A longitudinal study on patients with diabetes and symptoms of gastroparesis – associations with impaired quality of life and increased depressive and anxiety symptoms

Aims

To examine patient reported outcomes (PRO) in patients previously assessed for diabetic gastroparesis, and to investigate how symptoms of gastroparesis evolve over time. In addition, to further evaluate outcomes in those with versus without diabetic gastroparesis at baseline.

Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: Phase I results of the Indian Council of Medical Research�CINdia DIABetes (ICMR�CINDIAB) study

Aims/hypothesis

This study reports the results of the first phase of a national study to determine the prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in India.

Methods

A total of 363 primary sampling units (188 urban, 175 rural), in three states (Tamilnadu, Maharashtra and Jharkhand) and one union territory (Chandigarh) of India were sampled using a stratified multistage sampling design to survey individuals aged ??20?years. The prevalence rates of diabetes and prediabetes were assessed by measurement of fasting and 2?h post glucose load capillary blood glucose.

Results

Of the 16,607 individuals selected for the study, 14,277 (86%) participated, of whom 13,055 gave blood samples. The weighted prevalence of diabetes (both known and newly diagnosed) was 10.4% in Tamilnadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh. The prevalences of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were 8.3%, 12.8%, 8.1% and 14.6% respectively. Multiple logistic regression analysis showed that age, male sex, family history of diabetes, urban residence, abdominal obesity, generalised obesity, hypertension and income status were significantly associated with diabetes. Significant risk factors for prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status.

Conclusions/interpretations

We estimate that, in 2011, Maharashtra will have 6 million individuals with diabetes and 9.2 million with prediabetes, Tamilnadu will have 4.8 million with diabetes and 3.9 million with prediabetes, Jharkhand will have 0.96 million with diabetes and 1.5 million with prediabetes, and Chandigarh will have 0.12 million with diabetes and 0.13 million with prediabetes. Projections for the whole of India would be 62.4 million people with diabetes and 77.2 million people with prediabetes.     

Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in β-cells

The circadian clock has been shown to regulate metabolic homeostasis. Mice with a deletion of Bmal1, a key component of the core molecular clock, develop hyperglycemia and hypoinsulinemia, suggesting β-cell dysfunction. However, the underlying mechanisms are not fully known. In this study, we investigated the mechanisms underlying the regulation of β-cell function by Bmal1. We studied β-cell function in global Bmal1-/- mice, in vivo and in isolated islets ex vivo, as well as in rat insulinoma cell lines with shRNA-mediated Bmal1 knockdown. Global Bmal1-/- mice develop diabetes secondary to a significant impairment in glucose-stimulated insulin secretion (GSIS). There is a blunting of GSIS in both isolated Bmal1-/- islets and in Bmal1 knockdown cells, as compared to controls, suggesting that this is secondary to a loss of cell-autonomous effect of Bmal1. In contrast to previous studies, in these Bmal1-/- mice on a C57Bl/6 background, the loss of stimulated insulin secretion, interestingly, is with glucose but not to other depolarizing secretagogues, suggesting that events downstream of membrane depolarization are largely normal in Bmal1-/- islets. This defect in GSIS occurs as a result increased mitochondrial uncoupling with consequent impairment of glucose-induced mitochondrial potential generation and ATP synthesis, due to an upregulation of Ucp2. Inhibition of Ucp2, in isolated islets, leads to a rescue of the glucose-induced ATP production and insulin secretion in Bmal1-/- islets. Thus, Bmal1 regulates mitochondrial energy metabolism to maintain normal GSIS and its disruption leads to diabetes due to a loss of GSIS.     

c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo

c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells in vivo, apoptosis is preceded by hyperglycemia, suggesting glucotoxicity might contribute to Myc-induced apoptosis. To address this question conditional Myc was activated in β-cells of adult pIns-c-MycER(TAM) mice in vivo in the presence or absence of various glucose-lowering treatments, including exogenous insulin and prior to transplantation with wild-type islets. Changes in blood glucose levels were subsequently correlated with changes in β-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of β-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of β-cells. Therefore, Myc can cause diabetes by direct effects on β-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of β-cell differentiation/function and hyperglycemia are not prevented by preventing β-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and β-cell failure through two distinct pathways.     

