Diabetes in Cystic Fibrosis: Multicenter Screening Results Based on Current Guidelines

Background

Published estimates on age-dependent frequency of diabetes in cystic fibrosis (CF) vary widely, and are based mostly on older data. However, CF treatment and prevention of comorbidities changed over recent years. In many studies, definition of cystic fibrosis-related diabetes (CFRD) is not in line with current guideline recommendations. Therefore, we evaluated age-dependent occurrence of glucose abnormalities and associated risk factors in CF patients who participated in a multicenter screening program using oral glucose tolerance tests (OGTT).

Methods

Between 2001 and 2010, 43 specialized CF centers from Germany and Austria serially performed 5,179 standardized OGTTs in 1,658 clinically stable, non-pregnant CF patients with no prior steroid medication or lung transplantation. Age-dependent occurrence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, one (DGT) or two consecutive (CFRD) diabetic OGTTs was analyzed, using Kaplan Meier curves. Cox proportional-hazards models were created to elucidate the influence of sex or underweight.

Results

At baseline/last OGTT, median age was 15.9 years/18.2 years and 30.6%/31.8% of patients were underweight. 25% of patients showed IFG at age 14.3 years; IGT at age 16.3 years; IFG+IGT combined at age 17.7 years. DGT was observed in 25% of patients at age 22.6 years; CFRD at age 34.5 years. Females had a 3.54 [95% CI 1.23–10.18] times higher risk for CFRD; risk for DGT was 2.21 [1.22–3.98] times higher. Underweight was a risk factor for IGT (HR [95% CI]: 1.38 [1.11–1.71]) and IFG+IGT (1.43 [1.11–1.83]), and in males also for DGT (1.49 [1.09–2.04]).

Conclusions/Significance

If confirmation of diabetes by a second test is required, as recommended in current guidelines, age at CFRD diagnosis was higher compared to most previous studies. However, known risk factors for glucose abnormalities in CF were confirmed. Confirmation of diabetic OGT by a repeat test is important for a consistent diagnosis of CFRD.     

Glucose Intolerance and the Amount of Visceral Adipose Tissue Contribute to an Increase in Circulating Triglyceride Concentrations in Caucasian Obese Females

Context

Lipotoxicity is a risk factor for developing obesity-related metabolic complications, including non-alcoholic fatty liver disease, type 2 diabetes (DM2), cardiovascular disease and stroke. Yet, the mechanisms underlying the development of lipotoxicity itself remain poorly understood. Here, we investigated whether glucose intolerance aggravates lipotoxicity by evaluating the association between triglyceride (TG) concentrations and glucose tolerance status in a cross-sectional study on obese Caucasian women at risk for DM2.

Methods

913 obese females unknown to have diabetes were recruited (mean age: 41.2±SD 12.3; median BMI: 36.2, IQR 32.9–40.2). Visceral (VAT) and subcutaneous abdominal adipose tissue volumes were quantified with computed tomography. Glucose, insulin, and triglyceride concentrations were determined in fasting state and following a 75 gram oral glucose tolerance test.

Results

Based on fasting and 2 h post-load glucose levels, 27% of the women had impaired glucose tolerance (IGT), and 8% had newly diagnosed DM2. Fasting TG concentrations were similar between the IGT- and DM2-groups, and increased as compared to women with normal glucose tolerance (NGT). Even when adjusting for age, hip circumference and VAT, fasting TG concentrations remained elevated as compared to NGT. Mixed modelling analysis of post-load responses showed that TG concentrations declined more slowly in the DM2-group as compared to IGT and NGT. However, when adjusting for VAT the difference in decline between the glucose tolerance groups disappeared.

Conclusions

Glucose intolerance associates with elevated fasting TG concentrations in obese Caucasian women. We propose that glucose intolerance and increased VAT reduce lipid disposal mechanisms and may accelerate lipotoxicity.     

On the Status and Comparison of Glucose Intolerance in Female Breast Cancer Patients at Initial Diagnosis and during Chemotherapy through an Oral Glucose Tolerance Test

Aims

This study is to estimate the status and comparison of glucose intolerance in female breast cancer patients at initial diagnosis and during chemotherapy through an oral glucose tolerance test (OGTT), as well as to learn the effect of chemotherapy on the glucose metabolism of breast cancer patients.

