Long-term effect of pancreas transplantation on diabetic hyperglucagonemia

Pancreas isotransplantation was performed on streptozotocin-diabetic Wistar rats. To study the influence of the graft on diabetic hyperglucagonemia, immunoreactive glucagon (IRG) and its response to alanine (peak IRG) were determined in peripheral blood at intervals for up to 8 months after the transplantation. Concentrations of IRG and immunoreactive insulin (IRI) in effluent blood from host pancreas (portal vein) and graft (caval vein) were measured 4 months after the transplantation to estimate the hormone release from both organs. Following transplantation, caval IRI increased sixfold. Portal IRI increased 180% and reached 65% of the concentration observed in control rats. Peripheral basal and peak IRG were initially restored to normal, but were later increased to levels equal to those of diabetic rats. Also portal and caval IRG concentrations were similar in recipients and diabetic rats. The results show that relatively small amounts of glucagon are released from the graft, and that the exaggerated glucagon release from the host pancreas is only transiently normalized following pancreas transplantation.     

Effect of diabetes on fast response to norepinephrine in rat aorta.

The fast and slow components of the mechanical response to 1 microM norepinephrine (NE) were measured in aortic rings isolated from eight spontaneously diabetic rats, six streptozocin-induced diabetic (STZ-D) rats, six STZ-D rats treated with 2.5 U insulin/day during the 4 days before being killed, and six age- and sex-matched control rats. The total contraction to NE (i.e., the sum of fast and slow components) was similar in the four groups: spontaneously diabetic, 16.53 +/- 1.72 mN; STZ-D, 15.68 +/- 1.41 mN; insulin-treated, 16.17 +/- 2.05 mN; and control, 15.27 +/- 0.96 mN (NS). The fast component, measured graphically in a total contraction in 1.35 mM Ca, was greater in spontaneously diabetic (12.61 +/- 1.07 mN, P less than 0.05) and STZ-D (12.25 +/- 0.89 mN, P less than 0.05) rats compared with control (9.14 +/- 0.74 mN) or insulin-treated (8.58 +/- 1.23 mN) rats. The same increase of the fast component was detectable after 3 min of incubation in Ca-free medium + 2 mM EGTA (control 6.54 +/- 0.47 mN, spontaneously diabetic 9.07 +/- 0.76 mN, P less than 0.05; STZ-D 8.82 +/- 0.72 mN, P less than 0.05), and it was also abolished by insulin treatment (insulin-treated 6.29 +/- 0.36 mN). We conclude that the diabetic state increases the fast component of NE-induced contraction either in the absence or presence of Ca in the medium. This suggests that such an increase depends on a larger release of Ca from intracellular stores.     

Reciprocal gastropancreatic modulations for the release of somatostatin-like immunoreactivity, glucagon, and insulin in the rat

In order to assess the interrelationships between stomach and pancreas regarding the secretions of somatostatin-like immunoreactivity (SLI), glucagon (IRG), and insulin (IRI), concentrations of the three hormones were assayed in portal plasma and portal blood flow was measured in enterectomized rats before and after the selective removal of stomach or pancreas. Portal plasma SLI, IRG, and IRI concentrations were significantly increased by i.v. arginine in control rats (pancreas + stomach present). After gastrectomy, SLI, IRG, and IRI concentrations were, respectively, 52 +/- 13% (N = 15; P less than 0.005), 234 +/- 40% (P less than 0.001), and 119 +/- 15% (NS) of the pregastrectomy values. A decreased SLI secretion, an increased IRG release, and an unmodified basal IRI release were estimated by portal flow measurement. The A- and B-cell responses to arginine in the gastrectomized rats were significantly higher than in the control rats, while the D-cell response was no longer detectable. After pancreatectomy, by contrast, SLI concentrations were 360 +/- 75% of the prepancreatectomy values (N = 12; P less than 0.001). This reflected an actual increment of SLI release, taking into account the concomitant measurement of portal blood flow. The concentrations of IRG declined by 51 +/- 5% (P less than 0.001) and IRI was no longer measurable. A- and B-cell responses to arginine also were no longer detectable. These results suggest that in these experimental conditions (1) the stomach restrained pancreatic A- and B-cell responses to arginine, perhaps through the SLI released from the stomach and (2) the pancreas restrained gastric SLI secretion, perhaps through insulin.     

