About

Franz M. Matschinsky is a faculty member in the Department of Biochemistry and Biophysics at the University of Pennsylvania's Perelman School of Medicine. His research focuses on the biochemical basis of fuel sensing by pancreatic islet cells, particularly the molecular mechanisms of glucose sensing and glucose-stimulated insulin release (GSIR). His laboratory investigates the endocrine, neural, and pharmacological modifications of GSIR, as well as the molecular genetic basis of glucokinase (GK) linked hypo- and hyperglycemia syndromes caused by mutations of the GK gene. He studies the therapeutic potential of pharmacological agents called GK activators (GKAs) using recombinant human wildtype and mutant GK, pancreatic islet cells, and animal models. Matschinsky's work has contributed to understanding the regulation of glucose homeostasis and the genetic and molecular mechanisms underlying diabetes-related conditions.

Research topics

• Internal medicine
• Endocrinology
• Biology
• Chemistry
• Biochemistry

Selected publications

• Allosteric and substrate site effects of relevant amino acids on structural stability and flexibility of glutamate dehydrogenase-1 (GDH-1)

  Biophysical Journal · 2023-02-01 · 1 citations

  articleSenior author
  PublisherDOI

• Integration of Eukaryotic Energy Metabolism: The Intramitochondrial and Cytosolic Energy States ([ATP]f/[ADP]f[Pi])

  International Journal of Molecular Sciences · 2022-05-16 · 29 citations

  reviewOpen accessSenior author

  Maintaining a robust, stable source of energy for doing chemical and physical work is essential to all living organisms. In eukaryotes, metabolic energy (ATP) production and consumption occurs in two separate compartments, the mitochondrial matrix and the cytosol. As a result, understanding eukaryotic metabolism requires knowledge of energy metabolism in each compartment and how metabolism in the two compartments is coordinated. Central to energy metabolism is the adenylate energy state ([ATP]/[ADP][Pi]). ATP is synthesized by oxidative phosphorylation (mitochondrial matrix) and glycolysis (cytosol) and each compartment provides the energy to do physical work and to drive energetically unfavorable chemical syntheses. The energy state in the cytoplasmic compartment has been established by analysis of near equilibrium metabolic reactions localized in that compartment. In the present paper, analysis is presented for energy-dependent reactions localized in the mitochondrial matrix using data obtained from both isolated mitochondria and intact tissues. It is concluded that the energy state ([ATP]f/[ADP]f[Pi]) in the mitochondrial matrix, calculated from the free (unbound) concentrations, is not different from the energy state in the cytoplasm. Corollaries are: (1) ADP in both the cytosol and matrix is selectively bound and the free concentrations are much lower than the total measured concentrations; and (2) under physiological conditions, the adenylate energy states in the mitochondrial matrix and cytoplasm are not substantially different.

  PublisherOA PDFDOI

• α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

  Journal of Clinical Investigation · 2022-05-31 · 65 citations

  articleOpen access

  BACKGROUNDMultiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA+ state may represent an early stage of T1D.METHODSHere, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTSSimilar to the few remaining β cells in the T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA+ and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA+ α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA+ donor islets.CONCLUSIONWe found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D.FUNDINGThis work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).

  PublisherOA PDFDOI

• Genetic activation of glucokinase in a minority of pancreatic beta cells causes hypoglycemia in mice

  Life Sciences · 2022-09-11 · 3 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• The basis of metabolic homeostasis: Demand regulated energy metabolism

  Trends in Diabetes and Metabolism · 2021-01-01 · 1 citations

  articleOpen accessSenior author

  This concept is extended in the present paper with proposal of a general schema in which near equilibrium reactions coupled to ATP synthesis determine the flux through a downstream irreversible reaction. This design is shown to apply to ATP production by both glycolysis and oxidative phosphorylation, providing a thermodynamic base for energy metabolism that is stable over time yet exquisitely sensitive to temporal changes in metabolic status. Energy (ATP) is provided "on demand" through direct coupling of the rate of ATP production to the rate of ATP consumption. Flux is dependent on the mass action ratio of the near equilibrium reactions, and this functionally stabilizes the cellular energy

  PublisherOA PDFDOI

• Metabolic Homeostasis in Life as We Know It: Its Origin and Thermodynamic Basis

