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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 · 36 Not checked yet · 18 Own interpretation · 3 No basis given · 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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- 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 · 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.
- 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: § 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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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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- Load-bearing: passes — The paper’s conclusions depend on it.
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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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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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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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
“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 -cells.”
- Also stated in: § CNS leptin infusion normalizes blood glucose levels in STZ-induced diabetes · plain
“blood glucose levels normalized to nondiabetic levels by d 7 in STZ-diabetic rats receiving icv leptin (Fig. 1D).”
- Also stated in: § Discussion · boosted
“We 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 recovery of pancreatic -cells and does not involve a peripheral action of leptin.”
boosteddirect- 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
“our findings demonstrate that this can occur in insulin-deficient rats”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
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In the paper
“plasma levels of both insulin and leptin (Fig. 1, A and B) were significantly reduced within 48 h in all animals that received STZ and remained very low relative to nondiabetic controls”
§ 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
“basal Rd values were similar between STZdiabetic animals receiving leptin and nondiabetic controls”
§ 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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Because the effect of leptin to ameliorate diabetic hyperglycemia could not be explained by reduced food intake, increased urinary glucose excretion, or a recovery of pancreatic -cells”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
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In the paper
“basal Ra measured by tracer dilution were markedly elevated in STZ-veh-PF animals compared with nondiabetic controls (Fig. 3A).”
§ 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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In the paper
“icv leptin treatment further increased glucose uptake into BAT (Fig. 5, I and J).”
§ 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
“the effect of hyperglycemia to increase Rg in skeletal muscle and heart was similar between STZ-leptin and nondiabetic controls”
§ 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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“After the induction of diabetes in STZ-treated rats receiving icv veh, body weight continuously decreased despite pronounced hyperphagia”
§ 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
“hepatic expression of Igfbp2 mRNA was increased by mote than 25-fold in leptin-deficient STZ-diabetic rats compared with nondiabetic controls.”
§ 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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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
“the severe insulin deficiency (under both basal and glucose-stimulated conditions) caused by STZ-induced -cell destruction was not ameliorated by icv leptin.”
§ 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
“Even though hepatic Igfbp2 mRNA levels were further increased by 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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In the paper
“liver glycogen levels were dramatically reduced in STZ-treated animals receiving icv leptin compared with the other groups (Fig. 4E)”
§ 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
“STZ-leptin-treated animals exhibited near normal glucose tolerance compared with nondiabetic controls”
§ 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
“Our finding that icv leptin reversed the effect of STZ diabetes to increase both glucagon secretion and the expression of these gluconeogenic genes (6)”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [6] Hidaka, 2002, Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats., FASEB J source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“our finding that icv leptin also increases glucose uptake in rats with 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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In the paper
“despite markedly increased HGP and reduced plasma leptin levels.”
§ 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
“during the hyperglycemic clamp, whole-body Rd were substantially increased in STZ-diabetic animals receiving icv leptin”
§ 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
“combined with the marked reduction of circulating leptin levels in this setting”
§ 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
“despite markedly increased HGP and reduced plasma leptin levels.”
§ 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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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Our finding that icv leptin reversed the effect of STZ diabetes to increase both glucagon secretion and the expression of these gluconeogenic genes (6)”
- Also stated in: § Discussion · plain
“our finding that the effect of STZ diabetes to raise plasma glucagon levels is prevented by icv leptin”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [6] Hidaka, 2002, Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats., FASEB J source
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
“Using tracer dilution techniques, we found that Rd was similar between STZ-diabetic rats receiving icv leptin and nondiabetic controls.”
§ 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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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
“our finding of increased glucose uptake in muscle, brain, BAT, and heart in STZ-diabetic animals receiving icv leptin compared with icv veh.”
- Also stated in: § Discussion · plain
“CNS leptin suppresses HGP and increases Rg 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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- Also stated in: § Discussion · plain
None of the sources cited for this claim have been checked yet.
In the paper
“this effect was prevented by icv leptin treatment.”
§ 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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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 observed that in diabetic animals, hepatic expression of Igfbp2 was elevated more than 25-fold over nondiabetic controls”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“despite the absence of any glucose-stimulated increase of circulating insulin”
§ 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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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
“CNS leptin infusion normalizes hepatic gluconeogenic gene expression 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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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
“CNS leptin normalizes blood glucose 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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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
“this effect was accompanied by a further increase in glucose uptake in BAT.”
