Gastroenterology – Amal Mattu

If I hadn’t just read Horowitz & Samsom’s book I’m fairly sure this lecture would have been difficult to follow, but a lot of the stuff covered here is (naturally) closely related to the stuff covered in that book; this is mostly a revision lecture aimed at reminding you of stuff you already (supposedly?) know and/or dealing with topics closely related to stuff you already know, I don’t think it’s the right lecture for someone who knows very little about gastroenterology. I like Mattu’s approach to lecturing; this lecture was both fun and enjoyable to watch, despite (?) including a lot of information.

A few links to stuff covered/mentioned in the lecture:

Boerhaave syndrome.
Does This Patient Have a Severe Upper Gastrointestinal Bleed? (JAMA).
Acute Liver Failure (NEJM review article).
Charcot’s cholangitis triad.
Ranson criteria.
Crohn’s disease.
Ulcerative colitis.
Abdominal aortic aneurysm.
Mesenteric ischemia.
Shigella infection.
Clostridium perfringens.
Pseudomembranous colitis.


September 11, 2017 Posted by | Gastroenterology, Lectures, Medicine, Microbiology | Leave a comment

Gastrointestinal Function in Diabetes Mellitus (III)

Below some observations from chapters 5 and 6.

“The major functions of the small intestine are to digest and absorb nutrients, while those of the large bowel are to extract water and process faeces before expulsion. Diabetes mellitus may be associated with both small intestinal and colonic dysfunction, potentially resulting in a wide range of clinical manifestations, including gastrointestinal symptoms, poor nutritional status and impaired glycaemic control. […] The prevalence of small intestinal and colonic dysfunction in diabetes has not been formally evaluated and remains uncertain. However, small intestinal motor abnormalities are evident in about 80% of patients with diabetic gastroparesis, suggesting that the prevalence of intestinal dysmotility is likely to be comparable to the prevalence of gastroparesis in diabetic patients, i.e. 30–50% of unselected patients [1–6]. […] symptoms resulting from intestinal dysfunction are not cause-specific and are heterogeneous, potentially giving rise to diverse complaints, including anorexia, nausea, vomiting, constipation, diarrhoea and abdominal pain or discomfort. […] Transport of chyme through the small intestine is closely linked to intraluminal digestion and absorption of nutrients. The efficacy of absorption of nutrients is, therefore, potentially affected by dysmotility of the small intestine observed in diabetes, and by alterations in the transport mechanisms facilitating nutrient uptake across the intestinal membrane.”

“After meal ingestion, food is initially stored in the proximal stomach, then triturated in the distal stomach, and finally transported to the small intestine […]. The major functions of the small intestine are to mix and propel food particles in order to optimise intraluminal digestion and absorption. Those food particles that escape absorption, as well as indigestible solids, are transported to the colon, where water is extracted and faeces processed before expulsion. The motility patterns of the small intestine and colon are designed to efficiently serve these functions of controlled mixing and transport. When the small intestine is not exposed to nutrients, it exhibits a cyclic pattern of motility […] termed the migrating motor complex (MMC). […] The major function of the colon is to absorb water and electrolytes in order to concentrate and solidify the intraluminal content. Colonic motility plays an important role in these processes. In contrast to small intestinal motility, colonic motility follows a diurnal rhythm, with relative motor quiescence during sleep [55,56]. […] Transit and absorption of intestinal contents are regulated by the autonomic and enteric nervous systems. […] Numerous neuropeptides have been shown to play an important role in controlling the smooth muscle function of the small intestine and colon […] studies using experimental animal models of diabetes have shown altered activity of many neurotransmitters known to be of importance in preserving the integrity of intestinal motility […] Recently, the so-called interstitial cells of Cajal have been identified in the gastrointestinal tract [64–66] and appear to be responsible for the generation of the slow wave activity present in the entire gastrointestinal tract. […] The interplay between the enteric nervous system and the interstitial cells of Cajal is essential for normal gut motility.”

“[N]europathy of the autonomic (vagal and sympathetic) and enteric nerves may result in intestinal dysmotility. Autonomic neuropathy at the level of the gut can be assessed using cardiac autonomic nerve (CAN) function tests as a surrogate marker […] at present CAN function tests are the best tests available in the clinical situation. Studies using CAN function tests to assess involvement of the autonomic nerve system indicate that in patients with CAN the prevalence and severity of dysmotility of the small intestine and colon is substantially greater when compared to patients with normal CAN function. […] there is evidence that intestinal secretion may be abnormal in diabetes, due to increased secretion of fluids in response to a meal, rather than an increased basal secretory state [176]. […] These observations suggest that progressive neuropathy of the enteric and autonomic nervous system is likely to be responsible for the impaired intestinal secretion, rather than hyperglycaemia.”

“Studies that have investigated small intestinal motility in diabetes mellitus have revealed a wide spectrum of motor patterns, ranging from normal to grossly abnormal motility […] Postprandial small intestinal motor abnormalities include early recurrence of phase III and burst activity […] Both […] are thought to indicate neuropathic changes in either the intrinsic or extrinsic innervation of the gut. […] The data relating to colonic function in patients with diabetes mellitus are even more limited than those that exist for the small intestine […] [Some results suggest that] symptoms may not be a good indicator of the presence or absence of delayed colonic transit in diabetic patients.”

