About

Nicolai M Doliba, D.Sc., Ph.D., is a Research Associate Professor of Biochemistry and Biophysics at the University of Pennsylvania's Perelman School of Medicine. He serves as the Technical Director of the Pancreatic Islet Cell Biology Core, which supports academic and industry partners in the functional characterization of pancreatic islets as part of the NIH-funded Diabetes Research Center at Penn's Institute for Diabetes, Obesity and Metabolism. Dr. Doliba oversees the islet physiology arm of the Human Pancreas Analysis Program, a multi-institutional initiative aimed at characterizing cellular and molecular events leading to dysfunction in Type 1 and Type 2 Diabetes. His research focuses on developing bioenergetic methods to understand stimulus-secretion coupling and neuro-endocrine regulation, as well as their changes during diabetes mellitus. He has established relationships between energy production and insulin secretion using novel phosphorescence methods for measuring oxygen consumption. In partnership with Hua Medicine, Dr. Doliba is studying the reparative effects of dorzagliatin, a novel antidiabetic drug currently in phase III clinical trials. His group investigates the role of bioenergetics, ion transport, and metabolic coupling factors in nutrient- and hormone-stimulated insulin and glucagon release in healthy and diabetic pancreatic islets. His ongoing projects include exploring the role of alpha cells in the pathogenesis of Type 1 Diabetes, mechanisms of beta cell glucose sensing, and the involvement of G protein–coupled receptors in insulin and glucagon secretion.

Research topics

• Internal medicine
• Endocrinology
• Biology
• Medicine
• Chemistry

Selected publications

• Cardioprotective effect of genetic ablation of the G-protein-coupled receptor kinase GRK2 in adult pancreatic β-cells during high-fat diet

  Journal of Biological Chemistry · 2025-03-05 · 1 citations

  articleOpen access

  Cardiovascular diseases are a major comorbidity factor in patients with type 2 diabetes and a leading cause of death among them. Yet, mechanistically, how impairment in pancreatic islets alters cardiac function under different metabolic states remains largely unknown. Here, we investigate the role of the G-protein-coupled receptor kinase 2 (GRK2) in regulating islet adaptations to an obesogenic diet and its impact on myocardial function. Using a novel inducible β-cell-specific GRK2 knockout mouse model (βGRK2KO), we establish that loss of adult β-cell GRK2 delays metabolic islet maladaptation, protecting the heart against obesity-induced cardiac dysfunction. βGRK2KO are more insulin-sensitive than control mice and have improved cardiac function and myocardial morphology. Thus, genetic ablation of GRK2 in adult β-cells during an obesogenic diet play a cardioprotective role. This study prompts a novel therapeutic window for GRK2 intervention strategies for diabetic patients prone to cardiac dysfunction.

  PublisherOA PDFDOI

• <b>A functional and mechanistic explanation for the unique clinical success of the glucokinase activator dorzagliatin for treatment of type 2 diabetes</b>

  2025-04-24

  preprintOpen accessSenior author

  <p dir="ltr">Glucokinase activators (GKA) are a long-sought therapeutic modality for the treatment of Type 2 Diabetes (T2D). However, all GKAs failed clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perfusions, enzyme kinetics, x-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with the failed GKA MK-0941 (Merck Pharmaceuticals), which is well-characterized both clinically and mechanistically. Dorzagliatin improves glucose stimulation of insulin secretion (GSIS) in a dose- and glucose-dependent manner, in contrast to MK-0941 which induces maximal insulin secretion at low doses and glucose concentrations. To understand these functional differences, the atomic resolution structure of the dorzagliatin-glucokinase (GK) complex was determined and compared with the GK/MK-0941 structure. MK-0941 binds to a pocket accessible in both open and closed conformations, has a strong interaction with Y214, mutation of which produces the most clinically severe activating mutation, and produces a high energy barrier for the open-to-close transition. In contrast, dorzagliatin only binds favorably to the closed form of glucokinase, interacting primarily with R63, and causing a low energy barrier for the open-to-close transition. This provides the molecular rationale for the clinical success of dorzagliatin which can guide the future development of next-generation allosteric activators of GK.</p>

  PublisherDOI

• <b>A functional and mechanistic explanation for the unique clinical success of the glucokinase activator dorzagliatin for treatment of type 2 diabetes</b>

