In vivo inhibition of glucagon secretion by paracrine beta cell activity in man.

Abstract

A B S T R A C T The close anatomical relationships between pancreatic alpha and beta cells makes possible their interaction at a local (paracrine) level. To demonstrate this in vivo, we have compared the acute glucagon response to intravenous arginine in the basal state and after beta cell suppression by infusions of insulin. The plasma glucose concentration was maintained by the glucose clamp technique. In six normal weight nondiabetics, infusion of insulin at 0.2 mU/kg per min (rate 1) raised the mean±SEM plasma insulin levels from 10±3 to 32±4 mU/liter and at 1 mU/kg per min (rate 2) raised plasma insulin to 84±8 mU/liter. This resulted in beta cell suppression, as shown by a diminution in the acute insulin response (incremental area under the insulin response curve, 0-10 min): basal = 283+61, 199±66 (rate 1) and 143±48 mU/liter per 10 min (rate 2) and a fall in prestimulus C-peptide from 1.05±0.17 to 0.66±0.15 and to 0.44±0.15 nM/liter (all P < 0.01). This beta cell suppression was associated with increased glucagon responses to arginine: 573±75 (basal), 829±114 (rate 1), and 994±136 ng/liter per 10 min (rate 2) and increased peak glucagon responses 181±11 (basal), 214±16 (rate 1), and 259±29 ng/liter (rate 2) (all P < 0.01). In all subjects, there was a proportional change between the rise in the acute glucagon response to arginine and the fall in the prearginine C-peptide level. To demonstrate that augmented glucagon response was due to beta cell suppression, and not to the metabolic effect of infused insulin, similar studies were performed in C-peptide-negative-diabetics. Their acute glucagon response to arginine was

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

“…They concluded that insulin maintains an ongoing restraint on ␣-cell secretion and that loss of this inhibition by insulin may account for the hyperglucagonemia observed in insulin-deficient states. These initial observations were followed by a series of in vivo and in vitro experiments (23)(24)(25)(26)(27)(28)(29)(30) [AICAR]) and phlorizin. This combination induced moderate and equivalent hypoglycemia in both diabetic and nondiabetic animals in the absence of marked hyperinsulinemia.…”

Dipeptidyl Peptidase IV Inhibition Reduces the Degradation and Clearance of GIP and Potentiates Its Insulinotropic and Antihyperglycemic Effects in Anesthetized Pigs

“…stimulating glucagon secretion. The apparent paradox, whereby GIP potentiates the reduction in glucagon levels in response to the glucose load, could be a consequence of an indirect effect caused by the inhibitory effect of GIPinduced insulin secretion (52).…”

“…An intravenous infusion of glucose (0.2 g/kg; 50% solution) was administered between minutes 38 and 47. Arterial blood samples (4 ml) were collected at Ϫ10, 0, 10,20,30,32,35,37,42,47,49,52,54, and 57 min from the start of the infusion. After 57 min, the GIP infusion was stopped, and further blood samples were collected at 5,10,15,20,30,45,60, and 90 min.…”

Retrograde perfusion as a model for testing the relative effects of glucose versus insulin on the A cell.

“…The retrogradely perfused A cell may mimic the behavior of the A cell in islets from C-peptide negative type I diabetics (1,6,7), as well as from animals with experimentally induced diabetes (5,14). It has been well documented that glucose poorly restrains glucagon secretion in the absence of insulin (1-4).…”