Changes In Insulin Secretion Research Articles

Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis

The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.

Dietary Supplementation with Cholic Acid Reduces Insulin Secretion in Response to Intraperitoneal Glucose Administration in Rats.

The major characteristic of type 2 diabetes is insulin resistance, which is associated with plasma level of 12-hydroxylated bile acids (BAs) in humans. In this study, we investigated whether the rise of enterohepatic 12-hydroxylated BAs associates with glucose tolerance and/or insulin secretion using rats fed a diet supplemented with cholic acid (CA) at a level of 0.5 g/kg diet. Almost no increase was observed in plasma insulin in response to the intraperitoneal glucose administration in the CA-fed rats despite the significant increase of plasma insulin in control with the same treatment. In contrast, the changes in insulin secretion were observed in both groups and no difference was detected between the groups in the oral glucose tolerance test. Increases were observed in pancreatic expressions of Ins1 and Ins2 although the insulin protein content decreased in the pancreas without any sign in ectopic fat accumulation and histological damage in the CA-fed rats. Our results suggest that enterohepatic 12-hydroxylated BAs modulate insulin secretion in response to intraperitoneal glucose administration. The decrease in insulin store might be responsible for the reduction in the insulin secretion in the CA-fed rats.

Acute Poisoning of Benzodiazepines Among Patients Admitted to Loghman Hakim Hospital

Background: Benzodiazepines have been highly prescribed by physicians and have attracted public attention due to their high safety. These drugs have sedative, hypnotic, anti-anxiety, and anti-seizure properties. However, these drugs are also widely used for suicide. The present study was designed and implemented to determine the distribution of patients poisoned with benzodiazepines in terms of clinical and demographic characteristics. Methods: Investigation of poisoning with benzodiazepines in one year in the poisoning department of Loghman Medical Center in Tehran City, Iran, was carried out as a descriptive-prospective study. In this research, 458 poisoned patients were studied to collect data on their age, gender, drug dosage, type of drug, duration of hospitalization, blood analysis results, and mortality. Results: The majority of patients poisoned with benzodiazepines were women (62.2%). The mean age of people was 31.67 years. The most frequently used drugs were clonazepam and alprazolam. Other drugs used with benzodiazepines were propranolol, methadone, and acetaminophen. The death rate was 1.7%. The incidence of hypoglycemia and creatinine above 1.3 was 8.53% and 11.3%, respectively. Hyperglycemia was 10.6%. There were 11, 80, and 178 cases of elevated alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, respectively. Conclusion: Benzodiazepines have the potential to cause liver and kidney damage and changes in insulin secretion and blood sugar. This issue should be considered when dealing with a poisoned patient to prevent serious injuries.

Long non-coding RNA LncCplx2 regulates glucose homeostasis and pancreatic β cell function

ObjectiveNumerous studies have highlighted the role of clock genes in diabetes disease and pancreatic β cell functions. However, whether rhythmic long non-coding RNAs involve in this process is unknown. MethodsRNA-seq and 3’ rapid amplification of cDNA ends (RACE)-PCR were used to identify the rat LncCplx2 in pancreatic β cells. The subcellular analysis with qRT-PCR and RNA-Scope were used to assess the localization of LncCplx2. The effects of LncCplx2 overexpression or knockout (KO) on the regulation of pancreatic β cell functions were assessed in vitro and in vivo. RNA-seq, immunoblotting (IB), Immunoprecipitation (IP), RNA pull-down, and chromatin immunoprecipitation (ChIP)-PCR assays were employed to explore the regulatory mechanisms through LncRNA-protein interaction. Metabolism cage was used to measure the circadian behaviors. ResultsWe first demonstrate that LncCplx2 is a conserved nuclear long non-coding RNA and enriched in pancreatic islets, which is driven by core clock transcription factor BMAL1. LncCplx2 is downregulated in the diabetic islets and repressed by high glucose, which regulates the insulin secretion in vitro and ex vivo. Furthermore, LncCplx2 KO mice exhibit diabetic phenotypes, such as high blood glucose and impaired glucose tolerance. Notably, LncCplx2 deficiency has significant effects on circadian behavior, including prolonged period duration, decreased locomotor activity, and reduced metabolic rates. Mechanistically, LncCplx2 recruits EZH2, a core subunit of polycomb repression complex 2 (PRC2), to the promoter of target genes, thereby silencing circadian gene expression, which leads to phase shifts and amplitude changes in insulin secretion and cell cycle genes. ConclusionsOur results propose LncCplx2 as an unanticipated transcriptional regulator in a circadian system and suggest a more integral mechanism for the coordination of circadian rhythms and glucose homeostasis.

