Development Of Overt Diabetes Research Articles

Beta cell endoplasmic reticulum stress drives diabetes in the KINGS mouse without causing mass beta cell loss.

Beta cell endoplasmic reticulum (ER) stress can cause cellular death and dysfunction and has been implicated in the pathogenesis of diabetes. Animal models of beta cell ER stress are critical in further understanding this and for testing novel diabetes therapeutics. The KINGS mouse is a model of beta cell ER stress driven by a heterozygous mutation in Ins2. In this study, we investigated how beta cell ER stress in the KINGS mouse drives diabetes. We investigated whether the unfolded protein response (UPR) was activated in islets isolated from male and female KINGS mice and whether this impacted beta cell mass and turnover. Whilst the UPR was up-regulated in KINGS islets, with increased protein expression of markers of all three UPR arms, this was not associated with a mass loss of beta cells; beta cell apoptosis rates did not increase until after the development of overt diabetes, and did not lead to substantial changes in beta cell mass. We propose that the KINGS mouse represents a model where beta cell maladaptive UPR signalling drives diabetes development without causing mass beta cell loss.

Time to Development of Overt Diabetes and Macrovascular and Microvascular Complications Among Patients With Prediabetes: A Retrospective Cohort Study.

ObjectiveIn this study, we aimed to determine the effect of age, gender, race, and obesity on the development of overt diabetes and macro/microvascular events among patients with prediabetes.MethodsThis was a retrospective cohort study of patient records available through a national electronic health record (EHR) database from 2012 to 2017. Patients with prediabetes in the baseline year of 2012 were identified. Macro/microvascular events were defined as the diagnosis of myocardial infarction (MI), stroke, or chronic kidney disease (CKD). The effects of age, gender, race, and obesity on the incidence of diabetes and macro/microvascular events between 2013-2017 were assessed using the multivariate Cox proportional-hazards model.ResultsAmong the total 5,230 patients with prediabetes in 2012, 16.7% developed overt diabetes, and 19.7% developed a macro/microvascular event. Elderly patients (HR: 2.96, 95% CI: 2.12-4.13), males (HR: 1.38, 95% CI: 1.20-1.59), and African-Americans (HR: 1.47, 95% CI: 1.26-1.73) were at a higher risk of experiencing a macro/microvascular event. Additionally, male gender (HR: 1.27, 95% CI: 1.11-1.46) and obesity (HR: 1.24, 95% CI: 1.08-1.43) were significant factors associated with the development of overt diabetes. Furthermore, when diabetes status was added as an interaction term to the Cox proportional-hazards model, no statistical difference was found with respect to any of the other independent variables. It can therefore be inferred that those with prediabetes and overt diabetes had a similar risk of developing macro/microvascular events.ConclusionsBased on our findings, factors including advanced age, obesity, male gender, and African race significantly impact the progression to diabetes and associated macro/microvascular events.

Prognostic Impact of Prediabetes on Patient Outcomes After Coronary Artery Bypass Grafting: A Single-center Cohort Study.

Prediabetes, as a precursor stage, has an important role in development of overt diabetes as well as coronary artery disease (CAD). The aim of this study is to evaluate the association between prediabetes and adverse outcomes (major adverse cardiovascular and cerebrovascular events [MACCE] and all-cause mortality) in patients who underwent coronary artery bypass grafting (CABG). In this prospective study, we included 3754 patients with CAD who underwent elective isolated CABG between January 2016 to January 2020. Patients were categorized based on their glycemic status at the time of CABG as follows: diabetics (n = 2707), prediabetics (n = 471), and nondiabetics (n = 576). Primary endpoints were occurrence of all-cause mortality and MACCE. We studied 3754 patients for a median of 32.25 months after CABG. MACCE occurred in 474 (12.6%) patients. After adjusting for potential confounders, diabetic patients had a higher risk of MACCE (hazard ratio [HR] 1.69; 95% confidence intervals [CI], 1.24-2.29) and death (HR 2.33, 95% CI, 1.45-3.7) compared with nondiabetic and prediabetic ones. However, patients with prediabetes had lower HR of MACCE, but the association was nonsignificant (HR 1.02; 95% CI, 0.67-1.56). Diabetes is significantly associated with higher risk of mortality and MACCE; however, prediabetes did not show a prognostic impact in terms of overall and MACCE-free survival.

