Diabetes is characterized by “glucotoxic” loss of pancreatic β cell function and insulin content, but underlying mechanisms remain unclear. A mouse model of insulin-secretory deficiency induced by β ...cell inexcitability (KATP gain of function) demonstrates development of diabetes and reiterates the features of human neonatal diabetes. In the diabetic state, β cells lose their mature identity and dedifferentiate to neurogenin3-positive and insulin-negative cells. Lineage-tracing experiments show that dedifferentiated cells can subsequently redifferentiate to mature neurogenin3-negative, insulin-positive β cells after lowering of blood glucose by insulin therapy. We demonstrate here that β cell dedifferentiation, rather than apoptosis, is the main mechanism of loss of insulin-positive cells, and redifferentiation accounts for restoration of insulin content and antidiabetic drug responsivity in these animals. These results may help explain gradual decrease in β cell mass in long-standing diabetes and recovery of β cell function and drug responsivity in type 2 diabetic patients following insulin therapy, and they suggest an approach to rescuing “exhausted” β cells in diabetes.
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•Loss of pancreatic β cell insulin content in long-standing glucotoxic diabetes•β cell dedifferentiation to neurogenin3-positive/insulin-negative cells in diabetes•Redifferentiation to insulin-positive β cells after normalization of blood glucose
Wang et al. show that loss of insulin in pancreatic β cells in response to glucotoxicity stems from a dedifferentiation rather than apoptosis. This process is reversible, such that the same cell can regain an insulin-positive β cell fate on restoration of normoglycemia following insulin therapy, suggesting a mechanism for rescue of “exhausted” β cells in diabetes.
Progressive loss of pancreatic β-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and β-cell ...exhaustion. However, loss of β-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional β-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes. These early events were accompanied by a marked increase in β-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring β-cell function in NDM mice when it was initiated at >40 days of diabetes, when loss of β-cell mass and identity had already occurred. Our data from mouse models demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives β-cell failure in diabetes, ii) recovery of β-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent β-cell failure when used in early stages of diabetes, but not when loss of β-cell mass/identity already occurred, iv) common execution pathways may underlie loss and recovery of β-cell function in different forms of diabetes. These results may have important clinical implications for optimal therapeutic interventions in individuals with diabetes, particularly for those with long-standing diabetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Type 2 diabetes (T2DM) is caused by the interaction of multiple genes and environmental factors. T2DM is characterized by hyperglycemia, insulin secretion deficiency and insulin resistance. Chronic ...hyperglycemia induces β-cell dysfunction, loss of β-cell mass/identity and β-cell dedifferentiation. Intermittent fasting (IF) a commonly used dietary regimen for weight-loss, also induces metabolic benefits including reduced blood glucose, improved insulin sensitivity, reduced adiposity, inflammation, oxidative-stress and increased fatty-acid oxidation; however, the mechanisms underlying these effects in pancreatic β-cells remain elusive. KK and KKAy, mouse models of polygenic T2DM spontaneously develop hyperglycemia, glucose intolerance, glucosuria, impaired insulin secretion and insulin resistance. To determine the long-term effects of IF on T2DM, 6-weeks old KK and KKAy mice were subjected to IF for 16 weeks. While KKAy mice fed ad-libitum demonstrated severe hyperglycemia (460 mg/dL) at 6 weeks of age, KK mice showed blood glucose levels of 230 mg/dL, but progressively became severely diabetic by 22-weeks. Strikingly, both KK and KKAy mice subjected to IF showed reduced blood glucose and plasma insulin levels, decreased body weight gain, reduced plasma triglycerides and cholesterol, and improved insulin sensitivity. They also demonstrated enhanced expression of the β-cell transcription factors NKX6.1, MAFA and PDX1, and decreased expression of ALDH1a3 suggesting protection from loss of β-cell identity by IF. IF normalized glucose stimulated insulin secretion in islets from KK and KKAy mice, demonstrating improved β-cell function. In addition, hepatic steatosis, gluconeogenesis and inflammation was decreased particularly in KKAy-IF mice, indicating peripheral benefits of IF. These results have important implications as an optional intervention for preservation of β-cell identity and function in T2DM.
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•Intermittent fasting (IF) decreases hyperglycemia and body weight gain in T2DM.•IF reduces plasma triglycerides and cholesterol, and improves insulin sensitivity.•IF protects β-cell identity and function in T2DM.•IF decreases hepatic steatosis, gluconeogenesis and inflammation in T2DM.
