Proinsulin and Insulin Release with a Human Insulinoma and Adjacent Nonadenomatous Pancreas

Gutman, R.; Fink, Gloria; Shapiro, Jay R.; Selawry, Helena; Recant, Lillian

doi:10.1210/jcem-36-5-978

Cited by 16 publications

(8 citation statements)

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“…The proinsulin content of extracted pancreas is less than 7% of the immunoreactive insulin level (26)(27)(28)(29)(30)(31)(32), while basal values in peripheral blood are higher, comprising approximately 20% of total IRI (7,(33)(34)(35)(36). Although it has been suggested that the higher circulating proinsulin content indicates preferential release of newly formed granules, which contain a higher proportion of proinsulin, our data on portal vein blood indicate that the ratio of proinsulin to insulin being secreted is similar to that present in the pancreas.…”

Section: Discussioncontrasting

confidence: 51%

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Horwitz¹,

Starr²,

Mako³

et al. 1975

J. Clin. Invest.

476

229

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A B S T R A C T Concentrations of insulin, proinsulin, and C-peptide were measured in portal and peripheral venous blood in six nondiabetic, nonobese subjects. Portal vein samples were obtained by umbilical vein catheterization. Three subj ects were studied with intravenous infusion of 25 g glucose, and three with 30 g arginine. Insulin and proinsulin were determined in the insulin immunoassay after separation by gel filtration, and C-peptide was measured by direct immunoassay.With both glucose and arginine stimulation, portal vein levels of all three peptides peaked at 90-120 s after the onset of the stimulus. Relative increases in insulin concentration were greater than those of proinsulin or C-peptide. In peripheral venous blood, maximal levels of the three peptides were observed later (2-5 min), and the increase in insulin relative to proinsulin and C-peptide was not as great. At the time of peak secretion, portal vein insulin and C-peptide approached equimolar concentrations, and proinsulin, as measured against an insulin standard, comprised approximately 2.5% of the total immunoreactive insulin.After stimulation by glucose or arginine, portal insulin, proinsulin, and C-peptide levels were not correlated with the concentrations measured in simultaneously drawn peripheral samples. At all sampling times, however, significant correlation was found between insulin and C-peptide in both peripheral and portal blood. The results indicate that under the conditions studied, insulin and C-peptide are secreted in equimolar concentrations in man, and that proinsulin is secreted in the same proportion to insulin as found in the pancreas.

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Section: Discussioncontrasting

confidence: 51%

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Horwitz¹,

Starr²,

Mako³

et al. 1975

J. Clin. Invest.

476

229

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“…These ratios are shown in line 3 of Table 3, and Table 2. X Insulin secretion rates used in this calculation were taken from an earlier study and are 139 ± 11 (10) and 65.4 ± 7.9 (10) pg/min for islets of 2-and 12-mo-old donors, respectively. 1 Fractional secretory rates for total insulin are obtained by dividing these rates by the islet insulin content in Table 2. suggest that newly synthesized and stored insulin pools are not in equilibrium after the min 45 of glucose stimulation.…”

Section: Differences In the Fractional Secretion Rate Of Stored (Unlamentioning

confidence: 99%

“…For insulin, Sando et al 9 have shown that newly synthesized hormone is preferentially secreted (over older, stored insulin) in normal, isolated rat islets, provided that incubation periods extend beyond 1 h. In some human insulinoma tissue, proinsulin and insulin are preferentially released over the corresponding stored species after glucose stimulation. 10 Furthermore, in aging humans, elevated levels of proinsulin-like material exist in plasma samples taken during glucose tolerance tests, 11 suggesting that aging may influence the maturation of the secreted insulin.…”

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confidence: 99%

Effect of Age on Proinsulin and Insulin Secretory Patterns in Isolated Rat Islets

