About

Christopher Hupfeld is a Clinical Professor in the Department of Medicine at UC San Diego. His research activities include using BRET to measure insulin resistance and receptor cross-talk, with funding from NIH grants such as R03DK075389 and K08DK065127. His publication record encompasses a range of topics related to endocrinology, metabolism, and cellular signaling, with notable contributions to understanding insulin signaling pathways, GPCR receptor cross-talk, and the effects of various pharmacological agents on metabolic processes. His work has been published in reputable journals, and he has contributed to advancing knowledge in diabetic cardiovascular disease, insulin resistance mechanisms, and receptor regulation.

Research topics

• Internal medicine
• Endocrinology
• Medicine
• Chemistry
• Organic chemistry
• Ophthalmology
• Biology
• Neuroscience

Selected publications

• MON-081 ACTH Secretion from Gallbladder Neuroendocrine Tumor: A Rare Late-Onset Presentation of Ectopic Cushing’s Syndrome

  Journal of the Endocrine Society · 2025-10-01

  articleOpen access

  Abstract Disclosure: T. Wolinsky: None. C. Gu: None. A. Nichol: None. C. Hupfeld: None. N. Shah: None. Introduction: Ectopic Cushing’s syndrome is most commonly caused by the secretion of adrenocorticotropic hormone (ACTH) from neuroendocrine tumors (NETs) and manifests with signs of hypercortisolism. Common sources of paraneoplastic ACTH production include small-cell lung cancer, thymic tumors, and pancreatic neoplasms. Cases arising from gallbladder NETs are exceedingly rare. Here, we present a unique case of ectopic Cushing’s syndrome that developed acutely ten months after gallbladder malignancy diagnosis. Case: A 72-year-old woman with a history of gallbladder adenocarcinoma (diagnosed ten months prior with subsequent radical cholecystectomy), prediabetes, hypertension, hyperlipidemia, and osteoporosis presented to our hospital with two weeks of progressive facial swelling. Her exam was notable for moon facies and abdominal distension. Laboratory findings revealed hypokalemia (serum potassium 2.8 mEq/L), hyperglycemia (serum glucose 453 mg/dL, A1c of 7.0%), and elevated cortisol. Morning cortisol was 45.3 µg/dL (compared to 18 µg/dL 33 days prior), ACTH 288 pg/mL, and urine free cortisol 1,263.1 µg/day. Late-night serum cortisol was 36.4 µg/dL, and AM cortisol post 8 mg dexamethasone suppression test was 49 µg/dL. Brain MRI revealed no pituitary lesion. CT abdomen showed enlarging hepatic metastases and unremarkable adrenal glands. Pathology of initial gallbladder resection demonstrated a 10.3 cm poorly differentiated adenocarcinoma that was negative for chromogranin A, synaptophysin, and insulinoma-associated protein 1 staining. Subsequent molecular profiling favored a neuroendocrine neoplasm with 87% predicted probability (73% large cell neuroendocrine cancer). Given the clinical presentation and imaging findings, metastases from her gallbladder cancer were suspected as the source of ectopic ACTH secretion. Osilodrostat 2 mg twice daily and second-line chemotherapy (carboplatin and etoposide) were initiated with rapid improvement of hypercortisolism. Five days after initiation of osilodrostat, her AM cortisol decreased to 18.6 µg/dL and hypokalemia resolved. Conclusion: Comprehensive literature review identified only six reported cases of ACTH secretion from gallbladder malignancies, all of which presented with hypercortisolism as the initial manifestation of their malignancy. This is a rare presentation of acute worsening severe hypercortisolemia presenting ten months after initial diagnosis of gallbladder adenocarcinoma. Ectopic Cushing’s syndrome is associated with significant morbidity. Early identification of ectopic Cushing’s syndrome is thus critical. This case underscores the importance of considering ectopic ACTH production from a known malignancy in patients presenting with symptoms of hypercortisolism. Presentation: Monday, July 14, 2025

  PublisherOA PDFDOI

• Abstract #1183899: Hepatoadrenal Syndrome – Can Serum Free Cortisol Concentration Free us from Empiric Glucocorticoids?

