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.     

Pilot Study to Evaluate the Effect of Short-Term Improvement in Vitamin D Status on Glucose Tolerance in Patients With Type 2 Diabetes Mellitus

ObjectiveTo study the effect of improvement in vitamin D status on glucose tolerance in Asian Indian patients with moderately controlled type 2 diabetes mellitus (T2DM).MethodsThis randomized, double-blind, placebocontrolled pilot study was conducted in 28 Asian Indian patients with T2DM. Study participants were randomly assigned to a vitamin D-treated group (group D) or a placebo group (group P). Serum 25-hydroxyvitamin D, hemoglobin A1c, and serum fructosamine levels were measured, and an oral glucose tolerance test (OGTT) was performed in all patients at baseline and 4 weeks after intervention. During the OGTT, plasma glucose and serum insulin levels were measured at 0, 30, 60, 90, and 120 minutes. The unpaired t test was used to compare the groups at baseline and to compare the differences in changes from baseline to 4 weeks between the 2 study groups.ResultsGroup D and group P were similar with respect to their fasting plasma glucose and serum insulin concentrations, post-OGTT plasma glucose and serum insulin levels, and hemoglobin A1c and fructosamine values at baseline. Serum 25-hydroxyvitamin D levels increased significantly in group D at 4 weeks. No significant differences were found between the groups at baseline and 4 weeks with respect to serum fructosamine, fasting plasma glucose and serum insulin, post-OGTT plasma glucose and serum insulin levels, and homeostasis model assessment of insulin resistance.ConclusionIn this study, short-term improvement in vitamin D status was not associated with improvement in glucose tolerance, insulin secretion, or insulin sensitivity in Asian Indian patients with moderately controlled T2DM.(Endocr Pract. 2010;16:600-608)     

Analysis of Fasting Plasma Glucose Values for Optimal Detection of Abnormal Responses on the Oral Glucose Tolerance Test in at-Risk Study Subjects

ObjectiveTo identify the fasting plasma glucose (FPG) value with the best performance for detecting an abnormal response on the oral glucose tolerance test (OGTT) in patients at risk for having type 2 diabetes.MethodsAll patients who underwent a 2-hour OGTT during an 18-month period were included in this study. Pretest and posttest odds, likelihood ratios, and receiver operating characteristic curves were used to identify the FPG value most strongly associated with an abnormal result on the OGTT (either diabetes or impaired glucose tolerance [IGT]).ResultsOf the 1,371 patients who underwent an OGTT during the designated study period, 1,239 fulfilled the inclusion criteria. The prevalence of IGT was 25.34% (314 patients). Diabetes was diagnosed in 141 patients (11.38%). IGT was more commonly found in the FPG strata below 115 mg/dL; above this value, diabetes was more frequently diagnosed. In general, the percentage of cases of IGT increased progressively throughout the “normal” FPG range. The prevalence varied from 11.4% (in patients with FPG values < 80 mg/dL) to 32% (in those with FPG levels from 95 to 99.9 mg/dL). FPG values between 95 and 99.9 mg/dL had a likelihood ratio of 2.1 for detecting an abnormal OGTT response, of 1.8 for detecting diabetes, and of 1.66 for detecting IGT. The odds ratio for detecting either IGT or diabetes was increased 2-fold by performing an OGTT. The FPG threshold with the best ability for detecting an abnormal response on the OGTT was 95 mg/dL (sensitivity of 0.72 and specificity of 0.65).ConclusionIn patients at risk for type 2 diabetes, the FPG cut point (95 mg/dL) most useful for detecting an abnormal OGTT response is included in the normal range of the FPG. (Endocr Pract. 2007;13:583-589)     

High Incidence of Impaired Glucose Regulation in Patients With no Known History of Diabetes Mellitus But With Hyperglycemia After Undergoing a Cardiac Surgical Procedure

