Longitudinal study investigating serum metabolites and their association with type 2 diabetes risk in a Korean population

Aim

The lack of longitudinal metabolomics data and the statistical techniques to analyse them has limited the understanding of the metabolite levels related to type 2 diabetes (T2D) onset. Thus, we carried out logistic regression analysis and simultaneously proposed new approaches based on residuals of multiple logistic regression and geometric angle-based clustering for the analysis in T2D onset-specific metabolic changes.

Materials and methods

We used the sixth, seventh and eighth follow-up data from 2013, 2015 and 2017 among the Korea Association REsource (KARE) cohort data. Semi-targeted metabolite analysis was performed using ultraperformance liquid chromatography/triple quadrupole-mass spectrometry systems.

Results

As the results from the multiple logistic regression and a single metabolite in a logistic regression analysis varied dramatically, we recommend using models that consider potential multicollinearity among metabolites. The residual-based approach particularly identified neurotransmitters or related precursors as T2D onset-specific metabolites. By using geometric angle-based pattern clustering studies, ketone bodies and carnitines are observed as disease-onset specific metabolites and separated from others.

Conclusion

To treat patients with early-stage insulin resistance and dyslipidaemia when metabolic disorders are still reversible, our findings may contribute to a greater understanding of how metabolomics could be used in disease intervention strategies during the early stages of T2D.     

Association of polymorphisms in the insulin-degrading enzyme gene with type 2 diabetes in the Korean population

Insulin-degrading enzyme (IDE) is a metalloproteinase which degrades insulin and terminates its action. Homologous deletion of IDE gene resulted in hyperinsulinemia and glucose intolerance in a rat model of type 2 diabetes mellitus. Several genetic association studies examined IDE as a susceptibility gene for type 2 diabetes in European descents. Here we investigated the genetic association of IDE polymorphisms with the risk of type 2 diabetes and its related phenotypes in the Korean population. Among six single nucleotide polymorphisms analyzed, g.-179T>C (OR=1.73, P=0.04), and g.IVS18+99G>A (OR=1.23, P=0.02) revealed borderline association with increased risk of type 2 diabetes. Combining our results with previous data obtained from the European population, g.-179T>C (OR=1.11, P=0.03), and g.IVS24-64A>T (OR=1.18, P=0.005) showed significant association with type 2 diabetes. Haplotype consisting of common alleles of the six polymorphisms was associated with decreased risk of type 2 diabetes (OR=0.82, P=0.02). However, none of the polymorphisms was significantly associated with metabolic phenotypes. We can conclude that variations in IDE might contribute to diabetes susceptibility in the Korean population.     

Is there an excess in maternal transmission of NIDDM?

Summary Family studies have demonstrated that there is a strong genetic component to the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), although the mode of inheritance is unknown. A number of recent family history studies, including one in Mexican Americans, have suggested that there is an excess of maternal transmission of NIDDM. Family history studies are subject to various types of bias, however, and the potential for bias in many of these studies has not been thoroughly evaluated. We therefore tested the hypothesis that diabetes is more likely to be transmitted from mothers than from fathers using data collected from a large family study of low-income Mexican Americans in San Antonio, Texas. The parents and offspring from 318 different nuclear families attended our medical clinic, where they received a 2-h oral glucose test. Diabetes was diagnosed on the basis of World Health Organization criteria. The sibships were classified into diabetic sibships (at least one sibling in the sibship was diabetic; n=54) and non-diabetic siblings (no diabetic siblings; n=264). The prevalence of diabetes among mothers of diabetic siblings was 61.4% (27 of 44) compared to 64.3% (18 of 28) among fathers of diabetic siblings (rate ratio=0.95; 95% confidence interval: 0.51–1.84). For the non-diabetic sibships, the prevalence of diabetes was 31.7% (78 of 246) and 28.9% (37 of 128) among mothers and fathers, respectively (rate ratio=1.09; 95% confidence interval: 0.73–1.67). These data provide no evidence for an excess maternal transmission of diabetes in Mexican Americans.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - OGTT glucose tolerance test - IDDM insulin-dependent diabetes     

