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1.  Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies 
Background
To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.
Materials and methods
In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.
Results
Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.
Conclusion
GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.
doi:10.1186/1472-6823-10-16
PMCID: PMC2955624  PMID: 20863361
2.  Diabetes: cost of illness in Norway 
Background
Diabetes mellitus places a considerable burden on patients in terms of morbidity and mortality and on society in terms of costs. Costs related to diabetes are expected to increase due to increasing prevalence of type 2 diabetes. The aim of this study was to estimate the health care costs attributable to type 1 and type 2 diabetes in Norway in 2005.
Methods
Data on inpatient hospital services, outpatient clinic visits, physician services, drugs, medical equipment, nutrition guidance, physiotherapy, acupuncture, foot therapy and indirect costs were collected from national registers and responses to a survey of 584 patients with diabetes. The study was performed with a prevalence approach. Uncertainty was explored by means of bootstrapping.
Results
When hospital stays with diabetes as a secondary diagnosis were excluded, the total costs were €293 million, which represents about 1.4% of the total health care expenditure. Pharmaceuticals accounted for €95 million (32%), disability pensions €48 million (16%), medical devices €40 million (14%) and hospital admissions €21 million (7%). Patient expenditures for acupuncture, physiotherapy and foot therapy were many times higher than expenditure for nutritional guidance. Indirect costs (lost production from job absenteeism) accounted for €70.1 million (24% of the €293 million) and included sick leave (€16.7 million), disability support and disability pensions (€48.2 million) and other indirect costs (€5.3 million). If all diabetes related hospital stays are included (primary- and secondary diagnosis) total costs amounts to €535 million, about 2.6% of the total health care expenditure in Norway.
Conclusions
Diabetes represents a considerable burden to society in terms of health care costs and productivity losses.
doi:10.1186/1472-6823-10-15
PMCID: PMC2954862  PMID: 20854689
3.  Associations of age with serum insulin, proinsulin and the proinsulin-to-insulin ratio: a cross-sectional study 
Background
Insulin responses and insulin levels seem to decline with age. However, the question of beta cell impairment attributable to ageing has been sparsely addressed in population-based studies. Non-fasting insulin levels are determined by the ambient degree of insulin resistance together with the capacity of beta cells to compensate by insulin secretion to prevent hyperglycaemia. A raised proinsulin-to-insulin ratio (proinsulin/insulin) due to impaired processing of proinsulin is an early marker of beta cell dysfunction. We hypothesised that in a general population, signs of beta cell failure with advancing age manifest not only by decreases in random insulin, but also with a corresponding increase in its precursor proinsulin.
Methods
In the Tromsø Study 1994-95 we measured insulin and proinsulin concentrations in random blood samples from 6212 persons without self-reported diabetes mellitus and plotted the levels as percentiles according to age. In regression analyses we assessed the relationships between age and insulin, proinsulin, and proinsulin/insulin, while adjusting for the concomitant measurements of glucose and other metabolic variables, and the time since the last meal.
Results
Median insulin concentrations declined significantly with advancing age group in men, but not in women. Proinsulin levels and proinsulin/insulin increased across age groups in both genders. After adjustment, greater age was associated with lower log10(insulin) and higher log10(proinsulin) and log10(proinsulin/insulin) (p = 0.0001 for all).
Conclusions
Negative associations of age with random insulin levels, together with positive associations of age with proinsulin and proinsulin/insulin, point towards a loss of beta cell function inherent in the ageing process.
doi:10.1186/1472-6823-10-21
PMCID: PMC3020169  PMID: 21162746
4.  Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis 
Background
Glucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs.
Methods
MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events.
Results
Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily.
Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta-cell function, but this is not sustained after the drug is stopped.
Conclusions
GLP-1 agonists are effective in improving glycaemic control and promoting weight loss.
doi:10.1186/1472-6823-10-20
PMCID: PMC3017518  PMID: 21143938
5.  Symptomatic hypopituitarism revealing primary suprasellar lymphoma 
Background
The most common cause of hypopituitarism is pituitary adenoma. However, in the case of suprasellar masses different etiologies are possible. We report an unusual case of primary suprasellar lymphoma presented with hypopituitarism.
