Diabetic Phenotype Research Articles

Imaging biomarkers and clinical factors associated with the rate of progressive inner and outer retinal thinning in patients with diabetic macular edema

The aim of this study was to assess the relationship of clinical characteristics to the rate of retinal thinning in eyes with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (VEGF) therapy. We analyzed subjects with a long-term follow-up (≥ 3 years) and evidence of resolved DME after the initiation of anti-VEGF therapy (baseline visit). To measure the long-term rate of retinal thinning during treatment, a second visit (first visit with evidence of resolved DME after 3 years) was also considered. A longitudinal quantitative topographical assessment of the inner and outer retinal thicknesses was provided. Clinical characteristics were associated with the rate of longitudinal retinal thinning. We included 56 eyes (50 patients) in the analysis. A significant longitudinal thinning in the inner and outer retina was detected in all the analyzed regions (p values between 0.027 and < 0.0001). In the multivariable analysis, type of diabetes (type 2 vs. type 1) was associated with increased foveal inner retinal thinning (p = 0.019). A higher number of subfoveal neuroretinal detachment during follow-up (p = 0.006) was associated with faster rates of foveal outer retinal thinning. Type of diabetes (p < 0.0001), higher age (p = 0.033) and cystoid macular edema phenotype (p = 0.040) were associated with increased parafoveal inner retinal thinning. Gender (p = 0.003) and diabetic retinopathy stage (p = 0.013) were associated with faster rates of perifoveal inner retinal thinning, while diabetic retinopathy stage (p = 0.036) was associated with increased perifoveal outer retinal thinning. In conclusion, clinical factors, including DME phenotypes, were associated with the rates of retinal thinning in patients undergoing anti-VEGF treatment.

High-fat-diet induced obesity and diabetes mellitus in Th1 and Th2 biased mice strains: A brief overview and hypothesis.

Obesity and diabetes mellitus are common metabolic diseases prevalent worldwide. Mice are commonly used to study the pathogenesis of these two conditions. Obesity and diabetes mellitus are induced by administering a high-fat diet in many studies although other diet-induced models are also used. Several factors may influence the outcome of the studies done to study diet-induced obesity in mice. The immune system plays a crucial role in the susceptibility of mice to develop obesity and metabolic disease. In this article, the reasons for differences in susceptibility to develop obesity and diabetes mellitus in mice in response to high-fat-diet feeding and the influence of immunological bias of the mice strain used in studies are evaluated. Mice strains that induce proinflammatory and Th1-type immune responses are found to be susceptible to high-fat-diet-induced obesity. A few studies which directly compared the effect of a high-fat diet on obesity and diabetic phenotype in Th1- and Th2-biased mice strains were briefly analyzed. Based on the observations, it is proposed that the liver and adipose tissue may respond differently to high-fat-diet feeding regimens in Th1- and Th2-biased mice strains. For instance, in Th1-biased mice, adipose tissue fat content was high both in the baseline as well as in response to a high-fat diet whereas in the liver, it was found to be less. It can be inferred that the immune responses to diet-induced models may provide insights into the pathogenesis of obesity and diabetes mellitus.

High fat diet is protective against kidney injury in hypertensive-diabetic mice, but leads to liver injury.

Chronic kidney disease (CKD) is a worldwide health burden with increases risk of end-stage renal function if left untreated. CKD induced in the context of metabolic syndrome (MS) increases risks of hypertension, hyperglycemia, excess body fat and dyslipidemia. To test if combining a high-fat diet (HFD) regimen onto the hypertensive/ diabetic phenotype would mimic features of MS induced-CKD in mice, hyperglycemia was induced in genetically hypertensive mice (Lin), followed by HFD regimen. For that, 8-week-old male were subjected to streptozotocin (STZ) intraperitoneal (i.p.) injections (50 mg/kg, 5 days consecutive). LinSTZ were fed a 60% kCal HFD for 8 weeks. Lin mice treated with STZ developed polydipsia, became hypertensive and hyperglycemic. HFD induced weight gain, protected against glomerular hypertrophy, scarring, and albuminuria at endpoint compared to regular diet fed LinSTZ. On the other hand, HFD induced steatosis, liver fibrosis, inflammation, and increase in AST/ALT ratio, characteristics of non-alcoholic liver disease. Taken together, our results show that LinSTZ mice fed a HFD did not lead to a more robust model of MS-induced CKD, protected against kidney injury, but inducing liver damage. More studies are necessary to understand the kidney protective mechanisms of HFD when superimposed with hypertension and type 1 diabetes.