§ 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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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
“Because this suppression of HGP occurs despite near undetectable plasma insulin levels, it differs from the previously documented effect of CNS leptin to increase hepatic insulin sensitivity (10 -13) and implies the existence of an insulinindependent mechanism.”
- Also stated in: § Discussion · boosted
“Because each of these effects occurs despite persistent, severe insulin deficiency, even during a hyper-glycemic clamp, our findings constitute direct support for the existence of a novel brain mechanism for insulin-independent normalization of blood glucose in animals with uDM.”
§ 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
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Discussion · boosted
In the paper
“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
“However, 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).”
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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- Load-bearing: passes — 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 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
“To directly test the hypothesis that icv leptin suppresses HGP and stimulates glucose utilization in animals with uDM through an insulin-independent mechanism, we subjected both leptin-treated STZ-diabetic animals and veh-treated nondiabetic controls to a hyperglycemic clamp (Fig. 5).”
- Also stated in: § Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes · plain
“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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- Also stated in: § Effect of icv leptin infusion on HGP and glucose uptake in STZ-induced diabetes · plain
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
“suggesting that leptin action in the brain reduces HGP in rats with uDM by inhibiting gluconeogenic gene expression, independent of insulin signaling (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
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
“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.”
- Also stated in: § Discussion · plain
“This leptin effect is distinct from its previously reported action to increase hepatic insulin sensitivity (10 -13) and suggests that through its central action, leptin has important potential as an effective, insulin-independent adjunct to the treatment of type 1 diabetes in humans.”
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
plain- 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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- Also stated in: § Discussion · plain
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
“offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.”
- Also stated in: § Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia · boosted
“These data establish that the brain has an ability to normalize diabetic hyperglycemia”
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia · boosted
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
“a finding that may underlie the effect of icv leptin to reduce HGP.”
§ 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
hedgedconditional- 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
“this effect seems unlikely to explain the effect of leptin to normalize HGP (P Ͻ 0.05) (Fig. 4C).”
§ 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
hedged- 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
“suggests that through its central action, leptin has important potential as an effective, insulin-independent adjunct to the treatment of type 1 diabetes in humans.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedgedconditional- 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
“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 > CNS leptin infusion normalizes plasma glucagon and corticosterone levels in STZ-induced diabetes
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“unrestrained HGP (through increases of both glycogenolysis and gluconeogenesis) to severe hyperglycemia in uDM”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [32] Wahren, 2007, Splanchnic regulation of glucose production., Annu Rev Nutr source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Insulin-mediated inhibition of HGP is essential for normal glucose homeostasis”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [32] Wahren, 2007, Splanchnic regulation of glucose production., Annu Rev Nutr source
plaindirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“tracer-based estimates of the Rd are artificially increased in STZ-diabetic animals receiving veh, because Rd values encompass both whole-body glucose utilization and urinary glucose loss (Fig. 3B).”
§ 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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None of the sources cited for this claim have been checked yet.
In the paper
“Elevated plasma glucagon and corticosterone levels are implicated in the pathogenesis of hyperglycemia in uDM (29 -31).”
§ 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
- Not checked yetcites [29] Müller, 1971, The effect of experimental insulin deficiency on glucagon secretion., J Clin Invest source
- Not checked yetcites [30] Dobbs, 1975, Glucagon: role in the hyperglycemia of diabetes mellitus., Science source
- Not checked yetcites [31] Scribner, 1991, Chronic streptozotocin diabetes in rats facilitates the acute stress response without altering pituitary or adrenal responsiveness to secretagogues., Endocrinology source
plainconditional- 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
“recent evidence suggests that pharmacological administration of leptin systemically (3,4) can also normalize blood glucose levels in rodent models of uncontrolled diabetes mellitus (uDM).”
What the sources say
- Not checked yetcites [3] Chinookoswong, 1999, Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat., Diabetes source
- Not checked yetcites [4] Yu, 2008, Making insulin-deficient type 1 diabetic rodents thrive without insulin., Proc Natl Acad Sci USA source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“confirming previous reports that uDM is a model of leptin and insulin deficiency (24).”
