Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity

The presence of methane on lactulose breath test among irritable bowel syndrome (IBS) subjects is highly associated with the constipation-predominant form. Therefore, we set out to determine whether methane gas can alter small intestinal motor function. In dogs, small intestinal fistulae were created to permit measurement of intestinal transit. Using a radiolabel, we evaluated transit during infusion of room air and subsequently methane. In this model, small intestinal infusion of methane produced a slowing of transit in all dogs by an average of 59%. In a second experiment, guinea pig ileum was pinned into an organ bath for the study of contractile activity in response to brush strokes applied to the mucosa. The force of contraction was measured both orad and aborad to the stimulus. The experiment was repeated while the bath was gassed with methane. Contractile activities orad and aborad to the stimulus were significantly augmented by methane compared with room air (P < 0.05). In a third experiment, humans with IBS who had undergone a small bowel motility study were compared such that subjects who produced methane on lactulose breath test were compared with those producing hydrogen. The motility index was significantly higher in methane-producing IBS patients (1,851 +/- 861) compared with hydrogen producers (1,199 +/- 301) (P < 0.05). Therefore, methane, a gaseous by-product of intestinal bacteria, slows small intestinal transit and appears to do so by augmenting small bowel contractile activity.     

Prolonged small-intestinal transit time in cystic fibrosis.

A lactulose hydrogen breath test was performed on 10 patients with cystic fibrosis and 15 control subjects matched for age and sex. All normal subjects had a fasting breath hydrogen concentration of less than 20 ppm. In contrast, seven of the patients with cystic fibrosis had high concentrations (25-170 ppm), which fell to 20 ppm or below on prolonged fasting (14-23 hours). Two patients showed no rise in breath hydrogen concentrations after lactulose, and in one patient the breath hydrogen concentration rose at 15 minutes, suggesting bacterial colonisation of the small bowel. Seven of the patients had prolonged small-bowel transit times (160-390 minutes) compared with those in the control group (50-150 minutes).     

Pupillary signs in diabetic autonomic neuropathy.

Pupillary function was investigated in 36 insulin-dependent diabetics and 36 controls matched for age and sex. About half of the diabetics had evidence of peripheral somatic or autonomic neuropathy, or both. The diabetic patients had abnormally small pupil diameters in the dark and less fluctuation in pupil size (hippus) during continuous illumination than the controls. They also had reduced reflex responses to light flashes of an intensity adjusted for individual retinal sensitivities. The pupillary findings were compared with results of five tests of cardiovascular function and five tests of peripheral sensory and motor nerve function. Almost all the patients with autonomic neuropathy had pupillary signs, which we therefore conclude are a common manifestation of diabetic autonomic neuropathy.     

Delayed small-intestinal transit in tropical malabsorption.

The time of breath hydrogen appearance (T) after oral lactulose was determined in 98 patients in London who had been to the tropics. Fifty-six controls from three different ethnic groups had no evidence of gastrointestinal disease; 23 had tropical malabsorption, which was severe in 10; and 19 had chronic diarrhoea without malabsorption. Mean T was significantly delayed in patients with tropical malabsorption compared with controls, indicating that their mouth-caecum transit rate was abnormally slow. In six patients with tropical malabsorption who were reinvestigated after treatment a fall in the value for T seemed to parallel clinical improvement. Three patients with diarrhoea due to chronic colonic disease had delayed T. Patients with tropical malabsorption have bacterial colonisation of the small intestine, which is important in the pathogenesis of the disease. Bacterial overgrowth, which sometimes occurs after infective diarrhoea in the tropics and gives rise to tropical sprue, is a result of stasis.     

Decreased response of epinephrine and norepinephrine to insulin-induced hypoglycemia in diabetic autonomic neuropathy

The responses of epinephrine, norepinephrine and other counter-regulatory hormones to insulin-induced hypoglycemia were investigated in 5 diabetics who showed signs of autonomic neuropathy, in 7 age-matched diabetics without autonomic neuropathy and in 7 healthy subjects. The presence of autonomic neuropathy was evaluated by decreased beat-to-beat variation in heat rates during hyperventilation or orthostatic hypotension. Catecholamines were determined by a totally automated plasma catecholamine analyzing system using a two-column system of high performance liquid chromatography. Plasma epinephrine and norepinephrine responses to hypoglycemia in diabetics with autonomic neuropathy were significantly lower than those in diabetics without autonomic neuropathy. Plasma glucagon response in diabetics was apparently attenuated compared to normal controls and there was no significant difference in glucagon response between the two patient groups. Other counter-regulatory hormone responses did not differ among the three groups. The data demonstrate that the responses of plasma epinephrine and norepinephrine to insulin-induced hypoglycemia are impaired in diabetics with autonomic neuropathy.     

