Stealthy progression of type 2 diabetes mellitus due to impaired ketone production in an adult patient with multiple acyl-CoA dehydrogenase deficiency.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disorder caused by biallelic pathogenic variants in genes related to the flavoprotein complex. Dysfunction of the complex leads to impaired fatty acid oxidation and ketone body production which can cause hypoketotic hypoglycemia with prolonged fasting. Patients with fatty acid oxidation disorders (FAODs) such as MADD are treated primarily with a dietary regimen consisting of high-carbohydrate foods and avoidance of prolonged fasting. However, information on the long-term sequelae associated with this diet have not been accumulated. In general, high-carbohydrate diets can induce diseases such as type 2 diabetes mellitus (T2DM), although few patients with both MADD and T2DM have been reported. Case: We present the case of a 32-year-old man with MADD who was on a high-carbohydrate diet for >30 years and exhibited symptoms resembling diabetic ketoacidosis. He presented with polydipsia, polyuria, and weight loss with a decrease in body mass index from 31 to 25 kg/m2 over 2 months. Laboratory tests revealed a HbA1c level of 13.9%; however, the patient did not show metabolic acidosis but only mild ketosis. Discussion/conclusion: This report emphasizes the potential association between long-term adherence to high-carbohydrate dietary therapy and T2DM development. Moreover, this case underscores the difficulty of detecting diabetic ketosis in patients with FAODs such as MADD due to their inability to produce ketone bodies. These findings warrant further research of the long-term complications associated with this diet as well as warning of the potential progression of diabetes in patients with FAODs such as MADD.

Optogenetic stimulation of vagal nerves for enhanced glucose-stimulated insulin secretion and ß cell proliferation.

The enhancement of insulin secretion and of the proliferation of pancreatic ß cells are promising therapeutic options for diabetes. Signals from the vagal nerve regulate both processes, yet the effectiveness of stimulating the nerve is unclear, owing to a lack of techniques for doing it so selectively and prolongedly. Here we report two optogenetic methods for vagal-nerve stimulation that led to enhanced glucose-stimulated insulin secretion and to ß cell proliferation in mice expressing choline acetyltransferase-channelrhodopsin 2. One method involves subdiaphragmatic implantation of an optical fibre for the photostimulation of cholinergic neurons expressing a blue-light-sensitive opsin. The other method, which suppressed streptozotocin-induced hyperglycaemia in the mice, involves the selective activation of vagal fibres by placing blue-light-emitting lanthanide microparticles in the pancreatic ducts of opsin-expressing mice, followed by near-infrared illumination. The two methods show that signals from the vagal nerve, especially from nerve fibres innervating the pancreas, are sufficient to regulate insulin secretion and ß cell proliferation.

Anti-GAD antibody-positive fulminant type 1 diabetes developed following SARS-CoV-2 vaccination.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been used worldwide since the 2020 coronavirus pandemic. However, several negative side-effects of these vaccines have been reported. Herein, we present a case of a patient with fulminant type 1 diabetes that developed shortly after administration of the SARS-CoV-2 vaccine. A 47-year-old man with no medical history presented with hyperglycemia-related symptoms shortly after receiving the third messenger ribonucleic acid SARS-CoV-2 vaccine. Based on hyperglycemia, diabetic ketoacidosis at onset, relatively low hemoglobin A1c levels, and complete depletion of endogenous insulin secretion, the patient was diagnosed with fulminant type 1 diabetes and insulin therapy was initiated. Through human leukocyte antigen genotyping, the disease-susceptible alleles for type 1 diabetes, DRB1*04:05 and DQB1*04:01, were identified. The patient tested positive for serum anti-glutamic acid decarboxylase antibodies, which are normally negative for fulminant type 1 diabetes, implying that immunomodulation triggered by SARS-CoV-2 vaccination influenced the onset of type 1 diabetes.

Phagocytosis by macrophages promotes pancreatic ß cell mass reduction after parturition in mice.

Elucidating the mechanism(s) modulating appropriate tissue size is a critical biological issue. Pancreatic ß cells increase during pregnancy via cellular proliferation, but how ß cells promptly decrease to the original amount after parturition remains unclear. Herein, we demonstrate the role and mechanism of macrophage accumulation in this process. In the final stage of pregnancy, HTR1D signaling upregulates murine ß cell CXCL10, thereby promoting macrophage accumulation in pancreatic islets via the CXCL10-CXCR3 axis. Blocking this mechanism by administering an HTR1D antagonist or the CXCR3 antibody and depleting islet macrophages inhibited postpartum ß cell mass reduction. ß cells engulfed by macrophages increased in postpartum islets, but Annexin V administration suppressed this engulfment and the postpartum ß cell mass reduction, indicating the accumulated macrophages to phagocytose ß cells. This mechanism contributes to both maintenance of appropriate ß cell mass and glucose homeostasis promptly adapting to reduced systemic insulin demand after parturition.