The CCR4-NOT Complex Maintains ß-Cell Identity through the Repression of ß-Cell Disallowed Genes

Loss of β-cell identity, dedifferentiation and reprogramming are recognized as mechanisms of β-cell dysfunction in diabetes. Molecular β-cell identity is not only defined by the expression of signature functional β-cell specific genes but also the repression of several genes recently identified in β-cell research as β-cell disallowed genes. The molecular mechanisms involved in the repression of β-cell disallowed genes are largely unknown. Here, we show that the CCR4-NOT complex, a major deadenylase conserved in eukaryotes, is involved in post-transcriptional regulation of β-cell disallowed genes. β-cell specific depletion of CNOT3 (CNOT3βKO), a CCR4-NOT complex subunit, in mice promotes deceased insulin secretion, early impaired glucose tolerance and the development of overt diabetes at 12 weeks of age. CNOT3βKO islets display decreased insulin content and decreased glucose responsiveness. Furthermore, CNOT3 depleted ß cells exhibit ultrastructural abnormalities including: degranulated β cells, increased immature insulin granules and abnormal mitochondria. RNAseq and qRT-PCR analyses revealed that CNOT3βKO islets have decreased expression of β-cell functional genes: (Ins1, Ins2, MafA, Pcsk2 and Cpe) and increased expression of 9 of the 11 core β-cell disallowed genes: (Slc16A1, Ldha, Pdgfra, Cxcl12, Igfbp4, Oat, Maf, Smad3 and Cd302) and progenitor-like cells genes: (Nanog and Ngn3) supporting the loss of β-cell identity. Using the total RNAseq data, we assessed mRNA stability by calculating the relative amounts of introns and exons for a given mRNA. RNA immunoprecipitation revealed that the CCR4-NOT complex directly binds several upregulated stabilized β-cell disallowed genes: Slc16A1, Tgm2, Cat and Parp3 genes. The present data highlight deadenylation as a novel molecular mechanism regulating β-cell disallowed genes. Thus, we further propose that the CCR4-NOT complex is essential for maintaining β-cell identity by repressing β-cell disallowed genes. Disclosure D. Mostafa: None. A. Takahashi: None. A. Yanagiya: None. T. Yamamoto: None.

Atrial conduction times and left atrial mechanical functions and their relation with diastolic function in prediabetic patients.

Background/AimsThe aim of this study was to investigate atrial conduction times and left atrial mechanical functions, the noninvasive predictors of atrial fibrillation, in prediabetic patients with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).MethodsStudy included 59 patients (23 males, 36 females; mean age 52.5 ± 10.6 years) diagnosed with IFG or IGT by the American Diabetes Association criteria, and 43 healthy adults (22 males, 21 females; mean age 48.5 ± 12.1 years). Conventional and tissue Doppler echocardiography were performed. The electromechanical delay parameters were measured from the onset of the P wave on the surface electrocardiogram to the onset of the atrial systolic wave on tissue Doppler imaging from septum, lateral, and right ventricular annuli. The left atrial volumes were calculated by the disk method. Left atrial mechanical functions were calculated.ResultsThe mitral E/A and E’/A’ ratios measured from the lateral and septal annuli were significantly lower in the prediabetics compared to the controls. The interatrial and left atrial electromechanical delay were significantly longer in prediabetic group compared to the controls. Left atrial active emptying volume (LAAEV) and fraction (LAAEF) were significantly higher in the prediabetics than the controls. LAAEV and LAAEF were significantly correlated with E/A, lateral and septal E’/A’.ConclusionsIn the prediabetic patients, the atrial conduction times and P wave dispersion on surface electrocardiographic were longer before the development of overt diabetes. In addition, the left atrial mechanical functions were impaired secondary to a deterioration in the diastolic functions in the prediabetic patients.

Beta Cell Function and the Nutritional State: Dietary Factors that Influence Insulin Secretion.