  Endocrine Practice · 2022

  • Medicine
  • Internal medicine
  • Endocrinology
  PublisherDOI

• SGLT2 Inhibitor–Induced Low-Grade Ketonemia Ameliorates Retinal Hypoxia in Diabetic Retinopathy—A Novel Hypothesis

  The Journal of Clinical Endocrinology & Metabolism · 2021 · 38 citations

  • Medicine
  • Endocrinology
  • Internal medicine

  Diabetic retinopathy (DR) is a well-recognized microvascular complication of diabetes. Growing evidence suggests that, in addition to retinal vascular damage, there is significant damage to retinal neural tissue in DR. Studies reveal neuronal damage before clinically evident vascular lesions and DR is now classified as a neurovascular complication. Hyperglycemia causes retinal damage through complex metabolic pathways leading to oxidative stress, inflammation, vascular damage, capillary ischemia, and retinal tissue hypoxia. Retinal hypoxia is further worsened by high oxygen consumption in the rods. Persistent hypoxia results in increases in vascular endothelial growth factor (VEGF) and other pro-angiogenic factors leading to proliferative DR/macular edema and progressive visual impairment. Optimal glucose control has favorable effects in DR. Other treatments for DR include laser photocoagulation, which improves retinal oxygenation by destroying the high oxygen consuming rods and their replacement by low oxygen consuming glial tissue. Hypoxia is a potent stimulator of VEGF, and intravitreal anti-VEGF antibodies are effective in regressing macular edema and in some studies, retinal neovascularization. In this review, we highlight the complex pathophysiology of DR with a focus on retinal oxygen/fuel consumption and hypoxic damage to retinal neurons. We discuss potential mechanisms through which sodium-glucose cotransporter 2 (SGLT2) inhibitors improve retinal hypoxia-through ketone bodies, which are energetically as efficient as glucose and yield more ATP per molecule of oxygen consumed than fat, with less oxidative stress. Retinal benefits would occur through improved fuel energetics, less hypoxia and through the anti-inflammatory/oxidative stress effects of ketone bodies. Well-designed studies are needed to explore this hypothesis.

  PublisherOA PDFDOI

• Sodium-Glucose Cotransporter Type 2 (SGLT-2) Inhibitors and Ketogenesis: the Good and the Bad

  Current Diabetes Reports · 2020 · 32 citations

  • Endocrinology
  • Internal medicine
  • Chemistry
  PublisherDOI

• Author response for "Navigating the “MACE” in Cardiovascular Outcomes Trials and Decoding the Relevance of Atherosclerotic CVD Benefits versus Heart Failure Benefits"

  2019-03-29

  peer-review1st authorCorresponding
  PublisherDOI

• MON-LB067 AAA Syndrome in a 30 Year Old Man Presenting for Primary Adrenal Insufficiency Management

  Journal of the Endocrine Society · 2019-04-01

  articleOpen access

  AAA syndrome or Allgrove Syndrome is a rare autosomal recessive congenital disease characterized by the triad of adrenal insufficiency (Addison's disease), failure of the lower esophageal sphincter to relax (achalasia) and absence of tear secretion (alacrima). The syndrome is frequently seen in childhood. Here we describe a 30 year old man who presented to an adult endocrinology clinic for continued management of primary adrenal insufficiency, which had been diagnosed at age 2 and considered a sequela of a disseminated meningococcal infection (Waterhouse-Friderichsen syndrome). He had been treated chronically with cortisone acetate and fludrocortisone. Multiple subsequent hospitalizations for treatment of adrenal crises occurred in childhood. Dysphagia associated with poor weight gain was present since birth. There had been an absence of tear production. An ACTH level was elevated, and cosyntropin administration had failed to augment the serum cortisol level. He has had negative Schirmer test, distal esophageal narrowing on barium esophagram and multiple esophageal dilation therapy for treatment of achalasia. AAAS gene sequencing showed homozygous mutations of AAAS gene on chromosome 12q13 which encodes ALADIN. Based on clinical features and investigation noted upon presentation to our clinic, followed by genetic testing, the diagnosis of AAA syndrome (or Allgrove syndrome) was made. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