A highly sensitive strategy for monitoring real-time proliferation of targeted cell types in vivo.

Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter. Crossing these with tissue-specific Cre-expressing mice allows us to monitor the proliferation time course of pancreatic ß-cells, which are few in number and weakly proliferative, by measuring plasma luciferase activity. Physiological time courses, during obesity development, pregnancy and juvenile growth, as well as diurnal variation, of ß-cell proliferation, are clearly detected. Moreover, this strategy can be utilized for highly sensitive ex vivo screening for proliferative factors for targeted cells. Thus, these technologies may contribute to advancements in broad areas of biological and medical research.

Inter-organ insulin-leptin signal crosstalk from the liver enhances survival during food shortages.

Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages.

Roles of FoxM1-driven basal ß-cell proliferation in maintenance of ß-cell mass and glucose tolerance during adulthood.

AIMS/INTRODUCTION: Whether basal ß-cell proliferation during adulthood is involved in maintaining sufficient ß-cell mass, and if so, the molecular mechanism(s) underlying basal ß-cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in 'adaptive' ß-cell proliferation, which facilitates rapid increases in ß-cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of ß-cell FoxM1 in 'basal' ß-cell proliferation under normal conditions and in the maintenance of sufficient ß-cell mass as well as glucose homeostasis during adulthood. MATERIALS AND METHODS: FoxM1 deficiency was induced specifically in ß-cells of 8-week-old mice, followed by analyzing its short- (2 weeks) and long- (10 months) term effects on ß-cell proliferation, ß-cell mass, and glucose tolerance. RESULTS: FoxM1 deficiency suppressed ß-cell proliferation at both ages, indicating critical roles of FoxM1 in basal ß-cell proliferation throughout adulthood. While short-term FoxM1 deficiency affected neither ß-cell mass nor glucose tolerance, long-term FoxM1 deficiency suppressed ß-cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long-term ß-cell FoxM1 deficiency. Therefore, ß-cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long-term ß-cell FoxM1 deficiency. CONCLUSIONS: Basal low-level proliferation of ß-cells during adulthood is important for maintaining sufficient ß-cell mass and good glucose tolerance and ß-cell FoxM1 underlies this mechanism. Preserving ß-cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.

Continuous glucose monitoring in patients with remission of type 2 diabetes after laparoscopic sleeve gastrectomy without or with duodenojejunal bypass.

Bariatric surgery is associated with a high remission rate of type 2 diabetes mellitus. However, it is unclear whether patients showing remission of diabetes actually have normal blood glucose levels throughout the day. We therefore performed continuous glucose monitoring (CGM) in 15 ambulatory patients showing remission of diabetes after laparoscopic sleeve gastrectomy (LSG) without or with duodenojejunal bypass (DJB) at the time of diabetic remission (12.9 ± 1.8 months after bariatric surgery). The definition of remission of diabetes was based on the American Diabetes Association criteria. The mean, SD, and coefficient of variation (CV) of glucose calculated from CGM were 6.2 ± 0.6 mmol/L, 1.5 ± 0.4 mmol/L, and 23.7 ± 6.2%, respectively. These values were higher than those of healthy participants without diabetes previously reported. The percentages of time spent above 10.0 mmol/L and below 3.9 mmol/L were 2.6 (IQR 0-5.0)% and 0 (IQR 0-8.0)%, respectively. Thus, patients with remission of diabetes after LSG or LSG/DJB still had substantial periods of hyperglycemia and hypoglycemia throughout the day. Therefore, we must manage patients with diabetes carefully, even after apparent remission of type 2 diabetes in response to bariatric surgery.

Extraordinarily long-inactive solitary fibrous tumor transformed to produce big insulin-like growth factor-2, leading to hypoglycemia and rapid liposarcoma growth: a case report.

