Non-fasting Plasma Glucose Levels Research Articles

Genetic Connection between Hyperglycemia and Carotid Atherosclerosis in Hyperlipidemic Mice.

Type 2 diabetes (T2D) is a major risk for atherosclerosis and its complications. Apoe-null (Apoe−/−) mouse strains exhibit a wide range of variations in susceptibility to T2D and carotid atherosclerosis, with the latter being a major cause of ischemic stroke. To identify genetic connections between T2D and carotid atherosclerosis, 145 male F2 mice were generated from LP/J and BALB/cJ Apoe−/− mice and fed 12 weeks of a Western diet. Atherosclerotic lesions in the carotid arteries, fasting, and non-fasting plasma glucose levels were measured, and genotyping was performed using miniMUGA arrays. Two significant QTL (quantitative trait loci) on chromosomes (Chr) 6 and 15 were identified for carotid lesions. The Chr15 QTL coincided precisely with QTL Bglu20 for fasting and non-fasting glucose levels. Carotid lesion sizes showed a trend toward correlation with fasting and non-fasting glucose levels in F2 mice. The Chr15 QTL for carotid lesions was suppressed after excluding the influence from fasting or non-fasting glucose. Likely candidate genes for the causal association were Tnfrsf11b, Deptor, and Gsdmc2. These results demonstrate a causative role for hyperglycemia in the development of carotid atherosclerosis in hyperlipidemic mice.

The Healthy Aging Index analyzed over 15 years in the general population: The Doetinchem Cohort Study

The Healthy Aging Index (HAI), an index of physiological aging, has been demonstrated to predicts mortality, morbidity and disability. We studied the longitudinal development of the HAI to identify aging trajectories and evaluated the role of baseline sociodemographic characteristics and lifestyle factors of the trajectories. Four measurements with intervals of 5 years were included from the Doetinchem Cohort Study. The HAI reflects levels of systolic blood pressure, non-fasting plasma glucose levels, global cognitive functioning, plasma creatinine levels and lung functioning. The HAI score ranges from 0 to 10: higher scores indicate a better health profile. Latent class mixture modelling was used to model within-person change and to identify aging trajectories. Area under the curve was calculated per trajectory to estimate total healthy years. In total, 2324 women and 2013 men were included. One HAI trajectory was identified for women, and two trajectories for men, labelled ‘gradual’ aging (76%) and ‘early’ aging (24%). Men who were medium/high educated, below 36 years at baseline, complied with guidelines on physical activity and were not obese in any round were associated with increased odds to ‘gradual’ aging of 1.46 (CI: 1.18–1.81), 1.93 (CI: 1.42–2.62), 1.26 (1.02–1.57) and 1.76 (1.32–2.35), respectively. Between 30 and 70 years of age, men in the ‘early’ aging trajectory had the least healthy years (29.6 years), followed by women (30.1 years), and ‘gradual’ aging men (34.7 years). This study emphasizes that ‘physiological aging’ is not only an issue of older ages. Between 30 and 70 years of age, ‘early’ aging men and women had approximately five healthy years less compared to ‘gradual’ aging men. Lifestyle factors (e.g. nutrition and physical activity) seem to play an important role in optimal aging.

A Simplified Streptozotocin-Induced Diabetes Model in Nude Mice.

Preclinical studies of human cellular and tissue-based products (HCT/Ps) for transplantation therapy of type 1 diabetes mellitus (T1DM) necessarily involve animal models, particularly mouse models of diabetes induced by streptozotocin (STZ). These models should mimic the clinical and metabolic manifestations of T1DM in humans (face validity) and be similar to T1DM in terms of the pathogenetic mechanism (construct validity). Furthermore, since HCT/Ps contain human cells, modeling of diabetes in immune-deficient animals is obligatory. Here we describe the most simplified diabetes model in Nude mice. Diabetes was induced in 31 males by a single intraperitoneal injection of STZ in normal saline at a medium-to-high dose of 150 mg/kg body weight. Fourteen control animals received only saline. Non-fasting plasma glucose (PG) levels were measured periodically for 50 days. All STZ-treated mice survived beyond 50 days. By day 15 after STZ administration, 22 of 31 (71%) mice developed stable diabetes based on the following criteria: (1) non-fasting PG ≥ 15 mmol/L on consecutive measurements up until day 50; (2) no diabetes remission. The mean non-fasting PG in mice with stable diabetes over the period of 35 days was equal to 25.7 mmol/L. On day 50, mean plasma insulin concentration, mean pancreatic insulin content, and the average number of β-cells in pancreatic islets were 2.6, 8.4, and 50 times lower, respectively, than in the control animals. We consider that our Nude mouse model of diabetes meets face validity and construct validity criteria and can be used in preclinical studies of HCT/Ps.

