A study of the morphological changes in the small intestine of the spontaneously diabetic Chinese hamster

Summary Several morphological changes were observed microscopically in the small intestine of some diabetic Chinese hamsters. Although some alterations lacked statistical significance due to variation, most diabetics displayed a greater incidence and severity compared with nondiabetic controls. The following structural deviations were seen in the small intestines of some diabetics: increased surface area, elevated number of goblet cells per villus, decreased muscle thickness with connective tissue infiltration, reduced number of Auerbach's plexuses, lymphocyte aggregations accompanied by blunted villi, blood vascular lesions and deformed villi due to excessive loss of epithelial cells.Supported in part by Upjohn Company grantSupported in part by Western Michigan University Summer Faculty Fellowship (1974)     

There are no morphologic abnormalities of the gastric wall or abdominal vagus in patients with diabetic gastroparesis

Because there is evidence for vagal autonomic neuropathy as the cause of diabetic gastroparesis, we hypothesized that this disorder should be associated with morphologic abnormalities of the abdominal vagus nerve or gastric myenteric plexus, or both. We studied the smooth muscle and myenteric plexus of the stomach in 18 nondiabetic controls and 16 patients with long-standing diabetes. Five of the diabetics had gastroparesis and 11 did not. We utilized conventional histology and Smith's silver technique for visualizing the myenteric plexus. Neurons within the myenteric plexus were quantified in sections stained with each technique. The abdominal vagus nerves from 5 diabetics (2 with gastroparesis) and 12 nondiabetic controls were stained with hematoxylin and eosin, Gomori trichrome, luxol-fast blue, and Holmes' silver stains. There were no abnormalities in the numbers or appearance of neurons or axons in the myenteric plexus of the stomach of diabetics, with or without gastroparesis. Also absent were abnormalities of the smooth muscle or vagus nerve. Thus, no morphologic abnormalities of the gastric wall or abdominal vagus were identified in diabetic gastroparesis.     

Chronic Intestinal Pseudoobstruction as a Possible Sequel to Encephalitis

A patient is reported who presented with a typical intestinal pseudoobstruction syndrome. Before this illness, the patient had suffered from measles encephalitis at the age of 15 months. A postencephalitic syndrome was present which included severe mental retardation, parkinsonism, and epilepsy. There were no relatives with a similar disease. Clinically, there was a frank recurrent pseudoobstruction syndrome with occasional diarrhea. Radiographic barium studies showed delayed transit, hypomotility of the intestines, and gross distension of the esophagus, stomach, small intestine, and colon. Histological examination of the gastrointestinal tract revealed a normal appearance of the mucosa; however, there was a hypertrophic muscle layer with abnormalities of the plexuses. Both the submucosal and the myenteric plexuses were reduced in number and size. They showed a decreased number of ganglion cells, proliferation of Schwann cells and infiltration by lymphocytes. The abnormalities were most strikingly present in the esophagus and the small intestine. The intestinal neuropathy resulting in clinical pseudoobstruction is proposed to be part of the generalised neurological pathology as a late sequel to the measles encephalitis.     

Erythrocyte aggregation in relation to diabetic retinopathy

Summary Erythrocyte aggregation, plasma fibrinogen concentrations and serum protein fractions have been studied in 19 diabetic patients without retinopathy, 18 patients with retinopathy and 41 non-diabetic controls. — Significant differences in the parameters were observed between diabetics and controls. The differences between the diabetics with and without retinopathy were not significant. — The role of abnormal erythrocyte aggregation in the development of diabetic retinopathy is discussed. — Striking parallels were found with similar findings concerning platelet aggregation in diabetics.     

