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Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia
Open accessAbstract
The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.
Overview
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Written from the paper’s full text.
TL;DR
In streptozotocin-induced uncontrolled diabetic rats, intracerebroventricular leptin normalized blood glucose by day 7 independently of food intake, urinary glucose loss, or pancreatic β-cell recovery. The effect involved insulin-independent suppression of hepatic glucose production and increased tissue glucose uptake, with normalization of plasma glucagon and corticosterone.
Key findings
- Intracerebroventricular leptin (1 g/d) normalized blood glucose by day 7 in STZ-diabetic rats, whereas subcutaneous leptin at the same dose did not; pair feeding to leptin-treated intake also did not attenuate hyperglycemia.
- Urinary glucose was undetectable in icv leptin-treated diabetic rats versus marked glycosuria in STZ-veh rats; plasma insulin remained very low, pancreatic preproinsulin mRNA was reduced by >95%, and glucose tolerance was near normal despite no increase in circulating insulin.
- Tracer studies showed icv leptin reduced glucose appearance/HGP to nondiabetic values and increased glucose uptake in red gastrocnemius muscle, brain, BAT, and heart; during a hyperglycemic clamp at approximately 210 mg/dl, HGP was suppressed and glucose utilization increased despite severe insulin deficiency.
- Hepatic G6Pase and Pepck expression was reduced by icv leptin; plasma glucagon and corticosterone elevations in STZ diabetes were prevented by icv leptin; hepatic Igfbp2 mRNA was increased >25-fold in diabetic rats and further increased by leptin, which the authors argue is unlikely to explain the HGP effect.
Methods
- Adult male Wistar rats received two daily sc injections of STZ (40 mg/kg body weight) to induce uncontrolled diabetes, plus lateral ventricle cannula and sc osmotic minipump for icv vehicle or leptin (1 g/d) for up to 11 days; five groups (n = 7–9 per group): veh-veh, STZ-veh, STZ-leptin, STZ-veh-pair-fed, and STZ-leptin-sc.
- Daily food intake, body weight, water intake, and blood glucose were measured; ip glucose tolerance tests (2 g/kg) were performed on day 9; arterial catheters were used for plasma glucagon, corticosterone, and catecholamine measurements.
- Glucose turnover was assessed with [3-3H]glucose and 2[14C]deoxyglucose tracer dilution, including a hyperglycemic clamp at approximately 210 mg/dl; hepatic gene expression was measured by real-time PCR, and liver triglyceride/glycogen and body composition were also analyzed.
Limitations
- The paper states that Rd could not be compared between icv leptin-treated and veh-treated STZ-diabetic rats because glycosuria confounds Rd; it also states that whether reduced glucagon contributes to, or results from, leptin-mediated resolution of hyperglycemia is unknown, and that mechanisms of leptin regulation of the hypothalamic-pituitary-adrenal axis remain incompletely understood.
- The paper states that autonomic/SNS involvement is suspected but not directly tested here; it notes that prior denervation or adrenergic blockade studies did not measure Rg.
- Evident from the text: findings are limited to male Wistar rats with STZ-induced diabetes and short-term central leptin infusion, so human type 1 diabetes and long-term outcomes are not established; causal roles of glucagon and corticosterone normalization are not definitively separated from other mechanisms.
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41 Own result · 35 Not checked yet · 18 Own interpretation · 3 No basis given · 1 Supported · 1 Own method
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In the paper
“Plasma corticosterone levels were similarly elevated in animals with STZ diabetes, a response also prevented by icv leptin but not PF (Fig. 6B).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes plasma glucagon and corticosterone levels in STZ-induced diabetes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the action of leptin in the CNS was also associated with normalization of elevated plasma glucagon levels, consistent with an earlier report (4), our data suggest that factors, in addition to glucagon, contribute to the glucoselowering effect of CNS leptin action.”
- Also stated in: § CNS leptin infusion normalizes plasma glucagon and corticosterone levels in STZ-induced diabetes · plain
“the elevation in plasma glucagon levels observed in STZ-treated animals was prevented by central leptin administration (Fig. 6A).”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Also stated in: § CNS leptin infusion normalizes plasma glucagon and corticosterone levels in STZ-induced diabetes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency.”
- Also stated in: § Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes · plain
“glucose uptake was significantly increased in red gastrocnemius muscle and brain in STZdiabetic animals that received icv leptin relative to veh (Fig. 3C).”
- Also stated in: § Discussion · boosted
“we demonstrate that leptin acts in the CNS to potently inhibit glucose production and simultaneously increase tissue glucose utilization in diabetic animals.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic -cells.”