Methods

All the 79 breast cancer patients at initial diagnosis, with the mean age of 53.2 years, and 96 breast cancer patients before the 5th or 6th cycle of chemotherapy, with the mean age of 51.5 years, participated in the study from December 2012 to October 2013. After an overnight fast, participants underwent OGTT test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance) in them. Previously diagnosed diabetes among the female breast cancer patients was determined on the self-report and the medical record.

Results

The overall incidences of total normal glucose tolerance, prediabetes, diabetes in female breast cancer patients at initial diagnosis and during chemotherapy were 24.1% and 38.5% (p<0.05), 50.6% and 28.1% (p<0.05), and 25.3% and 33.3% (p>0.05), respectively, and the differences of normal glucose tolerance and prediabetes instead of diabetes between the two groups were statistically significant. About 84% of the total diabetes and prediabetes in the female breast cancer patients at initial diagnosis and 79.7% of those during chemotherapy need to be diagnosed with OGTT.

Conclusions

Breast cancer patients have high incidences of diabetes and prediabetes. After chemotherapy even with steroids, some breast cancer patients with abnormal glucose metabolism may even become normal. Isolated hyperglycemia 2 hours after glucose loading is common, and OGTT should be made for breast cancer patients at initial diagnosis and during chemotherapy.     

Age at menarche and its association with the metabolic syndrome and its components: results from the KORA F4 study

Objective

The metabolic syndrome is a major public health challenge and identifies persons at risk for diabetes and cardiovascular disease. The aim of this study was to examine the association between age at menarche and the metabolic syndrome (IDF and NCEP ATP III classification) and its components.

Design

1536 women aged 32 to 81 years of the German population based KORA F4 study were investigated. Data was collected by standardized interviews, physical examinations, and whole blood and serum measurements.

Results

Young age at menarche was significantly associated with elevated body mass index (BMI), greater waist circumference, higher fasting glucose levels, and 2 hour glucose (oral glucose tolerance test), even after adjusting for the difference between current BMI and BMI at age 25. The significant effect on elevated triglycerides and systolic blood pressure was attenuated after adjustment for the BMI change. Age at menarche was inversely associated with the metabolic syndrome adjusting for age (p-values: <0.001 IDF, 0.003 NCEP classification) and additional potential confounders including lifestyle and reproductive history factors (p-values: 0.001, 0.005). Associations remain significant when additionally controlling for recollected BMI at age 25 (p-values: 0.008, 0.033) or the BMI change since age 25 (p-values: 0.005, 0.022).

Conclusion

Young age at menarche might play a role in the development of the metabolic syndrome. This association is only partially mediated by weight gain and increased BMI. A history of early menarche may help to identify women at risk for the metabolic syndrome.     

Insulin Dynamics in Young Women with Polycystic Ovary Syndrome and Normal Glucose Tolerance across Categories of Body Mass Index

Background

Evidence favours insulin resistance and compensatory hyperinsulinemia as the predominant, perhaps primary, defects in polycystic ovary syndrome (PCOS). The aim of the present study was to evaluate insulin metabolism in young women with PCOS but normal glucose tolerance as compared with age, body mass index and insulin resistance-matched controls to answer the question whether women with PCOS hypersecrete insulin in comparison to appropriately insulin resistance-matched controls.

Research Design and Methods

Sixty-nine cases were divided according to their body mass index (BMI) in normal-weight (N = 29), overweight (N = 24) and obese patients (N = 16). Controls were 479 healthy women (age 16–49 y). Whole body Insulin Sensitivity (WBISI), fasting, and total insulin secretion were estimated following an oral glucose tolerance test (C-peptide deconvolution method).

Results

Across classes of BMI, PCOS patients had greater insulin resistance than matched controls (p<0.0001 for all the comparisons), but they showed higher fasting and total insulin secretion than their age, BMI and insulin resistance-matched peers (p<0.0001 for all the comparisons).

Conclusion

Women with PCOS show higher insulin resistance but also larger insulin secretion to maintain normal glucose homeostasis than age-, BMI- and insulin resistance-matched controls.     

