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Liver-specific Expression of Constitutively Active Gsα Leads to Hyperglycemia With Impaired Insulin Secretion?The ubiquitously-expressed G protein Gsα couples hormone receptors to the stimulation of intracellular cAMP generation. We previously showed that mice with liver-specific Gsα deficiency (LGsKO) have improved glucose tolerance and enlarged pancreatic islets1. In the present study, we have generated mice with liver-specific expression of a constitutively activated Gsα (LGsR201C) by breeding mice containing a Lox-STOP-Lox-GsαR201C transgene within the Hipp11 locus with albumin-Cre mice. Male LGsR201C mice had normal survival but reduced body weight and increased liver weight. Compared to control littermates, LGsR201C mice had significantly increased hepatic cAMP levels and enhanced hyperglycemic response to glucagon, confirming the activation of liver Gsα/cAMP signaling in LGsR201C mice. As a consequence, LGsR201C mice showed elevated blood glucose levels during both fed and fasting states, as well as enhanced hepatic gluconeogenesis evidenced by pyruvate tolerance test. Serum levels of insulin, glucagon, free fatty acids and triglycerides were comparable between control and LGsR201C mice in the fed state. Results of glucose and insulin tolerance tests showed that LGsR201C mice had severe glucose intolerance with normal insulin sensitivity. Unlike control mice, when given a high dose of glucose (3mg/g ip.), LGsR201C mice had completely blunted first- and second-phase insulin secretory responses to glucose. Since LGsR201C mice exhibited normal pancreatic islet size and insulin content examined with immunohistochemistry, the impaired glucose tolerance in LGsR201C mice probably resulted from an impaired insulin secretion. Results of RNA-seq analysis revealed that an array of genes was oppositely regulated in the liver of LGsKO mice vs. LGsR201C mice. Thus, our data indicate possible organ-to-organ communication between liver and pancreatic β-cells that is regulated by liver Gsα signaling. 1.Chen M., et al., JCI 115:3217, 2005?? 

ENDO 2021

Liver-Specific Expression of Constitutively Active Gsα Leads to Hyperglycemia With Impaired Insulin Secretion

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ENDO 2020

ENDO is the place where leading experts, researchers, and the most respected clinicians in the field come together to share the latest findings in hormone science and discuss breakthroughs in clinical care.

technical paper

Growth hormone (GH) serves an important role in early and adult life. Reduction of GH action has been shown to increase life span in many species of animals. In fact, mice bearing a congenital disruption of GH receptor (GHR) gene (GHRKO) hold the record for the longest-lived laboratory mice. In addition to extended life span, these mice show improved health with lower rates of cancer, increased insulin sensitivity, and resistance to age-associated cognitive decline. Furthermore, humans with decreased GH action due to inactivating mutations in the GHR (Laron Syndrome patients) are resistant to cancer and diabetes. Even though the beneficial effects of congenital Ghr gene disruption are well studied, the consequences of postnatal disruption of GH action were unknown. Previously our laboratory generated a mouse line with disrupted GH action at 1.5 months of age (1.5mGHRKO mice). Results showed that these mice had improved insulin sensitivity and increased maximal lifespan only in females, yet growth retardation was still present.?To consider decreased GH action as a possible therapeutic to extend healthy lifespan, it was imperative to elucidate the effects of disrupting Ghr gene at a mature-adult age, well after the developmental and growth period of the mice. To this end, we hypothesized that removal of GH action in adult life would convey some of the same health and life span benefits seen in the GHRKO mice without the reduced body length. To test this hypothesis, we used the cre-lox system to generate mice with a disrupted Ghr gene at a mature-adult age (6 months), referred as 6mGHRKO mice. We then performed a phenotypic and lifespan characterization, and tested for molecular mechanisms known to be associated with extended longevity, namely oxidative stress resistance and mTOR modulation. We found that similar to GHRKO and 1.5mGHRKO mice, disruption of GHR at 6 months of age resulted in mice with increased adipose tissue mass, decreased lean mass, high circulating GH, but decreased insulin growth factor-1 levels compared?to control mice. Furthermore, the 6mGHRKO mice displayed significantly improved insulin sensitivity in males, with no changes in glucose tolerance. Also, serum levels of inflammatory markers and liver triglycerides were unchanged in these mice. Experiments to evaluate the status of oxidative damage and mTOR activation in liver, skeletal muscle and subcutaneous adipose tissue of male and female 6mGHRKO mice showed a tissue-specificity and sexual dimorphism in these results. Importantly, male and female 6mGHRKO mice showed no change in body length, but mean, median and maximal lifespan were significantly extended in females. In conclusion, disruption of GH action well past sexual maturation produces beneficial effects on insulin sensitivity and aging in mice.?Acknowledgements: This work is supported by the State of Ohio's Eminent Scholar Program, by NIH grant AG059779 and by the AMVETS.?? 

