Diabetes Mellitus and the Skin: Recognition and Management of Cutaneous Manifestations.

Diabetes mellitus (DM) is a heterogeneous condition characterized by hyperglycemia as a consequence of defects in insulin secretion and variable degrees of insulin resistance. DM is the most common endocrine disorder in the United States, affecting 9.3% of the population (29.1 million people) in 2014. Skin disorders are present in 79.2% of patients with DM, and cutaneous disease may appear as the first sign of DM or develop at any time in the course of the disease. Given the increasing incidence and prevalence of DM in the United States, primary care physicians should be aware of the associated cutaneous manifestations. This clinical review provides a brief guide to primary care physicians for recognizing and managing skin conditions that they may encounter when caring for patients with DM.

A role for 1-acylglycerol-3-phosphate-O-acyltransferase-1 in myoblast differentiation.

AGPAT isoforms catalyze the acylation of lysophosphatidic acid (LPA) to form phosphatidic acid (PA). AGPAT2 mutations are associated with defective adipogenesis. Muscle and adipose tissue share common precursor cells. We investigated the role of AGPAT isoforms in skeletal muscle development. We demonstrate that small interference RNA-mediated knockdown of AGPAT1 expression prevents the induction of myogenin, a key transcriptional activator of the myogenic program, and inhibits the expression of myosin heavy chain. This effect is rescued by transfection with AGPAT1 but not AGPAT2. Knockdown of AGPAT2 has no effect. The regulation of myogenesis by AGPAT1 is associated with alterations on actin cytoskeleton. The role of AGPAT1 on actin cytoskeleton is further supported by colocalization of AGPAT1 to areas of active actin polymerization. AGPAT1 overexpression was not associated with an increase in PA levels. Our observations strongly implicate AGPAT1 in the development of skeletal muscle, specifically to terminal differentiation. These findings are linked to the regulation of actin cytoskeleton.

The role of sodium glucose co-transporter inhibitors in heart failure prevention.

The worldwide prevalences of diabetes mellitus (DM) and of heart failure (HF) have collectively been on the rise. HF accounts for a large portion of the cardiovascular mortality and morbidity associated with DM. DM increases the risk of developing heart failure by promoting atherosclerosis and exerting direct deleterious effects on the myocardium. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are agents approved for the treatment of DM; they exert their anti-hyperglycemic effects by blocking renal reabsorption of glucose and inducing glycosuria. SGLT-2 inhibitors have consistently decreased the hospitalization rate of HF and cardiovascular mortality in several clinical trials. SGLT-2 inhibitors also possess anti-inflammatory, anti-fibrotic, and antihypertensive in addition to beneficial effects on the myocardial metabolism, which may account for their heart failure benefits. However, further research still needs to be done to evaluate the use of SGLT-2 inhibitors in non-diabetic patients and their efficacy in preventing or treating different heart failure phenotypes.

Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings.

BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.

Osteitis fibrosa cystica masquerading as bone neoplasm.

A 50-year-old female patient with no significant medical history presented with left knee pain. Radiographs of the knee showed a circumferential swelling of the distal femur suggestive of neoplasia. Further evaluation revealed multiple lesions in the left iliac bone and proximal femur. Biopsy was suggestive of a reparative granuloma or an aneurysmal bone cyst. Laboratory assessment showed hypercalcaemia and elevated parathyroid hormone consistent with severe primary hyperparathyroidism. Osseous survey was significant for salt and pepper appearance of the skull. Ultrasound of the neck and 99mTc-sestamibi parathyroid scintigraphy localised a left parathyroid adenoma/carcinoma. Parathyroidectomy was successful, and a large parathyroid adenoma was excised. Six months later, the patient was doing fine with her gait returning to normal. On follow-up 2 years later, she had no recurrence of the lesions.

Hungry bone syndrome secondary to prostate cancer successfully treated with radium therapy.