- Also stated in: § CNS leptin infusion normalizes blood glucose levels in STZ-induced diabetes · plain
“This effect was due neither to a leptin-mediated reversal of diabetic hyperphagia, because hyperglycemia was not attenuated in STZ-veh-PF animals”
- Also stated in: § Discussion · plain
“via a mechanism that cannot be explained by reduced food intake, increased urinary glucose losses, or recovery of pancreatic -cells”
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § CNS leptin infusion normalizes blood glucose levels in STZ-induced diabetes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency.”
- Also stated in: § Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes · hedged
“Central leptin administration dramatically reduced Ra to nondiabetic control values (Fig. 3A), strongly suggesting that normalization of diabetic hyperglycemia resulted, at least in part, from reduced HGP.”
- Also stated in: § Discussion · boosted
“we demonstrate that leptin acts in the CNS to potently inhibit glucose production and simultaneously increase tissue glucose utilization in diabetic animals.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By comparison, hepatic expression of these genes was significantly reduced in STZ-diabetic rats receiving icv leptin”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic -cells.”
- Also stated in: § Potential mechanism(s) mediating the glucose-lowering action of CNS leptin · plain
“the severe insulin deficiency (under both basal and glucose-stimulated conditions) caused by STZ-induced -cell destruction was not ameliorated by icv leptin.”
- Also stated in: § Discussion · plain
“via a mechanism that cannot be explained by reduced food intake, increased urinary glucose losses, or recovery of pancreatic -cells”
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Potential mechanism(s) mediating the glucose-lowering action of CNS leptin · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nor to a peripheral effect of leptin, because sc infusion of leptin at the same dose did not affect blood glucose in STZ-diabetic rats (Fig. 1D).”
- Also stated in: § Discussion · plain
“does not involve a peripheral action of leptin.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes blood glucose levels in STZ-induced diabetes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic -cells.”
- Also stated in: § Potential mechanism(s) mediating the glucose-lowering action of CNS leptin · plain
“urinary glucose was undetectable in diabetic animals that received icv leptin similar to nondiabetic controls, whereas STZ-veh-treated animals displayed the expected, marked glycosuria (Fig. 2A).”
- Also stated in: § Discussion · plain
“via a mechanism that cannot be explained by reduced food intake, increased urinary glucose losses, or recovery of pancreatic -cells”
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Potential mechanism(s) mediating the glucose-lowering action of CNS leptin · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“hepatic expression of the key gluconeogenic genes G6Pase and Pepck were markedly increased in the liver of STZ-veh-treated animals relative to nondiabetic controls (Fig. 4, A and B).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 4
Every source the paper cites for this claim was checked and supports it.
In the paper
“we recently reported that in rats with STZ diabetes, physiological leptin replacement is sufficient to normalize cir-culating glucagon and corticosterone levels, yet does not reverse hyperglycemia (20).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes plasma glucagon and corticosterone levels in STZ-induced diabetes
What the sources say
- Supportedcites [20] German, 2010, Leptin deficiency causes insulin resistance induced by uncontrolled diabetes., Diabetes source
The Results section on potential mechanisms says physiological leptin replacement prevented the rise in plasma glucagon, attenuated the rise in corticosterone, and describes both levels as normalized. The Results section on glucose homeostasis says leptin-treated STZ rats remained markedly hyperglycemic, although their glucose levels were modestly lower than those of vehicle-treated rats. Page numbers were not provided in our copy. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“plasma levels of NEFAs and ketone bodies were also elevated in STZ-veh animals and normalized with icv leptin administration but only after blood glucose levels had returned to normal (Fig. 6, E and F).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes plasma glucagon and corticosterone levels in STZ-induced diabetes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“water intake was markedly increased in both groups of STZ-veh-treated animals, owing to the dehydrating effect of pronounced glycosuria in uDM (26), whereas water intake in diabetic animals receiving icv leptin was equivalent to that of nondiabetic controls (Fig. 2B).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Potential mechanism(s) mediating the glucose-lowering action of CNS leptin
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“leptin-treated STZ-diabetic rats exhibited similar weight loss to STZ-diabetic rats receiving icv veh but exhibited a greater loss of fat mass (Supplemental Fig. 1”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes blood glucose levels in STZ-induced diabetes