Blunting of Colon Contractions in Diabetics with Gastroparesis Quantified by Wireless Motility Capsule Methods

Generalized gut transit abnormalities are observed in some diabetics with gastroparesis. Relations of gastric emptying abnormalities to colon contractile dysfunction are poorly characterized. We measured colon transit and contractility using wireless motility capsules (WMC) in 41 healthy subjects, 12 diabetics with gastroparesis (defined by gastric retention >5 hours), and 8 diabetics with normal gastric emptying (≤5 hours). Overall numbers of colon contractions >25 mmHg were calculated in all subjects and were correlated with gastric emptying times for diabetics with gastroparesis. Colon transit periods were divided into quartiles by time and contraction numbers were calculated for each quartile to estimate regional colon contractility. Colon transit in diabetics with gastroparesis was prolonged vs. healthy subjects (P<0.0001). Overall numbers of colon contractions in gastroparetics were lower than controls (P = 0.02). Diabetics with normal emptying showed transit and contraction numbers similar to controls. Gastric emptying inversely correlated with overall contraction numbers in gastroparetics (r = -0.49). Numbers of contractions increased from the 1^st to 4^th colon transit quartile in controls and diabetics with normal emptying (P≤0.04), but not gastroparetics. Numbers of contractions in the 3^rd and 4^th quartiles were reduced in gastroparetics vs. healthy controls (P≤0.05) and in the 4^th quartile vs. diabetics with normal emptying (P = 0.02). Numbers of contractions were greatest in the final 15 minutes of transit, but were reduced in gastroparetics vs. healthy controls and diabetics with normal emptying (P≤0.005). On multivariate analyses, differences in numbers of contractions were not explained by demographic or clinical variables. In conclusion, diabetics with gastroparesis exhibit delayed colon transit associated with reductions in contractions that are prominently blunted in latter transit phases and which correlate with delayed gastric emptying, while diabetics with normal emptying show no significant colonic impairments. These findings emphasize diabetic gastroparesis may be part of a generalized dysmotility syndrome.     

Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes.

The immediate heart-rate response to standing was measured in 22 normal controls and 25 patients with diabetes, 15 of whom had autonomic neuropathy. The response in the controls and patients without autonomic neuropathy was characteristic and consistent, with tachycardia maximal at around the 15th beat and relative bradycardia maximal at around the 30th beat. The diabetics with autonomic neuropathy, however, showed a flat response. In three controls the response was abolished with intravenous atropine but not with propranolol, showing that it is mediated through the vagus. A simplified test using routine ECGs and measuring the R-R interval at beats 15 and 30 with a ruler is easily performed as an outpatient procedure and may be used as a measure of autonomic function in diabetes.     

Medial arterial calcification and diabetic neuropathy.

X-ray examinations of the feet, knees, and hands were performed on 20 diabetics with severe neuropathy and 20 diabetics with no evidence of neuropathy but with a similar mean age and duration of diabetes. All were under 53 years old with no clinical evidence of peripheral vascular disease. Medial arterial calcification was much more common and extensive in the patients with neuropathy, occurring in the feet in 15 and in the hands in eight compared with in four (p less than 0.001) and none (p less than 0.001) of the controls respectively. Although there was some correlation between calcification and both proteinuria (p less than 0.05) and proliferative retinopathy (p less than 0.02), the association between calcification and neuropathy (p less than 0.001) was much stronger. Neuropathy, with sympathetic denervation of the smooth muscle of the tunica media, may be important in the aetiology of medial arterial calcification.     

Altered bile in diabetic diarrhoea.

The size and composition of the bile-salt pools in a group of diabetics with neuropathy but no diarrhoea and a group with "diabetic diarrhoea" were compared with those in a group of stable, uncomplicated diabetics. The diabetics with neuropathy had significantly more dihydroxy bile salts, a larger bile-salt pool, and a higher faecal excretion of bile than the controls. The diabetics with diarrhoea had significantly more dihydroxy bile salts, a higher glycine to taurine ratio, a smaller bile-salt pool, and increased excretions of 14C-tracer and total bile salts. We conclude that considerable alterations occur in the bile of diabetics with neuropathy or diarrhoea, and we suggest that in some cases at least these abnormalities may indicate a mechanism for diabetic diarrhoea.     

