The Role of Heat Shock Response in Insulin Resistance and Diabetes

The expansion of life-style related diseases, such as metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM), appears to be unstoppable. It is also difficult to cease their complications in spite of many antidiabetic medications or intervention of public administration. We and our collaborators found that physical medicine using simultaneous stimulation of heat with mild electric current activates heat shock response, thereby reducing visceral adiposity, insulin resistance, chronic inflammation and improving glucose homeostasis in mice models of T2DM, as well as in humans with MS or T2DM. This combination therapy exerts novel action on insulin signaling, β-cell protection and body compositions, and may provide a new therapeutic alternative in diabetic treatment strategy

Identification of microRNA that represses IRS-1 expression in liver.

MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally regulate gene expression and have been shown to participate in almost every cellular process. Several miRNAs have recently been implicated in glucose metabolism, but the roles of miRNAs in insulin-resistant conditions, such as obesity or type 2 diabetes, are largely unknown. Herein, we focused on miR-222, the expression of which was increased in the livers of high fat/high sucrose diet-fed mice injected with gold thioglucose (G+HFHSD). Overexpression of miR-222 in primary mouse hepatocytes attenuated Akt phosphorylation induced by insulin, indicating that miR-222 negatively regulates insulin signaling. As per in silico analysis, miR-222 potentially binds to the 3' untranslated region (3' UTR) of the IRS-1 gene, a key insulin signaling molecule. In fact, IRS-1 protein expression was decreased in the livers of G+HFHSD-fed mice. We further confirmed a direct interaction between miR-222 and the 3' UTR of IRS-1 via luciferase assays. Our findings suggest that up-regulation of miR-222 followed by reduction in IRS-1 expression may be a viable mechanism of insulin resistance in the liver

Impacts of the 2016 Kumamoto Earthquake on glycemic control in patients with diabetes

Abstract Aims/Introduction On April 14 and 16 2016, the Kumamoto area was severely damaged by several massive magnitude 7 class earthquakes. Materials and Methods To examine the effects of these earthquakes on glycemic control and stress factors, glycated hemoglobin, glycated albumin, other biochemical parameters, a self‐administered lifestyle‐associated questionnaire and disaster‐associated stress scores were analyzed. A total of 557 patients with diabetes were enrolled, and data were collected at 13 months before to 13 months after the earthquakes. Results In patients with type 1 diabetes and specific types of diabetes due to other causes, glycemic control was not altered during the observational period. This glycemic stability in type 1 diabetes might result from self‐management of insulin doses. In patients with type 2 diabetes, glycated hemoglobin decreased by 0.11% (from 7.33 to 7.22%) at 1–2 months after the earthquakes, and increased thereafter. The reduction of glycated hemoglobin after 1–2 months in type 2 diabetes was associated with ‘early restoration of lifelines’ and ‘sufficient sleep.’ The glycemic deterioration at a later stage was related to ‘shortage of antidiabetic agents,’ ‘insufficient amount of food,’ ‘largely destroyed houses’ and ‘changes in working environments.’ Disaster‐associated stress levels were positively correlated with ‘age,’ ‘delayed restoration of lifelines,’ ‘self‐management of antidiabetic agents’ and ‘increased amount of physical activity/exercise,’ and negatively associated with ‘early restoration of lifelines’ and ‘sufficient sleep.’ Conclusions Glycemic control, associated factors and stress levels are altered in chronological order. Post‐disaster diabetic medical care must consider these corresponding points in accordance with the time‐period

Mild Electrical Stimulation with Heat Shock Reduces Visceral Adiposity and Improves Metabolic Abnormalities in Subjects with Metabolic Syndrome or Type 2 Diabetes: Randomized Crossover Trials