Secretin-induced exocrine secretion in perfused pancreas isolated from diabetic rats

Exocrine secretory function in response to 10 pM to 10 nM synthetic secretin was evaluated in perfused pancreas isolated from control, streptozocin-induced diabetic (STZ-D), alloxan-induced diabetic (ALX-D), and insulin-treated STZ-D rats. In STZ-D rats, the basal rate of pancreatic juice flow was significantly increased (10.3 +/- 1.0 microliters/20 min) compared with control rats (4.4 +/- 0.2 microliters/20 min). The basal rate of amylase output as well as pancreatic amylase content were significantly decreased to less than 5% of control values. The basal rates of protein and trypsinogen outputs were similar in both groups. In both control and diabetic rats, secretin caused a dose-dependent increase in exocrine secretion. Secretin (10 pM to 10 nM) induced 1.1- to 11.7-fold increases in exocrine secretion in STZ-D rats. These increases were significantly lower than the 2.1- to 20.8-fold increases in control rats. Furthermore, there was no significant increase in exocrine secretion from STZ-D rats in response to 10 pM secretin, although this concentration of secretin caused a significant increase in control rats. Secretin-induced exocrine secretion in ALX-D rats was similar to that in STZ-D rats. In insulin-treated STZ-D rats, the basal rates of pancreatic secretion were not significantly different from those of control rats. These results suggest that insulin resistance in this patient was due to a circulating factor of low molecular weight that uncoupled insulin stimulation of glucose transport from receptor binding and phosphorylation. The factor appears to increase the binding activity of the alpha-subunit of the insulin receptor without affecting the kinase activity of the beta-subunit.     

Effect of insulin on glucose utilization in epitrochlearis muscle of rats with streptozocin-induced NIDDM

Because skeletal muscle plays a major role in glucose disposal, it may be the primary site of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). Rates of glycogen synthesis (GS), glucose utilization via glycolysis, glycolytic utilization (GU), and glucose transport (GT) were studied in epitrochlearis muscles (EMs) obtained from 10-wk-old nonfasted Sprague-Dawley rats in which NIDDM was neonatally induced with streptozocin. Plasma glucose in NIDDM rats was elevated (P less than 0.001), whereas plasma insulin was similar in NIDDM and control rats. No differences in muscle weight, protein, glycogen, ATP, phosphocreatine, lactate, lactate-pyruvate ratios, or glucose-6-phosphate were noted in EMs of control and NIDDM rats. EMs were incubated in medium containing 5.6 or 11.2 mM glucose with tracer D-[5-3H]glucose and insulin from 0 to 7.18 x 10(-7) M for 1 or 2 h, and GS, GT, and GU were evaluated. Similar rates of basal (non-insulin-mediated) and insulin-stimulated GS, GU, and GT were observed in EMs of NIDDM and control rats incubated in 5.6 mM glucose for 2 h. Insulin dose-response curves revealed similar sensitivities and responsiveness. Increasing glucose concentration (from 5.6 to 11.2 mM) induced significant increases in basal rates of GS, GU, and GT in EMs of control but not NIDDM rats. Insulin dose-response curves for GS and GT revealed decreased sensitivity and no change in responsiveness in EMs of control and NIDDM rats, even though GU of EMs of NIDDM rats was significantly lower at basal and all other insulin concentrations. These data revealed that both insulin resistance and glucose resistance contribute to the impaired glucose metabolism in EMs of the NIDDM rat.     

Functional and morphological aspects of impaired TRH release by mediobasal hypothalamus of STZ-induced diabetic rats