Approximately 366 million people worldwide have been diagnosed with type-2 diabetes (T2D). Chronic insulin resistance, decreased functional β-cell mass, and elevated blood glucose are defining characteristics of T2D. Great advances have been made in understanding the pathogenesis of T2D with respect to the effects of dietary macronutrient composition and energy intake on β-cell physiology and glucose homeostasis. It has been further established that obesity is a leading pathogenic factor for developing insulin resistance. However, insulin resistance may not progress to T2D unless β-cells are unable to secret an adequate amount of insulin to compensate for decreased insulin sensitivity. Therefore, pancreatic β-cell dysfunction plays an important role in the development of overt diabetes. This paper reviews recent research findings on the effects of several micronutrients (zinc, vitamin D, iron, vitamin A), leucine, and the phytochemical, genistein on pancreatic β-cell physiology with emphasis on their effects on insulin secretion, specifically in the context of T2D.

To explain the variation of OGTT dynamics by biological mechanisms: a novel approach based on principal components analysis in women with history of GDM.

Early reexamination of carbohydrate metabolism via an oral glucose tolerance test (OGTT) is recommended after pregnancy with gestational diabetes (GDM). In this report, we aimed to assess the dominant patterns of dynamic OGTT measurements and subsequently explain them by meanings of the underlying pathophysiological processes. Principal components analysis (PCA), a statistical procedure that aims to reduce the dimensionality of multiple interrelated measures to a set of linearly uncorrelated variables (the principal components) was performed on OGTT data of glucose, insulin and C-peptide in addition to age and body mass index (BMI) of 151 women (n = 110 females after GDM and n = 41 controls) at 3-6 mo after delivery. These components were explained by frequently sampled intravenous glucose tolerance test (FSIGT) parameters. Moreover, their relation with the later development of overt diabetes was studied. Three principal components (PC) were identified, which explained 71.5% of the variation of the original 17 variables. PC1 (explained 47.1%) was closely related to postprandial OGTT levels and FSIGT-derived insulin sensitivity (r = 0.68), indicating that it mirrors insulin sensitivity in the skeletal muscle. PC2 (explained 17.3%) and PC3 (explained 7.1%) were shown to be associated with β-cell failure and fasting (i.e., hepatic) insulin resistance, respectively. All three components were related with diabetes progression (occurred in n = 25 females after GDM) and showed significant changes in long-term trajectories. A high amount of the postpartum OGTT data is explained by principal components, representing pathophysiological mechanisms on the pathway of impaired carbohydrate metabolism. Our results improve our understanding of the underlying biological processes to provide an accurate postgestational risk stratification.

A Random Plasma Glucose in Gynecologic Patients

Objective: To determine gynecologic pathologies associated with abnormal plasma glucose in order to provide clinicians with an opportunity to achieve prevention or early detection of diabetes and better control of co-morbidities linked to hyperglycemia. Methods: This is a cross-sectional study including all adult gynecologic non pregnant patients admitted for routine consultation between 1st and 30th August 2012 at the university clinics of Kinshasa, DR Congo, irrespective of their clinical status. Information generated by their charts was used for extensive identification of general characteristics. Random venous blood glucose was assayed upon recruitment by use of One Touch Profile Meters (Lifescan, Johnson & Johnson, High Wycombe, U.K.). Using Odds ratios and logistic regression calculation we assessed risk for abnormal glucose concentration. Results: This study recruited 99 participants whose general characteristics are (mean ± SD): 34.3 ± 13.0 years, 1.7 ± 2.7 and 2.3 ± 1.2 for age, parity and gravidity, respectively. The five major complaints were: pelvic/back pain (33.3%), vaginal discharge with/without pruritus (10.1%), mastodynia (8.1%), amenorrhea (7.1%), infertility and abnormal uterine bleeding (6.1% each). The major diagnoses were myoma (13.1%), urinary infection (11.1%), polycystic ovaries syndrome (9.1%), breast cancer 9.1%), infertility (9.1%), cervicitis (7.1%), vaginitis (5.1%) and ovarian cyst (4%). The mean plasma glucose concentrations of the sample was 123.7 ± 51.6 mg/dL, and none of the 11 (11.1%) who qualified as diabetic patients (having >200 mg/dL) presented with symptoms of marked hyperglycemia. Micropolycystic ovaries syndrome and cervical cancer significantly raised the risk for pathologic glucose concentration (OR 9.8; CI 1.1-86.8 and OR 35.1; CI 1.6-75.1, respectively), mostly when patients were either ≥ 35 years old or overweight/obese or both. Conclusions: Ignored hyperglycemia that can be present in certain gynecological situations years before the development of overt diabetes could be regarded as missed opportunity for early detection of diabetes. In turn, better glycemic control is expected to improve the situations concerned.

