Insulin Signaling in Arthritis.

Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.

Analysis of the clinical characteristics of insulin autoimmune syndrome induced by alpha-lipoic acid.

WHAT IS KNOWN AND OBJECTIVE: Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. METHODS: We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. RESULTS AND DISCUSSION: The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 µIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36). WHAT IS NEW AND CONCLUSION: ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

Insulin Autoimmune Syndrome Diagnosis and Therapy in a Single Chinese Center.

PURPOSE: Insulin autoimmune syndrome (IAS) is a relatively rare cause of hypoglycemia characterized by endogenous hyperinsulinism and autoantibodies against endogenous insulin despite no prior exposure to exogenous insulin. We present a series of IAS cases and describe the clinical characteristics of these cases. METHODS: The medical records of inpatients with the final diagnosis of IAS were collected from August 2007 to August 2017 in Peking Union Medical College Hospital. Clinical characteristics and laboratory test results were summarized. The results of serum glucose, insulin, true insulin, and C-peptide testing during 5-h oral glucose tolerance tests were also summarized. Circulating immune complexes were assessed qualitatively by precipitation with polyethylene glycol (PEG) in some patients. FINDINGS: Sixteen patients were included in this study. Insulin autoimmune antibody test results were found positive in 12 patients and weakly positive in 1 patient. Nine patients had an insulin to C-peptide molar ratio >1, whereas 6 patients had an insulin to C-peptide molar ratio <1. Circulating immune complexes were verified in all 4 patients who had been assessed with PEG. During 5-h oral glucose tolerance tests, the C-peptide level responded earlier to the glucose tolerance and had a shorter peak value period compared with insulin, although C-peptide's fluctuation still lagged behind the glucose fluctuation. Three patients presented with self-limited disease courses or limited disease course after discontinuing use of the sulfhydryl group drugs. Some patients' symptoms were relieved after small frequent meals, and some were relieved after taking acarbose. Only 3 patients took glucocorticoids as the anti-immune therapy. IMPLICATIONS: The insulin to C-peptide molar ratios were not consistently >1 in patients with confirmed diagnoses of IAS in our study, which suggested the low sensitivity of insulin to C-peptide molar ratio to detect IAS. The therapy in our study also revealed the self-limited disease course of IAS, and despite the effectiveness of anti-immunity therapy, convenient therapy, such as frequent small meals and adding acarbose, performed well in many patients.

Potential cause-effect relationship between insulin autoimmune syndrome and alpha lipoic acid: Two case reports.

OBJECTIVES: Insulin autoimmune syndrome (IAS) or Hirata disease is a rare cause of autoimmune hypoglycemia with apparent high insulin levels and anti-insulin autoantibodies and was first described by Hirata in Japan in 1970. IAS cases are usually related to exposure to sulfhydryl-containing drugs, which stimulate the production of insulin autoantibodies. Among sulfhydryl-containing compounds, alpha lipoic acid (ALA) has recently emerged as a cause of IAS. After the first observations of ALA-induced IAS were reported in Japan in 2006, an increasing number of cases related to ALA administration have been described. An Italian group recently reported on six cases of IAS of which one was associated with HLA-DRB1*04:06 and the remaining five with HLA-DRB1*04:03. This suggests that the latter is potentially involved in the genetic susceptibility of people of European descent to IAS. METHODS: Here, we describe two new cases of IAS in women that were triggered by ALA. RESULTS: Both cases are associated with HLA-DRB1*04:03 and confirm the evidence that HLA-DRB1*04:03 rather than HLA-DRB1*04:06 is specifically related to IAS susceptibility in Europeans. CONCLUSIONS: Case reports of ALA-induced hypoglycemic episodes highlight the need for greater care in prescribing ALA supplementation as well as the identification of specific and personalized therapeutic targets.

High-Fat Diets Containing Different Amounts of n3 and n6 Polyunsaturated Fatty Acids Modulate Inflammatory Cytokine Production in Mice.

