Gestational glucose intolerance among pregnant women at the Cape Coast Teaching Hospital.

BACKGROUND: Malaria in pregnancy can have adverse outcomes if untreated. Both malaria and pregnancy are associated with insulin resistance and diabetes. Although malaria is treated prophylactically with gestational diabetes mellitus (GDM) screened for in pregnancy as part a routine antenatal care, their impacts have not been examined in terms of other forms of dysglycaemia. This cross-sectional study examined insulin resistance and its relationship with dysglycaemia and malaria among pregnant women in the Cape Coast Teaching Hospital (CCTH). METHODS: Using a structured questionnaire, demographic and clinical information were obtained from 252 pregnant women aged 18-42 years. Weight and height were measured for computation of body mass index (BMI). Measurement of insulin, lipid profile and glucose were taken under fasting conditions followed by oral glucose tolerant test. Insulin resistance and beta-cell function were assessed by the homeostatic model as malaria was diagnosed by microscopy. RESULTS: The respective prevalence of GDM, gestational glucose intolerance (GGI) and insulin resistance were 0.8% (2/252), 19.44% (49/252) and 56.75% (143/252). No malaria parasite or dyslipidaemia was detected in any of the participants. Apart from BMI that increased across trimesters, no other measured parameter differed among the participants. Junior High School (JHS) education compared with no formal education increased the odds (AOR: 2.53; CI: 1.12-5.71; P = 0.03) but 2nd trimester of pregnancy compared to the 1st decreased the odds (AOR: 0.32; CI: 0.12-0.81; P = 0.02) of having insulin resistance in the entire sample. In a sub-group analysis across trimesters, pregnant women with JHS education in their 3rd trimester had increased odds (AOR: 4.41; CI: 1.25-15.62; P = 0.02) of having insulin resistance. CONCLUSION: Prevalence of GDM and GGI were 0.8% and 19.44% respectively. The odds of insulin resistance increased in pregnant women with JHS education in the 3rd trimester. Appropriate measures are needed to assuage the diabetogenic risk posed by GGI in our setting.

Oral glucose tolerance test clearance in type 2 diabetes patients who underwent remission following intense lifestyle modification: A quasi-experimental study.

Achieving diabetes remission (HbA1c<48mmol/mol without the use of anti-diabetic medication for 3 months) might not assure restoration of a normal glycemic profile [fasting blood sugar level <5.6 mmol/L and Post-Prandial (PP) blood glucose <7.8mmol/L]. The study investigates the factors associated with OGTT clearance in patients under type 2 diabetes remission. Four hundred participants who achieved remission during a one-year online structured lifestyle modification program, which included a plant-based diet, physical activity, psychological support, and medical management (between January 2021 and June 2022), and appeared for the OGTT were included in the study. OGTT clearance was defined by fasting blood glucose < 5.6 mmol/L and 2-hour post-prandial blood glucose <7.8 mmol/L post-consumption of 75g glucose solution. Of the 400 participants, 207 (52%) cleared OGTT and 175 (44%) had impaired glucose tolerance (IGT). A shorter diabetes duration (<5 years) was significantly associated with OGTT clearance (p<0.05). Pre-intervention use of glucose-lowering drugs showed no association with OGTT clearance (p<0.1). Post-intervention, the OGTT-cleared group showed significantly higher weight loss (p<0.05) and a decrease in HbA1c compared to the IGT group (p<0.05). Improvement in Insulin resistance and ß-cell function was also higher in the OGTT-cleared group compared to the IGT group (p<0.05). In conclusion, clearing the OGTT is a possibility for those achieving remission through lifestyle interventions. Higher weight loss, a shorter duration of diabetes, and improvement in insulin resistance were significantly associated with OGTT clearance in participants in remission. Future randomized controlled trials with longer follow-ups may help substantiate our findings.

Impact of infrasound exposure and streptozotocin-induced glucose intolerance on bone composition in Wistar rats.

The elemental composition of chemical elements can vary between healthy and diseased tissues, providing essential insights into metabolic processes in physiological and diseased states. This study aimed to evaluate the calcium (Ca) and phosphorus (P) levels in the bones of rats with/without streptozotocin-induced diabetes and/or exposure to infrasound. X-ray fluorescence spectroscopy was used to determine the concentrations of Ca and P in Wistar rat tibiae samples.The results showed a significant decrease in bone P concentration in streptozotocin-induced diabetic rats compared to untreated animals. Similarly, the Ca/P ratio was higher in the streptozotocin-induced diabetic group. No significant differences were observed in bone Ca concentration between the studied groups or between animals exposed and not exposed to infrasound.Moreover, streptozotocin-induced diabetic rats had lower bone P concentration but unaltered bone Ca concentration compared to untreated rats. Infrasound exposure did not impact bone Ca or P levels. The reduced bone P concentration may be associated with an increased risk of bone fractures in diabetes.