Streptozocin-induced diabetes (STZ-D) in rats is associated with marked hypothyroidism characterized by functional impairment and structural lesions of the pituitary-thyroid axis. Degenerative axonal lesions, which can be prevented by insulin administration, have been reported in the mediobasal hypothalamus (MBH) of STZ-D rats. However, direct evidence connecting anatomic MBH lesions with functional impairment is still missing. We therefore performed a combined functional and morphological investigation in 4-mo-old STZ-D male rats (diabetes lasted 1 mo), applying an in vitro model to study in the same isolated MBH 1) the basal and depolarization-induced thyrotropin-releasing hormone (TRH) release during two successive incubations of 20 min each and 2) morphological and morphometric aspects, including distribution and amount (densitometric evaluation) of immunoreactive TRH in the incubated tissue. In basal conditions, TRH release was much lower in diabetic than control MBH during both incubations (P less than .01 vs. P less than .05). In depolarizing conditions, TRH release was increased during the second incubation in control (P less than .05) and during both incubations in diabetic (P less than .01) rats, the percentage increase of the TRH release due to ionic stimulation being much higher in diabetic than control animals (P less than .01). As determined by light-microscope morphometry, the total area of dilated-axon cross sections was larger in diabetic than control MBH under basal conditions (P less than .01), thus confirming degenerative axonopathy in diabetic rats. By densitometry determination, the amount of immunoreactive TRH was higher in stimulated diabetic MBH compared with both stimulated control and basal diabetic MBH (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic responses to enteral and parenteral nutrition.

Seven pairs of rats were simultaneously infused with a chemically formulated nutritionally complete amino acid-glucose diet which was delivered, at the same rate, into a central vein or into a feeding gastrostomy. The intragastrically infused rats showed greater weight gain than did the intravenously infused rats. This could not be explained by fluid retention since intake and output were similar in the two groups of animals. There was a greater increase in serum immunoreactive insulin (IRI) at day 8 in the intragastrically infused animals, but a smaller increment in serum immunoreactive pancreatic glucagon (IRG) at that point. Levels of enteroglucagon or glucagon-like immunoreactivity (GLI) were maintained in the intragastrically infused rats but declined markedly in the intravenously infused rats. It is possible that the greater release of IRI seen with the intragastric amino acid-glucose feeding contributes to better disposal of nutrients and greater weight gain. The presence of nutrients in the intestinal lumen may have stimulated the release of GLI, which in turn is insulinotropic.     

Reduced insulinotropic effects of glucagonlike peptide I-(7-36)-amide and gastric inhibitory polypeptide in isolated perfused diabetic rat pancreas

The pathophysiological role of incretin in diabetes mellitus has not been established. We therefore examined the effects of glucagonlike peptide I-(7-36)-amide (truncated GLP-I) and gastric inhibitory polypeptide (GIP) on insulin and glucagon release from isolated perfused pancreases of diabetic rats (12-14 wk of age, mean +/- SE fasting plasma glucose 8.9 +/- 0.6 mM, n = 25) after an injection of 90 mg/kg streptozocin on the 2nd day after birth and compared the results with those of nondiabetic control rats. In diabetic rats, the infusion of 1 nM GLP-I or GIP in perfusates with varying glucose concentrations (2.8, 5.6, 8.3, 11.1, or 22.2 mM) caused a nearly equal degree of insulin stimulation from a similar basal insulin level. Meanwhile, basal and GLP-I- or GIP-stimulated insulin release increased in correlation with the ambient glucose concentration in nondiabetic rats. The degree of stimulation of insulin release at glucose concentrations of 5.6 mM in diabetic rats was approximately 33% that of nondiabetic rats. The stimulation potency was the same between GLP-I and GIP. The insulin treatment for diabetic rats (5 U/kg NPH insulin at 0900 and 2100 for 6 days) brought only a slight improvement in the glucose dependency of GLP-I-stimulated insulin release. The effects of GLP-I and GIP on glucagon release were completely opposite. GLP-I suppressed release; GIP stimulated it. In diabetic rats, the degree of suppression by GLP-I and stimulation by GIP were almost the same with similar basal glucagon levels in the perfusate with varying glucose concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective neurohormonal interactions in islet cell secretion in the isolated perfused human pancreas