Gold¹,

Reaven²,

Reaven³

1981

Diabetes

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Although isolated islets from older rats store ample insulin, they do not respond as efficiently as do islets from young animals to a glucose or leucine challenge. The current study was conducted to determine if this decline in insulin secretion is associated with abnormalities in islet content or conversion of proinsulin, or in the mobilization of insulin that is newly synthesized. Isolated islets from 2-, 12-, and 18-mo-old rats were assayed for total islet proinsulin and insulin content, and after stimulation with glucose the incubation medium was assayed for secreted proinsulin and insulin. In addition, islets from 2-and 12-mo-old donors were pulse-labeled with 3 H-leucine, after which the temporal conversion and pattern of release of newly synthesized hormone was compared. The results show that the ratio of proinsulin to insulin declines progressively with age for both the stored and secreted hormone. Incorporation of 3 H-leucine into proinsulin during glucose stimulation also decreases with age. However, the onset, time course, and endpoint of the conversion of this labeled proinsulin to insulin did not change with age. Although the fractional secretion rate of newly synthesized hormone (whether proinsulin or insulin) is similar in 2-and 12-mo-old rats, it exceeds that of the unlabeled, or stored, insulin. When the wave of labeled protein enters the secretory pool it apparently equilibrates with a portion of the insulin pool, which is more rapidly secreted than the total pool of insulin. We considered this the glucose responsive pool, and estimate that this pool is actually smaller in islets from 12-as compared with 2-mo-old rats. The reduction in size of this responsive compartment of insulin in the older rats may, in part, explain

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“…In previous in vitro investigations of human insulinoma cells, insulin secretion was unaffected by high glucose concentrations in five case patients from three studies (11,12,16) and was variably augmented in seven single case patients (9,10,14,(17)(18)(19)(20). Other agents were rarely tested: insulin secretion was increased by a sulfonylurea in two insulinomas (18,19) and leucine was ineffective in one of one insulinoma (11).…”

Section: Discussionmentioning

confidence: 99%

“…First, the techniques used were disparate. Minced pieces of the tumor were incubated either immediately (9,10) or after culture for several days or weeks (11)(12)(13). In other studies, pieces of the tumor were digested with collagenase before the measurement of insulin secretion either immediately (14,15) or after 1-8 weeks of culture (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro

Henquin¹,

Nenquin²,

Guiot

et al. 2015

Diabetes

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Insulinomas are β-cell tumors that cause hypoglycemia through inappropriate secretion of insulin. Characterization of the in vitro dynamics of insulin secretion by perifused fragments of 10 human insulinomas permitted their subdivision into three functional groups with similar insulin content. Group A (four patients with fasting and/or postprandial hypoglycemic episodes) showed qualitatively normal responses to glucose, leucine, diazoxide, tolbutamide, and extracellular CaCl2 omission or excess. The effect of glucose was concentration dependent, but, compared with normal islets, insulin secretion was excessive in both low- and high-glucose conditions. Group B (three patients with fasting hypoglycemic episodes) was mainly characterized by large insulin responses to 1 mmol/L glucose, resulting in very high basal secretion rates that were inhibited by diazoxide and restored by tolbutamide but were not further augmented by other agents except for high levels of CaCl2. Group C (three patients with fasting hypoglycemic episodes) displayed very low rates of insulin secretion and virtually no response to stimuli (including high CaCl2 concentration) and inhibitors (CaCl2 omission being paradoxically stimulatory). In group B, the presence of low-Km hexokinase-I in insulinoma β-cells (not in adjacent islets) was revealed by immunohistochemistry. Human insulinomas thus show distinct, though not completely heterogeneous, defects in insulin secretion that are attributed to the undue expression of hexokinase-I in 3 of 10 patients.

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Proinsulin and Insulin Release with a Human Insulinoma and Adjacent Nonadenomatous Pancreas

Cited by 16 publications

References 0 publications

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Effect of Age on Proinsulin and Insulin Secretory Patterns in Isolated Rat Islets

Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro

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