ObjectiveTo determine the implications of the presence of hyperglycemia after a cardiac surgical procedure in patients with no history of diabetes mellitus (DM).MethodsWe conducted a prospective study of 50 consecutive patients with no known history of DM who underwent a cardiac surgical procedure and had postoperative hyperglycemia (plasma glucose levels ≥ 110 mg/dL), requiring an insulin drip to achieve tight glucose control. These patients underwent a 2-hour oral glucose tolerance test (OGTT) at 6 weeks postoperatively to determine the percentage of subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or type 2 DM.ResultsOf the 50 patients, 32 (64%) were found to have persistent glucose dysregulation. On the basis of OGTT results, 20% had IFG, 16% had both IFG and IGT, 10% had only IGT, and 18% had type 2 DM. Of the patients with newly diagnosed diabetes, 89% had a 6-week postoperative fasting plasma glucose (FPG) concentration of < 126 mg/dL. There was a significant correlation between the preoperative FPG levels and the 6-week postoperative 2-hour OGTT glucose levels (P < .01). No correlation was found between the 6-week postoperative FPG levels and the 2-hour OGTT glucose levels (P = .26).ConclusionHyperglycemia after a cardiac surgical procedure implies a high risk of persistent glucose dysregulation. Preoperative FPG levels correlated better with 2-hour OGTT results than did the 6-week postoperative FPG values, but both were insensitive markers for diagnosing type 2 DM in these patients. In our cohort, hemoglobin A1c was not predictive of abnormalities of glucose metabolism. Our data support the need for performing a postoperative OGTT in patients with no known history of DM but the presence of hyperglycemia after a cardiac operation. (Endocr Pract. 2009;15:425-430)     

Continuous glucose monitoring in cystic fibrosis patients according to the glucose tolerance.

Cystic fibrosis (CF) is associated with a long preclinical state of abnormal glucose tolerance. The aim of this study was (i) to evaluate the profile of glucose tolerance in young adults with CF and (ii) to compare these results with those obtained by a continuous subcutaneous glucose monitoring (CGMS). CF subjects with fasting glycemia inferior to 126 mg/dl were included in the study. An oral glucose tolerance test (OGTT) identified the subjects either with a normal glucose tolerance (NGT), or impaired glucose tolerance (IGT), or diabetes. CGMS (Medtronic) was performed during 3 days to analyze mean glucose level, high glucose excursions, and glucose area under the curve (AUC). Forty-nine patients were included in the study. NGT (n=22), IGT (n=17), and diabetes groups (n=10) were comparable except with regard to age and BMI (p<0.001). HbA1c values in diabetes group were significantly higher (p<0.001) than in NGT and IGT groups. CGMS revealed peaks of glucose values superior to 200 mg/dl at least once after a meal in 8 patients (36%) with NGT, in 9 patients (52%) with IGT, and in all patients with diabetes (p<0.01). Mean CGMS glucose and glucose AUC values increased in patients with diabetes compared to patients with NGT and IGT (p<0.05). Peak of CGMS glucose reached 182+/-60 mg/dl in NGT group despite the normal glucose profile at OGTT. In conclusion, CGMS revealed pathological glucose excursions not only in patients with impaired glucose tolerance at OGTT but also in patients with a normal glycemic profile. CGMS could be a useful tool for the early detection of hyperglycemia in patients with CF.     

Markedly Delayed Insulin Secretion and a High Rate of Undetected Overt Diabetes Characterize Glucose Metabolism in Adult Patients with Cystic Fibrosis After Lung Transplantation