“There is little or no evidence that diabetes per se affects protein absorption to a clinically relevant extent. However, when diabetes mellitus is associated with severe pancreatic insufficiency […], coeliac disease […] or bacterial overgrowth, malabsorption of protein may occur. […] Since lipid absorption is dependent on the interplay of several organs (small intestine, pancreas, liver, gall bladder), diabetes mellitus has the potential to be associated with fat malabsorption […] Although it is not known whether small intestinal dysmotility per se can lead to fat malabsorption, it certainly can when the dysmotility is associated with bacterial overgrowth [160,161]. […] Recently, drug-induced malabsorption of fat has become a treatment option in diabetes mellitus. The inhibition of pancreatic lipase activity by orlistat prevents the hydrolysis of triglycerides, resulting in fat malabsorption. This approach has been reported to improve glycaemic control in type 2 diabetes”.

“The superior and inferior mesenteric arteries supply blood to the small and large intestine, while the superior, middle and inferior rectal arteries provide the arterial blood supply of the rectum. About 25% of the cardiac output in the fasting state circulates through the splanchnic arteries […] Animal models of diabetes are associated with abnormalities of neurotransmitters in the mesenteric veins and arteries […] Human diabetes may be associated with abnormalities in mesenteric blood flow. In diabetic patients with autonomic neuropathy, preprandial superior mesenteric arterial blood flow is greater than that in both control subjects and patients without autonomic neuropathy […] patients with autonomic dysfunction […] are at particular risk of postprandial hypotension and often exhibit a marked fall in systemic blood pressure after a meal […] the magnitude of the postprandial fall in blood pressure is dependent on meal composition (glucose has the greatest effect) and the rate of nutrient entry into the small intestine [196]. […] Patients with diabetes mellitus also frequently report symptoms attributable to orthostatic hypotension. A large survey of type 1 diabetes mellitus reported that the frequency of feeling faint on standing was 18% [200]. Symptomatic orthostatic hypotension in diabetic patients has been shown to be related to cardiovascular autonomic neuropathy”.

“Disordered defaecation, characterised by incontinence, constipation and diarrhoea, occurs frequently in patients with diabetes mellitus [1–3] but is often overlooked as a cause of morbidity. For example, in a study of 136 unselected diabetic outpatients referred to a tertiary centre, Feldman and Schiller found that constipation occurred in 60%, diarrhoea in 22% and faecal incontinence in 20% of their patients [1]. […] Disordered defaecation appears to be less common among patients with diabetes attending secondary referral centres [4,5], where constipation has been reported in about 20% and faecal incontinence in about 9% [5].”

“[D]efaecation and the preservation of continence are both complex territorial behaviours in humans. They are generated in the cerebral cortex and are […] markedly influenced by psychosocial factors. The multiple physiological functions required to control the passage of faeces are under the influence of a control centre in the pontine brain stem and orchestrated by the neuronal activity in the terminal expansion of the spinal cord. The instructions are conveyed via pelvic parasympathetic nerves, lumbar sympathetic nerves and sacral somatic nerves, influencing the function of the enteric nervous system and visceral smooth muscle and also the muscles of the pelvic floor. […] the muscles of the colon, abdominal wall and pelvic floor must be able to contract with sufficient power to propel faeces or resist that propulsion. But more important, the arrival of faeces in the rectum or even quite small increases in intra-abdominal pressure need to be detected immediately, so that appropriate responses can be rapidly triggered through spinal and enteric reflexes. These actions can be influenced at many levels by the diabetic process. […] Impairment of neural function caused by diabetic microangiopathy can affect to a lesser or greater extent all the mechanisms involved in the maintenance of faecal continence. So whether a person develops faecal incontinence or not depends on the interplay between all of these. Physiological studies have demonstrated that cohorts of patients with long-standing diabetes have an abnormally low anal tone, weak squeeze pressures and impaired rectal sensation [58–60]. […] Patients with long-standing diabetes mellitus are more likely to be afflicted by the shame of nocturnal incontinence of faeces than non-diabetics with faecal incontinence. […] Faecal incontinence in diabetic patients is also often associated with urinary incontinence [63]. […] Patients with faecal incontinence may only rarely be ‘cured’ — the major aim of treatment is to improve symptoms to a level where there is minimal impact on lifestyle.”

“It is important to recognise that the most common factor responsible for pudendal neuropathy in women is […] damage to the pelvic floor sustained during childbirth. […] Endo-anal ultrasonography has shown that 35% of primiparous women tested after delivery had sustained sphincter damage that persisted for at least 6 months [66]. The percentages are higher in those who had undergone forceps delivery and for multiparous women […] Diabetic women, especially those with less than optimal diabetic control, are more liable to suffer from obstetric complications, such as traumatic disruption of the anal sphincter or weakness of the pelvic floor, leading to chronic stretching of the pudendal nerve. This is because diabetics tend to give birth to large babies when glycaemic control is poor, and are more likely to experience long and difficult labours and require assisted delivery with forceps or ventouse [67].”

September 10, 2017 Posted by | Books, Diabetes, Gastroenterology, Neurology | Leave a comment

Gastrointestinal Function in Diabetes (II)

Some more observations from the book below.

“In comparison with other parts of the gastrointestinal tract, the human oesophagus is a relatively simple organ with relatively simple functions. Despite this simplicity, disordered oesophageal function is not uncommon. […] The human oesophagus is a muscular tube that connects the pharyngeal cavity to the stomach. […] The most important functions of the human oesophagus and its sphincters are to propel swallowed food boluses to the stomach and to prevent gastro-oesophageal and oesophagopharyngeal reflux. […] Whereas the passage of liquid and solid food boluses through the oesophagus, and even acid gastrooesophageal reflux, are usually not perceived, the likelihood of perception is greater under pathological circumstances […] However, the relationship between oesophageal perception and stimulation is highly variable, e.g. patients with severe oesophagitis may deny any oesophageal symptom, while others with an endoscopically normal oesophagus may suffer from severe reflux symptoms.”