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In nondiabetic animals, plasma insulin and C-peptide levels were significantly increased during the hyperglycemic clamp (P Ͻ 0.05) (Fig. 5, A and B), resulting in complete suppression of HGP and enhancement of glucose utilization by more than 250% (Fig. 5, E-H).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, despite persistent, severe insulin deficiency, HGP was suppressed and glucose utilization was increased in STZ-diabetic rats receiving icv leptin, although less than that observed in nondiabetic animals (Fig. 5, E-H).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“food intake was significantly increased by d 5 after STZ administration in diabetic animals receiving icv veh, and this effect was completely blocked by icv leptin (Fig. 1C).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes blood glucose levels in STZ-induced diabetes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We recently observed that in rats with STZ diabetes, physiological leptin replacement is sufficient to normalize plasma glucagon levels but has little effect on diabetic hyperglycemia (20).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [20] German, 2010, Leptin deficiency causes insulin resistance induced by uncontrolled diabetes., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CNS leptin suppresses HGP and increases glucose utilization in uDM during a hyperglycemic clamp.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CNS leptin normalizes plasma glucagon and corticosterone levels in uDM.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Although accumulating evidence suggests that leptin (10 -13), insulin (14,15), and nutrient-related signals (16 -18) in the CNS improve hepatic insulin sensitivity”
What the sources say
- Not checked yetcites [10] Liu, 1998, Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes., J Biol Chem source
- Not checked yetcites [11] Pocai, 2005, Central leptin acutely reverses diet-induced hepatic insulin resistance., Diabetes source
- Not checked yetcites [12] Park, 2008, Long-term effects of central leptin and resistin on body weight, insulin resistance, and β-cell function and mass by the modulation of hypothalamic leptin and insulin signaling., Endocrinology source
- Not checked yetcites [13] German, 2009, Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve., Endocrinology source
- Not checked yetcites [14] Obici, 2002, Hypothalamic insulin signaling is required for inhibition of glucose production., Nat Med source
- Not checked yetcites [15] Pocai, 2005, Hypothalamic K(ATP) channels control hepatic glucose production., Nature source
- Not checked yetcites [16] Obici, 2002, Central administration of oleic acid inhibits glucose production and food intake., Diabetes source
- Not checked yetcites [17] Lam, 2005, Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis., Nat Med source
- Not checked yetcites [18] Pocai, 2005, A brain-liver circuit regulates glucose homeostasis., Cell Metabolism source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Several lines of evidence suggest that like leptin, insulin action in the brain of nondiabetic animals lowers ambient glycemia by increasing hepatic insulin sensitivity (14,15).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“leptin adminis-tration directly into the brain normalizes blood glucose in rats with uDM (5)(6)(7)(8)(9) at doses that are ineffective when administered peripherally.”
What the sources say
- Not checked yetcites 5)(6)(7)(8)(9
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These data suggest that icv leptin treatment reduces food intake and stimulates energy expenditure”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes blood glucose levels in STZ-induced diabetes
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“hepatic Igfbp-2 expression is tonically inhibited by insulin and hence dramatically up-regulated by insulin deficiency (50 -52).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [50] Böni-Schnetzler, 1990, Insulin regulates the expression of the insulin-like growth factor binding protein 2 mRNA in rat hepatocytes., Mol Endocrinol source
- Not checked yetcites [51] Ooi, 1992, Post-transcriptional regulation of insulin-like growth factor binding protein-2 mRNA in diabetic rat liver., Biochem Biophys Res Commun source
- Not checked yetcites [52] White, 1993, Insulin-like growth-factor binding protein (IGFBP) serum levels and hepatic IGFBP-2 and -3 mRNA expression in diabetic and insulin-treated swine (Sus scrofa)., Comp Biochem Physiol B source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“conditions associated with leptin deficiency, such as fasting and uDM, clearly raise corticosterone levels via a mechanism that can be reversed with leptin treatment (44,45,49).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [44] Schwartz, 1997, Evidence that elevated plasma corticosterone levels are the cause of reduced hypothalamic corticotrophin-releasing hormone gene expression in diabetes., Regul Pept source
- Not checked yetcites [45] Strack, 1995, Glucocorticoids and insulin: reciprocal signals for energy balance., Am J Physiol
- Not checked yetcites [49] Ahima, 1996, Role of leptin in the neuroendocrince response to fasting., Nature source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting a shared neuronal mechanism mediating effects of both hormones on glucose metabolism (34,35).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [34] Obici, 2002, Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats., Nat Neurosci source
- Not checked yetcites [35] Morton, 2005, Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons., Cell Metab source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations are distinct from any previously described CNS leptin action”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“nor was activation of the 3-adrenergic receptors required or sufficient to mediate the effects of leptin on blood glucose levels (7)”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [7] da Silva, 2006, Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity., Am J Physiol Regul Integr Comp Physiol source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on these data, we infer that icv leptin normalizes blood glucose levels in STZ-diabetic rats at least in part via an insulin-independent mechanism that increases glucose utilization in tissues such as BAT and skeletal muscle.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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The authors state this as an assumption.