Growth Hormone Receptor Gene Disruption in Mature-Adult Mice Improves Glucose Metabolism and Lifespan in Females

High Dietary Fat Intake Exacerbates Insulin Resistance in a Type 2 Diabetes Genetic Mouse Model

Insulin Resistance and Gender Define a Cell Autonomous Supernetwork of Protein Phosphorylation

Employing User-Centered Design and Learning Science Theory to Enhance Remote Delivery of Diabetes Mellitus (DM) Education and Survival Skills at Hospital Discharge

Introduction?Diabetic ketoacidosis (DKA) is an endocrinological emergency that may be associated with inpatient mortality. This hyperglycemic state is more common in type 1 diabetics (T1DM) as insulin deficiency promotes lipolysis and ketogenesis. Due to the difference in epidemiologic and comorbidity profiles between T1DM and other types of diabetes, it is important to investigate factors affecting this unique group. This study assessed the rate and predictors of readmission in adults with T1DM hospitalized for DKA.?Methods?The National Readmission Database for 2017 was searched for hospitalizations involving persons 18 years or older with T1DM who were principally admitted for DKA from January 1 to November 30, 2017. Patients admitted electively or traumatic admissions were excluded from the analysis. Outcomes assessed were 30-day readmission rates, mortality, length of stay (LOS) and hospitalization charges (THC). Multivariate cox regression model was adapted to identify independent predictors of readmission.?Results?A total of 91,625 hospitalizations involved adult with T1DM for DKA with 91,401 discharged alive. Of the patients discharged alive, the rate of 30-day readmission was 20.2%, involving 18,553 patients. A majority of patients had a principal readmission for DKA. Compared to the index admission, a 30-day readmission was associated with over two times the mortality rate (Risk ratio 2.06, 95% CI: 1.74 - 2.43, p<0.001). Readmission was associated with increased mean LOS in days (1.0, 95% CI: 0.9 - 1.2, p<0.001) and THC in USD (8217, 95% CI: 6940 - 9492, p<0.001). Independent predictors of readmission included female sex (Hazard Ratio [HR]: 1.14, 95% CI: 1.74 - 1.20, p<0.001), discharge against medical advice (HR: 1.54, 95% CI: 1.43 - 1.66, p<0.001), hypertension (HR: 1.28, 95% CI: 1.20 - 1.35, p<0.001), chronic kidney disease (HR: 1.13, 95% CI: 1.04 - 1.22, p<0.001) and anemia (HR: 1.42, 95% CI: 1.34 - 1.51, p<0.001). However, obesity (HR: 0.70, 95% CI: 0.62 - 0.79, p<0.001) and hyperlipidemia (HR: 0.92, 95% CI: 0.87 - 0.98, p=0.007) were associated with lower rate of readmission for DKA.?Conclusion?About a fifth of T1DM patients hospitalized for DKA are readmitted within 30 days of discharge. A 30-day readmission following hospitalization for DKA is associated with higher inpatient mortality in this group. Hypertension, chronic kidney disease, and anemia are amongst the predictors of readmission in patients with DKA. However, comorbid obesity and hyperlipidemia were associated with lower rates of readmissions. Healthcare utilization costs are significantly higher in readmitted patients compared to index admissions for DKA. Efforts should be channeled towards identifying these predictors in hospitalized patients as well as proper discharge planning to decrease the burden of readmissions.?? 

Rates and Predictors of 30-Day Readmission in Adults with Type 1 Diabetes Hospitalized for Diabetic Ketoacidosis in the US: A Nationwide Study

