ABSTRACT
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.
Subject(s)
Hypoglycemia/pathology , Insulin-Like Growth Factor II/metabolism , Liposarcoma/pathology , Solitary Fibrous Tumors/complications , Aged , Humans , Hypoglycemia/etiology , Hypoglycemia/metabolism , Liposarcoma/etiology , Liposarcoma/metabolism , Male , Prognosis , Solitary Fibrous Tumors/metabolismABSTRACT
PURPOSE: To compare clinical findings, including ocular blood flow and intima-media thickness (IMT) of the carotid artery, in mild nonproliferative diabetic retinopathy (NPDR) and no diabetic retinopathy (NDR) patients, and to determine risk factors contributing to mild NPDR. METHODS: In 129 subjects (129 eyes) with type-2 diabetes patients and mild NPDR or NDR, standard statistical techniques were used to determine associations between clinical findings, including diabetes duration, blood levels of creatinine and hemoglobin A1c (HbA1c), central macular thickness (CMT; measured with optical coherence tomography), mean blur rate (MBR; measured with laser speckle flowgraphy), and ultrasound-measured carotid IMT. RESULTS: Diabetes duration, IMT, and CMT were significantly higher in the mild NPDR patients than the NDR patients (P=0.004, P=0.004, and P=0.003, respectively), while conversely, MBR in the overall optic nerve head (MBR-A) was lower in the mild NPDR patients. Furthermore, a logistic regression analysis showed that diabetes duration (OR, 1.11; P=0.006), diastolic blood pressure (OR, 0.93; P=0.025), heart rate (OR, 1.07; P=0.004), IMT (OR, 8.65; P=0.005), and CMT (OR, 1.03; P=0.007) were independent contributing factors to mild NPDR. Spearman's rank correlation test also showed that IMT was negatively correlated with MBR-A (P=0.011). CONCLUSIONS: Increased IMT showed a close association with ocular ischemia in patients with type-2 diabetes and contributed to the presence of mild NPDR. These findings suggest that IMT may be an early biomarker of mild NPDR.
ABSTRACT
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 â regular human insulinâ 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.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/drug therapy , Hyperglycemia/drug therapy , Hypoglycemia/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin Secretion , Insulin/blood , Postprandial Period , Aged , Blood Glucose/drug effects , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Diabetic Angiopathies/blood , Diabetic Angiopathies/physiopathology , Drug Therapy, Combination , Glycated Hemoglobin/drug effects , Humans , Hyperglycemia/etiology , Hypoglycemia/etiology , Inositol/analogs & derivatives , Inositol/therapeutic use , Insulin/therapeutic use , Insulin Antibodies/blood , Isoindoles/therapeutic use , Liraglutide/therapeutic use , Male , Treatment OutcomeABSTRACT
Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1-3 litters of sweet beverages daily to quench his thirst. Therefore, "soft-drink diabetic ketosis" was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.
Subject(s)
Diabetes Mellitus, Type 2/diagnosis , Diabetic Ketoacidosis/diagnosis , Hypertriglyceridemia/diagnosis , Xanthomatosis/diagnosis , 3-Hydroxybutyric Acid/blood , Acetoacetates/blood , Adolescent , Apolipoprotein E2 , Apolipoprotein E4 , Carbonated Beverages/adverse effects , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetic Ketoacidosis/drug therapy , Diabetic Ketoacidosis/etiology , Diabetic Ketoacidosis/metabolism , Diet, Fat-Restricted , Glycated Hemoglobin/metabolism , Humans , Hypertriglyceridemia/complications , Hypertriglyceridemia/diet therapy , Hypertriglyceridemia/metabolism , Hypoglycemic Agents/therapeutic use , Inositol/analogs & derivatives , Inositol/therapeutic use , Insulin/therapeutic use , Ketosis/diagnosis , Ketosis/etiology , Male , Metformin/therapeutic use , Obesity/complications , Obesity/metabolism , Xanthomatosis/etiology , Xanthomatosis/pathologyABSTRACT
PURPOSE: Nerve conduction velocity (NCV) is an indicator of neuronal damage in the distal segment of the peripheral nerves. Here, we determined the association between NCV and other systemic and ocular clinical findings, in type 2 diabetes patients with early diabetic retinopathy (DR). METHODS: This study included 42 eyes of 42 type 2 diabetes patients (median age: 54 years) with no DR or with mild nonproliferative DR. Standard statistical techniques were used to determine associations between clinical findings. RESULTS: Sural sensory conduction velocity (SCV) and tibial motor conduction velocity (MCV) were significantly lower in mild nonproliferative DR patients than patients with no DR (P = 0.008 and P = 0.01, resp.). Furthermore, logistic regression analyses revealed that sural SCV and tibial MCV were independent factors contributing to the presence of mild nonproliferative DR (OR 0.83, P = 0.012 and OR 0.69 P = 0.02, resp.). Tibial MCV was correlated with choroidal thickness (CT) (P = 0.01), and a multiple regression analysis revealed that age, tibial MCV, and carotid intima-media thickness were independent associating factors with CT (P = 0.035, P = 0.015, and P = 0.008, resp.). CONCLUSIONS: Our findings suggest that reduced NCV may be closely associated with early DR in type 2 diabetes patients. Thus, reduced nerve conduction is a potential early biomarker of DR.
