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INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS |
Departments of Pediatrics (M.F., D.F., P.D., J.O.), Cell Biology (M.F., A.P.), and Surgery (E.O., W.K., S.B.), Duke University Medical Center, Durham, North Carolina 27710; Institut National de la Santé et de la Recherche Médicale 344 (N.B., P.A.K.), Necker Faculty of Medicine, Paris 15F-75730, France; and Institut National de la Santé et de la Recherche Médicale 457 (I.A., B.B.), Hopital Robert Debre, Paris F-75019, France
Address all correspondence and requests for reprints to: Dr. Michael Freemark, Department of Pediatrics, Box 3080, Duke University Medical Center, Durham, North Carolina 27710. E-mail: . freem001{at}mc.duke.edu
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Abstract |
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Introduction |
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Efforts to define a physiological role for the lactogens in pancreatic development or carbohydrate metabolism have been hampered by the absence of a human model of total lactogen deficiency or of lactogen resistance. A deficiency of PRL in hypopituitary dwarf mice and hypophysectomized rats is associated with reduced islet mass, relative hypoinsulinemia, diminished pancreatic insulin content, and an impaired insulin secretory response to glucose (21, 22, 23). However, these rodent models are accompanied by a deficiency of GH as well as PRL. Because GH modulates insulin production and glucose uptake in peripheral tissues, the roles of the lactogens in pancreatic function cannot be elucidated by studies of hypopituitary mice and rats.
To clarify the roles of the lactogens in pancreatic development and insulin production, we measured islet density (the number of islets per square centimeter of pancreatic tissue), mean islet size, ß-cell mass, pancreatic insulin mRNA levels, and the insulin secretory response to glucose in an experimental model of lactogen resistance: the PRL receptor (PRLR)-deficient mouse. This model was created by targeted deletion of the gene encoding the mouse PRLR (24). PRLR knockout mice are resistant to the actions of mouse PRL and mouse PL, which bind only to the mouse PRLR. In contrast, the mice respond normally to mouse GH, which binds only to the GH receptor. Female homozygous PRLR-deficient mice are sterile, a consequence of progesterone deficiency, hypoestrogenemia, and defects in egg transport and implantation (25, 26). The male homozygous mutants, on the other hand, seem to have near-normal reproductive capacity and normal serum T concentrations (25). PRLR-deficient mice also have reduced rates of bone formation and decreased bone mineralization (25), but the effects of PRLR deficiency on pancreatic development or insulin production have not been examined previously.
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Materials and Methods |
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Tissue processing for morphometry
Fixation and processing for immunohistochemistry.
The animals (homozygous +/+ and -/-) were killed by decapitation, after an overnight fast. The whole pancreas was excised and weighed and cut into two pieces corresponding to the head (duodenal) and the tail (spleen) parts of the organ. The tissues were separately fixed in a 3.7% formalin solution, dehydrated in 100% ethanol/100% toluene, and embedded in paraffin. Each entire pancreatic piece was cut, throughout its length, into 5-µm thick sections, which were collected on gelatin-coated slides. The slides were left at 37 C overnight, then stored at 4 C until processing for immunohistochemical studies. Every 40th section from each pancreatic piece (head or tail) was immunostained for insulin, yielding eight sections per animal. ß-Cells were detected with a polyclonal guinea pig antiinsulin antibody (DAKO Corp., Trappes, France) revealed after incubation with a peroxidase anti-guinea-pig antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) and visualized in brown with 3,3'-diaminobenzidine (Vector Laboratories, Inc., Compiegne, France).
Morphometry measurements
Pancreatic tissue area and insulin-positive-cell area were determined by computer-assisted measurements using a Leica Corp. (Deerfield, IL) DMRB microscope equipped with a color video camera coupled to a Q500IW computer (screen magnification, x24), as previously described (27). Briefly, the number of islets (defined as insulin-positive aggregates at least 25 µm in diameter) was scored and used to calculate the islet numerical density (number of islets per square centimeter of tissue). Islets ranging from 25–100 µm in diameter were defined as small; those ranging from 101–150 µm, as medium; and those exceeding 150 µm, as large. Mean islet size was calculated as the ratio of the total insulin cell area to the total islet number on the sections. The percent ß-cell fraction was measured as the ratio of the insulin-positive cell area to the total tissue area on the entire section. Mean ß-cell fraction per pancreas was calculated as the ratio of the sum of insulin-positive area [(head sections1 to n) + (tail sections1 to n)] to the sum of pancreatic tissue area [(head sections1 to n) + (tail sections1 to n)]. The ß-cell mass was obtained by multiplying the ß-cell fraction by the weight of the pancreas. Apoptosis in pancreatic islets was assessed using the nonradioactive terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling reagent (Roche Molecular Biochemicals, Indianapolis, IN). Four animals were studied per group and age, unless otherwise stated in the figure legends.
