DIABETES TECHNOLOGY & THERAPEUTICS Volume 17, Number 1, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.0214
Diabetes Technology & Therapeutics 2015.17:29-34. Downloaded from online.liebertpub.com by KUNGLIGA TEKNISKA HOGSKOLAN on 08/13/15. For personal use only.
ORIGINAL ARTICLE
Relationship Between b-Cell Function, Metabolic Control, and Microvascular Complications in Type 2 Diabetes Mellitus Lihua Zhao, MD, Jing Ma, MD, Shaoxin Wang, MD, and Yun Xie, MD
Abstract
Background: This study investigated the relationship among b-cell function, metabolic control, and diabetic microvascular complications in patients with type 2 diabetes mellitus (T2DM). Subjects and Methods: In total, 885 patients with type 2 diabetes mellitus (DM) were recruited from January 2012 to January 2014 and grouped into three groups according to the area under the curve of C-peptide [AUC(C-pep)] during the 75-g oral glucose tolerance test. Logistic regression analyses were used to evaluate the association between C-peptide and microvascular complications. Results: The prevalence of diabetic microvascular complications decreased from the first to the third AUC(Cpep) tertile (P < 0.01 for all), whereas the rates of nonalcoholic fatty liver disease (NAFLD) was positively associated with AUC(C-pep) values. Patients with lower AUC(C-pep) tertile exhibited higher levels of glycosylated hemoglobin and high-density lipoprotein cholesterol and longer duration of DM; however, levels of triglycerides, fasting C-peptide, 2-h C-peptide, body mass index, and homeostasis model assessment of insulin resistance index were lower compared with the third tertile. Comparison among patients with a similar DM duration showed a higher level of AUC(C-pep) was inversely associated with prevalence of microvascular complications. The odds ratios for nephropathy, retinopathy, and neuropathy in the lowest versus the highest AUC(C-pep) tertile were 3.10 (95% confidence interval, 2.01–4.78), 2.83 (1.73–4.64), and 2.04 (1.37–3.04) after adjustment for confounding factors. Conclusions: Higher AUC(C-pep) levels were associated with a decreased prevalence of microvascular complications and a good level of glycemic control, whereas higher endogenous insulin levels were linked to the components of metabolic syndrome and increased rates of NAFLD. more than an inactive by-product of insulin synthesis. More recently, accumulating evidence indicated C-peptide was a hormonally active peptide itself. It has been found to exert beneficial effects on the vascular dysfunction of T1DM, especially on microvascular disease.2–4 It was assigned a multitude of physiological actions affecting renal, retinal, neural, and circulatory functions. In contrast to these studies in T1DM, data on the relationship between C-peptide and type 2 diabetes mellitus (T2DM) were controversial. Some studies5–9 showed that C-peptide had a positive influence on chronic vascular complications in patients with T2DM, whereas others did not.10,11 Previous studies used fasting or postprandial C-peptide levels as a surrogate of b-cell function. However, the relationship between the area under the curve of C-peptide [AUC(C-pep)], which is the gold standard measure of b-cell
Introduction
H
yperglycemia as an important causal factor for the initiation and progression of diabetic angiopathy has been generally accepted. The Diabetes Control and Complications Trial established the importance of glycemic control to ameliorate diabetes-related complications of type 1 diabetes mellitus (T1DM).1 However, patients with tight glycemic control faced a higher incidence of hypoglycemia, and the end-organ diabetes complications still remained. A previous study2 implicated that preserving b-cell function led to improved glycemic control and diabetic vascular disease. The C-peptide level is a robust measure of b-cell function as it is secreted in equimolar amounts with insulin from b-cells of the pancreas and exempted from first-pass metabolism by the liver. Previously, C-peptide was considered to be little
Department of Diabetic Neurology, Hospital of Metabolic Disease, Tianjin Medical University, Tianjin, China.