Plasma lipoproteins and lipoprotein lipase in young diabetics with and without ketonuria

Plasma lipoprotein and lipoprotein lipase activity have been evaluated in young diabetics with and without ketonuria and in healthy controls of the same age. Fifteen (age range 7-23 years) newly detected diabetics (8 with ketonuria, 7 non ketonuric) have been examined before starting the treatment. Five healthy medical students (age range 19-21 years) have also been studied. Both ketotic and non ketotic patients showed an impaired insulin and C-peptide response to the glucose load in comparison to controls. Ketotic patients had low lipoprotein lipase activity (p less than 0.01) and high density lipoprotein (p less than 0.01); total plasma Triglycerides and VLDL Triglyceride and Cholesterol were higher than in controls. Plasma Triglyceride and VLDL Triglyceride and Cholesterol were inversely related to lipoprotein lipase activity. Low lipoprotein lipase activity, from adipose tissue and muscle, has been found to be associated with hypertriglyceridemia and reduced HDL Cholesterol in young diabetic patients with ketonuria.     

Ano-rectal manometry as an evaluating test for impaired ano-rectal function in diabetes mellitus

Summary Diarrhea and/or rectal incontinence may represent a sign of autonomic neuropathy in diabetes. The present investigation was performed to study ano-rectal function and reactivity to appropriate stimuli in 20 diabetic patients with or without autonomic neuropathy (14 insulindependent diabetics; 6 non-insulin-dependent diabetics; mean age 39.2 years; mean duration of diabetes 12.6 years). Twenty-five healthy subjects (mean age 43.5 years) were studied as controls. All subjects underwent ano-rectal manometry by means of special open-ended-tip catheters connected with a 6-channel polygraph. A rectal latex balloon was inflated with 30 or 60 ml air to induce a stimulus which, under normal conditions, is apt to relax the internal sphincter and to contract the external one (ano-rectal inhibitory reflex). Eleven diabetics had symptoms and signs of autonomic neuropathy: 8 of these (73%) showed marked abnormalities of ano-rectal function (i.e. no response even to maximum stimulus or contraction of both sphincters). All non-neuropathic patients showed a normal pattern of ano-rectal manometry. A relationship between abnormal response to rectal stimulation and the presence of autonomic neuropathy involving the pelvic parasympathetic section or regional intramural plexuses may be suspected and demonstrated in diabetic neuropathic patients.     

Immunohistochemical study on gastroenteric nervous system in trisomy 16 mice:an animal model of Down syndrome

AIM:To study the development of gastroenteric nervous system in trisomy 16 mouse embryos.The gastroenteric nervous system in trisomy 16 mice and their normal littermates, serving as controls from embryonic days 13 to 18 (ED13-18) was identified by using primary antibody against protein gene product (PGP) 9.5.METHODS:Trisomy 16 mouse breeding and trisomy 16 mouse embryos were identified from their normal littermates by chromosome examination; PGP 9.5 immunohistochemical stainning.RESULTS:In normal littermates embryos, the precursor cells from the neural crest migrated into stomach and intestine at ED 13 and ED 14 respectively.Numerous nervous processes connected to each other and formed early nervous networks at ED 14 stomach and ED 15 intestine. Original ganglia in the muscular nervous plexus of the stomach appeared at ED15 with very simple arrangement. At ED 16 the early developed myenteric nervous plexuses were regularly found in the stomach and intestine respectively. In both stomach and intestine, the development of submucosal nervous plexuses were finished at ED17. However, the myenteric nervous plexus and the internal and external submucosal nervous plexuses were differentiated only in the stomach at ED 18.In comparison with the normal littermates, stomach and intestine nervous system developed much slower in trisomy 16 mice. Their immature neurons did not appear in the stomach and intestine until ED 14 and ED 15. Between ED 14 and ED 16, the gastroenteric nervous system was composed of only some scattered neurons with different distribution density and size. The development and differentiation of the gastroenteric nervous system were delayed and the myenteric nervous plexus did not appear until ED 18. There was no submucosal nervous plexus in all stomach and intestine specimens. A semiquantitative analysis and rank sum test of the data showed that the trisomy 16 mouse embryos were markedly retarded in the gastroenteric nervous development compared with their normal littermates.CONCLUSION:Trisomy 16 mice, as an animal model for Down syndrome, has abnormality not only in several systems and organs but also in gastroenteric innervation. This report describes for the first time that the development of the gastroenteric nervous system was not only delayed but also pathological.     