The chinchilla as a novel animal model of gestational diabetes

BackgroundGestational diabetes occurs in 3–4% of all pregnancies, thereby being one of the leading pregnancy diseases in developed countries. The disease poses important health implications for both mother and child. Several animal models exist in this field, but with significant limitations. Consequently we want to introduce the pregnant chinchilla as a novel animal model of gestational diabetes. The chinchilla is excelled for various reasons; it gives birth to one or two cubs, is pregnant for 115 day and has a histological similar placenta barrier as compared with the human one. Since the chinchilla has never been used in diabetic studies, we aimed to show that it is possible to make it diabetic, before making a gestational model.Streptozotocin is by far the most applied method to induce diabetes in animal models, mimicking the ethology of diabetes type 1. However, since gestational diabetes is due to insulin resistance, we wanted to use high fructose feed as a method to induce diabetes.MethodsTwelve chinchillas were included in the study, six of which received high fructose diet to induce diabetes and six who received control diets. Blood glucose was monitored using Abbott Libre Freestyle glucometer. After 19 weeks the animals were euthanized and organs and blood withdrawn for analysis.Preliminary resultsNon‐fasting plasma glucose levels in chinchillas fed with high fructose diet was 19.3 ± 6.9 mmol/l, compared to controls 11.1 ± 2.2 mmol/l, p=0.056. Furthermore, DXA scans showed significant higher body fat percentage among fructose animals, p=0.043 compared to controls. HBA1C was, however, not affected in any of the groups.ConclusionWe have proven it possible to induce high blood glucose levels in the chinchilla by using high fructose diet. Because of the low sample size the blood glucose levels were, however, not statistically significant between groups. In spite of this, we consider the chinchilla a promising option for a future model of gestational diabetes.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

2-Acyl-3-carboxyl-tetrahydroisoquinoline Derivatives: Mixed-Type PTP1B Inhibitors without PPARγ Activation.

A novel series of 2-acyl-3-carboxyl-tetrahydroisoquinoline derivatives were synthesized and biologically evaluated. Among them, (S)-2-{(E)-3-furan-2-ylacryloyl}-7-[(2E,4E)-5-(2,4,6-trifluorophenyl)penta-2,4-dienyloxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 17u) was identified as a potent protein tyrosine phosphatase 1B (PTP1B) inhibitor without peroxisome proliferator-activated receptor (PPAR) γ activation: PTP1B inhibition IC50=0.19 µM and PPARγ ΕC50>10 µM. Compound 17u exhibited mixed-type inhibition for PTP1B, and this mode of inhibition was rationalized by computational ligand docking into the catalytic and allosteric sites of PTP1B. Compound 17u also showed high oral absorption at 10 mg/kg (per os (p.o.), Cmax=4.67 µM) in rats, significantly reduced non-fasting plasma glucose and triglyceride levels with no side effects at 30 mg/kg/d (p.o.) for 4 weeks, and attenuated elevations in plasma glucose levels in the oral glucose tolerance test performed 24 h after its final administration in db/db mice. In conclusion, the substituted 2-acyl-3-carboxyl-tetrahydroisoquinoline is a novel scaffold of mixed-type PTP1B inhibitors without PPARγ activation, and compound 17u has potential as an efficacious and safe anti-diabetic drug as well as a useful tool for investigations on the physiological and pathophysiological effects of mixed-type PTP1B inhibition.

Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice

The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. OBJECTIVE: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance. MethodsWe generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action. ResultsL-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded. ConclusionIDE is not a rate-limiting regulator of plasma insulin levels in vivo.

Influence of maternal adiposity, preterm birth and birth weight centiles on early childhood obesity in an Indigenous Australian pregnancy-through-to-early-childhood cohort study.

Childhood obesity rates are higher among Indigenous compared with non-Indigenous Australian children. It has been hypothesized that early-life influences beginning with the intrauterine environment predict the development of obesity in the offspring. The aim of this paper was to assess, in 227 mother-child dyads from the Gomeroi gaaynggal cohort, associations between prematurity, Gestation Related-Optimal Weight (GROW) centiles, maternal adiposity (percentage body fat, visceral fat area), maternal non-fasting plasma glucose levels (measured at mean gestational age of 23.1 weeks) and offspring BMI and adiposity (abdominal circumference, subscapular skinfold thickness) in early childhood (mean age 23.4 months). Maternal non-fasting plasma glucose concentrations were positively associated with infant birth weight (P=0.005) and GROW customized birth weight centiles (P=0.008). There was a significant association between maternal percentage body fat (P=0.02) and visceral fat area (P=0.00) with infant body weight in early childhood. Body mass index (BMI) in early childhood was significantly higher in offspring born preterm compared with those born at term (P=0.03). GROW customized birth weight centiles was significantly associated with body weight (P=0.01), BMI (P=0.007) and abdominal circumference (P=0.039) at early childhood. Our findings suggest that being born preterm, large for gestational age or exposed to an obesogenic intrauterine environment and higher maternal non-fasting plasma glucose concentrations are associated with increased obesity risk in early childhood. Future strategies should aim to reduce the prevalence of overweight/obesity in women of child-bearing age and emphasize the importance of optimal glycemia during pregnancy, particularly in Indigenous women.

Longitudinal association between toenail zinc levels and the incidence of diabetes among American young adults: The CARDIA Trace Element Study.

Data on primary prevention of zinc status and diabetes risk are sparse and inconsistent. Of note, the previous studies measured either dietary zinc intake with questionnaire or zinc status in serum or hair. Toenail zinc levels are reliable biomarkers of a relatively long-term exposure. A total of 3,960 American young adults, aged 20–32 years, free of diabetes at baseline in 1987 when toenail clippings were collected, were examined for incident diabetes through 2010. Toenail zinc levels were measured with an inductively-coupled-plasma mass spectroscopy method. Incident diabetes cases were identified by fasting or non-fasting plasma glucose levels, oral glucose tolerance tests, hemoglobin A1C levels, and/or antidiabetic medications. During the 23-year follow-up, 418 incident diabetes occurred. After adjusted for age, sex, ethnicity, study center, body mass index, education, smoking status, alcohol consumption, physical activity, family history of diabetes, homeostasis model assessment of insulin resistance, and other dietary and non-dietary potential confounders, the hazard ratio of incident diabetes comparing the highest to the lowest quartile of toenail zinc levels was 1.21 (95% CI: 0.90–1.63; Ptrend = 0.20). Findings from this study do not support the hypothesis that zinc status is inversely and longitudinally associated with the incidence of diabetes in American young adults.

Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

Follow-up of patients with hyperglycemia in the emergency department without a history of diabetes mellitus

ObjectivesThe aim of this study is to determine the prevalence of hyperglycemia in emergency department patients without a history of diabetes mellitus, and to investigate whether these patients were referred to a general practitioner or to the outpatient clinic for follow-up with further diagnostic testing and treatment. MethodsWe conducted a retrospective cohort pilot study of adult patients who were seen at the emergency department of an urban academic hospital in the Netherlands between the 1st of January and the 29th of February 2008, who had an initial (unknown fasting or non-fasting) plasma glucose level ≥7.8mmol/L (140mg/dL). The medical records of these patients were retrieved to evaluate whether these patients were referred for follow-up. ResultsDuring the data collecting period 5317 patients presented at the ED, 343 of these patients were identified with a plasma glucose ≥7.8mmol/L. Using exclusion criteria, eventually 154 patients were included in this study. The prevalence of incidentally found hyperglycemia in emergency department patients without a history of diabetes mellitus in this period was 2.9%.For 98.7% of the hyperglycemic patients no follow-up was arranged by the treating physician. None of the patients was treated with a hypoglycemic agent in the emergency department. ConclusionA substantial percentage (2.9%) of our study population had hyperglycemia and thus was at risk for undiagnosed diabetes mellitus and prediabetes. To date, recognition and follow-up of hyperglycemia in emergency department patients is poor. We presume that major health benefits may be achieved when the follow-up of hyperglycemia is performed more frequently.