Background: Iatrogenic hypoglycemia is an unintended, though common, occurrence in individuals with diabetes. There is a clear association between hypoglycemia exposure and an increase in mortality in individuals with type 2 diabetes (T2DM). It is well-established that recurrent hypoglycemic episodes impair the counterregulatory hormone responses; however, it is yet to be determined if in T2DM there are more global effects of hypoglycemia on autonomic control of cardiovascular function (baroreflex sensitivity, BRS), as has been shown in healthy individuals. This is a clinically relevant knowledge gap as decreases in BRS are pro-arrhythmogenic and associated with decreases in mortality in individuals with diabetes.?Objective: We tested the hypothesis that in individuals with T2DM, hypoglycemia impairs baroreflex sensitivity (BRS), a robust measure of cardiovascular autonomic control.?Methods: Individuals with well-controlled T2DM and without known cardiovascular disease were exposed to two 90-minute episodes of experimental hypoglycemia (50 mg/dl) in the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). BRS was assessed using the modified Oxford method (sequential administration of nitroprusside and phenylephrine) before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 minutes of hypoglycemia, and the following day.?Results: The study included 16 individuals with a diagnosis of T2DM (6 men and 10 women) with the following characteristics (mean ± SD): age 45 ± 11 years, BMI 32 ± 6 kg/m2, hemoglobin A1c 6.4 ± 0.9%, and diabetes duration 8 ± 5 years. At baseline, individuals with T2DM had a BRS of 7.7 ± 3.6 ms/mmHg, which is reduced compared to a BRS of 21.3 ± 13.8 ms/mmHg in a historical healthy control group of 54 subjects (p<0.001). A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on BRS (p=0.008). Pairwise comparisons revealed a significant decrease in BRS during the PM clamp as compared with BRS assessed at baseline (5.5 ± 5.0 vs 7.7 ± 3.6 ms/mmHg, p=0.045), during the AM clamp (5.5 ± 5.0 vs 10.5 ± 5.6 ms/mmHg, p=0.43), and the following day (5.5 ± 5.0 vs 8.6 ± 3.8 ms/mmHg, p=0.33). Of note, there was no significant difference between BRS at baseline and during the AM clamp (p=0.44). Additionally, insulin levels positively and strongly correlated with BRS at baseline (R2 0.52) and during the AM clamp (R2 0.67).?Discussion: Insulin may have a stimulatory effect on BRS during a hyperinsulinemic hypoglycemic clamp that counters the inhibitory effect of hypoglycemia during the first episode of hypoglycemia. However, with exposure to a second hypoglycemic clamp, BRS decreases. ?Conclusion: Individuals with T2DM have low BRS at baseline, which is further reduced after 2 episodes of hypoglycemia.??? 

Hypoglycemia Impairs Baroreflex Sensitivity: Implications for Autonomic Control of Cardiovascular Function in Diabetes

Basal insulin Fc (BIF; LY3209590) is a novel, once-weekly, long-acting IgG Fc-fusion protein that is being assessed for the treatment of diabetes mellitus. The presented study evaluated the safety and efficacy of BIF compared to insulin degludec over 32 weeks in patients with T2DM previously treated with oral antidiabetic drugs and a basal insulin. The study design included 2 different dosing algorithms for BIF (BIF-A1 and BIF-A2) with two different fasting glucose (FG) targets of ≤140 mg/dL (BIF-A1) and ≤120 mg/dL (BIF-A2). Insulin degludec was titrated to a FG target of ≤100mg/dL using a modified Riddle treat-to-target algorithm. Study participants (N=399) were randomized in a 1:1:1 ratio to 1 of 3 parallel treatment groups. The average age of participants was 60.2 years, baseline HbA1c was 8.1% and duration of diabetes 14.7 years. There were no statistically significant differences in demographics or baseline characteristics across the 3 treatment groups. Both BIF groups achieved non-inferiority (non-inferiority margin = 0.4%) for the primary endpoint of HbA1c change from baseline to Week 32 with a mean±SE reduction for BIF-A1, BIF-A2 and insulin degludec of 0.6±0.1%, 0.6±0.1% and 0.7±0.1%, respectively. In line with the different fasting serum glucose (FSG) targets, insulin degludec achieved greater FSG lowering from baseline as compared to the BIF arms. Similarly, both BIF dosing groups showed significantly fewer hypoglycemic events compared to insulin degludec (all documented events as well as nocturnal events) when assessing events ≤70 mg/dL (3.9 mmol/L). Hypoglycemic events <54 mg/dL (3.0 mmol/L - all documented events as well as nocturnal events) were not significantly different between the three dosing groups. Two severe hypoglycemic events were reported in BIF-A2. The reported treatment-emergent adverse events and serious adverse events were balanced across the 3 treatment groups. Both BIF groups had a statistically significantly smaller increase in body weight compared to insulin degludec from baseline to Week 32. In summary, BIF, when administered weekly according to either dosing algorithm, was noninferior to insulin degludec for glycemic control as measured by change in HbA1c after 32 weeks with a lower rate of documented and nocturnal hypoglycemia ≤70 mg/dL and less weight gain. Additionally, no safety signals were detected. While higher FG targets were chosen in this first Phase 2 study with BIF, the safety and tolerability results allow assessment of lower target glucose ranges in future trials. The results from this study support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.?? 

Liver-Specific Expression of Constitutively Active Gsα Leads to Hyperglycemia With Impaired Insulin Secretion

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