ABSTRACT
Fulminant type 1 diabetes is characterized by remarkably rapid and complete ß-cell destruction. The established diagnostic criteria include the occurrence of diabetic ketosis soon after the onset of hyperglycemic symptoms, elevated plasma glucose with relatively low HbA1c at the first visit, and extremely low C-peptide. Serum C-peptide levels remain extremely low over a prolonged period. A 26-year-old-man with diabetic ketosis was admitted to our hospital. His relatively low HbA1c (7.6%), despite marked hyperglycemia (593 mg/dL) with marked ketosis, indicated abrupt onset. Islet-related autoantibodies were all negative. His data at onset, including extremely low serum C-peptide (0.11 ng/mL), fulfilled the diagnostic criteria for fulminant type 1 diabetes. However, his fasting serum C-peptide levels subsequently showed substantial recovery. While fasting C-peptide stayed below 0.30 ng/mL during the first two months post onset, the levels gradually increased and thereafter fluctuated between 0.60 ng/mL and 0.90 ng/mL until 24 months post onset. By means of multiple daily insulin injection therapy, his glycemic control has been well maintained (HbA1c approximately 6.0%), with relatively small glycemic fluctuations evaluated by continuous glucose monitoring. This clinical course suggests that, despite the abrupt diabetes onset with extremely low C-peptide levels, substantial numbers of ß-cells had been spared destruction and their function later showed gradual recovery. Diabetes has come to be considered a much more heterogeneous disease than the present subdivisions suggest. This case does not fit into the existing concepts of either fulminant type 1 or ketosis-prone diabetes, thereby further highlighting the heterogeneity of idiopathic type 1 diabetes.
Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Diabetic Ketoacidosis/therapy , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Adult , Blood Glucose/analysis , C-Peptide/blood , Combined Modality Therapy , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Diabetic Ketoacidosis/prevention & control , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/therapeutic use , Insulin/blood , Insulin/therapeutic use , Insulin Secretion , Insulin-Secreting Cells/drug effects , Japan , Male , Severity of Illness Index , Treatment OutcomeABSTRACT
AIMS: To determine whether skin autofluorescence (SAF) and serum pentosidine, biomarkers of advanced glycation end products (AGEs), were associated with ocular microcirculation in type 2 diabetes patients with early diabetic retinopathy (DR). METHODS: This study included 46 eyes of 46 type 2 diabetes patients with no DR or non-proliferative DR. SAF was measured with an autofluorescence reader. Optic nerve head (ONH) microcirculation, represented by mean blur rate (MBR), was measured with laser speckle flowgraphy. Overall MBR, vascular MBR, and tissue MBR were calculated in software. MBR, SAF, pentosidine levels, and clinical findings, including central macular thickness (CMT), were then compared. RESULTS: SAF in the diabetes patients was correlated with age (P=0.018). Serum pentosidine was correlated with age, vascular MBR and tissue MBR (P=0.046, P=0.035, and P=0.01, respectively). CMT was correlated with tissue MBR (P=0.016), but not with vascular MBR or overall MBR. Separate multiple regression analyses of independent contributing factors revealed that age, SAF, serum pentosidine, duration of diabetes, and pulse rate contributed to tissue MBR (P=0.041, P=0.046, P=0.022, P=0.011 and P=0.036, respectively), while SAF, HbA1c, pulse rate, tissue MBR, diastolic blood pressure, and creatinine contributed to CMT (P=0.005, P=0.039, P<0.001, P<0.001, P=0.022 and P=0.001, respectively). CONCLUSIONS: Tissue MBR may be closely related to AGE levels and CMT in type 2 diabetes patients with early DR, suggesting that ocular circulation might be potential early biomarkers of DR.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Retinopathy/physiopathology , Glycation End Products, Advanced/blood , Microcirculation , Optic Disk/blood supply , Adult , Arginine/analogs & derivatives , Arginine/blood , Cross-Sectional Studies , Female , Humans , Laser-Doppler Flowmetry , Lysine/analogs & derivatives , Lysine/blood , Male , Middle Aged , Optical Imaging , SkinABSTRACT
Stress-mediated apoptosis may play a crucial role in loss of pancreatic beta-cell mass, contributing to the development of diabetes. We have recently identified that translational control involving the translational suppressor eIF4E binding protein-1 (4E-BP1) which is important for beta-cell survival under endoplasmic reticulum (ER) stress. The Eif4ebp1 gene, encoding 4E-BP1, is a direct target of a transcription factor activating transcription factor-4 (ATF4), a master regulator of gene expression in stress responses. In the current study, we investigated 4E-BP1 expression in mouse insulinoma line 6 (MIN6) cells treated with arsenite, an inducer of oxidative stress which is another contributor of beta-cell loss. We found that arsenite-induced 4E-BP1 expression level was lower than that induced by thapsigargin, an ER stress inducer, although ATF4 was similarly induced by these agents. The ratio of the dephosphorylated form of 4E-BP1, which has the highest activity, to phosphorylated forms was, however, greater in MIN6 cells treated with arsenite as compared to that in thapsigargin-treated cells. Arsenite-induced 4E-BP1 mRNA and protein expressions were augmented by simultaneous treatment with a c-Jun N-terminal kinase (JNK) specific inhibitor, SP600125. The agent also suppressed the level of the dephosphrylated form of 4E-BP1 in arsenite-treated MIN6 cells. Thus, JNK activated by oxidative stress is involved in the modulation of 4E-BP1 expression and phosphorylation in MIN6 cells, which may contribute to fine tuning of translational control under stress conditions.