A 50-year-old man with a history of prostate cancer with extensive bone metastasis and hypocalcaemia presented with muscle aches and cramps. Physical exam was significant for Chvostek's and Trousseau's sign. Laboratory assessment was consistent with profound hypocalcaemia. This was believed to be due to hungry bone syndrome secondary to advanced prostate cancer. He was treated with intravenous calcium, vitamin D and calcitriol. He also received three doses of radium223 therapy. After therapy, hypocalcaemic episodes resolved. Follow-up after 2.5 years showed continued resolution of hypocalcaemia.

Metabolic Parameters, Weight Loss, and Comorbidities 4 Years After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy.

BACKGROUND: Sleeve gastrectomy (LSG) is now the predominant bariatric surgery performed, yet there is limited long-term data comparing important outcomes between LSG and Roux-en-Y gastric bypass (RYGB). This study compares weight loss and impact on comorbidities of the two procedures. METHODS: We retrospectively evaluated weight, blood pressure, hemoglobin A1c, cholesterol, and medication use for hypertension, diabetes, and hyperlipidemia at 1-4 years post-operatively in 380 patients who underwent RYGB and 334 patients who underwent LSG at the University of Michigan from January 2008 to November 2013. Follow-up rates from 714 patients initially were 657 (92%), 556 (78%), 507 (71%), and 498 (70%) at 1-4 years post-operatively. RESULTS: Baseline characteristics were similar except for higher weight and BMI in LSG. There was greater weight loss with RYGB vs. LSG at all points. Hemoglobin A1c and total cholesterol improved more in RYGB vs. LSG at 4 years. There was greater remission of hypertension and discontinuation of all medications for hypertension and diabetes with RYGB at 4 years. CONCLUSIONS: Weight loss, reduction in medications for hypertension and diabetes, improvements in markers of diabetes and hyperlipidemia, and remission rates of hypertension were superior with RYGB vs. LSG 4 years post-operatively. Choice of bariatric procedures should be tailored to surgical risk, comorbidities, and weight loss goals.

Glucose sensor-augmented continuous subcutaneous insulin infusion in patients with diabetic gastroparesis: An open-label pilot prospective study.

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85-1.64, P = 0.33). CGM time in hypoglycemia (<70 mg/dL) decreased from 3.9% to 1.8% (P<0.0001), time in euglycemia (70-180 mg/dL) increased from 44.0% to 52.0% (P = 0.02), time in severe hyperglycemia (>300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P<0.0001) and volumes of liquid nutrient meals tolerated increased from 420±258 to 487±312 mL (P = 0.05) at 24 weeks. In conclusion, CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis.

Fatty Liver Disease, Women, and Aldosterone: Finding a Link in the Jackson Heart Study.

CONTEXT: Fatty liver disease is one of the most common forms of chronic liver disease. The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of fatty liver. OBJECTIVE: Determine the relationship between fatty liver and aldosterone in a large cohort study. DESIGN: Community-based, observational cohort study of African Americans. SETTING: The original Jackson Heart Study cohort enrolled African American participants from the Jackson, Mississippi, metropolitan area in Hinds, Madison, and Rankin Counties. PARTICIPANTS: Our study population consisted of 2507 Jackson Heart Study participants (1625 women and 882 men) who had liver attenuation measured per computed tomography scans, had aldosterone measurements, and were not taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or mineralocorticoid receptor antagonists. INTERVENTION: There was no intervention. MAIN OUTCOME MEASURE: Liver attenuation on computed tomography scans. RESULTS: Univariate regression analysis demonstrated a statistically significant correlation between aldosterone levels and liver attenuation. Each doubling of aldosterone was associated with 1.08 Hounsfield unit decrease (95% confidence interval, 1.47 to -0.69, P < 0.001). A multivariable model adjusted for body mass index, age, alcohol intake, and homeostatic model assessment of insulin resistance determined that the association was statistically significant only for women. CONCLUSION: Our data demonstrate a positive association between aldosterone levels and fatty liver in African American women.

Roux-En-Y Gastric Bypass Vs. Sleeve Gastrectomy: Balancing the Risks of Surgery with the Benefits of Weight Loss.

