Enhanced Insulin Secretion Research Articles

1963-P: Undercarboxylated Osteocalcin Is Correlated with Insulin Secretion in Japanese Individuals with Diabetes

Background and Aims: Undercarboxylated osteocalcin (ucOC) is a secreted protein produced by osteoblasts. UcOC can regulate insulin secretion and insulin sensitivity in rodents. Pharmacological administration of ucOC enhances insulin secretion which could be mediated by GLP-1 in mice. However, pathophysiological roles of ucOC in glucose intolerance in human remain unknown. In this study, we aimed to investigate the association between ucOC and glucose metabolism in individuals with varying degrees of glucose tolerance. Materials and Methods: The 75-g oral glucose tolerance test was carried out in 75 Japanese individuals not taking diabetes medications [age: 65±11 (mean±SD); male/female: 34/41; BMI: 24.9±3.8]. Individuals were classified as normal (NGT), impaired glucose tolerance (IGT), and diabetes (DM) groups (each group: n=25). The insulinogenic index (IGI) as an index of insulin secretion, and QUICKI and the Matsuda Index (MI) as indices of insulin sensitivity were calculated. Fasting serum levels of ucOC and leptin were assayed by ECLIA and by ELISA, respectively. Normally-distributed loge-transformed (ln-)values were used for regression analysis in some cases. Results: Although fasting and 2h after glucose loading plasma glucose, HbA1c, IGI, QUICKI and MI were significantly different among the 3 groups, age, sex, BMI, and ucOC were not different. In simple regression analysis in each group, ln-ucOC was not correlated with QUICKI and ln-MI in all 3 groups. Interestingly, ln-ucOC was correlated with ln-IGI (r=0.422, P=0.0345) and HbA1c (r=-0.574, P=0.0022) only in DM. In multiple regression analysis in DM, ln-IGI was independently predicted by BMI (β=0.598) and ln-ucOC (β=0.641) (R2=0.488, P=0.0006) and by ln-leptin (β=0.624) and ln-ucOC (β=0.448) (R2=0.568, P<0.0001). Conclusion: UcOC was correlated with insulin secretion independently of adiposity in Japanese individuals with diabetes. Disclosure S. Funakoshi: None. S. Ohmi: None. E. Amano: None. Y. Terada: None. S. Fujimoto: None.

Effects of islet neogenesis associated protein depend on vascular endothelial growth factor gene expression modulated by hypoxia-inducible factor 1-alpha

BackgroundPharmacology has provided efficient tools to improve insulin effect/secretion but the decrease in β-cell mass remains elusive. INGAP-PP could provide a therapeutic alternative to meet that challenge. AimTo further understand the mechanism that links INGAP-PP effects upon β-cell mass and function with islet angiogenesis. MethodologyNormal male Wistar rats were divided into 2 groups and injected with a single dose of 100 mg/Kg suramin or saline. Both groups were divided into 2 subgroups that received daily doses of 2 mg/kg INGAP-PP or saline for ten days. Plasma glucose, triacylglycerol, TBARS, and insulin levels were measured. Pancreas immunomorphometric analyses were also performed. Pancreatic islets were isolated to measure glucose-stimulated insulin secretion (GSIS). Specific islet mRNA levels were studied by qRT-PCR. Statistical analysis was done using ANOVA. ResultsNo differences were recorded in body weight, food intake, or any other plasma parameter measured in all groups. Islets from INGAP-PP-treated rats significantly increased GSIS, β-cell mass, and mRNA levels of Bcl-2, Ngn-3, VEGF-A, VEGF-R2, CD31, Ang1 and Ang2, Laminin β-1, and Integrin β-1, and decreased mRNA levels of Caspase-8, Bad, and Bax. Islets from suramin-treated rats showed significant opposite effects, but INGAPP-PP administration rescued most of the suramin effects in animals treated with both compounds. ConclusionOur results reinforce the concept that INGAP-PP enhances insulin secretion and β-cell mass, acting through PI3K/Akt/mTOR pathways and simultaneously activating angiogenesis through HIF-1α-mediated VEGF-A secretion. Therefore, INGAP-PP might be a suitable antidiabetic agent able to overcome two major alterations present in T2D.

Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets.

The utilization of mesenchymal stem cells (MSCs) is a promising approach to serve as adjuvant therapy for islet transplantation. But the inability to translate promising preclinical results into sound therapeutic effects in human subjects indicates a lack of key knowledge of MSC-islet interactions that warrant further research. Hypoxia and oxidative stress are critical factors which lead to a tremendous loss of islet grafts. However, previous studies mainly focused on other aspects of MSC protection such as inducing revascularization, enhancing insulin secretion, and reducing islet apoptosis. In this study, we aim to investigate whether MSC can protect islet cells from hypoxic damage by inhibiting ROS production and the potential underlying pathways involved. We also explore the effects of MSC-derived exosomes and IL-6 on hypoxia-injured islets. Our data provide new molecular targets for developing MSC applications, and this may ultimately promote the efficiency of clinical islet transplantation.

MON-122 Familial Clinical Heterogeneity Manifested by the Presence of Either Diabetes or Deafness in a Pedigree of a Patient with Maternally Inherited Diabetes Mellitus and Deafness and Mitochondrial DNA M.3243a>G Mutation

Introduction: Mitochondrial DNA mutation is a rare cause for diabetes mellitus (DM) and deafness that is often misdiagnosed as type 1 or type 2 DM. Unique management issues, associated comorbidities and fertility plans require proper diagnosis. Proband: a 25 year-old female presented with a fasting glucose 205 mg/dl, Hb A1c 8.5% with intolerance to metformin. She has been previously diagnosed with sensorineural hearing loss. Her physical examination was unremarkable, except for a BMI of 20kg/m2 and a short stature. Her parents were not blood-related. The family history was notable for several relatives with either diabetes or deafness. Her twin sister had prediabetes, her older sister had deafness, her brother had muscle cramps and her mother had both DM and hearing loss, and was also diagnosed with "fibromyalgia". From the mother side; her grandmother had DM, her aunt had deafness and her daughter had DM, 2 uncles had DM. GAD antibodies, Islet cell antibodies and Zinc transporter 8 antibodies were negative. Renal function was normal. She responded well to basal insulin treatment, with an achieved Hb A1c of 7%. Her genetic workup identified a mutation in the mitochondrial DNA m.3243A>G which is associated with MIDD (maternally inherited diabetes and deafness) and MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like episodes). The following specific recommendations were made, which differ from the standard practice and guidelines in the care of classical type 1 or type 2 diabetes: 1) avoid metformin; 2) rigidly maintain adequate carbohydrate consumption when ill, as stroke- like episodes have been described in this condition during acute illness when carbohydrate supply was inadequate; 3) use Coenzyme Q10 which might enhance insulin secretion and potentially improve symptoms of myopathy. 4) attempt not to postpone fertility due to the risk of premature ovarian failure; 5) for pregnancy planning, consider "three parent IVF" with mitochondria and cytoplasm from a donated ovum, thus potentially avoiding transmitting the defect. Conclusion: Diagnosis of MIDD should be considered in subjects with family history of premature deafness and diabetes, not necessarily in the same subjects. The correct diagnosis may offer multiple therapeutic advantages. With accurate genetic diagnose, appropriate therapy, family screening, genetic counseling and surveillance for existing and future complications can be applied.