Objective: Cystic fibrosis–related diabetes (CFRD) is associated with adverse clinical outcomes and should be screened for by an annual oral glucose tolerance test (OGTT). Since pathophysiologic studies have mainly been performed in a pediatric/adolescent, nontransplanted collective, we aimed to assess parameters of insulin secretion and sensitivity in adult cystic fibrosis (CF) patients after lung transplantation (LT).Methods: Twelve adult CF patients after LT without known diabetes (33.3 ± 11.5 years; body mass index &lsqb;BMI] 21.5 ± 3.3 kg/m²) and 8 control subjects matched by age (36.0 ± 6.6 years; P>.05), BMI (22.3 ± 1.5 kg/m²; P>.05), and gender (CON group) underwent a 3-hour OGTT with glucose, insulin, and C-peptide measurements. Parameters of insulin secretion and sensitivity as well as lipid profiles were assessed.Results: In the CF group, 4 patients were diagnosed with overt diabetes (CFRD) compared to CF patients without diabetes (CF-noDM), of whom 6 had indeterminate glycemia with 1-h glucose values >200 mg/dL. The insulin peak after glucose load occurred after 30 minutes in CON, after 90 minutes in CF-noDM, and was missing in CFRD. Insulin sensitivity was comparable between the groups. Beta-cell glucose sensitivity was markedly reduced in CFRD (10.7 ± 5.8 pmol/min*m²*mM), higher in CF-noDM (39.9 ± 23.4 pmol/min*m²*mM), but still significantly lower compared to CON (108.3 ± 53.9 pmol/min*m²*mM; P = .0008). CFRD patients exhibited increased triglyceride levels and decreased high-density lipoprotein levels.Conclusion: Adult CF patients after LT have profound disturbances in glucose metabolism, with a high rate of undetected diabetes and markedly delayed insulin secretion. Curbed beta-cell glucose sensitivity rather than insulin resistance explains postprandial hyperglycemia and is accompanied by abnormalities in lipid metabolism.Abbreviations: AUC = area under the curve; BMI = body mass index; CF = cystic fibrosis; CFRD = cystic fibrosis–related diabetes; CFTR = cystic fibrosis transmembrane-conductance regulator; CF-TX = cystic fibrosis patients who underwent lung transplantation; CGM = continuous glucose monitoring; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; INDET = indeterminate glycemia; LDL = low-density lipoprotein; LT = lung transplantation; OGIS = oral glucose sensitivity index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index     

Glycemic Variability Is an Independent Predictive Factor for Development of Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease

Patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) often have metabolic disorders including insulin resistance and type 2 diabetes mellitus (T2DM). We clarified the predictive factors in glucose metabolism for progression of hepatic fibrosis in patients with NAFLD by the 75-g oral glucose tolerance test (75gOGTT) and a continuous glucose monitoring system (CGMS). One hundred sixty-nine patients (68 female and 101 male patients) with biopsy-proven NAFLD with performance with 75gOGTT were enrolled and divided into four groups according to the stage of hepatic fibrosis (F0–3). The proportion of patients with T2DM significantly gradually increased, HbA1c and the homeostasis model assessment of insulin resistance were significantly elevated, and 1,5-anhydroglucitol (1,5-AG) was remarkably decreased with the progression of fibrosis. In the 75gOGTT, both plasma glucose and insulin secretion were remarkably increased with the progression of fibrosis. The only factor significantly associated with advanced fibrosis was 1,5-AG (P = 0.008) as determined by multivariate logistic regression analysis. We next evaluated the changes in blood glucose during 24 hours by monitoring with the CGMS to confirm the relationship between glycemic variability and progression of fibrosis. Variability of median glucose, standard deviation of median glucose (P = 0.0022), maximum blood glucose (P = 0.0019), and ΔMin–max blood glucose (P = 0.0029) were remarkably higher in severe fibrosis than in mild fibrosis.

Conclusion

Hyperinsulinemia and hyperglycemia, especially glycemic variability, are important predictive factors in glucose impairment for the progression of hepatic fibrosis in NAFLD.     

The role of serum fructosamine as a screening test for gestational diabetes mellitus

The serum fructosamine concentration indicates the degree of glycation of serum proteins, particularly albumin, and reflects an average blood glucose level over the previous 1-3 weeks. Serum fructosamine, glycated haemoglobin (HbA1c), total serum protein, serum albumin, fasting plasma glucose and oral glucose tolerance test (OGTT) have been measured in 127 healthy control subjects, 102 type 1 and 152 type 2 diabetes mellitus patients and 106 nondiabetic pregnant women. Fructosamine concentration of 2.24 +/- 0.16 and 3.21 +/- 0.41 mmol/l (mean +/- S.D.) has been found in control subjects and diabetics respectively (P less than 0.001). During the second trimester a significantly lower fructosamine level (1.92 +/- 0.21 mmol/l) has been found in pregnant women, most likely due to the low serum albumin concentration (31.35 +/- 3.97 g/l). None of them had a fructosamine level above the normal limit of 2.55 mmol/l. On the other hand, 12 pregnant women showed a disturbed OGTT with normal fructosamine. If the serum fructosamine concentration was adjusted for 40 g/l albumin, then a mean fructosamine of 2.16 +/- 0.24 mmol/l was found in patients with gestational diabetes. Our results show that serum fructosamine has a similar diagnostic value as HbA1c for non-pregnant adults, but neither can replace OGTT for the diagnosis of gestational diabetes.     