Type 2 Diabetes and Cardiovascular Risk in Women

Type 2 Diabetes and Cardiovascular Risk in Women

Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes.

Islet amyloid accumulation is a hallmark of human type 2 diabetes (T2D). In contrast to human islet amyloid polypeptide (hIAPP), murine islet amyloid polypeptide (mIAPP) does not exhibit amyloidogenic propensity. Because autophagy is important in the clearance of amyloid-like proteins, we studied transgenic mice with β cell-specific expression of hIAPP to evaluate the contribution of autophagy in T2D-associated accumulation of hIAPP. In mice with β cell-specific expression of hIAPP, a deficiency in autophagy resulted in development of overt diabetes, which was not observed in mice expressing hIAPP alone or lacking autophagy alone. Furthermore, lack of autophagy in hIAPP-expressing animals resulted in hIAPP oligomer and amyloid accumulation in pancreatic islets, leading to increased death and decreased mass of β cells. Expression of hIAPP in purified monkey islet cells or a murine β cell line resulted in pro-hIAPP dimer formation, while dimer formation was absent or reduced dramatically in cells expressing either nonamyloidogenic mIAPP or nonfibrillar mutant hIAPP. In autophagy-deficient cells, accumulation of pro-hIAPP dimers increased markedly, and pro-hIAPP trimers were detected in the detergent-insoluble fraction. Enhancement of autophagy improved the metabolic profile of hIAPP-expressing mice fed a high-fat diet. These results suggest that autophagy promotes clearance of amyloidogenic hIAPP, autophagy deficiency exacerbates pathogenesis of human T2D, and autophagy enhancers have therapeutic potential for islet amyloid accumulation-associated human T2D.

Vascular endothelial growth factor-B as a therapeutic target to prevent ectopic fat deposition.

Vascular endothelial growth factor-B as a therapeutic target to prevent ectopic fat deposition.

In vivo postprandial lipid partitioning in liver and skeletal muscle in prediabetic and diabetic rats

Aims/hypothesisInsulin resistance and type 2 diabetes have been associated with ectopic lipid deposition. This study investigates the derangements in postprandial lipid handling in liver and skeletal muscle tissue at different stages during the pathogenesis of type 2 diabetes in a rat model.MethodsFour groups (n = 6) of male Zucker diabetic fatty rats were used for this study: prediabetic fa/fa rats and healthy fa/+ littermates at the age of 6 weeks, and diabetic fa/fa rats and healthy fa/+ littermates at the age of 12 weeks. In vivo 1H-[13C] magnetic resonance spectroscopy measurements were performed in liver and tibialis anterior muscle at baseline and 4, 24 and 48 h after oral administration of 1.5 g [U-13C]algal lipid mixture per kilogram body weight. Total and 13C-labelled intracellular lipid contents were determined from the magnetic resonance spectra.ResultsIn both prediabetic and diabetic rats, total lipid contents in muscle and liver were substantially higher than in healthy controls and this was accompanied by a 2.3-fold greater postprandial lipid uptake in the liver (p < 0.001). Interestingly, in prediabetic rats, skeletal muscle appeared to be protected from excess lipid uptake whereas after developing overt diabetes muscle lipid uptake was 3.4-fold higher than in controls (p < 0.05). Muscle lipid use was significantly lower in prediabetic and diabetic muscle, indicative of impairments in lipid oxidation.Conclusions/interpretationIn vivo postprandial lipid handling is disturbed in both liver and skeletal muscle tissue in prediabetic and diabetic rats, but the uptake of dietary lipids in muscle is only increased after the development of overt diabetes.