Fasting Plasma Glucose as Initial Screening for Diabetes and Prediabetes in Irish Adults: The Diabetes Mellitus and Vascular Health Initiative (DMVhi)

Objective

Type 2 diabetes has a long pre clinical asymptomatic phase. Early detection may delay or arrest disease progression. The Diabetes Mellitus and Vascular health initiative (DMVhi) was initiated as a prospective longitudinal cohort study on the prevalence of undiagnosed Type 2 diabetes and prediabetes, diabetes risk and cardiovascular risk in a cohort of Irish adults aged 45-75 years.

Research Design and Methods

Members of the largest Irish private health insurance provider aged 45 to 75 years were invited to participate in the study. Exclusion criteria: already diagnosed with diabetes or taking oral hypoglycaemic agents. Participants completed a detailed medical questionnaire, had weight, height, waist and hip circumference and blood pressure measured. Fasting blood samples were taken for fasting plasma glucose (FPG). Those with FPG in the impaired fasting glucose (IFG) range had a 75gm oral glucose tolerance test performed.

Results

122,531 subjects were invited to participate. 29,144 (24%) completed the study. The prevalence of undiagnosed diabetes was 1.8%, of impaired fasting glucose (IFG) was 7.1% and of impaired glucose tolerance (IGT) was 2.9%. Dysglycaemia increased among those aged 45-54, 55-64 and 65-75 years in both males (10.6%, 18.5%, 21.7% respectively) and females (4.3%, 8.6%, 10.9% respectively). Undiagnosed T2D, IFG and IGT were all associated with gender, age, blood pressure, BMI, abdominal obesity, family history of diabetes and triglyceride levels. Using FPG as initial screening may underestimate the prevalence of T2D in the study population.

Conclusions

This study is the largest screening study for diabetes and prediabetes in the Irish population. Follow up of this cohort will provide data on progression to diabetes and on cardiovascular outcomes.     

The “hypertriglyceridemic waist” phenotype and glucose intolerance in pregnancy

Background

Abdominal visceral adiposity in early pregnancy has been associated with impaired glucose tolerance in later pregnancy. The “hypertriglyceridemic waist” phenotype (i.e., abdominal obesity in combination with hyper-triglyceridemia) is a clinical marker of visceral obesity. Our study aimed to assess the association between the hyper-triglyceridemic-waist phenotype in early pregnancy and glucose intolerance in later pregnancy.

Methods

Plasma triglycerides and waist girth were measured at 11–14 weeks of gestation among 144 white pregnant women. Glycemia was measured following a 75-g oral glucose tolerance test performed at 24–28 weeks of gestation.

Results

A waist girth greater than 85 cm in combination with a triglyceride level ≥ 1.7 mmol/L in the first trimester was associated with an increased risk of two-hour glucose ≥ 7.8 mmol/L following the 75-g oral glucose tolerance test (odds ratio [OR] 6.1, p = 0.002). This risk remained significant even after we controlled for maternal age, fasting glucose at first trimester and previous history of gestational diabetes (OR 4.7, p = 0.02).

Interpretation

Measurement of waist girth in combination with measurement of triglyceride concentrations in the first trimester of pregnancy could improve early screening for gestational glucose intolerance.Early and accessible screening tools for gestational diabetes mellitus are needed to improve pregnancy-related outcomes for women and children.¹ Diagnostic tools currently used for gestational diabetes (most commonly the fasting oral glucose tolerance test) are expensive, time-consuming, uncomfortable for pregnant women and do not allow diagnosis before the end of the second trimester of pregnancy.² Some earlier screening tools have been suggested, such as a 50-g glucose load followed by a one-hour plasma glucose analysis that can be performed at any time of the day and early in pregnancy. Although this test is less uncomfortable than the fasting oral glucose tolerance test, it remains time-consuming and unpleasant for women. Its use is therefore restricted mainly to women at risk for gestational diabetes.Several attempts have been made to simplify these tests to promote wider use. However, no results have yet identified the means to carry out early and widely accessible screening. Interesting positive and negative predictive values have been obtained for first-trimester fasting glucose and insulin for subsequent gestational diabetes expression.^3–5 However, these studies have been performed among women at risk of gestational diabetes and should be replicated in samples of women with various risk levels. Regardless of pregnancy, a person with normal fasting glucose can still meet the criteria for glucose intolerance or diabetes during an oral glucose tolerance test. Several studies have also shown that maternal pre-pregnancy obesity is directly associated with an increased risk of gestational diabetes. However, results vary widely across studies, possibly because of lack of specificity of tools for measurement of adiposity.⁶ A recent study has suggested that abdominal visceral adiposity, specifically, is associated with risk of gestational diabetes expression.⁷The hypertriglyceridemic-waist phenotype has been identified as a simple, easily available clinical marker of visceral obesity and related metabolic abnormalities.^8,9 It is defined as the simultaneous presence of abdominal obesity (i.e., a waist girth greater than 85 cm in women or greater than 90 cm in men) and hypertriglyceridemia (i.e., a triglyceride concentration ≥ 2 mmol/L). The aim of our study was to document the association between the presence of the hypertriglyceridemic-waist phenotype in early pregnancy and impaired glucose tolerance in later pregnancy.     