“While it is clear that oesophageal dysfunction occurs frequently in diabetes mellitus, there is considerable variation in the reported prevalence between different studies. […] Numerous studies have shown that oesophageal transit, as measured with radionuclide techniques, is slower in patients with diabetes than in age- and sex-matched healthy controls […] oesophageal transit appears to be delayed in 40–60% of patients with long-standing diabetes […] Although information relating to the prevalence of manometric abnormalities of the oesophagus [relevant link] is limited, the available data indicate that these are evident in approximately 50% of patients with diabetes […] A variety of oesophageal motor abnormalities has been demonstrated in patients with diabetes mellitus […]. These include a decreased amplitude […] and number […] of peristaltic contractions […], and an increased incidence of simultaneous […] and nonpropagated [10] contractions, as well as abnormal wave forms [17,30,32]. […] there is unequivocal evidence of damage to the extrinsic nerve supply to the oesophagus in diabetes mellitus. The results of examination of the oesophagus in 20 patients who died from diabetes disclosed histologic abnormalities in 18 of them […] The available information indicates that the prevalence of gastro-oesophageal reflux disease is higher in diabetes. Murray and co-workers studied 20 diabetic patients (14 type 1, six type 2), of whom nine (45%) were found to have excessive gastro-oesophageal acid reflux […] In a larger study of 50 type 1 diabetic patients without symptoms or history of gastro-oesophageal disease, abnormal gastro-oesophageal reflux, defined as a percentage of time with esophageal pH < 4 exceeding 3.5%, was detected in 14 patients (28%) [37].”

“Several studies have shown that the gastrointestinal motor responses to various stimuli are impaired during acute hyperglycaemia in both healthy subjects and diabetic patients […] acute hyperglycaemia reduces LOS [lower oesophageal sphincter, US] pressure and impairs oesophageal motility […] Several studies have shown that abnormal oesophageal motility is more frequent in diabetic patients who have evidence of peripheral or autonomic neuropathy than in those without […] In one of the largest studies that focused on the relationship between neuropathy and disordered oesophageal function, 50 […] insulin-requiring diabetics were stratified into three groups: (a) patients without peripheral neuropathy (n = 18); (b) patients with peripheral neuropathy but no autonomic neuropathy (n = 20); and (c) patients with both peripheral and autonomic neuropathy (n = 12). Radionuclide oesophageal emptying was found to be abnormal in 55%, 70% and 83% of patients in groups A, B and C, respectively [17]. […] It must be emphasised, however, that although several studies have provided evidence for the existence of a relationship between disordered oesophageal function and diabetic autonomic neuropathy, this relationship is relatively weak [13,14,17,27,37,49].”

“There is considerable disagreement in the literature as to the prevalence of symptoms of oesophageal dysfunction in diabetes mellitus. Some publications indicate that patients with diabetes mellitus usually do not complain about oesophageal symptoms, even when severe oesophageal dysfunction is present. […] However, in other studies a high prevalence of oesophageal symptoms in diabetics has been documented. For example, 27% of 137 unselected diabetics attending an outpatient clinic admitted to having dysphagia when specifically asked […] The poor association between oesophageal dysfunction and symptoms in patients with diabetes may reflect impaired perception of oesophageal stimuli caused by neuropathic abnormalities in afferent pathways. The development of symptoms and signs of gastro-oesophageal reflux disease in diabetics may in part be counteracted by a decrease in gastric acid secretion [59]. […] [However] oesophageal acid exposure is increased in about 40% of diabetics and it is known that the absence of reflux symptoms does not exclude the presence of severe oesophagitis and/or Barrett’s metaplasia. Due to impaired oesophageal perception, the proportion of asymptomatic patients with reflux disease may be higher in the presence of diabetes than when diabetes is absent. It might, therefore, be argued that a screening upper gastrointestinal endoscopy should be performed in diabetic patients, even when no oesophageal or gastric symptoms are reported. However, [a] more cost-effective
and realistic approach may be to perform endoscopy in diabetics with other risk factors for reflux disease, in particular severe obesity.
[…] Since upper gastrointestinal symptoms correlate poorly with objective abnormalities of gastrointestinal motor function in diabetes, the symptomatic benefit that could be expected from correction of these motor abnormalities is questionable. […] Little or nothing is known about the prognosis of disordered oesophageal function in diabetes. Long-term follow-up studies are lacking.

“Abnormally delayed gastric emptying, or gastroparesis, was once considered to be a rare sequela of diabetes mellitus, occurring occasionally in patients who had long-standing diabetes complicated by symptomatic autonomic neuropathy, and inevitably associated with both intractable upper gastrointestinal symptoms and a poor prognosis [1]. Consequent upon the development of a number of techniques to quantify gastric motility […] and the rapid expansion of knowledge relating to both normal and disordered gastric motor function in humans over the last ∼ 20 years, it is now recognised that these concepts are incorrect. […] Delayed gastric emptying represents a frequent, and clinically important, complication of diabetes mellitus. […] Cross-sectional studies […] have established that gastric emptying of solid, or nutrient liquid, meals is abnormally slow in some 30–50% of outpatients with longstanding type 1 [7–20] or type 2 [20–26] diabetes […]. Early studies, using insensitive barium contrast techniques to quantify gastric emptying, clearly underestimated the prevalence substantially [1,27]. The reported prevalence of delayed gastric emptying is highest when gastric emptying of both solid and nutrient-containing liquids (or semi-solids) are measured, either simultaneously or on separate occasions [17,28,29], as there is a relatively poor correlation between gastric emptying of solids and liquids in diabetes [28–30]. […] It is now recognised that delayed gastric emptying also occurs frequently (perhaps about 30%) in children and adolescents with type 1 diabetes [37–39]. […] intragastric meal distribution is also frequently abnormal in outpatients with diabetes, with increased retention of food in both the proximal and distal stomach [31,33]. The former may potentially be important in the aetiology of gastro-oesophageal reflux [34], which appears to occur more frequently in patients with diabetes […] Diabetic gastroparesis is often associated with motor dysfunction in other areas of the gut, e.g. oesophageal transit is delayed in some 50% of patients with long-standing diabetes [8].”

