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Division of Endocrinology and Diabetes (S.H.S., P.C.B.), Keck School of Medicine, University of Southern California, Los Angeles, California 90033; Pacific Northwest Research Institute (C.J.R.), Seattle, Washington 98122; and Division of Endocrinology (J.D.V.), Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Dr. Peter C. Butler, Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, BMT-B11, Los Angeles, California 90033. E-mail: pbutler{at}hsc.usc.edu.
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Abstract |
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11 mM) and impaired glucose-mediated insulin secretion characterized by impaired first-phase insulin release (FPIR) and pulsatile insulin release. Culture of islets from nondiabetic humans in very high glucose concentrations (20–30 mM) for 96 h causes impaired FPIR. We sought to determine 1) whether human islets cultured at a glucose concentration of approximately 11 mM (comparable to TTDM) recapitulates impaired insulin secretion in TTDM, specifically impaired FPIR and insulin pulse mass with an increased proinsulin/insulin (PI/I) secretion ratio; and 2) whether these changes can be attenuated by addition of diazoxide to islets cultured with 11 mM glucose. Islets cultured with 11 mM glucose for 96 h had 75% depleted insulin stores (P < 0.05), decreased FPIR and insulin pulse mass (P < 0.05), and an approximately 3-fold increase in the ratio of PI/I islet content and in secretion ratio (P < 0.05). Addition of diazoxide to islets cultured with 11 mM glucose decreased insulin secretion during static incubation, leading to relative preservation of insulin stores and enhanced insulin secretion during subsequent perifusion; FPIR increased by 162% (P < 0.05) and insulin pulse mass by 150% (P < 0.05) vs. no diazoxide. The mean islet PI/I content and islet PI/I secretion ratio were also decreased by approximately 70% (P < 0.05) by prior addition of diazoxide to islets during culture with 11 mM glucose. FPIR and insulin pulse mass were related to islet insulin stores (P < 0.001 for FPIR and P < 0.001 for pulse amplitude). In conclusion, the pattern of defects of insulin secretion present in TTDM (impaired FPIR and pulsatile insulin secretion, increased PI/I ratio) can be recapitulated in human islets cultured with 11 mM glucose for 96 h. These defects can be at least partially offset by concurrent inhibition of insulin secretion by diazoxide, which also preserves insulin stores. Defective insulin secretion in TTDM may be, at least in part, due to depletion of available insulin stores secondary to chronic increased demand (insulin resistance and hyperglycemia) in the setting of a decreased ß-cell mass. |
Introduction |
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Glucose-mediated insulin secretion is accomplished predominately through oxidation of glucose, which leads to changes in the ATP/ADP ratio that induce closure of ATP-sensitive potassium channels (6, 7). This causes membrane depolarization and permits entry of ionized calcium through voltage-gated calcium channels (8). The resulting increased intracellular ionized calcium concentration is believed to be responsible for stimulating exocytosis (9). Diazoxide activates KATP channels, inducing membrane hyperpolarization, thereby inhibiting Ca2+ influx through voltage-sensitive Ca2+ channels and glucose-mediated insulin secretion (10, 11). In animal models of chronic hyperglycemia, inhibition of insulin secretion by diazoxide restores islet insulin stores and first-phase and second-phase insulin secretion (12). In human studies, 1-wk treatment with diazoxide in patients with TTDM restored first-phase insulin secretion (13), and overnight inhibition of insulin secretion with somatostatin restored first-phase insulin secretion and pulsatile insulin secretion (14). These studies imply that impaired insulin secretion in TTDM is at least in part due to a reversible depletion of insulin stores as a consequence of hyperglycemia.
In the current studies, we addressed the following hypotheses. First, we hypothesized that culture of islets from nondiabetic humans at glucose concentrations typical for TTDM (11 mM) decreases islet insulin content and insulin secretion, with decreased first-phase insulin release (FPIR) and insulin pulse mass. Second, we hypothesized that addition of diazoxide to these islets during culture with 11 mM glucose would partially inhibit insulin secretion and preserve islet insulin stores and insulin secretion. To address these hypotheses, we cultured human (nondiabetic) islets with 11 mM glucose for 96 h in the presence and absence of diazoxide and subsequently quantified FPIR and pulsatile insulin secretion by a recently validated perifusion technique coupled with deconvolution of insulin secretion. The resulting measured secretion was related to the measured islet insulin content.
