An extract of Urtica dioica L. mitigates obesity induced insulin resistance in mice skeletal muscle via protein phosphatase 2A (PP2A)

The leaf extract of Urtica dioica L. (UT) has been reported to improve glucose homeostasis in vivo, but definitive studies on efficacy and mechanism of action are lacking. We investigated the effects of UT on obesity-induced insulin resistance in skeletal muscle. Male C57BL/6J mice were divided into three groups: low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with UT. Body weight, body composition, plasma glucose and plasma insulin were monitored. Skeletal muscle (gastrocnemius) was analyzed for insulin sensitivity, ceramide accumulation and the post translational modification and activity of protein phosphatase 2A (PP2A). PP2A is activated by ceramides and dephosphorylates Akt. C2C12 myotubes exposed to excess free fatty acids with or without UT were also evaluated for insulin signaling and modulation of PP2A. The HFD induced insulin resistance, increased fasting plasma glucose, enhanced ceramide accumulation and PP2A activity in skeletal muscle. Supplementation with UT improved plasma glucose homeostasis and enhanced skeletal muscle insulin sensitivity without affecting body weight and body composition. In myotubes, UT attenuated the ability of FFAs to induce insulin resistance and PP2A hyperactivity without affecting ceramide accumulation and PP2A expression. UT decreased PP2A activity through posttranslational modification that was accompanied by a reduction in Akt dephosphorylation

Arterial heparan sulfate is negatively associated with hyperglycemia and atherosclerosis in diabetic monkeys

BACKGROUND: Arterial proteoglycans are implicated in the pathogenesis of atherosclerosis by their ability to trap plasma lipoproteins in the arterial wall and by their influence on cellular migration, adhesion and proliferation. In addition, data have suggested an anti-atherogenic role for heparan sulfate proteoglycans and a pro-atherogenic role for dermatan sulfate proteoglycans. Using a non-human primate model for human diabetes, studies examined diabetes-induced changes in arterial proteoglycans that may increase susceptibility to atherosclerosis. METHODS: Control (n = 7) and streptozotocin-induced diabetic (n = 8) cynomolgous monkeys were assessed for hyperglycemia by measurement of plasma glycated hemoglobin (GHb). Thoracic aortas obtained at necropsy, were extracted with 4 M guanidine HCL and proteoglycans were measured as hexuronic acid. Atherosclerosis was measured by enzymatic analysis of extracted tissue cholesterol. Glycosaminoglycan chains of arterial proteoglycans were released with papain, separated by agarose electrophoresis and analysed by scanning densitometry. RESULTS: Tissue cholesterol was positively associated with hexuronic acid content in diabetic arteries (r = .82, p < .025) but not in control arteries. Glycosaminoglycan chain analysis demonstrated that dermatan sulfate was associated with increased tissue cholesterol in both control (r = .8, p < 0.05) and diabetic (r = .8, p < .025) arteries, whereas a negative relationship was observed between heparan sulfate and tissue cholesterol in diabetic arteries only (r = -.7, p < .05). GHb, which was significantly higher in diabetic animals (8.2 ± 0.9 vs 3.8 ± 0.2%, p < .0005) was negatively associated with heparan sulfate in diabetic arteries (r = -.7, p < .05). CONCLUSIONS: These data implicate hyperglycemia induced modifications in arterial proteoglycans that may promote atherosclerosis

Dietary chromium supplementation for targeted treatment of diabetes patients with comorbid depression and binge eating

Dietary chromium supplementation for the treatment of diabetes remains controversial. The prevailing view that chromium supplementation for glucose regulation is unjustified has been based upon prior studies showing mixed, modest-sized effects in patients with type 2 diabetes (T2DM). Based on chromium's potential to improve insulin, dopamine, and serotonin function, we hypothesize that chromium has a greater glucoregulatory effect in individuals who have concurrent disturbances in dopamine and serotonin function – that is, complex patients with comorbid diabetes, depression, and binge eating. We propose, as suggested by the collective data to date, the need to go beyond the “one size fits all” approach to chromium supplementation and put forth a series of experiments designed to link physiological and neurobehavioral processes in the chromium response phenotype

Tools for the identification of bioactives impacting the metabolic syndrome: Screening of a botanical extract library using subcutaneous and visceral human adipose-derived stem cell-based assays

Plant extracts continue to represent an untapped source of renewable therapeutic compounds for the treatment and prevention of illnesses including chronic metabolic disorders. With the increase in worldwide obesity and its related morbidities, the need for identifying safe and effective treatments is also rising. As such, use of primary human adipose-derived stem cells represents a physiologically relevant cell system to screen for bioactive agents in the prevention and treatment of obesity and its related complications. By using these cells in a primary screen, the risk and cost of identifying artifacts due to interspecies variation and immortalized cell lines is eliminated. We demonstrate that these cells can be formatted into 384-well high throughput screens to rapidly identify botanical extracts that affect lipogenesis and lipolysis. Additionally, counterscreening with human primary stem cells from distinct adipose depots can be routinely performed to identify tissue specific responses. In our study, over 500 botanical extracts were screened and 16 (2.7%) were found to affect lipogenesis and 4 (0.7%) affected lipolysis. © 2012 Elsevier Inc

Insulin therapy in people with type 2 diabetes:opportunities and challenges?

Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes

Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors’ Expert Forum

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors’ Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world