BACKGROUND: A high-molecular-weight form of insulin-like growth factor-2 (IGF-2), known as "big" IGF-2, is occasionally produced by various tumor types, leading to hypoglycemia. Although solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, it has been estimated that 4-6% of SFT patients develop hypoglycemia due to circulating big IGF-2. The mean time elapsed from tumor detection until the onset of hypoglycemia is reportedly less than one year (8.5 ± 1.9 months). CASE PRESENTATION: A 68-year-old man was hospitalized for exacerbation of recurring hypoglycemic episodes. He had been diagnosed with an SFT 17 years before the onset of hypoglycemia, and the SFT had already been very large at that time. The tumor, which was non-resectable and refractory to chemotherapies, had slowly increased in size since the initial diagnosis. Half a year before the hypoglycemic episodes manifested, another tumor, adjacent to the left kidney, was newly identified. Fluorodeoxyglucose positron emission tomography-computed tomography scanning, revealed the left peri-renal tumor to show much higher fluorodeoxyglucose uptake than the preexisting SFT, suggesting that it was unlikely to be a metastasis from the SFT. Abundant serum big IGF-2 was detected by western immunoblot analysis, indicating it to be the cause of the hypoglycemia. Since the 17 years between SFT detection and the onset of IGF-2-induced hypoglycemia was an extremely long period as compared with those in previous reports, we initially suspected that the new, peri-renal tumor had produced big IGF-2, but transcatheter arterial embolization of its feeding arteries did not suppress hypoglycemia. Notably, by measuring the tumor volume doubling time, the peri-renal tumor growth was shown to be markedly accelerated in parallel with exacerbation of the hypoglycemia. The patient died of heart failure 21 months after the onset of hypoglycemia. Unexpectedly, autopsy revealed that big IGF-2 had been produced only by the preexisting SFT, not the peri-renal tumor, and that the peri-renal tumor was a dedifferentiated liposarcoma. CONCLUSIONS: We should keep in mind that even a long-inactive SFT can undergo transformation to produce big IGF-2, which then acts on both insulin and IGF-1 receptors, possibly leading to both hypoglycemia and the development/growth of another tumor, respectively.

Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight Gain via Alleviation of Hypothalamic Leptin Resistance.

Leptin resistance is an important mechanism underlying the development and maintenance of obesity and is thus regarded as a promising target of obesity treatment. Plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue-type and urokinase-type plasminogen activators, is produced at high levels in adipose tissue, especially in states of obesity, and is considered to primarily be involved in thrombosis. PAI-1 may also have roles in inter-organ tissue communications regulating body weight, because PAI-1 knockout mice reportedly exhibit resistance to high fat diet (HFD)-induced obesity. However, the role of PAI-1 in body weight regulation and the underlying mechanisms have not been fully elucidated. We herein studied how PAI-1 affects systemic energy metabolism. We examined body weight and food intake of PAI-1 knockout mice fed normal chow or HFD. We also examined the effects of pharmacological inhibition of PAI-1 activity by a small molecular weight compound, TM5441, on body weight, leptin sensitivities, and expressions of thermogenesis-related genes in brown adipose tissue (BAT) of HFD-fed wild type (WT) mice. Neither body weight gain nor food intake was reduced in PAI-1 KO mice under chow fed conditions. On the other hand, under HFD feeding conditions, food intake was decreased in PAI-1 KO as compared with WT mice (HFD-WT mice 3.98 ± 0.08 g/day vs HFD-KO mice 3.73 ± 0.07 g/day, P = 0.021), leading to an eventual significant suppression of weight gain (HFD-WT mice 40.3 ± 1.68 g vs HFD-KO mice 34.6 ± 1.84 g, P = 0.039). Additionally, TM5441 treatment of WT mice pre-fed the HFD resulted in a marked suppression of body weight gain in a PAI-1-dependent manner (HFD-WT-Control mice 37.6 ± 1.07 g vs HFD-WT-TM5441 mice 33.8 ± 0.97 g, P = 0.017). TM5441 treatment alleviated HFD-induced systemic and hypothalamic leptin resistance, before suppression of weight gain was evident. Moreover, improved leptin sensitivity in response to TM5441 treatment was accompanied by increased expressions of thermogenesis-related genes such as uncoupling protein 1 in BAT (HFD-WT-Control mice 1.00 ± 0.07 vs HFD-WT-TM5441 mice 1.32 ± 0.05, P = 0.002). These results suggest that PAI-1 plays a causative role in body weight gain under HFD-fed conditions by inducing hypothalamic leptin resistance. Furthermore, they indicate that pharmacological inhibition of PAI-1 activity is a potential strategy for alleviating diet-induced leptin resistance in obese subjects.

Vascular resistance of carotid and vertebral arteries is associated with retinal microcirculation measured by laser speckle flowgraphy in patients with type 2 diabetes mellitus.