“Overall patterns of gastric emptying are critically dependent on the physical and chemical composition of a meal, so that there are substantial differences between solids, semi-solids, nutrient liquids and non-nutrient liquids [70]. […] The major factor regulating gastric emptying of nutrients (liquids and ‘liquefied’ solids) is feedback inhibition, triggered by receptors that are distributed throughout the small intestine [72]; as a result of this inhibition, nutrient-containing liquids usually empty from the stomach at an overall rate of about 2 kcal/min, after an initial emptying phase that may be somewhat faster [73]. These small intestinal receptors also respond to pH, osmolality and distension, as well as nutrient content. […] While the differential emptying rates of solids, nutrient and non-nutrient liquids when ingested alone is well established, there is much less information about the interaction between different meal components. When liquids and solids are consumed together, liquids empty preferentially (∼ 80% before the solid starts to empty) […] and the presence of a solid meal results in an overall slowing of a simultaneously ingested liquid [71,75,76]. Therefore, while it is clear that the stomach can, to some extent, regulate the emptying of liquids and solids separately, the mechanisms by which this is accomplished remain poorly defined. Extracellular fat has a much lower density than water and is liquid at body temperature. The pattern of gastric emptying of fat, and its effects on emptying of other meal components are, therefore, dependent on posture — in the left lateral posture oil accumulates in the stomach and empties early, which markedly delays emptying of a nutrient liquid [77]. Gastric emptying is also influenced by patterns of previous nutrient intake. In healthy young and older subjects, supplementation of the diet with glucose is associated with acceleration of gastric emptying of glucose [78,79], while short-term starvation slows gastric emptying”.

“[I]n animal models of diabetes a number of morphological changes are evident in the autonomic nerves supplying the gut and the myenteric plexus, including a reduction in the number of myelinated axons in the vagosympathetic trunk and neurons in the dorsal root ganglia, abnormalities in neurotransmitters […] as well as a reduced number of interstitial cells of Cajal in the fundus and antrum [89–92]. In contrast, there is hitherto little evidence of a fixed pathological process in the neural tissue of humans with diabetes […] While a clear-cut association between disordered gastrointestinal function in diabetes mellitus and the presence of autonomic neuropathy remains to be established, it is now recognised that acute changes in the blood glucose concentration have a substantial, and reversible, effect on gastric (as well as oesophageal, intestinal, gallbladder and anorectal) motility, in both healthy subjects and patients with diabetes […] Marked hyperglycaemia (blood glucose concentration ∼ 15 mmol/l) affects motility in every region of the gastrointestinal tract [103]. […] In healthy subjects [114] and patients with uncomplicated type 1 diabetes […] gastric emptying is accelerated markedly during hypoglycaemia […] this response is likely to be important in the counterregulation of hypoglycaemia. It is not known whether the magnitude of the effect of hypoglycaemia on gastric emptying is influenced by gastroparesis and/or autonomic neuropathy. Recent studies have established that changes in the blood glucose concentration within the normal postprandial range also influence gastric emptying and motility [104–106]; emptying of solids and nutrient-containing liquids is slower at a blood glucose of 8 mmol/l than at 4 mmol/l in both healthy subjects and patients with type 1 diabetes […] Recent studies suggest that the rate of gastric emptying is a significant factor in postprandial hypotension. The latter, which may lead to syncope and falls, is an important clinical problem, particularly in the elderly and patients with autonomic dysfunction (usually diabetes mellitus), occurring more frequently than orthostatic hypotension [154].”

“Gastric emptying is potentially an important determinant of oral drug absorption; most orally administered drugs (including alcohol) are absorbed more slowly from the stomach than from the small intestine because the latter has a much greater surface area [179,180]. Thus, delayed gastric emptying (particularly that of tablets or capsules, which are not degraded easily in the stomach) and a reduction in antral phase 3 activity, may potentially lead to fluctuations in the serum concentrations of orally administered drugs. This may be particularly important when a rapid onset of drug effect is desirable, as with some oral hypoglycaemic drugs […]. There is relatively little information about drug absorption in patients with diabetic gastroparesis [179] and additional studies are required.”

