Failure of Exogenous Insulin to Inhibit Insulin Secretion in Man
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Abstract:
In order to explore whether or not the negative feedback mechanism of insulin per se on insulin secretion exists in man, changes in plasma C-peptide immunoreactivity (CPR), as an index of pancreatic B cells secretory function, were studied in 6 nonobese healthy volunteers in the presence of high circulating levels of exogenous insulin. 10% glucose was infused concurrently so as to maintain blood sugar at the basal level. The insulin-glucose infusion was maintained for 120 minutes, achieving mean plasma levels of 140-180 mu1/ml. After this period, the insulin infusion was continued at the same rate for an additional 10 minutes while the glucose was omitted. Despite the elevated level of circulating insulin, no significant change in plasma CPR concentration was observed so long as the blood sugar was maintained at the basal levels. Following cessation of the glucose infusion, the plasma CPR levels declined with a decrease in blood sugar level. Under the conditions of the present study, no inhibitory effect of exogenous insulin on the secretory function of the B cells was noticed.Keywords:
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ABSTRACT The effects of insulin and adrenaline on cyclic AMP (cAMP) levels in diaphragms of normal, streptozotocin-diabetic and insulin-treated diabetic rats were studied. Adrenaline caused a biphasic rise in cAMP with peak values of cAMP within the first few minutes. Diaphragms of diabetic rats showed an increased responsiveness to adrenaline. Injection of insulin to diabetic rats normalized the rise in cAMP after addition of adrenaline. There was no difference in basal levels of cAMP between diaphragms of normal, diabetic or insulin-treated diabetic rats. Insulin in vitro did not affect basal cAMP-levels or the release of cAMP from the tissue but significantly decreased adrenaline-induced peak levels of cAMP. This effect of insulin was abolished by theophylline. The results of the present study suggest that experimental diabetes is associated with changes of the adenylate cyclase and/or phosphodiesterase enzyme activities in skeletal muscle resulting in an increased responsiveness to adrenaline. Since insulin in vitro depressed the adrenaline-induced elevation of cAMP the increased responsiveness in diaphragms of diabetic rats might be attributed to the specific lack of insulin.
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The effect of systemic administration of 6-hydroxydopamine to rats on glucose tolerance and insulin release in vivo, and insulin release in vitro, has been determined. Rats given SO mg⁄kg of 6-hydroxydopamine exhibited marked glucose intolerance 2, 4 and 6 weeks after injection. This was associated with markedly increased basal insulin levels and reduced insulin release in response to glucose in vivo at all times tested. Islets from pancreases removed from treated rats 1 month after injection exhibited diminished insulin release when tested with glucose in a perifusion system; both primary and secondary components of the biphasic insulin response to glucose were reduced in comparison with islets from untreated animals. (Endocrinology94: 1072, 1974)
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Oral glucose tolerance tests were done in eight insulin-requiring pancreatic diabetic patients to study the effect of withdrawal of insulin treatment on gut hormone release. Basal levels of gastric inhibitory polypeptide (GIP), glucagon-like immunoreactivity, and immunoreactive glucagon levels rose on insulin withdrawal, more so in patients on short-acting insulin, and were lowered by insulin treatment. Insulin treatment did not affect the GIP, glucagon-like immunoreactivity, or IRG responses to oral glucose. Improved glucose tolerance was greater in patients receiving soluble insulin than in those receiving lente insulin, and there was a significant positive linear correlation between basal plasma GIP and blood glucose levels in these patients. Therefore, it is suggested that insulin treatment lowers basal hormone levels, possibly via a metabolic effect, whereas the hormone responses to oral glucose may be controlled by several factors unrelated to insulin administration or changes in glucose homeostasis.