Glucagon-like peptide-1 (GLP-1) Biological Role in Patients of Type 2 Diabetes and Metabolic Syndrome

<p style="margin: 0in 0in 10pt; text-align: justify; line-height: 200%;">Type2 diabetes is estimated to affect 380 million people worldwide in 2025. Patients of this disease are at increased risk of cardiovascular diseases (CVD).The CVD risk is greater when diabetic patients have metabolic syndrome. Thus, the management of metabolic syndrome and CVD is crucial for diabetic patient’s life progress. GLP-1 has positive biological influences on glucose metabolism control by inhibiting glucagon secretion, enhancing insulin secretion and protecting the effects of cells. GLP-1 was also found to have other positive influences including weight loss, appetite sensation and food intake. These are important factors in metabolic disturbances control and CVD management. The paper reviewed several studies regarding the GLP-1 positive concerns. In conclusion, the paper supports the modern proposal of GLP-1 RAs as a first line therapy in initially diagnosed type 2 diabetes patients.</p>

Sympathetic Denervation of the Common Hepatic Artery Lessens Glucose Intolerance in the Fat- and Fructose-Fed Dog.

This study assessed the effectiveness of surgical sympathetic denervation of the common hepatic artery (CHADN) in improving glucose tolerance. CHADN eliminated norepinephrine content in the liver and partially decreased it in the pancreas and the upper gut. We assessed oral glucose tolerance at baseline and after 4 weeks of high-fat high-fructose (HFHF) feeding. Dogs were then randomized to sham surgery (SHAM) (n = 9) or CHADN surgery (n = 11) and retested 2.5 or 3.5 weeks later while still on the HFHF diet. CHADN improved glucose tolerance by ∼60% in part because of enhanced insulin secretion, as indicated by an increase in the insulinogenic index. In a subset of dogs (SHAM, n = 5; CHADN, n = 6), a hyperinsulinemic-hyperglycemic clamp was used to assess whether CHADN could improve hepatic glucose metabolism independent of a change in insulin release. CHADN reduced the diet-induced defect in net hepatic glucose balance by 37%. In another subset of dogs (SHAM, n = 4; CHADN, n = 5) the HFHF diet was continued for 3 months postsurgery and the improvement in glucose tolerance caused by CHADN continued. In conclusion, CHADN has the potential to enhance postprandial glucose clearance in states of diet-induced glucose intolerance.

Alginate-microencapsulation of human stem cell-derived β cells with CXCL12 prolongs their survival and function in immunocompetent mice without systemic immunosuppression.

Pancreatic β-cell replacement by islet transplantation for the treatment of type 1 diabetes (T1D) is currently limited by donor tissue scarcity and the requirement for lifelong immunosuppression. The advent of in vitro differentiation protocols for generating functional β-like cells from human pluripotent stem cells, also referred to as SC-β cells, could eliminate these obstacles. To avoid the need for immunosuppression, alginate-microencapsulation is widely investigated as a safe path to β-cell replacement. Nonetheless, inflammatory foreign body responses leading to pericapsular fibrotic overgrowth often causes microencapsulated islet-cell death and graft failure. Here we used a novel approach to evade the pericapsular fibrotic response to alginate-microencapsulated SC-β cells; an immunomodulatory chemokine, CXCL12, was incorporated into clinical grade sodium alginate to microencapsulate SC-β cells. CXCL12 enhanced glucose-stimulated insulin secretion activity of SC-β cells and induced expression of genes associated with β-cell function in vitro. SC-β cells co-encapsulated with CXCL12 showed enhanced insulin secretion in diabetic mice and accelerated the normalization of hyperglycemia. Additionally, SC-β cells co-encapsulated with CXCL12 evaded the pericapsular fibrotic response, resulting in long-term functional competence and glycemic correction (>150days) without systemic immunosuppression in immunocompetent C57BL/6 mice. These findings lay the groundwork for further preclinical translation of this approach into large animal models of T1D.