Steady-state pancreatic insulin mRNA levels
Total RNA from adult pancreas was prepared using Tri-Reagent (Molecular Research Center, Inc., Cincinnati, OH) according to the manufacturer’s instructions. Twenty micrograms of total RNA were separated on 1% formaldehyde-agarose gels and transferred to positively-charged nylon membranes (Roche Molecular Biochemicals) according to the directions of the manufacturer. The blots were washed in 5x saline sodium citrate (SSC), 50% formamide containing 0.1% Na lauroylsarcosine, 0.02% SDS, and 2% blocking reagent (Roche Molecular Biochemicals Standard hybridization buffer) and were incubated overnight in standard hybridization buffer at 68 C with a digoxigenin-labeled antisense RNA probe encoding the 700-bp coding sequence of rat insulin 1. The integrity and function of the antisense probe was confirmed in Northern analysis using RNA from rat INS-1 cells (7, 9). Parallel studies, using digoxigenin-labeled sense strand probes, confirmed the specificity of the reactions. The blots were washed twice at room temperature in 2x SSC, 0.1% SDS; twice at 68 C in 0.5x SSC, 0.1% SDS; and twice at 68 C in 0.1x SSC, 0.1% SDS and then incubated for 30 min at room temperature with deoxyribonuclease-free ribonuclease (100 µg/ml, Roche Molecular Biochemicals). After being washed three times with malate buffer, the blots were developed using the chemiluminescent reagent disodium 3-(4-methoxyspiro{1,2-dioxetane-3,2'-(5'-chloro)tricyclo[3.3.1.13,7]decan}-4-yl)phenyl phosphate (CSPD) (Tropix, Bedford, MA).
Insulin content of isolated pancreatic islets
Pancreatic islets of adult (3–4 months old) nonfasted PRLR-deficient and wild-type mice were isolated with collagenase using methods described in detail in previous manuscripts (28). The islets were extracted in ice-cold acid ethanol (49 parts 95% ethanol, 1 part concentrated HCl). The protein content of each extract was measured using the Bio-Rad Laboratories, Inc. (Hercules, CA) protein reagent, and the insulin content of each extract was measured using an ultrasensitive mouse insulin RIA (Linco, St. Louis, MO). Preliminary experiments demonstrated that the displacement curve generated by serial dilutions of the extracts was parallel to the curve generated by mouse insulin standards. The recovery of mouse insulin in the diluted extracts exceeded 90%, and interassay and intraassay variability was less than 7%.
Glucose and insulin responses to ip glucose
To assess glucose tolerance, we fasted adult (4–8 months old) mice for 2.5 h. Thirty minutes before blood sampling, the tail was cut. Tail capillary blood glucose concentrations were measured using a Fast-Take glucometer (Lifescan, Milpitas, CA), at time 0 and every 10–20 min thereafter, for a total of 2 h, after an ip injection of 10% dextrose in water (10 µl/g body weight).
In separate experiments, we measured the insulin secretory response to glucose in vivo in PRLR-deficient and wild-type mice. Preliminary experiments demonstrated that peak insulin concentrations in both the PRLR-deficient and wild-type mice occurred 30 min after the ip injection of 10% dextrose. To compare the maximal insulin secretory response to glucose in PRLR-deficient mice with the maximal insulin secretory response in wild-type mice, we fasted adult (4–8 months old) PRLR-deficient and wild-type mice for 2.5 h and measured plasma insulin concentrations before and 30 after an ip injection of glucose. Insulin concentrations were measured by RIA (ultrasensitive mouse insulin assay, Linco) in plasma obtained by retroorbital puncture, without anesthesia. Insulin levels were not obtained during the ip glucose tolerance test because the stress of the retroorbital puncture would increase plasma glucose concentrations.
Insulin secretion in isolated islets
Pancreatic islets of adult (4–8 months old) nonfasted PRLR-deficient and wild-type male mice were isolated with collagenase, using methods described in detail in previous manuscripts (28). Islets from 3–5 mice of each genotype were pooled and distributed in batches of 10 in each of 4 perifusion chambers. The chambers were preperifused at 37 C for 80 min in Krebs-Ringer bicarbonate buffer containing 5.5 mM glucose; perifusate samples were collected every 5 min during the final 20 min. The chambers were then perifused with Krebs-Ringer bicarbonate containing 22 mM glucose, for a total of 30 min; samples were collected, every 2 min, after the initiation of the glucose challenge. The perifusion buffer was then replaced with buffer containing 5.5 mM glucose, for a total of 20 min, followed by a solution containing 5.5 mM glucose and 20 mM KCl. The insulin content of each perifusate sample was determined by RIA using methods described previously (28). Only those islets that showed at least a 3-fold increase in insulin secretion, after the administration of 20 mM KCL, were included in the analysis. This insures the functionality of the islets studied.
