Insulin at 100 years – is rebalancing its action key to fighting obesity-related disease?

ABSTRACT One hundred years ago, insulin was purified and administered to people with diabetes to lower blood glucose, suppress ketogenesis and save lives. A century later, insulin resistance (IR) lies at the heart of the obesity-related disease pandemic. Multiple observations attest that IR syndrome is an amalgamation of gain and loss of insulin action, suggesting that IR is a misnomer. This misapprehension is reinforced by shortcomings in common model systems and is particularly pronounced for the tissue growth disorders associated with IR. It is necessary to move away from conceptualisation of IR as a pure state of impaired insulin action and to appreciate that, in the long term, insulin can harm as well as cure. The mixed state of gain and loss of insulin action, and its relationship to perturbed insulin-like growth factor (IGF) action, should be interrogated more fully in models recapitulating human disease. Only then may the potential of rebalancing insulin action, rather than simply increasing global insulin signalling, finally be appreciated.

Aberrant Ca2+ homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity

SummaryChronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+ channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposure in vitro or by obesity in vivo lead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+ and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+ is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+ homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity.

The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase–leukotriene B4axis

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3′-phosphoinositide–dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B4(LTB4) levels in plasma and in adipose tissue as well as the expression of 5-lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB4receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4production through down-regulation of 5-LO expression via the PDK1−FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB4via the PDK1−FoxO1 pathway and thereby maintains systemic insulin sensitivity.

Bilateral Interrelationship of Diabetes and Periodontium

: Periodontitis is a chronic inflammatory disease characterised by destruction of the supporting structures of the teeth which is a common cause of tooth mortality in all individuals throughout the world. Diabetes is a group of metabolic dysregulation, primarily of carbohydrate metabolism, characterized by hyperglycemia that results from defects in insulin secretion, impaired insulin action, or both. Systematic reviews and meta-analysis have shown that the prevalence of periodontitis is increased in diabetic patients. Based on the evidence, degree of hyperglycemia and severity of periodontitis are inter- related. Diabetic patients with severe periodontitis have six times more poor glycemic control than patients with healthy periodontium. However, improved glycemic control has been postulated to reduce the severity of periodontal disease. : In this mini-review, we have presented the previously reviewed studies from the literature and focused on a two-way relationship of diabetes and periodontitis, various pathways involved in it such as RANK/RANKL/OPG axis, AGE-RAGE pathway, Oxidative stress mechanism, and obesity that influence the possibility of periodontitis-Diabetes Mellitus (DM).

DIFFERENT EXPERIMENTAL MODELS USED TO INDUCE DIABETES MELLITUS IN RODENTS: A REVIEW

Diabetes is a metabolic disease characterized by the presence of hyperglycemia resulting from either defects in insulin secretion or action or both. Various processes are involved in the development of diabetes. These range from autoimmune destruction of the insulin-producing cells, β-cells of the pancreas, a dysfunction of the pancreatic β-cell, and impaired insulin action through insulin resistance. Experimental diabetes in animals are widely induced by administration of alloxan and streptozotocin at a proper dose. The mechanism of their action in pancreatic β-cells has been extensively investigated. Reactive oxygen species are responsible for the cytotoxic action of both these diabetogenic agents. However, the source of their generation is different in the case of alloxan (ALX) and streptozotocin (STZ). In one of the study, it is also showed that the administration of a high-fat diet (HFD) to rats for 16 w showed a progressive increase in body weight, energy intake, abdominal fat deposition, and abdominal circumference along with impaired glucose tolerance, dyslipidemia and hyperinsulinemia. Administration of alloxan or streptozotocin in addition with HFD is also able to induce diabetes in an experimental rat model.

Update on the synergistic effect of HSL and insulin in the treatment of metabolic disorders

Hormone-sensitive lipase (HSL) is one of the three lipases in adipose tissue present during periods of energy demand. HSL is tightly controlled by insulin regulation via the central and peripheral systems. The suppressive effects of insulin on HSL are also associated with complex crosstalk with other pathways in the metabolic network. Because impaired insulin action is the driving force behind the pathogenesis of diabetes and other metabolic complications, elucidation of the intricate relationships between HSL and insulin may provide an in-depth understanding of these pandemic diseases and potentially identify strategies to inhibit disease development. Insulin not only differentially regulates HSL isoform transcription but also post-transcriptionally affects HSL phosphorylation by stimulating PKA and endothelin (ET-1), and controls its expression indirectly via regulating the activity of growth hormone (GH). In addition, a rapid elevation of HSL levels was detected after insulin injection in patients, which suggests that the inhibitory effects of insulin on HSL can be overridden by insulin-induced hypoglycemia. Conversely, individuals with hereditary HSL deficiency, and animals with experimental HSL deletion, showed major disruptions in mRNA/protein expression in insulin signaling pathways, ultimately leading to insulin resistance, diabetes, and fatty liver. Notably, HSL inactivation could cause insulin-independent fatty liver, while insulin resistance induced by HSL deficiency may further aggravate disease progression. The common beliefs that HSL is the overall rate-limiting enzyme in lipolysis and that insulin is an inhibitor of HSL have been challenged by recent discoveries; therefore, a renewed examination of their relationships is required. In this review, by analyzing current data related to the role of, and mutual regulation between, HSL and insulin and discussing unanswered questions and disparities in different lines of studies, the authors intend to shed light on our understanding of lipid metabolism and provide a rational basis for future research in drug development.

Potential antidiabetic activity of medicinal plants – A short review

Diabetes mellitus is a dreadful disease caused by the increase in hepatic glucose production and impaired insulin action. The usage of herbal based medicine has been increasing tremendously in both developing and developed countries over the last three decades. The present study aims to provide a comprehensive review of antidiabetic activity of following medicinal plants like Gymnema sylvestris, Rubia cardifolia, Bilberry, Green Tea, Salacia reticulate, Berberis aristata, Pterocarpus marsupium, Fenugreek, Ashwagandha, Bitter melon. The efficiency of these medicinal plants may regulate the diabetic metabolic abnormalities. This work would help researchers to choose potential herbal for diabetic treatment

Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity

Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control.

Monitoring of Patient With Diabetes Mellitus

Diabetes mellitus is a disease characterized by hyperglycemia, which is caused by impaired insulin secretion, impaired insulin action, or both. Chronic hyperglycemia will lead to dysfunction and damage to various organs, such as the eyes, kidneys, nerves, heart, and blood vessels. This paper discusses the monitoring of patients with diabetes mellitus according to the laboratory tests, to know when the results of therapy has reached the optimum point as well as the prevention of complications that can occur.