“Glycated haemoglobin is influenced by both fasting and postprandial glucose levels; while their relative contributions have not been defined precisely [181], it is clear that improved overall glycaemic control, as assessed by glycated haemoglobin, can be achieved by lowering postprandial blood glucose concentrations, even at the expense of higher fasting glucose levels [182]. Accordingly, the control of postprandial blood glucose levels, as opposed to glycated haemoglobin, now represents a specific target for treatment […] It remains to be established whether postprandial glycaemia per se, including the magnitude of postprandial hyperglycaemic spikes, has a distinct role in the pathogenesis of diabetic complications, but there is increasing data to support this concept [181,183,184]. It is also possible that the extent of blood glucose fluctuations is an independent determinant of the risk for long-term diabetic complications [184]. […] postprandial blood glucose levels are potentially determined by a number of factors, including preprandial glucose concentrations, the glucose content of a meal, small intestinal delivery and absorption of nutrients, insulin secretion, hepatic glucose metabolism and peripheral insulin sensitivity. Although the relative contribution of these factors remains controversial, and is likely to vary with time after a meal, it is now recognised that gastric emptying accounts for at least 35% of the variance in peak glucose levels after oral glucose (75 g) in both healthy individuals and patients with type 2 diabetes […] It is also clear that even modest perturbations in gastric emptying of carbohydrate have a major effect on postprandial glycaemia [76,79]. […] it appears that much of the observed variation in the glycaemic response to different food types (‘glycaemic indices’) in both normal subjects and patients with diabetes is attributable to differences in rates of gastric emptying [103]. […] In type 1 patients with gastroparesis […] less insulin is initially required to maintain euglycaemia after a meal when compared to those with normal gastric emptying [187]. […] There are numerous uncontrolled reports supporting the concept […] that in type 1 patients gastroparesis is a risk factor for poor glycaemic control.”

“The potential for the modulation of gastric emptying, by dietary or pharmacological means, to minimise postprandial glucose excursions and optimise glycaemic control, represents a novel approach to the optimisation of glycaemic control in diabetes, which is now being explored actively. It is important to appreciate that the underlying strategies are likely to differ fundamentally between type 1 and type 2 diabetes. In type 1 diabetes, interventions that improve the coordination between nutrient absorption and the action of exogenous insulin are likely to be beneficial, even in those patients who have delayed gastric emptying, i.e. by accelerating or even slowing gastric emptying, so that the rate of nutrient delivery (and hence absorption) is more predictable. In contrast, in type 2 diabetes, it may be anticipated that slowing of the absorption of nutrients would be desirable […] In the treatment of type 2 diabetes mellitus, dietary modifications potentially represent a more attractive and cost-effective approach than drugs […] A number of dietary strategies may slow carbohydrate absorption […] an increase in dietary fibre […] Fat is a potent inhibitor of gastric emptying and […] these effects may be dependent on posture [77]; there is the potential for relatively small quantities of fat given immediately before consumption of, or with, a meal to slow gastric emptying of other meal components, so that the postprandial rise in blood glucose is minimised [210] (this is analogous to the slowing of alcohol absorption and liquid gastric emptying when alcohol is ingested after a solid meal, rather than in the fasted state [75]). […] there is evidence that the suppression of subsequent food intake by the addition of fat to a meal may exceed the caloric value of the fat load [212]. In the broadest sense, the glycaemic response to a meal is also likely to be critically dependent on whether food from the previous meal is still present in the stomach and/or small intestine at the time of its ingestion, so that glucose tolerance may be expected to be worse in the fasted state […] than after a meal.”

“At present it is not known whether normalisation of gastric emptying in either type 1 or type 2 patients with gastroparesis improves glycaemic control. […] prokinetic drugs would not be expected to have a beneficial effect on glycaemic control in type 2 patients who are not using insulin. Erythromycin may, however, as a result of its interaction with motilin receptors, also stimulate insulin secretion (and potentially improve glycaemic control by this mechanism) in type 2 diabetes [220] […] It should […] be recognised that any drug that slows gastric emptying has the potential to induce or exacerbate upper gastrointestinal symptoms, delay oral drug absorbtion and impair the counter-regulation of glycaemia. […] At present, the use of prokinetic drugs (mainly cisapride, domperidone, metoclopramide and erythromycin) forms the mainstay of therapy [167,244–259], and most patients will require drug treatment. In general, these drugs all result in dose-related improvements in gastric emptying after acute administration […] The response to prokinetic therapy (magnitude of acceleration in gastric emptying) tends to be greater when gastric emptying is more delayed. It should be recognised that relatively few controlled studies have evaluated the effects of ‘prolonged’ (> 8 weeks) prokinetic therapy, that in many studies the sample sizes have been small, and that the assessments of gastrointestinal symptoms have, not infrequently, been suboptimal; furthermore, the results of some of these studies have been negative [32]. There have hitherto been relatively few randomised controlled trials of high quality, and those that are available differ substantially in design. […] In general, there is a poor correlation between effects on symptoms and gastric emptying — prokinetic drugs may improve symptoms by effects unrelated to acceleration of gastric emptying or central anti-emetic properties [254].”

“Autoimmune factors are well recognised to play a role in the aetiology of type 1 diabetes [316,317]. In such patients there is an increased prevalence of autoimmune aggression against non-endocrine tissues, including the gastric mucosa. The reported prevalence of parietal cell antibodies in patients with type 1 diabetes is in the range 5–28%, compared to 1.4–12% in non-diabetic controls […] The autoimmune response to parietal cell antibodies may lead to atrophic gastritis, pernicious anaemia and iron deficiency anaemia […] Parietal cell antibodies can inhibit the secretion of intrinsic factor, which is necessary for the absorption of vitamin B12, potentially resulting in pernicious anaemia. The prevalence of latent and overt pernicious anaemia in type 1 diabetes has been reported to be 1.6–4% and 0.4%, respectively […] screening for parietal cell antibodies in patients with type 1 diabetes currently appears inappropriate. However, there should be a low threshold for further investigation in those patients presenting with anaemia”.