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We studied the dose-response characteristics of insulin's ability to modulate its own secretion in normal and type II diabetic (NIDDM) subjects by measuring suppression of serum C-peptide levels during insulin infusions witK the plasma glucose level held constant. In normal subjects at euglycemia, primed continuous insulin infusion rates of 15, 40, 120, and 240 mU/M2 min acutely raised serum insulin to steady state levels of 37 ± 2 (±SE), 96 ± 6, 286 ± 17, and 871 ± 93 µU/ml, respectively. During each infusion, maximal suppression of C-peptide to 30% of basal levels occurred by 130 min. At the higher insulin levels (≥100 µU/ml), C-peptide levels fell rapidly, with an apparent t½, of 13 min, which approximates estimates for the t½ of circulating C-peptide in man. This is consistent with an immediate 70% inhibition of the basal rate of insulin secretion. At the lower insulin level (37 ± 2 µU/ml), C-peptide levels fell to 30% of basal values less rapidly (apparent t½, 33 min), suggesting that 70% inhibition of basal insulin secretion rates was achieved more slowly. In NIDDM subjects, primed continuous insulin infusion rates of 15, 40, 120, and 1200 mU/M2-min acutely raised serum insulin to steady state levels of 49 ± 7, 93 ± 11, 364 ± 31, and 10,003 ± 988 µU/ml. During studies at basal hyperglycemia, only minimal C-peptide suppression was found, even at pharmacological insulin levels (10,003 ± 988 µU/ml). However, if plasma glucose was allowed to fall during the insulin infusions, there was a rapid decrease in serum C-peptide to 30% of basal levels, analogous to that in normal subjects. Three weeks of intensive insulin therapy did not alter C-peptide suppression under conditions of hyperinsulinemia and falling plasma glucose. The following conclusions were reached. 1) In normal subjects, insulin (40–1000 µU/ml) inhibits its own secretion in a dose-responsive manner; more time is required to achieve maximal 70% suppression at the lower insulin level (40 µU/ml). 2) In NIDDM studied at basal hyperglycemia, insulin has minimal ability to suppress its own secretion. Thus, impaired feedback inhibition could contribute to basal hyperinsulinemia. 3) Under conditions of hyperinsulinemia and falling plasma glucose, insulin secretion is rapidly suppressed in NIDDM (analogous to that in normal subjects studied during euglycemia.
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We have previously identified in fasting monkeys large amplitude, rapid oscillations in plasma levels of insulin, glucagon, and glucose. To determine whether such spontaneous oscillations also occur in man, we studied 9 healthy normal weight subjects and 11 obese volunteers (145–316% ideal body weight). During the morning hours after a 16-h fast, peripheral venous blood was withdrawn at precise 1- or 2-min intervals over 40–120 min. Spectral analysis of the assay results showed significant oscillations in plasma levels of insulin and glucose, with periods ranging from 8–16 min (P < 0.05). In this range, the means of the oscillatory periods in normal weight subjects were 12.1 ± 1.0 min for insulin and 11.2 ± 0.8 min for glucose. The oscillatory periods in obese subjects were not different from those in normal weight subjects (12.4 ± 0.7 min for insulin and 12.1 ± 0.9 min for glucose). Periodicity in plasma levels of glucagon was observed in the range of 12–23 min. Based on cross-correlation analysis, the periodic fluctuations in insulin, glucose, and glucagon showed no consistent relationships; the patterns observed did not support the presence of feedback loops among these parameters as the mechanism for these spontaneous fluctuations. Our data indicate that basal plasma levels of insulin, glucagon, and glucose fluctuate rapidly in man. The physiological function of these oscillations is yet to be identified; they may play a role in the regulation of responsiveness of the respective target tissues or of their own release into the circulation.
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ABSTRACT The acute effects of human growth hormone (GH) on the basal levels of glucose and insulin in blood were investigated in 11 healthy men. GH doses of 5, 10, 20, and 40 μg/kg body weight were given iv as a constantrate infusion over 30 min, and resulted in peak hormone levels (30 min) of 20.5 ± 1.0, 48.5 ± 2.2, 108.2 ± 4.5, and 229.2 ± 14.6 ng/ml, respectively. There was a small (max 9.8 ± 2.6 %) but significant decrease in the blood glucose level, observed already at 15 min after the beginning of the GH infusion and persisting up to 90 min. The highest dose of GH induced the most marked changes, but there was otherwise no clear correlation between dose and effect. The basal plasma insulin levels showed a more marked (max 16.0 ± 4.7 %) decrease which was not correlated, in time or in magnitude, with the changes in blood glucose. In some subjects, in whom no significant decrease in blood glucose was observed, plasma insulin still demonstrated a similar fall (max 20.2 ± 7.6 %). Neither were these changes in plasma insulin correlated to the dose of GH within the range used in this study. The findings suggest that the early, insulin-like effect of GH on blood glucose is distinct from its effect on the pancreas. The latter is a suppressive one, consistent with earlier findings on glucose-induced insulin release.