How CNS leptin signaling normalizes diabetic hyperglycemia in uDM, and whether this involves leptin-dependent effects on HGP or Rg, is unknown.
“how CNS leptin signaling normalizes diabetic hyperglycemia in uDM, and whether this involves leptin-dependent effects on hepatic glucose production (HGP) or tissue glucose uptake (Rg), is unknown.”
The paper relies on this without support.
Changes in plasma glucagon do not affect glucose utilization.
“an effect not readily explained by changes of plasma glucagon (which does not affect glucose utilization)”
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Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“we recently found that continuous infusion of leptin directly into the brain normalizes blood glucose levels in STZ-induced diabetic rats via a mechanism that cannot be explained by reduced food intake, increased urinary glucose losses or a recovery of pancreatic β-cells.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [67]
In the citing paper
“This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver (66, 146), and offers compelling evidence of a novel mechanism through which the brain normalizes diabetic hyperglycemia without the need for insulin (67).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [67]
In the citing paper
“Instead, leptin action in the brain potently suppressed hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency (67).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [67]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > CNS leptin infusion normalizes plasma glucagon and corticosterone levels in STZ-induced diabetes
“Although changes in plasma norepinephrine and epinephrine levels are unlikely to explain leptin's effects (Fig. 6, A and D)”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
“Plasma glucagon (A), plasma corticosterone (B), norepinephrine (NE) (C), epinephrine (EPI) (D)”
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“Leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency (German et al., 2011).”
BackgroundFGF19 action in the brain induces insulin-independent glucose lowering
Morton, G. J., Matsen, M. E., Bracy, D. P., Meek, T. H., Hồng, N. T., Stefanovski, D., Bergman, R. N., Wasserman, D. H., & Schwartz, M. W. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70710 · Cited by 218
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“Although it is unclear whether leptin acts directly on a-cells to diminish glucagon, systemic [20,63e65] or ICV [60,66] leptin administration in STZdiabetic and non-obese diabetic mice potently reduces plasma glucagon levels.”
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Self-citationMinireview: CNS Mechanisms of Leptin Action
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“Leptin suppresses hepatic glucose production by ameliorating hyperglucagonemia and stimulating peripheral glucose uptake through central mechanisms, possibly involving POMC and AgRP neurons in the ARC, and the modulation of the autonomic nervous system [38,52,53].”
BackgroundRole of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes
Vilariño‐García, T., Polonio-González, M., Pérez‐Pérez, A., Ribalta, J., Arrieta, F., Aguilar‐Diosdado, M., Obaya, J. C., Gimeno-Orna, J. A., Iglesias, P., Navarro, J., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042338 · Cited by 201
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BackgroundLeptin therapy, insulin sensitivity, and glucose homeostasis
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“[53] However, it has also been demonstrated that leptin ameliorates hyperglycemia by suppressing hepatic glucose production and by increasing tissue glucose uptake, independent of insulin.[54]”
BackgroundCentral nervous system regulation of organismal energy and glucose homeostasis
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Self-citationRole of leptin in the pancreatic β-cell: effects and signaling pathways
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Exercise, Energy Intake, Glucose Homeostasis, and the Brain
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“…observation that, when the adipocyte hormone leptin is administered at low doses into the brain of rats or mice with uncontrolled, insulindeficient diabetes, pronounced hyperglycemia is completely normalized despite persistent, severe insulin deficiency (da Silva et al., 2006; German et al., 2011).”
BackgroundInfluentialSelf-citationThe role of leptin in glucose homeostasis
Denroche, H. C., Huynh, F. K., & Kieffer, T. J. (2012) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2012.00203.x · Cited by 153
Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases
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“(5) to reverse hyperglycemia in rats with STZ-induced diabetes, a finding that has now been confirmed by others (6,7,37); interestingly, central leptin therapy can inhibit hepatic glucose production in rats with STZ-induced diabetes (37).”
BackgroundThe role of leptin in diabetes: metabolic effects
Meek, T. H., & Morton, G. J. (2016) · Diabetologia · doi:10.1007/s00125-016-3898-3 · Cited by 127
“Moreover, this glucose-lowering effect of leptin occurs via an insulinindependent mechanism characterised by a normalisation of hepatic glucose production (HGP) and increased rates of glucose uptake in peripheral tissues, including brown adipose tissue, muscle and heart [20].”
