Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo (original) (raw)
Related papers
Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations
Diabetes, 2006
Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25–30 mmol/l and In-R1-G9 cells at 12–20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the α-cells. Studies of isolated mouse α-cells indicated tha...
Brain Research, 1987
We have studied the involvement of central nervous system (CNS) insulin receptors in mediating the central hypoglycemic effect of insulin by using insulin derivatives modified at regions of the hormone necessary for receptor reactivity and peripheral bioactivity. Acetylation or succinylation of the 3 free amino groups of insulin at positions A1, B1 and B29 resulted in a corresponding decrease in lipogenic activity in isolated rat adipocytes, with concentrations of hormone required to produce half the maximal effect (EDs0) being 0.15 ng/ml, 3 ng/ml and 50 ng/ml for native insulin, acetyi 3 insulin and succinyl 3 insulin, respectively. Moreover, the modified insulins exhibited diminished hypoglycemic effect following central administration in mice, with the doses needed for suppression of plasma glucose to 50% of basal levels being 1/~g, 10/~g and 25 ~g for native insulin, acetyl 3 insulin and succinyl 3 insulin, respectively. Because binding of insulin derivatives to CNS receptors can be predicted from their peripheral bioactivity, the present finding of parallel decrements in lipogenic activity in vitro and central hypoglycemic effect in vivo, following modification of insulin at regions implicated in receptor activation, is consistent with the view that insulin exerts its central effect on plasma glucose by interacting with specific CNS receptor sites which are closely related to the peripheral insulin receptors.
Diabetes, 2005
The intraislet insulin hypothesis for the signaling of the glucagon secretory response to hypoglycemia states that a decrease in arterial glucose → a decrease in β-cell insulin secretion → a decrease in tonic α-cell inhibition by insulin → an increase in α-cell glucagon secretion. To test this hypothesis in humans, a hyperinsulinemic- euglycemic (∼5.0 mmol/l [90 mg/dl] × 2 h) and then a hypoglycemic (∼3.0 mmol/l [55 mg/dl] × 2 h) clamp was performed in 14 healthy young adults on two occasions, once with oral administration of the ATP-sensitive potassium channel agonist diazoxide to selectively suppress baseline insulin secretion and once with the administration of a placebo. The decrement in plasma C-peptide during the induction of hypoglycemia was reduced by ∼50% in the diazoxide clamps (from 0.3 ± 0.0 to 0.1 ± 0.0 nmol/l [0.8 ± 0.1 to 0.4 ± 0.1 ng/ml]) compared with the placebo clamps (from 0.4 ± 0.0 to 0.1 ± 0.0 nmol/l [1.2 ± 0.1 to 0.4 ± 0.1 ng/ml]) (P = 0.0015). This reduction ...
Diabetes, 2002
Glucagon is a potent stimulator of insulin release in the presence of a permissive glucose concentration, activating -cells in vitro via both glucagon-and glucagon-like peptide-1 (GLP-1)-receptors. It is still unclear whether locally released glucagon amplifies the secretory responsiveness of neighboring -cells in the intact pancreas. The present study investigates this question in the perfused pancreas by examining the effects of antagonists for glucagon receptors ([des-His 1 ,des-Phe 6 ,Glu 9 ]glucagon-NH 2 , 10 mol/l) and GLP-1-receptors [exendin-(9-39)-NH 2 , 1 mol/l] on the insulin secretory response to glucose. The specificity of both antagonists was demonstrated by their selective interaction with glucagon-receptor signaling in rat hepatocytes and GLP-1-receptor signaling in Chinese hamster lung (CHL) fibroblasts. In purified rat -cells, the glucagon-receptor antagonist (10 mol/l) inhibited the effect of 1 nmol/l glucagon upon glucose-induced insulin release by 78 ؎ 6%. In the perfused rat pancreas, neither of these antagonists inhibited the potent secretory response to 20 mmol/l glucose, although they effectively suppressed the potentiating effect of, respectively, an infusion of glucagon (1 nmol/l) or GLP-1 (1 nmol/l) on insulin release. When endogenous glucagon release was enhanced by isoproterenol (100 nmol/l), no amplification was seen in the simultaneous or subsequent insulin secretory response to glucose. It is concluded that, at least under the present selected conditions, the glucose-induced insulin release by the perfused rat pancreas seems to occur independent of an amplifying glucagon signal from neighboring ␣-cells.