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The effects of insulin treatment and dietary glucose on the responsiveness of adipose tissue to insulin and GH after hypophysectomy were studied. Male rats, 130–150 g, were hypophysectomized. Glucose metabolism was measured by determining the production of CO2 from [14C]glucose and the incorporation of glucose into lipids in the epididymal fat pad. Basal levels of glucose oxidation as well as the response to insulin were markedly decreased 7 days after hypophysectomy. In hypophysectomized animals given drinking water containing 10% glucose, insulin responsiveness was partially restored, and an enhanced response to the insulin-like effect of GH was observed. Plasma insulin levels decreased after hypophysectomy. Additional glucose caused a significant increase in plasma insulin levels, but these levels were still lower than those in shamoperated animals. To examine the possibility that endogenous insulin levels are important for the capacity of adipose tissue to metabolize glucose and respond to insulin and GH, hypophysectomized rats were injected with different, progressively increasing doses of insulin for 7 days, beginning on the day after the operation. Basal levels of glucose oxidation were decreased in hypophysectomized control animals and gradually increased in a dose-dependent manner in insulin-treated animals. Basal levels were normalized when the total dose of insulin injected was 16.5 U. In these animals, the response to insulin was enhanced, and there was an increase in the magnitude of the response to GH. Similar results were obtained when glucose incorporation into lipids was determined. The decrease in basal and insulin-stimulated glucose oxidation levels after hypophysectomy were most pronounced when measured at a high glucose concentration (50 mm), when glucose transport is not rate limiting. The results indicate that the changes in glucose metabolism and hormonal responsiveness of adipose tissue after hypophysectomy are, at least in part, dependent upon the decrease in endogenous insulin levels. (Endocrinology116: 945–951, 1985)
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Previous studies have shown cellular insulin resistance in conventionally treated insulin-dependent diabetics. To determine whether insulin resistance is also present in insulin-dependent diabetics before the commencement of insulin therapy, we studied nine newly diagnosed untreated insulin-dependent diabetics and nine control subjects. Insulin binding to adipocytes, monocytes, and erythrocytes was normal in the diabetic individuals. Basal (noninsulin stimulated) glucose transport rate was normal, whereas the maximal insulin responsiveness of glucose transport was severely impaired (P less than 0.02). Insulin sensitivity as judged by left or rightward shifts in the insulin dose-response curves was unchanged. Moreover, the basal lipogenesis rate measured at a glucose concentration of 0.5 mmol/liter was decreased in the diabetics (P less than 0.05), and the maximal insulin responsiveness of lipogenesis was also reduced (P less than 0.05). We conclude that fat cells from untreated insulin-deficient diabetics are insulin resistant. The major defects are (1) reduced maximal insulin responsiveness of glucose transport and conversion to lipids that are postbinding abnormalities, and (2) reduced basal glucose conversion to lipids.
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Glucose and insulin relationships with aging were studied in fed rats. Levels of basal circulating glucose did not change while those of RIA-insulin increased and RIA-glucagon decreased lineary with animal weight. The oral glucose tolerance test revealed a greater increase in blood glucoe in adult and old rats than in prepuberals, while the rise in plasma insulin was faster and greater in the oldest group. After intravenous glucose load, plasma insulin increase was greater in adult than in prepuberal and old rats, and in the latter grup values remained elevated for a longer period. The hypoglycemic response to i.v. insulin was greatest in the prepuberals with no difference between adult and old rats. In prepuberals, the augmented insulin sensitivity was counteracted by retarded insulinotropic glucose action and an enhanced basal glucagon level, while in the old animals normoglycemia was maintained due to an augmented secretory response of B cells, counteracted by reduced sensitivity to endogenous insulin.
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