Dysregulation of adipokines is a hallmark of obesity. Polyunsaturated fatty acids in fish oil may exert anti-inflammatory effects on adipose tissue mitigating the dysregulation of adipokines thereby preventing obesity. This study investigated the effects of high-fat diets containing different amounts of n3 polyunsaturated fatty acids (PUFA) on adiposity and adipokine production in mice. Mice were fed a low-fat or a high-fat diet with 16 or 45 % of energy from corn oil (low n3 PUFA) in comparison with a high-fat diet containing soybean or high-oleic sunflower oil (adequate n3 PUFA) or flaxseed or fish oil (high n3 PUFA) for 11 weeks. High-fat diets, regardless of types of oils, significantly increased body fat mass and body weights compared to the low-fat diet. Adipose fatty acid composition and contents reflected dietary fatty acid profiles. The high-fat fish oil diet significantly increased adiponectin and reduced leptin concentrations in both plasma and adipose tissue; it did not elevate plasma insulin concentration compared to the high-fat corn oil diet. All high-fat diets elevated concentrations of plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1) but lowered resistin concentrations in both plasma and adipose tissue. In conclusion, fish oil may be beneficial in improving insulin sensitivity by upregulation of adiponectin and downregulation of leptin production; n3 and n6 PUFA do not play a role at the dietary levels tested in reducing adiposity and production of pro-inflammatory cytokines (leptin, PAI-1, MCP-1 and resistin) and anti-inflammatory cytokine adiponectin.

Medical Nutrition Therapy Is Effective in the Management of Hypoglycemia Caused by Insulin Antibodies: A Case Report and Literature Review.

Autoimmune antibodies, induced by exogenous insulin preparations, may result in labile glucose control and frequent hypoglycemia in some rare cases. In addition to insulin cessation, immune suppressants and/or plasmapheresis have been used as the primary remedies for these patients. Some previous studies also indicate that the condition tends to remit spontaneously after discontinuation of insulin exposure. Because of this, the clinical importance of nutritional interventions and behavioral approaches, which may play a role in ameliorating the symptoms, should also be emphasized. Herein, we report on a 64-year-old man with hypoglycemia induced by insulin antibodies (IAs), whose hypoglycemic symptoms significantly improved after the implementation of nutrition therapy. This rare case expands our knowledge of the management of hypoglycemia, and for the first time highlights the significance of nutritional and lifestyle intervention in treatment of IA-induced hypoglycemia.

Genistein protects female nonobese diabetic mice from developing type 1 diabetes when fed a soy- and alfalfa-free diet.

The objective of this study was to determine the effects of the phytoestrogen genistein (GEN) on the time of onset and/or the incidence of type 1 diabetes (T1D) in female nonobese diabetic (NOD) mice, when administered GEN by gavage once every day for up to 180 days. Five groups of mice (approximately 24 animals/group; 6-7 weeks of age) were included: naive control, vehicle control (25 mM Na2CO3 in water), and 3 GEN treatment groups (2 mg/kg, 6 mg/kg, and 20 mg/kg). Mice were maintained on a soy- and alfalfa-free diet (5K96) during the study and were monitored for blood glucose changes every week. When compared to the vehicle control, exposure to 2-mg/kg GEN produced significant decreases ranging from 55 to 79% in the total incidences of diabetes (blood glucose ≥ 250 mg/dl) and severe diabetes (blood glucose ≥ 400 mg/dl) starting at week 14 of the study. However, during the later stages of the study (i.e., after week 23), the 2-mg/kg dose had no effect on disease incidence. In animals treated with 6-mg/kg and 20-mg/kg GEN, significant decreases in the total incidence of diabetes were observed starting at week 16, while the incidence of severe diabetes was significantly decreased with the changes being observed initially at weeks 18 and 17 for the 6-mg/kg and 20-mg/kg GEN treatment groups, respectively. Several lines of evidence, including histopathological analysis, suggested that GEN protected the pancreas from autoimmune destruction. However, this protective effect of GEN was absent when female NOD mice were maintained on NTP-2000 rodent diet, which contained 5% soybean meal and 7.5% alfalfa meal (the total concentrations of phytoestrogens ranged between 95 and 134 mg/kg). In summary, oral dosing of GEN reduced the incidence and increased the time to onset of T1D in female NOD mice but only when fed a soy- and alfalfa-free diet.