Early occurrence of new-onset diabetes after transplantation is related to type of liver graft and warm ischaemic injury.

We studied new-onset diabetes after transplantation (NODAT) in liver transplantation with grafts donated after brain death (DBD) or circulatory death (DCD), focusing on the early post-transplant period. A total of 430 non-diabetic primary liver transplant recipients [DCD, n = 90 (21%)] were followed up for 30 months (range 5-69). NODAT was defined as the composite endpoint of one of following: (i) Two non-fasting plasma glucose levels > 11.1 mmol/L ≥ 30 days apart, (ii) oral hypoglycaemic drugs ≥ 30 days consecutively (iii) insulin therapy ≥ 30 days and (iv) HbA1c ≥ 48 mmol/L. Resolution of NODAT was defined as cessation of treatment or hyperglycaemia. Total of 81/430 (19%) patients developed NODAT. Incidence and resolution of NODAT over time showed significantly different patterns between DCD and DBD liver graft recipients; early occurrence, high peak incidence and early resolution were seen in DCD. In multivariate logistic regression including age, ethnicity, HCV, tacrolimus level and pulsed steroids, only DCD was independently associated with NODAT at day 15 post-transplant (OR 6.5, 95% CI 2.3-18.4, P < 0.001), whereas age and pulsed steroids were significant factors between 30-90 days. Combined in multivariate Cox regression model for NODAT-free survival, graft type, age and pulsed steroids were each independent predictor for decreased NODAT-free survival in the first 90-postoperative days. Early peak of NODAT in DCD graft recipients is a novel finding, occurring independently from known risk factors. Donor warm ischaemia and impact on insulin sensitivity should be further studied and could perhaps be associated with graft function.

Early Occurrence of New-Onset Diabetes After Transplant Is Related to the Type of Liver Graft and Warm Ischaemic Injury.

New-onset diabetes after transplantation(NODAT) occurs in 25-40% of liver transplant(LT) recipients. Cold ischemia and other etiologies have been attributed; however its association with grafts exposed to warm ischemia(WI) has not been documented. We studied NODAT in LT recipients including grafts donated after circulatory death(DCD). 430 non-diabetic primary LT recipients [DCD,n=90(21%)] were followed up for 929(142-2058) days. NODAT was defined as the composite endpoint of one of following 1. Two non-fasting plasma glucose levels>11.1mmol/L ≥30 days apart, 2. oral hypoglycemics ≥30 days consecutively 3. insulin therapy ≥30 days and 4. HbA1c ≥48 mmol/l. Resolution of NODAT was defined as cessation of treatment/hyperglycemia. Temporal association of NODAT with patient and graft characteristics was analysed. Cumulatively 81/430(19%) developed NODAT after median of 152 days. NODAT was associated with HCV infection (29% vs. 18%;p=0.03), but not with age, sex, ethnicity and BMI. DCD recipients developed NODAT earlier in the postoperative course than DBD grafts (15 vs.32 days;p=0.037) with cumulative peak incidence at 60-90 days of 20% vs. 12% (p 0.048)(Fig 1). Early NODAT(within 30 days) was associated with shorter overall survival in DCD recipients(Log rank test p=0.02;n=90 at risk, n=7 events). Early NODAT in DCD graft recipients is a novel finding in this study. Donor WI and the impact on insulin sensitivity should be further studied and this could perhaps be associated with graft function.Figure 1.: Temporal distribution of occurrence and resolution of NODAT at 15-365 days post-transplant in DBD and DCD graft recipients (Fisher’s exact/Chi2/Linear-by-Linear Association, as appropriate. P-value < 0.05= significant)