Metabolic Profiling of the Response to an Oral Glucose Tolerance Test Detects Subtle Metabolic Changes

Background

The prevalence of overweight is increasing globally and has become a serious health problem. Low-grade chronic inflammation in overweight subjects is thought to play an important role in disease development. Novel tools to understand these processes are needed. Metabolic profiling is one such tool that can provide novel insights into the impact of treatments on metabolism.

Methodology

To study the metabolic changes induced by a mild anti-inflammatory drug intervention, plasma metabolic profiling was applied in overweight human volunteers with elevated levels of the inflammatory plasma marker C-reactive protein. Liquid and gas chromatography mass spectrometric methods were used to detect high and low abundant plasma metabolites both in fasted conditions and during an oral glucose tolerance test. This is based on the concept that the resilience of the system can be assessed after perturbing a homeostatic situation.

Conclusions

Metabolic changes were subtle and were only detected using metabolic profiling in combination with an oral glucose tolerance test. The repeated measurements during the oral glucose tolerance test increased statistical power, but the metabolic perturbation also revealed metabolites that respond differentially to the oral glucose tolerance test. Specifically, multiple metabolic intermediates of the glutathione synthesis pathway showed time-dependent suppression in response to the glucose challenge test. The fact that this is an insulin sensitive pathway suggests that inflammatory modulation may alter insulin signaling in overweight men.     

Inclusion of Plasma Lipid Species Improves Classification of Individuals at Risk of Type 2 Diabetes

Background

A significant proportion of individuals with diabetes or impaired glucose tolerance have fasting plasma glucose less than 6.1 mmol/L and so are not identified with fasting plasma glucose measurements. In this study, we sought to evaluate the utility of plasma lipids to improve on fasting plasma glucose and other standard risk factors for the identification of type 2 diabetes or those at increased risk (impaired glucose tolerance).

Methods and Findings

Our diabetes risk classification model was trained and cross-validated on a cohort 76 individuals with undiagnosed diabetes or impaired glucose tolerance and 170 gender and body mass index matched individuals with normal glucose tolerance, all with fasting plasma glucose less than 6.1 mmol/L. The inclusion of 21 individual plasma lipid species to triglycerides and HbA1c as predictors in the diabetes risk classification model resulted in a statistically significant gain in area under the receiver operator characteristic curve of 0.049 (p<0.001) and a net reclassification improvement of 10.5% (p<0.001). The gain in area under the curve and net reclassification improvement were subsequently validated on a separate cohort of 485 subjects.

Conclusions

Plasma lipid species can improve the performance of classification models based on standard lipid and non-lipid risk factors.     

Effects of Fortunella margarita Fruit Extract on Metabolic Disorders in High-Fat Diet-Induced Obese C57BL/6 Mice

Introduction

Obesity is a nutritional disorder associated with many health problems such as dyslipidemia, type 2 diabetes and cardiovascular diseases. In the present study, we investigated the anti-metabolic disorder effects of kumquat (Fortunella margarita Swingle) fruit extract (FME) on high-fat diet-induced C57BL/6 obese mice.

Methods

The kumquat fruit was extracted with ethanol and the main flavonoids of this extract were analyzed by HPLC. For the preventive experiment, female C57BL/6 mice were fed with a normal diet (Chow), high-fat diet (HF), and high-fat diet with 1% (w/w) extract of kumquat (HF+FME) for 8 weeks. For the therapeutic experiment, female C57BL/6 mice were fed with high-fat diet for 3 months to induce obesity. Then the obese mice were divided into two groups randomly, and fed with HF or HF+FME for another 2 weeks. Body weight and daily food intake amounts were recorded. Fasting blood glucose, glucose tolerance test, insulin tolerance test, serum and liver lipid levels were assayed and the white adipose tissues were imaged. The gene expression in mice liver and brown adipose tissues were analyzed with a quantitative PCR assay.

