Managing weight and glycaemic targets in people with type 2 diabetes—How far have we come?

Introduction: As the vast majority of people with type 2 diabetes (T2D) are also overweight or obese, healthcare professionals (HCP) are faced with the task of addressing both weight management and glucose control. In this narrative review, we aim to identify the challenges of reaching and maintaining body weight targets in people with T2D and highlight current and future treatment interventions. Methods: A search of the PubMed database was conducted using the search terms “diabetes” and “weight loss.”. Results: According to emerging evidence, treating obesity may be antecedent to the development and progression of T2D. While clinical benefits typically set in upon achieving a weight loss of 3–5%, these benefits are progressive leading to further health improvements, and weight loss of >15% can have a disease-modifying effect in people with T2D, an outcome that up to recently could not be achieved with any blood glucose-lowering pharmacotherapy. However, advanced treatment options with weight-loss effects currently in development including the dual GIP/GLP-1 receptor agonists may enable simultaneous achievement of individual glycemic and weight goals. Conclusion: Despite considerable therapeutic progress, there is still a large unmet medical need in patients with T2D who miss their individualized glycemic and weight-loss targets. Nonetheless, it is to be expected that development of future therapies and their use will favourably change the scenario of weight and glucose control in T2D

Serum Levels of the Adipokine FGF21 Depend on Renal Function

OBJECTIVE—To investigate renal elimination of the adipokine fibroblast growth factor 21 (FGF21) by determining circulating FGF21 levels in patients on chronic hemodialysis (CD) as compared with control subjects with a glomerular filtration rate (GFR) >50 ml/min

Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth

OBJECTIVE—IGF-1 and the IGF-1 receptor (IGF-1R) have been implicated in the regulation of adipocyte differentiation and lipid accumulation in vitro

Defective Peripheral Nerve Development Is Linked to Abnormal Architecture and Metabolic Activity of Adipose Tissue in Nscl-2 Mutant Mice

BACKGROUND: In mammals the interplay between the peripheral nervous system (PNS) and adipose tissue is widely unexplored. We have employed mice, which develop an adult onset of obesity due to the lack the neuronal specific transcription factor Nscl-2 to investigate the interplay between the nervous system and white adipose tissue (WAT). METHODOLOGY: Changes in the architecture and innervation of WAT were compared between wildtype, Nscl2-/-, ob/ob and Nscl2-/-//ob/ob mice using morphological methods, immunohistochemistry and flow cytometry. Metabolic alterations in mutant mice and in isolated cells were investigated under basal and stimulated conditions. PRINCIPAL FINDINGS: We found that Nscl-2 mutant mice show a massive reduction of innervation of white epididymal and paired subcutaneous inguinal fat tissue including sensory and autonomic nerves as demonstrated by peripherin and neurofilament staining. Reduction of innervation went along with defects in the formation of the microvasculature, accumulation of cells of the macrophage/preadipocyte lineage, a bimodal distribution of the size of fat cells, and metabolic defects of isolated adipocytes. Despite a relative insulin resistance of white adipose tissue and isolated Nscl-2 mutant adipocytes the serum level of insulin in Nscl-2 mutant mice was only slightly increased. CONCLUSIONS: We conclude that the reduction of the innervation and vascularization of WAT in Nscl-2 mutant mice leads to the increase of preadipocyte/macrophage-like cells, a bimodal distribution of the size of adipocytes in WAT and an altered metabolic activity of adipocytes

PCBs and dioxins/furans in attic dust collected near former PCB production and secondary copper facilities in Sauget, IL

AbstractSamples of settled attic dust from fourteen buildings located within two miles of the Solutia W.G. Krummrich and Cerro Flow Products facilities in Sauget, Illinois were analyzed for PCBs and dioxins/furans using HRGC/HRMS. The facilities released vast quantities of PCBs and dioxins/furans into the environment over many decades. The concentrations and homologues present in the samples of attic dust and in samples of soil collected by U.S. EPA demonstrate atmospheric transport of PCBs and dioxins/furans from these manufacturing sites and local dumps contaminated with these pollutants. The results demonstrate that attic dust is a useful metric for assessing historical exposure to atmospheric emissions