29
30
Diabetes Technology & Therapeutics 2015.17:29-34. Downloaded from online.liebertpub.com by KUNGLIGA TEKNISKA HOGSKOLAN on 08/13/15. For personal use only.
function,12 and diabetic microvascular complications was not well evaluated. In this study performed in T2DM, b-cell function was assessed using calculated AUC(C-pep) during near-normal life condition, the 75-g oral glucose tolerance test (OGTT). The aims of this retrospective study were to evaluate relationship among serum C-peptide levels, microvascular complications, and metabolic control in T2DM. Study Design and Methods Subjects
The study enrolled 885 consecutive patients with T2DM from January 2012 to January 2014. Data for these patients (508 males [57.4%], 377 females [42.6%]) were analyzed cross-sectionally. Diagnosis of T2DM was based on 1999 World Health Organization criteria, clinical manifestation, diabetic autoimmune antibody, and islet b-cell function. Patients diagnosed with acute complications of diabetes, renal impairment, uncontrolled hypertension, chronic infection, and malignancy were excluded. Ethics statement
All the patients signed the consent form for allowing their information for research. The study was approved by the ethics committee of the Hospital of Metabolic Disease, Tianjin Medical University. Measurements
Anthropometric measurements at admission were collected, including gender, age, height, weight, duration of diabetes mellitus (DM), and associated comorbidities. Venous blood was collected in the fasting state for laboratory analysis. Biochemical measurements included fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, lowdensity lipoprotein cholesterol, triglycerides (TG), glycosylated hemoglobin (HbA1c), creatinine (CR), and 24-h urine albumin excretion. Glucose and C-peptide concentrations were measured at 0, 30, 60, and 120 min after oral administration of 75 g of glucose. AUC(C-pep) and area under the curve of glucose [AUC(Glu)] were computed using the trapezoidal rule.13 The homeostasis model assessment of insulin resistance index (HOMA-IR) was calculated based on fasting glucose and C-peptide, based on the following formula: HOMA-IR = fasting plasma glucose (mmol/L) · fasting serum C-peptide (ng/mL)/22.5. Diabetic nephropathy was established by the presence of a urine albumin excretion rate (AER) of >30 mg/24 h in at least two out of three urine collections. The results were defined as nonalbuminuria with AER of 300 mg/ 24 h. Patients with an estimated glomerular filtration rate of £60 mL/min/1.73 m2, which was estimated by the Modification of Diet in Renal Disease equation recalibrated for Chinese people,14 and those taking drugs that may have an impact on urine AER were excluded from our study. Diagnosis of diabetic retinopathy was performed through fundoscopic examination by certified photographers experienced in diabetic retinopathy. The results were graded as no apparent retinopathy, nonproliferative diabetic retinopathy (mild, moderate, and severe), and proliferative diabetic retinopathy according to the new diabetic retinopathy disease
ZHAO ET AL.
severity scale.15 Diabetic neuropathy was confirmed by the presence of an abnormal objective quantitative test (nerve conduction velocity or current perception threshold test) and symptom (e.g., numbness, prickling or stabbing, and burning or aching pain) or sign (pressure sensation with the 10-g monofilament, needle pain sensation, vibration, and ankle reflexes) of neuropathy. Nonalcoholic fatty liver disease (NAFLD) was diagnosed based on clinical information and ultrasonography performed by an experienced radiologist, excluding alcoholic fatty liver disease and viral hepatitis. Statistical analyses
The patients were analyzed according to the AUC(C-pep) tertiles. SPSS version 19.0 software (SPSS Inc., Chicago, IL) was used for statistical analysis. The characteristics of the patients were described using mean and SD values for continuous variables or percentage frequencies for categorical variables. The one-way analysis of variance method, v2 test, and Kruskal–Wallis test were used according to the type of variables. Spearman’s correlation coefficient r was used to measure the correlation between AUC(C-pep) and fasting C-peptide (FCP) or 2-h C-peptide (2-h CP) concentrations. Odds ratios were estimated using logistic regression to evaluate the association between C-peptide tertiles and microvascular complications after adjusting for other confounding factors such as age, duration of DM, and degree of glycemic control (HbA1c). A P value of
Diabetes Technology & Therapeutics 2015.17:29-34. Downloaded from online.liebertpub.com by KUNGLIGA TEKNISKA HOGSKOLAN on 08/13/15. For personal use only.