  2025-04-24

  preprintOpen accessSenior author

  <p dir="ltr">Glucokinase activators (GKA) are a long-sought therapeutic modality for the treatment of Type 2 Diabetes (T2D). However, all GKAs failed clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perfusions, enzyme kinetics, x-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with the failed GKA MK-0941 (Merck Pharmaceuticals), which is well-characterized both clinically and mechanistically. Dorzagliatin improves glucose stimulation of insulin secretion (GSIS) in a dose- and glucose-dependent manner, in contrast to MK-0941 which induces maximal insulin secretion at low doses and glucose concentrations. To understand these functional differences, the atomic resolution structure of the dorzagliatin-glucokinase (GK) complex was determined and compared with the GK/MK-0941 structure. MK-0941 binds to a pocket accessible in both open and closed conformations, has a strong interaction with Y214, mutation of which produces the most clinically severe activating mutation, and produces a high energy barrier for the open-to-close transition. In contrast, dorzagliatin only binds favorably to the closed form of glucokinase, interacting primarily with R63, and causing a low energy barrier for the open-to-close transition. This provides the molecular rationale for the clinical success of dorzagliatin which can guide the future development of next-generation allosteric activators of GK.</p>

  PublisherDOI

• The pancreatic β-cell incretin response is modulated by mitochondrial transaminase GPT2

  Research Square · 2025-06-30

  preprintOpen access
  PublisherOA PDFDOI

• Functional and Mechanistic Explanation for the Unique Clinical Success of the Glucokinase Activator Dorzagliatin in the Treatment of Type 2 Diabetes

  Diabetes · 2025-04-24 · 5 citations

  articleOpen accessSenior author

  Glucokinase (GK) activators (GKAs) are a long-sought therapeutic modality for the treatment of type 2 diabetes. However, GKAs have failed in clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with those of the unsuccessful GKA MK-0941 (Merck Pharmaceuticals), which is well characterized both clinically and mechanistically. Dorzagliatin improved glucose-stimulated insulin secretion in a dose- and glucose-dependent manner, in contrast to MK-0941, which induced maximal insulin secretion at low doses and glucose concentrations. To understand these functional differences, the atomic resolution structure of the dorzagliatin-GK complex was determined and compared with the GK-MK-0941 structure. MK-0941 bound to a pocket accessible in both open and closed conformations; had a strong interaction with Y214, the mutation of which produces the most clinically severe activating mutation; and produced a high energy barrier for the open-to-closed transition. In contrast, dorzagliatin only bound favorably to the closed form of GK, interacting primarily with R63 and causing a low energy barrier for the open-to-closed transition. This provides the molecular rationale for the clinical success of dorzagliatin, which can guide the future development of next-generation allosteric activators of GK. ARTICLE HIGHLIGHTS: The type 2 diabetes (T2D) treatment dorzagliatin has achieved singular success among its drug class, known as glucokinase (GK) activators (GKAs). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies revealed the unique mechanism by which dorzagliatin activates GK. Dorzagliatin dose-dependently reduces the glucose threshold for stimulation of insulin secretion and binds preferably to the closed form of GK, preventing overstimulation of the enzyme. A renewed interest in GKAs, coupled with modern tools to assess their molecular interactions with GK, should guide the future development of novel GKA treatments for T2D.

  PublisherOA PDFDOI

• Human Peripancreatic Adipose Tissue Paracrine Signaling Impacts Insulin Secretion, Blood Flow, and Gene Transcription

  The Journal of Clinical Endocrinology & Metabolism · 2024-10-30 · 2 citations

  article

  CONTEXT: Adipose tissue accumulation around nonadipose tissues is associated with obesity and metabolic disease. One relatively unstudied depot is peripancreatic adipose tissue (PAT) that accumulates in obesity and insulin resistance and may impact β-cell function. Pancreatic lipid accumulation and PAT content are negatively related to metabolic outcomes in humans, but these studies are limited by the inability to pursue mechanisms. OBJECTIVE: We obtained PAT from human donors through the Human Pancreas Analysis Program to evaluate differences in paracrine signaling compared to subcutaneous adipose tissue (SAT), as well as effects of the PAT secretome on aortic vasodilation, human islet insulin secretion, and gene transcription using RNA sequencing. RESULTS: PAT had greater secretion of interferon-γ and most inflammatory eicosanoids compared to SAT. Secretion of adipokines negatively related to metabolic health were also increased in PAT compared to SAT. We found no overall effects of PAT compared to SAT on human islet insulin secretion; however, insulin secretion was suppressed after PAT exposure from men compared to women. Vasodilation was significantly dampened by PAT conditioned media, an effect explained almost completely by PAT from men and not women. Islets treated with PAT showed selective changes in lipid metabolism pathways while SAT altered cellular signaling and growth. RNA sequencing analysis showed changes in islet gene transcription impacted by PAT compared to SAT, with the biggest changes found between PAT based on sex. CONCLUSION: The PAT secretome is metabolically negative compared to SAT, and impacts islet insulin secretion, blood flow, and gene transcription in a sex-dependent manner.

  PublisherDOI

• E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells

  Genes & Development · 2024-12-30

  articleOpen access

  The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain ( Spop βKO ) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α–XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation.