Physiologic Adaptation to Macronutrient Change Distorts Findings from Short Dietary Trials: Reanalysis of a Metabolic Ward Study

An influential 2-wk cross-over feeding trial without a washout period purported to show advantages of a low-fat diet (LFD) compared with a low-carbohydrate diet (LCD) for weight control. In contrast to several other macronutrient trials, the diet order effect was originally reported as not significant. In light of a new analysis by the original investigative group identifying an order effect, we aimed to examine, in a reanalysis of publicly available data (16 of 20 original participants; 7 female; mean BMI, 27.8 kg/m2), the validity of the original results and the claims that trial data oppose the carbohydrate–insulin model of obesity (CIM). We found that energy intake on the LCD was much lower when this diet was consumed first compared with second (a difference of −1164 kcal/d, P = 3.6 × 10-13); the opposite pattern was observed for the LFD (924 kcal/d, P = 2.0 × 10-16). This carry-over effect was significant (P interaction = 0.0004) whereas the net dietary effect was not (P = 0.4). Likewise, the between-arm difference (LCD - LFD) was −320 kcal/d in the first period and +1771 kcal/d in the second. Body fat decreased with consumption of the LCD first and increased with consumption of this diet second (−0.69 ± 0.33 compared with 0.57 ± 0.32 kg, P = 0.007). LCD-first participants had higher β-hydroxybutyrate levels while consuming the LCD and lower respiratory quotients while consuming LFD when compared with LFD-first participants on their respective diets. Change in insulin secretion as assessed by C-peptide in the first diet period predicted higher energy intake and less fat loss in the second period. These findings, which tend to support rather than oppose the CIM, suggest that differential (unequal) carry-over effects and short duration, with no washout period, preclude causal inferences regarding chronic macronutrient effects from this trial.

A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of β- cell function and insulin sensitivity in patients with transfusion-dependent β- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate β-cell response, and the ability of β-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent β-thalassemia (β-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for β-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with β-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

Carnosine supplementation improves glucose control in adults with pre-diabetes and type 2 diabetes: A randomised controlled trial

Background and aimsType 2 diabetes (T2DM) is a major cause of morbidity and mortality globally. Carnosine, a naturally occurring dipeptide, has anti-inflammatory, antioxidant, and anti-glycating effects, with preliminary evidence suggesting it may improve important chronic disease risk factors in adults with cardiometabolic conditions. Methods and resultsIn this randomised controlled trial, 43 adults (30%F) living with prediabetes or T2DM consumed carnosine (2 g) or a matching placebo daily for 14 weeks to evaluate its effect on glucose metabolism assessed via a 2-h 75 g oral glucose tolerance test. Secondary outcomes included body composition analysis by dual energy x-ray absorptiometry (DEXA), calf muscle density by pQCT, and anthropometry. Carnosine supplementation decreased blood glucose at 90 min (−1.31 mmol/L; p = 0.02) and 120 min (−1.60 mmol/L, p = 0.02) and total glucose area under the curve (−3.30 mmol/L; p = 0.04) following an oral glucose tolerance test. There were no additional changes in secondary outcomes. The carnosine group results remained significant before and after adjustment for age, sex, and change in weight (all>0.05), and in further sensitivity analyses accounting for missing data. There were no significant changes in insulin levels. ConclusionThis study provides preliminary support for larger trials evaluating carnosine as a potential treatment for prediabetes and the initial stages of T2DM. Likely mechanisms may include changes to hepatic glucose output explaining the observed reduction in blood glucose without changes in insulin secretion following carnosine supplementation.

Suppression of Endogenous Insulin Secretion by Euglycemic Hyperinsulinemia.