§ 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
What the sources say
- Not checked yetcites [24] Havel, 1998, Marked and rapid decreases of circulating leptin in streptozotocin diabetic rats: reversal by insulin., Am J Physiol
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“constituting direct evidence of a brain mechanism for reducing HGP independent of insulin (33).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [33] Chari, 2008, Activation of central lactate metabolism lowers glucose production in uncontrolled diabetes and diet-induced insulin resistance., Diabetes source
boosteddirect- 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 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
“Given the already elevated levels of Igfbp2 in uDM, a further increase in hepatic Igfbp2 by leptin seems unlikely to inhibit HPG.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedged- 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
“Leptinmediated normalization of glucocorticoid levels may therefore have contributed to reversal of diabetic hyperglycemia.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Glucocorticoids can exacerbate hyperglycemia by increasing hepatic gluconeogenesis (by inducing expression of G6Pase and Pepck) (46)”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [46] Exton, 1979, Regulation of gluconeogenesis by glucocorticoids., Monogr Endocrinol source
plaindirect- 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
“we conclude that mechanisms in addition to normalization of glucagon levels likely contribute to leptin's antidiabetic effects.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“this is partially reversed with corticosteroid replacement (45).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [45] Strack, 1995, Glucocorticoids and insulin: reciprocal signals for energy balance., Am J Physiol
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Increased glucocorticoid secretion is thought to contribute to hyperglycemia in uDM”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [45] Strack, 1995, Glucocorticoids and insulin: reciprocal signals for energy balance., Am J Physiol
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent study demonstrated that adenovirally induced hyperleptinemia ameliorates hyperglycemia in STZ diabetes”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [4] Yu, 2008, Making insulin-deficient type 1 diabetic rodents thrive without insulin., Proc Natl Acad Sci USA source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“adrenalectomy attenuates the rise in blood glucose in STZ-diabetic rats”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [45] Strack, 1995, Glucocorticoids and insulin: reciprocal signals for energy balance., Am J Physiol
plaindirect- 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.
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In the paper
“and glycogen synthesis (47)”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [47] Stalmans, 1979, Glucocorticoids and hepatic glycogen metabolism., Monogr Endocrinol source
plaindirect- 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.
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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
“In uDM, therefore, reduced leptin signaling in the brain may constitute a stimulus to the hypothalamic-pituitary-adrenal axis, raising plasma corticosterone levels.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedgedconditional- 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
“these effects are in fact mediated on distinct proopiomelanocortin neuronal subsets (37,38).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [37] Hill, 2010, Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility., Cell Metab source
- Not checked yetcites [38] Williams, 2010, Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons., J Neurosci source
plaindirect- 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
“suggesting that the neurocircuitry that mediates leptin's glucose-lowering effects is distinct from those CNS pathways activated by insulin.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“icv infusion of insulin at a dose that attenuates diabetic hyperphagia fails to normalize blood glucose levels in STZ-diabetic rats (36)”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [36] Sipols, 1995, Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression., Diabetes source
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.
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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
“This effect, in concert with insulin deficiency and glucagon excess, may help to drive hyperglycemia.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
hedgedconditional- 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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None of the sources cited for this claim have been checked yet.
In the paper
“although both hormones exert phosphatidylinositol-3-OH kinase-dependent effects on hypothalamic POMC cells”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [37] Hill, 2010, Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility., Cell Metab source
- Not checked yetcites [38] Williams, 2010, Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons., J Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Hyperglucagonemia contributes to diabetic hyperglycemia (29,30) in part by driving hepatic expression of the key gluconeogenic enzymes Pepck and G6Pase.”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
plaindirect- 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.
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None of the sources cited for this claim have been checked yet.
In the paper
“hypothalamic effects of both insulin and leptin are dependent on neuronal phosphatidylinositol-3-OH kinase signaling”
§ 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“and inhibiting peripheral glucose uptake in muscle and adipose tissue (48).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [48] Rizza, 1982, Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action., J Clin Endocrinol Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“circulating levels of corticosterone were elevated in STZ-diabetic rats (44)”
§ 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
plaincorrelational- 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.
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None of the sources cited for this claim have been checked yet.
In the paper
“leptin activation of BAT in nondiabetic animals clearly involves increased sympathetic nervous system (SNS) outflow that in turn induces uncoupling protein-1 (53,54).”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [53] Scarpace, 1998, Leptin induction of UCP1 gene expression is dependent on sympathetic innervation., Am J Physiol
- Not checked yetcites [54] Scarpace, 1997, Leptin increases uncoupling protein expression and energy expenditure., Am J Physiol
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“neither chemical denervation of the SNS (8) nor combined ␣and b-adrenergic receptor blockade attenuated the effect of leptin to restore euglycemia in rats with uDM”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [8] Wang, 2008, Guanethidine treatment does not block the ability of central leptin administration to decrease blood glucose concentrations in streptozotocin-induced diabetic rats., J Endocrinol source
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.