Elevated serum γ-glutamyltransferase predicts the development of impaired glucose metabolism in middle-aged and elderly Chinese

The aim of this article is to prospectively investigate the association of the liver enzyme γ-glutamyltransferase (GGT) with the development of diabetes and impaired glucose regulation (IGR) in a Chinese population. Seven hundred and sixty normoglycaemic subjects aged 40?years or older randomly selected from an urban community of Shanghai received a baseline investigation in May 2005. The participants were invited to receive a standard 75-g oral glucose tolerance test (OGTT) in November 2008. Incident diabetes and IGR were determined according to the 1999 WHO criteria. Serum GGT levels were significantly associated with incident diabetes or combined diabetes and IGR prospectively. After extensive adjustment, the diabetes risk was significantly increased with incrementing serum GGT quartiles (P value for trend?=?0.0027). As compared with the lowest quartile of GGT, the highest quartile had an adjusted hazard ratio of 1.30 (95% CI 1.03-1.65) for developing combined diabetes and IGR. Furthermore, a high serum GGT level at baseline was independently associated with an increase in the index of homeostasis model assessment of insulin resistance (HOMA-IR) at follow-up. Serum GGT concentration, even within its normal range, is a risk marker for developing impaired glucose metabolism in middle-aged and elderly Chinese.     

c-Myc directly induces both impaired insulin secretion and loss of β-cell mass,independently of hyperglycemia in vivo

c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells in vivo, apoptosis is preceded by hyperglycemia, suggesting glucotoxicity might contribute to Myc-induced apoptosis. To address this question conditional Myc was activated in β-cells of adult pIns-c-MycERTAM mice in vivo in the presence or absence of various glucose-lowering treatments, including exogenous insulin and prior to transplantation with wild-type islets. Changes in blood glucose levels were subsequently correlated with changes in β-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of β-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of β-cells. Therefore, Myc can cause diabetes by direct effects on β-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of β-cell differentiation/function and hyperglycemia are not prevented by preventing β-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and β-cell failure through 2 distinct pathways.     

Is spleen circulation impaired in systemic sclerosis and what is the role of liver fibrosis？

AIM:To investigate the spleen vascular involvement and the presence of liver fibrosis in a population of subjects with established systemic sclerosis(SSc).METHODS:In a cross-sectional fashion,17 patients with SSc were compared with 18 patients suffering from hepatitis C virus(HCV) -related liver cirrhosis,grade A and B Child-Pugh classification.Eighteen non elderly subjects,apparently healthy,were used as the control group.Splenic artery resistivity index(SARI) at doppler ultraSound,transient elastography o...     

Intermediate postchallenge hyperglycemia in overweight and obese subjects: a new marker of impaired glucose regulation?

The objective of this study was to compare subjects with intermediate postchallenge hyperglycemia (INPH) to those with normal glycemic status, impaired fasting glucose (IFG), and/or impaired glucose tolerance (IGT), as well as type 2 diabetes mellitus. Furthermore, the authors evaluated the impact of INPH on target organ damage. In total, 487 overweight and obese adults (BMI > or =27 kg/m(2)), 252 men and 235 women, mean age 52.9 +/-10.2 years, were studied. All participants underwent a clinical and laboratory evaluation, as well as an oral glucose tolerance test (OGTT). They were also investigated by echocardiography, carotid ultrasonography, and pulse wave analysis. Overall, 302 (62%) subjects had normal glycemic status, 64 (13.1%) had IFG and/or IGT, 95 (19.5%) had type 2 diabetes mellitus, and 26 (5.4%) had INPH. Individuals with INPH had an increased index of insulin resistance (higher homeostasis model assessment-insulinogenic index [HOMA-IR], p<0.0001), impaired insulin secretion (lower insulinogenic index, p<0.0001), and higher glycosylated hemoglobin (HbA(1c)) levels (p<0.0001) in comparison with the normoglycemic subjects, but not to those with IFG and/or IGT or diabetes (p = 0.6). No difference was observed concerning the risk factors studied, left ventricular mass and vascular remodeling, among subjects with INPH, IFG and/or IGT, and diabetes. However, individuals with INPH had a higher proportion of echolucent carotid artery plaques in comparison with the normoglycemic subjects (p = 0.04) and those with IFG and/or IGT (p = 0.01). Intermediate postchallenge hyperglycemia seems to represent a new category of glucose metabolism disturbances with increased atherogenic impact. Therefore, evaluating intermediate glucose levels in an OGTT could contribute to better identify overweight individuals at risk of developing diabetes mellitus and cardiovascular events.     

