturity-onset type 2 diabetic patients with hypertension and dyslipidemia in Korea are not associated with obesity. However, these patients are at risk for developing macrovascular complications such as atherosclerosis due to hyperinsulinemia, insulin resistance and abdominal obesity. The aims of this study were to compare the clinical and biochemical differences between the type 2 diabetic patients that are with and without abdominal obesity, and we also wished to investigate the degree of insulin resistance and atherosclerosis in these patients. METHODS: Among 530 type 2 diabetes mellitus (DM) patients, the percentages of under-weight (UW), normal-weight (NW), over-weight (OW) and obese (OB) (BMI <20, 20-25, 25-29.9 and > or =30, respectively) subjects were 8.9%, 62.1%, 25.1% and 3.9%, respectively. To evaluate the severity of their atherosclerosis, the coronary artery calcification (CAC) score was measured by electron beam computed tomography, and the intima-media thickness (IMT) of the common carotid artery and the ankle-brachial pressure index (ABPI) were also measured. The Insulin sensitivity index (ISI) was measured by the plasma glucose disappearance rate (kitt: %/min). RESULTS: 1. There were no differences in age, duration of DM and the HbA1c levels according to BMI for both the men and women, but the waist-hip ratio (WHR) and systolic blood pressure (SBP) were significantly different among each group. Serum triglyceride (TG), HDL-cholesterol (HDL-C), free fatty acid (FFA), fibrinogen, and fasting c-peptide levels, {excluding total cholesterol (TC)}, were also significantly different. The ISI, which is a marker for insulin resistance, as well correlated with the patients' BMI. Subjects having an with ISI above 2.5%/min were considered as having insulin resistance, and 28%, 60%, 68% and 75% of patients in the UW, NW, OW and OB groups, respectively, demonstrated insulin resistance. The visceral fat area/subcutaneous fat area ratio and visceral fat area/thigh muscle area ratio also increased with BMI. 2. The median values of the WHR were 0.95 for the men and 0.91 for the women. There were no significant differences for age, BMI, duration of DM and HbA1c between patients with and without abdominal obesity, but the SBP, TG, HDL-C, FFA, fibrinogen and ISI were significantly different between those two groups. 3. For the OW group as well as the NW group, the carotid IMT, ABPI and CAC scores were significantly different between the patients with and without abdominal obesity. However, there were no differences between the NW group and the OW group. CONCLUSION: In conclusion, those patients with abdominal obesity, regardless of their BMIs, have a higher prevalence for atherosclerosis, dyslipidemia, and hypertension, compared to those patients without abdominal obesity. Therefore, it is important to screen for atherosclerosis and to manage it accordingly, for the patients with insulin resistance or abdominal obesity in order to decrease their risk of developing atherosclerotic events.

Role of Activation of NF- B and AP-1 by Oxidative Stress in Atherosclerosis in Diabetic Patients.: Chul Sik Kim, Geun Taek Lee, Jina Park, Min Ho Cho, Joo Young Nam, Jong Suk Park, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(4):255-264. Published online August 1, 2004

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Abstract PDF: BACKGROUND
The aim of this study was to evaluate the possible role of NF- B activation and AP-1 by oxidative stress in atherosclerosis in diabetic patients by measuring the carotid intima-media thickness, intracellular ROS generation and activation of transcription factors, including nuclear factor-kappa B (NF- B) and activator protein-1 (AP-1). METHODS: Sixty-six patients (28 males, 38 females; age 56.1 13.4 years; duration of diabetes 115.7 83.4 months) with type 2 diabetes mellitus (DM) were selected for this study. The DM patients included in this study were divided into those with a normal carotid intima-media thickness (Group II) and those with an increased intima-media thickness (Group III). 57 healthy controls matched for age and sex with the DM patients (Group I) were randomly selected. Dichlorodifluorescein (DCF)-sensitive intracellular ROS was measured by fluorescent spectrometry. The activities of NF- B and AP-1 in PBMCs were measured by an electrophoretic mobility shift assay. RESULTS: No differences were evident between the groups in terms of gender, age, BMI, blood pressure, total cholesterol, triglyceride, LDL-cholesterol and HDL-cholesterol. Spontaneous and H2O2 (or phorbol-12-myristate-13-acetate, PMA) stimulated ROS were significantly higher in the PBMCs from the DM patients with an increased intima-media thickness (Group III) than in those without (Group II), and were also higher in the control group (Group I). Moreover, the activities of NF- B and AP-1 were significantly higher in Group III than in Groups I or II. CONCLUSION: The present study demonstrates that intracellular ROS generation, and NF- B and AP-1 activation in PBMCs strongly correlates with the carotid artery IMT. These clinical results suggest that increased oxidative stress in PBMCs may play a role in the pathogenesis of atherosclerosis in DM patients .

Frequency of Anti-GAD Antibody in Non-obese, Adult-onset Type 2 Diabetes in Korea and Clinical and Biological Characteristics According to Anti-GAD Antibody.: Chul Sik Kim, Jina Park, Min Ho Cho, Jong Suk Park, Joo Young Nam, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(2):66-74. Published online April 1, 2004

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Abstract PDF: BACKGROUND
Some of the characteristic features of diabetes mellitus in Korea are that 70-80% of patients are non-obese or adult-onset type, and type 1 diabetes is very rare. Occasionally, autoantibodies to glutamic acid decarboxylase(GAD) are found in typical, type 2 diabetes mellitus patients(T2DM). The role of the autoantibody to GAD in T2DM is unknown. The aim of this study was to determine the clinical and biochemical characteristics between GAD-positive and GAD-negative non-obese, adult-onset diabetics in Korea. METHODS: A cohort of 428 type 2 diabetes patients was included. The measured autoantibodies to GAD were measured, and the C-peptide and HbA1c levels, anthropometric data(weight, height, body mass index and waist circumference), blood pressure and lipid profiles compared between the two groups. RESULTS: Compared to the antibody-negative group(n=374; 87.4%), patients with the anti-GAD antibody(n=54; 12.6%) had significantly lower C-peptide levels and were significantly younger. The anti GAD-positive group had a lower BMI, more frequently needed insulin supplements, and a lower prevalence of hypertension. There were no significant differences in gender and family history of diabetes between the two groups. CONCLUSION: The presence of the autoantibody to GAD allowed the group with more deteriorated beta-cell function and more frequent need for insulin supplements, but a lower prevalence of obesity and hypertension to be determined.