Glucose response to ip insulin
To assess the glucose response to insulin infusion, adult mice received an ip injection of Humalog insulin (Eli Lilly \|[amp ]\| Co., Indianapolis, IN) at a dose of 1 U/kg body weight. Glucose concentrations in tail blood were measured by glucometer just before the injection (time 0) and during the subsequent 45–60 min.
Expression of data and statistical analysis
Plasma glucose and insulin concentrations and all morphometric data are expressed as mean ± SE. Steady-state insulin mRNA levels were quantitated by densitometric analysis of Northern blots and were expressed as the ratio of insulin mRNA to 28S RNA. The amount of 28S RNA was used to control for RNA integrity and loading because there is no islet-specific protein that is known to be free from regulation by PRL. In selected studies, we used an RNA probe encoding mouse ß-actin to standardize for RNA loading; the results were comparable with those obtained using 28S RNA as a control. Insulin content of isolated islets is expressed per milligram protein.
In perifusion studies, insulin production was measured in the perifusates of chambers containing 10 islets. Because the islets may have differed in size or insulin secretory capacity, it was necessary to correct for differences in the basal insulin production by the perifused islets. Thus, the changes in insulin secretion during glucose (22 mM) administration are expressed as fold-increase above mean baseline values. The data are plotted as fold-increase vs. time. The area under the insulin curve represents the area of the curve of insulin values during perifusion with 22 mM glucose; baseline values were arbitrarily set at 1.0. As noted previously, data from islet perifusions were included only if KCl caused a 3-fold or greater increase in insulin secretion above baseline values.
Plasma glucose concentrations after ip injections of glucose or insulin were analyzed by two-way ANOVA followed by Bonferroni’s test of multiple comparisons. In all other cases, differences among sample means were assessed by ANOVA followed by the Newman-Keuls test of multiple comparisons. All experiments were repeated on at least three occasions. A P value less than 0.05 was considered statistically significant.
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Results |
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As shown in Table 1
, total pancreatic weight and mean islet size in wild-type males increased 2.8-fold and 1.8-fold, respectively, between 3 wk and 4–8 months of age. In contrast, islet density, a measure of islet number relative to total pancreatic mass, declined with age. Pancreatic weight was normal in PRLR-deficient mice at 21–24 d and at 4–8 months of age. On the other hand, islet density in PRLR-deficient mice was reduced 26% in weanling males (P = 0.07), 36% in adult males (P < 0.001), and 38% in adult females (P = 0.015). Mean islet size was reduced 22% in weanling males (+/+, 4480 ± 279 µm2, n = 4; -/-, 3486 ± 37 µm2, n = 4, P = 0.012), in which there was an increased proportion of small (25–100 µm in diameter) islets (P = 0.012) and a decreased proportion of large (>150 µm in diameter) islets (P = 0.0027). In contrast, islet size was normal in adult PRLR-deficient males and females (Table 1).
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and Fig. 2). Relative to wild-type littermates, PRLR-deficient males had 33–42% reductions in ß-cell fraction (P < 0.01) and 27–40% reductions in ß-cell mass at 21–24 d (P < 0.01) and at 4–8 months of age (P < 0.05).
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There was no evidence of apoptosis in islets of PRLR-deficient or wild-type mice at 3 wk of age or at 4–8 months of age (data not shown).
Fig. 1 is a representative photograph showing the reductions in islet density in PRLR-deficient mice. Data summarizing the effects of PRLR deficiency on ß-cell mass are displayed graphically in Fig. 2.
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). Similar findings were obtained in 6-wk-old mice (data not shown).
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, the insulin content of isolated islets of PRLR-deficient mice was 21% less than that of wild-type mice (n = 7 in each group, P < 0.05, PRLR-deficient vs. wild-type mice).
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). Thus, the insulin secretory response to glucose in vivo was blunted in PRLR-deficient males.
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, the insulin secretory response to 22 mM glucose was blunted in islets of PRLR-deficient mice; the area under the insulin curve for islets of PRLR-deficient males was 57.6 ± 18.3% less than that of wild-type males (P < 0.01), whereas the area under the insulin curve for islets of PRLR-deficient females was 29.9 ± 10.3% less than that of wild-type females (P < 0.05).