In the paper
“neither chemical denervation of the SNS (8) nor combined ␣and b-adrenergic receptor blockade attenuated the effect of leptin to restore euglycemia in rats with uDM”
§ Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia > Discussion
What the sources say
- Not checked yetcites [8] Wang, 2008, Guanethidine treatment does not block the ability of central leptin administration to decrease blood glucose concentrations in streptozotocin-induced diabetic rats., J Endocrinol source
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.
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
“In summary, these findings suggest that in response to leptin stimulation, the brain has the inherent ability to normalize blood glucose levels in uDM via a novel, insulin-independent mechanism characterized by reduced rates of glucose production and increased rates of glucose uptake.”
§ 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.
- 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.
- It may state two separate claims as one. 16
- Probably not a substantial claim. 4
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
“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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“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.
- 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.
It may state two separate claims as one.
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-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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“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.
- 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.
It may state two separate claims as one.
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
“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.
- 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.
It may state two separate claims as one.
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
“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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.
- 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.
It may state two separate claims as one.
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
“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.
- 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.
It may state two separate claims as one.
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
“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.
- 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.
It may state two separate claims as one.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- 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.
It may state two separate claims as one.
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 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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
- 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.
- 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.
It may state two separate claims as one.
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.
- 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.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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.
- 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.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
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.
- 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.
It may state two separate claims as one.
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.
- 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.
It may state two separate claims as one.
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)”
Claims other papers make about this one
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]
Self-check
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)”
Citations
Cites
The rat brain in stereotaxic coordinates
Palkovits, M. (1983) · Neuropeptides · doi:10.1016/0143-4179(83)90049-5 · Cited by 28,959
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585
Role of leptin in the neuroendocrine response to fasting
Ahima, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996) · Nature · doi:10.1038/382250a0 · Cited by 3,117
Hypothalamic insulin signaling is required for inhibition of glucose production
Obici, S., Zhang, B. B., Karkanias, G., & Rossetti, L. (2002) · Nature Medicine · doi:10.1038/nm1202-798 · Cited by 904
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G., & Rossetti, L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-861 · Cited by 719
RIZZA, R. A., MANDARINO, L. J., & GERICH, J. E. (1982) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-54-1-131 · Cited by 696
Central Administration of Oleic Acid Inhibits Glucose Production and Food Intake
Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G., & Rossetti, L. (2002) · Diabetes · doi:10.2337/diabetes.51.2.271 · Cited by 654
Hypothalamic KATP channels control hepatic glucose production
Pocai, A., Lam, T. K. T., Gutierrez-Juarez, R., Obici, S., Schwartz, G. J., Bryan, J., Aguilar-Bryan, L., & Rossetti, L. (2005) · Nature · doi:10.1038/nature03439 · Cited by 645
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G. B., et al. (2002) · Nature Neuroscience · doi:10.1038/nn861 · Cited by 572
DeFronzo, R. A., Simonson, D. C., & Ferrannini, E. (1982) · Diabetologia · doi:10.1007/bf00253736 · Cited by 539
Research works printed but not linked: 1
- Maghnie, 2003, Diabetes insipidus., Horm Res, 59, 42
Cited by
Sorted by citations
Thyroid Hormone Regulation of Metabolism
Mullur, R., Liu, Y.-Y., & Brent, G. A. (2014) · Physiological Reviews · doi:10.1152/physrev.00030.2013 · Cited by 2,421
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484
Neurobiology of food intake in health and disease
Morton, G. J., Meek, T. H., & Schwartz, M. W. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3745 · Cited by 748
Self-citationPhysiology of leptin: energy homeostasis, neuroendocrine function and metabolism
Park, H. K., & Ahima, R. S. (2014) · Metabolism · doi:10.1016/j.metabol.2014.08.004 · Cited by 710
“Leptin potently suppresses hepatic glucose production partly by ameliorating hyperglucagonemia and increases peripheral glucose uptake, via multiple mechanisms including POMC- and AgRP-expressing neurons in the ARC [105–108].”
BackgroundLeptin in Human Physiology and Pathophysiology
Mantzoros, C. S., Magkos, F., Brinkoetter, M., Sienkiewicz, E., Dardeno, T. A., Kim, S.-Y., Hamnvik, O.-P. R., & Koniaris, A. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00315.2011 · Cited by 593
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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