The ultrastructural study of glycogen and lamellar bodies in the development of fetal monkey lung

Developing fetal monkey lung tissues were studied at the gestational period of 135-145 days. In general, glycogen is distributed throughout the cytoplasm of the type II pneumocytes at this gestational period. It is of interest that we found a structural relationship between glycogen particles and lamellar body formation in the type II pneumocytes. The glycogen particles were found inside the electron-dense pre-granules and the immature lamellar bodies. Some of the fully matured lamellar bodies also contained glycogen. This phenomenon has not been observed previously, and it supports the evidence that there is a close and direct structural relationship between glycogen and the development of lamellar bodies at this stage of lung development in the type II pneumocytes.     

Influence of the diabetic state on isoproterenol-induced cardiac necrosis

Isoproterenol-induced myocardial necrosis was examined in male mice with alloxan-induced and genetically transmitted diabetes. Ten days after alloxan treatment, mice exhibited an elevation in blood glucose concentrations, weight loss, polyuria and decreased heart rates (510 +/- 15 v. 675 +/- 11 beats/min) compared with matched control mice. Similarly, genetically diabetic mice exhibited lower heart rates than the corresponding age-matched controls (383 +/- 30 v. 603 +/- 30 beats/min). In comparison to matched controls, both groups of diabetic mice had a significant decrease in the severity of the cardiac necrosis which was induced by the administration of isoproterenol. The reduction in isoproterenol-induced cardiac lesions was similar in mice with chemically induced diabetics and mice with genetically transmitted diabetes. Biochemical studies of ventricular slices revealed no change in basal cAMP levels and no differences in isoproterenol-induced changes in cAMP levels in mouse hearts from both models of diabetes. Insulin treatment corrected the chemically induced diabetic state and restored the cardiotoxic potential of isoproterenol.     

Effects of diabetes on cardiac glycogen metabolism in rats

Summary The effects of diabetes on myocardial glycogen metabolism in rats were examined and compared with those of fasting. Male Wistar rats were divided into three groups: controls, streptozotocininduced diabetics, and one-week fasted. Isolated rat hearts were subjected to substrate-free 30-min Langendorff perfusion followed by 60-min working heart perfusion with glucose alone or in combination with insulin or insulin plus -hydroxybutyrate (BHB). Myocardial glycogen contents were determined before or 30 min after Langendorff perfusion, or 60 min after working heart perfusion. Before Langendorff perfusion, tissue glycogen concentrations in control, diabetic, and fasted hearts were 3.3 ± 0.2, 10.0 ± 0.9, and 5.7 ± 0.5 (mg/g wet weight), respectively. In diabetic rats, the myocardial glycogen concentration was markedly decreased after working heart perfusion of any of the substrate combinations, even those with insulin and BHB. In contrast, myocardial glycogen in control or fasted rats was not reduced after the addition of glucose with insulin, and/or glucose with insulin and BHB. These results suggest that degradation of tissue glycogen occurs in isolated perfused hearts from diabetic rats, while a clearly different response is shown by fasted hearts.     

Platelet shape change abnormalities in diabetic retinopathy

Summary In vitro platelet aggregation has been studied in 29 normal subjects and 35 diabetic patients with retinopathy by conventional aggregating agents and by a new technique which evaluates the platelet shape change. — Platelet shape change, expressed as % light transmission variation induced by the addition of ADP (10 mol/l) in calcium-deprived platelet rich plasma, was determined. Significant differences were found between the controls (12.6±0.7%) and the 35 diabetics (15.6±1.0%, p <0.02) and between controls and the subgroup of patients with proliferative retinopathy (17.3±1.1%, n=15, p<0.001). Platelet aggregation induced by ADP, collagen and ristocetin did not show significant differences between normal and diabetic subjects. — The shape change is the physiological early phase of platelet aggregation and is related to energy requiring mechanisms. As yet unexplored metabolic abnormalities at this stage could account for previously described platelet abnormalities in diabetes.     