Leptin-deficient ob/ob mice exhibit periodontitis phenotype and altered oral microbiome.

Leptin-deficient obesity is associated with various systemic diseases including diabetes and low bone mass phenotype. However, the periodontal status of leptin-deficient obese individuals is still unclear. In this study, we aimed to analyze the periodontal status, alveolar bone phenotype, and oral microbiome status in leptin-deficient obese mice (ob/ob mice). This study used 12-week-old wild-type and ob/ob male mice. The alveolar bone phenotype and periodontal status in the maxilla were analyzed by micro-CT and histological analysis. Osteoclasts in alveolar bone were visualized by TRAP staining. Expressions of inflammatory markers (MMP-9, IL-1β, and TGF-β1) and osteoclastogenic markers (RANKL and OPG) in periodontium were analyzed by immunohistochemistry and RT-qPCR. The oral microbiome was analyzed by 16 S rDNA sequencing. CEJ-ABC distance in maxillary molars (M1-M3) of ob/ob mice was significantly higher compared with that of wild-type. The alveolar bone BV/TV ratio was reduced in ob/ob mice compared with wild-type. Higher numbers of osteoclasts were observed in ob/ob mice alveolar bone adjacent to the molar root. Epithelial hyperplasia in gingiva and disordered periodontal ligaments was observed in ob/ob mice. RANKL/OPG expression ratio was increased in ob/ob mice compared with wild-type. Expressions of inflammatory markers MMP-9, IL-1β, and TGF-β1 were increased in ob/ob mice compared with wild-type. Oral microbiome analysis showed that beneficial bacteria Akkermansia and Ruminococcaceae_UCG_014 were more abundant in the wild-type mice while the inflammation-related Flavobacterium was more abundant in ob/ob mice. In conclusion, ob/ob mice showed higher expressions of inflammatory factors, increased alveolar bone loss, lower abundance of the beneficial bacteria, and higher abundance of inflammatory bacteria in the oral cavity, suggesting leptin-deficient obesity as a risk factor for periodontitis development in ob/ob mice.

Urinary Markers of Tubular Injury and Renal Fibrosis in Patients with Type 2 Diabetes and Different Phenotypes of Chronic Kidney Disease

This study assessed the urinary excretion of markers and mediators of tubular injury and renal fibrosis in patients with type 2 diabetes (T2D) and non-albuminuric and albuminuric patterns of chronic kidney disease (CKD). One hundred and forty patients with long-term T2D and different patterns of CKD and twenty non-diabetic individuals were included. Urinary retinol-binding protein 4 (RBP-4), glutathione-S-transferase α1 and π (GST-α1 and GST-π), transforming growth factor β (TGF-β), type I and type IV collagen (Col1 and Col4), bone morphogenic protein 7 (BMP-7), and hepatocyte growth factor (HGF) were assessed by ELISA. Patients with T2D demonstrated increased urinary excretion of RBP-4, GST-π, Col4, BMP-7, and HGF (all p < 0.05 vs. control). The excretion of RBP-4, GST-π, Col1, and Col4 was increased in patients with elevated albumin-to-creatinine ratio (UACR; all p < 0.05 vs. control), while BMP-7 and HGF were increased innormoalbuminuric patients also (p < 0.05). Urinary RBP-4, GST-α1, Col1, Col4, and HGF correlated positively with UACR; meanwhile, no correlations with glomerular filtration rate were found. The results demonstrate that elevated urinary excretions of the markers of tubular injury (RBP-4, GST-π) and renal fibrosis (Col1, Col4), as well as HGF, an antifibrotic regulator, are associated with the albuminuric pattern of CKD in subjects with T2D.

Identifying the necessary capacities for the adaptation of a diabetes phenotyping algorithm in countries of differing economic development status