BACKGROUND: The purpose of the study was to compare weight loss, metabolic parameters, and postoperative complications in patients undergoing Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG). METHODS: We retrospectively studied 30-day postoperative complications as well as change in weight, blood pressure, cholesterol, hemoglobin, hemoglobin A1C, and creatinine from baseline to 2, 6, 12, and 24 months postoperatively in 383 patients undergoing GB and 336 patients undergoing SG at the University of Michigan from January 2008 to November 2013. For a study population which typically has high attrition rates, there were excellent follow-up rates (706/719 at 2 months, 566/719 at 6 months, 519/719 at 12 months, and 382/719 at 24 months). RESULTS: Baseline characteristics were similar in both groups except for higher weight and BMI in the SG group. The GB group experienced greater total body weight loss at 6, 12, and 24 months (41.9 vs. 34.6 kg at 24 months, p < 0.0001). Excess weight loss was 69.7 and 51.7 % following GB and SG respectively at 24 months (p < 0.0001). BP improved significantly in both groups. Surgical complication rates were greater after GB (10.1 vs. 3.5 %, p = 0.0007) with no significant difference in life-threatening or potentially life-threatening complications. CONCLUSIONS: Weight loss was greater following GB compared to SG at 2 years. The risk for surgical complications was greater following GB. Surgical intervention should be tailored to surgical risk, comorbidities, and desired weight loss.

Milestone Weight Loss Goals (Weight Normalization and Remission of Obesity) after Gastric Bypass Surgery: Long-Term Results from the University of Michigan.

BACKGROUND: Rates of weight normalization and obesity remission after Roux-en-Y gastric bypass (GB) are unknown. This study evaluated weight loss, rates of achieving body mass index (BMI) <25 or 30 kg/m2, recidivism, and predictors of success following GB. METHODS: We retrospectively studied weight and BMI at baseline, 2 and 6 months, and annually at 1-7 years in 219 patients undergoing GB at the University of Michigan from January 2008 to November 2010. RESULTS: Follow-up was excellent for a population traditionally associated with high attrition rates with data availability of 157/219, 145/219, 144/219, 134/219, 123/219, 82/161, and 29/64 patients at 1-7 years, respectively. Mean baseline BMI was 47.0 kg/m2. Weight normalization (BMI <25 kg/m2) occurred in 2.3-6.8% of patients. More importantly, 47% of patients achieved remission of obesity (BMI <30 kg/m2) at some time point and 24% (52/219) at the last observed time point. BMI <30 kg/m2 was associated with a lower initial BMI and follow-up for more than 2 years. CONCLUSIONS: Rates of weight normalization are low after GB; however, a large number of patients achieved BMI <30 kg/m2. While the percent total weight loss and excess weight loss are both quite high in the entire cohort and this is likely associated with significant health benefits, our results still underscore the need to address obesity with intensive clinical attention earlier in its course.

Prediction of Incident Diabetes in the Jackson Heart Study Using High-Dimensional Machine Learning.

Statistical models to predict incident diabetes are often based on limited variables. Here we pursued two main goals: 1) investigate the relative performance of a machine learning method such as Random Forests (RF) for detecting incident diabetes in a high-dimensional setting defined by a large set of observational data, and 2) uncover potential predictors of diabetes. The Jackson Heart Study collected data at baseline and in two follow-up visits from 5,301 African Americans. We excluded those with baseline diabetes and no follow-up, leaving 3,633 individuals for analyses. Over a mean 8-year follow-up, 584 participants developed diabetes. The full RF model evaluated 93 variables including demographic, anthropometric, blood biomarker, medical history, and echocardiogram data. We also used RF metrics of variable importance to rank variables according to their contribution to diabetes prediction. We implemented other models based on logistic regression and RF where features were preselected. The RF full model performance was similar (AUC = 0.82) to those more parsimonious models. The top-ranked variables according to RF included hemoglobin A1C, fasting plasma glucose, waist circumference, adiponectin, c-reactive protein, triglycerides, leptin, left ventricular mass, high-density lipoprotein cholesterol, and aldosterone. This work shows the potential of RF for incident diabetes prediction while dealing with high-dimensional data.