IGRP and insulin vaccination induce CD8+ T cell-mediated autoimmune diabetes in the RIP-CD80GP mouse.

Autoimmune diabetes is characterized by autoantigen-specific T cell-mediated destruction of pancreatic islet beta cells, and CD8(+) T cells are key players during this process. We assessed whether the bitransgenic RIP-CD80 x RIP-LCMV-GP (RIP-CD80GP) mice may be a versatile antigen-specific model of inducible CD8(+) T cell-mediated autoimmune diabetes. Antigen-encoding DNA, peptide-loaded dendritic cells and antigen plus incomplete Freund's adjuvant were used for vaccination. Of 14 pancreatic proteins tested by DNA vaccination, murine pre-proinsulin 2 (100% of mice; median time after vaccination, 60 days) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (77%, 58 days) could induce diabetes. Vaccination with DNA encoding for zinc transporter 8, Ia-2, Ia-2ß, glutamic acid decarboxylase 67 (Gad67), chromogranin A, insulinoma amyloid polypeptide and homeobox protein Nkx-2.2 induced diabetes development in 25-33% of mice. Vaccination with DNA encoding for Gad65, secretogranin 5, pancreas/duodenum homeobox protein 1 (Pdx1), carboxyl ester lipase, glucagon and control hepatitis B surface antigen (HBsAg) induced diabetes in <20% of mice. Diabetes induction efficiency could be increased by DNA vaccination with a vector encoding a ubiquitin-antigen fusion construct. Diabetic mice had florid T cell islet infiltration. CD8(+) T cell targets of IGRP were identified with a peptide library-based enzyme-linked immunospot assay, and diabetes could also be induced by vaccination with major histocompatibility complex (MHC) class I-restricted IGRP peptides loaded on mature dendritic cells. Vaccination with antigen plus incomplete Freund's adjuvant, which can prevent diabetes in other models, led to rapid diabetes development in the RIP-CD80GP mouse. We conclude that RIP-CD80GP mice are a versatile model of antigen specific autoimmune diabetes and may complement existing mouse models of autoimmune diabetes for evaluating CD8(+) T cell-targeted prevention strategies.

The clinical and immunological significance of GAD-specific autoantibody and T-cell responses in type 1 diabetes.

Antigen-specific interventions are desirable approaches in Type 1 Diabetes (T1D) as they can alter islet-specific autoimmunity without systemic side effects. Glutamic acid decarboxylase of 65 kDa (GAD65) is a major autoantigen in type 1 diabetes (T1D) and GAD-specific autoimmunity is a common feature of T1D in humans but also in mouse models of the disease. In humans, administration of the GAD65 protein in an alum formulation has been shown to reduce C-peptide decline in recently diagnosed patients, however, these observations were not confirmed in subsequent phase II/III clinical trials. As GAD-based immune interventions in different formulations have successfully been employed to prevent the establishment of T1D in mouse models of T1D, we sought to analyze the efficacy of GAD-alum treatment and the effects on the GAD-specific immune response in two different mouse models of T1D. Consistent with the latest clinical trials, mice treated with GAD-alum were not protected from diabetes, although GAD-alum induced a GAD-specific Th2-deviated immune response in transgenic rat insulin promoter-glycoprotein (RIP-GP) mice. These observations underline the importance of a thorough, preclinical evaluation of potential drugs before the initiation of clinical trials.

Insulin autoimmune syndrome in a health supplement user: the effectiveness of cornstarch therapy for treating hypoglycemia.

A 70-year-old woman with no history of diabetes was admitted to the hospital for the management of hypoglycemia. Her fasting plasma glucose level was 54 mg/dL with an extremely high serum immunoreactive insulin level (1210 µU/mL). She had high titers of anti-insulin antibodies and exhibited the DRB1*0406 genotype for HLA-DR4, leading to a diagnosis of insulin autoimmune syndrome. She had been taking several health preparations for approximately 10 years; however, all were thiol group-free. Due to frequent episodes of nocturnal hypoglycemia, the health preparations were discontinued and the patient was treated with cornstarch. This protocol successfully ameliorated the hypoglycemic episodes and normalized the patient's laboratory and serological test results.