AIMS: Evaluation of the retinal microcirculation is key to understanding retinal vasculopathies, such as diabetic retinopathy. Laser speckle flowgraphy (LSFG) has recently enabled us to directly evaluate the vascular resistance in both retinal vessels and capillaries, non-invasively. We therefore assessed whether retinal vessel blood flow and/or the capillary microcirculation are associated with blood flow in the cervical arteries in diabetic patients without severe retinopathy. METHODS: We enrolled 110 type 2 diabetes patients, with no or mild non-proliferative diabetic retinopathy, in this prospective cross-sectional study. We measured the resistivity indices (RIs) of the retinal vessel and capillaries by LSFG and those of cervical arteries by Doppler ultrasonography, followed by analyzing associations. RESULTS: The RIs of not only the carotid but also vertebral arteries were associated with those of retinal vessel blood flow and the retinal capillary microcirculation. Multiple regression analyses revealed these associations to be independent of other explanatory variables including age and diabetes duration. CONCLUSIONS: We obtained novel and direct evidence demonstrating a close association between the retinal microcirculation and cervical artery hemodynamics in diabetic patients. These findings suggest shared mechanisms to underlie micro- and macro-angiopathies. Thus, high vascular resistance of cervical arteries may be a risk of developing retinopathy.

Native Valve Endocarditis due to Staphylococcus warneri Developing in a Patient with Type 1 Diabetes.

A 59-year-old man with type 1 diabetes presented with heart failure. Echocardiography showed large vegetations on the mitral and aortic valves. Blood bacterial culture was positive for Staphylococcus warneri, a coagulase-negative staphylococcus (CoNS) family member. He was diagnosed with native valve endocarditis (NVE) induced by the resident bacteria and ultimately underwent double valve replacement. Retrospectively, slight laboratory data abnormalities and weight loss beginning four months before may have been signs of NVE. He had no history of immunosuppressive therapies or medical device implantation. Thus, CoNS can cause NVE after a long asymptomatic course in patients with poorly controlled diabetes.

Enhancement of postprandial endogenous insulin secretion rather than exogenous insulin injection ameliorated insulin antibody-induced unstable diabetes: a case report.

BACKGROUND: Insulin injection, especially with insulin analogs, occasionally induces the production of insulin antibodies with high binding capacity and low affinity, similar to the insulin autoantibodies characteristic of insulin autoimmune syndrome (IAS). Production of these "IAS-like" insulin antibodies causes marked glycemic fluctuations with postprandial hyperglycemia and fasting hypoglycemia. CASE PRESENTATION: A 66-year-old man with a 27-year history of diabetes was admitted because of marked glycemic fluctuations. Human insulin treatment had been initiated at age 56, followed by multiple daily injections of insulin analogs 5 years later. After the initial year of insulin analog treatment, the patient began to experience frequent morning hypoglycemic attacks and day-time hyperglycemia. Marked hyperinsulinemia (4500 µU/mL) and high titers of insulin antibodies (80.4%) with high binding capacity and low affinity indicated that IAS-like insulin antibodies were causing severe glucose fluctuations. Altering insulin formulations (insulin aspart → regular human insulin→ insulin lispro) proved to be ineffective. After several therapeutic trials, cessation of exogenous insulin and addition of mitiglinide to liraglutide with voglibose finally attenuated glycemic fluctuations with increased postprandial insulin secretion. Continuous glucose monitoring revealed improvement of morning hypoglycemia and postprandial hyperglycemia with smaller mean amplitude of glycemic excursion. Therefore, compared to exogenously injected insulin, endogenously secreted insulin directly and rapidly acts on hepatocytes and suppresses postprandial glucose output. CONCLUSIONS: Proper enhancement of postprandial endogenous insulin aimed at suppressing postprandial glucose output without stimulating excessive glucose uptake in the periphery is potentially useful for treating diabetes with insulin antibody-induced glycemic instability.

Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation.

The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival.

Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers.

BACKGROUND/OBJECTIVE: Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). SUBJECTS/METHODS: We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. RESULTS: In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. CONCLUSION: These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.

Serum cystatin C level is associated with carotid arterial wall elasticity in subjects with type 2 diabetes mellitus: A potential marker of early-stage atherosclerosis.

AIMS: Detection of early-stage atherosclerosis in type 2 diabetes mellitus (T2DM) patients is important for preventing cardiovascular disease. A phased tracking method for evaluating arterial wall elasticity sensitively detects early-stage atherosclerosis. However, biochemical markers for early-stage atherosclerosis have yet to be established. METHODS: This cross-sectional study enrolled 180 T2DM patients, who were classified as not having atherosclerosis according to the carotid intima-media thickness (IMT) criteria. We measured serum cystatin C, the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR), and analyzed the associations between these markers and arterial wall elasticity (Eθ), IMT and the cardio-ankle velocity index. RESULTS: Multiple linear regression analyses revealed that cystatin C was significantly associated with Eθ, while neither eGFR nor ACR showed an association. Furthermore, among the examined atherosclerotic markers, Eθ was most reliably associated with cystatin C. Additionally, the association between cystatin C and Eθ disappeared in the low elasticity subgroup, which included subjects in whom no atherosclerotic changes had yet been initiated. CONCLUSIONS: In T2DM patients without apparent arterial wall thickening, cystatin C is strongly and independently associated with arterial wall elasticity, which reflects the degree of subclinical atherosclerosis. Thus, cystatin C is a potentially useful marker of early-stage atherosclerosis.

