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Query: UMLS:C0011849 (diabetes)
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The genetically obese fa/fa rat is glucose intolerant when tested in a conscious state after the spontaneous ingestion of a glucose solution. The aim of this study was to investigate the mechanism(s) underlying the abnormal oral glucose tolerance test of obese animals with the non-steady-state measurement of glucose turnover proposed by Steele et al. in 1968. Our results show that the total rate of glucose appearance is enhanced in obese compared with lean animals. This abnormality is not due to an increased gut glucose absorption but to a lack of suppression and even a transient stimulation of hepatic glucose production after the ingestion of glucose. The rate of glucose utilization by the obese animals is somewhat increased compared with controls or unchanged when expressed as glucose metabolic clearance rate, thus excluding this parameter from the factors contributing to the observed glucose intolerance. The results obtained with genetically obese rats agree with those reported for type II diabetes in humans. The observed defect of the obese group could be related to an abnormal regulation of insulin counterregulatory hormone(s) or of hepatic innervation as well as to other defects of hepatic glycogen handling.
Diabetes 1986 Dec
PMID:Mechanism of abnormal oral glucose tolerance of genetically obese fa/fa rats. 353 82

Previous studies have demonstrated that reflexes originating from the oral cavity at the start of food intake are necessary to ensure a normal glucose tolerance. In our experiment, the underlying mechanisms of these reflexes were studied in conscious, freely moving rats bearing chronic catheters. A double-isotope technique was used to measure, under non-steady-state conditions, rates of total glucose appearance (total Ra), total glucose disappearance (Rd), gut glucose absorption (gut Ra), hepatic glucose production (HGP), and the metabolic clearance rate of glucose (MCRg). In random order, 1 wk apart, rats either spontaneously drank 1 ml of a 60% glucose solution or were given the same dose into the stomach via a chronic gastric catheter. Glycemia and insulinemia were lower when glucose was taken orally than when the same amount of the substrate was administered intragastrically. Total Ra after glucose administration was the same in both groups throughout the experiment. Despite lower insulin and glucose values, the increase in Rd was initially higher in the oral group than in the intragastric group. This was accompanied by initial higher MCRg values in the oral group than in animals that received the glucose load directly into their stomachs. We conclude that a series of reflexes elicited by oral glucose ingestion improve glucose tolerance by increasing the efficiency of glucose disposal in the early stages after a glucose load, with a smaller amount of insulin released.
Diabetes 1987 Jul
PMID:Role of the oropharynx in regulation of glycemia. 355 78

Figure 18 outlines a summary of the results obtained in our laboratory and how these might be interpreted. Following a 100-g oral glucose load, about 25 g is taken up by the liver. About 5 g or 5% of this would be removed on a first-pass basis since only about a fifth of the portal vein glucose is newly absorbed. The remainder of the glucose is disposed of in peripheral tissues. This disposal is enhanced by intestinal insulinotropic factors that stimulate insulin secretion. Lactate is produced peripherally (with the red cells as one of the most important sources) by the gut and, perhaps, by hepatocytes. It is taken up by gluconeogenetic hepatocytes to form glycogen. This pathway appears to account for half to two-thirds of glycogen synthesis, the remainder being by direct uptake of glucose. The gluconeogenetic pathway of glycogen formation may be important in that it clears the obligatory production of lactate from certain tissues. The only difference between intravenous and oral glucose loading is that there is no absorbed glucose in the portal vein when glucose is infused. The glucose concentrations here are, however, almost the same as during oral glucose loading since peripheral clearance of glucose is slower in the absence of insulinotropic intestinal factors. This helps to explain why liver handling of intravenous glucose and glycogen formation are almost identical to the case of oral loading.
Diabetes Metab Rev 1987 Jan
PMID:Tracer methods and the metabolic disposal of a carbohydrate load in man. 356 79