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Materials and Methods |
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Having established that insulin stores in human islets were depleted at a glucose concentration of 11 mM over 96 h (Table 1
), and that diazoxide largely prevented this loss, we performed studies of the dynamics of insulin secretion in islets previously exposed to these conditions to establish whether retention of insulin stores by diazoxide led to retention of first-phase insulin secretion and pulsatile insulin secretion. To measure first-phase and pulsatile insulin secretion, islets (removed from static incubation and diazoxide) were immediately perifused at a glucose concentration of 20 mM, and perifusate was collected at 1-min intervals for 40 min. After islet perifusion, the islets were salvaged to measure the total islet insulin. This provided the opportunity to examine the relationship between changes in islet insulin content (achieved during the static incubations) and subsequent first-phase and pulsatile insulin secretion.
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It was important to have islets of comparable insulin content at the start of each protocol arm. We therefore sized islets (by microscopy) and distributed islets to each group for subsequent study so that they included comparable proportions of small (80–160 µm), intermediate (160–240 µm), and large (240–300 µm) islets.
Glucose-stimulated insulin secretion by the islets in the present experiment was comparable to that observed by us in prior studies using both the same apparatus and deconvolution techniques for measurement of insulin secretion (15), i.e. 5–25 fmol/islet·min for first-phase and 1–5 fmol/islet·min for second-phase.
Experimental protocol
Static incubation.
Islets were cultured at 37 C with an atmosphere of 5% CO2/95% O2. The islets were incubated for three different time periods (1, 24, and 96 h) in 3 ml of RPMI 1640 culture medium, and at either 5.5 or 11 mM glucose and for each time period and glucose concentration either in the presence of 0.5 mM diazoxide or control RPMI 1640 medium. At the end of each incubation period, the culture medium was collected for analysis of insulin concentration to allow calculation of insulin secretion during the static incubation. The islets were transferred immediately to the perifusion protocol.
Islet perifusion.
We have recently validated the islet perifusion system used here for measurement of pulsatile insulin secretion (16). In brief, after static incubation, 10 islets per chamber were periperfused using a temperature-controlled multichamber perifusion system (ACUSYST-S; Cellex Biosciences, Minneapolis, MN). Islets were removed from the static incubation media and immediately suspended in Bio-Gel P-2 beads (Bio-Rad Laboratories, Hercules, CA) and placed into the 500-µl perifusion chambers. The perifusion system consisted of a multichannel peristaltic pump, which delivered perfusate through six parallel tubing sets via a heat exchanger and six perifusion chambers. The peristaltic pump drew perifusate at a rate of 0.3 ml/min and delivered it through the heat exchanger where it was warmed to 37 C and gassed with 95% O2. From the heat exchanger, the perifusate was delivered to the perifusion chambers containing the human islets. The perifusion protocol consisted of exposing the islets to Kreb’s Ringer bicarbonate buffer perifusate (115 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2, 5 mM NaOH) supplemented with 0.2% human serum albumin, 10 mM HEPES, 2 mM glutamine, 100 U/ml benzylpenicillin, 0.1 mg/ml streptomycin, and 20 mM glucose for 45 min. Effluent perifusate was collected at 1-min intervals, stored at -20 C, and subsequently analyzed for insulin concentration.
Measurement of islet insulin content post perifusion.
At the end of perifusion period, islets were recovered from the perifusion chamber for the measurement of insulin content as previously described (17). The islets were washed in RPMI 1640 and lysed with 600 µl ice-cold lysis buffer [50 mM HEPES, 0.1% (vol/vol) Triton X-100, 1 µM phenylmethylsulfonyl fluoride, 10 µM E-64, 10 µM pepstatin A, 10 µM tosyl-Lys-chloromethyl ketone, 100 µM leupeptin (pH 8.0)]. After sonication (25 W for 40 sec) and centrifugation (12,000 x g for 5 min), the resultant supernatants were stored at -20 C and subsequently analyzed for insulin concentration and, thus, islet insulin content.
Assays
Glucose concentrations were measured by glucose oxidation method using a glucose analyzer (Beckman, Palo Alto, CA). Insulin concentrations were measured in duplicate by two-site immunospecific insulin ELISA assay as previously described (18). The assay uses two monoclonal murine antibodies (Novo Nordisk, Bagsvaerd, Denmark) specific for insulin. There is no cross-reactivity with proinsulin and split 32,33 and 31,32 proinsulins. Sensitivity of the assay is 5 pM, and the detection range is 5–2000 pM. The intraassay and interassay coefficients of variation ranged from 2.0–2.3% and 3.7–4.5%, respectively. Proinsulin was measured by a two-site immunospecific proinsulin ELISA assay as previously described (19).