Case presentation
A 26 year old woman presented with amenorrhea, galactorrhea and neurological disorders. Also, the laboratory work-up revealed partial hypopituitarism. The magnetic resonance imaging of the head showed a suprasellar mass. A presumptive diagnosis of granulomatous processes was made and the patient was given steroid therapy. Repeated brain MRI detected new lesions in the brain with regression of the suprasellar mass. Stereotactic biopsy of the paraventricular lesion revealed the diagnosis of B-cell lymphoma.
Conclusion
This case presentation reports a rare cause of hypopituitarism. Primary suprasellar lymphoma is extremely rare and represented a real diagnostic challenge. Besides, suprasellar masses are varied in aetiology and can present diagnostic problems for a radiologist. Also, because of the increased incidence of PCNSL, lymphoma must be kept in mind in the differential diagnosis of lesions in the suprasellar region.
doi:10.1186/1472-6823-10-19
PMCID: PMC3006376  PMID: 21114849
6.  Short term effects of a low-carbohydrate diet in overweight and obese subjects with low HDL-C levels 
Background
The aim of this study was to evaluate short-term effects of a low-carbohydrate diet in overweight and obese subjects with low HDL-C levels.
Methods
Overweight (BMI between 25-30 kg/m2) or obese (BMI over 30 kg/m2) subjects with low HDL-C levels (men with HDL-C <1.03, women <1.29 mmol/l) were invited to the study. A 1400 kcal 75-gram carbohydrate (CHO) diet was given to women and an 1800 kcal 100-gram CHO diet was given to men for four weeks. The distribution of daily energy of the prescribed diet was 21-22% from CHO, 26-29% from protein and 49-53% from fat. Subjects completed a three-day dietary intake record before each visit. Anthropometric indices, body fat ratio, blood lipids, glucose and insulin were measured. Baseline and week-four results were compared with a Wilcoxon signed ranks test.
Results
Twenty-five women and 18 men participated. Basal median LDL-C level of men was 3.11 and basal median LDL-C level of women was 3.00 mmol/l. After four weeks of a low-carbohydrate diet, the median energy intake decreased from 1901 to 1307 kcal/day, daily energy from carbohydrate from 55% to 33%, body weight from 87.7 to 83.0 kg and HDL-C increased from 0.83 to 0.96 mmol/l in men (p < 0.002, for all). After four weeks of a low-carbohydrate diet, the median energy intake tended to decrease (from 1463 to 1243 kcal, p = 0.052), daily energy from carbohydrate decreased from 53% to 30% (p < 0.001) and body weight decreased from 73.2 to 70.8 kg (p < 0.001) in women, but HDL-C did not significantly change (from 1.03 to 1.01 mmol/l, p = 0.165). There were significant decreases in body mass index, waist circumference, body fat ratio, systolic blood pressure, total cholesterol, triglyceride and insulin levels in all subjects.
Conclusions
HDL-C levels increased significantly with energy restriction, carbohydrate restriction and weight loss in men. HDL-C levels didn't change in women in whom there was no significant energy restriction but a significant carbohydrate restriction and a relatively small but significant weight loss. Our results suggest that both energy and carbohydrate restriction should be considered in overweight and obese subjects with low HDL-C levels, especially when LDL-C levels are not elevated.
doi:10.1186/1472-6823-10-18
PMCID: PMC2994852  PMID: 21062488
7.  Study on administration of 1,5-anhydro-D-fructose in C57BL/6J mice challenged with high-fat diet 
1,5-Anhydro-D-fructose (AF) is a mono-saccharide directly formed from starch and glycogen by the action of α-1,4-glucan lyase (EC 4.2.2.13). Our previous study has indicated that AF increases glucose tolerance and insulin secretion in NMRI mice after administration through a gastric gavage in a single dose at 150 mg per mouse. In this study, we used high-fat feeding of C57BL/6J mice to examine the influence of long-term administration of AF on glucose-stimulated insulin secretion in vivo and in vitro. We found that 8-weeks of high-fat feeding increased body weight, fasting blood glucose and insulin levels in C57BL/6J mice when compared to mice fed normal diet. Impaired glucose tolerance was also observed in mice receiving 8-weeks of high-fat diet. In contrast, AF (1.5 g/kg/day), administered through drinking water for 8-weeks, did not affect body weight or food and water intake in mice fed either the high-fat or normal diet. There was no difference in basal blood glucose or insulin levels between AF-treated and control group. Oral glucose tolerance test (OGTT) showed that AF did not affect glucose-stimulated insulin secretion in mice. In in vitro studies with isolated islets, AF did not influence glucose-stimulated insulin secretion in mice receiving either high-fat or normal diet. We therefore conclude that when given through drinking water for 8 weeks at 1.5 g/kg/day, AF has no effect on glucose-stimulated insulin secretion in C57BL/6J mice challenged with a high-fat diet.