Subject(s)
Carrier Proteins/metabolism , Insulin-Secreting Cells/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Oxidative Stress , Phosphoproteins/metabolism , Activating Transcription Factor 4/metabolism , Adaptor Proteins, Signal Transducing , Animals , Anthracenes/pharmacology , Arsenites/toxicity , Carrier Proteins/genetics , Cell Cycle Proteins , Cell Line, Tumor , Eukaryotic Initiation Factors , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mice , Phosphoproteins/genetics , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Thapsigargin/pharmacologyABSTRACT
Endoplasmic reticulum (ER) stress-mediated apoptosis may play a crucial role in loss of pancreatic beta cell mass, contributing to the development of diabetes. Here we show that induction of 4E-BP1, the suppressor of the mRNA 5' cap-binding protein eukaryotic initiation factor 4E (eIF4E), is involved in beta cell survival under ER stress. 4E-BP1 expression was increased in islets under ER stress in several mouse models of diabetes. The Eif4ebp1 gene encoding 4E-BP1 was revealed to be a direct target of the transcription factor ATF4. Deletion of the Eif4ebp1 gene increased susceptibility to ER stress-mediated apoptosis in MIN6 beta cells and mouse islets, which was accompanied by deregulated translational control. Furthermore, Eif4ebp1 deletion accelerated beta cell loss and exacerbated hyperglycemia in mouse models of diabetes. Thus, 4E-BP1 induction contributes to the maintenance of beta cell homeostasis during ER stress and is a potential therapeutic target for diabetes.
Subject(s)
Activating Transcription Factor 4/metabolism , Apoptosis , Carrier Proteins/metabolism , Diabetes Mellitus/metabolism , Endoplasmic Reticulum/metabolism , Insulin-Secreting Cells/metabolism , Phosphoproteins/metabolism , Stress, Physiological/metabolism , Transcriptional Activation , Activating Transcription Factor 4/genetics , Adaptor Proteins, Signal Transducing , Animals , Carrier Proteins/genetics , Cell Cycle Proteins , Cell Line, Tumor , Cell Survival , Diabetes Mellitus/genetics , Diabetes Mellitus/pathology , Disease Models, Animal , Endoplasmic Reticulum/pathology , Eukaryotic Initiation Factors , Glucose Intolerance/genetics , Glucose Intolerance/metabolism , Glucose Intolerance/pathology , Homeostasis , Insulin Resistance/genetics , Insulin-Secreting Cells/pathology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , Phosphoproteins/genetics , Protein Folding , Stress, Physiological/pathology , Time Factors , Transduction, Genetic , Up-Regulation , Wolfram Syndrome/genetics , Wolfram Syndrome/metabolism , Wolfram Syndrome/pathologyABSTRACT
Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. Herein, we report that pancreatic islets of wfs1-deficient mice exhibit increases in phosphorylation of RNA-dependent protein kinase-like ER kinase, chaperone gene expressions and active XBP1 protein levels, indicating an enhanced ER stress response. We established wfs1-deficient MIN6 clonal beta-cells by crossing wfs1-deficient mice with mice expressing simian virus 40 large T antigen in beta-cells. These cells show essentially the same alterations in ER stress responses as wfs1-deficient islets, which were reversed by re-expression of WFS1 protein or overexpression of GRP78, a master regulator of the ER stress response. In contrast, these changes are not observed in heart, skeletal muscle or brown adipose tissues with WFS1-deficiency. The increased ER stress response was accompanied by reduced BrdU incorporation and increased caspase-3 cleavage, indicating impaired cell cycle progression and accelerated apoptotic processes in the mutant islets. These changes are associated with increased expression of the cell cycle regulator p21(CIP1) in wfs1-deficient islets and clonal beta-cells. Treatment of islets with thapsigargin, an ER stress inducer, caused upregulation of p21(CIP1). In addition, forced expression of p21(CIP1) resulted in reduced MIN6 beta-cell numbers, suggesting the ER stress-induced increase in p21(CIP1) expression to be involved in beta-cell loss in the mutant islets. These data indicate that WFS1-deficiency activates the ER stress response specifically in beta-cells, causing beta-cell loss through impaired cell cycle progression and increased apoptosis.