Whole Grain, Bran, and Germ Intake and Risk of Type 2 Diabetes: A Prospective Cohort Study and Systematic Review

Background: Control of body weight by balancing energy intake and energy expenditure is of major importance for the prevention of type 2 diabetes, but the role of specific dietary factors in the etiology of type 2 diabetes is less well established. We evaluated intakes of whole grain, bran, and germ in relation to risk of type 2 diabetes in prospective cohort studies. Methods and Findings: We followed 161,737 US women of the Nurses' Health Studies (NHSs) I and II, without history of diabetes, cardiovascular disease, or cancer at baseline. The age at baseline was 37–65 y for NHSI and 26–46 y for NHSII. Dietary intakes and potential confounders were assessed with regularly administered questionnaires. We documented 6,486 cases of type 2 diabetes during 12–18 y of follow-up. Other prospective cohort studies on whole grain intake and risk of type 2 diabetes were identified in searches of MEDLINE and EMBASE up to January 2007, and data were independently extracted by two reviewers. The median whole grain intake in the lowest and highest quintile of intake was, respectively, 3.7 and 31.2 g/d for NHSI and 6.2 and 39.9 g/d for NHSII. After adjustment for potential confounders, the relative risks (RRs) for the highest as compared with the lowest quintile of whole grain intake was 0.63 (95% confidence interval [CI] 0.57–0.69) for NHSI and 0.68 (95% CI 0.57–0.81) for NHSII (both: p-value, test for trend <0.001). After further adjustment for body mass index (BMI), these RRs were 0.75 (95% CI 0.68–0.83; p-value, test for trend <0.001) and 0.86 (95% CI 0.72–1.02; p-value, test for trend 0.03) respectively. Associations for bran intake were similar to those for total whole grain intake, whereas no significant association was observed for germ intake after adjustment for bran. Based on pooled data for six cohort studies including 286,125 participants and 10,944 cases of type 2 diabetes, a two-serving-per-day increment in whole grain consumption was associated with a 21% (95% CI 13%–28%) decrease in risk of type 2 diabetes after adjustment for potential confounders and BMI. Conclusions: Whole grain intake is inversely associated with risk of type 2 diabetes, and this association is stronger for bran than for germ. Findings from prospective cohort studies consistently support increasing whole grain consumption for the prevention of type 2 diabetes

Management of patients with diabetes and CKD : conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference

The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.Peer reviewe

A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.

Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis

A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

Correction: Volume65, Issue5 Page: 912-912 DOI: 10.1007/s00125-022-05663-z Published: MAY 2022 Early Access: MAR 2022Aims/hypothesis Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. Methods We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. Results Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m(2) units of BMI, p=2.2 x 10(-4), using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 mu mol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 mu mol/l, p=3.1 x 10(-5)). Conclusions/interpretation The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.Peer reviewe

Regulation and Function of FTO mRNA Expression in Human Skeletal Muscle and Subcutaneous Adipose Tissue

OBJECTIVE-Common variants in FTO (the fat mass- and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and nongenetic regulation of FTO mRNA in skeletal muscle and adipose tissue and their influence on in vivo glucose and fat metabolism. RESEARCH DESIGN AND METHODS-The FTO rs9939609 polymorphism was genotyped in two twin cohorts: 1) 298 elderly twins aged 62-83 years with glucose tolerance ranging from normal to type 2 diabetes and 2) 196 young (25-32 years) and elderly (58-66 years) nondiabetic twins examined by a hyperinsulinemic-euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n = 226) and skeletal muscle biopsies (n = 158). RESULTS-Heritability of FTO expression in both tissues was low, and FTO expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle, FTO mRNA expression was negatively associated to fat and positively to glucose oxidation rates as well as positively correlated with expression of genes involved in oxidative phosphorylation including PGC1 alpha. CONCLUSIONS-The heritability of FTO expression in adipose tissue and skeletal muscle is low and not influenced by obesity-associated FTO genotype. The age-dependent decline in FTO expression is associated with peripheral defects of glucose and fat metabolism. Diabetes 58:2402-2408, 200

Discerning the ancestry of European Americans in genetic association studies

European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false-positive or false-negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European, and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data

The Presence and Severity of Chronic Kidney Disease Predicts All-Cause Mortality in Type 1 Diabetes

OBJECTIVES: This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type 1 diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland. RESULTS: During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2-4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in individuals with chronic kidney disease. Individuals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5-1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroalbuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that individuals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death. CONCLUSIONS: An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of individuals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes

The ac magnetic response of mesoscopic type II superconductors

The response of mesoscopic superconductors to an ac magnetic field is numerically investigated on the basis of the time-dependent Ginzburg-Landau equations (TDGL). We study the dependence with frequency $\omega$ and dc magnetic field $H_{dc}$ of the linear ac susceptibility $\chi(H_{dc}, \omega)$ in square samples with dimensions of the order of the London penetration depth. At $H_{dc}=0$ the behavior of $\chi$ as a function of $\omega$ agrees very well with the two fluid model, and the imaginary part of the ac susceptibility, $\chi"(\omega)$, shows a dissipative a maximum at the frequency $\nu_o=c^2/(4\pi \sigma\lambda^2)$. In the presence of a magnetic field a second dissipation maximum appears at a frequency $\omega_p\ll\nu_0$. The most interesting behavior of mesoscopic superconductors can be observed in the $\chi(H_{dc})$ curves obtained at a fixed frequency. At a fixed number of vortices, $\chi"(H_{dc})$ continuously increases with increasing $H_{dc}$. We observe that the dissipation reaches a maximum for magnetic fields right below the vortex penetration fields. Then, after each vortex penetration event, there is a sudden suppression of the ac losses, showing discontinuities in $\chi"(H_{dc})$ at several values of $H_{dc}$. We show that these discontinuities are typical of the mesoscopic scale and disappear in macroscopic samples, which have a continuos behavior of $\chi(H_{dc})$. We argue that these discontinuities in $\chi(H_{dc})$ are due to the effect of {\it nascent vortices} which cause a large variation of the amplitude of the order parameter near the surface before the entrance of vortices.Comment: 12 pages, 9 figures, RevTex