Does super efficient starch absorption promote diverticular disease?

The amount of starch escaping absorption in the small intestine was measured in eight patients with symptomatic diverticular disease and eight controls. Unabsorbed starch was calculated from breath hydrogen measurements after a potato meal compared with the hydrogen response to lactulose. The proportion of unabsorbed starch was low in all the patients (mean 3.3%) and was only about a quarter of that in the controls (12.4%; p less than 0.01). These findings confirm that unabsorbed starch provides an important quantity of carbohydrate reaching the colon and suggest that super efficient starch absorption, by reducing this provision, may promote the development of diverticular disease.     

Neuropathy in latent hereditary hepatic porphyria.

Peripheral nerve conduction velocoties were measured in 20 patients with acute intermittent porphyria and five with variegate porphyria and in 25 controls matched for age and sex. None of the porphyric patients had acute symptoms on examination, and nine had never had symptoms. Compared with the controls, patients had a significantly slower conduction velocity of the slower motor fibres of the ulnar nerve (P less than 0-001) and a slower sensory conduction velocity of the ulnar and median nerves (P less than 0-05). There was no significant difference between the patients and controls in the maximum motor conductionvelocity of the median, ulnar, deep peroneal, or posterior tibial nerves. Slight peripheral neuropathy seems to be associated with latent hereditary hepatic porphyria, even in patients who have never had symptoms.     

Diabetic dimorphism according to acetylator status.

Two groups of diabetics and 19 normal controls had their rate of acetylation of sulphadimidine measured. Among 47 patients with maturity onset diabetes the 29 fast acetylators were older at diagnosis and, at a given glucose concentration, had a higher pretreatment fasting insulin concentration than slow acetylators. They also had a larger first-phase insulin secretion in response to intravenous glucose both before and after one month''s dietary treatment. The greatest difference between fast and slow acetylators was in the first-phase secretion of insulin after a month''s treatment. The proportion of fast acetylators among the second group of diabetics, who had been admitted to improve their glucose concentrations or for treatment of tissue damage, was similar to that among the normal controls (50% and 47% respectively). The data seem to indicate that diabetics are fast acetylators unexpectedly often, but it is not clear whether the dimorphism according to acetylator status produces a differential risk of neuropathy or of any other type of diabetic tissue damage.     

Cardiac Denervation in Diabetes

Evidence for vagal denervation of the heart as a feature of diabetic autonomic neuropathy has been obtained by monitoring beat-to-beat variation in heart rate. Nine diabetics with autonomic neuropathy were assessed; each showed a marked reduction or absence of beat-to-beat variation in comparison with controls. Beat-to-beat variation in normal subjects is abolished by parasympathetic blockade but unaffected by sympathetic blockade. These findings suggest that spontaneous vagal denervation of the heart was present in the cases studied. Measurement of beat-to-beat variation provides a simple test whereby cases of autonomic neuropathy can be screened for cardiac involvement.     

Effect of wheat bran on weight of stool and gastrointestinal transit time: a meta analysis

Twenty original papers that reported on the effect of wheat bran on large bowel function were analysed. Bran increased the stool weight and decreased the transit time in each study in healthy controls and in patients with the irritable bowel syndrome, with diverticula, and with chronic constipation. Statistical evaluation of the data showed, however, that constipated patients had lower stool output and slower transit whether or not they had taken bran, and they responded less well to bran treatment than controls. From these data it is concluded that bran can be expected to be only partially effective in restoring normal stool weight and transit time in patients who are constipated.     

Vagal impairment of gastric secretion in diabetic autonomic neuropathy.

Gastric acid output in response to insulin-induced hypoglycaemia and pentagastrin was measured in 18 diabetic patients with symptoms of autonomic neuropathy. Two patients had achlorhydria but the rest responded normally to pentagastrin. The acid output evoked by insulin-induced hypoglycaemia was low in 10 of the 16 patients who secreted acid in response to pentagastrin. These changes suggest that vagal impairment is common in diabetics with autonomic symptoms, which might explain the infrequency of duodenal ulcer in diabetics.     

Circulatory and temperature regulatory responses to exercise in a warm environment in insulin-dependent diabetics.