Results

In the preventive treatment, FME controlled the body weight gain and the size of white adipocytes, lowered the fasting blood glucose, serum total cholesterol (TC), serum low density lipoprotein cholesterol (LDL-c) levels as well as liver lipid contents in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, FME decreased the serum triglyceride (TG), serum TC, serum LDL-c, fasting blood glucose levels and liver lipid contents, improved glucose tolerance and insulin tolerance. Compared with the HF group, FME significantly increased the mRNA expression of PPARα and its target genes.

Conclusion

Our study suggests that FME may be a potential dietary supplement for preventing and ameliorating the obesity and obesity-related metabolic disturbances.     

Hemoglobin A1c Levels and Aortic Arterial Stiffness: The Cardiometabolic Risk in Chinese (CRC) Study

Objective

The American Diabetes Association (ADA) recently published new clinical guidelines in which hemoglobin A1c (HbA1c) was recommended as a diagnostic test for diabetes. The present study was to investigate the association between HbA1c and cardiovascular risk, and compare the associations with fasting glucose and 2-hour oral glucose tolerance test (2 h OGTT).

Research Design and Methods

The study samples are from a community-based health examination survey in central China. Carotid-to-femoral pulse wave velocity (cfPWV) and HbA1c were measured in 5,098 men and women.

Results

After adjustment for age, sex, and BMI, the levels of HbA1c were significantly associated with an increasing trend of cfPWV in a dose-dependent fashion (P for trend <0.0001). The associations remained significant after further adjustment for blood pressure, heart rate, and lipids (P = 0.004), and the difference in cfPWV between the highest and the lowest quintiles of HbA1c was 0.31 m/s. Fasting glucose and 2 h OGTT were not associated with cfPWV in the multivariate analyses. HbA1c showed additive effects with fasting glucose or 2 h OGTT on cfPWV. In addition, age and blood pressure significantly modified the associations between HbA1c and cfPWV (P for interactions <0.0001 for age; and  = 0.019 for blood pressure). The associations were stronger in subjects who were older (≥60 y; P for trend = 0.004) and had higher blood pressure (≥120 [systolic blood pressure]/80 mmHg [diastolic blood pressure]; P for trend = 0.028) than those who were younger and had lower blood pressure (P for trend >0.05).

Conclusions

HbA1c was related to high cfPWV, independent of conventional cardiovascular risk factors. Senior age and high blood pressure might amplify the adverse effects of HbA1c on cardiovascular risk.     

Cognitive Functions in Middle Aged Individuals Are Related to Metabolic Disturbances and Aerobic Capacity: A Cross-Sectional Study

Aims

Metabolic disturbances may contribute to cognitive dysfunction in patients with type 2 diabetes. We investigated the relation between cognitive impairment and metabolic deteriorations, low physical fitness, low-grade inflammation and abdominal obesity in middle aged individuals.

Methods

We conducted a cross-sectional study including 40 to 65 year-old patients with type 2 diabetes and limited co morbidity (N = 56), age-matched individuals with impaired glucose tolerance (N = 56) as well as age-matched controls with normal glucose tolerance (N = 72). Specific cognitive functions were assessed with focus on verbal memory, processing speed, executive functions, and a composite overall mean score. Oral glucose tolerance test, VO₂max test, systemic inflammation, DXA scanning and abdominal MRI were measured.

Results

Multiple linear regression analyses adjusting for age, gender and verbal intelligence demonstrated that a low score in processing speed, executive functions and overall cognitive function were related to high fasting C-peptide, as well as low insulin sensitivity, beta-cell function and VO₂max. Measurements of blood glucose, obesity and inflammation were not associated with cognitive function.

Conclusion

Low cognitive scores are seen in middle aged individuals with hyperinsulinemia, low insulin sensitivity, beta-cell function and low aerobic capacity. These findings emphasize the importance of appropriate lifestyle and not only blood glucose control in prevention of cognitive disability.     

Left Ventricular Hypertrophy and Insulin Resistance in Adults from an Urban Community in the Gambia: Cross-Sectional Study

Objective

To determine the association between left ventricular hypertrophy and insulin resistance in Gambians.