934 IMPAIRED FASTING GLUCOSE AND GLUCOSE INTOLERANCE IN NON-DIABETIC HYPERTENSIVE PATIENTS ARE ASSOCIATED TO DIASTOLIC DYSFUNCTION DETECTED BY TISSUE DOPPLER IMAGING

Objectives: The aim of this study was to evaluate the relationship between markers of glucose intolerance and left ventricular (LV) diastolic function in non-diabetic, untreated hypertensive patients. Design and Methods: In 98 patients (age 48±12 ys; 55 M/43F), we measured anthropometric variables, fasting glucose (FG), insulin (INS), and calculated HOMA-index. In a subset of 69 patients we also performed an oral glucose tolerance test. Myocardial early- (E’) and end- (A’) diastolic velocities of the mitral annulus were measured by Tissue Doppler Imaging. Results: E/A trans-mitral ratio was inversely related to age, FG, variables of reduced glucose tolerance, and LV mass. E’ and E’/A’ were lower (both P=0.028) and E/E’ was higher (P=0.014) in patients with reduced glucose tolerance than in patients with normal glucose tolerance. E/E’ and left atrium area (LAA) were higher (P=0.016 and P=0.001, respectively) in patients with impaired FG than in patients with normal FG. E’ and E’/A’ were inversely related, among others, to FG and variables of reduced glucose tolerance. E/E’ was directly related, among others, to the area under the curve of insulin. Multivariate analysis showed an independent relationships between E’ (and E’/A’) and FG, between E/E’ and glucose levels at 120 min. of glucose load, and between LAA and FG (and HOMA). Conclusions: In non-diabetic hypertensive patients, diastolic dysfunction is independently related with impaired FG or impaired glucose tolerance. This might suggest the need for early correction of glucose levels in hypertensive patients even before the development of overt diabetes.

Apigenin Attenuates 2-Deoxy-D-ribose-Induced Oxidative Cell Damage in HIT-T15 Pancreatic .BETA.-Cells

Glucose toxicity contributes to progressive β-cell failure and the development of overt diabetes. Oxidative stress is an important aspect of glucose toxicity in pancreatic β-cells. We investigated whether the flavonoid apigenin protects pancreatic β-cells from 2-deoxy-D-ribose (dRib)-induced oxidative cell damage. HIT-T15 pancreatic β-cells were cultured with or without apigenin in the presence of dRib. Time- and dose-dependent cell viability was monitored using a cell counting kit (CCK-8), while the induction of apoptosis was analyzed using a cell death enzyme-linked immunosorbent assay (ELISA) kit. Mitochondrial membrane potential (ΔΨ(m)) was determined using the JC-1 kit. Intracellular oxidative stress was measured by fluorometric analysis of DCFH oxidation using 2',7'-dichlorofluorescin diacetate (DCFH-DA) as the probe. In addition, the DNA binding activity of the oxidative stress-related transcriptional factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) were analyzed. dRib reduced cell survival and ΔΨ(m), while it markedly increased intracellular levels of reactive oxygen species (ROS), apoptosis, and the activity of the oxidative stress-related transcription factors NF-κB and AP-1. However, pretreatment of cells with apigenin attenuated all the dRib-induced effects. The anti-oxidants, N-acetyl-L-cysteine (NAC) and alpha lipoic acid (ALA), also prevented both dRib-induced oxidative damage and activation of NF-κB and AP-1. Taken together, these results suggest that apigenin attenuates dRib-induced cell damage in pancreatic β-cells via oxidative stress-related signaling.

Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator‐Activated Receptor (PPAR) γ/δ Agonists with High Potency and in vivo Efficacy

Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high-throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X-ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC₅₀ values of 1.6 and 336 nM for PPARδ and γ, respectively. The X-ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n = 546; HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.

Silent ischemia in relation to insulin resistance in normotensive prediabetic adults: early detection by single photon emission computed tomography (SPECT)

Myocardial perfusion imaging (MPI) is a powerful diagnostic and prognostic tool for evaluating coronary artery disease (CAD). Several studies have shown that it is increased in individuals with type 2 diabetes. Also, insulin resistance is generally considered to be of major importance in the pathophysiology of type 2 diabetes mellitus. However the area of screening prediabetics for coronary artery disease remains unclear. Given that glucose intolerance and insulin resistance precede the development of overt diabetes, these factors would be associated with ischemic heart disease. Evaluate the state of myocardial perfusion in prediabetic adults detected by Single photon emission computed tomography (SPECT) in relation to insulin resistance. A descriptive study was performed. For 163 consecutive prediabetic adults of whom 62 had insulin resistance (group A) and 101 had insulin sensitivity (group B). All were subjected to full medical history and clinical examination including blood pressure, waist circumference body mass index. Biochemical studies including lipids profile, fasting glucose and HOMA test. Exercise treadmill technetium 99 sestamibi SPECT scintigraphy were done for assessment of myocardial perfusion assessed by summed difference score as well as occurrence of transient left ventricular dilatation. Significant increase in summed difference score as well as transient left ventricular dilatation were observed in group A than group B. It is correlated with insulin resistance and the correlation appears to be independent of glucose tolerance status and obesity. Similar correlations were observed with age, triglycerides and waist circumference. Prediabetics have myocardial perfusion defects which represent a pattern of cardiovascular risk factors. These changes are predominantly observed in these prediabetics with increased HOMA IR and visceral obesity independent of glucose levels.