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, fasting blood glucose concentrations in PRLR-deficient males and females were comparable with those in wild-type mice. However, after an ip injection of 10% dextrose (1 g/kg body weight), blood glucose levels in adult PRLR-deficient males and females were slightly, but significantly (P < 0.02 by two-way ANOVA), higher than those in wild-type littermates. Maximal differences in blood glucose concentrations among the groups (10–20%, P < 0.05 by Bonferroni’s test of multiple comparisons) were detected 20–30 min after the glucose injection. By 60 min, blood glucose concentrations in PRLR-deficient females were indistinguishable from those in wild-type littermates. Mild elevations of blood glucose persisted in PRLR-deficient males for 80–120 min. Thus, PRLR deficiency in adult mice is accompanied by a mild impairment in glucose tolerance after a glucose load.
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, the glucose disappearance curves were comparable in adult PRLR-deficient and wild-type mice. Thus, we did not identify obvious PRLR-dependent changes in peripheral insulin sensitivity using this experimental approach. Nevertheless, we cannot rule out small changes in insulin sensitivity in PRLR-deficient mice that might be detected only in a formal insulin clamp study.
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Discussion |
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The reductions in islet density and ß-cell mass persist well into adulthood in both males and females. Because islet size is normal in PRLR-deficient adults, the reductions in ß-cell mass in adult mice likely reflect the decrease in total islet number, rather than a reduction in the number or size of ß-cells within individual islets. Given that PRLRs are expressed in pancreatic islets throughout the life span (31), the effect of PRLR deficiency on islet number in adult mice may implicate a continuous requirement for lactogen signaling for normal islet formation. Alternatively, the absence of lactogen signaling in the perinatal period might alter permanently the timing and/or magnitude of islet or ß-cell development in later life. In addition, the absence of PRLRs in knockout mice conceivably could alter the expression or actions of other hormones known to regulate ß-cell development and function, including GH and PTH-related peptide (32). The latter possibilities will require additional investigation.
The reductions in islet number and ß-cell mass in PRLR-deficient mice were accompanied by reductions in pancreatic insulin mRNA levels and in glucose-dependent insulin secretion in vivo and in vitro. Clearly, the reductions in islet number could explain, in part, the reductions in insulin mRNA and in glucose-dependent insulin secretion in vivo. Nevertheless, there are at least two other possible contributing factors. First, the production of insulin by individual islets may be reduced in PRLR-deficient mice because the insulin content of isolated islets, expressed per milligram protein, was reduced in PRLR-deficient males and females. This observation, which suggests a defect in insulin biosynthesis in PRLR-deficient mice, is consistent with previous studies demonstrating that PRL and PL increase insulin gene transcription and insulin mRNA levels in isolated islets and rat insulinoma cells (7, 9, 10). Second, the reductions in glucose-stimulated insulin secretion might result, in part, from reduced expression of glucose transporter 2 and/or glucokinase. Glucose transporter 2 and glucokinase are essential for glucose-stimulated insulin secretion (33, 34) and are induced in pancreatic islets and rat insulinoma cells by lactogenic hormones (7, 8, 9).
The reductions in ß-cell mass and insulin production in PRLR-deficient mice likely explain the supranormal rise in blood glucose levels that exist 20–30 min after a glucose challenge. The results of the ip glucose and insulin tolerance tests suggest that the glucose intolerance results from a blunted insulin secretory response, rather than a reduction in insulin sensitivity. Nevertheless, the changes in glucose tolerance in PRLR-deficient mice were modest; fasting blood sugar levels were normal and postinjection glucose levels in PRLR-deficient mice were only 10–20% higher than those in wild-type mice. In the absence of insulin resistance, it is likely that severe ß-cell hypoplasia or dysfunction are required to produce severe glucose intolerance or overt diabetes.
It is interesting that mild glucose intolerance is observed in hyperprolactinemic (12, 13, 14), as well as lactogen-resistant, rodents. Whereas the glucose intolerance of lactogen resistance seems to be caused by ß-cell hypoplasia and insulin deficiency, the glucose intolerance in hyperprolactinemic states is thought, though not proved, to be attributable to a reduction in peripheral insulin sensitivity (1, 2, 3). The effects of lactogens on ß-cell proliferation and insulin production are direct and well-established, but the mechanisms by which lactogens are presumed to reduce insulin sensitivity are unknown.
In summary, PRLR deficiency is accompanied by islet and ß-cell hypoplasia, reduced pancreatic insulin mRNA levels, a blunted insulin secretory response to glucose, and mild glucose intolerance. The defects in islet number, ß-cell mass, and glucose-dependent insulin production in PRLR-deficient mice establish a physiological role for the lactogens in islet and ß-cell maturation, development, and function.
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Acknowledgments |
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Footnotes |
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Abbreviations: PL, Placental lactogen; PRLR, PRL receptor.
Received September 7, 2001.
Accepted for publication December 1, 2001.
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