Correspondence to "association of sleep patterns and cardiovascular disease risk is modified by glucose tolerance status".

After reading the article written by Wang et al., we have encountered several concerns that may compromise the credibility of the article. There are some factors, such as changes in sleep patterns, glucose tolerance status, and the use of hypnotics, which may interfere with the research results. Additionally, the design of the sleep pattern could lead to biased outcomes. Therefore, we are writing this letter to recommend that further research should take these concerns into consideration.

Prenatal Choline Supplementation Improves Glucose Tolerance and Reduces Liver Fat Accumulation in Mouse Offspring Exposed to Ethanol during the Prenatal and Postnatal Periods.

Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber-DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha (Ppara) and low-density lipoprotein receptor (Ldlr), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice.

Characterization of the gut bacterial and viral microbiota in latent autoimmune diabetes in adults.

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by autoantibodies against insulin producing pancreatic beta cells and initial lack of need for insulin treatment. The aim of the present study was to investigate if individuals with LADA have an altered gut microbiota relative to non-diabetic control subjects, individuals with type 1 diabetes (T1D), and individuals with type 2 diabetes (T2D). Bacterial community profiling was performed with primers targeting the variable region 4 of the 16S rRNA gene and sequenced. Amplicon sequence variants (ASVs) were generated with DADA2 and annotated to the SILVA database. The gut virome was sequenced, using a viral particle enrichment and metagenomics approach, assembled, and quantified to describe the composition of the viral community. Comparison of the bacterial alpha- and beta-diversity measures revealed that the gut bacteriome of individuals with LADA resembled that of individuals with T2D. Yet, specific genera were found to differ in abundance in individuals with LADA compared with T1D and T2D, indicating that LADA has unique taxonomical features. The virome composition reflected the stability of the most dominant order Caudovirales and the families Siphoviridae, Podoviridae, and Inoviridae, and the dominant family Microviridae. Further studies are needed to confirm these findings.

Mechanism of muscle atrophy in a normal-weight rat model of type 2 diabetes established by using a soft-pellet diet.

Dietary factors such as food texture affect feeding behavior and energy metabolism, potentially causing obesity and type 2 diabetes. We previously found that rats fed soft pellets (SPs) were neither hyperphagic nor overweight but demonstrated glucose intolerance, insulin resistance, and hyperplasia of pancreatic ß-cells. In the present study, we investigated the mechanism of muscle atrophy in rats that had been fed SPs on a 3-h time-restricted feeding schedule for 24 weeks. As expected, the SP rats were normal weight; however, they developed insulin resistance, glucose intolerance, and fat accumulation. In addition, skeletal muscles of SP rats were histologically atrophic and demonstrated disrupted insulin signaling. Furthermore, we learned that the muscle atrophy of the SP rats developed via the IL-6-STAT3-SOCS3 and ubiquitin-proteasome pathways. Our data show that the dietary habit of consuming soft foods can lead to not only glucose intolerance or insulin resistance but also muscle atrophy.

Glucagon kinetics assessed by mathematical modelling during oral glucose administration in people spanning from normal glucose tolerance to type 2 diabetes.

Background/Objectives: Glucagon is important in the maintenance of glucose homeostasis, with also effects on lipids. In this study, we aimed to apply a recently developed model of glucagon kinetics to determine the sensitivity of glucagon variations (especially, glucagon inhibition) to insulin levels ("alpha-cell insulin sensitivity"), during oral glucose administration. Subjects/Methods: We studied 50 participants (spanning from normal glucose tolerance to type 2 diabetes) undergoing frequently sampled 5-hr oral glucose tolerance test (OGTT). The alpha-cell insulin sensitivity and the glucagon kinetics were assessed by a mathematical model that we developed previously. Results: The alpha-cell insulin sensitivity parameter (named SGLUCA; "GLUCA": "glucagon") was remarkably variable among participants (CV=221%). SGLUCA was found inversely correlated with the mean glycemic values, as well as with 2-hr glycemia of the OGTT. When stratifying participants into two groups (normal glucose tolerance, NGT, N=28, and impaired glucose regulation/type 2 diabetes, IGR_T2D, N=22), we found that SGLUCA was lower in the latter (1.50 ± 0.50·10-2 vs. 0.26 ± 0.14·10-2 ng·L-1 GLUCA/pmol·L-1 INS, in NGT and IGR_T2D, respectively, p=0.009; "INS": "insulin"). Conclusions: The alpha-cell insulin sensitivity is highly variable among subjects, and it is different in groups at different glucose tolerance. This may be relevant for defining personalized treatment schemes, in terms of dietary prescriptions but also for treatments with glucagon-related agents.