Raffia palm (Raphia hookeri G. Mann & H. Wendl) wine modulates glucose homeostasis by enhancing insulin secretion and inhibiting redox imbalance in a rat model of diabetes induced by high fructose diet and streptozotocin

Ethnopharmacological relevanceRaffia palm (Raphia hookeri) wine (RPW) is amongst the natural products from plants, utilized singly or in combination with other medicinal plants for the treatment of several ailments including Diabetes Mellitus (DM). However, there is a scientific dearth on its antidiabetic activity. AimThe antidiabetic effect of RPW and its possible mechanism of actions were investigated in diabetic rats. MethodsFour groups of male SD rats were first supplied with 10% fructose solution ad libitum for 2 weeks instead of drinking water followed by an intraperitonial injection of streptozotocin (40 mg/kg) to induce diabetes. Two diabetic groups were administered RPW at 150 and 300 mg/kg bodyweight (BW) respectively; a group was administered with metformin, while the other one was served as a negative control. Two groups of normal rats were administered with water and RPW (300 mg/kg BW) and served as normal control and normal toxicology group, respectively. ResultsFive weeks treatment of RPW led to significant (p < 0.05) increase in serum insulin and HDL-c levels with concomitant reduction in blood glucose, fructosamine, ALT, uric acid, triglycerides and LDL-c levels in diabetic rats. Rats treated with RPW had elevated levels of GSH, SOD, catalase, ATPase and α-amylase activities, while reduced NO level and myeloperoxidase activity was observed in their serum and pancreatic tissues. RPW also improved pancreatic β-cell function and restored β- and acinar cells morphology, and capillary networks. The activities of glycogen phosphorylase, fructose 1,6 biphosphatase, glucose-6-phosphatase, and acetylcholinesterase were also inhibited in RPW-treated diabetic rats, with concomitant down regulation of Nrf2 gene expression. ConclusionThe data of this study suggest that RPW modulates glucose homeostasis by enhancing insulin secretion as well as inhibiting redox imbalance in diabetic rats, which may be attributed to the synergetic effects of its phytochemical constituents as identified by GC-MS analysis.

Fat Quantity and Quality, as Part of a Low-Fat, Vegan Diet, Are Associated with Changes in Body Composition, Insulin Resistance, and Insulin Secretion. A 16-Week Randomized Controlled Trial.

Macronutrient composition of the diet influences the development of obesity and insulin resistance. The aim of this study was to assess the role of dietary fat quantity and fatty acid composition in body composition, insulin resistance, and insulin secretion. An open parallel randomized trial design was used. Overweight participants (n = 75) were randomized to follow a low-fat vegan (n = 38) or control diet (n = 37) for 16 weeks. Dual X-ray absorptiometry was used to measure body composition. Insulin resistance was assessed with the Homeostasis Model Assessment (HOMA-IR) index. Insulin secretion was assessed after stimulation with a liquid breakfast (Boost Plus, Nestle, Vevey, Switzerland). Self-reported 3-day diet records were used to assess dietary intake. A linear regression model was used to test the relationship between fat intake and body composition, insulin resistance, and insulin secretion. Changes in fat intake expressed as percent of total energy consumed correlated positively with changes in fat mass (r = 0.52; p < 0.001; and 0.347; p = 0.006, respectively), even after adjustment for changes in body-mass index (BMI) and energy intake (0.33; p = 0.01). Decreased intakes of C18:0 (r = 0.37, p = 0.004) and CLA-trans-10-cis12 (r = 0.40, p = 0.002), but increased intake of C18:2 (r = −0.40, p = 0.002) and C18:3 (p = −0.36, p = 0.006), were associated with a decrease in HOMA-IR, independent on changes in BMI and energy intake. The main fatty acids associated with changes in fasting insulin secretion were C12:0 (r = −0.31, p = 0.03), and TRANS 16:1 (r = −0.33, p = 0.02), both independent on changes in BMI and energy intake. Our findings demonstrate that, in the context of a low-fat vegan diet, decreased intake of saturated and trans fats and increased relative content of polyunsaturated fatty acids, particularly linoleic and α-linolenic acids, are associated with decreased fat mass and insulin resistance, and enhanced insulin secretion.