Design

Cross-sectional study.

Setting

Outpatient clinics of Royal Victoria Teaching Hospital and Medical Research Council Laboratories in Banjul.

Participants

Three hundred and sixteen consecutive patients were enrolled from outpatient clinics. The data of 275 participants (89 males) were included in the analysis with a mean (± standard deviation) age of 53.7 (±11.9) years.

Interventions

A questionnaire was filled and anthropometric measurements were taken. 2-D guided M-mode echocardiography, standard 12-1ead electrocardiogram, fasting insulin and the oral glucose tolerance test were performed.

Main Outcome Measures

The Penn formula was used to determine the left ventricular mass index, 125 g/m² in males and 110 g/m² in females as the cut-off for left ventricular hypertrophy. Using the fasting insulin and fasting glucose levels, the insulin resistance was estimated by the homeostatic model assessment formula. Logistic regression analysis was used to determine the association between left ventricular hypertrophy and insulin resistance.

Results

The mean Penn left ventricular mass index was 119.5 (±54.3) and the prevalence of Penn left ventricular mass index left ventricular hypertrophy was 41%. The mean fasting glucose was 5.6 (±2.5) mmol/l, fasting insulin was 6.39 (±5.49) μU/ml and insulin resistance was 1.58 (±1.45). There was no association between Penn left ventricular mass index left ventricular hypertrophy and log of insulin resistance in univariate (OR = 0.98, 95% CI = 0.80 – 1.19, p = 0.819) and multivariate logistic regression (OR = 0.93, 95% CI = 0.76–1.15, p = 0.516) analysis.

Conclusion

No association was found in this study between left ventricular hypertrophy and insulin resistance in Gambians and this does not support the suggestion that insulin is an independent determinant of left ventricular hypertrophy in hypertensives.     

Blood Glucose Homeostasis in the Course of Partial Pancreatectomy – Evidence for Surgically Reversible Diabetes Induced by Cholestasis

Background and Aim

Partial pancreatic resection is accompanied not only by a reduction in the islet cell mass but also by a variety of other factors that are likely to interfere with glucose metabolism. The aim of this work was to characterize the patient dynamics of blood glucose homeostasis during the course of partial pancreatic resection and to specify the associated clinico-pathological variables.

Methods

In total, 84 individuals undergoing elective partial pancreatic resection were consecutively recruited into this observational trial. The individuals were assigned based on their fasting glucose or oral glucose tolerance testing results into one of the following groups: (I) deteriorated, (II) stable or (III) improved glucose homeostasis three months after surgery. Co-variables associated with blood glucose dynamics were identified.

Results

Of the 84 participants, 25 (30%) displayed a normal oGTT, 17 (20%) showed impaired glucose tolerance, and 10 (12%) exhibited pathological glucose tolerance. Elevated fasting glucose was present in 32 (38%) individuals before partial pancreatic resection. Three months after partial pancreatic resection, 14 (17%) patients deteriorated, 16 (19%) improved, and 54 (64%) retained stable glucose homeostasis.Stability and improvement was associated with tumor resection and postoperative normalization of recently diagnosed glucose dysregulation, preoperatively elevated tumor markers and markers for common bile duct obstruction, acute pancreatitis and liver cell damage. Improvement was linked to preoperatively elevated insulin resistance, which normalized after resection and was accompanied by a decrease in fasting- and glucose-stimulated insulin secretion.

Conclusions

Surgically reversible blood glucose dysregulation diagnosed concomitantly with a (peri-) pancreatic tumor appears secondary to compromised liver function due to tumor compression of the common bile duct and the subsequent increase in insulin resistance. It can be categorized as “cholestasis-induced diabetes” and thereby distinguished from other forms of hyperglycemic disorders.     

Adipocyte Hypertrophy,Inflammation and Fibrosis Characterize Subcutaneous Adipose Tissue of Healthy,Non-Obese Subjects Predisposed to Type 2 Diabetes

Background

The adipose tissue is important for development of insulin resistance and type 2 diabetes and adipose tissue dysfunction has been proposed as an underlying cause. In the present study we investigated presence of adipocyte hypertrophy, and gene expression pattern of adipose tissue dysfunction in the subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes compared to matched control subjects with no known genetic predisposition for type 2 diabetes.