Ciliary Neurotrophic Factor Stimulates Muscle Glucose Uptake by a PI3-Kinase–Dependent Pathway That Is Impaired With Obesity

OBJECTIVE: Ciliary neurotrophic factor (CNTF) reverses muscle insulin resistance by increasing fatty acid oxidation through gp130-LIF receptor signaling to the AMP-activated protein kinase (AMPK). CNTF also increases Akt signaling in neurons and adipocytes. Because both Akt and AMPK regulate glucose uptake, we investigated muscle glucose uptake in response to CNTF signaling in lean and obese mice. RESEARCH DESIGN AND METHODS: Mice were injected intraperitoneally with saline or CNTF, and blood glucose was monitored. The effects of CNTF on skeletal muscle glucose uptake and AMPK/Akt signaling were investigated in incubated soleus and extensor digitorum longus (EDL) muscles from muscle-specific AMPKalpha2 kinase-dead, gp130(DeltaSTAT), and lean and obese ob/ob and high-fat-fed mice. The effect of C2-ceramide on glucose uptake and gp130 signaling was also examined. RESULTS: CNTF reduced blood glucose and increased glucose uptake in isolated muscles in a time- and dose-dependent manner with maximal effects after 30 min with 100 ng/ml. CNTF increased Akt-S473 phosphorylation in soleus and EDL; however, AMPK-T172 phosphorylation was only increased in soleus. Incubation of muscles from AMPK kinase dead (KD) and wild-type littermates with the PI3-kinase inhibitor LY-294002 demonstrated that PI3-kinase, but not AMPK, was essential for CNTF-stimulated glucose uptake. CNTF-stimulated glucose uptake and Akt phosphorylation were substantially reduced in obesity (high-fat diet and ob/ob) despite normal induction of gp130/AMPK signaling--effects also observed when treating myotubes with C2-ceramide. CONCLUSIONS: CNTF acutely increases muscle glucose uptake by a mechanism involving the PI3-kinase/Akt pathway that does not require AMPK. CNTF-stimulated glucose uptake is impaired in obesity-induced insulin resistance and by ceramide

Cannabinoid Receptor Stimulation Impairs Mitochondrial Biogenesis in Mouse White Adipose Tissue, Muscle, and Liver: The Role of eNOS, p38 MAPK, and AMPK Pathways

OBJECTIVE - Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism. We asked whether CB1 receptor stimulation was able to decrease mitochondrial biogenesis in different metabolically active tissues of obese high-fat diet (HFD)-fed mice. RESEARCH DESIGN AND METHODS - The effects of selective CB1 agonist arachidonyl-2-chloroethanolamide (ACEA) and endocannabinoids anandamide and 2-arachidonoylglycerol on endothelial nitric oxide synthase (eNOS) expression were examined, as were mitochondrial DNA amount and mitochondrial biogenesis parameters in cultured mouse and human white adipocytes. These parameters were also investigated in white adipose tissue (WAT), muscle, and liver of mice chronically treated with ACEA. Moreover, p38 mitogen-activated protein kinase (MAPK) phosphorylation was investigated in WAT and isolated mature adipocytes from eNOS-/- and wild-type mice. eNOS, p38 MAPK, adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial biogenesis were investigated in WAT, muscle, and liver of HFD mice chronically treated with ACEA. RESULTS - ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes. The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing. White adipocytes from eNOS-/- mice displayed higher p38 MAPK phosphorylation than wild-type animals under basal conditions, and ACEA was ineffective in cells lacking eNOS. Moreover, mitochondrial biogenesis was downregulated, while p38 MAPK phosphorylation was increased and AMPK phosphorylation was decreased in WAT, muscle, and liver of ACEA-treated mice on a HFD. CONCLUSIONS - CB1 receptor stimulation decreases mitochondrial biogenesis in white adipocytes, through eNOS downregulation and p38 MAPK activation, and impairs mitochondrial function in metabolically active tissues of dietary obese mic

An ACACB Variant Implicated in Diabetic Nephropathy Associates with Body Mass Index and Gene Expression in Obese Subjects

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