Elevated Fructosamine Levelsin Acquired Immunodeficiency Syndrome

ObjectiveTo investigate whether the mechanism of increased glycation in acquired immunodeficiency syndrome (AIDS) is due to an alteration in a circulatory plasma enhancer.MethodsWe assessed glycation of serum protein and hemoglobin in patients with AIDS without altered carbohydrate metabolism. Fasting concentrations of glucose, ethanol, vitamin E, fructosamine, hemoglobin, hemoglobin A1c (A1C), and partial pressure of alveolar oxygen (Pao₂) were determined in 50 men with AIDS and in 25 age-matched healthy men in whom normal glucose tolerance was established by oral glucose tolerance tests.ResultsFasting serum glucose was not significantly different between the men with AIDS (87 ± 4 mg/dL) and the healthy male volunteers (84 ± 6 mg/dL); however, A1C (6.9 ± 0.2%) and serum fructosamine levels (288 ± 15 μmol/L) were significantly higher (P < .01) in the patients with AIDS than in the normal subjects (A1C, 5.6 ± 0.1%; fructosamine, 204 ± 14 μmol/L). Moreover, both A1C and fructosamine concentrations were significantly higher (P < .01) in the patients with AIDS than in the normal subjects divided into subgroups on the basis of fasting plasma glucose concentrations (70 to 79 mg/dL, 80 to 89 mg/dL, and 90 to 99 mg/dL). None of the study participants had anemia (hemoglobin < 12 g/dL) or hypoxia (Pao₂ < 95 mm Hg), and serum ethanol was undetectable. Furthermore, vitamin E concentrations were not significantly different between the patients with AIDS (25 ± 3 mg/L) and the normal subjects (22 ± 4 mg/L).ConclusionOn the basis of this study, glycation of some circulating proteins appears to be enhanced in AIDS and may be induced by an undetermined plasma enhancer, inasmuch as known circulating factors promoting glycation were absent. (Endocr Pract. 2008;14:686-690)     

Cystic Fibrosis-Related Diabetes Mellitus: Etiology,Evaluation, and Management

ObjectiveTo review the pathophysiology, diagnosis, and management of cystic fibrosis-related diabetes mellitus (CFRD).MethodsWe performed a MEDLINE search of the literature, using the search terms “cystic fibrosis-related diabetes, “CFRD,” and “cystic fibrosis and diabetes,” to identify pertinent articles available in English.ResultsIn patients with cystic fibrosis (CF), CFRD is a major cause for an accelerated decline in health. It is the result of multiple pathophysiologic mechanisms, including destruction of pancreatic islet cells, impaired hepatic response to the antigluconeogenic effects of insulin, and impaired insulin sensitivity. Nutritional management and adequate caloric intake are paramount to successful management of CF. Although insulin remains the standard of care for treating CFRD in conjunction with fasting hyperglycemia, a small but growing body of literature supports the use of oral therapies. In this article, we discuss the benefits of and possible adverse reactions to the various classes of oral and injectable agents used in the treatment of diabetes mellitus, with special attention to the population of patients with CF.ConclusionOrally administered agents can have a role in the treatment of CFRD. Further study is needed to determine the optimal combination of therapeutic modalities for CFRD. (Endocr Pract. 2008;14:1169-1179)     

Transport of 1,5-anhydro-D-glucitol into insulinoma cells by a glucose-sensitive transport system