How much can you drink before driving? The influence of riding with impaired adults and peers on the driving behaviors of urban and rural youth

AIMS: Following an ecological model to specify risks for impaired driving, we assessed the effects of youth attitudes about substance use and their experiences of riding in cars with adults and peers who drove after drinking alcohol or smoking cannabis on the youths' own driving after drinking or using cannabis. DESIGN AND METHODS: Participants were 2594 students in grades 10 and 12 (mean age = 16 years and 2 months; 50% girls) from public high schools in urban (994) and rural communities (1600) on Vancouver Island in British Columbia, Canada; 1192 of these were new drivers with restricted licenses. Self-report data were collected in anonymous questionnaires. Regression analyses were used to assess the independent and interacting effects of youth attitudes about substance use and their experiences of riding in cars with adults or peers who drove after drinking alcohol or smoking cannabis on youth driving. FINDINGS: Youth driving risk behaviors were associated independently with their own high-risk attitudes and experiences riding with peers who drink alcohol or use cannabis and drive. However, risks were highest for the youth who also report more frequent experiences of riding with adults who drink alcohol or use cannabis and drive. CONCLUSIONS: Prevention efforts should be expanded to include the adults and peers who are role models for new drivers and to increase youths' awareness of their own responsibilities for their personal safety as passengers.     

Primary aldosteronism and impaired natriuresis in mice underexpressing TGFβ1

To uncover the potential cardiovascular effects of human polymorphisms influencing transforming growth factor β1 (TGFβ1) expression, we generated mice with Tgfb1 mRNA expression graded in five steps from 10% to 300% normal. Adrenal expression of the genes for mineralocorticoid-producing enzymes ranged from 50% normal in the hypermorphs at age 12 wk to 400% normal in the hypomorphs accompanied with proportionate changes in plasma aldosterone levels, whereas plasma volumes ranged from 50% to 150% normal accompanied by marked compensatory changes in plasma angiotensin II and renin levels. The aldosterone/renin ratio ranged from 0.3 times normal in the 300% hypermorphs to six times in the 10% hypomorphs, which have elevated blood pressure. Urinary output of water and electrolytes are markedly decreased in the 10% hypomorphs without significant change in the glomerular filtration rate. Renal activities for the Na⁺, K⁺-ATPase, and epithelial sodium channel are markedly increased in the 10% hypomorphs. The hypertension in the 10% hypomorphs is corrected by spironolactone or amiloride at doses that do not change blood pressure in wild-type mice. Thus, changes in Tgfb1 expression cause marked progressive changes in multiple systems that regulate blood pressure and fluid homeostasis, with the major effects being mediated by changes in adrenocortical function.     

Determinants of progression from impaired fasting glucose and impaired glucose tolerance to diabetes in a high-risk screened population: 3 year follow-up in the ADDITION study,Denmark

Aims/hypothesis We sought to identify determinants of progression from impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) to diabetes in high-risk screened individuals. Methods In general practices in Denmark, stepwise screening for type 2 diabetes mellitus in persons aged 40 to 69 years included a risk questionnaire, random blood glucose, HbA_1c, fasting blood glucose and an OGTT. The 1,821 individuals with IGT or isolated IFG (WHO 1999) were re-invited after 1 and 3 years. Follow-up data on glucose measurements were available in 1,510 individuals and additional clinical data in 1,002 collected at the 3-year visits. Regression models using interval censoring were used. Results Progression rates from IFG and IGT to diabetes over 3.5 years were 11.8 and 17.0 per 100 person-years, respectively and were particularly high in the first year. Baseline determinants of progression were: IFG: glucose measures, BMI [per kg/m², rate ratio (RR) 1.04 (95% CI, 1.01–1.08)] and triacylglycerol [per twofold increase, RR 2.19 (1.49–3.22)]; and IGT: glucose measures and known hypertension [RR 1.46 (1.11–1.93)]. Weight reduction and decreased triacylglycerol were inversely associated with development of diabetes in IFG individuals [per 1 kg/year, RR 0.81 (0.66–0.98) and per 1 mmol l⁻¹ year⁻¹, RR 0.08 (0.01–0.51), respectively], whereas in IGT participants only weight reduction was inversely associated [per 1 kg/year, RR 0.80 (0.67–0.96)]. Conclusions/interpretation Higher levels of glucose measures, larger BMI, known hypertension and hypertriacylglycerolaemia are significant determinants of progression in high-risk screened individuals. Weight loss of 1 kg/year or reduction of hypertriacylglycerolaemia markedly reduced the risk of diabetes.     