  Frontiers in Physiology · 2021-04-23 · 42 citations

  articleOpen accessSenior author

  Living organisms require continuous input of energy for their existence. As a result, life as we know it is based on metabolic processes that extract energy from the environment and make it available to support life (energy metabolism). This metabolism is based on, and regulated by, the underlying thermodynamics. This is important because thermodynamic parameters are stable whereas kinetic parameters are highly variable. Thermodynamic control of metabolism is exerted through near equilibrium reactions that determine. (1) the concentrations of metabolic substrates for enzymes that catalyze irreversible steps and (2) the concentrations of small molecules (AMP, ADP, etc.) that regulate the activity of irreversible reactions in metabolic pathways. The result is a robust homeostatic set point (−ΔG ATP ) with long term (virtually unlimited) stability. The rest of metabolism and its regulation is constrained to maintain this set point. Thermodynamic control is illustrated using the ATP producing part of glycolysis, glyceraldehyde-3-phosphate oxidation to pyruvate. Flux through the irreversible reaction, pyruvate kinase (PK), is primarily determined by the rate of ATP consumption. Change in the rate of ATP consumption causes mismatch between use and production of ATP. The resulting change in [ATP]/[ADP][Pi], through near equilibrium of the reactions preceding PK, alters the concentrations of ADP and phosphoenolpyruvate (PEP), the substrates for PK. The changes in ADP and PEP alter flux through PK appropriately for restoring equality of ATP production and consumption. These reactions appeared in the very earliest lifeforms and are hypothesized to have established the set point for energy metabolism. As evolution included more metabolic functions, additional layers of control were needed to integrate new functions into existing metabolism without changing the homeostatic set point. Addition of gluconeogenesis, for example, resulted in added regulation to PK activity to prevent futile cycling; PK needs to be turned off during gluconeogenesis because flux through the enzyme would waste energy (ATP), subtracting from net glucose synthesis and decreasing overall efficiency.

  PublisherOA PDFDOI

• Alpha cell dysfunction in early type 1 diabetes

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-10-16

  preprintOpen access

  Summary Multiple islet autoantibodies (AAb) predict type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in just ∼15% of single AAb+ (generally against glutamic acid decarboxylase, GADA+) individuals; hence the single GADA+ state may represent an early stage of T1D amenable to interventions. Here, we functionally, histologically, and molecularly phenotype human islets from non-diabetic, GADA+ and T1D donors. Similar to the few remaining beta cells in T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, alpha cell glucagon secretion was dysregulated in both T1D and GADA+ islets with impaired glucose suppression of glucagon secretion. Single cell RNA sequencing (scRNASeq) of GADA+ alpha cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of PKIB , providing a molecular basis for the loss of glucose suppression and the increased effect of IBMX observed in GADA+ donor islets. The striking observation of a distinct early defect in alpha cell function that precedes beta cell loss in T1D suggests that not only overt disease, but also the progression to T1D itself, is bihormonal in nature.

  PublisherOA PDFDOI

• 322-OR: Impairment of Alpha-Cell Bioenergetics Contributes to Increased Basal Yet Decreased Glucose Stimulated Oxygen Consumption Rates of Isolated Human Pancreatic Islets in T1DM and T2DM

  Diabetes · 2020-06-01

  articleSenior author

  Fuel stimulated hormone release (HR) and the oxygen consumption rates (OCR) of isolated normal pancreatic islets are positively correlated illustrating that cellular energy state is a critical determinant of stimulus-secretion coupling. We investigated the relationship between hormone release and OCR in islets from donors with T1DM and T2DM, using unique oxygen measurement technology and optimized perifusion protocols. HR and OCR were quantified in 20 human donor islet preparations obtained from the Human Islet Resource Center at the University of Pennsylvania within 3-4 days after isolation (5 each of nondiabetic, T1DM, T2DM and anti-islet AutoAntiBody positive (AAB+). A physiological amino acid mixture (4mM) was used to stimulate glucagon release, then 3 and 16.7mM glucose were added to stimulate insulin release and inhibit glucagon release. Respiration was then uncoupled with FCCP and finally blocked by NaN3. Basal OCR was increased in islets from AAB+, T1DM and T2DM donors compared to controls. Low glucose failed to increase OCR in T1DM and T2DM islets while high glucose-stimulated OCR was both decreased and delayed. Glucose stimulated insulin release much less effectively and failed to suppress glucagon release in both T1DM and T2DM islets. AAB+ islets showed normal insulin release but lacked glucose suppression of glucagon release. The observation of increased basal-OCR of islets in all diabetes related conditions and reduced glucose-stimulated-OCR in T1DM and T2DM islets unrelated to hormone release rates is striking and indicates a profound alteration of bioenergetics regulation in these conditions hitherto unrecognized. Common to this pathophysiology are an increase in relative alpha-cell mass (T1DM and T2DM) or a functional defect of these cells (AAB+) providing a plausible explanation for this phenomenology and implying impaired alpha-cell energy metabolism. Disclosure N.M. Doliba: None. A.V. Rozo: None. W. Qin: None. J. Roman: None. C. Liu: None. A. Naji: None. K.H. Kaestner: None. D.A. Stoffers: None. F. Matschinsky: None. Funding National Institutes of Health (UC4DK112217)