doi:10.1186/1472-6823-10-17
PMCID: PMC2974679  PMID: 20958989
8.  Predictors of mortality of patients newly diagnosed with clinical type 2 diabetes: a 5-year follow up study 
Background
At diabetes diagnosis major decisions about life-style changes and treatments are made based on characteristics measured shortly after diagnosis. The predictive value for mortality of these early characteristics is widely unknown. We examined the predictive value of patient characteristics measured shortly after diabetes diagnosis for 5-year all-cause and cardiovascular mortality with special reference to self-rated general health.
Methods
Data were from a population-based sample of 1,323 persons newly diagnosed with clinical diabetes and aged 40 years or over. Possible predictors of mortality were investigated in Cox regression models.
Results
Multivariately patients who rated their health less than excellent experienced increased all-cause and cardiovascular mortality. These end-points also increased with sedentary life-style, relatively young age at diagnosis and presence of cardiovascular disease (CVD) at diagnosis. Further predictors of all-cause mortality were male sex, low body mass index and cancer, while cardiovascular mortality increased with urinary albumin concentration.
Conclusions
We found that patients who rated their health as less than excellent had increased 5-year mortality, similar to that of patients with prevalent CVD, even when biochemical, clinical and life-style variables were controlled for. This finding could motivate doctors to discuss perceptions of health with newly diagnosed diabetic patients and be attentive to patients with suboptimal health ratings. Our findings also confirm that life-style changes and optimizing treatment are particularly relevant for relatively young and inactive patients and those who already have CVD or (micro)albuminuria at the time of diabetes diagnosis.
doi:10.1186/1472-6823-10-14
PMCID: PMC2928228  PMID: 20698977
9.  Whether to report diabetes as the underlying cause-of-death? a survey of internists of different sub-specialties 
Background
Cause-specific mortality is a commonly used endpoint of clinical trials or prospective studies. However, it is sometimes difficult for physician to determine the underlying-cause-of-death (UCD), especially for diabetic patients coexisted with cardiovascular diseases (CVD). The aim of this survey was to examine whether internists with different specialties have different opinions on the reporting of diabetes as the UCD.
Methods
A total of 549 physicians completed the questionnaire in Taiwan, which comprised seven hypothetical case scenarios, each indicating a different level of contribution of diabetes in initiating the chain of events leading to death.
Results
As a whole, endocrinologists were more likely than cardiologists and nephrologists to report diabetes as the UCD. The differences were more prominent when the diabetic patient had a coexisting CVD. In scenario 3 (a diabetic patient with hypertension who died from acute myocardial infarction), the percentage was 56% in endocrinologists, which was significantly higher than in cardiologists (42%) and nephrologists (41%). In scenario 4 (a diabetic patient with hypertension who died from cerebrovascular infarction), the percentage was 45% in endocrinologists, and only 31% in cardiologists and 36% in nephrologists.
Conclusions
Internists of different sub-specialties do have different opinions on the reporting of diabetes as the UCD, especially when the diabetic patient has a coexisting CVD.
doi:10.1186/1472-6823-10-13
PMCID: PMC2912904  PMID: 20653939
10.  Increases in summer serum 25-hydroxyvitamin D (25OHD) concentrations in elderly subjects in São Paulo, Brazil vary with age, gender and ethnicity 
Background
Hypovitaminosis D is a common condition among elderly individuals in temperate-climate countries, with a clear seasonal variation on 25 hydroxyvitamin D levels, increasing after summer and decreasing after winter, but there are few data from sunny countries such as Brazil. Many factors can interfere on vitamin D cutaneous synthesis. We aimed at studying the 25OHD variations during winter and summer in an outdoor physically active elderly population living in São Paulo city, and analysed their determining factors.