Baseline phenotypes with preserved ß-cell function and high insulin concentrations have the best improvements in glucose tolerance after weight loss: results from the prospective DEXLIFE and EGIR-RISC studies.

BACKGROUND: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. METHODS: In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538). RESULTS: Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and ß-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. CONCLUSIONS: Individuals with preserved ß-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss.

Genetics and diet shape the relationship between islet function and whole body metabolism.

Despite the fact that genes and the environment are known to play a central role in islet function, our knowledge of how these parameters interact to modulate insulin secretory function remains relatively poor. Presently, we performed ex vivo glucose-stimulated insulin secretion and insulin content assays in islets of 213 mice from 13 inbred mouse strains on chow, Western diet (WD), and a high-fat, carbohydrate-free (KETO) diet. Strikingly, among these 13 strains, islets from the commonly used C57BL/6J mouse strain were the least glucose responsive. Using matched metabolic phenotyping data, we performed correlation analyses of isolated islet parameters and found a positive correlation between basal and glucose-stimulated insulin secretion, but no relationship between insulin secretion and insulin content. Using in vivo metabolic measures, we found that glucose tolerance determines the relationship between ex vivo islet insulin secretion and plasma insulin levels. Finally, we showed that islet glucose-stimulated insulin secretion decreased with KETO in almost all strains, concomitant with broader phenotypic changes, such as increased adiposity and glucose intolerance. This is an important finding as it should caution against the application of KETO diet for beta-cell health. Together these data offer key insights into the intersection of diet and genetic background on islet function and whole body glucose metabolism.NEW & NOTEWORTHY Thirteen strains of mice on chow, Western diet, and high-fat, carbohydrate-free (KETO), correlating whole body phenotypes to ex vivo pancreatic islet functional measurements, were used. The study finds a huge spectrum of functional islet responses and insulin phenotypes across all strains and diets, with the ubiquitous C57Bl/6J mouse exhibiting the lowest secretory response of all strains, highlighting the overall importance of considering genetic background when investigating islet function. Ex vivo basal and stimulated insulin secretion are correlated in the islet, and KETO imparts widescale downregulation of islet insulin secretion.

Glucose tolerance and insulin resistance/sensitivity associate with retinal layer characteristics: the LIFE-Adult-Study.

AIMS/HYPOTHESIS: As the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset. METHODS: The LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA1c 5.7-6.4% [39-47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings. RESULTS: In the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised ß=-0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; ß=-0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (ß=0.090; p<0.001 for eGDR) and MZ (ß=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis. CONCLUSIONS/INTERPRETATION: An impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes.

A maternal low-protein diet impaired glucose metabolism and altered the lncRNA profiles of islets in adult offspring.

A maternal low-protein diet during pregnancy can increase children's susceptibility to diabetes mellitus in adulthood. However, whether long noncoding RNAs (lncRNAs) in islets participate in the development of diabetes in adult offspring following maternal protein restriction is not fully understood. Female mice were fed a low-protein (LP) diet or control diet throughout gestation and lactation. The male offspring were then randomly divided into two groups according to maternal diet: offspring from control diet group dams (Ctrl group) and offspring from LP group dams (LP group). We observed the glucose metabolism of adult offspring. A lncRNA microarray was constructed for the islets from the LP group and Ctrl group to explore the differently expressed lncRNAs. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes analyses were subsequently used to predict the functions of the differently expressed lncRNAs. The body weight from birth to 12 weeks of age was significantly lower in the LP offspring. Adult LP offspring exhibited impaired glucose tolerance and decreased insulin secretion, consistent with the reduction in ß-cell proliferation. According to the lncRNA microarray, four lncRNAs, three upregulated lncRNAs, and one downregulated lncRNA were differently expressed in LP offspring islets compared with Ctrl offspring. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed lncRNAs were mostly associated with the hypoxia-inducible factor-1α signaling pathway. Additionally, we validated the expression of these four differentially expressed lncRNAs via quantitative real-time polymerase chain reaction. Our findings demonstrated the expression patterns of lncRNAs in islets from adult offspring of mothers who consumed a maternal low-protein diet.

[Association between abnormal oral glucose tolerance test patterns in the second trimester and large for gestational age newborns].

