accili

Insulin-deficient (type 1) diabetes is treated by providing insulin to maintain euglycemia. The current standard of care is a quasi-closed loop integrating automated insulin delivery with a continuous glucose monitoring sensor. Cell replacement technologies are advancing as an alternative treatment and have been tested as surrogates to cadaveric islets in transplants. In addition, immunomodulatory treatments to delay the onset of type 1 diabetes in high-risk (stage 2) individuals have gained regulatory approval...

Diabetes mellitus is characterized by insulin resistance and β-cell failure. The latter involves impaired insulin secretion and β-cell dedifferentiation. Sulfonylurea (SU) is used to improve insulin secretion in diabetes, but it suffers from secondary failure. The relationship between SU secondary failure and β-cell dedifferentiation has not been examined. Using a model of SU secondary failure, we have previously shown that functional loss of oxidoreductase Cyb5r3 mediates effects of SU failure through interactions with glucokinase...

OBJECTIVE: Notch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant insulin secretory defects in obese mice. METHODS: We assessed expression of Notch pathway components in high-fat diet-fed (HFD) or leptin receptor-deficient (db/db) mice, and performed single-cell RNA sequencing (scRNA-Seq) in islets from patients with and without type 2 diabetes (T2D)...

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Insulin activates insulin receptor (IR) signaling and subsequently triggers IR endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis upon insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly...

The maintenance of glucose homeostasis is fundamental for survival and health. Diabetes develops when glucose homeostasis fails. Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell failure. The failure of β-cells to compensate for insulin resistance results in hyperglycemia, which in turn drives altered lipid metabolism and β-cell failure. Thus, insulin secretion by pancreatic β-cells is a primary component of glucose homeostasis. Impaired β-cell function and reduced β-cell mass are found in diabetes...

Over 100 years have passed since insulin was first administered to a diabetic patient. Since then great strides have been made in diabetes research. It has determined where insulin is secreted from, which organs it acts on, how it is transferred into the cell and is delivered to the nucleus, how it orchestrates the expression pattern of the genes, and how it works with each organ to maintain systemic metabolism. Any breakdown in this system leads to diabetes. Thanks to the numerous researchers who have dedicated their lives to cure diabetes, we now know that there are three major organs where insulin acts to maintain glucose/lipid metabolism: the liver, muscles, and fat...

Calorie restriction increases lifespan. While some tissue-specific protective effects of calorie restriction have been described, the impact of calorie restriction on the gastrointestinal tract remains unclear. We found increased abundance of chromogranin A+, including orexigenic ghrelin+, endocrine cells in the stomach of calorie-restricted mice. This effect coincided with increased Notch target Hes1 and Notch ligand Jag1 and was reversed when Notch signaling was blocked using the γ-secretase inhibitor DAPT...

Type 2 diabetes (T2D) is associated with β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of β-cell dedifferentiation and correlates with T2D progression. However, it is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of ALDH1A3-positive β-cells (A+) following pair-feeding of diabetic animals is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes...

Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) down-regulation as a mechanism of secondary SU failure and successfully reverse it. Chronic exposure to SU lowered Cyb5r3 abundance and reduced islet glucose utilization in mice in vivo and in ex vivo murine islets. Cyb5r3 β cell-specific knockout mice phenocopied SU failure. Cyb5r3 engaged in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization...

Research on the etiology and treatment of diabetes has made substantial progress. As a result, several new classes of anti-diabetic drugs have been introduced in clinical practice. Nonetheless, the number of patients achieving glycemic control targets has not increased for the past 20 years. Two areas of unmet medical need are the restoration of insulin sensitivity and the reversal of pancreatic beta cell failure. In this review, we integrate research advances in transcriptional regulation of insulin action and pathophysiology of beta cell dedifferentiation with their potential impact on prospects of a durable "cure" for patients suffering from type 2 diabetes...

BACKGROUND: Atherosclerosis is a medical urgency manifesting at the onset of hypercholesterolemia and is associated with aging. Activation of PPARγ (peroxisome proliferator-activated receptor γ) counteracts metabolic dysfunction influenced by aging, and its deacetylation displays an atheroprotective property. Despite the marked increase of PPARγ acetylation during aging, it is unknown whether PPARγ acetylation is a pathogenic contributor to aging-associated atherosclerosis...

OBJECTIVE: Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. METHODS: We used Ngn3-or Villin-driven FoxO1 ablation to capture the distinctive developmental effects of FoxO1 on EEC pool. We combined FoxO1 ablation with Notch inhibition to enhance the expansion of EEC pool...

Ever since they were first observed in Purkinje fibers of the heart, funny channels have had close connections to potassium channels. Indeed, funny channels were initially thought to produce a potassium current in the heart called I K2 . However, funny channels are completely unlike potassium channels in ways that make their contributions to the physiology of cells unique. An important difference is the greater ability for sodium to permeate funny channels. Although it does not flow through the funny channel as easily as does potassium, sodium does permeate well enough to allow for depolarization of cells following a strong hyperpolarization...

OBJECTIVES: Insulin treatment remains the sole effective intervention for Type 1 Diabetes. Here, we investigated the therapeutic potential of converting intestinal epithelial cells to insulin-producing, glucose-responsive β-like cells by targeted inhibition of FOXO1. We have previously shown that this can be achieved by genetic ablation in gut Neurogenin3 progenitors, adenoviral or shRNA-mediated inhibition in human gut organoids, and chemical inhibition in Akita mice, a model of insulin-deficient diabetes...

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming to replace lost pancreatic β-cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by FoxO1 ablation, but their numbers are limited. In this study we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage tracing experiments show that upon genetic or pharmacologic FoxO1 ablation the Paneth/goblet lineage can also undergo conversion to the insulin lineage...

Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1/2, key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet...

Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin's action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another...

BACKGROUND AND AIMS: Stomach cells can be converted to insulin-producing cells by Neurog3, MafA, and Pdxl over-expression. Enteroendocrine cells can be similarly made to produce insulin by the deletion of FOXO1. Characteristics and functional properties of FOXO1-expressing stomach cells are not known. METHODS: Using mice bearing a FOXO1-GFP knock-in allele and primary cell cultures, we examined the identity of FOXO1-expressing stomach cells and analyzed their features through loss-of-function studies with red-to-green fluorescent reporters...

Increased hepatic glucose production (HGP) contributes to hyperglycemia in type 2 diabetes. Hormonal regulation of this process is primarily, but not exclusively, mediated by the AKT-FoxO1 pathway. Here, we show that cAMP and dexamethasone regulate the high-mobility group superfamily member TOX4 to mediate HGP, independent of the insulin receptor/FoxO1 pathway. TOX4 inhibition decreases glucose production in primary hepatocytes and liver and increases glucose tolerance. Combined genetic ablation of TOX4 and FoxO1 in liver has additive effects on glucose tolerance and gluconeogenesis...