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BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
Pancreatic β-cell expansion is a highly regulated metabolic adaptation to increased somatic demands, including obesity and pregnancy; adult β cells otherwise rarely proliferate. We previously showed that high-fat diet (HFD) feeding induces mouse β-cell proliferation in less than 1 wk in the absence of insulin resistance. Here we metabolically profiled tissues from a short-term HFD β-cell expansion mouse model to identify pathways and metabolite changes associated with β-cell proliferation. Mice fed HFD vs. chow diet (CD) showed a 14.3% increase in body weight after 7 days; β-cell proliferation increased 1.75-fold without insulin resistance. Plasma from 1-wk HFD-fed mice induced β-cell proliferation ex vivo. The plasma, as well as liver, skeletal muscle, and bone, were assessed by LC and GC mass-spectrometry for global metabolite changes. Of the 1,283 metabolites detected, 159 showed significant changes [false discovery rate (FDR) < 0.1]. The majority of changes were in liver and muscle. Pathway enrichment analysis revealed key metabolic changes in steroid synthesis and lipid metabolism, including free fatty acids and other bioactive lipids. Other important enrichments included changes in the citric acid cycle and 1-carbon metabolism pathways implicated in DNA methylation. Although the minority of changes were observed in bone and plasma (<20), increased p-cresol sulfate was increased >4 fold in plasma (the largest increase in all tissues), and pantothenate (vitamin B) decreased >2-fold. The results suggest that HFD-mediated β-cell expansion is associated with complex, global metabolite changes. The finding could be a significant insight into Type 2 diabetes pathogenesis and potential novel drug targets.
AIMS - Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations.
MATERIALS AND METHODS - The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration.
RESULTS - Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with t = 20 minutes in most cases. Median t was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively.
CONCLUSIONS - Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.
© 2018 John Wiley & Sons Ltd.
Adherence to diabetes management is a challenge for adolescents with type 1 diabetes (T1D). Positive psychology interventions have improved adherence to treatment recommendations in adults with chronic health conditions but have not been widely tested in pediatric populations. We hypothesized that higher engagement with a text-messaging intervention to promote positive affect would increase the effects on diabetes management among adolescents with T1D. Adolescents with T1D (n = 48) and their caregivers were randomized to either an attention control condition or a novel positive psychology intervention delivered through personalized automated text messaging. We examined rates of engagement (percent response to text messages) in relation to demographic factors, and we explored the effect of engagement in relation to adherence and glycemic control. Adolescent engagement was good (mean response rate of 76%) over the 8-week intervention. Engagement was related to adolescents' gender, race, baseline glycemic control, and blood glucose monitoring, but not to treatment type (pump vs. injection), diabetes duration, age, or household income. There was a significant effect of level of engagement on better caregiver-reported adherence, but adolescents' engagement was not related to self-reported adherence or glycemic control. These results indicate feasibility and initial efficacy of using automated text-messaging to deliver an intervention aimed at promoting adherence in adolescents with T1D.
Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is a gluconeogenic enzyme that is highly expressed in the liver and kidney but is also expressed at lower levels in a variety of other tissues where it may play adjunct roles in fatty acid esterification, amino acid metabolism, and/or TCA cycle function. PEPCK is expressed in the enterocytes of the small intestine, but it is unclear whether it supports a gluconeogenic rate sufficient to affect glucose homeostasis. To examine potential roles of intestinal PEPCK, we generated an intestinal PEPCK knockout mouse. Deletion of intestinal PEPCK ablated ex vivo gluconeogenesis but did not significantly affect glycemia in chow, high-fat diet, or streptozotocin-treated mice. In contrast, postprandial triglyceride secretion from the intestine was attenuated in vivo, consistent with a role in fatty acid esterification. Intestinal amino acid profiles and C tracer appearance into these pools were significantly altered, indicating abnormal amino acid trafficking through the enterocyte. The data suggest that the predominant role of PEPCK in the small intestine of mice is not gluconeogenesis but rather to support nutrient processing, particularly with regard to lipids and amino acids. NEW & NOTEWORTHY The small intestine expresses gluconeogenic enzymes for unknown reasons. In addition to glucose synthesis, the nascent steps of this pathway can be used to support amino acid and lipid metabolisms. When phosphoenolpyruvate carboxykinase, an essential gluconeogenic enzyme, is knocked out of the small intestine of mice, glycemia is unaffected, but mice inefficiently absorb dietary lipid, have abnormal amino acid profiles, and inefficiently catabolize glutamine. Therefore, the initial steps of intestinal gluconeogenesis are used for processing dietary triglycerides and metabolizing amino acids but are not essential for maintaining blood glucose levels.
Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are important regulators of excitability in neural, cardiac, and other pacemaking cells, which are often altered in disease. In mice, loss of HCN2 leads to cardiac dysrhythmias, persistent spike-wave discharges similar to those seen in absence epilepsy, ataxia, tremor, reduced neuropathic and inflammatory pain, antidepressant-like behavior, infertility, and severely restricted growth. While many of these phenotypes have tissue-specific mechanisms, the cause of restricted growth in HCN2 knockout animals remains unknown. Here, we characterize a novel, 3kb insertion mutation of Hcn2 in the Tremor and Reduced Lifespan 2 (TRLS/2J) mouse that leads to complete loss of HCN2 protein, and we show that this mutation causes many phenotypes similar to other mice lacking HCN2 expression. We then demonstrate that while TRLS/2J mice have low blood glucose levels and impaired growth, dysfunction in hormonal secretion from the pancreas, pituitary, and thyroid are unlikely to lead to this phenotype. Instead, we find that homozygous TRLS/2J mice have abnormal gastrointestinal function that is characterized by less food consumption and delayed gastrointestinal transit as compared to wildtype mice. In summary, a novel mutation in HCN2 likely leads to impaired GI motility, causing the severe growth restriction seen in mice with mutations that eliminate HCN2 expression.