Calculations and statistical analysis
All results are expressed as mean ± SEM. First-phase insulin secretion was defined by the mean secretion rate in the first 9 min after exposure to 20 mM glucose, and the second phase secretion was defined as the mean insulin secretion rate between 10 and 45 min of the perifusion experiment. The total insulin secretion during perifusion was calculated as the sum of first and second phase secretion.
(a) Islet insulin content at the end of the perifusion experiment was calculated by:
[Equation 1]: Islet insulin content post perifusion (fmol/islet) = insulin content in lysis buffer (fmol)/number of islets
(b) Islet insulin content at the end of the static incubation (and just before the perifusion) was calculated as follows:
[Equation 2]: Islet insulin content post static incubation (fmol/islet) = Islet insulin content post perifusion (fmol/islet) + (insulin released during perifusion (fmol))/number of islets
(c) Islet insulin content before static incubation was then calculated by:
[Equation 3]: Islet insulin content prior to static incubation (fmol/islet) = Islet insulin content post static incubation (fmol/islet) + (insulin released during static incubation (fmol)/number of islets).
Pulsatile insulin release was quantified by both cluster analysis and deconvolution using parameters specifically developed and validated for the present apparatus with human islets and the current assay (16). Deconvolution of the perfusate insulin concentrations was used to accomplish a minute-by-minute measure of the insulin secretion rate from the islets in the periperfusion apparatus. In a prior validation study of this apparatus, we mimicked islets by infusion of insulin directly into the perifusion chamber at a variety of rates and pulse waveforms and then measured the insulin concentration time profile in the effluent of the perfusion apparatus at 1-min intervals (16). This allowed us to determine both the volume of distribution and the half-life for insulin concentration decay in the perfusion effluent after an insulin pulse is delivered into the perifusion chambers of this apparatus. Equipped with these parameters, in the present studies, we were able to quantify the underlying insulin secretion rates and the position, duration, mass, and amplitude of insulin secretory bursts from islets in the perfusion chambers using the 1-min insulin concentration profile measured from the perfusate. Cluster analysis, in contrast, determines statistically significant up or down strokes in the serial insulin concentrations, providing information only about the frequency and amplitude of the oscillations in the data series without any assumptions or knowledge of the insulin half-life in the system of study or underlying secretory burst waveform. The t-statistics used for evaluating significant up strokes and down strokes in the insulin time series were taken as 2.0 based on prior simulation studies. The corresponding estimated cluster sizes of 2 and 2 in the nadirs and peaks were defined using signal-free insulin profiles.
Statistical comparison was made by use of either the paired or unpaired Student’s t test, ANOVA, or regression analysis. P < 0.05 was considered to be significant.
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Results |
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)From the static incubation studies, we therefore conclude that human islets exposed to glucose concentrations commonly present in type-2 diabetes (11 mM) for 96 h have approximately 70% depleted insulin stores. Inhibition of insulin secretion at this increased glucose concentration by diazoxide results in preservation of these stores. We therefore perifused human islets exposed to these conditions to establish whether diazoxide preserved first- and/or second-phase insulin secretion and pulsatile insulin secretion.
First- and second-phase insulin secretion during perifusion
To address the question of whether inhibition of insulin secretion by diazoxide during culture of human islets in the presence of physiological high glucose concentrations leads to subsequent protection of biphasic and pulsatile insulin secretion, islets were recovered from static incubation and perifused with 20 mM glucose (Fig. 1). Note that the islets were recovered from the static incubation in the presence or absence of diazoxide and then loaded into the perfusion chambers embedded in biogel in the absence of diazoxide. All perifusion experiments were therefore comparable (20 mM glucose and no diazoxide); the comparison was the conditions to which the islets had been exposed during the 96 h before perifusion (physiologic high glucose with or without diazoxide). First-phase insulin secretion was enhanced 1.5-fold in islets previously cultured with 11 mM diazoxide glucose compared with islets cultured at the same glucose without diazoxide (DZ vs. CON, 6.0 ± 0.97 vs. 3.7 ± 0.6 fmol/min per islet, P < 0.05). Similarly, second-phase insulin secretion (DZ vs. CON, 2.1 ± 0.4 vs. 1.2 ± 0.2 fmol/min per islet, P < 0.05) was 1.8-fold enhanced by prior addition of diazoxide to in human islets cultured at 11 mM glucose. Consistent with the hypothesis that the preservation of insulin secretion by islets previously cultured with diazoxide was accomplished by preservation of insulin stores, we observed a correlation between islet insulin stores at the start of the perifusion and first-phase (r = 0.40, P < 0.001) and second-phase (r = 0.60, P < 0.001) insulin secretion (Fig. 2).