BackgroundSelf-citationFGF1 — a new weapon to control type 2 diabetes mellitus
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“Recently, studies indicate that leptin suppresses the development of the impaired glucose metabolism in rodents treated with streptozotocin (STZ) and Akita mice with insulinopenia.[12-20] Hyperleptinemia induced by either pharmacologic leptin administration or with adenoviral infection, fully amieliorates hyperglycemi…”
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Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization
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“In white adipose tissue, we found significant down regulation of Glut4, a gene whose loss in adipose tissue results in hyperglycemia and impaired glucose handling [29,30]; leptin a gene whose product enhances peripheral glucose uptake [31] and perilipin, a white adipose protein whose over expression protects from diet…”
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Self-citationConsequences of Metabolic Disruption in Alzheimer's Disease Pathology
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“A similar study previously demonstrated that icv leptin injection can decrease hepatic G6Pase and PEPCK mRNA expression in rats with STZ diabetes [15].”
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“Uncontrolled insulindeficient diabetes is characterized by hyperglucagonemia and hypercorticosteronemia, responses that increase HGP and that are normalized when intracerebroventricular leptin is administered at doses that normalize hyperglycemia (1).”
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“This effect is likely mediated by the CNS as intracerebroventricular leptin lowers plasma glucose levels in insulin-deficient rodents (92, 93), emphasizing the insulin-independent ability of leptin to lower glucose levels.”
BackgroundGlucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice
Okamoto, H., Cavino, K., Na, E., Krumm, E. A., Kim, S. Y., Cheng, X., Murphy, A. J., Yancopoulos, G. D., & Gromada, J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1621069114 · Cited by 70
“Leptin could mediate this effect because it has been shown to normalize blood glucose levels in mice with no β cells (42, 43).”
BackgroundCyclic AMP sensor EPAC proteins and energy homeostasis
Almahariq, M. F., Mei, F. C., & Cheng, X. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.10.004 · Cited by 73
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Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?
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Self-citationNutrient-Sensing Mechanisms in the Gut as Therapeutic Targets for Diabetes
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Type 2 diabetes: one disease, many pathways
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“Euglycemic-Hyperinsulinemic Clamp To independently assess the effect of phentolamine on insulin sensitivity in cold-exposed rats, a euglycemichyperinsulinemic clamp was performed as previously described (21,22).”
MethodSelf-citationBrain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes
Alonge, K. M., D’Alessio, D. A., & Schwartz, M. W. (2020) · Diabetologia · doi:10.1007/s00125-020-05293-3 · Cited by 62
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Control of hepatic glucose metabolism by islet and brain
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“leptin involves normalization of elevated HGP [47], despite ongoing, severe insulin deficiency.”
BackgroundSelf-citationMeek, T. H., Matsen, M. E., Dorfman, M. D., Guyenet, S. J., Damian, V. M., Hồng, N. T., Taborsky, G. J., & Morton, G. J. (2013) · Endocrinology · doi:10.1210/en.2013-1328 · Cited by 51
Self-citationPhysiological role for leptin in the control of thermal conductance
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Self-citationPeripheral Mechanisms Mediating the Sustained Antidiabetic Action of FGF1 in the Brain
Scarlett, J. M., Muta, K., Brown, J. M., Rojas, J. M., Matsen, M. E., Acharya, N., Secher, A., Ingvorsen, C., Jørgensen, R., Høeg-Jensen, T., et al. (2018) · Diabetes · doi:10.2337/db18-0498 · Cited by 50
“In rodent models of uncontrolled diabetes induced by streptozotocin, for example, hyperglycemia can be reversed by continuous icv administration of leptin, even in the face of persistent, severe insulin deficiency (10,40).”
Self-citationParacrine signalling by pancreatic δ cells determines the glycaemic set point in mice
Huang, J. L., Pourhosseinzadeh, M. S., Lee, S. C. L., Krämer, N., Guillen, J. V., Cinque, N., Aniceto, P. A., Momen, A. T., Koike, S., & Huising, M. O. (2024) · Nature Metabolism · doi:10.1038/s42255-023-00944-2 · Cited by 49
Leptin, diabetes, and the brain
Morton, G. J., & Meek, T. H. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105568 · Cited by 47
“In a similar manner, leptin administration directly into the brain normalizes blood glucose levels in rodent models of uDM[42-46] at doses that are ineffective when administered systemically.”