Methods
Ninety-nine individuals (52 women and 47 men, from 55 to 83 years old) from different ethnic groups were selected from an outdoor physical activity group. Data are reported as Mean ± SD, and we used Pearson Linear Correlation, Student's t-test for non-related samples, Chi-square (χ²) test and One-way ANOVA for analysis.
Results
Mean 25OHD value for the whole group was 78.9 ± 30.9 nmol/L in the winter and 91.6 ± 31.7 nmol/L in the summer (p = 0.005). Mean winter serum 25OHD concentrations were not different between men and women (81.2 ± 30.1 nmol/L vs. 76.7 ± 31.8 nmol/L, respectively), and 19.2% of the individuals showed values < 50 nmol/L. In the summer, we noticed an increase only for men (107.6 ± 31.4 nmol/L) compared to women (76.7 ± 24.0 nmol/L), and 6.5% showed values < 50 nmol/L. A decrease in the mean PTH in the summer compared to the winter was noticed, with PTH levels showing a relationship with 25OHD concentrations only in the winter (r = -0.208, p = 0.041). White individuals showed an increase in mean serum 25OHD in the summer (p = 0.016) which was not noticed for other ethnic groups (Asians, native Brazilians and blacks). An increase in 25OHD values in the summer was observed in the age groups ranging from 51-60 and 61-70 years old (p < 0.05), but not in the age group from 71 years old on.
Conclusions
25OHD values increased during the summer in elderly residents of São Paulo, but to different extents depending on ethnicity, gender and age. This season-dependent increase was noticed only among men, white and who were in the youngest group of individuals.
doi:10.1186/1472-6823-10-12
PMCID: PMC2902474  PMID: 20546572
11.  Is impaired energy regulation the core of the metabolic syndrome in various ethnic groups of the USA and Taiwan? 
Background
The metabolic syndrome (MetS) concept is widely used in public health and clinical settings without an agreed pathophysiology. We have re-examined the MetS in terms of body fuels, so as to provide a coherent cross-cultural pathogenesis.
Methods
National Health and Nutrition Examination Survey (NHANES 2001-2) with n = 2254 and Taiwanese National Health Interview Survey (NHIS) sub-set for hypertension, hyperglycemia and hyperlipidemia assessment (TwSHHH 2002), n = 5786, were used to compare different ethnicities according to NCEP-ATPIII (NCEP-tw) criteria for METS. Exploratory factor analysis (EFA) using principal components (PC) was employed to differentiate and unify MetS components across four ethnicities, gender, age-strata, and urban-rural settings.
Results
The first two factors from the PC analysis (PCA) accounted for from 55.2% (non-Hispanic white) to 63.7% (Taiwanese) of the variance. Rotated factor loadings showed that the six MetS components provided three clusters: the impaired energy regulation (IER) components (waist circumference, WC, fasting triglycerides, TG, and fasting plasma glucose, FPG), systolic and diastolic blood pressures (BPs), and HDL-cholesterol, where the IER components accounted for 25-26% of total variance of MetS components. For the three US ethnic subgroups, factor 1 was mainly determined by IER and HDL-cholesterol, and factor 2 was related to the BP components. For Taiwanese, IER was determinant for both factors, and BPs and HDL-cholesterol were related to factors 1 and 2 respectively.
Conclusions
There is a MetS core which unifies populations. It comprises WC, TG and FPG as a core, IER, which may be expressed and modulated in various second order ways.
doi:10.1186/1472-6823-10-11
PMCID: PMC2891753  PMID: 20513248
12.  The transcription factor 7-like 2 (TCF7L2) polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study 
Background
Transcription factor 7-like 2 (TCF7L2) has emerged as a consistently replicated susceptibility gene for type 2 diabetes, however, whether the TCF7L2 gene also has similar effects on the retinal microvasculature is less clear. We therefore aimed to investigate the association between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and retinal microvascular phenotypes in the Atherosclerosis Risk in Communities (ARIC) Study (1993-1995).