To investigate the effects of stimulant interactions on alpha- and beta-cell secretions, the differential effects of gastric inhibitory polypeptide (GIP) and cholinergic stimulation (CS) on insulin (IRI) and glucagon (IRG) release were examined during euglycemic, single-pass perfusion in the isolated human pancreas. Pancreata obtained from 12 cadaver organ donors were perfused for 15-min test periods with (a) 1 nM GIP (b) intrinsic CS via bipolar electrical stimulation (10 V, 5 msec, 10 Hz) of the splanchnic neural fibers during simultaneous perfusion with 4 microM phentolamine and 6 microM propranolol, or (c) GIP and CS. The integrated response of IRI and IRG demonstrated that IRI release was stimulated 308 +/- 52 microU/g-min by GIP, 366 +/- 73 microU/g-min by CS, and 560 +/- 50 microU/g-min by GIP and CS (P less than 0.05). IRG release was stimulated 111 +/- 33 pg/g-min by GIP, 34 +/- 12 pg/g-min by CS, and 90 +/- 36 pg/g-min by GIP and CS. Combined hormonal and cholinergic stimulation was additive for IRI release, but not for IRG release. We conclude that the interaction of neural and hormonal islet cell stimuli is cell-type specific. This may result in selective impairment of hormone release after pancreatic denervation.     

Long-term effects of vanadyl treatment on streptozocin-induced diabetes in rats

The vanadate and vanadyl forms of vanadium have been shown by many investigators to have insulinlike effects on glucose metabolism. Many investigators have shown that vanadium, or its salts, counteracts the hyperglycemia associated with streptozocin-induced diabetes (STZ-D) in the rat, although insulin secretion remains depressed. Studies of the action of vanadate on insulin secretion and glucose metabolism have not addressed the question of possible long-term effects of this compound on glucose metabolism extending beyond the period of oral administration. This study was undertaken to assess the effects of treatment (3 wk) and withdrawal of vanadyl sulfate (13 wk) on glucose metabolism, insulin secretion, and islet insulin content of STZ-D rats. Our results indicate that STZ-D rats that have had blood glucose levels normalized by 3 wk of vanadyl treatment remain normoglycemic after 13 wk of withdrawal from treatment. Normal glucose tolerance was observed in vanadyl-treated diabetic animals despite depressed fasting and glucose-stimulated plasma insulin levels. Insulin secretion from the isolated perfused pancreas was greater after vanadyl treatment than in untreated diabetic rats, although it was only 12% of values from controls. Three weeks of vanadyl treatment of STZ-D rats, followed by 13 wk of withdrawal, yielded islets close in size and insulin content of control islets, even though in vivo and in vitro insulin secretion was impaired. This study has shown that short-term vanadyl treatment of STZ-D rats yields normalization of glucose tolerance and protection of islets from destruction by STZ.(ABSTRACT TRUNCATED AT 250 WORDS)     

Allelic variants at insulin-receptor and insulin gene loci and susceptibility to NIDDM in Welsh population

A cohort of 132 well-documented White Welsh non-insulin-dependent diabetic (NIDDM) subjects were genotyped for 5 restriction-fragment-length polymorphisms (RFLPs) at the insulin-receptor gene (IRG) locus and a polymorphic locus 5' to the insulin gene. There was no significant difference in RFLP frequencies between the NIDDM subjects and a group of 87 matched White control subjects. Paired haplotype analysis of the IRG RFLPs suggested a difference between NIDDM and control groups for the endonuclease combinations Bgl II-Rsa I and Bgl II-Xba I. Analysis of implied haplotypes defined by the endonucleases Bgl II, Rsa I, and Xba I revealed one haplotype to be more prevalent in the NIDDM group; whereas, another haplotype was associated with the control group (P less than 0.02). Subset analysis within the NIDDM cohort compared the metabolic response of NIDDM subjects with the differing IRG haplotypes to a standard meal tolerance test. Both groups showed equivalent basal and postprandial glucose excursions, but one group revealed a significantly exaggerated plasma insulin response compared with the other (P less than 0.05). This may reflect the influence of genetic variation at the IRG locus on insulin sensitivity in patients with NIDDM.     

Unresponsiveness to glucose in a streptozocin model of diabetes. Inappropriate insulin and glucagon responses to a reduction of glucose concentration