Type 2 diabetes (T2DM) , caused by the interaction of multiple genes and environmental factors, is characterized by hyperglycemia, insulin secretion deficiency and insulin resistance. Chronic ...hyperglycemia induces β-cell dysfunction and loss of β-cell mass/identity, increased apoptosis and β-cell dedifferentiation. Intermittent fasting (IF) , either alternate-day fasting (ADF) or time-restricted feeding, commonly used regimens for weight-loss, also induces metabolic benefits including reduced blood glucose, improved insulin sensitivity, reduced adiposity, inflammation and oxidative-stress, and increased fatty-acid oxidation; however, the mechanisms underlying these effects remain elusive. KK and KKAy, mouse models of polygenic T2DM spontaneously develop hyperglycemia, glucose intolerance, glucosuria, impaired insulin secretion and insulin resistance. To determine the long-term effects of IF on T2DM, 6-weeks old KK and KKAy mice were subjected to ADF for 16-weeks. While KKAy mice fed ad-libitum demonstrated severe hyperglycemia (˜500mg/dL) , increased plasma insulin, impaired glucose tolerance and insulin resistance at 8 weeks of age, KK mice showed blood glucose levels of ˜200mg/dL, but progressively became as severely diabetic as KKAy mice by 22-weeks. Strikingly, both KK and KKAy mice subjected to ADF showed reduced blood glucose and plasma insulin levels, decreased body weight gain despite increased food intake, reduced plasma triglycerides and cholesterol, and improved insulin sensitivity. They also demonstrated enhanced expression of the β-cell transcription factors PDX1 and NKX6.1, suggesting protection from loss of β-cell identity/dedifferentiation by IF. In addition, respiratory exchange ratio (RER) and movement were significantly enhanced in the ADF group, indicating peripheral benefits of IF. These results have important implications as an optional intervention for preservation of β-cell mass and function in T2DM.
Disclosure
S.Patel: None. Z.Yan: None. M.S.Remedi: None.
Funding
National Institutes of Health (R01DK123163)
Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin ...production and secretion was previously attributed to apoptosis of insulin-producing β-cells, recent studies indicate that β-cell apoptosis rates are relatively low in diabetes. Instead, β-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to β-cell failure. The underlying mechanisms driving β-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the potential to inform innovative therapeutic approaches aimed at reversing β-cell dedifferentiation in T2D. This review explores the proposed drivers of β-cell dedifferentiation leading to β-cell failure, and discusses current interventions capable of reversing this process, thus restoring β-cell identity and function.
Patients with type 2 diabetes (T2D) fail to secrete insulin in response to increased glucose levels that occur with eating. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic ...polypeptide (GIP) are two incretins secreted from gastrointestinal cells that amplify insulin secretion when glucose is high. In this issue of the JCI, Oduori et al. explore the role of ATP-sensitive K+ (KATP) channels in maintaining glucose homeostasis. In persistently depolarized β cells from KATP channel knockout (KO) mice, the researchers revealed a shift in G protein signaling from the Gs family to the Gq family. This shift explains why GLP-1, which signals via Gq, but not GIP, which signals preferentially via Gs, can effectively potentiate secretion in islets from the KATP channel-deficient mice and in other models of KATP deficiency, including diabetic KK-Ay mice. Their results provide one explanation for differential insulinotropic potential of incretins in human T2D and point to a potentially unifying model for T2D progression itself.
Chronic hyperglycemia increases pancreatic β-cell metabolic activity, contributing to glucotoxicity-induced β-cell failure and loss of functional β-cell mass, potentially in multiple forms of ...diabetes. In this perspective we discuss the novel paradoxical and counterintuitive concept of inhibiting glycolysis, particularly by targeted inhibition of glucokinase, the first enzyme in glycolysis, as an approach to maintaining glucose sensing and preserving functional β-cell mass, thereby improving insulin secretion, in the treatment of diabetes.
Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) ...channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.
Understanding mechanisms for maintaining pancreatic islet cell fate and function is important for addressing the urgent challenge of restoring islet β- and α-cell function in T1DM. In this issue of ...Cell Metabolism, Chakravarthy et al. (2017) identify a genetic mechanism by which mouse β-cells are spontaneously regenerated from adult α-cells.
Understanding mechanisms for maintaining pancreatic islet cell fate and function is important for addressing the urgent challenge of restoring islet β- and α-cell function in T1DM. In this issue of Cell Metabolism, Chakravarthy et al. (2017) identify a genetic mechanism by which mouse β-cells are spontaneously regenerated from adult α-cells.
Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP ...channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can be reversed once manifest. Using combined transgenic and pharmacological approaches in a knockin mouse model of CS, we have shown that reversal of vascular and cardiac phenotypes can be achieved by genetic downregulation of KATP channel activity specifically in VSM, and by chronic administration of the clinically used KATP channel inhibitor, glibenclamide. These findings demonstrate that VSM KATP channel GoF underlies CS cardiac enlargement and that CS-associated abnormalities are reversible, and provide evidence of in vivo efficacy of glibenclamide as a therapeutic agent in CS.
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