Diabetes, 2002
Glucagon is a potent stimulator of insulin release in the presence of a permissive glucose concentration, activating -cells in vitro via both glucagon-and glucagon-like peptide-1 (GLP-1)-receptors. It is still unclear whether locally released glucagon amplifies the secretory responsiveness of neighboring -cells in the intact pancreas. The present study investigates this question in the perfused pancreas by examining the effects of antagonists for glucagon receptors ([des-His 1 ,des-Phe 6 ,Glu 9 ]glucagon-NH 2 , 10 mol/l) and GLP-1-receptors [exendin-(9-39)-NH 2 , 1 mol/l] on the insulin secretory response to glucose. The specificity of both antagonists was demonstrated by their selective interaction with glucagon-receptor signaling in rat hepatocytes and GLP-1-receptor signaling in Chinese hamster lung (CHL) fibroblasts. In purified rat -cells, the glucagon-receptor antagonist (10 mol/l) inhibited the effect of 1 nmol/l glucagon upon glucose-induced insulin release by 78 ؎ 6%. In the perfused rat pancreas, neither of these antagonists inhibited the potent secretory response to 20 mmol/l glucose, although they effectively suppressed the potentiating effect of, respectively, an infusion of glucagon (1 nmol/l) or GLP-1 (1 nmol/l) on insulin release. When endogenous glucagon release was enhanced by isoproterenol (100 nmol/l), no amplification was seen in the simultaneous or subsequent insulin secretory response to glucose. It is concluded that, at least under the present selected conditions, the glucose-induced insulin release by the perfused rat pancreas seems to occur independent of an amplifying glucagon signal from neighboring ␣-cells.
Metabolism-clinical and Experimental, 2000
The study aim was to investigate the effect of the route of insulin treatment on the glucagon and glucose production (GP) responses to hypoglycemia in the diabetic rat. Experiments were performed in 4 groups of rats: (1) streptozotocin (STZ)-induced diabetic, untreated (D, n ؍ 7), (2) diabetic treated with subcutaneous insulin (DSC, n ؍ 8), (3) diabetic treated with intraperitoneal insulin (DIP, n ؍ 6), and (4) normal control (N, n ؍ 10). Slow-release insulin implants were used in DSC and DIP rats for 10 to 14 days (3 U/d). A hyperinsulinemic (120 pmol · kg ؊1 · min ؊1 insulin)-hypoglycemic (glycemia ؍ 2.5 ؎ 0.1 mmol/L) clamp following an isoglycemic basal period was performed in 5-hour fasted rats. Basal plasma glucose was normalized in both DSC and DIP rats; however, in DSC but not DIP rats, glucose normalization required peripheral hyperinsulinemia. Tracer-determined GP, which was elevated in D rats, was completely normalized in DIP but only partially corrected in DSC rats. Basal glucagon levels were similar in all groups. During hypoglycemia, GP was suppressed in D rats (⌬, ؊28.9 ؎ 5.0 mol · kg ؊1 · min ؊1 ), moderately increased in DSC rats (⌬, 6.1 ؎ 5.6, P F .01 v D), but markedly increased in DIP and N rats (⌬, 34.5 ؎ 4.5 for DIP and 16.8 ؎ 2.8 for N; P F .01 v D, P F .05 for DIP v DSC or N). Plasma glucagon increased 6-fold in N (945 ؎ 129 pg/mL), only doubled in D (424 ؎ 54), and tripled in DSC (588 ؎ 83), but increased 5-fold in DIP rats (1,031 ؎ 75, P F .05 v D and DSC). We conclude that in STZ-diabetic rats, (1) intraperitoneal but not subcutaneous insulin treatment normalizes basal GP, and (2) intraperitoneal insulin treatment as compared with subcutaneous treatment alleviates peripheral hyperinsulinemia and results in increased glucagon and GP responses to hypoglycemia.
Insulin and glucagon release of human islets in vitro: effects of chronic exposure to glucagon
Journal of Endocrinology, 1997
Hyperglucagonemia is commonly found in insulin\x=req-\ dependent as well as in non-insulin-dependent diabetes mellitus, and is likely to be caused by absolute or relative insulin deficiency. The aim of the present study was to evaluate whether a chronic glucagon exposure (1\m=.\0\ g=m\m for 4 h) modifies the insulin response to acute stimuli with glucagon (1\m=.\0\g=m\m),arginine (10\m=.\0 mm) and glucose (16\m=.\7 mm), or the glucagon response to arginine and glucose, in human islets. Chronic exposure to glucagon did not affect the insulin response to glucose and arginine, but inhibited its response to glucagon (44\m=.\6\ m=+-\ 9\m=.\3 vs 168\m=.\6\ m=+-\52\m=.\3 pg/islet per 20 min, P<0\m=.\05); the latter effect was not observed when exposure to glucagon was discontinuous (2\m=.\0\g=m\mglucagon alternated with control medium for 30 min periods). The chronic exposure to glucagon also reduced the glucagon response to arginine ( \ m=-\4\ m=. \ 9\ m=+-\ 5\m=.\7 vs 19\m=.\9\ m=+-\ 7\ m=. \ 9pg/islet per 20 min, P<0\m=.\05) without affecting the inhibition of glucagon release exerted by glucose. These data indicate that chronic exposure to glucagon desensitizes pancreatic \g=a\and \ g=b\ cells in response to selected stimuli.