Methods
This was a population-based, cross-sectional study of 10,320 middle-aged African American (n = 2,199) and Caucasian (n = 8,121) men and women selected from four United States communities to examine the association between TCF7L2 rs7903146 polymorphism and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking, arteriolar and venular calibers). Photographs on one randomly selected eye were graded for presence of retinal microvascular signs and used to measure retinal vessel calibres.
Results
After adjusting for age, sex, study center, mean arterial blood pressure, total serum cholesterol, triglycerides, and other covariates, few associations of TCF7L2 rs7903146 and retinal microvascular signs were noted. TCF7L2 rs7903146 T risk allele was significantly associated with focal arteriolar narrowing in Caucasians with hypertension [odds ratio (OR)CT vs. CC (95% CI) = 1.25 (1.09-1.44); ORTT vs. CC = 1.56 (1.18-2.06); P = 0.002] and in Caucasians without diabetes [OR CT vs. CC = 1.18 (1.06-1.32); OR TT vs. CC = 1.40 (1.12, 1.75); P = 0.003]. No significant association of the TCF7L2 rs7903146 polymorphism and retinal vascular signs was noted among African American individuals.
Conclusions
TCF7L2 rs7903146 is not consistently associated with retinal microvascular signs. However, we report an association between the TCF7L2 rs7903146 polymorphism and focal arteriolar narrowing in Caucasians with hypertension or without diabetes. Further research in other large, population-based studies is needed to replicate these findings.
doi:10.1186/1472-6823-10-9
PMCID: PMC2879252  PMID: 20478041
13.  Prolactinomas, Cushing's disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas 
Pituitary adenomas are associated with a variety of clinical manifestations resulting from excessive hormone secretion and tumor mass effects, and require a multidisciplinary management approach. This article discusses the treatment modalities for the management of patients with a prolactinoma, Cushing's disease and acromegaly, and summarizes the options for medical therapy in these patients.
First-line treatment of prolactinomas is pharmacotherapy with dopamine agonists; recent reports of cardiac valve abnormalities associated with this class of medication in Parkinson's disease has prompted study in hyperprolactinemic populations. Patients with resistance to dopamine agonists may require other treatment.
First-line treatment of Cushing's disease is pituitary surgery by a surgeon with experience in this condition. Current medical options for Cushing's disease block adrenal cortisol production, but do not treat the underlying disease. Pituitary-directed medical therapies are now being explored. In several small studies, the dopamine agonist cabergoline normalized urinary free cortisol in some patients. The multi-receptor targeted somatostatin analogue pasireotide (SOM230) shows promise as a pituitary-directed medical therapy in Cushing's disease; further studies will determine its efficacy and safety. Radiation therapy, with medical adrenal blockade while awaiting the effects of radiation, and bilateral adrenalectomy remain standard treatment options for patients not cured with pituitary surgery.
In patients with acromegaly, surgery remains the first-line treatment option when the tumor is likely to be completely resected, or for debulking, especially when the tumor is compressing neurovisual structures. Primary therapy with somatostatin analogues has been used in some patients with large extrasellar tumors not amenable to surgical cure, patients at high surgical risk and patients who decline surgery. Pegvisomant is indicated in patients who have not responded to surgery and other medical therapy, although there are regional differences in when it is prescribed.
In conclusion, the treatment of patients with pituitary adenomas requires a multidisciplinary approach. Dopamine agonists are an effective first-line medical therapy in most patients with a prolactinoma, and somatostatin analogues can be used as first-line therapy in selected patients with acromegaly. Current medical therapies for Cushing's disease primarily focus on adrenal blockade of cortisol production, although pasireotide and cabergoline show promise as pituitary-directed medical therapy for Cushing's disease; further long-term evaluation of efficacy and safety is important.
doi:10.1186/1472-6823-10-10
PMCID: PMC2887860  PMID: 20478050
14.  Thyroid function derangement and childhood obesity: an Italian experience 
Background
In recent years, there has been an increasing attention to thyroid function in paediatric obese patients. In the present study we aimed 1) to determine the prevalence of abnormally elevated thyroid-stimulating hormone (TSH) levels in Italian obese children and adolescents 2) to investigate whether hyperthyrotropinemia in obese children cardiovascular and metabolic risk factors 3) to verify if TSH elevation is reversible after weight loss.