ABSTRACT Background In 2019, the World Health Organization recognised diabetes as a clinically and pathophysiologically heterogeneous set of related diseases. Little is currently known about the diabetes phenotypes in the population of low- and middle-income countries (LMICs), yet identifying their different risks and aetiology has great potential to guide the development of more effective, tailored prevention and treatment. Objectives This study reviewed the scope of diabetes datasets, health information ecosystems, and human resource capacity in four countries to assess whether a diabetes phenotyping algorithm (developed under a companion study) could be successfully applied. Methods The capacity assessment was undertaken with four countries: Trinidad, Malaysia, Kenya, and Rwanda. Diabetes programme staff completed a checklist of available diabetes data variables and then participated in semi-structured interviews about Health Information System (HIS) ecosystem conditions, diabetes programme context, and human resource needs. Descriptive analysis was undertaken. Results Only Malaysia collected the full set of the required diabetes data for the diabetes algorithm, although all countries did collect the required diabetes complication data. An HIS ecosystem existed in all settings, with variations in data hosting and sharing. All countries had access to HIS or ICT support, and epidemiologists or biostatisticians to support dataset preparation and algorithm application. Conclusions Malaysia was found to be most ready to apply the phenotyping algorithm. A fundamental impediment in the other settings was the absence of several core diabetes data variables. Additionally, if countries digitise diabetes data collection and centralise diabetes data hosting, this will simplify dataset preparation for algorithm application. These issues reflect common LMIC health systems’ weaknesses in relation to diabetes care, and specifically highlight the importance of investment in improving diabetes data, which can guide population-tailored prevention and management approaches.

Diet supplementation with egg yolk powder fattens the beetle Tribolium castaneum.

Insects have become essential models in studying human metabolic diseases, mainly due to their low maintenance cost and available tools. Both mutations and modified diets induce metabolic states similar to human obesity and diabetes. Here, we explore the effect of a high-calorie, high-fat diet on the metabolism of the beetle Tribolium castaneum. Supplementation of the wheat flour diet with powdered egg yolk for 3 weeks increased the total triacylglycerol and accelerated larval development. In addition, this diet increased the triacylglycerol levels of adult beetles. However, this egg yolk supplementation did not alter the larvae's total glucose levels or lipogenic capacity and ATP citrate lyase activity. The diet also did not change the expression profile of several lipid and carbohydrate metabolism genes and insulin-like peptides. Thus, we conclude that the diet supplemented with egg yolk induces increased fat without causing diabetes phenotypes, as seen in other hypercaloric diets in insects.

Dysregulated UPR and ER Stress Related to a Mutation in the Sdf2l1 Gene Are Involved in the Pathophysiology of Diet-Induced Diabetes in the Cohen Diabetic Rat.

The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs/y) and resistant (CDr/y) strains. Diabetes develops in CDs/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr/y given either diet. We recently identified in CDs/y a deletion in Sdf2l1, a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs/y by impairing UPR, enhancing ER stress, and preventing CDs/y from secreting sufficient insulin upon demand. We studied SDF2L1 expression in CDs/y and CDr/y. We evaluated UPR by examining expression of key proteins involved in both strains fed either RD or DD. We assessed the ability of all groups of animals to secrete insulin during an oral glucose tolerance test (OGTT) over 4 weeks, and after overnight feeding (postprandial) over 4 months. We found that SDF2L1 was expressed in CDr/y but not in CDs/y. The pattern of expression of proteins involved in UPR, namely the PERK (EIF2α, ATF4 and CHOP) and IRE1 (XBP-1) pathways, was different in CDs/y DD from all other groups, with consistently lower levels of expression at 4 weeks after initiation of DD and coinciding with the development of diabetes. In CDs/y RD, insulin secretion was mildly impaired, whereas in CDs/y DD, the ability to secrete insulin decreased over time, leading to the development of the diabetic phenotype. We conclude that in CDs/y DD, UPR participating proteins were dysregulated and under-expressed at the time point when the diabetic phenotype became overt. In parallel, insulin secretion in CDs/y DD became markedly impaired. Our findings suggest that under conditions of metabolic load with DD and increased demand for insulin secretion, the lack of SDF2L1 expression in CDs/y is associated with UPR dysregulation and ER stress which, combined with oxidative stress previously attributed to the concurrent Ndufa4 mutation, are highly likely to contribute to the pathophysiology of diabetes in this model.

Gut Microbiota of the Asian-Indian Type 2 Diabetes Phenotype: How Different It Is from the Rest of the World?

Gut Microbiota of the Asian-Indian Type 2 Diabetes Phenotype: How Different It Is from the Rest of the World?

An approach for collaborative development of a federated biomedical knowledge graph-based question-answering system: Question-of-the-Month challenges.

Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph-based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly "Question-of-the-Month (QotM) Challenge" series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.