BackgroundMethodSelf-citationThe ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis
Tu, L., Fukuda, M., Tong, Q., & Xu, Y. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00799-2 · Cited by 50
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“Based on these observations, the brain was identified as a likely mediator of leptin’s antidiabetic actions, and an insulin-independent glucose-lowering mechanism was implied since the effect occurs despite persistent, severe insulin deficiency (3, 4).”
BackgroundSelf-citationCNS Control of Glucose Metabolism: Response to Environmental Challenges
Arble, D. M., & Sandoval, D. A. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00020 · Cited by 44
“, 2005b) independently of insulin levels (German et al., 2011).”
BackgroundHow Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes?
Deem, J. D., Muta, K., Scarlett, J. M., Morton, G. J., & Schwartz, M. W. (2017) · Diabetes · doi:10.2337/dbi16-0067 · Cited by 42
“This leptin effect appears to be mediated centrally because it is replicated by administration of leptin directly into the brain at a dose below that needed to affect glucose homeostasis when given systemically (21,22).”
BackgroundSelf-citationA critical update on the l eptin‐melanocortin system
Lavoie, O., Michael, N. J., & Caron, A. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15765 · Cited by 43
“It should be noted that leptin also seemed to regulate hepatic glucose production independently of insulin (German et al., 2011).”
BackgroundAdipose Tissue as an Endocrine Organ
Musi, N., & Guardado‐Mendoza, R. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-408134-5.00014-7 · Cited by 46
Gut-brain mechanisms controlling glucose homeostasis
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“A role for the brain in this anti-diabetic leptin action was identified initially on the basis of the finding that, in rats with STZ-diabetes, continuous ICV infusion of leptin normalized markedly elevated blood glucose levels at low doses that are ineffective when administered peripherally [55].”
BackgroundInfluentialSelf-citationLeptin, 20years of searching for glucose homeostasis
Fernández-Formoso, G., Perez‐Sieira, S., González-Touceda, D., Diéguez, C., & Tovar, S. A. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.02.008 · Cited by 39
Brain derived neurotrophic factor in newly diagnosed diabetes and prediabetes
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Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice
Cheng, L., Yu, Y., Zhang, Q., Szabo, A., Wang, H., & Huang, X. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.04.025 · Cited by 34
“For instance, leptin administration in rodents enhances insulin mediated suppression of hepatic glucose production [14, 15] and suppress [16] hepatic gluconeogenesis.”
Perfluorooctanoic acid impaired glucose homeostasis through affecting adipose AKT pathway
Du, G., Sun, J., & Zhang, Y. (2018) · Cytotechnology · doi:10.1007/s10616-017-0164-6 · Cited by 33
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“A parallel line of study has shown that leptin action in the brain normalizes blood glucose levels in uDM via an insulin-independent mechanism characterized by a normalization of both HGP and elevated plasma glucagon levels (9,10).”
BackgroundMethodResultInfluentialSelf-citationJejunal Leptin-PI3K Signaling Lowers Glucose Production
Rasmussen, B. A., Breen, D. M., Duca, F. A., Côté, C. D., Zadeh‐Tahmasebi, M., Filippi, B., & Lam, T. K. T. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.014 · Cited by 34
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Interaction of glucose sensing and leptin action in the brain
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Glucose Effectiveness in Obese Children: Relation to Degree of Obesity and Dysglycemia
Weiss, R., Magge, S. N., Santoro, N., Giannini, C., Boston, R. C., Holder, T. A., Shaw, M. M., Duran, E. J., Hershkop, K. J., & Caprio, S. (2015) · Diabetes Care · doi:10.2337/dc14-2183 · Cited by 31
“diabetic hyperglycemia in rodents in the presence of sufficient amounts of central nervous system leptin (30).”
BackgroundYue, J. T. Y., Abraham, M. A., Bauer, P. V., LaPierre, M. P., Wang, P., Duca, F. A., Filippi, B., Chan, O. T. M., & Lam, T. K. T. (2016) · Nature Communications · doi:10.1038/ncomms13501 · Cited by 30
CNS Regulation of Glucose Homeostasis: Role of the Leptin-Melanocortin System
da Silva, A. A., do Carmo, J. M., & Hall, J. E. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01311-1 · Cited by 30
Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives
Tchang, B. G., Shukla, A. P., & Aronne, L. J. (2015) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2015.1052789 · Cited by 28
“Studies in lipoatrophic mice show that leptin replacement prevents insulin resistance at the level of the liver, independently of its effects on food intake and body weight, via reduction of hepatic triglyceride content, decreases in hepatic expression of gluconeogenic genes and improvement of insulin signaling [10].”