Objective: To investigate the impact of abnormal patterns of 75 g oral glucose tolerance test (OGTT) in the second trimester on the risk of large for gestational age (LGA) newborn deliveries. Methods: General clinical data and OGTT results of 66 290 pregnant women who received regular prenatal care and delivered in Guangdong Maternal and Child Health Hospital from December 24, 2016 to July 26, 2022 were collected. According to the results of OGTT, the pregnant women were divided into 8 groups: normal blood glucose group (normal fasting blood glucose, 1-hour and 2-hour after oral glucose, 54 518 cases), gestational diabetes mellitus (GDM) 0 group (only abnormal fasting blood glucose, 1 430 cases), GDM 1 group (only abnormal blood glucose at 1-hour after oral glucose, 2 150 cases), GDM 2 group (only abnormal blood glucose at 2-hour after oral glucose, 3 736 cases), GDM 0+1 group (both fasting blood glucose and 1-hour after oral glucose were abnormal, 371 cases), GDM 0+2 group (both fasting blood glucose and 2-hour after oral glucose were abnormal, 280 cases), GDM 1+2 group (abnormal blood glucose at 1-hour and 2-hour after oral glucose, 2 981 cases) and GDM 0+1+2 group (abnormal fasting blood glucose, 1-hour and 2-hour after oral glucose, 824 cases). Multivariate logistic regression was used to analyze the effects of different abnormal OGTT patterns on LGA. In addition, the blood glucose measurements at the three time points of OGTT were combined and used as continuous variables in the receiver operating characteristic (ROC) curve to evaluate the predictive value of each blood glucose measurement mode for LGA and the area under the curve (AUC) was compared. Results: (1) Multivariate logistic regression analysis showed that the risks of LGA were significantly increased in GDM 0 group (OR=1.76, 95%CI: 1.50-2.08; P<0.001), GDM 0+1 group (OR=2.29, 95%CI: 1.72-3.04; P<0.001), and GDM 0+1+2 group (OR=1.98, 95%CI: 1.61-2.43; P<0.001). (2) ROC curve analysis showed that fasting blood glucose, 1-hour after oral glucose, 2-hour after oral glucose, fasting+1-hour after oral glucose, fasting+2-hour after oral glucose, 1-hour+2-hour after oral glucose, and fasting+1-hour+2-hour after oral glucose had certain predictive value for LGA (all P<0.001). The AUC of fasting blood glucose measurement was higher than that of 2-hour blood glucose measurement in predicting LGA, and the difference was statistically significant (P<0.05). There was no significant difference in the AUC between fasting blood glucose and other blood glucose measurement modes for predicting LGA (all P>0.05). Conclusions: In the abnormal OGTT patterns, pregnant women with abnormal fasting blood glucose, abnormal fasting+1-hour after oral glucose, and abnormal fasting+1-hour+2-hour after oral glucose have an increased risk of LGA. Fasting blood glucose measurement is of great significance for the prediction of LGA, and could be used as an optimal indicator to evaluate the risk of LGA in clinical practice.

The prostaglandin E2 EP3 receptor has disparate effects on islet insulin secretion and content in ß-cells in a high-fat diet-induced mouse model of obesity.

Signaling through prostaglandin E2 EP3 receptor (EP3) actively contributes to the ß-cell dysfunction of type 2 diabetes (T2D). In T2D models, full-body EP3 knockout mice have a significantly worse metabolic phenotype than wild-type controls due to hyperphagia and severe insulin resistance resulting from loss of EP3 in extra-pancreatic tissues, masking any potential beneficial effects of EP3 loss in the ß cell. We hypothesized ß-cell-specific EP3 knockout (EP3 ßKO) mice would be protected from high-fat diet (HFD)-induced glucose intolerance, phenocopying mice lacking the EP3 effector, Gαz, which is much more limited in its tissue distribution. When fed a HFD for 16 wk, though, EP3 ßKO mice were partially, but not fully, protected from glucose intolerance. In addition, exendin-4, an analog of the incretin hormone, glucagon-like peptide 1, more strongly potentiated glucose-stimulated insulin secretion in islets from both control diet- and HFD-fed EP3 ßKO mice as compared with wild-type controls, with no effect of ß-cell-specific EP3 loss on islet insulin content or markers of replication and survival. However, after 26 wk of diet feeding, islets from both control diet- and HFD-fed EP3 ßKO mice secreted significantly less insulin as a percent of content in response to stimulatory glucose, with or without exendin-4, with elevated total insulin content unrelated to markers of ß-cell replication and survival, revealing severe ß-cell dysfunction. Our results suggest that EP3 serves a critical role in temporally regulating ß-cell function along the progression to T2D and that there exist Gαz-independent mechanisms behind its effects.NEW & NOTEWORTHY The EP3 receptor is a strong inhibitor of ß-cell function and replication, suggesting it as a potential therapeutic target for the disease. Yet, EP3 has protective roles in extrapancreatic tissues. To address this, we designed ß-cell-specific EP3 knockout mice and subjected them to high-fat diet feeding to induce glucose intolerance. The negative metabolic phenotype of full-body knockout mice was ablated, and EP3 loss improved glucose tolerance, with converse effects on islet insulin secretion and content.