The uptake of 1,5-anhydro-D-glucitol (1,5-AG) occurs by passive mechanisms in cells or tissues that have passive glucose transporters. It is known that serum 1,5-AG concentrations are reduced in patients with diabetes mellitus. To elucidate the metabolism of this substance and its physiological role in pancreatic β-cells, we assayed 1,5-AG transport in the insulinoma-derived cell lines, RINr and MIN6. Both cell lines showed an insulin-insensitive, concentration-dependent uptake of 1,5-AG with a saturation time of approximately 120 min, and most of the 1,5-AG in the cytoplasm was in the free form. A biphasic saturation curve was obtained using a wide range of 1,5-AG concentrations, suggesting that accumulation was mediated by a high affinity and a low affinity transporter. The high affinity transporter had a K_m of 10.4 in RINr cells and 13.0 mM in MIN6 cells, and the low affinity transporter had a K_m of 131 in RINr cells and 211 mM in MIN6 cells. Uptake of 1,5-AG was markedly inhibited by phloretin and cytochalasin B, but was only slightly affected by phloridzin. Uptake of 1,5-AG was markedly inhibited by glucose at physiological concentrations (1.0–10 mM), as well as by galactose and mannose. The 1,5-AG concentration required to inhibit 2-deoxyglucose uptake exceeded that of glucose by >100 times, being much higher than the physiological concentrations of 1,5-AG. These results indicate that the 1,5-AG carrier system in insulinoma cells is distinct from that in either the somatic cells or renal tubular cells. These findings also suggest that a unique 1,5-AG transport system is present in pancreatic β-cells.     

Utility of Hemoglobin-A1C in Nondiabetic Women With Polycystic Ovary Syndrome

ObjectiveHemoglobin A1c (A1C) >5.7% is now accepted as a biomarker for identifying individuals at risk for diabetes. Compared to the general population, women with polycystic ovary syndrome (PCOS) have a higher risk for diabetes. Our goal was to determine what glucose homeostasis abnormalities can be identified by A1C >5.7% in women with PCOS.MethodsIn a cross-sectional study, nondiabetic women with PCOS (according to the National Institutes of Health [NIH] criteria) were divided into 2 groups based on A1C (<5.7% [n = 23] and >5.7% [n = 25]). Oral glucose tolerance tests (OGTT) and frequently sampled intravenous glucose tolerance tests (FS-IVGTT) were conducted, and body composition, cardiovascular risk factors, and sex steroid levels were assessed.ResultsCompared to women with A1C <5.7%, those with A1C >5.7% were older (35.1 ± 1.1 years vs. 31.1 ± 1.1 years; P = .04), had higher glucose levels at fasting and during OGTT, and had a lower insulin sensitivity index (SI: 2.0 ± 0.2 vs. 4.2 ± 0.6; P = .0195) and disposition index (DI: 1,014 ± 82 vs. 1,901 ± 217; P = .011) during FS-IVGTT. They also had higher triglycerides, high-sensitivity C-reactive protein (hs-CRP), and fatty acid-binding protein 4 (FABP4) levels. There was no difference in serum androgen levels.ConclusionA1C >5.7% identified the subgroup of PCOS patients with higher insulin resistance, inadequate compensatory insulin response, impaired glucose disposition, and increased cardiovascular risk factors. Thus, A1C represents an inexpensive and informative biomarker to identify PCOS patients at risk for metabolic abnormalities. (Endocr Pract. 2013;19:284-289)     

Mechanisms of insulin resistance in cystic fibrosis

Cystic fibrosis (CF) is associated with a high incidence of diabetes. Studies evaluating causes of CF-related diabetes (CFRD) have consistently documented decreased insulin secretion. In patients with CFRD, insulin sensitivity has been documented to be decreased, but controversy exists in patients with normal or impaired glucose tolerance (IGT). We undertook this study 1) to reexplore insulin sensitivity in patients with IGT and 2) to evaluate potential mechanisms of insulin resistance in CF, including GLUT-4 translocation, elevation of serum cytokines, and free fatty acid (FFA) levels. We recruited nine CF subjects with impaired glucose tolerance (IGTCF) and nine age-, gender-, and body mass index-matched control volunteers. Each underwent a hyperinsulinemic euglycemic clamp (200 mU. m(-2). min(-1)) to measure insulin sensitivity. A muscle biopsy was obtained at maximal insulin stimulation for measure of GLUT-4 translocation with sucrose gradients. An oral glucose tolerance test and National Institutes of Health (NIH) clinical status scores were measured in all volunteers. We also measured tumor necrosis factor (TNF)-alpha levels and FFA in all subjects. Additionally, we report the results of TNF-alpha and FFA in 32 CF patients previously studied by our group. Results were that glucose disposal rate (GDR) was significantly lower in the CFIGT subjects than in controls, indicative of impaired insulin action. GLUT-4 translocation was impaired in CF and correlated with GDR. TNF-alpha levels were higher in all CF subjects than in controls and correlated with GDR. There was no difference in FFA between CF and control subjects. Modified NIH clinical status scores were inversely correlated with GDR and TNF-alpha levels. We conclude that IGTCF patients have decreased peripheral insulin sensitivity. Mechanisms include elevation of TNF-alpha and impaired translocation of GLUT-4.     