Diabetic muscle infarction: a systematic review.

CONTEXT: Diabetic muscle infarction (DMI) is a rare complication associated with poorly controlled diabetes mellitus. Less than 200 cases have been reported in the literature since it was first described over 45 years ago. There is no clear 'standard of care' for managing these patients. EVIDENCE ACQUISITION: PubMed searches were conducted for 'diabetic muscle infarction' and 'diabetic myonecrosis' from database inception through July 2014. All articles identified by these searches were reviewed in detail if the article text was available in English. EVIDENCE SYNTHESIS: The current literature exists as case reports or small case series, with no prospective or higher-order treatment studies available. Thus, an evidence-based approach to data synthesis was difficult. The available literature is presented objectively with an attempt to describe clinically relevant trends and findings in the diagnosis and management of DMI. CONCLUSIONS: Early recognition of DMI is key, so appropriate treatment can be initiated. MRI is the radiological study of choice. A combination of bed rest, glycemic control, and non-steroidal anti-inflammatory drug therapy appears to yield the shortest time to symptom resolution and the lowest risk of recurrence.

DGAT: novel therapeutic target for obesity and type 2 diabetes mellitus.

Obesity is currently an exceptionally common problem in humans. The last several years have produced a significant number of breakthroughs in obesity related areas of investigation. Triglycerides are considered the main form of storage of excess calories in fat. A key enzyme in the synthesis of triglycerides is acylCoA: diacylglycerol acyltransferase (DGAT). Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes.

Analysis of adipose tissue lipid using mass spectrometry.

Mass spectrometry technology has enabled significant advances in detailing the alterations of the lipidome in response to pathological conditions or experimental manipulations. Lipids comprise a wide range of compounds with functions that include structural, intracellular signaling, trafficking, and storage. Characterization of lipid species has evolved significantly over recent years due to the progress made in the area of mass spectrometry. This chapter details the methods used for the analysis of lipids tailored to the intrinsic characteristics of adipose tissue. Particular attention is given to the analysis of triglycerides, diacylglycerols, and phospholipid.

Retinoic acid regulates several genes in bile acid and lipid metabolism via upregulation of small heterodimer partner in hepatocytes.

Retinoic acid (RA) affects multiple aspects of development, embryogenesis and cell differentiation processes. The liver is a major organ that stores RA suggesting that retinoids play an important role in the function of hepatocytes. In our previous studies, we have demonstrated the involvement of small heterodimer partner (SHP) in RA-induced signaling in a non-transformed hepatic cell line AML 12. In the present study, we have identified several critical genes in lipid homeostasis (Apoa1, Apoa2 and ApoF) that are repressed by RA-treatment in a SHP dependent manner, in vitro and also in vivo with the use of the SHP null mice. In a similar manner, RA also represses several critical genes involved in bile acid metabolism (Cyp7a1, Cyp8b1, Mdr2, Bsep, Baat and Ntcp) via upregulation of SHP. Collectively our data suggest that SHP plays a major role in RA-induced potential changes in pathophysiology of metabolic disorders in the liver.

Impact of left ventricular assist device on diabetes management: an evaluation through case analysis and clinical impact.

BACKGROUND: Diabetes is a major risk factor for the development of heart failure (HF). In patients with advanced HF, left ventricular assist devices (LVADs) are increasingly used as a bridge to heart transplantation and destination therapy. It has been our observation that, post-LVAD implantation, diabetes management improves dramatically. OBJECTIVE: We evaluated insulin requirements in a group of type 2 diabetes patients after LVAD implantation, compared them to a small control group, and performed a pertinent literature review. METHODS: Relevant clinical and biochemical data were collected by chart review of 11 patients with known type 2 diabetes mellitus and HF who underwent LVAD implantation. Patients treated only with insulin were evaluated and compared with 5 control patients undergoing other cardiac procedures. RESULTS: Insulin requirement decreased by 73% at 6 months from the pre-LVAD dose despite no significant changes in weight or glomerular filtration rate. Mean hemoglobin A1c reduced post-LVAD to 6.4% from 8.6%. Patients undergoing other cardiac procedures showed no significant changes in hemoglobin A1c or insulin requirements. CONCLUSION: Patients with diabetes undergoing LVAD implantation demonstrated a significant reduction in insulin requirements. This finding underscores the importance of HF in the progression of insulin resistance.