Leanness and type 2 diabetes in a population of indigenous Australians

OBJECTIVE: To determine the prevalence of type 2 diabetes and its risk factors in a population of indigenous Australians. RESEARCH DESIGN AND METHODS: A cross-sectional study of 332 indigenous community residents aged 15 years and over with fasting blood samples and anthropometric measurements. RESULTS: Almost half of the study population (47.3%) was extremely lean (BMI<22 kg/m(2)). Leanness was particularly pronounced in the youngest age group (15<20 years), 78% of which had a BMI<22 kg/m(2). The prevalence of diabetes was 12%. It was highest in those 45-54 years and declined in older aged people. No cases of diabetes were detected in those aged less than 30 years. Diabetes prevalence was strongly linked to BMI and age (age-adjusted odds ratio=24.1, 95% CI 6.0-96.5, p<0.001) for BMI>or=25 kg/m(2) versus BMI<22 kg/m(2). Those with the lowest diabetes risk profile are lean (BMI<22 kg/m(2)) and/or young (age 15-34 years). CONCLUSIONS: These results highlight that strategies to prevent or delay the onset of diabetes should focus on the maintenance of leanness from adolescence and throughout adult life whilst young people are still in the process of forming lifelong habits.     

Rates of glycaemic deterioration in a real-world population with type 2 diabetes

Aims/hypothesis

There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on ‘time to failure’ methods, yet determining a ‘coefficient of failure’ has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration.

Methods

An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual’s observed HbA_1c measures from the first eligible HbA_1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA_1c measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution.

Results

The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA_1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA_1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA_1c per year.

Conclusions/interpretation

We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.

     

Microalbuminuria is associated with the insulin resistance syndrome independent of hypertension and type 2 diabetes in the Korean population

To investigate whether microalbuminuria is associated with the insulin resistance syndrome independent of hypertension and type 2 diabetes, we studied the association between microalbuminuria and features of insulin resistance syndrome in Korean general population. We selected 1006 subjects by a random cluster sampling among residents aged >40 years living in the Chung-Up district, a rural area of South Korea. Subjects were stratified by oral glucose tolerance status [normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus], and by the presence or absence of hypertension. Urinary albumin excretion rate (UAER) was determined using timed overnight urine collection. Various cardiovascular risk factors including anthropometric indices, serum lipid, true insulin and proinsulin concentrations were also measured. The prevalence of microalbuminuria (UAER between 20 and 200 microg/min) increased as the glucose tolerance worsened (6.0% in NGT, 11.8% in IGT, and 21.8% in diabetes; chi(2) trend=25.9, P<0.001). Subjects with microalbuminuria had a higher body mass index (BMI), waist-to-hip circumference ratio (WHR), systolic and diastolic blood pressure (BP), fasting and 2 h plasma glucose, fasting plasma insulin and proinsulin levels, and lower HDL-cholesterol level than subjects without microalbuminuria. In multiple regression analysis, BMI, diastolic BP, 2 h plasma glucose, and fasting plasma insulin levels were found to be independent factors associated with UAER. Multiple logistic regression analysis showed that not only diabetes mellitus and hypertension, but also fasting hyperinsulinemia and waist-to-hip ratio were independent factors associated with the presence of microalbuminuria. When the normotensive, non-diabetic subjects were analyzed separately, fasting hyperinsulinemia and impaired glucose tolerance remained independent variables associated with the presence of microalbuminuria. These results show that microalbuminuria in the Korean general population is associated with hyperinsulinemia and central obesity, and suggest that microalbuminuria is a feature of the insulin resistance syndrome independent of hypertension or type 2 diabetes.     

Lack of postprandial leptin peaks in patients with type 2 diabetes mellitus

Leptin production by the adipocyte is acutely stimulated by insulin in vitro. In normal individuals, postprandial insulin peaks are not accompanied by corresponding changes in circulating leptin. Postprandial regulation of leptin in individuals with type 2 diabetes, to our knowledge, has not been previously examined in detail. We examined the effect of meals on circulating leptin levels in six patients with type 2 diabetes who were not treated with insulin and in seven normal individuals. After informed consent was obtained, all subjects were admitted to the General Clinical Research Center for 6 days. They consumed four meals daily (breakfast, lunch, dinner and snack). Eighteen blood samples were drawn between 7.40 a.m. and midnight for the determination of serum leptin, insulin and glucose levels. Postprandial peaks were clearly identifiable for glucose and insulin levels both in normal subjects and in those with type 2 diabetes. However, no postprandial peaks of leptin levels were present. Correlation analysis demonstrated a lack of correlation between leptin levels and the levels of glucose or insulin. We conclude that, in spite of the presence of postprandial insulin peaks, there are no acute changes in circulating leptin levels postprandially in patients with type 2 diabetes who are not on insulin therapy. In this regard, in-vivo regulation of leptin by meals in patients with type 2 diabetes is similar to that in normal individuals.     

Impact of late complications in type 2 diabetes in a Dutch population.