Role of Tumor Suppressor P53 Family in Glucose Metabolism in Association with Diabetes

Subsequent manuscripts have shown that p53, a 391 amino acid protein, was associated with tumour suppression by inducing cell cycle arrest, senescence, or programmed cell death, and mainly focused on oncology. But recent studies are proclaiming that the p53 family of genes is also associated with regulating the balance of the glucose uptake via the many glucose transporters by directly repressing the expression of the GLUT1 &amp; GLUT4, use of glycolysis and oxidative phosphorylation. The p53 regulates phenotypes of diabetes as it is interjecting in many points in regulating the pancreatic function and apoptosis, dysregulation of the beta cells, and developing insulin resistance. In the context of pancreatic beta cells, which are functioning for insulin secretion, it is regulated by the p53 by multiple signalling pathways. Endoplasmic stress results in the accumulation of the p53 that interacts with PARK2 (parkin), leading to insulin deficiency. Additionally, several proteins (N-terminal truncated isoforms of p53, factor TCFL2, the microRNA miR 200) regulate the p53 pathway, which can also regulate its ability to mediate pancreatic beta cell death. While in glucose haemostasis, wild-type p53 negatively and mutant p53 positively regulate glucose transporters and glucose importers. P21/CDKNIA plays an important role in developing insulin resistance as the p53-mediated senescence of adipose tissue marks it. Also, excessive O-GLcynated p53 inhibits the insulin signalling pathway from acting on the liver, generating insulin resistance. Here, we present a literature review on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis, and insulin resistance. Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation.

A clinical mutation in glucokinase causing maturity-onset diabetes in the young type 2 increases enzyme activity.

Glucokinase (GCK) is the pancreatic β-cell glucose sensor, and its kinetics are key to that purpose. A slow transition step, displayed as non-hyperbolic kinetics, and a low affinity for glucose characterize GCK. Mutations in GCK associated with maturity-onset diabetes of the young type 2 (MODY2) previously describedreduce the functionality of the human pancreatic β-cell, leading to diabetic clinical phenotypes. We present a kinetic characterization of the G448D mutation identified in a MODY2 patient, which is one of the first mutations to exhibit increased functionality. This mutant displays increased activity, high affinity for both Mg2+ -ATP and glucose, hyperbolic kinetics and increased phosphorylation potential. Hyperbolic kinetics and assays in the presence of glycerol indicate that G448D lacks the slow transition step crucial for the pancreatic β-cell glucose sensor function.

Do diabetes phenotypes in US women differ by race/ethnicity? A population-based cluster analysis

ObjectiveUS women exhibit racial disparities in the lifetime risk of diabetes and related outcomes. Identifying heterogeneity in clinical presentation may assist with reducing racial disparities in diabetes outcomes. We identified clinical phenotypes of diabetes and examined their racial and ethnic distribution in US women. Research design and methodsWe conducted cluster analysis based on five factors in US women with diagnosed diabetes assessed in the National Health and Nutrition Examination Surveys 1999–2018 (n = 825). Multinomial logistic regression analysis was performed to identify racial and ethnic differences in the distribution of phenotypes. ResultsWe identified four distinct clinical phenotypes. Two phenotypes, mild age-related and severe insulin-deficient diabetes, each included approximately a third of women. Mild insulin-resistant and severe insulin-resistant diabetes phenotypes accounted for 19.9% and 13.7%, respectively. The distribution of clusters did not differ by race and ethnicity. ConclusionsThe prevalence of four clinically distinct diabetes phenotypes identified in US women did not differ by race and ethnicity.

The mitigative effect of isorhamnetin against type 2 diabetes via gut microbiota regulation in mice.

In order to demonstrate the effects of isorhamnetin (IH) on the symptoms of type 2 diabetes mellitus (T2DM) and the role of gut microbiota in this process, an T2DM mouse model was established via a high-fat diet and streptozotocin. After 6 weeks of IH intervention and diabetes phenotype monitoring, the mice were dissected. We detected blood indicators and visceral pathology. Contents of the cecum were collected for 16S rRNA sequencing and short chain fatty acid (SCFAs) detection. The results showed that after IH intervention, the body weight of type 2 diabetic mice was gradually stabilized, fasting blood glucose was significantly decreased, and food intake was reduced (P < 0.05). Isorhamnetin significantly increased the level of SCFAs and decreased the levels of blood lipids and inflammatory factors in mice (P < 0.05). 16S rRNA sequencing results showed that Lactobacillus were significantly decreased and Bacteroidales S24-7 group_norank were significantly increased (P < 0.05). Interestingly, gut microbiota was significantly correlated with inflammatory factors, blood lipids, and SCFAs (P < 0.05). Taken together, our data demonstrated that isorhamnetin could improve the diabetic effects in T2DM mice, which might be mediated by gut microbiota.