Xenograft of Microencapsulated Sertoli Cells for the Cell Therapy of Type 2 Diabetes Mellitus in Spontaneously Diabetic Nonhuman Primates: Preliminary Data

Insulin resistance in type 2 diabetes mellitus (T2DM) may be due to a chronic inflammation of the visceral adipose tissue (VAT) leading to local and systemic increases in proinflammatory cytokines. Microencapsulated porcine Sertoli cells (MC-pSC), by provision of immunomodulatory and trophic factors, have been successfully used to reduce such inflammation in rodent animal models of type 1 diabetes with no complications or deleterious side effects. Herein, we have begun to investigate this novel and safe therapeutic approach in the spontaneously obese nonhuman primate with spontaneous, insulin-dependent T2DM. After MC-pSC intraperitoneal injection we have evaluated, throughout a 6-month follow-up period, daily ad libitum fed glucose levels, daily exogenous insulin supplementation, biweekly body weight measurements, periodic fasting blood glucose concentrations, glycated hemoglobin (HbA1c) levels, glucose tolerance tests (GTT), and fluorescence-activated cell sorting cytometry (FACS) assessment of peripheral blood mononuclear cells. Very preliminarily, we have observed a slight reduction in fasting (FPG) and mean nonfasting (NF) plasma glucose levels. We found minimal changes, only in 1 animal, in daily exogenous insulin requirements and HbA1c levels. Flow cytometric analysis was associated with decrease in CD8+ cells only in 1 recipient with a reduction in mean regulatory T Cells (Treg), whereas interestingly, decrease of B lymphocytes was observed in both animals. These results may suggest that this novel MC-SC–based transplantation protocol might possibly impact the metabolic status of T2DM in higher mammals that are close to humans.

Correlation of salivary glucose, blood glucose and oral candidal carriage in the saliva of type 2 diabetics: A case-control study.

Objectives:To study the correlation between blood glucose levels and salivary glucose levels in type 2 diabetic patients, to study the relationship between salivary glucose levels and oral candidal carriage in type 2 diabetic patients and to determine whether salivary glucose levels could be used as a noninvasive tool for the measurement of glycemic control in type 2 diabetics.Study Design:The study population consisted of three groups: Group 1 consisted of 30 controlled diabetics and Group 2 consisted of 30 uncontrolled diabetics based on their random nonfasting plasma glucose levels. Group 3 consisted of 30 healthy controls. Two milliliters of peripheral blood was collected for the estimation of random nonfasting plasma glucose levels and glycosylated hemoglobin (HbA1c). Unstimulated saliva was collected for the estimation of salivary glucose. Saliva was collected by the oral rinse technique for the estimation of candidal counts.Results:The salivary glucose levels were significantly higher in controlled and uncontrolled diabetics when compared with controls. The salivary candidal carriage was also significantly higher in uncontrolled diabetics when compared with controlled diabetics and nondiabetic controls. The salivary glucose levels showed a significant correlation with blood glucose levels, suggesting that salivary glucose levels can be used as a monitoring tool for predicting glycemic control in diabetic patients.Conclusion:The present study found that estimation of salivary glucose levels can be used as a noninvasive, painless technique for the measurement of diabetic status of a patient in a dental set up. Increased salivary glucose levels leads to increased oral candidal carriage; therefore, oral diagnosticians are advised to screen the diabetic patients for any oral fungal infections and further management.