The impact of insulin, particularly exogenous hyperinsulinemia, on insulin secretion in humans is debated. We assessed the effects of exogenous hyperinsulinemia on insulin secretion and whether the response is altered in insulin resistance associated with obesity. Insulin secretion rates (ISRs) during euglycemic hyperinsulinemic clamp studies (52 volunteers) were calculated using a model that employs plasma C-peptide concentrations. One study involved a 2-step insulin clamp and the other study was a single step insulin clamp. For both studies the goal was to achieve plasma glucose concentrations of 95 mg/dL during the clamp irrespective of fasting glucose concentrations. The percent change in ISR from fasting to the end of the insulin clamp interval was the main outcome. Linear regression and analysis of covariance were used to test for the effects of insulin on ISR and to test for group differences. ISR was greater in obese volunteers (P < .001) under fasting and hyperinsulinemic clamp conditions. The change in plasma glucose from baseline to the end of the insulin clamp interval was highly correlated with the change in ISR (r = 0.61, P < .001). From baseline to the end of the clamp we observed a 27% (SD 20) suppression of ISR. The participants who underwent a 2-step insulin clamp had greater suppression of ISR during the second step than the first step (P < .001). The proportional suppression of ISR during euglycemic hyperinsulinemia was not different between nonobese and obese groups (P = .19). Hyperinsulinemia suppresses endogenous insulin secretion and the relative change in insulin secretion produced by exogenous insulin did not differ between nonobese and obese people.

617-P: Time in Range following Mealtime Protein Supplementation Is Predicted by Liver Health and ß-Cell Function in Adults with Type 2 Diabetes

Background: Consuming mealtime whey protein supplementation increases daily time in euglycemic range [TIR] in adults with type 2 diabetes [T2D] with inter-individual responses. The present post-hoc analysis aimed to identify metabolic predictors to the effectiveness of pre-meal whey protein. Methods: In a randomized-crossover design, 16 individuals with T2D [HbA1c 57±9 mmol/mol) underwent two 7d free-living periods where they consumed a whey protein (15g) or placebo beverage before each main meal. Glucose control was captured by blinded continuous glucose monitoring. Patient anthropometric and fasting markers of liver health and glucose metabolism were obtained at baseline. β-cell function was determined by the ratio of the incremental changes in insulin secretion to glucose during a feeding test. The relationship between TIR and clinical markers were analyzed by correlational analysis, and predictors of TIR were determined by multiple regression. Results: β-cell function was a strong determinant to TIR during both the whey (rs=0.615; p=0.011) and placebo (rs=0.598; p=0.019) weeks. Around 76% of the variance in TIR during the whey week was accounted by β-cell function, and fasting insulin and alanine aminotransferase concentrations (adj R2=0.760; p&amp;lt;0.001). During the whey intervention, TIR was inversely associated with aspartate aminotransferase (rs=−0.506; p=0.046) and tended to be related to fasting glucagon (rs=−0.482; p=0.058), whereas there were no associations between liver health or fasting hormonal markers with TIR during placebo (p&amp;gt;0.05). Conclusions: In a small cohort of people with T2D, our data indicates that those with compromised liver health and reduced β-cell function may experience a reduction in TIR when consuming mealtime protein supplementation. This is possibly due to disruptions in the liver-α-cell axis, which may be further aggravated by increasing plasma amino acid availability from protein supplementation. Disclosure K.Smith: None. G.Taylor: None. M.Walker: None. K.A.Bowden davies: None. E.J.Stevenson: None. D.J.West: None. Funding Francis James Bell Endowment Fund; County Durham Community Foundation

Acute PDE4 Inhibition Induces a Transient Increase in Blood Glucose in Mice.

cAMP-phosphodiesterase 4 (PDE4) inhibitors are currently approved for the treatment of inflammatory diseases. There is interest in expanding the therapeutic application of PDE4 inhibitors to metabolic disorders, as their chronic application induces weight loss in patients and animals and improves glucose handling in mouse models of obesity and diabetes. Unexpectedly, we have found that acute PDE4 inhibitor treatment induces a temporary increase, rather than a decrease, in blood glucose levels in mice. Blood glucose levels in postprandial mice increase rapidly upon drug injection, reaching a maximum after ~45 min, and returning to baseline within ~4 h. This transient blood glucose spike is replicated by several structurally distinct PDE4 inhibitors, suggesting that it is a class effect of PDE4 inhibitors. PDE4 inhibitor treatment does not reduce serum insulin levels, and the subsequent injection of insulin potently reduces PDE4 inhibitor-induced blood glucose levels, suggesting that the glycemic effects of PDE4 inhibition are independent of changes in insulin secretion and/or sensitivity. Conversely, PDE4 inhibitors induce a rapid reduction in skeletal muscle glycogen levels and potently inhibit the uptake of 2-deoxyglucose into muscle tissues. This suggests that reduced glucose uptake into muscle tissue is a significant contributor to the transient glycemic effects of PDE4 inhibitors in mice.

