Pancreatic Beta-cell Response Research Articles

The mechanism of abnormal pancreatic beta cell response to food following acute hypoglycaemia in man.

Following acute insulin-induced hypoglycaemia, an abnormal pattern of insulin secretion in response to a meal has been demonstrated in six healthy volunteers. This is characterized by an initial impairment in insulin secretion and late hyperinsulinaemia. Postprandial gastrointestinal hormone levels were normal following hypoglycaemia in these subjects. In four other subjects, the administration of intravenous glucose prior to the meal partially reversed the abnormal pattern of secretion. In two patients with a total pre-ganglionic sympathectomy, the pattern of blood glucose, plasma insulin and C-peptide was similar to that observed following hypoglycaemia in normal subjects. It is unlikely that an abnormal entero-insular axis or an elevation of plasma catecholamine levels are primarily responsible for this phenomenon. This effect of hypoglycaemia on postprandial insulin secretion may be caused by glucopenia of the pancreatic beta cells.

Diabetogenic effects of chronic oral cadmium adminstration to neonatal rats.

1 Chronic exposure of neonatal rats to oral cadmium (Cd) (0.1 and 1.0 micrograms/g daily for 45 days) disturbed glucose homeostasis, as reflected by hyperglycaemia, reduced liver glycogen and enhanced gluconeogenic potential of hepatic tissue. 2 This Cd-exposure regimen also increased hepatic cyclic adenosine 3',5'-monophosphate (cyclic AMP) which was accompanied by enhancement of basal, adrenaline and glucagon-stimulated form(s) of adenylate cyclase. 3 In order to assess the responsiveness of pancreatic beta cells to glucose, islets isolated from control as well as Cd-exposed animals were incubated in vitro and their rate of insulin secretion determined. In the presence of glucose 0.5 mg/ml, there was no significant difference in the rate of insulin release. However, at higher glucose concentrations (1.5 and 3.0 mg/ml), the islets from Cd-exposed rats released significantly less insulin than those of control animals. 4 The results are discussed in relation to the possible mechanism of the diabetogenic effect of Cd.

Attenuation of the pancreatic beta cell response to a meal following hypoglycaemia in man.

The plasma concentration of C-peptide, insulin (IRI) and glucose was measured in 9 healthy subjects during insulin-induced hypoglycaemia followed by a meal. Identical observations were made in the same subjects after an equivalent period of fasting without hypolycaemia (control study). Endogenous secretion of insulin was suppressed following administration of exogenous insulin and this persisted long after the blood glucose concentration had returned to normal. After the meal the mean blood glucose rose to a peak of 8.4 +/- 0.3 mmol/l (mean +/- SEM) at 60 min and was still raised at 7.5 +/- 0.3 mmol/l at 120 min, compared with a peak value of only 5.1 +/- 0.2 mmol/l at 30 min after the meal in the control study. Following hypoglycaemia the mean plasma IRI rose from 8.3 +/- 1.3 mU/l to a delayed peak of 81.6 +/- 12.7 mU/l at 60 min and was 123.5 +/- 14 mU/l at 120 min post-prandially, compared with a peak of 72.4 +/- 0.5 mU/l at 30 min after the meal in the control study. Acute hypoglycaemia may thus induce in abnormal pattern of insulin secretion in response to a meal, with impaired carbohydrate tolerance in normal subjects.

Ethnic Variability in the Plasma Insulin Response to Oral Glucose in Polynesian and Micronesian Subjects

The pattern of insulin response to oral glucose over a wide range of glucose tolerance has been studied in two separate ethnic groups--Polynesians and Micronesians. Fasting insulin concentrations were relatively unchanged over the entire range of glucose tolerance in both populations, irrespective of whether comparable lean or obese samples of both groups were studied. The patterns of 2-h plasma insulins were similar over the whole range of glucose tolerance in Polynesians and Micronesians. However, in the comparisons of all subjects, or lean or obese groups of these populations, the plasma insulin concentrations of the Micronesians were both consistently and significantly higher. As the data analysis was arranged to take into account groups with identical 2-h plasma glucose concentrations and comparable degrees of obesity, the differences cannot be attributed to differences in the glucose levels or in obesity. In the presence of similar fasting insulin concentrations, these findings imply an ethnic variability in the pancreatic beta-cell response to oral glucose.

Insulin sensitivity of adipose tissue in vitro and the response to exogenous insulin in obese human subjects

The effect of varying concentrations of insulin on 1- 14C-glucose conversion to 14CO 2 was measured in subcutaneous adipose tissue samples obtained from 16 obese human subjects (10 nondiabetic, 6 diabetic). An index of insulin sensitivity in vitro, K ins, was calculated as the concentration of insulin stimulating one-half maximal 14CO 2 production. An index of insulin sensitivity in vivo, K itt, was calculated as the rate constant for decrease in blood glucose after rapid intravenous administration of 0.05 U/kg insulin. There was, over-all, a significant correlation between K ins and K itt, indicating that insulin sensitivity of 1- 14C-glucose oxidation by adipose tissue in vitro reflects the general state of sensitivity of glucose metabolism to insulin in vivo in obese human subjects. The mean values for both K ins and K itt in the nondiabetic subjects were significantly different from those in the diabetic subjects, indicating greater sensitivity to insulin in the former group. The nondiabetic group was also distinguished by a significantly greater plasma insulin: blood glucose ratio in the oral glucose tolerance test. These results support the view that tissue insulin sensitivity as well as pancreatic beta cell response play an important role in determining glucose tolerance in obesity.