Method

Seventeen healthy and non-obese subjects with known genetic predisposition for type 2 diabetes (first-degree relatives, FDRs) and 17 control subjects were recruited. The groups were matched for gender and BMI and had similar age. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was calculated using HOMA-index. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene expression analysis and adipocyte cell size measurement.

Results

Our findings show that, in spite of similar age, BMI and percent body fat, FDRs displayed adipocyte hypertrophy, as well as higher waist/hip ratio, fasting insulin levels, HOMA-IR and serum triglycerides. Adipocyte hypertrophy in the FDR group, but not among controls, was associated with measures of impaired insulin sensitivity. The adipocyte hypertrophy was accompanied by increased inflammation and Wnt-signal activation. In addition, signs of tissue remodeling and fibrosis were observed indicating presence of early alterations associated with adipose tissue dysfunction in the FDRs.

Conclusion

Genetic predisposition for type 2 diabetes is associated with impaired insulin sensitivity, adipocyte hypertrophy and other markers of adipose tissue dysfunction. A dysregulated subcutaneous adipose tissue may be a major susceptibility factor for later development of type 2 diabetes.     

The Association between HbA1c,Fasting Glucose, 1-Hour Glucose and 2-Hour Glucose during an Oral Glucose Tolerance Test and Cardiovascular Disease in Individuals with Elevated Risk for Diabetes

Objective

To determine the association between HbA1c, fasting plasma glucose (FPG), 1-hour (1 hPG) and 2-hour (2 hPG) glucose after an oral glucose tolerance test (OGTT) and cardiovascular disease in individuals with elevated risk for diabetes.

Design

We studied the relationship between baseline, updated mean and updated (last) value of HbA1c, FPG, 1 hPG and 2 hPG after an oral 75 g glucose tolerance test (OGTT) and acute CVD events in 504 individuals with impaired glucose tolerance (IGT) at baseline enrolled in the Finnish Diabetes Prevention Study.

Setting

Follow-up of clinical trial.

Participants

504 individuals with IGT were followed with yearly evaluations with OGTT, FPG and HbA1c.

Main Outcome Measure

Relative risk of CVD.

Results

Over a median follow-up of 9.0 years 34 (6.7%) participants had a CVD event, which increased to 52 (10.3%) over a median follow-up of 13.0 years when including events that occurred among participants following a diagnosis of diabetes. Updated mean HbA1c, 1 hPG and 2 hPG, HR per 1 unit SD of 1.57 (95% CI 1.16 to 2.11), p = 0.0032, 1.51 (1.03 to 2.23), p = 0.036 and 1.60 (1.10 to 2.34), p = 0.014, respectively, but not FPG (p = 0.11), were related to CVD. In analyses of the last value prior to the CVD event the same three glycaemic measurements were associated with the CVD events, with HRs per 1 unit SD of 1.45 (1.06 to 1.98), p = 0.020, 1.55 (1.04 to 2.29), p = 0.030 and 2.19 (1.51 to 3.18), p<0.0001, respectively but only 2 hPG remained significant in pairwise comparisons. Including the follow-up period after diabetes onset updated 2 hPG (p = 0.003) but not updated mean HbA1c (p = 0.08) was related to CVD.

Conclusions and Relevance

Current 2 hPG level in people with IGT is associated with increased risk of CVD. This supports its use in screening for prediabetes and monitoring glycaemic levels of people with prediabetes.     

Glucose Tolerance and Weight Loss in Obese Women with Obstructive Sleep Apnea

Background

The association of obstructive sleep apnea (OSA) with glucose intolerance and the beneficial effect of lifestyle intervention have been poorly investigated in women particularly before menopausal status. The study explored 1) whether OSA is associated with impaired glucose homeostasis in obese non diabetic premenopausal and menopausal women and 2) the effects of a 3- month lifestyle intervention on glucose homeostasis in OSA women.

Design and Methods

We consecutively recruited 98 obese women (39 premenopausal) from those referred for a weight loss intervention. Ambulatory nocturnal polysomnography, body composition, oral glucose tolerance test, insulin sensitivity and β cell function were assessed before and after intervention.