Establishing a Type 2 Diabetes phenotype in APPxhQC transgenic mice expressing N‐terminally modified pGlu Aβ peptides.

AbstractBackgroundAlzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Aβ peptides are commonly subjected to post‐translational modifications like truncation known to play pivotal role in Aβ plaque aggregation. N‐terminally truncated Aβ peptides containing pyroglutamatic acid (pGlu) catalyzed by glutaminyl cyclase (QC) e.g., pGlu3‐Aβ (3‐40/42) are the major Aβ peptide fragments within the core of the neuritic plaques and correlate with disease severity and progression. Type 2 diabetes (T2D) is one of the major risk factors associated with AD and compelling evidence supports the notion that insulin resistance, a key feature of T2D, is involved in AD‐type neurodegeneration. Hence, in this study, we aim to establish a T2D phenotype in APPxhQC transgenic using low‐dose Streptozocin injection in combination with high fat diet (HFD).MethodsAPPxhQC mice, crossbreds of APPSL and hQC mice, were used. APPSL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice on B6CBAF1/J background express human glutaminyl cyclase (QC) enzyme. The cross‐breeding results in an increased generation of N‐terminal modified pGlu Aβ peptides. To establish a T2D phenotype, 8‐9 months old APPxhQC transgenic mice were allocated to 4 treatment groups receiving: standard chow diet, HFD, standard chow diet in combination with streptozocin injections and HFD in combination with streptozocin injections. The intraperitoneal glucose tolerance test (ipGTT) and intraperitoneal insulin tolerance test (ipITT) were performed at 6 and 7 weeks after the initiation of the diet, as a relevant parameter of T2D progression.ResultsStreptozocin‐injected mice maintained on HFD had the least tolerance to injected glucose as shown by ipGTT. Impaired glucose clearance was observed at 15, 30, 60 and 120 mins after intraperitoneal glucose injection (2g/kg). Also, impaired glucose clearance at 15 mins after intraperitoneal insulin injection (0.75U/kg) was observed in the same group.ConclusionCombination of high‐fat diet and streptozocin injections leads to the development of robust T2D symptoms in APPxhQC transgenic mice. Current experiments are focusing on combinational effects of T2D and post‐translationally modified amyloid peptides in AD progression and pathophysiology.

Effect and mechanism of Buyang Huanwu decoction on retinal inflammation in streptozotocin-induced diabetic rats

ObjectiveTo observe the protective effect of Buyang Huanwu decoction (BYHWD) against retinal inflammation in diabetic rats. MethodsHealthy male Wistar rats were randomly divided into normal and diabetic model groups. Diabetic rats were given a one-time intraperitoneal injection of streptozotocin (STZ) to establish a diabetic phenotype and were randomly assigned to the negative control (saline), positive control (calcium dobesilate), and BYHWD treatment groups. After 8 weeks of treatment, fluorescein-labeled dextran and Evans blue dye were injected into the tail vein to observe vascular permeability and vascular leakage in the retina, respectively. Perfusion of fluorescein-labeled concanavalin was used to detect adhesion in rat retinal leukocytes. Western blotting was used to quantify the expression levels of the inflammatory factors TNF-α, NF-κBp65, and p-NF-κBp65 in retinal tissue. ResultsCompared with nondiabetic rats, saline-treated diabetic rats showed significantly increased retinal vascular leakage, leukocyte adhesion, and protein levels of TNF-α and p-NF-κBp65 (P<0.05). These effects were significantly reduced in the positive control and BYHWD groups (P<0.05). ConclusionBuyang Huanwu decoction can ameliorate retinal inflammation in STZ-induced diabetic rats. Its mechanism of action may be related to the inhibition of TNF-α expression and NF-κB pathway activation.

Perioperative blood glucose variability and autonomic nervous system activity in on-pump cardiac surgery patients: Study protocol of a single-center observational study.