September 1, 2017 Posted by | Books, Diabetes, Gastroenterology, Immunology, Medicine, Neurology | Leave a comment

Gastrointestinal Function in Diabetes (I)

“During the last 15–20 years, primarily as a result of the application of novel investigative techniques, there has been a rapid expansion of knowledge relating to the function of the gastrointestinal tract in diabetes mellitus. These insights have been substantial and have led to the recognition that gastrointestinal function represents a hitherto inappropriately neglected, as well as important, aspect of diabetes management. In particular, disordered gastrointestinal motor and sensory function occur frequently in both type 1 and type 2 diabetes and may be associated with significant clinical sequelae. Recent epidemiological studies have established that there is a high prevalence of gastrointestinal symptoms in the diabetic population and that these are associated with impaired quality of life. Furthermore, upper gastrointestinal motility, even when normal, is central to the regulation of postprandial blood glucose concentrations. Hence, diabetes and the gastrointestinal tract are inextricably linked. […] This book, which to our knowledge represents the first of its kind, was stimulated by the need to consolidate these advances, to illuminate an area that is perceived as increasingly important, but somewhat difficult to understand. […] The book aims to be comprehensive and to present the relevant information in context for both the clinician and clinical researcher. There are nine chapters: five are organ-specific, relating to oesophageal, gastric, intestinal, anorectal and hepatobiliary function; the four other chapters address epidemiological aspects of gastrointestinal function in diabetes, the effects of diabetes mellitus on gastrointestinal function in animal models, the impact of gastrointestinal function on glycaemic control, and the evaluation of gastrointestinal autonomic function. All of the authors are recognised internationally for their expertise in the field”.

I added this book to my list of favourite books on goodreads – it’s a great book, from which I learned a lot.

I have added some more quotes and observations from the book below, as well as a few comments.

“Population-based studies of gastrointestinal symptoms in diabetic patients have been relatively few and the results conflicting […] To date, a total of nine population-based studies have been undertaken evaluating gastrointestinal symptoms in subjects with diabetes mellitus […] Depending on the population studied, the prevalence of symptoms has varied considerably in patients with both type 1 and type 2 diabetes mellitus. […] there is evidence that gastrointestinal symptoms are linked with diabetes mellitus, but the prevalence over and above the general population is at most only modestly increased. Some studies have failed to detect an association between diabetes and gastrointestinal symptoms, but several confounders may have obscured the findings. For example, it is well documented that chronic gastrointestinal symptoms are common in non-diabetics in the community, presumably due to functional gastrointestinal disorders such as the irritable bowel syndrome [33,34]. Moreover, the presence of diabetic complications and possibly long-term glycaemic control appear to be important factors in symptom onset [31,32]. This may explain the difficulty in establishing a firm link between diabetes and chronic gastrointestinal complaints in population-based studies.”

It is perhaps important to interpose already at this early stage of the coverage that diabetes seems to be related to many changes in gastrointestinal function that do not necessarily cause symptoms which lead to patient complaints, but which even so may still affect individuals with the disease in a variety of ways. For example drug metabolism may be altered in diabetics secondary to hyperglycemia-induced delayed gastric emptying, which can naturally be very important in some situations (drugs don’t work, or don’t work when they’re supposed to). Symptomatic disease is important to observe and address, but there are many other aspects that may be relevant as well. The symptomatology of diabetes-related gastrointestinal changes is of course complicated by the fact that nervous system involvement is an important player, and a player we know from other contexts may both generate symptoms (in this setting you’d e.g. think of altered peristalsis in severe neuropathy, causing constipation) and may also lead to an absence of symptoms in settings where symptoms would otherwise have been present (‘silent ischemia‘ is common in diabetics). I may or may not go much more into these topics, there’s a lot of interesting stuff in this book.

“In patients with long-standing type 1 and type 2 diabetes, the prevalence of delayed gastric emptying of a nutrient meal is reported to range from 27% to 40% [40–42] and the prevalence is similar in insulin-dependent and non-insulindependent diabetes mellitus […]. In a minority of patients (less than 10%) with long-standing diabetes, gastric emptying is accelerated [42–44]. […] A number of studies have shown that acute changes in blood glucose concentrations can have a profound effect on motor function throughout the gastrointestinal tract in both normal subjects and patients with diabetes mellitus [54]. Recent studies have demonstrated that the blood glucose concentration may also modulate the perception of sensations arising from the gastrointestinal tract [56–58]. However, there is relatively little information about the mechanisms mediating the effects of the blood glucose concentration on gastrointestinal motility. While some studies have implicated impaired glycaemic control in the genesis of chronic gastrointestinal symptoms [24,31], this remains controversial.”

“As part of the Medical Outcomes Study, that determined the impact of nine different chronic illnesses upon HRQL [Health-Related Quality of Life, US], Stewart et al. [90] used the Short Form (SF-20) of the General Health Survey to evaluate HRQL ratings in 9385 patients, 844 of whom had diabetes […] gastrointestinal disorders had a more negative impact on HRQL than all other conditions with the exception of heart disease [90]. Others have reported similar findings [120,121]. […] A study of diabetic patients undergoing transplantation [122] indicated that, of all the factors likely to compromise HRQL, the single most important one was gastrointestinal dysfunction.”

“In animal studies of gastrointestinal function in diabetes mellitus, most information has been generated using insulinopenic rats with severe hyperglycaemia; around one-third of the literature has been generated using BB rats (autoimmune spontaneous diabetic) and two-thirds using streptozotocin (STZ; chemically-induced) diabetic models. In the choice of these animal models, an assumption appears to have been often made that hyperglycaemia per se, or at least some aspect of the metabolic disturbance secondary to insulin lack, is the aetiopathologic insult. A common hypothesis is that neurotoxicity of the autonomic nervous system, secondary to this metabolic insult, is responsible for the gastrointestinal effects of diabetes. This hypothesis is described here as the ‘autonomic neuropathic’ hypothesis.”