Anti-diabetic properties of different fractions of Korean red ginseng

Ethnopharmacological relevanceKorean red ginseng (KRG) has been traditionally used to treat diabetes. Ginsenosides are considered as the major bioactive components mediating anti-diabetic effects of KRG. However, considering that ginsenosides account for only about 3–4% of ginsengs, other fractions of KRG may also carry potential anti-diabetic effects. There is no study reporting the differentiated effects of ginsenosides (Spn) and non-saponin fractions (NSpn) of KRG on glycemic control. Aim of the studyWe investigated the effects of KRG, Spn, and NSpn on the indications of glycemic control and sought to elucidate physiological factors contributing their effects. Materials and methodsHuman T2DM mimicking Nagoya-Shibata-Yasuda (NSY/hos) mice were given KRG, Spn, or NSpn admixed in rodent diet at 200 mg/kg/day for 24 weeks. Glycemic and obesity indications, blood lipid profile, systematic and local oxidative stress markers in metabolically important organs, and systematic inflammatory markers were assessed. Molecular assessments associated with glycemic control in liver and skeletal muscle were further performed. ResultsKRG attenuated deterioration in glucose homeostasis as evidenced by significantly lower fasting blood glucose from 22nd week and AUC during GTT at the end of the experiment compare to control. Spn enhanced insulin secretion in response to glucose stimulation and reduced protein level of glycogen phosphorylase in liver. On the other hand, NSpn ameliorated oxidative stress and inflammation. Some beneficial effects of Spn and NSpn were reflected in KRG treated mice. KRG also attenuated the accumulation of malondialdehyde in skeletal muscle and, accordingly, enhanced insulin responsiveness compare to control. ConclusionAnti-diabetic properties of KRG are not solely determined by the contents of ginsenosides but the harmonic functions of its different fractions.

Glutamate decarboxylase 67 contributes to compensatory insulin secretion in aged pancreatic islets

ABSTRACTPancreatic islets play an essential role in regulating blood glucose levels. Age-dependent development of glucose intolerance and insulin resistance results in hyperglycemia, which in turn stimulates insulin synthesis and secretion from aged islets, to fulfill the increased demand for insulin. However, the mechanism underlying enhanced insulin secretion remains unknown. Glutamic acid decarboxylase 67 (GAD67) catalyzes the conversion of glutamate into γ-aminobutyric acid (GABA) and CO2. Both glutamate and GABA can affect islet function. Here, we investigated the role of GAD67 in insulin secretion in young (3 month old) and aged (24 month old) C57BL/6J male mice. Unlike young mice, aged mice displayed glucose-intolerance and insulin-resistance. However, aged mice secreted more insulin and showed lower fed blood glucose levels than young mice. GAD67 levels in primary islets increased with aging and in response to high glucose levels. Inhibition of GAD67 activity using a potent inhibitor of GAD, 3-mercaptopropionic acid, abrogated glucose-stimulated insulin secretion from a pancreatic β-cell line and from young and aged islets. Collectively, our results suggest that blood glucose levels regulate GAD67 expression, which contributes to β-cell responses to impaired glucose homeostasis caused by advanced aging.

Sleeve gastrectomy rapidly enhances islet function independently of body weight.

Bariatric surgeries including vertical sleeve gastrectomy (VSG) ameliorate obesity and diabetes. Weight loss and accompanying increases to insulin sensitivity contribute to improved glycemia after surgery; however, studies in humans also suggest weight-independent actions of bariatric procedures to lower blood glucose, possibly by improving insulin secretion. To evaluate this hypothesis, we compared VSG-operated mice with pair-fed, sham-surgical controls (PF-Sham) 2 weeks after surgery. This paradigm yielded similar postoperative body weight and insulin sensitivity between VSG and calorically restricted PF-Sham animals. However, VSG improved glucose tolerance and markedly enhanced insulin secretion during oral nutrient and i.p. glucose challenges compared with controls. Islets from VSG mice displayed a unique transcriptional signature enriched for genes involved in Ca2+ signaling and insulin secretion pathways. This finding suggests that bariatric surgery leads to intrinsic changes within the islet that alter function. Indeed, islets isolated from VSG mice had increased glucose-stimulated insulin secretion and a left-shifted glucose sensitivity curve compared with islets from PF-Sham mice. Isolated islets from VSG animals showed corresponding increases in the pulse duration of glucose-stimulated Ca2+ oscillations. Together, these findings demonstrate a weight-independent improvement in glycemic control following VSG, which is, in part, driven by improved insulin secretion and associated with substantial changes in islet gene expression. These results support a model in which β cells play a key role in the adaptation to bariatric surgery and the improved glucose tolerance that is typical of these procedures.