Insulin-like antigen of mangrove leaves and its anti-diabetic activity in alloxan-induced diabetic rats.

The objective of this study was to evaluate the anti-diabetic potential of three mangrove plants, Rhizophora mucronata, Rhizophora apiculata and Rhizophora annamalayana, and to detect the presence of their insulin-like protein. The in vivo anti-diabetic experiment was done on male albino Wister rats. Oral administration of 60 mg kg(-1) leaf powder extract of the three different mangrove plants for 30 days modulated the parameters such as blood glucose, plasma insulin, body weight, total haemoglobin, glycosylated haemoglobin, liver glycogen, plasma and tissue lipids, cholesterol, triglycerides, free fatty acids and phospholipids to normal levels in the alloxan-induced diabetic rats. The anti-diabetic activity of R. apiculata was more pronounced than that of the other mangrove extracts, but it was on a par with the commercial drug glibenclamide. The presence of an insulin-like protein in the mangrove extracts was detected by SDS-PAGE analysis and confirmed through ELISA. Hence, the anti-diabetic activity and the presence of an insulin-like protein in Rhizophora species were proved scientifically.

Cinnamon extract attenuates TNF-alpha-induced intestinal lipoprotein ApoB48 overproduction by regulating inflammatory, insulin, and lipoprotein pathways in enterocytes.

We have previously reported that the obesity-associated proinflammatory cytokine, TNF-alpha, stimulates the overproduction of intestinal apolipoprotein (apo) B48 containing lipoproteins. In the current study, we have evaluated whether a water-soluble cinnamon extract [CE (Cinnulin PF)] attenuates the dyslipidemia induced by TNF-alpha in Triton WR-1339 treated hamsters, and whether CE inhibits the oversecrection of apoB48-induced by TNF-alpha in enterocytes in a 35S labeling study. In vivo, oral treatment of Cinnulin PF (50 mg per kg BW), inhibited the postprandial overproduction of apoB48-containing lipoproteins and serum triglyceride levels. In ex vivo 35S labeling studies, CE (10 and 20 microg/ml) inhibited the oversecretion of apoB48 induced by TNF-alpha treated enterocytes into the media. To determine the molecular mechanisms, TNF-alpha treated primary enterocytes isolated from chow-fed hamsters, were incubated with CE (10 microg/ml), and the expression of the inflammatory factor genes, IL1-beta, IL-6, and TNF-alpha, insulin signaling pathway genes, insulin receptor (IR), IRS1, IRS2, phosphatidylinositol 3-kinase (PI3-K), Akt1 and phosphatase and tensin homology (PTEN), as well as the key regulators of lipid metabolism, cluster of differentiation (CD)36, microsomal triglyceride transfer protein (MTTP), and sterol regulatory element binding protein (SREBP)-1c were evaluated. Quantitative real-time PCR assays showed that CE treatment decreased the mRNA expression of IL-1beta, IL-6 and TNF-alpha, improved the mRNA expression of IR, IRS1, IRS2, PI3K and Akt1, inhibited CD36, MTTP, and PTEN, and enhanced the impaired SREBP-1c expression in TNF-alpha treated enterocytes. These data suggest that a water extract of cinnamon reverses TNF-alpha-induced overproduction of intestinal apoB48 by regulating gene expression involving inflammatory, insulin, and lipoprotein signaling pathways. In conclusion, Cinulin PF improves inflammation related intestinal dyslipidemia.

Camel milk as an adjuvant therapy for the treatment of type 1 diabetes: verification of a traditional ethnomedical practice.