Diabetes and the Prostate: Elevated Fasting Glucose, Insulin Resistance and Higher Levels of Adrenal Steroids in Prostate Cancer.

Although epidemiological studies suggest a lower prostate cancer incidence rate in patients with type 2 diabetes, cancer survival is markedly reduced. Underlying mechanisms that connect the two diseases are still unclear. Potential links between type 2 diabetes and prostate cancer are hallmarks of the metabolic syndrome, such as hyperglycemia and dyslipidemia. Therefore, we explored the systemic metabolism of 103 prostate cancer patients with newly diagnosed and yet untreated prostate cancer compared to 107 healthy controls, who were carefully matched for age and BMI. Here, we report that patients with prostate cancer display higher fasting blood glucose levels and insulin resistance, without changes in insulin secretion. With respect to lipid metabolism, serum triglyceride levels were lower in patients with prostate cancer. In addition, we report increased adrenal steroid biosynthesis in these patients. Our results indicate that higher fasting glucose levels in patients with prostate cancer may be explained at least in part by insulin resistance, due to the enhanced synthesis of adrenal steroids.

Insulin secretion and action with increasing age - A comparison between Middle Eastern immigrants and native Swedes

AimsLittle is known how insulin secretion and action change over time in populations of different ethnicities. We studied changes in insulin secretion and action with increasing age in Iraqi-born immigrants and native Swedes, and investigated if the changes were modified by region of origin. MethodsResidents of Malmö, 30–75 years of age born in Iraq or Sweden, were invited to participate in this population-based, cross-sectional study. Health examination, medical history, lifestyle, sociodemographic data, and fasting blood samples were assessed. Oral glucose tolerance tests were performed and insulin secretion (disposition index, DIo) and insulin sensitivity index (ISI) calculated using the Matsuda indices. ResultsIn total 1881 people participated; 1193 Iraqi- and 688 Swedish born. DIo decreased with increasing age in the total study population (β for the effect of age on ln DIo: -0.018, 95% CI -0.023 to -0.013, P < 0.001), adjusted for origin, lifestyle and anthropometric measures. DIo was generally lower in Iraqis vs. Swedes (median: 12,712.9 vs. 14,659.2, P = 0.004), but the difference disappeared when adjusted for BMI.Further, ISI declined with increasing age in both Iraqis and Swedes. ISI was generally lower among Iraqis compared to Swedes, (median: 76.9 vs. 102.3, p < .001). The difference could not be fully explained by age, sex, lifestyle, and anthropometric measures. No significant interactions were observed. ConclusionsThe levels of DIo and ISI were lower among Iraqis compared to Swedes and declined with increasing age, irrespective of origin.

In vitro assessment of pancreatic hormone secretion from isolated porcine islets.

The potential use of porcine islets for transplantation in humans has triggered interest in understanding porcine islet physiology. However, the number of studies dedicated to this topic has remained limited, as most islet physiologists prefer to use the less time-consuming rodent model or the more clinically relevant human islet. An often-overlooked aspect of pig islet physiology is its alpha cell activity and regulation of its glucagon secretion. In vitro islet perifusion is a reliable method to study the dynamics of hormone secretion in response to different stimuli. We thus used this method to quantify and study glucagon secretion from pig islets. Pancreatic islets were isolated from 20 neonatal (14 to 21-day old) and 5 adult (>2 years) pigs and cultured in appropriate media. Islet perifusion experiments were performed 8 to 10 days post-isolation for neonatal islets and 1 to 2 days post-isolation for adult islets. Insulin and glucagon were quantified in perifusion effluent fractions as well as in islet extracts by RIA. Increasing glucose concentration from 1 mM to 15 mM markedly inhibited glucagon secretion independently of animal age. Interestingly, the effect of high glucose was more drastic on glucagon secretion compared to its effect on insulin secretion. In vivo, glucose injection during IVGTT initiated a quick (2-10 minutes) 3-fold decrease of plasmatic glucagon whereas the increase of plasmatic insulin took 20 minutes to become significant. These results suggest that regulation of glucagon secretion significantly contributes to glucose homeostasis in pigs and might compensate for the mild changes in insulin secretion in response to changes in glucose concentration.