BackgroundTrajectory of leptin and leptin receptor in vertebrates: Structure, function and their regulation
Bakshi, A., Singh, R. K., & Rai, U. (2021) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2021.110652 · Cited by 28
Leptin Is Required for Glucose Homeostasis after Roux-en-Y Gastric Bypass in Mice
Mokadem, M., Zechner, J. F., Uchida, A., & Aguirre, V. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139960 · Cited by 25
Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol
Denroche, H. C., Kwon, M., Quong, W. L., Neumann, U. H., Kulpa, J. E., Karunakaran, S., Clee, S. M., Brownsey, R. W., Covey, S. D., & Kieffer, T. J. (2015) · Diabetologia · doi:10.1007/s00125-015-3529-4 · Cited by 25
“Leptin depletes hepatic energy-yielding stores in STZ-diabetic mice Several studies have shown that leptin reduces endogenous glucose production in rodent models of type 1 diabetes [1, 6, 11], suggesting that this may drive the glucose-lowering effect of leptin.”
BackgroundResultInfluentialRap1 in the VMH regulates glucose homeostasis
Kaneko, K., Lin, H., Fu, Y., Saha, P., la Puente-Gomez, A. B. D., Xu, Y., Ohinata, K., Chen, P., Morozov, A., & Fukuda, M. (2021) · JCI Insight · doi:10.1172/jci.insight.142545 · Cited by 25
Kim, G. H., Szabo, A., King, E. M., Ayala, J., Ayala, J. E., & Altarejos, J. Y. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.12.006 · Cited by 24
Foster, S. R., Omoruyi, F. O., Bustamante, J. J., Alexander-Lindo, R. L., & Dilworth, L. (2016) · International Journal of Experimental Pathology · doi:10.1111/iep.12210 · Cited by 24
Leptin deficiency affects glucose homeostasis and results in adiposity in zebrafish
He, J., Ding, Y., Nowik, N., Jager, C., Eeza, M. N. H., Alia, A., Baelde, H. J., & Spaink, H. P. (2021) · Journal of Endocrinology · doi:10.1530/joe-20-0437 · Cited by 23
Insulin Knockout Mice Have Extended Survival but Volatile Blood Glucose Levels on Leptin Therapy
Neumann, U., Denroche, H. C., Mojibian, M., Covey, S. D., & Kieffer, T. J. (2015) · Endocrinology · doi:10.1210/en.2015-1890 · Cited by 24
Leptin therapy in type 2 diabetes
Cummings, B. P. (2012) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12048 · Cited by 24
“Furthermore, leptin has been suggested to exert important glucoregulatory and insulin-sensitizing effects through central signalling pathways [6,14,33,37,38].”
BackgroundMeek, T. H., Matsen, M. E., Damian, V. M., Cubelo, A., Chua, S. C., & Morton, G. J. (2014) · Endocrinology · doi:10.1210/en.2014-1169 · Cited by 22
Self-citationCurrent and Emerging Treatment Options in Diabetes Care
Clemmensen, C., Müller, T. D., Finan, B., Tschöp, M. H., & DiMarchi, R. D. (2015) · Handbook of experimental pharmacology · doi:10.1007/164_2015_7 · Cited by 22
Boychuk, C. R., & Smith, B. N. (2016) · Journal of Neurophysiology · doi:10.1152/jn.00325.2016 · Cited by 22
da Silva, A. A., Spradley, F. T., Granger, J. P., Hall, J. E., & do Carmo, J. M. (2015) · Journal of Neurophysiology · doi:10.1152/jn.00911.2014 · Cited by 21
Matsen, M. E., Thaler, J. P., Wisse, B. E., Guyenet, S. J., Meek, T. H., Ogimoto, K., Cubelo, A., Fischer, J. D., Kaiyala, K. J., Schwartz, M. W., et al. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00488.2012 · Cited by 21
Self-citationExpanding neurotransmitters in the hypothalamic neurocircuitry for energy balance regulation
Xu, Y., & Tong, Q. (2011) · Protein & Cell · doi:10.1007/s13238-011-1112-4 · Cited by 20
“Strikingly, both peripheral and central administration of leptin effectively lowers glucose to a normal range, which is independent of its effects on body weight (Yu et al., 2008; Fujikawa et al., 2010; Wang et al., 2010; German et al., 2011).”