ORIGINAL ARTICLE
Relationship Between b-Cell Function, Metabolic Control, and Microvascular Complications in Type 2 Diabetes Mellitus Lihua Zhao, MD, Jing Ma, MD, Shaoxin Wang, MD, and Yun Xie, MD
Abstract
Background: This study investigated the relationship among b-cell function, metabolic control, and diabetic microvascular complications in patients with type 2 diabetes mellitus (T2DM). Subjects and Methods: In total, 885 patients with type 2 diabetes mellitus (DM) were recruited from January 2012 to January 2014 and grouped into three groups according to the area under the curve of C-peptide [AUC(C-pep)] during the 75-g oral glucose tolerance test. Logistic regression analyses were used to evaluate the association between C-peptide and microvascular complications. Results: The prevalence of diabetic microvascular complications decreased from the first to the third AUC(Cpep) tertile (P < 0.01 for all), whereas the rates of nonalcoholic fatty liver disease (NAFLD) was positively associated with AUC(C-pep) values. Patients with lower AUC(C-pep) tertile exhibited higher levels of glycosylated hemoglobin and high-density lipoprotein cholesterol and longer duration of DM; however, levels of triglycerides, fasting C-peptide, 2-h C-peptide, body mass index, and homeostasis model assessment of insulin resistance index were lower compared with the third tertile. Comparison among patients with a similar DM duration showed a higher level of AUC(C-pep) was inversely associated with prevalence of microvascular complications. The odds ratios for nephropathy, retinopathy, and neuropathy in the lowest versus the highest AUC(C-pep) tertile were 3.10 (95% confidence interval, 2.01–4.78), 2.83 (1.73–4.64), and 2.04 (1.37–3.04) after adjustment for confounding factors. Conclusions: Higher AUC(C-pep) levels were associated with a decreased prevalence of microvascular complications and a good level of glycemic control, whereas higher endogenous insulin levels were linked to the components of metabolic syndrome and increased rates of NAFLD. more than an inactive by-product of insulin synthesis. More recently, accumulating evidence indicated C-peptide was a hormonally active peptide itself. It has been found to exert beneficial effects on the vascular dysfunction of T1DM, especially on microvascular disease.2–4 It was assigned a multitude of physiological actions affecting renal, retinal, neural, and circulatory functions. In contrast to these studies in T1DM, data on the relationship between C-peptide and type 2 diabetes mellitus (T2DM) were controversial. Some studies5–9 showed that C-peptide had a positive influence on chronic vascular complications in patients with T2DM, whereas others did not.10,11 Previous studies used fasting or postprandial C-peptide levels as a surrogate of b-cell function. However, the relationship between the area under the curve of C-peptide [AUC(C-pep)], which is the gold standard measure of b-cell
Introduction
H
yperglycemia as an important causal factor for the initiation and progression of diabetic angiopathy has been generally accepted. The Diabetes Control and Complications Trial established the importance of glycemic control to ameliorate diabetes-related complications of type 1 diabetes mellitus (T1DM).1 However, patients with tight glycemic control faced a higher incidence of hypoglycemia, and the end-organ diabetes complications still remained. A previous study2 implicated that preserving b-cell function led to improved glycemic control and diabetic vascular disease. The C-peptide level is a robust measure of b-cell function as it is secreted in equimolar amounts with insulin from b-cells of the pancreas and exempted from first-pass metabolism by the liver. Previously, C-peptide was considered to be little
Department of Diabetic Neurology, Hospital of Metabolic Disease, Tianjin Medical University, Tianjin, China.