Islet autoimmunity identifies a unique pattern of impaired pancreatic beta-cell function, markedly reduced pancreatic beta cell mass and insulin resistance in clinically diagnosed type 2 diabetes.

There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired ß-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic ß-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.

Alterations in lipid signaling underlie lipodystrophy secondary to AGPAT2 mutations.

Congenital generalized lipodystrophy (CGL), secondary to AGPAT2 mutation is characterized by the absence of adipocytes and development of severe insulin resistance. In the current study, we investigated the adipogenic defect associated with AGPAT2 mutations. Adipogenesis was studied in muscle-derived multipotent cells (MDMCs) isolated from vastus lateralis biopsies obtained from controls and subjects harboring AGPAT2 mutations and in 3T3-L1 preadipocytes after knockdown or overexpression of AGPAT2. We demonstrate an adipogenic defect using MDMCs from control and CGL human subjects with mutated AGPAT2. This defect was rescued in CGL MDMCs with a retrovirus expressing AGPAT2. Both CGL-derived MDMCs and 3T3-L1 cells with knockdown of AGPAT2 demonstrated an increase in cell death after induction of adipogenesis. Lack of AGPAT2 activity reduces Akt activation, and overexpression of constitutively active Akt can partially restore lipogenesis. AGPAT2 modulated the levels of phosphatidic acid, lysophosphatidic acid, phosphatidylinositol species, as well as the peroxisome proliferator-activated receptor γ (PPARγ) inhibitor cyclic phosphatidic acid. The PPARγ agonist pioglitazone partially rescued the adipogenic defect in CGL cells. We conclude that AGPAT2 regulates adipogenesis through the modulation of the lipome, altering normal activation of phosphatidylinositol 3-kinase (PI3K)/Akt and PPARγ pathways in the early stages of adipogenesis.

The CD40-autophagy pathway is needed for host protection despite IFN-Γ-dependent immunity and CD40 induces autophagy via control of P21 levels.

Autophagy degrades pathogens in vitro. The autophagy gene Atg5 has been reported to be required for IFN-γ-dependent host protection in vivo. However, these protective effects occur independently of autophagosome formation. Thus, the in vivo role of classic autophagy in protection conferred by adaptive immunity and how adaptive immunity triggers autophagy are incompletely understood. Employing biochemical, genetic and morphological studies, we found that CD40 upregulates the autophagy molecule Beclin 1 in microglia and triggers killing of Toxoplasma gondii dependent on the autophagy machinery. Infected CD40(-/-) mice failed to upregulate Beclin 1 in microglia/macrophages in vivo. Autophagy-deficient Beclin 1(+/-) mice, mice with deficiency of the autophagy protein Atg7 targeted to microglia/macrophages as well as CD40(-/-) mice exhibited impaired killing of T. gondii and were susceptible to cerebral and ocular toxoplasmosis. Susceptibility to toxoplasmosis occurred despite upregulation of IFN-γ, TNF-α and NOS2, preservation of IFN-γ-induced microglia/macrophage anti-T. gondii activity and the generation of anti-T. gondii T cell immunity. CD40 upregulated Beclin 1 and triggered killing of T. gondii by decreasing protein levels of p21, a molecule that degrades Beclin 1. These studies identified CD40-p21-Beclin 1 as a pathway by which adaptive immunity stimulates autophagy. In addition, they support that autophagy is a mechanism through which CD40-dependent immunity mediates in vivo protection and that the CD40-autophagic machinery is needed for host resistance despite IFN-γ.