Results

41% of premenopausal and 64% of menopausal women had OSA which was associated with worse glucose homeostasis before menopausal status. Mean and minimal nocturnal oxygen saturation (SaO₂) was associated with neck/height ratio (NHR), independently of total and central obesity. Mean and minimal nocturnal SaO₂ and NHR were correlated with insulin sensitivity and fasting glucose. In multivariate analyses, nocturnal mean SaO₂ was negatively and independently correlated with fasting glucose (p<0.0001) and NHR with insulin sensitivity (p<0.0001). In OSA women, the intervention induced a 5% weight reduction and a significant increase in minimal nocturnal SaO₂, insulin sensitivity and β cell function. Changes in fasting glucose and insulin sensitivity were associated with those in minimal nocturnal SaO₂ (p<0.05) and not with weight loss.

Conclusions

In obese women, glucose homeostasis worsens due to nocturnal hypoxia and increased neck circumference through mechanisms partially independent of obesity. OSA is more clearly associated with glucose intolerance in premenopausal than in menopausal women. In OSA women, the improvement of nocturnal hypoxia induced by lifestyle modifications is associated with that of glucose homeostasis.     

Hyperuricemia Is a Risk Factor for the Onset of Impaired Fasting Glucose in Men with a High Plasma Glucose Level: A Community-Based Study

Background

It is not clear whether elevated uric acid is a risk factor for the onset of impaired fasting glucose after stratifying by baseline fasting plasma glucose levels. We conducted a community-based retrospective longitudinal cohort study to clarify the relationship between uric acid levels and the onset of impaired fasting glucose, according to baseline fasting plasma glucose levels.

Methods

We enrolled 6,403 persons (3,194 men and 3,209 women), each of whom was 18–80 years old and had >2 annual check-ups during 2003–2010. After excluding persons who had fasting plasma glucose levels ≥6.11 mM and/or were currently taking anti-diabetic agents, the remaining 5,924 subjects were classified into quartiles according to baseline fasting plasma glucose levels. The onset of impaired fasting glucose was defined as fasting plasma glucose ≥6.11 mM during the observation period.

Results

In the quartile groups, 0.9%, 2.1%, 3.4%, and 20.2% of the men developed impaired fasting glucose, respectively, and 0.1%, 0.3%, 0.5%, and 5.6% of the women developed impaired fasting glucose, respectively (P trend <0.001). After adjusting for age, body mass index, systolic blood pressure, triacylglycerols, high density lipoprotein-cholesterol, creatinine, fatty liver, family history of diabetes, alcohol consumption, and current smoking, uric acid levels were positively associated with onset of impaired fasting glucose in men with highest-quartile fasting plasma glucose levels (adjusted hazard ratio, 1.003; 95% confidence interval, 1.0001–1.005, P = 0.041).

Conclusions

Among men with high fasting plasma glucose, hyperuricemia may be independently associated with an elevated risk of developing impaired fasting glucose.     

Final Height and Cardiometabolic Outcomes in Young Adults with Very Low Birth Weight (<1500 g)

Objective

Individuals with very low birth weight (VLBW; <1500 g) are known to be predisposed to both short final height and cardiometabolic disorders. However, associations between final height and cardiometabolic outcomes including glucose metabolism in VLBW individuals in young adulthood are not fully investigated.

Methods

We investigated glucose metabolism and other cardiometabolic outcomes such as lipid profiles, blood pressure, renal function, urinary albumin, and thyroid function in young adults with VLBW born between 1980 and 1990. Short stature was defined as a final height <10th percentile. Glucose intolerance [diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG)] was determined using 75-g oral glucose tolerance tests. Associations between final height and cardiometabolic outcomes were examined using logistic or multiple linear regression.

Results

A total of 628 VLBW individuals were screened and 111 young adults with VLBW (19–30 years) participated in the study. Of the participants, 40 subjects (36%) had short stature with a final height <10th percentile. Eight subjects (7.2%) had glucose intolerance (1, diabetes; 6, IGT; 1, IFG). Short stature was correlated with glucose intolerance (odds ratio 11.1; 95% CI 1.92, 99.7; P = 0.006). Final height was inversely associated with the homeostatic model assessment (HOMA) of insulin resistance, HOMA-β, insulinogenic index, and total/LDL-cholesterol. The associations of final height with insulin sensitivity and lipid profiles remained after adjustment for target height and age at puberty onset.

Conclusions

Shorter final height was associated with less favorable metabolic profiles in young adults with VLBW, and may be partly mediated by reduced insulin sensitivity. These associations were independent of target height or age at puberty onset.