The prevalence of late complications was determined in four general practices in a representative group of 137 patients with Type 2 diabetes and a control group of 128 non-diabetic individuals. Retinopathy was found in 35% of all diabetic patients, with the same prevalence below and above the age of 70 years. Microalbuminuria was found in 42% of diabetic patients and in 22% of the control group (p less than 0.001). Above 70 years of age microalbuminuria was found with increasing frequency in the control group and was not significantly higher in the diabetes group. Serum creatinine was the same in the diabetic patients and the control group. Peripheral neuropathy was found frequently in the diabetes group, but was not uncommon in the control group (abnormal temperature sensation 63 vs 49% (p less than 0.05), abnormal vibration perception 53 vs 33% (p less than 0.001), absent tendon reflex 62 vs 21% (p less than 0.001]. Above age 70 years there was again a reduction in the difference in prevalence of neuropathy between the diabetes and control groups. Ischaemic heart disease was found more frequently in the diabetes group, but only below 70 years of age (32% of diabetic patients and 14% of the control group with ischaemic changes on ECG (p less than 0.01]. Above that age 46% of the diabetes group and 45% of the control group had ECG signs of ischaemic heart disease.     

Excess maternal transmission and familial aggregation of Type 2 diabetes in Sri Lanka

INTRODUCTION: An excess of maternal transmission of Type 2 diabetes mellitus has been reported in Europid populations, but not in South India. METHOD: A questionnaire-based survey was carried out in 1000 (502 male) people with Type 2 diabetes to establish whether there is an excess of maternal transmission and familial aggregation in a Sri Lankan population. RESULTS: Mean age of onset was 47+/-12 (+/-S.D.) years and duration of diabetes was 9+/-7 years. Thirty-seven percent reported parents with diabetes, 46.9% had no parents with diabetes, 16.1% did not know the diabetes status of at least one parent and there was no diabetes in the other. Of the probands, 59.4% had at least one affected relative. When both parents' diabetes status was known and only one was affected, diabetes was more common among mothers (n = 156) than fathers (n = 125) of probands (P < 0.001). A further 54 probands had both parents with diabetes. Mean age of onset and duration of the disease among probands with parental diabetes was 43.1+/-(11.1) and 9.6+/-(6.8). In the previous generation, 21.2% of maternal grandmothers and 17.3% of maternal grandfathers in the maternal diabetes group and 4.8% of maternal grandmothers and 17% of maternal grandfathers in the paternal diabetes group had diabetes. Diabetes in siblings and children was more common in those with mothers who had diabetes (53.8% and 4.5%) when compared with those in whom fathers had diabetes (42.4% and 1.6%) (P < 0.0001 and P < 0.01). CONCLUSION: Familial aggregation and excess maternal transmission were observed in people with Type 2 diabetes in Sri Lanka.     

Variants of the adiponectin gene and type 2 diabetes in a Polish population

Several association studies of type 2 diabetes mellitus (T2DM) and adiponectin gene polymorphisms have been reported with conflicting results. Our aim was to search for the association of three polymorphisms (−11.391G>A, +45T>G, and +276G>T) in the adiponectin gene with T2DM and prediabetic quantitative traits in Polish Caucasians. The study groups comprised 495 unrelated T2DM cases and 435 controls. We compared the distribution of genotypes between study groups. In addition, genotype-quantitative trait analyses were also done in the controls. The study subjects were genotyped using the restriction fragment length polymorphism technique. The frequencies of the minor alleles were as follows: 10.6 versus 8.2% for −11.391G>A (p = 0.0722), 7.0 versus 8.0% for +45T>G (p = 0.48), and 15.5% in T2DM versus 19.8% in controls (p = 0.0145) for +276G>T, respectively. The difference for genotype distribution between the groups was statistically significant (p = 0.0247) for the +276G>T variant: 71.31 versus 62.99%, 26.46 versus 34.48% and 2.22 versus 2.53%, respectively, for GG, GT and TT. In quantitative traits analysis, the T allele of +276G>T was associated (p < 0.05) with lower insulin resistance (HOMA-IR, fasting insulin) among controls. Additionally, the A allele at position −11.391 was associated (p < 0.05) with higher insulin resistance (HOMA-IR, fasting insulin). In multiple regression analysis, all identified association remained significant after the inclusion in the model of gender, BMI and age. In addition, in this model, −11.391G>A and +276G>T were independently associated with T2DM. Finally, we conclude that the adiponectin gene polymorphisms are associated with T2DM and prediabetic quantitative traits in Polish Caucasians.     