Periodontal health in type 2 diabetics

Background: Periodontitis has been reported as the sixth complication of diabetes in addition to other microvascular and macrovascular complications. Prevention and management of periodontitis is an important component in the management of diabetes mellitus (DM) and physicians treating patients with DM should be alert to recognize the signs of severe periodontitis and refer patients for appropriate management. The aim of this study was to estimate and to compare the periodontal status in diabetics and non-diabetics. Materials and Methods: A total of 150 adults, 100 with type 2 diabetes and 50 without diabetes (control subjects), aged 40-60 years, participated in the study. Diabetic status was determined by estimation of random non-fasting plasma glucose levels and glycosylated hemoglobin levels. Periodontal health was assessed by simplified-oral hygiene index (OHI-S), Loe and Silness gingival index (GI) and community periodontal index (CPI). The data were analyzed using Chi-square, Fisher exact test, analysis of variance and Kruskal-Wallis test. Results: The mean GI, mean OHI and mean CPI score were significantly higher in diabetics than non-diabetics. However, mean OHI was similar in controlled diabetics and non-diabetics. Mean CPI score was significantly increased in controlled diabetics compared to uncontrolled diabetics. Conclusion: Gingivitis, poor oral hygiene and periodontitis were more prevalent in diabetics compared to non-diabetics. Presence of poor periodontal health in diabetics, in spite of similar oral hygiene measures suggest the possibility of altered host response in periodontal tissues in these patients.

Variability between self-reported diabetes and measured glucose among health screening participants in South Central Kentucky

AimsTo assess self-reported diabetes and random glucose among health screening participants and examine factors associated with these two diabetes outcomes. MethodsStudy subjects were adults aged ≥18 years who participated in diabetes screenings via a mobile health clinic operated by the Institute for Rural Health at Western Kentucky University from 2006 to 2011. Data on self-reported diabetes were based on physicians’ past diagnosis. Random plasma glucose was obtained during the screenings. Non-fasting plasma glucose levels of ≥180mg/dl and ≥140mg/dl were used as cutoffs to determine diabetes and diabetes or pre-diabetes, respectively. Logistic regression was used to examine factors associated with self-reported diabetes and elevated non-fasting glucose levels controlling for comorbidities and sociodemographic factors. ResultsThe proportion of self-reported diabetes was 9.6%. The proportion of participants with ≥180mg/dl was 3.2% and that with ≥140mg/dl was 7.4%. Odds ratios indicated that self-reported diabetes was higher in older and obese groups and those who had hypertension and hypercholesterolemia and family history of diabetes, while elevated non-fasting glucose levels were higher among participants without health insurance and those who reported they had diabetes. ConclusionsVariability in risks between self-reported diabetes and measured glucose should be incorporated in diabetes self-care.

Long-term treatment with EXf, a peptide analog of Exendin-4, improves β-cell function and survival in diabetic KKAy mice

EXf is a C-terminally truncated fragment of Exendin-4 with two amino acid substitutions. Previous studies showed that EXf controls plasma glucose level acting as a glucagon-like peptide 1 (GLP-1) receptor agonist. The purpose of this study was to evaluate the effects of EXf on β-cell function and survival in diabetic KKAy mice. EXf treatment significantly improved the glucose intolerance and reduced non-fasting and fasting plasma glucose levels, as well as plasma triglyceride levels in diabetic KKAy mice. In hyperglycemic clamp test, EXf-treated mice displayed an increased glucose infusion rate and first-phase insulin secretion. Treatment with EXf also led to a significant restoration of islet morphology, an increase in Ki67 expression in β-cells, and a reduction in the number of TUNEL positive β-cells. In the pancreas, comparative transcription analysis showed up-regulation of Akt1. The up-regulation of phosphorylated Akt1 was confirmed by Western blot, and changes in the protein levels of members of the Akt1 pathway, such as PI3K, Bim, Bcl-2, Bax, Caspase-3, and Caspase-9, PDX-1, were observed as well. Therefore, EXf treatment could improve β-cell function and survival in diabetic KKAy mice, likely as a result of islet morphology restoration, stimulation of β-cell proliferation, and inhibition of β-cell apoptosis.