Aggregation of erythrocyte suspensions of diabetic patients in dextran 70 solutions]

Our previous studies have shown an erythrocyte hyperaggregation during diabetes. This hyperaggregation phenomenon seems usually be promoted by quantitative plasma protein's changes mainly fibrinogen. The aim of the present work is to appreciate the possible effect of only diabetic red cells on aggregation induced by dextran 70 (Dx 70). Aggregation measurements were performed with Sefam aggregometer. Patients were insulin-dependent (IDD) and non insulin-dependent diabetics (NIDD), divided in two groups of 11 well controlled diabetics (HbA1C 6.8 +/- 0.5%) (7 IDD and 4 NIDD) and 11 poorly controlled diabetics (HbA1C 10.8 +/- 2.7%) (7 IDD and 4 NIDD). They were compared with a control group consisting of 22 healthy subjects. Results can be summarized as follows: red cell aggregation induced by Dx 70 was not significantly different between the well controlled diabetics and controls. Similar results were obtained for the poorly controlled diabetics. By contrast, when studying red cell aggregation in autologous plasma (H = 40%), aggregation was found to be significantly more important in both diabetic groups than that of the controls. Thus, results emphasize the importance of suspending medium in erythrocyte hyper-aggregation phenomenon during diabetes. Cellular factors do not seem to interfere on aggregation phenomenon for diabetics included in this study.     

Gastrointestinal complications in diabetes mellitus

Impaired function of the gastrointestinal tract related to diabetes mellitus (DM) results from diabetic autonomous neuropathy, impaired sensory innervation and a direct effect of chronic hyperglycaemia. Another possible connection between DM and the gastrointestinal tract can be infrequent autoimmune diseases associated with type I DM (celiac disease, autoimmune gastropathy, autoimmune chronic pancreatitis). Functional or organic changes resulting from diabetes can be seen in every organ of the gastrointestinal tract. Some of the diabetic gastrointestinal tract difficulties affect almost 60% of patients with long lasting diabetes. On one side, impaired function of individual organs in diabetics can significantly influence level of diabetes compensation and vice versa. On the other side, unsatisfactory diabetes compensation can result in manifestation of digestive problems. The most frequent and the most serious clinical complication is diabetic gastroparesis (DG). The highest incidence of impaired evacuation and motility of the stomach (and the small intestine) is described in diabetics with long lasting unsatisfactory diabetes compensation, microangiopathic complications, and diabetic neuropathy (55-75% in type I diabetes and 15-20% in type II diabetes). Symptoms accompanying impaired motility and emptying of the stomach (feeling of early fullness, eructation, nausea, vomiting and abdominal pains) can be only temporary or can be missing in some patients. Hyperglycaemia accompanied by slowing down evacuation of the stomach is different in patients with an empty stomach--glycaemia over 7.8 mmol/l, and postprandially--antral motility decreases after blood glucose levels get over 9.7 mmol/l. Treatment options for symptomatic diabetic gastroparesis are limited. Achieving normoglycaemia usually improves diabetic gastroparesis but in up to 80% of cases simultaneous administration of prokinetics is necessary.     

No effect of growth hormone treatment on axonal transport of slow component a in diabetic and nondiabetic rats.

A decreased axonal transport of slow component a (SCa), i.e., neurofilaments, is an early event in experimental diabetes as well as hypothyroidism, and common to these metabolic derangements are decreased levels of serum insulin-like growth factor I (IGF-I). To evaluate the possible connection between these facts, we investigated the effect of growth hormone (GH), which stimulates IGF-I production, on axonal transport of SCa in diabetic and nondiabetic rats. Serum concentrations of IGF-I fell from about 1500 micrograms/L in controls to about 600 micrograms/L in diabetics. GH treatment (100 mu/rat twice daily) normalized IGF-I for the first week of diabetes, after which the level decreased to the level of the untreated diabetics. The SCa transport velocity was found to be decreased in the diabetic nerves as previously reported [0.91 +/- 0.07 = mm/day, n = 9; (mean +/- SD) versus 1.01 +/- 0.09 mm/day, n = 8, in controls, 2 p less than 0.05). No changes were seen for the GH-treated groups (1.03 +/- 0.06 mm/day, (n = 11) in GH-treated controls). The lack of effect of GH treatment can be due to blockage of IGF-I synthesis or the decreased level of thyroid hormone, triiodothyronine (T3), in the diabetic rats.     