Ablation of triadin causes loss of cardiac Ca2+ release units,impaired excitation–contraction coupling,and cardiac arrhythmias

Heart muscle excitation–contraction (E-C) coupling is governed by Ca²⁺ release units (CRUs) whereby Ca²⁺ influx via L-type Ca²⁺ channels (Cav1.2) triggers Ca²⁺ release from juxtaposed Ca²⁺ release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn^−/−). The structure and protein composition of the cardiac CRU is significantly altered in Trdn^−/− hearts. jSR proteins (RyR2, Casq2, junctin, and junctophilin 1 and 2) are significantly reduced in Trdn^−/− hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn^−/− myocytes. CRU function is impaired in Trdn^−/− myocytes, with reduced SR Ca²⁺ release and impaired negative feedback of SR Ca²⁺ release on Cav1.2 Ca²⁺ currents (I_Ca). Uninhibited Ca²⁺ influx via I_Ca likely contributes to Ca²⁺ overload and results in spontaneous SR Ca²⁺ releases upon β-adrenergic receptor stimulation with isoproterenol in Trdn^−/− myocytes, and ventricular arrhythmias in Trdn^−/− mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.     

Pan-enteric dysmotility, impaired quality of life and alexithymia in a large group of patients meeting ROME Ⅱ criteria for irritable bowel syndrome

AIM: Psychological factors, altered motility and sensationd isorders of the intestine can be variably associated with irritable bowel syndrome (IBS). Such aspects have not been investigated simultaneously. The aim of this paper was to evaluate gastrointestinal motility and symptoms, psychological spectrum and quality of life in a large group of IBS patients in southern Italy. METHODS: One hundred IBS patients (F:M=73:27, age48&#177;2 years, mean&#177;SE) fulfilling ROME Ⅱ criteria matched with 100 healthy subjects (F:M=70:30, 45&#177;2 years). Dyspepsia,bowel habit, alexithymia, psycho-affective profile and quality of life were assessed using specific questionnaires. Basally and postprandially, changes in gallbladder volumes and antral areas after liquid meal and orocaecal transit time (OCTT) were measured respectively by ultrasonography and H2-breath test. Appetite, satiety, fullness, nausea, and epigastric pain/discomfort were monitored using visual-analogue scales. RESULTS: Compared with controls, IBS patients had increased dyspepsia (score 12.6&#177;0.7 vs 5.1&#177;0.2, P&lt;0.0001),weekly bowel movements (12.3&#177;0.4 vs 5.5&#177;0.2, P&lt;0.00001, comparable stool shape), alexithymia (score 59.1&#177;1.1 vs40.5&#177;1.0, P=0.001), poor quality of life and psychoaffective profile. IBS patients had normal gallbladder emptying, but delayed gastric emptying (T50:35.5&#177;1.0 vs 26.1&#177;0.6 min, P=0.00001) and OCTT (163.0&#177;5.4 vs 96.6&#177;1.8min, P=0.00001). Fullness, nausea, and epigastric pain/discomfort were greater in IBS than in controls. CONCLUSION: ROME Ⅱ IBS patients have a pan-enteric dysmotility with frequent dyspepsia, associated with psychological morbidity and greatly impaired quality of life. The presence of alexithymia, a stable trait, is a novel finding of potential interest to detect subgroups of IBS patients with different patterns recoveed after therapy.     

Left and right ventricular function is impaired in Behçet's disease

Objectives: Subclinical cardiac involvement may occur in patients with Behçet's disease (BD). The purpose of our study was to assess the noninvasive parameters of biventricular function derived from Doppler tissue imaging (DTI) of the tricuspid and mitral annular motion in BD. Methods: Twenty‐one patients with BD and 20 control subjects were enrolled in this study. All subjects were selected to exclude those with cardiovascular risk factors. Standard echocardiography and pulsed DTI were obtained in every patient. Results: Peak systolic (13.71 ± 2.09 vs 20.01 ± 1.57, P < 0.001), peak early diastolic (11.26 ± 2.52 vs 15.35 ± 2.06, P < 0.001) tricuspid annular velocities were significantly lower in patients than controls. Peak systolic (8.68 ± 1.4 vs 12.25 ± 1.7, P < 0.001), peak early diastolic (7.89 ± 1.07 vs 9.94 ± 1.12, P < 0.001), and peak end diastolic (8.30 ± 1.32 vs 9.23 ± 0.91, P = 0.013) lateral mitral annular velocities were significantly lower in patients than controls. Conclusions: We demonstrated that myocardial velocities, were affected in patients with BD. Therefore, we conclude that right and left ventricular function is impaired in patients with BD.