Because diabetics are prone to the development of neuropathy and microvascular disease, abnormalities of cardiovascular reactivity and capillary permeability in response to acute exercise and/or an increase in environmental temperature might presage the development of clinically overt complications. In the present study insulin-dependent diabetics without evidence of microangiopathy or neuropathy and controls matched for the same level of physical fitness performed cycle ergometer exercise for 20 minutes at 65 percent VO2 max in a temperature maintained at 35 percent C. Ther rise in heart rate (82-85 beats min-1), the fall in plasma volume (11-13 percent), and the increase in total serum proteins (13-16 percent) induced by exercise were the same in the two groups. Furthermore, comparable increments in skin blood flow (two- to threefold) and in core and skin temperatures were observed. The relationship between increases in body core temperature and increases in skin blood flow and the vasodilatory threshold (37.0 percent C) were also the same in the diabetics and controls.     

Diabetic autonomic neuropathy and iritis: an association suggesting an immunological cause.

Of 47 insulin requiring diabetics aged 21-40 years with autonomic neuropathy (heart rate variability less than 10), 14 had previously developed iritis. In all except two cases the iritis preceded the autonomic symptoms. The autonomic neuropathy was very severe, 10 patients having two or more characteristic symptoms. Ten of the patients with iritis were women. The association of iritis (itself an immune disorder) with severe symptomatic autonomic neuropathy raises the possibility of an underlying immunological basis for autonomic neuropathy.     

Effect of skin pressure by clothing on small bowel transit time

We examined the effect of increased skin pressure from tight clothing on small bowel transit time by means of the breath hydrogen test, using milk that contained lactulose as an additional indigestible disaccharide, which is used as a test meal after overnight fasting. In this experiment, we measured the small bowel transit time from 9 healthy and non-constipated female subjects with two different skin pressures that were applied by loose-fitting experimental garment or an additional tight-fitting girdle on two consecutive days. The skin pressure of the latter condition was 8-9 mmHg higher than that of the former one on the participants' waist, abdomen and hip region. The experimental order of the two skin pressure conditions was counterbalanced. As a result, the small bowel transit time obtained with and without girdle did not differ significantly (165.0 +/- 26.0 minutes for less skin pressure condition and 173.3 +/- 26.8 minutes for more skin pressure condition, n = 9, p = 0.43). This result indicated that the skin pressure from clothing has no effect on the passage rate of food through the small intestine.     

Relationship between thromboxane/prostacyclin ratio and diabetic vascular complications.

To elucidate the relationship between the thromboxane A2/prostacyclin (TXA2/PGI2) ratio and diabetic complications, the levels of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1alpha, the urinary metabolites of thromboxane A2 and prostacyclin, were measured in diabetics by gas chromatography/selected ion monitoring. We compared the TXA2/PGI2 ratio in healthy volunteers and diabetics. The TXA2/PGI2 ratio of diabetics was significantly higher than that of healthy volunteers and we could reconfirm the hypercoagulable condition in diabetics. We also investigated the difference of TXA2/PGI2 levels in diabetics with retinopathy and neuropathy. The TXA2/PGI2 ratio of diabetics with retinopathy showed significantly higher level than without retinopathy. However, the TXA2/PGI2 ratio of diabetics with neuropathy was the same as without neuropathy. These results suggest that the TXA2/PGI2 ratio reflects the pathological conditions of diabetes, especially the change of vasculature. The monitoring and improvement of TXA2/PGI2 ratio could be useful for the prevention of diabetic vascular complications.     

Plasma renin activity in diabetic patients.

Plasma renin activity (PRA) in 40 diabetic patients and 42 healthy controls was investigated using the method of Pickens in modification of Serebrovskaja et al. (1967). PRA was slightly lower in the whole group of diabetes but the difference was not significant. The subgroup of 20 maturity-onset diabetics had significantly lower PRA in comparison with 22 controls of similar age, while PRA in juvenile diabetics did not differ significantly from matched controls. In patients without clinical signs and symptoms of microangiopathy PRA was as high as in the controls. In diabetics with microangiopathy PRA was significantly lower. PRA was also lower in patients with longer duration of the disease. The stimulation of juxtaglomerular apparatus with sodium free diet and diuretic drugs resulted in an increase of PRA both in controls and diabetics. This suggests a functional depression of PRA in diabetic patients. In diabetics with ketoacidosis PRA was higher than in control subjects and decreased after disappearance of ketoacidosis. A high level was recorded in a patient with hyperosmolar coma and a very low level in a patient with polyneuropathy and severe orthostatic hypotension. The possible mechanisms involved in the changes of PRA in diabetic patients are discussed.