29
30
Diabetes Technology & Therapeutics 2015.17:29-34. Downloaded from online.liebertpub.com by KUNGLIGA TEKNISKA HOGSKOLAN on 08/13/15. For personal use only.
function,12 and diabetic microvascular complications was not well evaluated. In this study performed in T2DM, b-cell function was assessed using calculated AUC(C-pep) during near-normal life condition, the 75-g oral glucose tolerance test (OGTT). The aims of this retrospective study were to evaluate relationship among serum C-peptide levels, microvascular complications, and metabolic control in T2DM. Study Design and Methods Subjects
The study enrolled 885 consecutive patients with T2DM from January 2012 to January 2014. Data for these patients (508 males [57.4%], 377 females [42.6%]) were analyzed cross-sectionally. Diagnosis of T2DM was based on 1999 World Health Organization criteria, clinical manifestation, diabetic autoimmune antibody, and islet b-cell function. Patients diagnosed with acute complications of diabetes, renal impairment, uncontrolled hypertension, chronic infection, and malignancy were excluded. Ethics statement
All the patients signed the consent form for allowing their information for research. The study was approved by the ethics committee of the Hospital of Metabolic Disease, Tianjin Medical University. Measurements
Anthropometric measurements at admission were collected, including gender, age, height, weight, duration of diabetes mellitus (DM), and associated comorbidities. Venous blood was collected in the fasting state for laboratory analysis. Biochemical measurements included fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, lowdensity lipoprotein cholesterol, triglycerides (TG), glycosylated hemoglobin (HbA1c), creatinine (CR), and 24-h urine albumin excretion. Glucose and C-peptide concentrations were measured at 0, 30, 60, and 120 min after oral administration of 75 g of glucose. AUC(C-pep) and area under the curve of glucose [AUC(Glu)] were computed using the trapezoidal rule.13 The homeostasis model assessment of insulin resistance index (HOMA-IR) was calculated based on fasting glucose and C-peptide, based on the following formula: HOMA-IR = fasting plasma glucose (mmol/L) · fasting serum C-peptide (ng/mL)/22.5. Diabetic nephropathy was established by the presence of a urine albumin excretion rate (AER) of >30 mg/24 h in at least two out of three urine collections. The results were defined as nonalbuminuria with AER of 300 mg/ 24 h. Patients with an estimated glomerular filtration rate of £60 mL/min/1.73 m2, which was estimated by the Modification of Diet in Renal Disease equation recalibrated for Chinese people,14 and those taking drugs that may have an impact on urine AER were excluded from our study. Diagnosis of diabetic retinopathy was performed through fundoscopic examination by certified photographers experienced in diabetic retinopathy. The results were graded as no apparent retinopathy, nonproliferative diabetic retinopathy (mild, moderate, and severe), and proliferative diabetic retinopathy according to the new diabetic retinopathy disease
ZHAO ET AL.
severity scale.15 Diabetic neuropathy was confirmed by the presence of an abnormal objective quantitative test (nerve conduction velocity or current perception threshold test) and symptom (e.g., numbness, prickling or stabbing, and burning or aching pain) or sign (pressure sensation with the 10-g monofilament, needle pain sensation, vibration, and ankle reflexes) of neuropathy. Nonalcoholic fatty liver disease (NAFLD) was diagnosed based on clinical information and ultrasonography performed by an experienced radiologist, excluding alcoholic fatty liver disease and viral hepatitis. Statistical analyses
The patients were analyzed according to the AUC(C-pep) tertiles. SPSS version 19.0 software (SPSS Inc., Chicago, IL) was used for statistical analysis. The characteristics of the patients were described using mean and SD values for continuous variables or percentage frequencies for categorical variables. The one-way analysis of variance method, v2 test, and Kruskal–Wallis test were used according to the type of variables. Spearman’s correlation coefficient r was used to measure the correlation between AUC(C-pep) and fasting C-peptide (FCP) or 2-h C-peptide (2-h CP) concentrations. Odds ratios were estimated using logistic regression to evaluate the association between C-peptide tertiles and microvascular complications after adjusting for other confounding factors such as age, duration of DM, and degree of glycemic control (HbA1c). A P value of