Alteration of Sweet and Bitter Taste Sensitivity with Development of Glucose Intolerance in Non-insulin-Dependent Diabetes Mellitus Model OLETF Rats.

Patients with diabetes exhibit altered taste sensitivity, but its details have not been clarified yet. Here, we examined alteration of sweet taste sensitivity with development of glucose intolerance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of non-insulin-dependent diabetes mellitus. Compared to the cases of Long Evans Tokushima Otsuka (LETO) rats as a control, glucose tolerance of OLETF rats decreased with aging, resulting in development of diabetes at 36-weeks-old. In brief-access tests with a mixture of sucrose and quinine hydrochloride, OLETF rats at 25 or more-weeks-old seemed to exhibit lower sweet taste sensitivity than age-matched LETO ones, but the lick ratios of LETO, but not OLETF, rats for the mixture and quinine hydrochloride solutions decreased and increased, respectively, aging-dependently. Expression of sweet taste receptors, T1R2 and T1R3, in circumvallate papillae (CP) was almost the same in LETO and OLETF rats at 10- and 40-weeks-old, while expression levels of a bitter taste receptor, T2R16, were greater in 40-weeks-old rats than in 10-weeks-old ones in both strains. There was no apparent morphological alteration in taste buds in CP between 10- and 40-weeks-old LETO and OLETF rats. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. Collectively, we concluded that the apparent higher sweet taste sensitivity in 25 or more-weeks-old OLETF rats than in age-matched LETO rats was due to the aging-dependent increase of bitter taste sensitivity in LETO rats with alteration of the gut microbiota.

Natural History of Type 2 Diabetes in Indians: Time to Progression.

OBJECTIVE: To describe the natural history of diabetes in Indians. RESEARCH DESIGN AND METHODS: Data are from participants older than 20 years in the Centre for Cardiometabolic Risk Reduction in South Asia longitudinal study. Glycemic states were defined per American Diabetes Association criteria. Markov models were used to estimate annual transition probabilities and sojourn time through states. RESULTS: Among 2,714 diabetes-free participants, 641 had isolated impaired fasting glucose (iIFG), and 341 had impaired glucose tolerance (IGT). The annual transition to diabetes for those with IGT was 13.9% (95% CI 12.0, 15.9) versus 8.6% (7.3, 9.8) for iIFG. In the normoglycemia ↔ iIFG → diabetes model, mean sojourn time in normoglycemia was 40.3 (34.6, 48.2) years, and sojourn time in iIFG was 9.7 (8.4, 11.4) years. For the normoglycemia ↔ IGT → diabetes model, mean sojourn time in normoglycemia was 34.5 (29.5, 40.8) years, and sojourn time in IGT was 6.1 (5.3, 7.1) years. CONCLUSIONS: Individuals reside in normoglycemia for 35-40 years; however, progression from prediabetes to diabetes is rapid.

Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene.

Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT.

Tipepidine activates AMPK and improves adipose tissue fibrosis and glucose intolerance in high-fat diet-induced obese mice.

Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) (TP) is a non-narcotic antitussive used in Japan. Recently, the potential application of TP in the treatment of neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder, has been suggested; however, its functions in energy metabolism are unknown. Here, we demonstrate that TP exhibits a metabolism-improving action. The administration of TP reduced high-fat diet-induced body weight gain in mice and lipid accumulation in the liver and increased the weight of epididymal white adipose tissue (eWAT) in diet-induced obese (DIO) mice. Furthermore, TP inhibited obesity-induced fibrosis in the eWAT. We also found that TP induced AMP-activated protein kinase (AMPK) activation in the eWAT of DIO mice and 3T3-L1 cells. TP-induced AMPK activation was abrogated by the transfection of liver kinase B1 siRNA in 3T3-L1 cells. The metabolic effects of TP were almost equivalent to those of metformin, an AMPK activator that is used as a first-line antidiabetic drug. In summary, TP is a potent AMPK activator, suggesting its novel role as an antidiabetic drug owing to its antifibrotic effect on adipose tissues.