The neonatal streptozocin (STZ) rat model of NIDDM has been previously found to have a markedly reduced insulin response to an acute increase in glucose concentration. We studied the effect of an acute reduction in glucose concentration on insulin and glucagon secretion in this model and contrasted the results with the effects of epinephrine and somatostatin using the in vitro isolated, perfused pancreas. The reduction in perfusate glucose concentration from 11.1 to 2.8 mM caused a rapid suppression of insulin release in the control rats, but had no inhibitory effect in the STZ group. Epinephrine (55 nM) and somatostatin (110 nM) caused similar decreases in insulin secretion in both groups. The glucose reduction also caused an increase in glucagon release in the controls, but had no effect in the STZ rats. Epinephrine, however, stimulated glucagon secretion in both groups in a similar fashion, and inhibition by somatostatin was also comparable. The baseline insulin and glucagon concentrations were enhanced in a separate series of experiments by the addition of arginine (5 mM) to the perfusate, and while the insulin and glucagon responses to the glucose reduction remained lost, appropriate inhibition of insulin secretion was demonstrated in the STZ rats with epinephrine. These data indicate that A- and B-cells in this rat model of NIDDM are selectively unresponsive to both increases and decreases in glucose concentration, while the responsiveness to nonglucose agents remains intact.     

Insulin effects on pantothenic acid uptake in isolated perfused working hearts from diabetic rats

Pantothenic acid uptake was studied in isolated working hearts from spontaneously diabetic BB Wistar and streptozocin-induced diabetic (STZ-D) rats. If insulin treatment was stopped for a 24-h period from spontaneously diabetic rats, a significant decrease in the rate of pantothenic uptake was noted (from 147.3 +/- 5.0 to 110.8 +/- 10.6 nmol.g-1 dry wt.30 min-1). Pantothenic acid uptake rates were also reduced in 48-h STZ-D rats (118.0 +/- 6.1 nmol.g-1 dry wt.30 min-1, compared to 158.2 +/- 5.3 in control rats). The decrease in pantothenic acid uptake in all diabetic animals occurred whether hearts were perfused with 1.2 mM palmitate or 1.2 mM palmitate and 11 mM glucose. If insulin (500 microU/ml) was added to the perfusion medium of hearts from spontaneously diabetic rats perfused with palmitate and glucose, a significant increase in pantothenic acid uptake was noted (from 110.8 +/- 10.6 to 167.0 +/- 9.4 nmol.g-1 dry wt.30 min-1). Insulin had no significant effect on pantothenic acid uptake in hearts from spontaneously diabetic rats perfused with palmitate alone. In STZ-D rats, insulin added to hearts perfused with palmitate and glucose resulted in a small but significant increase in pantothenic acid uptake (from 118.0 +/- 6.1 to 130.6 +/- 4.0 nmol.g-1 dry wt.30 min-1). Insulin had no effect on pantothenic acid uptake in control hearts perfused either in the presence or absence of glucose. These data suggest that insulin, in the presence of glucose, can increase pantothenic acid uptake in diabetic rats.     

Glucose cycling in islets from healthy and diabetic rats

Pancreatic islets from healthy (control) and neonatally streptozocin-induced diabetic (STZ-D) rats, a model for non-insulin-dependent diabetes mellitus, were incubated with 3H2O and 5.5 or 16.7 mM glucose. At 5.5 mM glucose, no detectable [3H]glucose was formed. At 16.7 mM, 2.2 patom.islet-1.h-1 of 3H was incorporated into glucose by the control islets and 5.4 patom.islet-1.h-1 by STZ-D islets. About 75% of the 3H was bound to carbon-2 of the glucose. Glucose utilization was 35.3 pmol.islet-1.h-1 by the control and 19.0 pmol.islet-1.h-1 by the STZ-D islets. Therefore, 4.5% of the glucose-6-phosphate formed by the control islets and 15.7% by the STZ-D islets was dephosphorylated. This presumably occurred in the beta-cells of the islets catalyzed by glucose-6-phosphatase. An increased glucose cycling, i.e., glucose----glucose-6-phosphate----glucose, in islets of STZ-D rats may contribute to the decreased insulin secretion found in these animals.     