Urinary proteomic analysis during pregnancy and its potential application in early prediction of gestational diabetes mellitus and spontaneous abortion.

BackgroundThe maternal physiological changes which occur during gestation are complex and affect diverse systems in the body. Elucidating the various changes that occur during pregnancy may assist with understanding maternal health and the factors affecting pregnancy outcomes.MethodsA longitudinal cohort of 84 pregnant women was established. The urinary proteomes of women in different trimesters of pregnancy (6–8, 22–24, and 32–34 weeks) were characterized using data-independent acquisition tandem mass spectrometry. Gestational diabetes mellitus (GDM) was diagnosed at 24 to 28 weeks. Functional analysis of serial changed proteins was performed.ResultsFifteen women had GDM, 50 were healthy, and 19 experienced spontaneous abortion (SA). Functional analysis showed that the urinary proteome reflected physiological and pathological changes during pregnancy. Compared to those of women with a normal pregnancy, the urinary proteomes of women with GDM and SA showed significant disease-related changes in insulin secretion and estrogen receptor activity, respectively, during the first trimester. Urinary protein during the first trimester of pregnancy achieved an area under the curve of 0.91 and 0.81 for GDM and SA, respectively.ConclusionsThe urinary proteome has the potential to reflect serial changes of pregnancy progression; therefore, its use might facilitate early diagnosis of pregnancy complications.

359-OR: Imaging Pancreatic Blood Flow during Stimulation of Insulin Secretion in Humans

Non-invasive imaging of endocrine pancreatic function could provide valuable insights into the magnitude and temporal pattern of β-cell dysfunction in diabetes. Islets comprise 1-2% of pancreatic mass, but receive about 10-20% of pancreatic blood flow, which increases further during stimulation of insulin secretion. We examined the relationship between pancreatic blood flow (PBF) and insulin secretory dynamics in 12 healthy volunteers (6M / 6F, age = 29 ± 5 yrs, BMI = 24.0 ± 2.7 kg/m², HbA1c = 5.1 ± 0.3 %, FPG = 88 ± mg/dl, fasting insulin = 3.7 ± 2.3 μU/ml) . PBF was measured by pseudo-continuous arterial spin labeling (ASL) MRI, with the labeling plane positioned 5-6 cm superior to the imaging slice to label blood in the descending aorta. Fasting subjects were placed in a 3T scanner, and PBF was measured during 1) a 15 min basal period, 2) a +100 mg/dl hyperglycemic clamp for 40 min, followed by 3) a 5 gm bolus of arginine to assess maximal acute insulin response (AIRmax) . First phase (0-min) insulin response to hyperglycemia was 181 ± 96 μU/ml · min, and AIRmax after arginine + hyperglycemia (40-50 min) was 1097 ± 629 μU/ml · min. Basal PBF (188 ± 53 ml/100 gm/min) increased during first phase insulin release, peaking at 212 ± 66 at 12 min, subsequently returned to basal levels (176 ± 59) from 10-40 min during sustained hyperglycemia,and peaked again at 2± 62 at 2 min after arginine. Although there were no significant correlations between glucose, insulin or c-peptide levels and PBF, time-series Granger causality analysis demonstrated that the time-derivative of c-peptide and insulin concentrations, reflectingacute changes in insulin secretion, preceded the increase in PBF (p=0.03 for d[c-peptide]/dt, and p = 0.for d[insulin]/dt) . Conclusions: 1) Changes in PBF during stimulation of insulin secretion in humans can be imaged non-invasively by ASL, 2) Insulin secretion precedes changes in PBF, and 3) The rate of change in insulin and c-peptide release predicts subsequent modulation of PBF. Disclosure D.C.Simonson: Stock/Shareholder; GI Windows, Phase V Technologies, Inc. M.Taso: Research Support; GE Healthcare Systems. C.Mcgrath: None. S.A.Waldman: None. F.Papadopoulou: None. D.C.Alsop: Other Relationship; GE Healthcare Systems, Hitachi, Ltd., Philips Healthcare, Siemens, UIH America, Research Support; GE Healthcare Systems.