Gallbladder volume and emptying in diabetics: the role of neuropathy and obesity.

Gallbladder (GB) volume was monitored by real-time sonography in diabetics (n = 21) and healthy volunteers (n = 55) after a test meal. Seventeen controls and seven diabetics were obese; six patients had both autonomous and somatic neuropathy, and four had somatic neuropathy. Fasting GB volume was similar in controls and diabetics with and without autonomic neuropathy; it was correlated with body mass index (controls, r = 0.43, P less than 0.002; diabetics, r = 0.46, P less than 0.04), and was increased in obese subjects. Post-prandial GB emptying was decreased in diabetics. Those with autonomous neuropathy exhibited larger residual volumes than controls (P less than 0.03). Post-prandial GB emptying was slower and less complete in (non-diabetic) obese subjects and deteriorated further in diabetic obese subjects. GB fasting tone was normal, but GB kinetics were impaired in diabetics; obesity and autonomous neuropathy were correlated with GB hypomotility.     

Deposition of eosinophil granule major basic protein in eosinophilic gastroenteritis and celiac disease.

Degrees of eosinophil infiltration and eosinophil degranulation, as evidenced by localization of the eosinophil granule major basic protein (MBP), were compared in patients with eosinophilic gastroenteritis, patients with celiac disease, and healthy controls using a specific indirect immunofluorescence technique for the localization of MBP. Formalin-fixed, paraffin-embedded biopsy specimens from the mucosa of the stomach and small intestine of 11 patients with eosinophilic gastroenteritis, from the small intestine of 4 patients with celiac disease, and from the stomach and/or upper small intestine of 18 healthy asymptomatic volunteers were tested. Degrees of eosinophil infiltration and extracellular deposition of MBP were graded by two blinded observers; each section was given a score from 0 (nil) to 4 (marked). In the small bowel biopsy specimens, both eosinophil infiltration and extracellular MBP deposition scores were significantly greater in patients with eosinophilic gastroenteritis and in patients with celiac disease than in controls. In the gastric biopsy specimens, extracellular MBP deposition scores were significantly increased in patients with eosinophilic gastroenteritis compared with controls even though eosinophil infiltration scores did not differ significantly at this site. The results support the hypothesis that the eosinophil, through toxic cationic proteins such as MBP, plays a role in the pathogenesis of these diseases.     

Rapid distal small bowel transit associated with sympathetic denervation in type I diabetes mellitus.

BACKGROUND: The pattern of progression of a meal from the stomach to the caecum in diabetes mellitus is controversial and the differential roles of transit through the jejunum and the ileum have not been investigated in diabetes. AIMS: To determine gastric emptying and transit rates through proximal and distal regions of the small bowel in type I diabetic patients. SUBJECTS: The study included six diabetic patients with evidence of autonomic neuropathy (DM-AN group), 11 diabetics without autonomic dysfunction (DM group), and 15 control volunteers. METHODS: Gastric emptying and small bowel transit of a liquid meal were evaluated scintigraphically in these subjects. Transit through regions of interest corresponding to the proximal and distal small intestine up to the caecum was determined and correlated with gastric emptying rates, cardiovascular measurements of autonomic function, and the occurrence of diarrhoea. RESULTS: Gastric emptying and transit through the proximal small bowel were similar in the three groups. The meal arrived to the caecum significantly earlier in DM-AN patients (median; range: 55 min; 22-->180 min) than in the DM group (100 min; 44-->180 min, p < 0.05) or in controls (120 min; 80-->180 min, p < 0.02). Accumulation of chyme in the distal small bowel was decreased in DM-AN patients, who showed values for peak activity (30%; 10-55%) significantly lower than in the DM group (49%; 25-77%, p = 0.02) and controls (50%; 30-81%, p = 0.02). In DM patients (n = 17), the time of meal arrival to the caecum was significantly correlated with both orthostatic hypotension (coefficient of contingency, C = 0.53, p < 0.01) and diarrhoea (C = 0.47, p < 0.05), but not with gastric emptying rates. CONCLUSIONS: Patients with type I diabetes mellitus and sympathetic denervation have abnormally rapid transit of a liquid meal through the distal small bowel, which may play a part in diarrhoea production.     