Background: The induction of heat shock protein (HSP) 72 by mild electrical stimulation with heat shock (MES + HS), which improves visceral adiposity and insulin resistance in mice, may be beneficial in treating metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM). Methods: Using open-label crossover trials, 40 subjects with MS or T2DM were randomly assigned using computer-generated random numbers to 12 weeks of therapeutic MES + HS followed by 12 weeks of no treatment, or vice versa. During the intervention period, physical and biochemical markers were measured. Findings: Compared to no treatment, MES + HS treatment was associated with a significant decrease in visceral adiposity (−7.54 cm2 (−8.61%), 95% CI −8.55 to −6.53 (p = 0.037) in MS, −19.73 cm2 (−10.89%), 95% CI −20.97 to −18.49 (p = 0.003) in T2DM). Fasting plasma glucose levels were decreased by 3.74 mg/dL (−5.28%: 95% CI −4.37 to −3.09 mg/dL, p = 0.029) in MS and by 14.97 mg/dL (10.40%: 95% CI −15.79 to 14.15 mg/dL, p < 0.001) in T2DM, and insulin levels were also reduced by 10.39% and 25.93%, respectively. HbA1c levels showed a trend toward reduction (−0.06%) in MS, and was significantly declined by −0.43% (95% CI −0.55 to −0.31%, p = 0.009) in T2DM. HbA1c level of less than 7.0% was achieved in 52.5% of the MES + HS-treated T2DM patients in contrast to 15% of the non-treated period. Several insulin resistance indices, inflammatory cytokines or adipokines, including C-reactive protein, adiponectin, and tumor necrosis factor-α, were all improved in both groups. In isolated monocytes, HSP72 expression was increased and cytokine expression was reduced following MES + HS treatment. Glucose excursions on meal tolerance test were lower after using MES + HS in T2DM. Interpretation: This combination therapy has beneficial impacts on body composition, metabolic abnormalities, and inflammation in subjects with MS or T2DM. Activation of the heat shock response by MES + HS may provide a novel approach for the treatment of lifestyle-related diseases. Funding: Funding for this research was provided by MEXT KAKENHI (Grants-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology, Japan)

Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets

Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic &#945;-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using &#945;-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in &#945;-cells. In &#945;-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in &#945;-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic &#946;-cells and improving glucose homeostasis

Effect of miR-222 overexpression on insulin signaling in primary mouse hepatocytes.

<p>(A) Primary hepatocytes were transfected with 30 nM negative control oligos (control) or miR-222 mimic using HilyMax. After 2 days of transfection, miR-222 overexpression in the cells was confirmed by qRT-PCR (n = 6 per group). (B) Cells overexpressing miR-222 were treated with insulin (100 nM) for 10 min. Cells were harvested, and protein levels involved in insulin signaling were determined by WB. The IRS-1 and P-Akt levels were quantified by normalization with β-actin and total Akt. The values are expressed as mean ± SD from 4 independent experiments. (C) <i>Irs-1</i> and <i>Irs-2</i> mRNA expression in the cells overexpressing miR-222 were analyzed by qRT-PCR. (D) Each mRNA involved in insulin signaling was analyzed in the cells overexpressing miR-222 (n = 10 per group). Data are presented as means ± SD. *<i>p</i> < 0.05, **<i>p</i> < 0.01 compared with the control group.</p

miR-222 expression is up-regulated in the livers of G+HFHSD-fed mice.

<p>(A) Body weight was measured during each treatment in NC or G+HFHSD-fed mice (n = 7–8 per group). (B, C) Fasting blood glucose and insulin levels were measured after 24 weeks of treatment. (D) HOMA-IR was calculated using fasting blood glucose and insulin levels after 24 weeks of treatment. (E, F) After 24 weeks of treatment, microRNA was collected from the livers of these mice. miR-222 and miR-221 expression were analyzed by qRT-PCR (n = 8 per group). (G) The proteins in the livers of these mice were analyzed with WB. The IRS-1 and IRS-2 levels were quantified by normalization with β-actin. (n = 4 per group). (H) <i>Irs-1</i> mRNA expression in the livers of these mice were analyzed by qRT-PCR. Data are presented as mean ± SD. *<i>p</i> < 0.05, **<i>p</i> < 0.01 compared with NC-fed mice.</p