Twincretin as a potential therapeutic for the management of type2 diabetes with obesity.

Unimolecular peptide‐based dual agonists against glucagon‐like peptide‐1 receptor (GLP‐1R) and glucose‐dependent insulinotropic polypeptide receptor (GIPR) have been gaining much attention recently as novel antidiabetic agents that can potentially control glycemia and bodyweight. Although GLP‐1 and GIP both enhance insulin secretion and subsequently ameliorate postprandial glucose excursion, most research has focused on GLP‐1R as a therapeutic target for type 2 diabetes. This is partly because the effects of GIPR activation on glycemia and bodyweight have been controversial. GIPR‐deficient mice showed impaired glucose tolerance with reduced β‐cell function and resistance to high‐fat diet‐induced obesity, whereas GIPR agonists improved glycemia and prevented high‐fat diet‐induced obesity in mice. Conflicting results in mice might be explained by pharmacological levels of GIP signal in the central nervous systems decreasing food intake and overcoming the obesogenic effects of GIP at physiological levels in adipose tissues. Thus, GIPR activation at pharmacological levels might result in bodyweight reduction. Indeed, bodyweight reduction by GIPR/GLP‐1R dual agonists was greater than GLP‐1R single agonists in individuals with type 2 diabetes. Thus, GLP‐1R/GIPR dual agonists can add additional therapeutic efficacy to tailored diabetes care, especially among obese individuals with type 2 diabetes. However, caution should be exercised as to whether or not these drugs are appropriate for the management of Asian type 2 diabetes patients, which are primarily characterized by non‐obesity and impaired β‐cell function, as well as in that of elderly adults with type 2 diabetes, who tend to develop sarcopenia and frailty as a result of poor energy intake.

Adipocyte expression of glucose transporter 1 and 4 in PCOS: Relationship to insulin-mediated and non-insulin-mediated whole-body glucose uptake.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder associated with insulin resistance (IR). In IR states, non-insulin-mediated glucose uptake (NIMGU) may increase to compensate for declining insulin-mediated glucose uptake (IMGU), although this does not appear to be the case in PCOS. The underlying molecular mechanisms for this deficiency remain unclear. To compare adipocyte glucose transporter 1 and 4 (GLUT-1 and GLUT-4) gene expression in PCOS women and matched controls, and to determine whether changes in GLUT-1 and GLUT-4 are associated with concomitant alterations in whole-body glucose uptake. In this prospective cross-sectional study, 23 women with PCOS (by NIH 1990 criteria) and 23 matched controls were studied for subcutaneous abdominal adipocyte GLUT-1 and GLUT-4 mRNA expression (by real-time PCR), and basal whole-body IR (by HOMA-IR) and insulin secretion (by HOMA-β%). A subset of six PCOS women and six matched controls also underwent a mFSIVGTT to determine dynamic state glucose uptake (by insulin sensitivity index [Si] and glucose effectiveness [Sg]) and insulin secretion (by the acute insulin response to glucose [AIRg] and the disposition index [Di]). For similar adiposity (BMI and waist-hip ratio), PCOS women tended to have higher HOMA-IR and lower Di and Si, and higher HOMA-β% and lower GLUT-4 than controls, while GLUT-1 was similar. GLUT-1 was positively associated with Sg (reflecting NIMGU) and GLUT-4 positively with Si (reflecting IMGU). GLUT-4 was associated negatively with HOMA-IR and HOMA-β% and positively with Di for the entire cohort but not with AIRg. Both GLUT-1 and GLU-4 were negatively associated with BMI, but not with each other. Our results suggest that IR secondary to a lower IMGU and enhanced insulin secretion in PCOS is in part attributable to a reduction in adipocyte GLUT-4 expression that is not accompanied by a compensatory increase in GLUT-1 expression.