Histological studies of Auerbach's plexuses of the oesophagus, stomach, jejunum, and colon in patients with achalasia of the oesophagus: correlation with gastric acid secretion, presence of parietal cells and gastric emptying of solids.

Histological changes in the Auerbach's plexuses of the oesophagus, stomach, jejunum, and colon were analysed in a prospective study in 34 patients with achalasia of the oesophagus. At the distal end of the oesophagus ganglia cells were absent in 91% of cases as well as in the middle third of the stomach (20%). The Auerbach's plexuses were normal in the jejunum and colon. The results of gastric acid secretion showed that the peak acid output was significantly lower in achalasia patients compared with controls (p less than 0.001). There was no correlation between the mean ganglion neuronal count in the gastric plexuses and the rate of gastric acid output (r = 0.33). Gastric emptying of solids was also evaluated, but there was no correlation between gastric emptying and the mean ganglion neuronal count in the gastric Auerbach's plexuses. The rate of gastric emptying of solids was similar in controls and patients with achalasia. These studies suggest that denervation of the oesophagus in patients with achalasia, which is a constant finding in several previous reports may extend beyond the oesophagus to the stomach in nearly half the cases.     

Is Exercise-induced Blood Pressure Rise Predictive of Nephropathy in Insulin-dependent Diabetes?

ABSTRACT A follow-up study was performed in 48 male diabetics and 17 age-matched male controls, who in 1963 and 1971 participated in an exercise study to evaluate if the results could predict later development of diabetic nephropathy. The inclusion criteria were: Type I (insulin-dependent) diabetes with age below 40, onset of diabetes before age of 30, duration of diabetes more than 7 years and no proteinuria at the time for the first study. The diabetics demonstrated higher systolic blood pressure (BP) at work but as good physical condition as the controls. Thirteen developed nephropathy after 23 years (range 15–36) of diabetes duration. It was found that exercise-induced, abnormally raised systolic BP was not associated with later development of diabetic nephropathy.     

Gastric and oesophageal emptying in insulin-dependent diabetes mellitus

Abstract Gastric emptying of a digestible solid and liquid meal and oesophageal emptying of a solid bolus were measured with scintigraphic techniques in 45 randomly selected insulin-dependent diabetics and in 22 control subjects. In the diabetics, the relationships between oesophageal emptying, gastric emptying, age, duration of diabetes mellitus, upper gastrointestinal symptoms, glycaemic control and the complications, autonomic neuropathy, peripheral neuropathy and retinopathy were examined. The lag period before solid food left the stomach was not significantly different in diabetics compared with control subjects, but the percentage retention of solid food at 100 min was greater ( P < 0.001) in the diabetic subjects. Both the early phase (percentage retention at 10 min) and the 50% emptying time for liquid gastric emptying were delayed ( P < 0.001) in the diabetic subjects. Of the diabetics, 58% had delayed gastric emptying of either the solid and/or the liquid meal; oesophageal emptying was delayed in 42%. Upper gastrointestinal symptoms correlated poorly with both gastric and oesophageal emptying. Oesophageal emptying, solid gastric emptying and the liquid 50% emptying time correlated with the severity of autonomic nerve dysfunction ( P < 0.05). The early phase of liquid emptying (retention at 10 min) was significantly slower ( P < 0.05) in patients with mean plasma glucose concentrations of > 15 mmol/l during the gastric emptying test and the lag period for solid emptying correlated with both the glycosylated haemoglobin and mean plasma glucose concentrations.