Reversible impairment of glucose-induced insulin secretion in SHR/N-cp rats. Genetic model of type II diabetes

The SHR/N-cp rat is a new genetically obese model for non-insulin-dependent diabetes mellitus. Expression of the diabetes is enhanced by a high-sucrose (54%) diet. After 4 wk on the diet, the cp/cp rats weigh significantly more than their +/? controls, have postprandial hyperglycemia (greater than 400 mg/dl), and are hyperinsulinemic, with immunoreactive insulin (IRI) levels 10- to 20-fold greater than controls. Total pancreatic IRI tends to be increased 1.6-fold in the cp/cp rats (although not significantly). There is no increase in pancreatic proinsulin content as a percent of total IRI. Studies of in vitro pancreatic function were carried out with the isolated nonrecirculating perfused pancreas method. The cp/cp rats (n = 10) showed impaired or absent IRI responses to 16.5 mM glucose, whereas +/? rats (n = 9) responded with classic biphasic curves. Comparison of insulin secreted in 20 min revealed a greater than 53% decrease in IRI secretion in cp/cp rats (P less than .05). A paradoxical hypersecretion of IRI at glucose concentrations of 0-2.7 mM was noted in cp/cp but not lean rats, i.e., 1.8 +/- 0.2 mU/min IRI in cp/cp rats vs. 0.04 +/- 0.007 mU/min in +/? rats. Perfusion of pancreases for 45 min with buffers containing no glucose resulted in restoration of a normal biphasic IRI response to 16.5 mM glucose in the cp/cp rats, whereas response in the lean rats was markedly reduced. Brisk IRI responses to 10 mM arginine in buffers with no glucose also occurred in cp/cp but not +/? rats. Glucagon secretion was relatively suppressed in the cp/cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Remission of hypoglycemia after partial resection of a metastatic islet cell tumor.

The course of a malignant islet cell tumor, producing increased levels of both insulin and glucagon, was studied clinically and in vitro for two years. The patient presented with hypoglycemia, and extensive hepatic metastases were present. Instead of biopsy alone, it was elected to remove the primary in the tail of the pancreas, and subtotal pancreatectomy was performed. There followed a six month interval without hypoglycemia, during which immunoreactive insulin (IRI) decreased (though remaining elevated) and immunoreactive glucagon (IRG) increased markedly. The tumor and a liver metastasis contained elevated IRI and IRG with immunofluorescence for insulin, though typical beta and alpha cells were not present on electron microscopy. A preparation of a monolayer culture of a liver metastasis decreased its IRI production with a similar time course to the clinical improvement, though rapid cell growth continued. Streptozotocin in vitro was markedly cytotoxic. In vivo Streptozotocin caused tumor regression, increase in fasting plasma glucose, decrease in plasma IRI and IRG, and improvement of glucose tolerance. Thus, this case showed elevated IRG in plasma and tumor, improvement in glucoregulation upon excision of the primary, and both in vitro cytotoxicity and clinical improvement with Streptozotocin. It is suggested (1) that cases refractory to therapy directed toward suppression of insulin secretion might benefit from removal of the primary and (2) that further use of cultures of such tumors should be initiated to establish whether they might be useful for predicting in vivo effectiveness of cytotoxic agents.     

Increased activity of intestinal acyl-CoA: cholesterol acyltransferase in rats with streptozocin-induced diabetes and restoration by insulin supplementation

We examined the activities of intestinal acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol esterase, enzymes regulating cholesterol absorption, in rats with streptozocin-induced diabetes (STZ-D) to clarify the effect of diabetes on cholesterol absorption. Three weeks after the induction of diabetes, plasma cholesterol levels were slightly but significantly increased in diabetic rats compared with control animals, whereas a far more remarkable increase in plasma cholesterol was observed in diabetic rats when fed an atherogenic diet containing 1% cholesterol, 0.5% cholic acid, and 5% lard. Microsomal ACAT activity in intestinal mucosa was three times higher in diabetic than in control rats. However, no significant difference in the enzyme activity could be detected between diabetic animals fed control chow and those fed the atherogenic diet. Furthermore, insulin supplementation given to diabetic rats caused a reduction of enzyme activity to the levels found in control animals. In contrast, cholesterol esterase activity in rat intestinal mucosa was unaffected by either the induction of diabetes or the atherogenic diet feeding. In conclusion, we disclosed that apparent ACAT activity in intestinal mucosa is elevated in STZ-D rats. Therefore, we postulate that enhancement of CoA-dependent cholesterol esterification in the intestine might be one of the major factors responsible for hypercholesterolemia in diabetes.     