Methods
We examined 938 obese children and adolescents (450 females). Anthropometric, metabolic and hormonal variables were determined at baseline and, in a subgroup of children with hyperthyrotropinemia, after a six month weight loss program.
Results
Hyperthyrotropinemia (TSH ≥4.2 μUI/ml) was diagnosed in 120 patients (12,8%). Body mass index (BMI) z-score (p = 0.02) and free T3 (fT3) levels (p = 0.03) were higher in patients with elevated TSH compared to the group with normal TSH. There were not significant differences in other metabolic parameters between the two groups.
A positive correlation between baseline TSH and BMI z-score (p = 0.0045) and between Ft3 and BMI z-score (p = 0.0034) was observed, while there was no correlation between TSH and lipids. Twenty-three patients among those with hyperthyrotropinemia who participated to weight reduction intervention (64 patients), presented substantial weight loss and concomitantly a significant decrease in TSH and in fT3.
Conclusions
These results suggest that: (1) a moderate elevation of TSH concentrations, is frequently found in obese children; (2) in obese children increase of TSH is not associated to metabolic risk factors, (3) hyperthyrotropinemia is reversible after weight loss and these data suggest that it should not be treated.
doi:10.1186/1472-6823-10-8
PMCID: PMC2874556  PMID: 20441588
15.  Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes 
Background
In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.
Methods
The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.
Results
Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.
Conclusions
In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.
doi:10.1186/1472-6823-10-7
PMCID: PMC3161395  PMID: 20412573
16.  Low serum creatinine is associated with type 2 diabetes in morbidly obese women and men: a cross-sectional study 
Background
Low skeletal muscle mass is associated with insulin resistance and metabolic syndrome. Serum creatinine may serve as a surrogate marker of muscle mass, and a possible relationship between low serum creatinine and type 2 diabetes has recently been demonstrated. We aimed to validate this finding in a population of Caucasian morbidly obese subjects.
Methods
Cross-sectional study of 1,017 consecutive morbidly obese patients with an estimated glomerular filtration rate >60 ml/min/1.73 m2. Logistic regression (univariate and multiple) was used to assess the association between serum creatinine and prevalent type 2 diabetes, including statistically testing for the possibility of non-linearity in the relationship by implementation of Generalized Additive Models (GAM) and piecewise linear regression. Possible confounding variables such as age, family history of diabetes, waist-to-hip ratio, hypertension, current smoking, serum magnesium, albuminuria and insulin resistance (log HOMA-IR) were adjusted for in three separate multiple logistic regression models.
Results
The unadjusted GAM analysis suggested a piecewise linear relationship between serum creatinine and diabetes. Each 1 μmol/l increase in serum creatinine was associated with 6% (95% CI; 3%-8%) and 7% (95% CI; 2%-13%) lower odds of diabetes below serum creatinine levels of 69 and 72 μmol/l in women and men, respectively. Above these breakpoints the serum creatinine concentrations did not reduce the odds further. Adjustments for non-modifiable and modifiable risk factors left the piecewise effect for both women and men largely unchanged. In the fully adjusted model, which includes serum magnesium, albuminuria and log HOMA-IR, the piecewise effect for men was statistically non-significant, but it remained present for women. Patients with creatinine levels below median had approximately 50% (women) and 75% (men) increased odds of diabetes.
Conclusions
Low serum creatinine is a predictor of type 2 diabetes in Caucasian morbidly obese patients, independent of age, gender, family history of diabetes, anthropometric measures, hypertension, and current smoking. Longitudinal studies of both obese and non-obese populations are needed to investigate whether serum creatinine may be causally linked with type 2 diabetes, and if so, precisely how they are linked.
doi:10.1186/1472-6823-10-6
PMCID: PMC2861032  PMID: 20398422
17.  Comparison of endothelial progenitor cell function in type 2 diabetes with good and poor glycemic control 
Background
Endothelial progenitor cells (EPCs) play an important role in vascular repair and a decrease in the number of EPCs is observed in type 2 diabetes. However, there is no report on the change of EPCs after glycemic control. This study therefore aimed to investigate the EPC number and function in patients with good and poor glycemic control.