The effects of short- and long-term diabetes on the maximal activities of phosphate-dependent glutaminase and glutamine metabolism were studied in the colon and the small intestine of streptozotocin-diabetic rats. The maximal activity of colonic phosphate-dependent glutaminase was decreased [44% in mucosal scrapings (p less than 0.01); 29% in whole colon (p less than 0.001)] or unchanged in short- or long-term diabetes respectively. That of the small intestine was increased in both short- (110%) and long-term (200%-500%) diabetes; insulin treatment corrected this increase. Acute insulin-deficiency (using anti-insulin serum) resulted in the increase (18%, p less than 0.05) of the activity of only intestinal glutaminase. Chemically-induced acidosis and alkalosis decreased (46%, p less than 0.001) and increased (24%, p less than 0.001), respectively, the activity of intestinal glutaminase, but had no effect on the colonic enzyme. Changes in glutaminase of the enlarged colon and small intestine were only detectable when activities were measured in whole organ. Arteriovenous-difference measurements showed diminished metabolism of plasma glutamine by the gut which correlated with the duration of the state of diabetes, and was accompanied by enhanced release by skeletal muscle and increased uptake by both kidney and liver. It is concluded that insulin is directly or indirectly involved in the regulation of glutamine metabolism of the gut.
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PMID:The maximal activity of phosphate-dependent glutaminase and glutamine metabolism in the colon and the small intestine of streptozotocin-diabetic rats. 356 95

Diabetes mellitus has been associated with a variety of gastrointestinal motor disturbances. Pyloric activity, however, has not been specifically investigated. We have quantified the pyloric manometric profile in 24 diabetics with recurrent nausea or vomiting, or both, without evidence of mechanical obstruction. Twelve healthy volunteers served as controls. A multilumen pneumohydraulic perfusion assembly with five side openings, each 1 cm apart, was positioned fluoroscopically across the antroduodenal junction and used to monitor pressure activity for 5 h (3 h fasting and 2 h fed). Three patterns of pyloric activity were defined and quantified: (a) baseline elevation of greater than or equal to 3 mmHg for greater than or equal to 1 min (tonic pattern); (b) antral-type phasic pressure activity mixed with duodenal phasic activity (phasic pattern); and (c) phasic pattern superimposed on tonic activity (combined tonic-phasic pattern). The duration of the total pyloric activity before and after the meal was greater in diabetics than in controls (p less than 0.005). Furthermore, episodes of unusually prolonged (greater than or equal to 3 min) and intense (greater than or equal to 10 mmHg) tonic contraction, "pylorospasm," were observed in 14 of 24 diabetics but in only 1 control (p = 0.025). In diabetics, episodes of pylorospasm had a peak amplitude of tonic activity of 13 +/- 1 mmHg and a duration of 7 +/- 0.7 min (mean +/- SE). We conclude that pyloric dysmotility forms part of the widespread disruption of gut motility that affects some patients with diabetes.
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PMID:Pyloric dysfunction in diabetics with recurrent nausea and vomiting. 369 9

Enteric nerves in the ileum of rats 8 weeks after streptozotocin-induction of diabetes were examined under the electron microscope before and after immunolabeling for vasoactive intestinal polypeptide (VIP). These studies have provided evidence of degenerative changes in the myenteric nerve fibres of diabetic rats, many of which were shown to contain VIP. It is suggested that VIP-ergic nerves in the gut may play a role in the development of gastrointestinal dysfunction in diabetes.
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PMID:Enteric nerves in diabetic rats: electron microscopic evidence for neuropathy of vasoactive intestinal polypeptide-containing fibres. 373 23

Food can affect the production and secretion of hormones by direct actions on the gut, by nervous reflexes, through changes in the concentration of various metabolites in the blood, or secondary to changes in circulating gut hormone levels. Not only is the composition of the diet important but also its texture, quantity and duration. GIP and insulin are used as examples of hormones whose production and secretion are diet-dependent. Their possible involvement in the pathogenesis of obesity and non-insulin-dependent (type II) diabetes is discussed.
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PMID:How our food affects our hormones. 388 42