Case Reports

A Case of Primary Insulin Autoimmune Syndrome in a Patient Suspected of Having an Insulinoma.: Sung Ju Lee, Jee Hyun Kong, Joo Young Nam, Jong Suk Park, Chul Sik Kim, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(1):45-50. Published online February 1, 2004

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Abstract PDF: Insulin autoimmune syndrome consists of fasting hypoglycemia, hyperinsulinemia and detectable insulin-binding antibodies in patients never been exposed to exogenous insulin. Most affected patients present with other autoimmune disorders, most often Graves' disease. A significant increase in the insulin and C-peptide plasma concentrations and the presence of other anti organ antibodies are also observed. Awareness of insulin autoimmune syndrome hypoglycemia is important as this may produce severe neuroglycopenic symptoms, which may be confused with the presence of an insulinoma. The correct diagnosis is important to avoid unnecessary surgical intervention in patients who are best treated with conservative support, watchful waiting, or in some cases, immunosuppressive therapy. Herein, a case of autoimmune insulin syndrome, suspected as being an insulinoma is reported.

A Case of Primary Antiphospholipid Syndrome in a Patient with Diabetes Presenting as Foot Ulcer.: Chul Sik Kim, Dae Hoon Song, Jina Park, Jong Suk Park, Joo Young Nam, Young Kim, Hee Jung Yoon, Dol Mi Kim, Soo Jee Yoon, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2003;27(2):165-171. Published online April 1, 2003

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Abstract PDF: Antiphospholipid syndrome is a disorder characterized by recurrent vascular thrombosis, pregnancy loss and thrombocytopenia, and the presence of the lupus anticoagulant or a positive anticardiolipin test. A link of antiphospholipid syndrome to diabetes mellitus has not been established. There have been no reports of large artery thrombosis associated with antiphospholipid syndrome or diabetes mellitus. We present a case of an adult with large artery thrombosis, elevated anticardiolipin antibodies and lupus anticoagulant associated with diabetes. The patient was managed by successful primary percutaneous transluminal angioplasty and stent implantation, with accompanying anticoagulation therapy. To our knowledge, this is the first case where the occluded large artery was treated with primary stent implantation in primary antiphospholipid syndrome with diabetes mellitus

Original Article

The Effect of Growth Hormone on Insulin Resistance and Atherosclerotic Risk Factors in Obese Patients with Uncontrolled Type 2 Diabetes Mellitus.: Jae Hyun Nam, Soo Jee Yoon, Dol Mi Kim, Chul Sik Kim, Joo Young Nam, Jong Suk Park, Jina Park, Chul Woo Ahn, Suk Won Park, Bong Soo Cha, Young Duk Song, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 2003;27(2):141-152. Published online April 1, 2003

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Abstract PDF: BACKGROUND
Insulin resistance in visceral obesity constitutes a risk factor for the development of atherosclerosis. The insulin resistance in obese type 2 diabetic patients can be improved by a decrease in the visceral fat and an increase in the skeletal muscle, which may influence the insulin sensitivity. Growth hormone (GH) accelerates lipolysis and promotes protein conservation. The effects of GH therapy, with diet restriction, on lipolysis and protein anabolism, were evaluated, which may change body composition, insulin resistance and atherosclerotic risk factors in obese type 2 diabetes mellitus. METHODS: Sixteen obese type 2 diabetic patients (31~56yrs), who had high glucose levels (glucose 12.8+/-1.7 mmol/L, HbA1c 10.2+/-2.1%), were treated with recombinant human GH (GH; 1 unit/d, 5 times/week), diet restriction (25 kcal/kg ideal body weight/day) and exercise (250 kcal/day) for 12 weeks. They underwent anthropometric measurement, bioelectrical impedance for total body fat and lean body mass, as well as computed tomography, for visceral and subcutaneous fat, at the umbilicus and muscle area at the mid-thigh levels. All subjects underwent the test for GH response to hypoglycemia. The insulin sensitivity index (ISI) was measured using insulin tolerance tests (ITT). RESULTS: 1. The visceral fat area (VFA)/thigh muscle area (TMA) ratio was more decreased in the GH-treated group than in the control group, but there was no change of body weight. 2. The ISI was significantly increased in only the GH-treated group, which was negatively correlated with the VFA/TMA ratio. The serum free fatty acid, fibrinogen and plasminogen activator inhibitor-1 were significantly decreased after the GH treatment. The serum glucose level and HbA1c remained unchanged during the GH therapy, but were significantly decreased after 3 months. 3. The total cholesterol and triglyceride levels were decreased in the GH treated group. 4. The insulin-like growth factor-I, fasting c-peptide and insulin level were all significantly increased after the GH treatment. CONCLUSION: This study suggested that in type 2 diabetic patients, with insulin resistance and uncontrolled blood sugar, GH treatment caused a decrease in the visceral fat and an increase in the muscle mass, which could result in the improvement of the ISI, atherosclerotic risk factors and dyslipidemia.

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