Methods
The number of EPCs was studied using flow cytometry by co-expression of CD34 and VEGFR2. The EPCs were cultured and characterized by the expression of UEA-I, CD34, VEGFR2, vWF and Dil-Ac-LDL engulfment, as well as the ability to form capillary-like structures. An in vitro study on the effect of hyperglycemia on the proliferation and viability of the cultured EPCs was also performed.
Results
The number of EPCs in type 2 diabetes was significantly decreased compared with healthy controls and there was an inverse correlation between the EPC numbers and plasma glucose, as well as HbA1C. The number and function of EPCs in patients with good glycemic control were recovered compared with those with poor glycemic control. When glucose was supplemented in the culture in vitro, there was a negative effect on the proliferation and viability of EPCs, in a dose-dependent manner, whereas the enhancement of apoptosis was observed.
Conclusion
There was EPC dysfunction in type 2 diabetes which might be improved by strict glycemic control. However, the circulating EPC number and proliferative function in patients with good glycemic control did not reach the level in healthy controls.
doi:10.1186/1472-6823-10-5
PMCID: PMC2858721  PMID: 20374643
18.  Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration 
Background
Type 2 diabetes mellitus (T2DM) and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM.
Hypothesis
Limited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration.
Methods
Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 8 weeks. Cerebella were harvested to assess gene expression, and insulin and insulin-like growth factor (IGF) deficiency and resistance in the context of neurodegeneration.
Results
HFD ± NDEA caused T2DM, neurodegeneration with impairments in brain insulin, insulin receptor, IGF-2 receptor, or insulin receptor substrate gene expression, and reduced expression of tau and choline acetyltransferase (ChAT), which are regulated by insulin and IGF-1. In addition, increased levels of 4-hydroxynonenal and nitrotyrosine were measured in cerebella of HFD ± NDEA treated rats, and overall, NDEA+HFD treatment reduced brain levels of Tau, phospho-GSK-3β (reflecting increased GSK-3β activity), glial fibrillary acidic protein, and ChAT to greater degrees than either treatment alone. Finally, pro-ceramide genes, examined because ceramides cause insulin resistance, oxidative stress, and neurodegeneration, were significantly up-regulated by HFD and/or NDEA exposure, but the highest levels were generally present in brains of HFD+NDEA treated rats.
Conclusions
Early limited exposure to nitrosamines exacerbates the adverse effects of later chronic high dietary fat intake in promoting T2DM and neurodegeneration. The mechanism involves increased generation of ceramides and probably other toxic lipids in brain.
doi:10.1186/1472-6823-10-4
PMCID: PMC3161394  PMID: 20302640
19.  The weight lowering effect of sibutramine and its impact on serum lipids in cardiovascular high risk patients with and without type 2 diabetes mellitus - an analysis from the SCOUT lead-in period 
Background
Obesity, type 2 diabetes mellitus (T2D) and unhealthy blood lipid profile are strongly associated with the risk of developing cardiovascular disease (CVD). We examined whether blood lipid changes with short term administration of the weight lowering drug, sibutramine and lifestyle modification in obese and overweight high-risk patients was associated with T2D status at screening.
Methods
The Sibutramine Cardiovascular OUTcomes (SCOUT) trial included obese and overweight patients at increased risk of cardiovascular events. All patients received guidance on diet and exercise plus once-daily 10 mg sibutramine during the 6-week, single blind lead-in period. Multivariable regression models were used to investigate factors associated with changes in lipid levels during the first four weeks of treatment.
Results
A total of 10 742 patients received at least one dose of sibutramine during the 6-week lead-in period of SCOUT. After four weeks, patients experienced mean reductions in low density lipoprotein (LDL-C) 0.19 mmol/L, high density lipoprotein (HDL-C) 0.019 mmol/L, very low density lipoprotein (VLDL-C) 0.08 mmol/L, total cholesterol (TC) 0.31 mmol/L and triglycerides 0.24 mmol/L (p < 0.0001 for each). Four week changes in LDL-C, HDL-C and total cholesterol for patients without vs. with T2D were: LDL-C:-0.25 mmol/L vs. -0.18 mmol/L, P = 0.0004; HDL-C: -0.03 mmol/L vs. -0.02 mmol/L, P = 0.0014; total cholesterol: -0.37 mmol/l vs. -0.29 mmol/l, P = 0.0009. Multivariable regression analysis showed that similar decreases in body mass index (BMI) affected lipid changes differently according to diabetes status. A 1 kg/m2 decrease in BMI in patients with T2D was associated with -0.09 mmol/L in LDL-C (P < 0.0001) and -0.01 mmol/L in HDL-C (P = 0.0001) but larger changes of -0.16 mmol/L LDL-C and -0.03 mmol/L in HDL-C (P < 0.0001 for both) in patients without T2D.