Effects of ingestion of triglyceride or galactose on secretion of gastric inhibitory polypeptide and on responses to intravenous glucose in normal and diabetic subjects

Responses of plasma immunoreactive gastric inhibitory polypeptide (IRGIP) to oral triglyceride or galactose were compared in normal and mildly diabetic (non-insulin-dependent) subjects. After triglyceride the responses of IRGIP were similar, but after galactose those of the diabetics were slightly exaggerated. Both stimuli evoked increments of plasma immunoreactive glucagon (IRG) in diabetics but not in normal subjects. Plasma immunoreactive insulin (IRI) did not change. In normal subjects given oral triglyceride or galactose followed by intravenous (I.V.) glucose the early-phase response of plasma IRI was enhanced and glucose tolerance improved. In the diabetics, oral triglyceride did not affect insulin release or glucose tolerance after I.V. glucose; oral galactose elicited a slight increase of insulin release without improving glucose tolerance. In the diabetics the rise of plasma IRG after ingestion of triglyceride or galactose was maintained after I.V. glucose. It is concluded that endogenous GIP is insulinotropic and that there is partial resistance to this action in diabetes. The results were compatible with feedback inhibition of GIP secretion by insulin and with the suggestion that the rise of plasma IRG associated with secretion of GIP in diabetics may be due to the glucagonotropic action of this peptide.     

Effects of maternal diabetes on placental transfer of glucose in rats

In situ perfusion of the fetal side of the anesthetized rat placenta was used to monitor glucose fluxes in nondiabetic, streptozocin-induced diabetic (STZ-D), acutely hyperglycemic nondiabetic, and acutely normoglycemic STZ-D rats. STZ-D resulted in increased accumulation of glucose in the perfusate during a single passage through the fetal vasculature compared with nondiabetic rats, and this increase was maintained in normoglycemic STZ-D rats, indicating glucose release from placental stores. The fractional clearance of 3-O-[14C]methylglucose, a nonmetabolizable glucose analogue, across the placenta was decreased in both STZ-D groups compared with nondiabetic rats but unchanged in hyperglycemic nondiabetic rats, implying a reduction in glucose transporters in diabetic placentas. The difference between the transfer of D-[3H]glucose and 3-O-[14C]methylglucose indicated that 17% of the glucose was retained while traversing the placenta of nondiabetic rats, whereas a smaller percentage (8%) but a larger absolute amount (9 vs. 6 mumol/h) of glucose was retained by the placentas of the severely STZ-D rats. This retention was markedly enhanced in hyperglycemic nondiabetic rats and STZ-D rats when rendered normoglycemic. The net accumulation of perfusate glucose was less than that predicted from radiolabeled transfer data, indicating that glucose is also back transferred from the perfusate to the mother's placenta. We conclude that maternal diabetes markedly affects placental glucose flux.     

Functional and morphological changes in mediobasal hypothalamus of streptozocin-induced diabetic rats. In vitro study of LHRH release

To investigate the role of the mediobasal hypothalamus (MBH) in diabetic gonadal axis disorders, the MBHs of adult male streptozocin-induced diabetic (STZ-D) rats were examined after incubation in basal conditions or in K+-enriched medium and compared with those of controls. Diabetes lasted 1 mo. Both luteinizing-hormone-releasing hormone (LHRH) release and MBH morphology were studied. After incubation in basal conditions, the LHRH release was unchanged. By light microscopy, the dilated-axon cross sections were more numerous (P less than .01) in the basal arcuate nucleus and in the median eminence. By electron microscopy, the ratio of exocytoses to neurosecretory granules observed in the median eminence axon cross sections was smaller (P less than .05). The total LHRH immunoreactivity, the number of labeled axons, and the amount of positive material in the axons were reduced (P less than .05). After incubation in K+-enriched medium, the LHRH release was markedly reduced (P less than .01). The number and area of dilated-axon cross sections, possibly because of the relation between exocytosis and physiological dilation, were less augmented (P less than .01). Whereas the number of exocytoses and the ratio of exocytoses to neurosecretory granules were not decreased, the total LHRH immunoreactivity and the number of labeled axons were reduced (P less than .05). The releasable LHRH pool therefore seems to be exhausted in control MBH because of long-term stimulation and reduced in the MBH of STZ-D rats because of diabetes. In conclusion, STZ-D causes functional and anatomical MBH lesions that should be pathogenetically relevant for the disorders of the gonadal axis documented in this animal model.