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). Prior treatment with diazoxide had no effect on the insulin pulse interval (6.6 ± 0.4) during subsequent perifusion. The magnitude of insulin pulses correlated with islet content (r = 0.5, P < 0.001; Fig. 4).
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Islet perifusion.During perifusion at 20 mM glucose, there was no difference in the mean proinsulin secretion rate by islets previously cultured at 11 mM glucose with or without diazoxide (DZ vs. CON, 0.16 ± 0.03 vs. 0.20 ± 0.06 pmol/liter·min, P = NS). In contrast, the islet insulin secretion rate was higher during perifusion of islets previously cultured with diazoxide (DZ vs. CON, 72.8 ± 12.8 vs. 29.5 ± 3.0 pmol/liter·min, P < 0.01). Therefore, concurrent addition of diazoxide to islets cultured at 11 mM glucose for 96 h resulted in an approximately 70% decreased proinsulin/insulin secretion ratio (DZ vs. CON, 0.2 ± 0.03% vs. 0.7 ± 0.2%, P < 0.05) during subsequent perifusion at 20 mM glucose.
Islet content post perifusion.As described above, the islet insulin content was increased in islets cultured for 96 h at 11 mM glucose with vs. without diazoxide (DZ vs. CON, 579.7 ± 168 vs. 138.8 ± 60.8 fmol/islet, P < 0.05). In contrast, addition of diazoxide to islets cultured under these conditions did not alter islet proinsulin content (DZ vs. CON, 4.7 ± 1.2 vs. 3.5 ± 1.4 fmol/islet, P = NS). Therefore, addition of diazoxide to islets cultured at 11 mM glucose reduced the ratio of the islet proinsulin/insulin content by approximately 65% (DZ vs. CON, 0.85 ± 0.04% vs. 2.4 ± 0.3%, P < 0.001).
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Discussion |
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11 mM) for 96 h results in an approximately 70% depletion of insulin stores. Also, we report that this treatment reproduces the abnormalities in first-phase insulin secretion, pulsatile insulin secretion, and the increased PI/I secretion ratio present in TTDM. We also observed that the deleterious effects of physiologically high glucose are partially offset by concurrent incubation of the islets at high glucose with diazoxide.
It has previously been reported that human islets cultured at high glucose concentrations (20–30 mmol/liter) rarely encountered in life have depleted insulin stores and impaired glucose-induced insulin secretion (4, 20, 21). We now report that culture of islets at a glucose concentration commonly encountered in patients with TTDM also leads to the same deficit in pulsatile insulin secretion present in patients with TTDM; loss of insulin pulse mass (and amplitude) with no change in pulse frequency. Incubating nondiabetic human islets for 96 h at a physiologically high glucose concentration (11 mM) leads to partial depletion of islet insulin stores and associated impairment of both first- and second-phase insulin secretion. These data support the concept that one of the mechanisms by which prolonged hyperglycemia leads to ß-cell dysfunction is through the depletion of the available insulin stores. If this concept is valid, then enhancement of insulin stores in islets of patients with TTDM would be expected to lead to improved insulin secretion. Greenwood et al. (13) reported improvement in first-phase insulin secretion in a group of patients with TTDM diabetes who were treated with diazoxide for 1 wk. Normalizing plasma glucose concentration by diet, insulin, and sulfonylurea also led to improvement in endogenous insulin secretion (22). Also, temporary overnight inhibition of insulin secretion in patients with TTDM by somatostatin resulted in restoration of first-phase insulin secretion and pulsatile insulin release (14). Diazoxide treatment of rats subjected to a 90% pancreatectomy increased islet insulin content and led to increased insulin release during subsequent pancreatic perfusion (12). Human pancreatic islets cultured at 27 mM glucose for 48 h had impaired glucose-induced insulin secretion and depleted islet insulin stores, and both these defects were partially restored by prior treatment with diazoxide (20). Our data are therefore consistent with the concept that chronic stimulation of insulin secretion by the elevated glucose values present in TTDM may contribute to impaired insulin secretion at least in part through depletion of available insulin stores.