58-OR: Remission of Prediabetes upon Weight Loss Depends on Insulin Sensitivity

The Prediabetes Lifestyle Intervention Study (PLIS) - a multicenter study conducted by the German Center for Diabetes Research - showed that intensified compared to conventional lifestyle intervention led to higher probability to normalize glucose regulation. Here, we examined clinical traits determining remission of prediabetes in PLIS participants with a clinically relevant weight loss of ≥5% of their initial body weight after 12 months of lifestyle intervention. Of 11participants, 298 achieved a weight loss of ≥5 %. We classified individuals as responders, who returned to normal glucose regulation by fasting glucose, 2h OGTT plasma glucose and HbA1c (n=128) and compared them to non-responders (n =170) . There were no differences in BMI change (-3.43 ±2.02 kg/m2 in responders, -2.83 ±1.37 in non-responders, p = 0.68) , whole body fat mass loss (6.7 ± 4.9 l vs. 5.9 ±4.5, p = 0.25) or reduction in liver fat (6.1 ±6.3 percentage points vs. 6.6 ±6.4, p = 0.59) . Similarly, there was no difference in change of insulin secretion between responders and non-responders. In contrast, responders improved insulin sensitivity significantly more than non-responders (Insulin Sensitivity Index +4.5 ±4.7, vs. +2.3 ±3.1, p &amp;lt; 0.01) . We conclude that, in prediabetes, weight loss induced return to normal glucose regulation primarily depends on improvements in insulin sensitivity, contrasting recently reported mechanisms of diabetes remission. Disclosure A.Sandforth: None. K.D.Lange: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. German center for diabetes research: n/a. A.F.Pfeiffer: None. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Jumpertz von schwartzenberg: None. A.L.Birkenfeld: None.

A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD+ Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial.

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor required for proper functioning of all cells and its decline is correlated with advancing age and disease. This randomized, triple-blind, placebo-controlled, crossover pilot study assessed the efficacy and safety of a combination of nicotinamide with D-ribose (RiaGev) for NAD metabolome enhancement and related benefits in healthy middle-aged adults. Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD+ metabolome in blood, especially NADP+ by 27% compared to the placebo group (p = 0.033) and over the baseline (p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly (p = 0.013) reduced overall blood glucose without significant changes in insulin secretion (p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly decreased (p = 0.026) in the RiaGev group in contrast to the placebo. Subjects in the RiaGev group showed less fatigue, improved mental concentration and motivation over the baseline (p = 0.015, 0.018, and 0.012, respectively) as observed through the Checklist Individual Strength (CIS) questionnaire. There were no clinically relevant adverse events, or alterations in hematology, electrolytes, liver, and kidney markers pre- and post-supplementation. RiaGev appears to be safe and efficacious in increasing NAD+ metabolome in healthy middle-aged adults, as shown by this study.

Age, Body Mass Index, and Waist-to-Hip Ratio Related Changes in Insulin Secretion and Insulin Sensitivity in Women with Polycystic Ovary Syndrome: Minimal Model Analyses.

Insulin resistance is believed to be an integral component of the polycystic ovary syndrome (PCOS). Beta (ß) cell dysfunction is also found in PCOS. In the study, we determined the influence of age, body mass index (BMI), and waist-to-hip ratio (WHR) on insulin response to oral glucose load (OGTT) and on insulin sensitivity (Si) and ß-cell function in young women with PCOS. One hundred fourteen patients with PCOS and 41 controls with normal basal plasma glucose were studied. A 75-g OGTT was performed to determine glucose tolerance and insulin response. Insulin sensitivity and ß-cell function were studied using a modified frequently sampled IV glucose tolerance test (FISGTT) to determine the acute insulin response (AIRG), as well as Si by minimal model analysis. Si was decreased in PCOS women (2.49 0.18 vs. 3.41 ± 0.36, p < 0.05), but no difference in AIRG existed between the PCOS and control group (75.1 ± 4.6 vs. 63.4 ± 4.6, p < 0.05). BMI and WHR correlated negatively with Si (r = −0.43; r = −0.289, p < 0.001, respectively), but not with AIRG (r = 0.116; r = −0.02, p > 0.05, respectively). Increasing age correlated negatively with AIRG (r = −0.285, p < 0.001). There was a significant interaction between disease (PCOS), BMI, and WHR on Si as well as between age and PCOS on AIRG. Thus, patients below the age of 25 with PCOS showed enhanced AIRG (89.5 ± 7.1 vs. 65.1 ± 6.7, p < 0.05) and decreased Si (2.43 ± 0.25 vs. 4.52 ± 0.62, p < 0.05) compared to age-matched controls. In conclusion, these data suggest that not all patients with PCOS have basal and stimulated hyperinsulinemia, insulin resistance, and impaired glucose tolerance. Based on these data in young PCOS subjects, the development of insulin resistance and T2DM may be prevented with appropriate treatment strategies.