Bone Mineral Density in Prediabetic Men

BackgroundThere are many studies regarding the effects of insulin on bone metabolism and changes in bone mineral density (BMD) in the setting of diabetes. The effect of prediabetes on BMD is not known.MethodsA total of 802 men participated in the Korea Rural Genomic Cohort Study (in Geumsan County). According to the results of an oral glucose tolerance test, subjects were classified into normal, prediabetic, and diabetic categories. One hundred twenty-four subjects diagnosed with type 2 diabetes were excluded, leaving 678 subjects for the study inclusion. BMD was estimated with a quantitative ultrasonometer.ResultsThe average BMD T scores of normal and prediabetic subjects were -1.34 ± 1.42 and -1.33 ± 1.30, respectively; there was no significant difference in the BMD T scores between these groups. The BMD T score was inversely associated with age and positively correlated with body weight, body mass index, total cholesterol, low density lipoprotein cholesterol, and HbA1c. On multiple linear regression analysis, low density lipoprotein cholesterol was the only statistically significant variable for prediabetes (β = 0.007, P = 0.005). On the stepwise regression analysis, age (β = -0.026, P < 0.001), the body mass index (β = 0.079, P < 0.001), and low density lipoprotein cholesterol (β = 0.004, P = 0.016) were significant variables for prediabetes.ConclusionsThere was no significant difference in the BMD T score between the normal and prediabetic subjects. Further studies are needed regarding the association of fracture risk and changes in BMD with the development of overt diabetes.

Immune disturbance and pathogenesis of non-obese diabetes-prone (NOD) mice.

Manipulation and possible mechanism of pathogenesis in NOD mice were studied from the immunological standpoint. Disturbance of lymphocyte activity, particularly that of T-lymphocyte activity, greatly influenced the development of overt diabetes. Throughout the test period when the mice were between 24 and 30 weeks old, spontaneous diabetes in female mice was markedly suppressed by treatment with anti-thymocyte serum or with an anti-Thy 1,2 monoclonal antibody. Also, the appearance of diabetes was promoted by cyclophosphamide treatment in animals of both sexes. Evidence for the role of T-lymphocytes was provided by the experiments using the T-lymphocyte-depleted mice. Neither insulitis nor overt diabetes was observed in the athymic nude congenic mice with the genetic background of NOD even if they were given cyclophosphamide. Insulitis was induced in the athymic nude recipients by the transfer of thymocytes or of splenocytes from euthymic littermates, although an overt diabetes was not produced by cell transfer alone. An overt diabetes was induced in the congenitally athymic nude mice by a single transfer of T-lymphocytes and subsequent treatment with cyclophosphamide. From these results it can be concluded that T-lymphocytes play an obligatory role in the pathogenesis of diabetes in NOD mice.

Cystic fibrosis related diabetes

Diabetes is a frequent complication seen in cystic fibrosis patients as they reach adulthood. Cystic fibrosis related diabetes (CFRD) is distinguished as a separate entity with features that include progressive loss of islet beta cell mass and insulin deficiency, as well as insulin resistance. Abnormalities in glucose tolerance may be detectable for many years prior to the development of overt diabetes. Therefore oral glucose tolerance testing is the preferred screening method for the identification of those patients at the highest risk for progression to diabetes. Progression to diabetes has been linked to poor outcomes in CF including loss of pulmonary function and increased mortality among females. Given the role that insulin deficiency plays in CFRD, insulin replacement therapy remains the only recommended intervention. In the absence of definitive supportive data, the use of oral antidiabetic agents is not considered standard therapy and needs further study. As with other forms of diabetes, CFRD patients also experience microvascular complications and should be periodically evaluated for manifestations.