In normal man, glucose serves to regulate basal insulin secretion by its participation with insulin in a feedback loop. In addition, glucose stimulates insulin secretion directly and potentiates insulin responses to nonglucose stimuli such as amino acids, beta-adrenergic stimuli, and gut hormones. Maximal glycemic potentiation of the acute insulin response to IV arginine occurs at a glucose level of approx. 450 mg/dl. In patients with noninsulin dependent diabetes mellitus (NIDDM), basal insulin levels have usually been reported as normal, but if plasma glucose is lowered to normal levels, a deficiency of basal insulin becomes apparent. In addition, the first phase (0-10 min) insulin response to IV glucose is absent in virtually all patients with overt NIDDM. In contrast, the second-phase (greater than 10 min) response is often preserved in NIDDM due to its maintenance by ambient hyperglycemia. Similarly, insulin responses to nonglucose stimuli such as arginine often appear normal in NIDDM because of potentiation by hyperglycemia. However, insulin responses to arginine are lower than those of nondiabetic controls when compared at multiple matched glucose levels. Indeed, maximal potentiation by glucose of the insulin response to arginine is markedly subnormal in NIDDM, suggesting a loss of functional B cell secretory capacity. In patients with long-standing insulin-dependent diabetes mellitus (IDDM), basal insulin secretion and insulin responses to all stimuli are virtually absent. However, in a remission phase, or in IDDM of short duration, basal insulin secretion and insulin responses to nonglucose stimuli may be relatively preserved. Therefore, islet dysfunction in IDDM and NIDDM, while etiologically different, share some common pathophysiological features.
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PMID:Pathophysiology of insulin secretion in diabetes mellitus. 389 62

Experimental and clinical work over the last 6 years has confirmed and broadened, but also challenged, the incretin concept. The nervous component of the entero-insular axis is still poorly defined, especially the peptidergic nerves, of which several contain insulinotropic regulatory peptides. The incretin effect is preserved after complete denervation of the porcine pancreas. Type 2 (non insulin-dependent) diabetic patients have a significantly decreased incretin effect. GIP (gastric inhibitory polypeptide; glucose dependent insulin releasing peptide) remains the strongest incretin factor. Its secretion depends on the absorption of nutrients. However, the correlation between the GIP response and disturbances of the entero-insular axis in some gastrointestinal diseases and, in particular, Type 2 diabetes, is poor. Furthermore, physiological concentrations of exogenous GIP do not produce fully the incretin effect and injection of GIP antibodies does not abolish the incretin effect. This suggests the existence of additional humoral incretin factors. On the other hand, GIP seems to have direct metabolic effects independent of its insulinotropic activity. The incretin effect of oral glucose is smaller if plasma levels of C-peptide rather than insulin are measured. However, decreased hepatic extraction of insulin after glucose ingestion only accounts partially for the incretin effect. GIP is unlikely to be the gut factor which regulates hepatic insulin extraction.
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PMID:New developments in the incretin concept. 390 45

This laboratory has proposed that endogenous gut-derived bacterial endotoxin primes the pancreatic secretion of insulin in normal rats. Endogenous lipopolysaccharide (LPS) is continually absorbed from the gut into intestinal capillaries, and low-grade portal venous endotoxemia is the status quo. Under physiologic conditions, Kupffer cells of the liver totally phagocytize and degrade endotoxin from the portal circulation. Evidence from this and other laboratories indicates that administration of exogenous LPS to humans and rats enhances pancreatic secretion of both insulin and glucagon. Conversely, findings of the present study demonstrate that restriction of endogenous LPS in fasted rats depresses the basal and arginine-stimulated concentrations of plasma insulin. Techniques used to restrict gut-derived LPS availability included chronic daily gavage with neomycin and cefazolin for gut sterilization and with cholestyramine or lactulose to reduce endotoxin within the gut. In addition, induction of endotoxin tolerance was produced by progressively higher doses of LPS intraperitoneally (i.p.), and polymyxin B was administered subcutaneously (s.c.) daily to neutralize the lipid A portion of circulating LPS. Finally, isolator-reared, defined flora rats, which were gram-negative-bacteria-deficient, and, therefore, LPS-deficient, were compared with conventional counterparts. Basal plasma insulin but not glucagon levels were consistently and significantly reduced in endogenous LPS-restricted animals. Glucose-stimulated plasma insulin was decreased only after parenteral treatment by tolerance induction and polymyxin B administration. Both plasma insulin and glucagon were depressed in response to arginine challenge in most LPS-restricted rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 Dec
PMID:Endogenous gut-derived bacterial endotoxin tonically primes pancreatic secretion of insulin in normal rats. 390 58


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