“Central nervous structures, especially those in the brain stem […] are implicated in the normal autonomic control of gastrointestinal function […] over two-thirds of the literature regarding gastrointestinal dysfunction in diabetes is derived from chemically-induced models in which, alarmingly, much of the reported gut dysfunction could be an artifact of selective damage to central structures. It is now recognised that there are major differences in gastrointestinal function between animals in which β-cell damage was caused by chemical means and those in which damage was a result of an autoimmune process. These differences prompt an examination of the extent to which gastrointestinal dysfunction in some models is a consequence of diabetes per se, perhaps applicable to human disease, as opposed to being a consequence of damage to specific central structures.”

“The […] most accepted hypothesis in the past to explain gastrointestinal dysfunction in diabetes has been the proposal that autonomic neuropathy has disturbed the normal regulation of gut function. But there are recently identified disturbances in several of the neurohormones found in gut in different diabetic states. Several of these, including amylin, GLP-1 and PYY have effects on gut function, and should now be considered in explanations of diabetes-associated changes in gut function. […] A ‘neurocrine’ alternative to the neuropathic hypothesis focuses on the possibility that absolute or relative deficiency of the pancreatic β-cell hormone, amylin, may be of importance in the aetiology of disordered gastrointestinal function in diabetes. […] STZ diabetic rats most often show increased gastric acid secretion [63,64] and increased rates of ulceration [65–71]. This effect is exacerbated by fasting [67] and is reversed by hyperglycaemia [72] but not by insulin replacement [73]. It thus appears that insulin lack is not the ulcerogenic stimulus, and raises the possibility that absence of gastric-inhibitory factors (e.g. amylin, PYY, GLP-1), which may be absent or reduced in diabetes, could be implicated. […] autoimmune type 1 diabetic BB rats [76] and autoimmune non-obese diabetic (NOD) mice [77] in which the gastric mucosa is not an immune target, also show a marked increase in gastric erosions. The constancy of findings of acid hypersecretion and ulceration in insulinopenic diabetes invoked by diverse insults (chemical and autoimmune) indicates that this gastrointestinal disturbance is a direct consequence of the diabetes, and perhaps of β-cell deficiency. […] Amylin […] is a potent inhibitor of gastric acid secretion [88], independent of changes in plasma glucose [89] and prevents gastric erosion in response to a number of irritants [90–92]. These effects appear to be specific to amylin […] It is possible that amylin deficiency could be implicated in a propensity to ulceration in some forms of diabetes. It is unclear whether such a propensity exists in type 1 diabetic adults. However, type 1 diabetic children are reported to have a three- to four-fold elevation in rate of peptic disease [93].”

“Changes in intestinal mucosal function are observed in diabetic rodents, but it is unclear whether these are intrinsic and contributory to the disease process, or are secondary to the disease. […] It […] appears likely […] that diabetes-associated changes in gut enzyme expression represent a response to some aspect of the diabetic state, since they occur in both chemically-induced and genetic models, and are reversible with vigorous treatment of the diabetes. […] While there appear to be no reports that quantify the relationship between acid secretion and rates of nutrient assimilation, there is evidence that type 1 diabetes, in animal models at least, is characterised by disturbed acid regulation.”

“[D]isordered gastrointestinal motility has long been recognised as a frequent feature in diabetic patients who also exhibit neuropathy [125]. Disturbances in gastrointestinal function have been estimated by some to have a prevalence of ∼ 30% (range 5–60% [126–128]). Both peripheral and autonomic [126–128] neuropathy are frequent complications of diabetes mellitus. Since the autonomic nervous system (ANS) plays a prominent role in the regulation of gut motility, a prevailing hypothesis has been that autonomic neuropathic dysfunction could account for much of this disturbance. […] Motor disturbances associated with autonomic neuropathy include dilation of the oesophagus, gastrointestinal stasis, accumulation of digesta and constipation, mainly signs associated with vagal (parasympathetic) dysfunction. There are also reports of faecal incontinence, related to decreased sphincter pressure, and diarrhoea.”

“The best-characterised signs of damage to the autonomic nervous system during diabetes are morphological […] For example, the number of myelinated axons in the vagosympathetic trunk is decreased in diabetic rats [131], as is the number of neurones in dorsal root ganglia and peripheral postganglionic sympathetic nerves. […] In addition to alterations in numbers and morphology of axons, the tissue around the axons is also often disturbed. […] It is of interest that autonomic neuropathy can be prevented or partially reversed by rigorous glycaemic control [137], suggesting that hyperglycaemia per se is of major aetiological importance in autonomic neuropathy. […] Morphological evidence of neuropathy in BB rats includes axonal degeneration, irregularity of myelin sheaths and Mullerian degeneration […] It has been proposed that periodic hypoglycaemia in BB rats may induce Wallerian degeneration and reduced conduction velocity […] while abnormalities associated with chronic hyperglycaemia include sensory (afferent) axonopathy […] The secretion of a number of neuroendocrine substances may be decreased in diabetes. Glucagon, pancreatic polypeptide, gastrin, somatostatin and gastric inhibitory peptide levels are reportedly reduced in the gastrointestinal tract of diabetic patients […] In addition to peripheral autonomic neuropathy, neurons within the central nervous system are also reported to be damaged in animal models of diabetes, including areas […] which are important in controlling those parts of the autonomic nervous system that innervate the gut.”