Insulin modulates glucose-dependent insulinotropic polypeptide (GIP) secretion from enteroendocrine K cells in rats

Effects of insulin excess and deficiency on glucose-dependent insulinotropic polypeptide (GIP) was examined in rats following insulinoma transplantation or streptozotocin (STZ) administration. Over 14 days, food intake was increased (p < 0.001) in both groups of rats, with decreased body weight (p < 0.01) in STZ rats. Non-fasting plasma glucose levels were decreased (p < 0.01) and plasma insulin levels increased (p < 0.001) in insulinoma-bearing rats, whereas STZ treatment elevated glucose (p < 0.001) and decreased insulin (p < 0.01). Circulating GIP concentrations were elevated (p < 0.01) in both animal models. At 14 days, oral glucose resulted in a decreased glycaemic excursion (p < 0.05) with concomitant elevations in insulin release (p < 0.001) in insulinoma-bearing rats, whereas STZ-treated rats displayed similar glucose-lowering effects but reduced insulin levels (p < 0.01). GIP concentrations were augmented in STZ rats (p < 0.05) following oral glucose. Plasma glucose and insulin concentrations were not affected by oral fat, but fat-induced GIP secretion was particularly (p < 0.05) increased in insulinoma-bearing rats. Exogenous GIP enhanced (p < 0.05) glucose-lowering in all groups of rats accompanied by insulin releasing (p < 0.001) effects in insulinoma-bearing and control rats. Both rat models exhibited increased (p < 0.001) intestinal weight but decreased intestinal GIP concentrations. These data suggest that circulating insulin has direct and indirect effects on the synthesis and secretion of GIP.

Functional, Metabolic, and Morphologic Characteristics of a Novel Rat Model of Type 2 Diabetes-associated Erectile Dysfunction

To conduct a pilot study to investigate functional, metabolic, and penile morphologic changes in a novel model of lean DM2. Erectile dysfunction (ED) is a frequent sequela in patients with type 2 diabetes mellitus (DM2). Eight rats received a high-fat diet and 2 weeks later, 2 intraperitoneal injections of streptozotocin (STZ, 30 mg/kg). Five age-matched rats served as controls. Insulin challenge tests were performed at 6 and 12 weeks after induction of DM2. At 12 weeks, erectile function was tested by measurement of intracavernous pressure (ICP) increase upon cavernous nerve stimulation. Penile tissue and serum samples were harvested for histology and biochemistry, respectively. A lean DM2 model was established as demonstrated by decreased insulin resistance, elevated nonfasting plasma glucose levels, hyperlipidemia, and decreased insulin concentration in the absence of obesity. ICP/mean arterial pressure was significantly decreased in DM2 animals (0.29) compared with controls (0.81). Expression of neuronal nitric oxide synthase and rat endothelial cell antigen-1, and the smooth muscle/collagen ratio were significantly decreased in the penis of DM2 animals. We propose an inexpensive nongenetic animal model of lean DM2-associated ED. Microanatomical changes in the erectile tissue that reflect an advanced stage of the disease were observed.

Obesity‐Induced Diabetes in Mouse Strains Treated With Gold Thioglucose: A Novel Animal Model for Studying β‐Cell Dysfunction

An obesity-induced diabetes model using genetically normal mouse strains would be invaluable but remains to be established. One reason is that several normal mouse strains are resistant to high-fat diet-induced obesity. In the present study, we show the effectiveness of gold thioglucose (GTG) in inducing hyperphagia and severe obesity in mice, and demonstrate the development of obesity-induced diabetes in genetically normal mouse strains. GTG treated DBA/2, C57BLKs, and BDF1 mice gained weight rapidly and exhibited significant increases in nonfasting plasma glucose levels 8-12 weeks after GTG treatment. These mice showed significantly impaired insulin secretion, particularly in the early phase after glucose load, and reduced insulin content in pancreatic islets. Interestingly, GTG treated C57BL/6 mice did not become diabetic and retained normal early insulin secretion and islet insulin content despite being as severely obese and insulin resistant as the other mice. These results suggest that the pathogenesis of obesity-induced diabetes in GTG-treated mice is attributable to the inability of their pancreatic β-cells to secrete enough insulin to compensate for insulin resistance. Mice developing obesity-induced diabetes after GTG treatment might be a valuable tool for investigating obesity-induced diabetes. Furthermore, comparing the genetic backgrounds of mice with different susceptibilities to diabetes may lead to the identification of novel genetic factors influencing the ability of pancreatic β-cells to secrete insulin.