Purpose - The current study compares the relative strength of associations of different adherence measures with glycemic control in adolescents with type 1 diabetes, while highlighting the challenges in using more objective measures (i.e., glucometer data).
Methods - Adolescents with type 1 diabetes ( = 149) and their caregivers completed a questionnaire measure assessing adolescents' adherence (Self-Care Inventory (SCI)) to the diabetes regimen. Adolescents' glucometers were downloaded to determine average blood glucose checks per day, as an objective measure of adherence. A measure of glycemic control (hemoglobin A1c (HbA1c)) was obtained as part of adolescents' regular clinic visits.
Results - Adolescents' self-reported adherence to the treatment regimen was more strongly correlated with HbA1c than caregivers' reports of adherence. In multivariate analyses, both adolescents' self-report of adherence and average blood glucose checks per day (obtained via a glucometer) were significant predictors of HbA1c. Challenges to obtaining glucometer data were identified.
Conclusions - The findings highlight adolescents' self-report of adherence using the SCI as a brief and meaningful measure to understand and improve adolescents' glycemic control, particularly when glucometer data is difficult to obtain.
An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic Gi signaling. Specifically, we used a chemogenetic approach to selectively activate Gi-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased Gi signaling stimulated glucose release in human hepatocytes. A lack of functional Gi-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic Gi signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic Gi-coupled GPCRs may prove beneficial as antidiabetic drugs.
OBJECTIVE - Hypoglycemia is common in patients with diabetes. The risk of hypoglycemia after acute kidney injury (AKI) is not well defined. The purpose of this study was to compare the risk for postdischarge hypoglycemia among hospitalized patients with diabetes who do and do not experience AKI.
RESEARCH DESIGN AND METHODS - We performed a propensity-matched analysis of patients with diabetes, with and without AKI, using a retrospective national cohort of veterans hospitalized between 2004 and 2012. AKI was defined as a 0.3 mg/dL or 50% increase in serum creatinine from baseline to peak serum creatinine during hospitalization. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia or as an outpatient blood glucose <60 mg/dL. Time to incident hypoglycemia within 90 days postdischarge was examined using Cox proportional hazards models. Prespecified subgroup analyses by renal recovery, baseline chronic kidney disease, preadmission drug regimen, and HbA were performed.
RESULTS - We identified 65,151 propensity score-matched pairs with and without AKI. The incidence of hypoglycemia was 29.6 (95% CI 28.9-30.4) and 23.5 (95% CI 22.9-24.2) per 100 person-years for patients with and without AKI, respectively. After adjustment, AKI was associated with a 27% increased risk of hypoglycemia (hazard ratio [HR] 1.27 [95% CI 1.22-1.33]). For patients with full recovery, the HR was 1.18 (95% CI 1.12-1.25); for partial recovery, the HR was 1.30 (95% CI 1.23-1.37); and for no recovery, the HR was 1.48 (95% CI 1.36-1.60) compared with patients without AKI. Across all antidiabetes drug regimens, patients with AKI experienced hypoglycemia more frequently than patients without AKI, though the incidence of hypoglycemia was highest among insulin users, followed by glyburide and glipizide users, respectively.
CONCLUSIONS - AKI is a risk factor for hypoglycemia in the postdischarge period. Studies to identify risk-reduction strategies in this population are warranted.
© 2018 by the American Diabetes Association.
Purpose - We previously demonstrated an association between European mitochondrial haplogroups and proliferative diabetic retinopathy (PDR). The purpose of this study was to determine how the relationship between these haplogroups and both diabetes duration and hyperglycemia, two major risk factors for diabetic retinopathy (DR), affect PDR prevalence.
Methods - Our population consisted of patients with type 2 diabetes with (n = 377) and without (n = 480) DR. A Kruskal-Wallis test was used to compare diabetes duration and hemoglobin A1c (HbA1c) among mitochondrial haplogroups. Logistic regressions were performed to investigate diabetes duration and HbA1c as risk factors for PDR in the context of European mitochondrial haplogroups.
Results - Neither diabetes duration nor HbA1c differed among mitochondrial haplogroups. Among DR patients from haplogroup H, longer diabetes duration and increasing HbA1c were significant risk factors for PDR (P = 0.0001 and P = 0.011, respectively). Neither diabetes duration nor HbA1c was a significant risk factor for PDR in DR patients from haplogroup UK.
Conclusions - European mitochondrial haplogroups modify the effects of diabetes duration and HbA1c on PDR risk in patients with type 2 diabetes. In our patient population, longer diabetes duration and higher HbA1c increased PDR risk in patients from haplogroup H, but did not affect PDR risk in patients from haplogroup UK. This relationship has not been previously demonstrated and may explain, in part, why some patients with nonproliferative DR develop PDR and others do not, despite similar diabetes duration and glycemic control.