The Role of Glycogen Synthase Kinase-3 in Insulin-resistant Skeletal Muscle

The metabolic syndrome is a multifaceted condition characterized by a clustering of metabolic and cardiovascular abnormalities, including insulin resistance in skeletal muscle, adipose tissue and liver, visceral adiposity, hyperinsulinemia, glucose intolerance, dyslipidemia, and essential hypertension. Those affected by this syndrome are at very high risk for developing type 2 diabetes and all of the related sequelae. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that contributes to the multi-factorial etiology of insulin resistance by attenuating insulin signaling in skeletal muscle, thereby decreasing glucose uptake. GSK- 3 is overactive in humans with type 2 diabetes, and in animal models of both type 2 diabetes and the metabolic syndrome (pre-diabetes). Selective GSK-3 inhibition reversed several facets of insulin resistance in the obese Zucker (fa/fa) rat, a model of pre-diabetes and the metabolic syndrome. Acute GSK-3 inhibition in skeletal muscle improved insulin-stimulated glucose uptake and glycogen synthase activity, and enhanced the functionality of key components of the insulin signaling pathway. In addition, GSK-3-β activity was decreased. Chronic selective GSK-3 inhibition improved whole-body insulin-sensitivity, reduced plasma free fatty acids, increased insulin-stimulated glucose uptake into isolated skeletal muscle, and enhanced insulin signaling in skeletal muscle. Oxidative stress is another etiologic component of insulin resistance, and type 2 diabetes is associated with higher levels of oxidant stress. Oxidant stress was induced in isolated muscle of insulin-sensitive lean Zucker rats, a model of normal glucose metabolism. Oxidant stress reduced insulin-stimulated glucose transport, glycogen synthesis, and glycogen synthase activity by ~50%, and reduced the ability of insulin to de-activate GSK-3ß. In the presence of oxidant stress, the GSK-3 inhibitor improved insulin-stimulated glucose transport, insulin stimulated glycogen synthesis, glycogen synthase activity and insulin signaling. Selective GSK-3 inhibition, therefore, partially ameliorated the skeletal muscle insulin resistance caused by oxidative stress. The results of the current study suggest that GSK-3 overactivity contributes to the multi-factorial etiology of obesity-associated insulin resistance as well as insulin resistance related to oxidative stress. Taken together, these findings support the potential of selective GSK-3 inhibition to ameliorate, in part, the insulin resistance associated with the metabolic syndrome and type 2 diabetes, and worsened by oxidative stress

Extended Use of the Control-IQ Closed-Loop Control System in Children With Type 1 Diabetes.

OBJECTIVE: To further evaluate the safety and efficacy of the Control-IQ closed-loop control (CLC) system in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: After a 16-week randomized clinical trial (RCT) comparing CLC with sensor-augmented pump (SAP) therapy in 101 children 6-13 years old with type 1 diabetes, 22 participants in the SAP group initiated use of the CLC system (referred to as SAP-CLC cohort), and 78 participants in the CLC group continued use of CLC (CLC-CLC cohort) for 12 weeks. RESULTS: In the SAP-CLC cohort, mean percentage of time in range 70-180 mg/dL (TIR) increased from 55 ± 13% using SAP during the RCT to 65 ± 10% using CLC (P < 0.001), with 36% of the cohort achieving TIR >70% plus time <54 mg/dL <1% compared with 14% when using SAP (P = 0.03). Substantial improvement in TIR was seen after the 1st day of CLC. Time <70 mg/dL decreased from 1.80% to 1.34% (P < 0.001). In the CLC-CLC cohort, mean TIR increased from 53 ± 17% prerandomization to 67 ± 10% during the RCT and remained reasonably stable at 66 ± 10% through the 12 weeks post-RCT. No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either cohort. CONCLUSIONS: This further evaluation of the Control-IQ CLC system supports the findings of the preceding RCT that use of a closed-loop system can safely improve glycemic control in children 6-13 years old with type 1 diabetes from the 1st day of use and demonstrates that these improvements can be sustained through 28 weeks of use

A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes

International audienceBackground: A closed-loop system of insulin delivery (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes.Methods: In a 16-week, multicenter, randomized, open-label, parallel-group trial, we assigned, in a 3:1 ratio, children 6 to 13 years of age who had type 1 diabetes to receive treatment with the use of either a closed-loop system of insulin delivery (closed-loop group) or a sensor-augmented insulin pump (control group). The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring.Results: A total of 101 children underwent randomization (78 to the closed-loop group and 23 to the control group); the glycated hemoglobin levels at baseline ranged from 5.7 to 10.1%. The mean (±SD) percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter increased from 53±17% at baseline to 67±10% (the mean over 16 weeks of treatment) in the closed-loop group and from 51±16% to 55±13% in the control group (mean adjusted difference, 11 percentage points [equivalent to 2.6 hours per day]; 95% confidence interval, 7 to 14; P<0.001). In both groups, the median percentage of time that the glucose level was below 70 mg per deciliter was low (1.6% in the closed-loop group and 1.8% in the control group). In the closed-loop group, the median percentage of time that the system was in the closed-loop mode was 93% (interquartile range, 91 to 95). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group.Conclusions: In this 16-week trial involving children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with the use of a closed-loop system than with the use of a sensor-augmented insulin pump. (Funded by Tandem Diabetes Care and the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT03844789.)