BackgroundLeptin modulates the daily rhythmicity of blood glucose
Grosbellet, E., Dumont, S., Schuster, C., Lemaître, B. J., Pévet, P., Criscuolo, F., & Challet, É. (2015) · Chronobiology International · doi:10.3109/07420528.2015.1035440 · Cited by 20
“, 2009), decreased hepatic glucose production, increased peripheral glucose uptake (German et al., 2011) and decreased insulin secretion as shown in ob/ob mice (Seufert et al.”
Backgrounddo Carmo, J. M., da Silva, A. A., Gava, F. N., Moak, S. P., Dai, X., & Hall, J. E. (2019) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00077.2019 · Cited by 19
Leptin Administration Enhances Islet Transplant Performance in Diabetic Mice
Denroche, H. C., Quong, W. L., Bruin, J. E., Tudurí, E., Asadi, A., Glavas, M. M., Fox, J. K., & Kieffer, T. J. (2013) · Diabetes · doi:10.2337/db12-1684 · Cited by 17
Does oral glutamine improve insulin sensitivity in adolescents with type 1 diabetes?
Torres‐Santiago, L., Mauras, N., Hossain, J., WELTMAN, A. L., & Darmaun, D. (2016) · Nutrition · doi:10.1016/j.nut.2016.09.003 · Cited by 20
Sweatman, C. Z. W. H. (2019) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2019.110037 · Cited by 19
Ito, Y., Sun, R., Yagimuma, H., Taki, K., Mizoguchi, A., Kobayashi, T., Sugiyama, M., Onoue, T., Tsunekawa, T., Takagi, H., et al. (2022) · Diabetes · doi:10.2337/db21-0953 · Cited by 19
Central regulation of glucose metabolism in an insulin‐dependent and ‐independent manner
Fujikawa, T. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12941 · Cited by 21
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The Brain–Liver Connection Between BDNF and Glucose Control
Jo, Y., & Chua, S. C. (2013) · Diabetes · doi:10.2337/db12-1824 · Cited by 18
“The current report by Morton and colleagues (3) builds upon the group’s previous work with leptin’s effect on diabetic rats (19) with the clear anticipation that BDNF is a mediator of leptin.”
BackgroundPitra, S., & Smith, B. N. (2020) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00368.2020 · Cited by 15
Chan, L. K. Y., & Leung, P. S. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00373.2015 · Cited by 17
Wegeberg, A., Meldgaard, T., Bæk, A., Drewes, A. M., Vyberg, M., Jessen, N., Brock, B., & Brock, C. (2021) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13575 · Cited by 16
A mathematical model of type 1 diabetes involving leptin effects on glucose metabolism
Kadota, R., Sugita, K., Uchida, K., Yamada, H., Yamashita, M., & Kimura, H. (2018) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2018.08.008 · Cited by 14
Metadata
- Authors
- German, J. P., Thaler, J. P., Wisse, B. E., Oh-I, S., Sarruf, D. A., Matsen, M. E., Fischer, J. D., Taborsky, G. J., Schwartz, M. W., & Morton, G. J.
- Affiliations
- University of Washington (US)
- Diabetes and Obesity Center of Excellence (J.P.G., J.P.T., B.E.W., S.O.-I., D.A.S., M.E.M., J.D.F., M.W.S., G.J.M.), Department of Medicine, University of Washington, Seattle, Washington 98109
- VA Puget Sound Health Care System (US)
- Corresponding author
- Morton, Gregory J.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2010-12-15
- Volume
- 152
- Issue
- 2
- Pages
- 394-404
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3037161
- OpenAlex
- W1996800212
- Semantic Scholar
- 7c46f9454e2b40dacf481b15d5c0a823b6dc64a7
- Cited by
- 169
- References
- 65
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 6 · 2017: 14 · 2016: 18 · 2015: 23 · 2014: 14 · 2013: 16 · 2012: 11
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- University of Washington
- National Institutes of Health (1u24dk076126-01)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074758, DK-083042, U24-DK076126, DK 035816, DK-050154-13, R56DK050154, R01DK050154, R01DK090320, P30DK035816, R01DK083042)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, diabetic hyperglycemia, insulin-independent glucose regulation, hepatic glucose production, tissue glucose uptake, streptozotocin-induced diabetes, insulin deficiency
- MeSH terms
- Animals, Blood Glucose, Body Composition, Brain, Corticosterone, Diabetes Mellitus, Experimental, Glucagon, Glucose Tolerance Test, Hyperglycemia, Insulin, Male, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Leptin, Rats
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