Effect of Age on Intravenous Glucose Tolerance and Insulin Secretion*

Twenty-seven normal volunteers whose ages ranged from 22 to 67 (mean, 37 years) were given intravenous glucose tolerance tests (IVGTT). Age was not correlated with the glucose disposal rate constant (KG), incremental insulin secretion (deltaI), or the "insulinogenic index (deltaI/DELATG). The volunteers were divided into three age groups: 1) mean age 25 years, 2) mean age 42 years, and 3) mean age 62 years. Groups 2 and 3 did not differ from Group 1 with respect to the mean level of fasting plasma glucose, KG, or deltaI/AG. Group 2 (but not Group 3) had a greater mean deltaI than Group 1, and Group 3 (but not Group 2) had a higher mean fasting insulin concentration than Group 1. No significant deterioration was detected in the intravenous glucose tolerance of healthy volunteers up to age 67. This may be attributable to the previously described feed-back system that calibrates the pancreatic beta-cell response according to the insulin sensitivity of the peripheral tissues.

Plasma insulin disturbances in primary hyperparathyroidism.

Plasma insulin dynamics were evaluated in 10 patients with primary hyperparathyroidism before and after parathyroidectomy and correction of hypercalcemia. Before surgery fasting plasma insulin concentrations and insulin responses to administered glucose, tolbutamide, and glucagon were significantly greater than postoperative values. Hyperinsulinemia was not associated with altered glucose curves during glucose or glucagon tolerance tests, but a relatively greater insulin response to tolbutamide resulted in an increased hypoglycemic effect following its administration. The glucose-lowering action of intravenous insulin was slightly impaired before treatment. Intramuscular injections of parathormone to six normal men for 8 days induced mild hypercalcemia and hypophosphatemia and reproduced augmented plasma insulin responses to oral glucose and intravenous tolbutamide. 4-hr intravenous infusions of calcium to another group of six normal men raised serum calcium concentrations above 11 mg/100 ml. This did not alter glucose or insulin curves during oral glucose tolerance but markedly accentuated insulin responses to tolbutamide and potentiated its hypoglycemic effect. When highly purified parathormone was incubated with isolated pancreatic islets of male rats, glucose-stimulated insulin secretion was unaffected. These findings suggest that chronic hypercalcemia of hyperparathyroidism sustains a form of endogenous insulin resistance that necessitates augmented insulin secretion to maintain plasma glucose homeostasis. This state is insufficient to oppose tolbutamide-induced hypoglycemia because of an additional direct, selective enhancement of hypercalcemia on pancreatic beta cell responsiveness to the sulfonylurea. The possible direct role of parathormone in these events has not been established.

Effect of theophylline on glucagon and glucose-mediated plasma insulin responses in subhuman primate fetus and neonate.

The fetal and maternal plasma glucose and insulin, and the fetal growth hormone responses to the fetal administration of theophylline combined with either glucagon or glucose were examined in the subhuman primate fetus (Macaca mulatta) in late gestation. Theophylline enhanced and potentiated the fetal insulin responses to glucagon. Glucose combined with theophylline elicited a prompt rise in fetal plasma insulin, whereas glucose or theophylline alone did not. The neonate responded similarly to the combined theophylline and glucose injections with a prompt increase in plasma insulin levels. Fetal and neonatal plasma insulin levels were also promptly increased during the infusion of the dibutyryl derivative of cyclic 3′,5′ adenosine monophosphate to the fetus and neonate, respectively. Growth hormone levels were not altered in a consistent pattern during any of these experiments. These data indicate that the defect in the fetal and neonatal pancreatic betacell response to glucose is in the insulin releasing mechanism, rather than the synthesis of the hormone. Whether the apparent insensitivity of the fetal and neonatal pancreatic islet cell to glucose alone is due to a limited capacity to form cyclic AMP or to accelerated destruction of cyclic AMP by excessive phosphodiesterase activity or both remains to be demonstrated. The fetal and maternal plasma glucose and insulin, and the fetal growth hormone responses to the fetal administration of theophylline combined with either glucagon or glucose were examined in the subhuman primate fetus (Macaca mulatta) in late gestation. Theophylline enhanced and potentiated the fetal insulin responses to glucagon. Glucose combined with theophylline elicited a prompt rise in fetal plasma insulin, whereas glucose or theophylline alone did not. The neonate responded similarly to the combined theophylline and glucose injections with a prompt increase in plasma insulin levels. Fetal and neonatal plasma insulin levels were also promptly increased during the infusion of the dibutyryl derivative of cyclic 3′,5′ adenosine monophosphate to the fetus and neonate, respectively. Growth hormone levels were not altered in a consistent pattern during any of these experiments. These data indicate that the defect in the fetal and neonatal pancreatic betacell response to glucose is in the insulin releasing mechanism, rather than the synthesis of the hormone. Whether the apparent insensitivity of the fetal and neonatal pancreatic islet cell to glucose alone is due to a limited capacity to form cyclic AMP or to accelerated destruction of cyclic AMP by excessive phosphodiesterase activity or both remains to be demonstrated.

Criteria for and interpretation of normal glucose tolerance tests.

Excerpt The old dictum that every diabetic has a high prolonged glucose tolerance curve, but that every high prolonged curve is not indicative of diabetes, still holds true. The lack of specificity...