On-pump coronary artery bypass graft (CABG) and surgical valve replacement (SVR) are high-risk procedures. Several studies reported that perioperative blood glucose (BG) variability was independently associated with impaired postoperative outcome. However, the underlying mechanisms contributing to increased perioperative BG variability and to its deleterious impact remain unknown. The hypothesis of the study is that perioperative BG variability could be related to perioperative alteration of the autonomic nervous system (ANS) activity and to preoperative BG variability. We designed a prospective observational single-center study. Four groups of 30 patients will be studied: group 1, including insulin-requiring type 2 diabetic patients undergoing on-pump CABG; group 2, including non-insulin-requiring type 2 diabetic patients undergoing on-pump CABG; group 3, including non-diabetic patients undergoing aortic SVR; and group 4, including non-diabetic patient undergoing on-pump CABG. Preoperative (baseline) and postoperative BG variability will be quantified using the Abbott's Freestyle Libre Pro sensor allowing for continuous subcutaneous BG monitoring. Preoperative (baseline) and postoperative ANS activity will be measured using noninvasive continuous heart rate monitoring (Mooky HR memory®). Blood level and urinary concentration of inflammatory and endothelial dysfunction biomarkers will be measured from blood and urinary samples at the end of the surgery and on postoperative day 1 and 2. The primary objective is to describe the relationship between baseline BG variability and postoperative BG variability. The secondary objectives are to describe the relationship: between baseline and postoperative BG variability according to the diabetes phenotype and to the type of surgery; between the ANS activity and the BG variability; and between postoperative BG variability and, urinary and blood biomarkers.

Genetic and Functional Analyses of the Novel KLF11 Pro193Thr Variant in a Three-Generation Family with MODY7.

KLF11 regulates insulin gene expression through binding to the insulin promoter and has been reported as a causative gene for maturity-onset diabetes of the young 7 (MODY7). Here, we report a novel KLF11 variant associated with a three-generation family with early childhood-onset diabetes and explore its clinical and functional characteristics. The three-generational pedigree contains five patients affected by diabetes. The pathogenic variant identified by whole-exome sequencing was further confirmed by Sanger sequencing and pedigree verification. Luciferase reporter assays and glucose-stimulated insulin secretion were used to examine whether the KLF11 variant binds to the insulin promoter and regulate insulin secretion in vitro. The proband, his son, and his uncle exhibited hyperglycemia at ages 32, 13 and 71 years, respectively. All three patients showed characteristics of metabolic syndrome (obesity, dyslipidemia, and diabetes), but the insulin secretion of islet β-cells was impaired. A novel heterozygous missense variant, c.577 C>A (p.Pro193Thr) of the KLF11 gene was detected in all three patients. This variant co-segregates with the diabetes phenotype, consistent with an autosomal dominant disorder. The identified KLF11 p.Pro193Thr variant drastically decreased the transcriptional activity of KLF11, as demonstrated by luciferase reporter assay. Functional analyses revealed that the KLF11 Pro193Thr variant inhibited glucose-stimulated insulin secretion. We identified a novel KLF11 Pro193Thr variant in a three generation family with MODY7. These findings shed light on the molecular mechanisms underlying the pathogenesis of MODY7 and expand the genotype and clinical spectrum of MODY7.

Pancreas Transplantation: Current Challenges, Considerations, and Controversies.

Pancreas transplantation (PTx) reestablishes an autoregulating source of endogenous insulin responsive to normal feedback controls. In addition to achieving complete β-cell replacement that frees the patient with diabetes from the need to monitor serum glucose and administer exogenous insulin, successful PTx provides counterregulatory hormone secretion and exocrine function. A functioning PTx mitigates glycemic variability, eliminates the daily stigma and burden of diabetes, restores normal glucose homeostasis in patients with complicated diabetes, and improves quality of life and life expectancy. The tradeoff is that it entails a major surgical procedure and requisite long-term immunosuppression. Despite the high likelihood of rendering patients euglycemic independent of exogenous insulin, PTx is considered a treatment rather than a cure. In spite of steadily improving outcomes in each successive era coupled with expansion of recipient selection criteria to include patients with a type 2 diabetes phenotype, a decline in PTx activity has occurred in the new millennium related to a number of factors including: (1) lack of a primary referral source and general acceptance by the diabetes care community; (2) absence of consensus criteria; and (3) access, education, and resource issues within the transplant community. In the author's experience, patients who present as potential candidates for PTx have felt as though they needed to circumvent the conventional diabetes care model to gain access to transplant options. PTx should be featured more prominently in the management algorithms for patients with insulin requiring diabetes who are failing exogenous insulin therapy or experiencing progressive diabetic complications regardless of diabetes type. Furthermore, all patients with diabetes and chronic kidney disease should undergo consideration for simultaneous pancreas-kidney transplantation independent of geography or location.

IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells

Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in β cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in β cells, named IER3IP1-βKO and IER3IP1-iβKO, respectively. We found that IER3IP1-βKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated β-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with β-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-βKO impaired β-cell maturation and proliferation, along with increased condensation of β-cell nuclear chromatin. Inducible β-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after β-cell early development. Importantly, IER3IP1 was decreased in β cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with β-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in β cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.