Impaired Glucose Tolerance or Newly Diagnosed Diabetes Mellitus Diagnosed during Admission Adversely Affects Prognosis after Myocardial Infarction: An Observational Study

Objective

To investigate the prognostic effect of newly diagnosed diabetes mellitus (NDM) and impaired glucose tolerance (IGT) post myocardial infarction (MI).

Research Design and Methods

Retrospective cohort study of 768 patients without preexisting diabetes mellitus post-MI at one centre in Yorkshire between November 2005 and October 2008. Patients were categorised as normal glucose tolerance (NGT n = 337), IGT (n = 279) and NDM (n = 152) on pre- discharge oral glucose tolerance test (OGTT). Primary end-point was the first occurrence of major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal MI, severe heart failure (HF) or non-haemorrhagic stroke. Secondary end-points were all cause mortality and individual components of MACE.

Results

Prevalence of NGT, impaired fasting glucose (IFG), IGT and NDM changed from 90%, 6%, 0% and 4% on fasting plasma glucose (FPG) to 43%, 1%, 36% and 20% respectively after OGTT. 102 deaths from all causes (79 as first events of which 46 were cardiovascular), 95 non fatal MI, 18 HF and 9 non haemorrhagic strokes occurred during 47.2 ± 9.4 months follow up. Event free survival was lower in IGT and NDM groups. IGT (HR 1.54, 95% CI: 1.06–2.24, p = 0.024) and NDM (HR 2.15, 95% CI: 1.42–3.24, p = 0.003) independently predicted MACE free survival. IGT and NDM also independently predicted incidence of MACE. NDM but not IGT increased the risk of secondary end-points.

Conclusion

Presence of IGT and NDM in patients presenting post-MI, identified using OGTT, is associated with increased incidence of MACE and is associated with adverse outcomes despite adequate secondary prevention.     

Glucose dysregulation in obese children: predictive, risk, and potential protective factors

Objective: The aim of our study was to determine the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (DM2) in obese children and adolescents of Greek origin and compare our data with pertinent literature findings in an attempt to uncover predictive, risk, and preventive factors. Research Methods and Procedures: A total of 117 obese children and adolescents 12.1 ± 2.7 years old underwent a 2‐hour oral glucose tolerance test (OGTT). Insulin resistance (IR) and β‐cell function were estimated using the homeostasis model assessment (HOMA)‐IR and the insulinogenic index, respectively. Results: A total of 17 patients (14.5%) had IGT, and none had DM2. The overall prevalence rates of both IGT and DM2 in our subjects were lower than those reported in a recent multiethnic U.S. study. Nevertheless, the difference between our IGT data and those of the U.S. study was due mostly to the prepubertal subjects (9% vs. 25.4%), whereas no difference was observed in the pubertal population (18% vs. 21%). Fasting glucose, insulin, and HOMA‐IR values were not predictive of IGT. The absolute value of insulin at 2 hours of the OGTT combined with the time‐integrated glycemia (AUCG) can strongly predict IGT, whereas higher area under the curve for insulin (AUCI) values were found to be protective. Discussion: In ethnic groups less prone to diabetes development, IGT or DM2 in obese subjects is more likely to develop at puberty than at the prepubertal stage. It is advisable that physicians caring for obese adolescents perform an OGTT for early detection of IGT because HOMA‐IR values, although higher in IGT subjects and indicative of IR, cannot predict IGT.     

Insulin secretion, glycosylated haemoglobin and islet cell antibodies in cystic fibrosis children and adolescents with different degrees of glucose tolerance.