There is a traditional belief in the Middle East that regular consumption of camel milk may aid in prevention and control of diabetes. The aim of this work was to evaluate the efficacy of camel milk as an adjuvant therapy in young type 1 diabetics. This 16-week randomized study enrolled 54 type 1 diabetic patients (average age 20 years) selected from those attending the outpatient diabetes clinic of the Menofia University Hospital, affiliated with Egypt's National Cancer Institute. Subjects were randomly divided into two groups of 27 patients: one received usual management (diet, exercise, and insulin), whereas the other received 500 mL of camel milk daily in addition to standard management. A control group of 10 healthy subjects was also assessed. The following parameters were evaluated at baseline and at 4 and 16 weeks: hemoglobin A1c (HbA1c), human C-peptide, lipid profile, serum insulin, anti-insulin antibodies, creatinine clearance, albumin in 24-hour urine, body mass index, and Diabetes Quality of Life score. The following parameters were significantly different between the usual-management group versus the camel milk group after 16 weeks: fasting blood sugar (227.2 +/- 17.7 vs. 98.9 +/- 16.2 mg/dL), HbA1c (9.59 +/- 2.05[%] vs. 7.16 +/- 1.84[%]), serum anti-insulin antibodies (26.20 +/- 7.69 vs. 20.92 +/- 5.45 microU/mL), urinary albumin excretion (25.17 +/- 5.43 vs. 14.54 +/- 5.62 mg/dL/24 hours), daily insulin dose (48.1 +/- 6.95 vs. 23 +/- 4.05 units), and body mass index (18.43 +/- 3.59 vs. 24.3 +/- 2.95 kg/m(2)). Most notably, C-peptide levels were markedly higher in the camel milk group (0.28 +/- 0.6 vs. 2.30 +/- 0.51 pmol/mL). These results suggest that, as an adjunct to standard management, daily ingestion of camel milk can aid metabolic control in young type 1 diabetics, at least in part by boosting endogenous insulin secretion.

Drug-induced insulin autoimmune syndrome.

Although insulin autoimmune syndrome (IAS) was found to be strongly related with methimazole, rapidly increasing numbers of cases with alpha lipoic acid-induced IAS have been confirmed to be reported since 2003. As alpha lipoic acid has gained popularity as a supplement for dieting and anti-aging, a warning should be issued.

Immunologic responses to therapeutic biologic agents.

Recombinant protein technology and the subsequent development of biologic agents for pharmacotherapy have greatly improved the treatment of a wide variety of diseases in humans. These products are subject to reactions not previously seen in other drug classes. Additionally, subtle alteration in the manufacture or administration of a biologic agent may cause reactions in subjects who previously tolerated it. This review highlights the unique immunologic reactions that are associated with the more commonly used biologic agents.

Is it dietary insulin?

In humans the primary trigger of insulin-specific immunity is a modified self-antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self-insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk-derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type 1 diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin-specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect beta cells, may release autoantigens and potentiate their presentation by an infection-associated "danger signal." This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin-reactive T cells to the pancreatic islets.

Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin.

Enteral virus infections may trigger the development of beta-cell-specific autoimmunity by interacting with the gut-associated lymphoid system. We analyzed the effect of three different virus infections on immunization to dietary insulin in children carrying increased genetic risk for type 1 diabetes. Forty-six of 238 children developed multiple diabetes-associated autoantibodies and 31 clinical diabetes (median follow-up time 75 months). Insulin-binding antibodies were measured with EIA method (median follow-up time 24 months). Antibodies to enteroviruses, rotavirus and adenovirus were measured with EIA in samples drawn at birth and the ages of 3 and 6 months. Nineteen enterovirus, 14 rotavirus and 8 adenovirus infections were diagnosed. At the ages of 6, 12, and 18 months, the concentrations of insulin-binding antibodies were higher in children with postnatal entero-, rota- and/or adenovirus infections than in children without these infections. Children who subsequently developed ICA or IA-2 antibodies or clinical type 1 diabetes had higher concentrations of insulin-binding antibodies than children who remained autoantibody negative. Our data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin in cow's milk. An enhanced antibody response to dietary insulin preceded the development of beta-cell specific autoimmunity and type 1 diabetes.

Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?

The neurodegeneration that occurs in sporadic Alzheimer's disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-beta deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3beta activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect this newly identified pathogenic mechanism of neurodegeneration.