Pathophysiologic heterogeneity in the development of type 2 diabetes mellitus in Korean subjects

OBJECTIVE: To investigate the clinical characteristics and predisposing metabolic abnormalities in the development of glucose intolerance and diabetes mellitus in obese and non-obese Korean subjects. METHODS: Four hundred Korean subjects were classified into five groups according to degree of glucose tolerance by OGTT: NGT, IGT alone, IFG alone, IFG+IGT, and DM. The groups were also subdivided into obese and non-obese group according to body mass index. Insulin resistance was assessed by using homeostasis model assessment of insulin resistance (HOMA-R), and insulinogenic index was used as an index of early-phase insulin secretion. RESULTS: Impaired early-phase insulin secretion was seen in non-obese IGT alone, IFG alone, and IFG+IGT, though more profound secretory defects were noted in IFG+IGT and DM. No significant difference were found in HOMA-R among non-obese IGT alone, IFG alone, or IFG+IGT, or in terms of early-phase insulin secretion in obese IGT alone, IFG alone, or IFG+IGT. However, the magnitude of insulin resistance differed in the obese group, IFG+IGT and DM being more insulin resistant than IGT alone or IFG alone. CONCLUSIONS: These results suggest that the predisposing metabolic abnormality in non-obese subjects with IGT alone or IFG alone and in progression to IFG+IGT might be deterioration of early phase insulin secretion, whereas insulin resistance might be the major contributory factor in obese subjects. The predisposing metabolic abnormality leading to diabetes in both obese and non-obese groups was deterioration of early-phase insulin secretion.     

Anthropometric parameters and type 2 diabetes: a case-control study in a Guadeloupean population

OBJECTIVE: The aim of this study was to quantify the association between three anthropometric parameters and type 2 diabetes in an adult population in Guadeloupe and to evaluate the effect of age on these associations. DESIGNS AND METHODS: We conducted a case-control study in a population recruited in an Health Center of Guadeloupe in Year 2000. A total of 309 subjects with documented type 2 diabetes were matched on sex and age (+/- 2 Years) with controls free of any glycemic abnormality. Student t-test was used and conditional logistic regressions were performed separately for men and women to quantify the association between type 2 diabetes and the explanatory variables, body mass index (BMI), waist to hip ratio (WHR) and waist circumference (WC). RESULTS: Mean (SD) WC was 89.0 cm (0.9) in non diabetics men and 97.3 cm (1.1) in diabetics ones, p<10-4. In women, it was 87.7 (0.8) cm for non diabetics and 96.3 cm (0.9) for diabetics. This difference was persistent for any tertile of age in each sex. It was discordant for BMI and WHR at higher tertile for men and women. In the multivariate analysis, Odds ratio[CI95%] for WC was 9.67 [2.32-40.20] in men and 2.97 [1.70-5.19] in women. It was 2.94 [0.99-8.74] in men and 6.15 [3.11-12.17] in women for WHR. Results for BMI were non significant in both sex. CONCLUSION: Differences between WC and WHR over age groups and sex in predicting type 2 diabetes should be taken into account when using these parameters routinely in medical practice.     

Breast-feeding and maternal risk of type 2 diabetes: a prospective study and meta-analysis

Aims/hypothesis

We aimed to examine the association between breast-feeding and maternal risk of type 2 diabetes and to investigate whether this association is mediated by anthropometric and biochemical factors.

Methods

A case–cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study between 1994 and 2005 including 1,262 childbearing women (1,059 in a random sub-cohort and 203 incident cases) mainly aged between 35 and 64 years at baseline was applied. Self-reported lifetime duration of breast-feeding was assessed by questionnaire. Blood samples were used for biomarker measurement (HDL-cholesterol, triacylglycerols, C-reactive protein, fetuin-A, γ-glutamyltransferase, adiponectin). A systematic literature search and meta-analysis was conducted of prospective cohort studies investigating breast-feeding and risk of type 2 diabetes.

Results

The HR for each additional 6 months of breast-feeding was 0.73 (95% CI 0.56, 0.94) in EPIC-Potsdam. Meta-analysis of three previous prospective studies and the current study revealed an inverse association between breast-feeding duration and risk of diabetes (pooled HR for lifetime breast-feeding duration of 6–11 months compared with no breast-feeding 0.89; 95% CI 0.82, 0.97). Adjustment for BMI and waist circumference attenuated the association (HR per six additional months in EPIC-Potsdam 0.80; 95% CI 0.61, 1.04). Further controlling for potentially mediating biomarkers largely explained this association (HR 0.89; 95% CI 0.68, 1.16).

Conclusions/interpretation

Longer duration of breast-feeding may be related to a lower risk of diabetes. This potentially protective effect seems to be reflected by a more favourable metabolic profile; however, the role of body weight as a mediator or confounder remains uncertain.