In comparison with 12 weight-matched controls, 39 children and adolescents with cystic fibrosis (CF) showed higher fasting glycaemic levels and both delayed and enhanced blood glucose responses to OGTT. Glycaemic response was normal in 30/39 patients (76.9%), impaired in other 7 cases (18%) and diabetic in the remnant two (5.1%). Fasting insulin levels and total insulin output during OGTT did not differ in patients and controls, but insulin peak in CF group was delayed and sustained. In the whole CF series mean HbA1c was higher than in controls but no difference was found between patients with normal and those with impaired glucose tolerance. Islet cell antibodies were absent in the entire CF group. In conclusion, our results confirm the raised prevalence in CF of glucose tolerance abnormalities, which do not seem to depend on auto-immune factor involvement. Delayed insulin response to OGTT can be considered a very early expression of beta cell impairment in the course of CF. In our experience HbA1c assay did not constitute a sensitive and specific screening test for detection of the C patients with glucose intolerance.     

Fasting Plasma Glucose (FPG) and the Risk of Impaired Glucose Tolerance in Obese Children and Adolescents

A timely diagnosis of impaired glucose tolerance (IGT) is desirable in obesity. The oral glucose tolerance test (OGTT), the gold standard to diagnose this condition, may not be realistically performed in all patients due to discomfort, labor, and cost. The aim of this study was to assess whether one or more biochemical indexes measured in fasting conditions could be used to identify obese children at risk of IGT. A cohort of 563 white obese children and adolescents (M/F: 315/248; aged 4–17 years) was recruited and underwent anthropometric evaluation and OGTT. Anthropometric parameters, fasting plasma glucose (FPG), fasting serum insulin (FSI), and homeostasis model assessment of insulin resistance (HOMA_IR) were tested in pursuit of a possible threshold to be used as a predictor of IGT. Thirty‐seven children (6.9%) had IGT and one child (0.1%) had type 2 diabetes (T2D). FPG, FSI, and HOMA_IR were all significantly higher in children with IGT than in children without IGT. Receiver‐operating characteristic (ROC) curve analyses run for gender and puberty‐adjusted FPG, FSI, and HOMA_IR were all significant: area under the curve (95% confidence interval) equaled 0.68 (0.59–0.76), 0.66 (0.56–0.76), and 0.68 (0.59–0.78), respectively. The three parameters did not show significantly different sensitivity/specificity in the pooled population or in the gender/puberty subgroups. Thresholds varied among gender/puberty subgroups for FSI and HOMA_IR, but not for FPG, which showed a fixed threshold of 86 mg/dl. A gender/puberty independent cutoff of FPG may be considered a screening tool to narrow clinical indication to OGTT in obese white children and adolescents.     

Serum Chemerin Concentrations Associate with Beta-Cell Function,but Not with Insulin Resistance in Individuals with Non-Alcoholic Fatty Liver Disease (NAFLD)

The novel adipokine chemerin has been related to insulin-resistant states such as obesity and non alcoholic fatty liver disease (NAFLD). However, its association with insulin resistance and beta cell function remains controversial. The main objective was to examine whether serum chemerin levels associate with insulin sensitivity and beta cell function independently of body mass index (BMI), by studying consecutive outpatients of the hepatology clinics of a European university hospital. Individuals (n=196) with NAFLD were stratified into persons with normal glucose tolerance (NGT; n=110), impaired glucose tolerance (IGT; n=51) and type 2 diabetes (T2D; n=35) and the association between serum chemerin and measures of insulin sensitivity and beta cell function as assessed during fasting and during oral glucose tolerance test (OGTT) was measured. Our results showed that serum chemerin positively associated with BMI (P=0.0007) and C peptide during OGTT (P<0.004), but not with circulating glucose, insulin, lipids or liver enzymes (all P>0.18). No BMI independent relationships of chemerin with fasting and OGTT derived measures of insulin sensitivity were found (P>0.5). Chemerin associated positively with fasting beta cell function as well as the OGTT derived insulinogenic index IGI_cp and the adaptation index after adjustment for age, sex and BMI (P=0.002-0.007), and inversely with the insulin/C peptide ratio (P=0.007). Serum chemerin neither related to the insulinogenic index IGI_ins nor the disposition index. In conclusion, circulating chemerin is likely linked to enhanced beta cell function but not to insulin sensitivity in patients with NAFLD.     