  PublisherDOI

• Ethanol metabolism: The good, the bad, and the ugly

  Medical Hypotheses · 2020-02-19 · 128 citations

  articleOpen accessSenior author

  Throughout the world, ethanol is both an important commercial commodity and a source of major medical and social problems. Ethanol readily passes through biological membranes and distributes throughout the body. It is oxidized, first to acetaldehyde and then to acetate, and finally by the citric acid cycle in virtually all tissues. The oxidation of ethanol is irreversible and unregulated, making the rate dependent only on local concentration and enzyme activity. This unregulated input of reducing equivalents increases reduction of both cytoplasmic and intramitochondrial NAD and, through the latter, cellular energy state {[ATP]/([ADP][Pi])}. In brain, this increase in energy state stimulates dopaminergic neural activity signalling reward and a sense of well being, while suppressing glutamatergic neural activity signalling anxiety and unease. These positive responses to ethanol ingestion are important to social alcohol consumption. Importantly, decreased free [AMP] decreases AMP-dependent protein kinase (AMPK) activity, an important regulator of cellular energy metabolism. Oxidation of substrates used for energy metabolism in the absence of ethanol is down regulated to accommodate the input from ethanol. In liver, chronic ethanol metabolism results in fatty liver and general metabolic dysfunction. In brain, transport of other oxidizable metabolites through the blood-brain barrier and the enzymes for their oxidation are both down regulated. For exposures of short duration, ethanol induced regulatory changes are rapid and reversible, recovering completely when the concentrations of ethanol and acetate fall again. Longer periods of ethanol exposure and associated chronic suppression of AMPK activity activates regulatory mechanisms, including gene expression, that operate over longer time scales, both in onset and reversal. If chronic alcohol consumption is abruptly ended, metabolism is no longer able to respond rapidly enough to compensate. Glutamatergic neural activity adapts to chronic dysregulation of glutamate metabolism and suppression of glutamatergic neural activity by increasing excitatory and decreasing inhibitory amino acid receptors. A point is reached (ethanol dependence) where withdrawal of ethanol results in significant metabolic energy depletion in neurons and other brain cells as well as hyperexcitation of the glutamatergic system. The extent and regional specificity of energy depletion in the brain, combined with hyperactivity of the glutamatergic neuronal system, largely determines the severity of withdrawal symptoms.

  PublisherDOI

• Cerebrovascular Blood Flow Design and Regulation; Vulnerability in Aging Brain

  Frontiers in Physiology · 2020-10-16 · 23 citations

  reviewOpen accessSenior author

  . Penetrating arterioles bud from surface arteries of the brain and penetrate downward through the cortex. Capillary networks spread from penetrating arterioles through the surrounding tissue. Each penetrating arteriole forms a vascular unit, with little sharing of flow among vascular units (collateral flow). Unlike cells in other tissues, neurons have to be operationally isolated, interacting with other neurons through specific electrical connections. Neuronal activation typically involves only a few of the cells within a vascular unit, but the local increase in nutrient consumption is substantial. The metabolic response to activation is transmitted to the feeding arteriole through the endothelium of neighboring capillaries and alters calcium permeability of smooth muscle in the wall resulting in modulation of flow through the entire vascular unit. Many age and trauma related brain pathologies can be traced to vascular malfunction. This includes: 1. Physical damage such as in traumatic injury with imposed shear stress as soft tissue moves relative to the skull. Lack of collateral flow among vascular units results in death of the cells in that vascular unit and loss of brain tissue. 2. Age dependent changes lead to progressive increase in vascular resistance and decrease in tissue levels of oxygen and glucose. Chronic hypoxia/hypoglycemia compromises tissue energy metabolism and related regulatory processes. This alters stem cell proliferation and differentiation, undermines vascular integrity, and suppresses critical repair mechanisms such as oligodendrocyte generation and maturation. Reduced structural integrity results in local regions of acute hypoxia and microbleeds, while failure of oligodendrocytes to fully mature leads to poor axonal myelination and defective neuronal function. Understanding and treating age related pathologies, particularly in brain, requires better knowledge of why and how vasculature changes with age. That knowledge will, hopefully, make possible drugs/methods for protecting vascular function, substantially alleviating the negative health and cognitive deficits associated with growing old.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AM022122

  NIH · $175k · 1986

• NIH Grant R01NS014843

  NIH · $148k · 1985

• NIH Grant R37DK022122

  NIH · $1.9M · 1994

• NIH Grant R01DK022122

  NIH · $7.3M · 2012

Frequent coauthors

• Mark A. Magnuson

  Vanderbilt University

  65 shared

• Nicolai M. Doliba

  54 shared

• Marko Z. Vatamaniuk

  Cornell University

  48 shared

• Klaus H. Kaestner

  University of Pennsylvania

  46 shared

• Anthony S. Pagliara

  Gundersen Health System

  43 shared

• Barbara E. Corkey

  Boston University

  40 shared

• Yin Liang

  39 shared

• Carol Buettger

  University of Pennsylvania

  36 shared

Labs

• Biochemistry and BiophysicsPI