Conclusion
Short term weight management with sibutramine therapy in obese or overweight high-risk patients induced significant mean reductions for all lipids. Those without T2D benefited most. Patients with hyperlipidaemia and the less obese patients also had greater falls in LDL-C and TC during weight loss. The trial is registered at ClinicalTrial.gov number: NCT00234832.
doi:10.1186/1472-6823-10-3
PMCID: PMC2848038  PMID: 20184783
20.  Hypothyroidism among military infants born in countries of varied iodine nutrition status 
Background
Iodine deficiency is a global problem representing the most common preventable cause of mental retardation. Recently, the impact of subtle deficiencies in iodine intake on children and pregnant women has been questioned. This study was designed to compare hypothyroidism among infants born to US military families in countries of varied iodine nutrition status.
Methods
A cohort design was used to analyze data from the Department of Defense Birth and Infant Health Registry for infants born in 2000-04 (n = 447,691). Hypothyroidism was defined using ICD-9-CM codes from the first year of life (n = 698). The impact of birth location on hypothyroidism was assessed by comparing rates in Germany, Japan, and US territories with the United States, while controlling for infant gender, plurality, gestational age, maternal age, maternal military status, and military parent's race/ethnicity.
Results
Hypothyroidism did not vary by birth location with adjusted odds ratios (OR) as follows: Germany (OR 0.82, [95% CI 0.50, 1.35]), Japan (OR 0.67, [95% CI 0.37, 1.22]), and US territories (OR 1.29, [95% CI 0.57, 2.89]). Hypothyroidism was strongly associated with preterm birth (OR 5.44, [95% CI 4.60, 6.42]). Hypothyroidism was also increased among infants with civilian mothers (OR 1.24, [95% CI 1.00, 1.54]), and older mothers, especially ages 40 years and older (OR 2.09, [95% CI 1.33, 3.30]).
Conclusions
In this study, hypothyroidism in military-dependent infants did not vary by birth location, but was associated with other risk factors, including preterm birth, civilian maternal status, and advanced maternal age.
doi:10.1186/1472-6823-10-2
PMCID: PMC2825206  PMID: 20205833
21.  Role of Receptor-Interacting Protein 140 in human fat cells 
Background
Mice lacking Receptor-interacting protein 140 (RIP140) have reduced body fat which at least partly is mediated through increased lipid and glucose metabolism in adipose tissue. In humans, RIP140 is lower expressed in visceral white adipose tissue (WAT) of obese versus lean subjects. We investigated the role of RIP140 in human subcutaneous WAT, which is the major fat depot of the body.
Methods
Messenger RNA levels of RIP140 were measured in samples of subcutaneous WAT from women with a wide variation in BMI and in different human WAT preparations. RIP140 mRNA was knocked down with siRNA in in vitro differentiated adipocytes and the impact on glucose transport and mRNA levels of target genes determined.
Results
RIP140 mRNA levels in subcutaneous WAT were decreased among obese compared to lean women and increased by weight-loss, but did not associate with mitochondrial DNA copy number. RIP140 expression increased during adipocyte differentiation in vitro and was higher in isolated adipocytes compared to corresponding pieces of WAT. Knock down of RIP140 increased basal glucose transport and mRNA levels of glucose transporter 4 and uncoupling protein-1.
Conclusions
Human RIP140 inhibits glucose uptake and the expression of genes promoting energy expenditure in the same fashion as the murine orthologue. Increased levels of human RIP140 in subcutaneous WAT of lean subjects may contribute to economize on energy stores. By contrast, the function and expression pattern does not support that RIP140 regulate human obesity.
doi:10.1186/1472-6823-10-1
PMCID: PMC2825205  PMID: 20205832

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