Neuronal signals regulate obesity induced ß-cell proliferation by FoxM1 dependent mechanism.

Under insulin-resistant conditions such as obesity, pancreatic ß-cells proliferate to prevent blood glucose elevations. A liver-brain-pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory ß-cell proliferation. We identify FoxM1 activation in islets from neuronal relay-stimulated mice. Blockade of this relay, including vagotomy, inhibits obesity-induced activation of the ß-cell FoxM1 pathway and suppresses ß-cell expansion. Inducible ß-cell-specific FoxM1 deficiency also blocks compensatory ß-cell proliferation. In isolated islets, carbachol and PACAP/VIP synergistically promote ß-cell proliferation through a FoxM1-dependent mechanism. These findings indicate that vagal nerves that release several neurotransmitters may allow simultaneous activation of multiple pathways in ß-cells selectively, thereby efficiently promoting ß-cell proliferation and maintaining glucose homeostasis during obesity development. This neuronal signal-mediated mechanism holds potential for developing novel approaches to regenerating pancreatic ß-cells.

ER Stress Protein CHOP Mediates Insulin Resistance by Modulating Adipose Tissue Macrophage Polarity.

Obesity represents chronic inflammatory states promoted by pro-inflammatory M1-macrophage infiltration into white adipose tissue (WAT), thereby inducing insulin resistance. Herein, we demonstrate the importance of an ER stress protein, CHOP, in determining adipose tissue macrophage (ATM) polarity and systemic insulin sensitivity. A high-fat diet (HFD) enhances ER stress with CHOP upregulation in adipocytes. CHOP deficiency prevents HFD-induced insulin resistance and glucose intolerance with ATM M2 predomination and Th2 cytokine upregulation in WAT. Whereas ER stress suppresses Th2 cytokine expression in cultured adipocytes, CHOP knockdown inhibits this downregulation. In contrast, macrophage responsiveness to Th1/Th2 cytokines is unchanged regardless of whether CHOP is expressed. Furthermore, bone marrow transplantation experiments showed recipient CHOP to be the major determinant of ATM polarity. Thus, CHOP in adipocytes plays important roles in ATM M1 polarization by altering WAT micro-environmental conditions, including Th2 cytokine downregulation. This molecular mechanism may link adipose ER stress with systemic insulin resistance.

Impacts of the Great East Japan Earthquake on diabetic patients.

AIMS/INTRODUCTION: We investigated impacts of the Great East Japan Earthquake on diabetic patients and characterized those with disaster-susceptible diabetes. MATERIALS AND METHODS: We enrolled 497 diabetic patients who had been followed at hospitals in devastated areas. We collected metabolic parameters prospectively, 1 and 3 months after the earthquake, and retrospectively for pre-earthquake time-points. Questionnaire surveys were carried out regarding earthquake-related damage and post-earthquake lifestyle alterations. Available data were analyzed to examine associations with post-earthquake glycosylated hemoglobin alterations. RESULTS: The mean glycosylated hemoglobin level of the participants was not elevated at 1 month, and was significantly decreased at 3 months as compared with the pre-earthquake glycosylated hemoglobin. There were no significant differences in earthquake-related damage or lifestyle alterations between the improved and worsened glycemic control groups according to the data obtained from the questionnaire survey. As reported, fasting serum C-peptide levels were significantly lower in the worsened glycemic control group (P < 0.05). Notably, plasma noradrenaline levels were significantly higher in the worsened glycemic control group (P < 0.05). Furthermore, at 1 month after the earthquake, the plasma noradrenaline level was significantly higher in the low C-peptide group (fasting serum C-peptide <1.0 ng/mL) than in the high C-peptide group (fasting serum C-peptide ≥1.0 ng/mL), but this difference had disappeared by 3 months after the earthquake. These findings show that post-earthquake plasma noradrenaline levels were temporarily increased in the low C-peptide group. CONCLUSIONS: Sympathetic nerve activation might be elicited more easily in subjects with lower endogenous insulin secretory capacity, and could be involved in the mechanism underlying post-earthquake worsening of glycemic control.