  PublisherOA PDFDOI

• 1736-P: Exploring Intrinsic Features of Human Pancreatic a- and ß-Cell Physiology Using Pseudoislets

  Diabetes · 2024-06-14

  articleSenior author

  Introduction: Mechanistic studies of pancreatic α- and β-cell physiology are challenging in whole islets due to interactions among different islet cell types. Reaggregation of sorted cell populations into pseudoislets offers the possibility to delineate the role of specific cell types, distinguish intrinsic cellular functions and paracrine interactions, and enhance accessibility for genetic interventions. Methods: Building on methods of Walker et al, 2020, we generated >90% enriched human α- and β-cell aggregates and studied hormone secretion by perifusion, mitochondrial function by Seahorse, Ca2+ flux by fluorescence imaging, and electrophysiology by whole-cell patch-clamp. Native islets and pseudoislets of dissociated unsorted islet cells served as controls. Results: The native islet kinetics of insulin and glucagon responses to glucose were preserved in β- and α-cell aggregates, indicating direct effects of glucose; however, rates of secretion, adjusted for IEQ and cell proportion, were markedly lower compared to native islets and reaggregated controls, suggesting that optimal α- and β-cell function depends on other islet cell types. The primary stimulus of oxygen consumption rate (OCR) and Ca2+ flux in β- and α-cell aggregates was glucose and amino acids, respectively. Baseline OCR (no substrate) was higher in α- than β-cell aggregates. Electrophysiologically, both native islet and α-cell aggregate action potentials (APs) were larger in size and faster in kinetics than β-cell APs; however, high glucose-induced inhibition of α-cell APs and subsequent hyperpolarization observed in native islets and control reaggregates was noticeably impaired in α-cell aggregates, suggesting a role for other cell types in glucose-mediated inhibition of α-cells. Conclusion: Cardinal features of α- and β-cell physiology are largely preserved in α- and β-cell enriched pseudoislets, establishing its feasibility in the study of intrinsic α- and β-cell physiology. Disclosure A.V. Rozo: None. J. Roman: None. W. Qin: None. C. Liu: None. A. Naji: None. K.H. Kaestner: None. T. Hoshi: None. D.A. Stoffers: Other Relationship; Eiger BioPharmaceuticals. N.M. Doliba: None. Funding National Institutes of Health (UC4DK 112217, U01DK123594)

  PublisherDOI

• DNA methylation-based assessment of cell composition in human pancreas and islets

  2024-01-24

  preprintOpen access

  <p dir="ltr">Assessment of pancreas cell type composition is crucial to the understanding of the genesis of diabetes. Current approaches use immunodetection of protein markers, for example insulin as a marker of beta-cells. A major limitation of these methods is that protein content varies in physiological and pathological conditions, complicating the extrapolation to actual cell number. Here we demonstrate the use of cell type-specific DNA methylation markers for determining the fraction of specific cell types in human islet and pancreas specimens. <a href="" target="_blank">We identified genomic loci that are uniquely demethylated in specific pancreatic cell types and applied targeted PCR to assess the methylation status of these loci in tissue samples, enabling inference of cell type composition.</a> In islet preparations, normalization of insulin secretion to beta-cell DNA revealed similar beta-cell function in pre-T1D, T1D and T2D , which was significantly lower than in non-diabetic donors. In histological pancreas specimens from recent-onset T1D this assay showed beta-cell fraction within the normal range, suggesting a significant contribution of beta-cell dysfunction. In T2D pancreata we observed increased alpha-cell fraction and normal beta-cell fraction. Methylation-based analysis provides an accurate molecular alternative to immune detection of cell types in the human pancreas, with utility in the interpretation of insulin secretion assays and the assessment of pancreas cell composition in health and disease.</p>

  PublisherDOI

• Intra-islet α-cell Gs signaling promotes glucagon release

  Nature Communications · 2024-06-15 · 11 citations

  articleOpen access

  Abstract Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell G s signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell G s signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α−cell G s -coupled A 2A adenosine receptors. Studies with α-cell-specific Gα s knockout mice showed that α-cell G s also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched G s -coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.

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Frequent coauthors

• Franz M. Matschinsky

  University of Pennsylvania

  54 shared

• Mary D. Osbakken

  Drexel University

  24 shared

• Ali Naji

  Hospital of the University of Pennsylvania

  24 shared

• Klaus H. Kaestner

  University of Pennsylvania

  23 shared

• Andriy M. Babsky

  Lviv University

  21 shared

• Changhong Li

  State Key Laboratory of Food Science and Technology

  19 shared

• Marko Z. Vatamaniuk

  Cornell University

  18 shared

• Wei Qin

  Shandong University

  17 shared

Education

• D.Sc., Physiology

  Lviv Medical University

• Ph.D., Physiology

  Lviv University