The circulating PI/I ratio is increased in TTDM (23, 24). Here we report that the islet PI/I content ratio and the PI/I secretion ratio are increased in islets obtained from nondiabetic humans cultured at a glucose concentration typical of TTDM, consistent with the notion that this defect is secondary to chronic stimulation rather than due to a fundamental defect of proinsulin processing in TTDM. This inference is further supported by the observation that both the islet PI/I content ratio and PI/I secretion ratio in islets previously cultured at a glucose concentration of 11 mM and diazoxide are comparable to islets cultured at a glucose concentration of 5.5 mM. The elevated PI/I ratio in TTDM has been postulated to be the consequence of intrinsic ß-cell defect in the processing of proinsulin (25, 26), preferential release of newly synthesized proinsulin (in hyperglycemic condition) (27), or the release of immature (proinsulin rich) granules that are accumulated in higher proportion than the mature (insulin rich) granules within the islet following hyperglycemia-induced hyperstimulation of the ß-cell (28, 29). The results of the present study support the latter hypothesis. In hyperglycemic condition, the rate of insulin secretion outweighs the rate of proinsulin biosynthesis, which depletes the insulin stores and leads to raised PI/I ratio. In contrast, diazoxide blocks glucose-induced insulin secretion but has no significant effect on proinsulin biosynthesis (30). Hence, during hyperglycemic stimulus in presence of diazoxide, a higher proportion of insulin is accumulated, whereas the absolute amount of proinsulin remains unchanged within the islet. This results in the reduction of the relative proportion of intraislet proinsulin (PI/I ratio) observed here. This effect is also seen in the dynamic perifusion in which a higher proportion of insulin is released relative to proinsulin from islets incubated in diazoxide at a physiologically high glucose concentration, presumably reflecting the mobilization of these mature insulin-rich granules.
Depletion of islet insulin content is associated with defective glucose-induced insulin secretion (4, 12, 20, 21). At autopsy, TTDM cases have a 50% or more reduced pancreatic insulin content (5). In the present study, we report a correlation between islet insulin content and both first- and second-phase insulin secretion. Pulsatile insulin secretion was also modulated by islet insulin content. We also report that the magnitude of insulin pulses is correlated with the quantity of islet insulin stores, whereas there is no such relationship for the interpulse interval. Furthermore, we documented restoration of the islet insulin secretion rate and magnitude of insulin pulses in islets cocultured with glucose (11 mM) and diazoxide vs. 11 mM glucose alone. This present study therefore yields further support for the role of islet insulin stores in the modulation of the magnitude of insulin secretion and reaffirms that the regulation of pulsatile insulin secretion is achieved through selective modulation of its pulse mass (and amplitude) at the level of human pancreatic islets. However, the proportion of insulin secreted in discrete pulses observed in this study was only 30–40%, which was in contrast to the almost exclusive secretion of insulin in the pulsatile component observed in in vivo studies (31, 32, 33). This difference might be due to inefficiency of insulin delivery from ß-cells in vitro into the perifusion system compared with insulin delivery into portal vein in vivo, resulting in the damping of insulin waveform released from the islets and subsequent underestimation of the proportion of insulin secreted in discrete bursts. Furthermore, removal of islets from the pancreatic neural network may influence the secretory behavior of these islets.
In summary, in the present study, we report that diazoxide confers beneficial effects on insulin secretion in human islets exposed to a glucose concentration comparable to that in TTDM, apparently by prevention of an approximately 70% loss of insulin stores that otherwise occurs under these conditions. This observation is in agreement with previous studies (12, 34, 35) that demonstrated the need for conditions that would otherwise lead to reduced insulin content to see a protective effect of diazoxide on insulin secretion (34, 35). Finally, our studies support the hypothesis that the defective FPIR and insulin pulse mass present in TTDM may be at least in part due to loss of islet insulin stores consequent upon chronic ß-cell stimulation arising from hyperglycemia and a decreased ß-cell mass (36).
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Acknowledgments |
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Footnotes |
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Abbreviations: FPIR, First-phase insulin release; PI/I, proinsulin/insulin; TTDM, type-2 diabetes mellitus.
Received January 13, 2003.
Accepted for publication April 25, 2003.
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