Zinc-induced activation of GPR39 regulates glucose homeostasis through glucose-dependent insulinotropic polypeptide secretion from enteroendocrine K-cells.

The role of Zn2+-sensing receptor GPR39 on glucose homeostasis and incretin regulation was assessed in enteroendocrine L- and K-cells. Anti-hyperglycaemic, insulinotropic and incretin secreting properties of Zn2+ were explored in normal, diabetic and incretin receptor knockout mice. Compared to intraperitoneal injection, oral administration of Zn2+ (50 μmol/kg body weight) with glucose (18 mmol/kg) in lean mice reduced the glycaemic excursion by 25-34% (p < 0.05-p < 0.001) and enhanced glucose-induced insulin release by 46-48% (p < 0.05-p < 0.01). In diabetic mice, orally administered Zn2+ lowered glucose by 24-31% (p < 0.01) and augmented insulin release by 32% (p < 0.01). In glucagon like peptide-1 (GLP-1) receptor knockout mice, Zn2+ reduced glucose by 15-28% (p < 0.05-p < 0.01) and increased insulin release by 35-43% (p < 0.01). In contrast Zn2+ had no effect on responses of glucose-dependent insulinotropic polypeptide (GIP) receptor knockout mice. Consistent with this, Zn2+ had no effect on circulating total GLP-1 whereas GIP release was stimulated by 26% (p < 0.05) in lean mice. Immunocytochemistry demonstrated GPR39 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Zn2+ had a direct effect on GIP secretion from pGIPneo STC-1 cells, increasing GIP secretion by 1.3-fold. GPR39 is expressed on intestinal L- and K-cells, and stimulated GIP secretion plays an integral role in mediating enhanced insulin secretion and glucose tolerance following oral administration of Zn2+. This suggests development of potent and selective GPR39 agonists as a therapeutic approach for diabetes.

Late-gestation protein restriction negatively impacts muscle growth and glucose regulation in steer progeny

The objective of this study was to determine whether the amount of protein provided to cows during late gestation would affect postnatal growth and lead to changes in glucose and insulin concentrations. At 129 d of gestation, 10 mature multiparous Angus cows were stratified by body weight (BW) and body condition score (BCS) and allotted to either low protein level (LP, 6% crude protein [CP]) or high protein level (HP, 12% CP) groups. After calving, cows were managed together on improved pastures, which provided forage in excess of requirements until weaning. Male calves were maintained as a group after weaning on native range until 23 mo of age when individual steers were placed in single pens and fed a finishing diet for 84 d. The 12th rib fat thickness and longissimus muscle area were measured during finishing phase by ultrasound. Twenty days before the end of the finishing phase, steers were subjected to an intravenous glucose tolerance test. Steers were harvested and carcass characteristics collected. Cows' BW and BCS were similar at the initiation of treatment. During treatment HP dams gained 21 kg, whereas LP dams lost 7 kg (P = 0.04). Protein nutrition during late gestation did not influence calf birth weight, BW at weaning, adjusted 205 d BW, or average daily gain during lactation (P > 0.10). Longissimus muscle area measure by ultrasound was greater (P = 0.02) in HP steers at the beginning and end of finishing phase. Fat thickness of the 12th rib was not different (P > 0.10) between treatments. Glucose concentration after intravenous administration decreased (P = 0.002) in LP compared with HP steers. Peak of serum insulin concentration was greater (P = 0.04) and serum insulin concentration tended to decrease (P = 0.08) more rapidly in LP compared with HP steers after glucose infusion. At harvest, hot carcass weight was similar between treatments, but dressing percentage was increased (P = 0.05) in HP compared with LP steers. These data demonstrate that a lower protein nutrition level of dams during late gestation affect carcass characteristics and alter glucose regulation enhancing insulin secretion in steer progeny.

