Background Type 2 diabetes (T2D) is a growing epidemic in the United States, and metabolic control has not been improved over the last 10 years. Glycemic excursion minimization (GEM) is an alternative lifestyle treatment option focused on reducing postnutrient glucose excursions rather than reducing weight. GEM has been proven to be superior to routine care when delivered face to face, and equivalent or superior to conventional weight loss therapy, but it has not been evaluated among patients newly diagnosed with T2D or in a self-administered format. Objective This pilot study evaluated the feasibility of a self-administered version of GEM, augmented with continuous glucose monitoring (CGM), to improve metabolic control (hemoglobin A1c [HbA1c]) while diminishing or delaying the need for diabetes medications in adults recently diagnosed with T2D. These primary objectives were hypothesized to be achieved by reducing carbohydrate intake and increasing physical activity to diminish CGM glucose excursions, leading to the secondary benefits of an increase in diabetes empowerment and reduced diabetes distress, depressive symptoms, and BMI. Methods GEM was self-administered by 17 adults recently diagnosed with T2D (mean age 52 years, SD 11.6 years; mean T2D duration 3.9 months, SD 2.5 months; mean HbA1c levels 8.0%, SD 1.6%; 40% female; 33.3% non-White), with the aid of a 4-chapter pocket guide and diary, automated motivational text messaging, and feedback from an activity monitor, along with CGM and supplies for the 6-week intervention and the 3-month follow-up. Treatment was initiated with one telephone call reviewing the use of the technology and 3 days later with a second call reviewing the use of the GEM pocket guide and intervention. Results At 3-month follow-up, 67% of the participants’ diabetes was in remission (HbA1c levels <6.5%), and only one participant started taking diabetes medication. Participants demonstrated a significant reduction in HbA1c levels (–1.8%; P<.001). Participants also experienced significant reductions in high-glycemic-load carbohydrates routinely consumed, CGM readings that were >140 mg/dL, diabetes distress, depressive symptoms, and BMI. Participants felt that use of the CGM was the most significant single element of the intervention. Conclusions GEM augmented with CGM feedback may be an effective initial intervention for adults newly diagnosed with T2D. A self-administered version of GEM may provide primary care physicians and patients with a new tool to help people recently diagnosed with T2D achieve remission independent of medication and without weight loss as the primary focus. Future research is needed with a larger and more diverse sample.

Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/Akt/mTOR pathway. OP449, a SET inhibitor, decreases Akt/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (p<0.05), and IR phosphorylation was 4.5-fold higher in these mice (p<0.05). Human and murine breast cancer tumors treated with OP449 were 47% and 39% smaller than controls (p<0.05, for both, respectively). Akt and S6RP phosphorylation were 82% and 34% lower in OP449 treated tumors compared with controls (p<0.05, p=0.06, respectively). Akt and S6RP phosphorylation in response to insulin was 30% and 12% lower in cells, pre-treated with OP449, compared with control cells (p<0.01, p<0.05, respectively). However, even with decreased Akt/mTOR activation, body weights and composition, blood glucose and plasma insulin, glucose tolerance, serum triglyceride and cholesterol levels were similar between OP449 treated mice and controls. Xenografts and liver tissue from OP449-treated mice showed a 64% and 70% reduction in STAT5 activation, compared with controls (p<0.01 and p=0.06, respectively). Our data support an anti-neoplastic effect of OP449 on human breast cancer cells in vitro and in xenografts in the setting of hyperinsulinemia. OP449 led to inhibition of Akt/mTOR signaling, albeit, not leading to metabolic derangements.

Aims Type 2 diabetes (T2D) is a complex metabolic disease leading to complications in multiple organs. Diabetic myopathy and liver disease are common complications of T2D, but are incompletely understood. To gain insight into the pathogenesis of these conditions we performed metabolomic analysis of skeletal muscle and liver in a mouse model of T2D. Methods Tissue metabolomics were performed by GC/MS and LC/MS of the skeletal muscle and liver in the MKR mouse model of T2D, compared with control mice. MKR mice were treated with the β-3 adrenergic receptor agonist, CL-316,243 to determine metabolite changes after correcting hyperglycemia. Results Blood glucose was higher in MKR vs WT mice, and normalized with CL-316,243 treatment. Compared with WT mice, MKR mice had 2.5 fold higher concentrations of sorbitol and 1.7 fold lower concentrations of reduced glutathione in skeletal muscle. In liver, MKR mice had 2 fold higher concentrations of the pentitol ribitol. CL-316,243 treatment normalized sorbitol and ribitol concentrations in MKR skeletal muscle and liver, respectively to the levels of the WT mice. Conclusions These results demonstrate tissue-specific accumulation of polyols in a mouse model of T2D and provide novel insights into the pathogenesis of myopathy and liver disease in T2D.

BACKGROUND Type 2 diabetes (T2D) is a growing epidemic in the United States, and metabolic control has not been improved over the last 10 years. Glycemic excursion minimization (GEM) is an alternative lifestyle treatment option focused on reducing postnutrient glucose excursions rather than reducing weight. GEM has been proven to be superior to routine care when delivered face to face, and equivalent or superior to conventional weight loss therapy, but it has not been evaluated among patients newly diagnosed with T2D or in a self-administered format. OBJECTIVE This pilot study evaluated the feasibility of a self-administered version of GEM, augmented with continuous glucose monitoring (CGM), to improve metabolic control (hemoglobin A_1c [HbA_1c]) while diminishing or delaying the need for diabetes medications in adults recently diagnosed with T2D. These primary objectives were hypothesized to be achieved by reducing carbohydrate intake and increasing physical activity to diminish CGM glucose excursions, leading to the secondary benefits of an increase in diabetes empowerment and reduced diabetes distress, depressive symptoms, and BMI. METHODS GEM was self-administered by 17 adults recently diagnosed with T2D (mean age 52 years, SD 11.6 years; mean T2D duration 3.9 months, SD 2.5 months; mean HbA_1c levels 8.0%, SD 1.6%; 40% female; 33.3% non-White), with the aid of a 4-chapter pocket guide and diary, automated motivational text messaging, and feedback from an activity monitor, along with CGM and supplies for the 6-week intervention and the 3-month follow-up. Treatment was initiated with one telephone call reviewing the use of the technology and 3 days later with a second call reviewing the use of the GEM pocket guide and intervention. RESULTS At 3-month follow-up, 67% of the participants’ diabetes was in remission (HbA_1c levels &lt;6.5%), and only one participant started taking diabetes medication. Participants demonstrated a significant reduction in HbA_1c levels (–1.8%; <i>P</i>&lt;.001). Participants also experienced significant reductions in high-glycemic-load carbohydrates routinely consumed, CGM readings that were &gt;140 mg/dL, diabetes distress, depressive symptoms, and BMI. Participants felt that use of the CGM was the most significant single element of the intervention. CONCLUSIONS GEM augmented with CGM feedback may be an effective initial intervention for adults newly diagnosed with T2D. A self-administered version of GEM may provide primary care physicians and patients with a new tool to help people recently diagnosed with T2D achieve remission independent of medication and without weight loss as the primary focus. Future research is needed with a larger and more diverse sample.