Characterizing the Role of the Neuroregulatory Protein Piccolo in Secretion of Insulin from Beta Pancreatic Islet Cells

Secretion of insulin from pancreatic beta‐cells is required for glucose homeostasis; however, the molecular mechanisms of insulin secretion have not been fully elucidated. In pancreatic beta‐cells, glucose‐induced insulin secretion is synergistically potentiated through a calcium (Ca2+)‐mediated Epac2‐Rim2‐Piccolo signaling response mechanism. Both Piccolo and Rim2 were originally identified in neurons as active zone proteins that regulate neurotransmitter secretion. It has been demonstrated that Piccolo is downregulated in human pancreatic islet cells isolated from patients with type 2 diabetes (T2D). We hypothesize that Piccolo plays a key role in regulated insulin secretion and further study of Piccolo in pancreatic islets cells may provide valuable insights into the etiology of T2D. The C‐terminus of Piccolo contains a Ca2+‐binding C2A domain and we hypothesize that in pancreatic beta‐cells, Piccolo may regulate insulin secretion by serving as a Ca2+‐sensor. Alternative splicing within the coding region of the C2A domain results in an exon‐skipping event generating either a splice variant that lacks the 27‐nucleotide exon 16 (e.g., short C2A) or a variant that retains this exon (e.g., long C2A). Due to this splicing event, the short C2A domain lacks 9 amino acids resulting in enhanced Ca2+‐binding affinity. In this study, we sought to examine the differential roles of the Piccolo splice variants in Ca2+‐mediated insulin secretion using a rat pancreatic beta‐cell line (INS‐832/13). We demonstrate that INS‐832/13 cells express both variants containing either the short or long C2A domains. We also demonstrate that these cells express an additional splice variant called Piccolino previously thought to be only expressed in neurons associated with the eye and ear. To further assess the role of Piccolo in regulating insulin secretion, we plan to use a gene knockdown approach employing multiple shRNAs expressed in lentivirus that target Piccolo RNA sequences. To assess the effect of knockdown of Piccolo, we will stimulate ß pancreatic islet cells with increasing glucose concentrations to quantify changes in insulin secretion.

Feasibility and Efficacy of Telehealth-Based Resistance Exercise Training in Adolescents with Cystic Fibrosis and Glucose Intolerance.

The aims of this study were to (1) determine the feasibility of a home-based resistance exercise training (RET) program in patients with cystic fibrosis and impaired glucose tolerance using virtual personal training and (2) observe the effects completion of the RET program had on glucose metabolism, pulmonary function, body composition, and physical fitness. The feasibility of the program was defined as 80% compliance. Ten participants (15.80 ± 2.20 yr, 25.1 ± 7.4 kg/m2) began a home-based resistance training program consisting of 36 sessions supervised via online videoconferencing. Compliance scores of 78.9% (all participants) and 81.8% (without one outlier) were observed. A significant increase was observed in 2-h C-peptide levels (2.1 ng/mL; p = 0.04), with a moderate decrease in fasting glucose (−5.2 mg/dL; p = 0.11) and a moderate increase in 2-h insulin (35.0 U/mL; p = 0.10). A small decrease in the fat percentage (−1.3%; p = 0.03) was observed in addition to increases in fat-free mass (1.5 kg; p = 0.01) and the fat-free mass index (0.4; p = 0.01). Small, yet statistically significant increases were observed in V̇O2peak (0.1 L/min p = 0.01), V̇CO2peak (0.1 L/min; p = 0.01), and ventilation (5.3 L/min; p = 0.04). Telehealth-based RET is feasible in adolescents with CF and impaired glucose tolerance and elicits small yet favorable changes in insulin secretion, body composition, and exercise capacity.