Enhanced Secretion of Functional Insulin with DNA-Functionalized Gold Nanoparticles in Cells.

We have previously shown the use of gold nanoparticles (AuNPs) functionalized with DNA (AuNP-DNA) to increase insulin mRNA translation in a cell-free system. In this study, we translate the concept into a whole cell system to demonstrate functionality despite the additional complexity of intracellular delivery and mRNA translation inside living cells. We selected an insulin-secreting pancreatic islet cell line, RIN-5F, as our model and designed a DNA oligomer (insDNA) that is complementary to the 3'-untranslated region of insulin mRNA for conjugation to AuNPs (AuNP-insDNA). AuNP-insDNA was stable in the extracellular environment of RIN-5F cells for up to 24 h, without eliciting any cell toxicity. Upon cellular entry, AuNP-insDNA was able to sustain enhanced insulin secretion from 6 to 12 h post-incubation, peaking at 10 h with an enhancement factor of 1.69-fold. This enhancement was not observed when insDNA was removed or replaced with poly thymine or poly adenine DNAs. The enhanced insulin secreted was 100% functional and capable of binding to its insulin receptor. The outcome of this study demonstrated the feasibility of AuNP-DNA to enhance the synthesis of proteins in whole cells and could serve as a new direction of invoking a patient's own beta cells to increase insulin secretion for treatment of diabetes.

Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery

SummaryBariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion.

Effects and Underlying Mechanisms of Bioactive Compounds on Type 2 Diabetes Mellitus and Alzheimer's Disease.

Type 2 diabetes mellitus is a complicated metabolic disorder characterized by hyperglycemia and glucose intolerance. Alzheimer's disease is a progressive brain disorder characterized by a chronic loss of cognitive and behavioral function. Considering the shared characteristics of both diseases, common therapeutic and preventive agents may be effective. Bioactive compounds such as polyphenols, vitamins, and carotenoids found in vegetables and fruits can have antioxidant and anti-inflammatory effects. These effects make them suitable candidates for the prevention or treatment of diabetes and Alzheimer's disease. Increasing evidence from cell or animal models suggest that bioactive compounds may have direct effects on decreasing hyperglycemia, enhancing insulin secretion, and preventing formation of amyloid plaques. The possible underlying molecular mechanisms are described in this review. More studies are needed to establish the clinical effects of bioactive compounds.

Oxygen Perfusion (Persufflation) of Human Pancreata Enhances Insulin Secretion and Attenuates Islet Proinflammatory Signaling.

All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration. In the present study, we investigated whether pancreas preservation by gaseous oxygen perfusion (persufflation) better preserved islet function versus SCS. Human pancreata were preserved by SCS or by persufflation in combination with SCS. Islets were subsequently isolated, and preparations in each group matched for SCS or total preservation time were compared using dynamic glucose-stimulated insulin secretion as a measure of β-cell function and RNA sequencing to elucidate transcriptomic changes. Persufflated pancreata had reduced SCS time, which resulted in islets with higher glucose-stimulated insulin secretion compared to islets from SCS only pancreata. RNA sequencing of islets from persufflated pancreata identified reduced inflammatory and greater metabolic gene expression, consistent with expectations of reducing cold ischemic exposure. Portions of these transcriptional responses were not associated with time spent in SCS and were attributable to pancreatic reoxygenation. Furthermore, persufflation extended the total preservation time by 50% without any detectable decline in islet function or viability. These data demonstrate that pancreas preservation by persufflation rather than SCS before islet isolation reduces inflammatory responses and promotes metabolic pathways in human islets, which results in improved β cell function.