  PublisherDOI

• Navigating the “MACE” in Cardiovascular Outcomes Trials and decoding the relevance of Atherosclerotic Cardiovascular Disease benefits versus Heart Failure benefits

  Diabetes Obesity and Metabolism · 2019-04-08 · 41 citations

  review1st author

  The publication of results from recent cardiovascular outcome trials (CVOTs) has transformed the landscape of diabetes treatment. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter-2 (SGLT2) inhibitors have demonstrated CV benefits in large, well-conducted, randomized studies. Today, empagliflozin, canagliflozin and liraglutide are US Food and Drug Administration-approved not only for glucose-lowering, but also to reduce the risk of cardiovascular (CV) events/CV mortality in people with type 2 diabetes (T2DM) and established CV disease (CVD)/high CVD risk. Although the CVOTs were primarily powered for CV safety (non-inferiority), they also demonstrated CV efficacy (superiority). This initially surprised many in the diabetes community, but the replication of the CV benefits with different compounds in the same class alleviated concerns about the CV benefits being chance findings. However, many questions remain. While the heterogeneity in the CV benefits in the various CVOTs can be attributed to the variability in CV risk in the different studies, the reason(s) for the differences in the CV benefits between the GLP-1RA class and the SGLT2 inhibitor class appear to be more complex. An analysis of major adverse cardiovascular events (MACE) in the CVOTs shows that the CV benefits of GLP-1RAs are predominantly specific to atherosclerotic CV events (non-fatal myocardial infarction [MI], non-fatal stroke and CV death). By contrast, the SGLT2 inhibitors do not have any significant effects on atherosclerotic CV events (non-fatal MI/stroke). Their benefits are predominantly on hospitalization for heart failure (HF), suggesting effects primarily on myocardial function ("the pump"), and not on the "pipes" (coronary arteries). In the present review, we discuss the rationale for the conduct of CVOTs, highlight the inability of the classic three-point MACE to capture the entire spectrum of atherosclerotic and non-atherosclerotic CVD morbidity, especially HF in T2DM, and discuss the results of the CVOTs with a focus on the clinical significance of atherosclerotic CVD (ASCVD) versus HF, which develops in a sizeable proportion of people with diabetes and without prior ASCVD.

  PublisherDOI

• Visual Vignette

  Endocrine Practice · 2019-01-18

  articleSenior author
  PublisherDOI

• Fishing for Digeorge Syndrome in A 40-YEAR-OLD Man

  AACE Clinical Case Reports · 2017-07-13

  articleOpen access1st authorCorresponding

  Objective: Identify an endocrine developmental syndrome (DiGeorge syndrome, or 22q11 deletion syndrome) that had been previously undiagnosed in an adult patient.Methods: The patient was evaluated in an adult endocrinology clinic. In particular, fluorescence in situ hybridization was used to identify a segmental deletion on chromosome 22.Results: DiGeorge syndrome was positively identified using fluorescence in situ hybridization in our patient.Conclusion: Rare developmental syndromes may be initially diagnosed in adult patients. DiGeorge syndrome should be among the differential diagnoses considered in an adult with hypocalcemia.Abbreviations: 22q11DS 22q11 deletion syndrome DGCR DiGeorge critical region FISH fluorescence in situ hybridization PTH parathyroid hormone

  PublisherDOI

• Type 2 Diabetes Mellitus

  Elsevier eBooks · 2015-04-03 · 4 citations

  book-chapter1st authorCorresponding
  PublisherDOI

Recent grants

• NIH Grant K08DK065127

  NIH · $609k · 2008

Frequent coauthors

• Jerrold M. Olefsky

  University of California, San Diego

  17 shared

• Carolyn A Allan

  Monash University

  5 shared

• Emma K. Beardsley

  Frankston Hospital

  4 shared

• Takeshi Imamura

  Tottori University

  4 shared

• Lloyd Paul Aiello

  Joslin Diabetes Center

  3 shared

• Lloyd Axelrod

  Massachusetts General Hospital

  3 shared

• Robert J. Lefkowitz

  3 shared

• Erik K. Alexander

  3 shared