1,5-Anhydroglucitol and Neonatal Complications in Pregnancy Complicated by Diabetes

Objective: To determine the association of 1,5-anhydroglucitol (1,5-AG) with neonatal birth weight (NBW) and neonatal hypoglycemia (+NH) in pregnancies complicated by diabetes.Methods: We assessed a retrospective cohort of 102 females, 17 with gestational diabetes (GDM), 48 with type 1 diabetes mellitus (T1DM), and 37 with type 2 diabetes mellitus (T2DM). 1,5-AG and glycated hemoglobin A1C (A1C) values throughout pregnancy were extracted. Linear regression was used to assess their association with NBWs z-scores adjusting for maternal age, ethnicity and body mass index (BMI). +NH was defined by a note in the infant record, glucose <1.7 mmol/L in the first 24 h, or <2.5 mmol/L in the first 48 h after birth. A t test or Welch's approximate t test was used to compare the mean 1,5-AG and A1C of mothers with +NH versus those without (-NH), adjusted for gestational age and analyzed by diabetes type and across trimesters.Results: Mean 1,5-AG significantly differed across groups: T1DM 3.77 ± 2.82 μg/mL, T2DM 5.73 ± 4.38 μg/mL, GDM 8.89 ± 4.39 μg/mL (P<.0001), suggesting less glucose exposure in GDM relative to T1DM or T2DM. A negative linear association was found between mean 1,5-AG and z-scores (R= -0.28, P = .005. In contrast, the association between mean A1C and z-scores was weaker (R = 0.15, P = .14). The mean 1,5-AG tended to be lower in the +NH cohort versus -NH (P = .08), and this was statistically significant (P = .01) among subjects with GDM.Conclusion: The association of 1,5-AG with complications related to glycemic exposure supports the notion of its utility as an adjunct glycemic biomarker in pregnancies complicated by diabetes and across trimesters.Abbreviations: 1,5-AG = 1,5-anhydroglucitol A1C = glycated hemoglobin A1C BMI = body mass index CGM = continuous glucose monitoring GDM = gestational diabetes mellitus LGA = large for gestational age MICC = maternal and infant care unit NBW = neonatal birth weight NH = neonatal hypoglycemia PPH = postprandial hyperglycemia SMBG = self-monitoring of blood glucose T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus     

Increased circulating RANTES in type 2 diabetes

Aim

The pro-atherogenic role of RANTES, a chemokine expressing pleiotropic activities, in the course of type 2 diabetes-related atherosclerosis has been well documented. However, it is not known which of the diabetes-related factors primarily influence serum RANTES levels in patients with type 2 diabetes. Our aim was to investigate relationships between several factors known to be related to an increased risk of atherosclerosis and serum RANTES levels in type 2 diabetic patients.

Methods

A total of 168 subjects were examined, which included 138 patients with type 2 diabetes and 30 non-diabetic controls. Measurements of venous, fasting, plasma glucose, HbA₁c, lipid profile, 1,5-anhydro-D-glucitol (1,5-AG) plasma levels, homocysteine and the fasting, serum C-peptide levels were performed. Serum concentrations of RANTES were assayed using BD? Cytometric Bead Array tests. Peripheral insulin resistance was expressed according to a new index defined by Ohkura et al.

Results

RANTES levels in type 2 diabetic patients correlated with 1,5-AG, fasting glycaemia, HbA₁c and the Ohkura index. Multivariate regression analysis was performed taking into consideration several factors related to the inflammatory process and atherosclerosis, namely the patient’s age, diabetes duration, waist circumference, 1,5-AG, HbA₁c, lipid profile parameters, serum homocysteine levels and Ohkura index, as independent variables potentially influencing serum RANTES levels in type 2 diabetic patients. It is shown that RANTES concentrations in the serum is primarily dependent upon 1,5-AG plasma levels.

Conclusion

Our results suggest that increased serum levels of RANTES in type 2 diabetic patients are closely related to postprandial (acute) hyperglycaemia.