“Despite ample evidence of morphologic and functional changes in nerves of rodent models of type 1 diabetes mellitus, it is not clear to what extent these changes underly the gastrointestinal dysfunction evident in these animals. Coincidence of neuropathic and gastrointestinal changes does not necessarily prove a causal association between autonomic neuropathy and gastrointestinal dysfunction in diabetes. […] recently recognised neuroendocrine disturbances in diabetes, especially of the β-cell hormone amylin, provide an alternative to the neuropathic hypothesis […] In considering primary endocrine changes associated with type 1 diabetes mellitus, it should be recognised that the central pathogenic event is a selective and near-absolute autoimmune destruction of pancreatic β-cells. Other cell types in the islets, and other tissues, are preserved. The only confirmed hormones currently known to be specific to pancreatic β-cells are insulin and amylin [251]. Recent evidence also suggests that C-peptide, cleaved from proinsulin during intracellular processing and co-secreted with insulin, may also be biologically active [252] […] It is therefore only insulin, C-peptide and amylin that disappear following the selective destruction of β-cells. The implications of this statement are profound; all diabetes-associated sequelae are somehow related to the absence of these (and/or other possibly undiscovered) hormones, whether directly or indirectly […]. Since insulin has minimal direct effect on gut function, until recently the most plausible explanation linking β-cell destruction to changes in gastrointestinal functions was a neuropathic effect secondary to hyperglycaemia. With the recent discovery of multiple physiological gastrointestinal effects of the second β-cell hormone, amylin [255], a plausible alternate explanation of gut dysfunction following β-cell loss has emerged. That is, instead of being due to insulin lack, some gut dysfunction in insulinopenic diabetes may instead be due to the loss of its co-secreted partner, amylin. […] While insulin and amylin are essentially absent in type 1 diabetes, in states of impaired glucose tolerance and early type 2 diabetes, each of these hormones may in fact be hypersecreted […] The ZDF rat is a model of insulin resistance, with some strains developing type 2 diabetes. These animals, which hypersecrete from pancreatic β-cells, exhibit both hyperinsulinaemia and hyperamylinaemia.”

If amylin is hypersecreted in type 2 diabetics and the hormone is absent in type 1 and you do population studies on mixed populations of type 1 and type 2 patients and try to figure out what is going on, you’re going to have some potential issues. The picture seems not too dissimilar to what you see when you look at bone disease in diabetes; type 1s have a high fracture risk, type 2s also have a higher than normal fracture risk, but ‘the effect of diabetes’ is in fact very different in the two groups (in part – but certainly not only – because most type 2s are overweight or obese, and overweight decreases the fracture risk). Some of the relevant pathways of pathophysiological interest are identical in the two patient populations (this is also the case here; acute hyperglycemia is known to cause delayed gastric emptying even in non-diabetics), some are completely different – it’s a mess. This is one reason why I don’t think the confusing results of some of the population studies included early in the book’s coverage – which I decided not to cover in detail here – are necessarily all that surprising.

“Many gastrointestinal reflexes are glucose-sensitive, reflecting their often unrecognised glucoregulatory (restricting elevations of glucose during hyperglycaemia) and counter-regulatory functions (promoting elevation of glucose during hypoglycaemia). Glucose-sensitive effects include inhibition of food intake, control of gastric emptying rate, and regulation of gastric acid secretion and pancreatic enzyme secretion […] Some gastrointestinal manifestations of diabetes may therefore be secondary, and compensatory, to markedly disturbed plasma glucose concentrations. […] It has emerged in recent years that several of the most potent of nearly 60 reported biological actions of amylin [286] are gastrointestinal effects that appear to collectively restrict nutrient influx and promote glucose tolerance. These include inhibition of gastric emptying, inhibition of food intake, inhibition of digestive functions (pancreatic enzyme secretion, gastric acid secretion and bile ejection), and inhibition of nutrient-stimulated glucagon secretion. […] In rats, amylin is the most potent of any known mammalian peptide in slowing gastric emptying […] An amylin agonist (pramlintide), several GLP-1 agonists and exendin-4 are being explored as potential therapies for the treatment of diabetes, with inhibition of gastric emptying being recognised as a mode of therapeutic action. […] The concept of the gut as an organ of metabolic control is yet to be widely accepted, and antidiabetic drugs that moderate nutrient uptake as a mode of therapy have only begun to emerge. A potential advantage such therapies hold over those that enhance insulin action, is their general glucose dependence and low propensity to (per se) induce hypoglycaemia.”

August 29, 2017 Posted by | Books, Diabetes, Gastroenterology, Medicine, Neurology | Leave a comment

A few diabetes papers of interest

i. Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis.

“This systematic review and meta-analysis evaluates the association between HbA1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes. […] Seven studies evaluated HbA1c variability among patients with type 1 diabetes and showed an association of HbA1c variability with renal disease (risk ratio 1.56 [95% CI 1.08–2.25], two studies), cardiovascular events (1.98 [1.39–2.82]), and retinopathy (2.11 [1.54–2.89]). Thirteen studies evaluated HbA1c variability among patients with type 2 diabetes. Higher HbA1c variability was associated with higher risk of renal disease (1.34 [1.15–1.57], two studies), macrovascular events (1.21 [1.06–1.38]), ulceration/gangrene (1.50 [1.06–2.12]), cardiovascular disease (1.27 [1.15–1.40]), and mortality (1.34 [1.18–1.53]). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA1c variability.

CONCLUSIONS HbA1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA1c level and might play a future role in clinical risk assessment.”

Two observations related to the paper: One, although only a relatively small number of studies were included in the review, the number of patients included in some of those included studies was rather large – the 7 type 1 studies thus included 44,021 participants, and the 13 type 2 studies included in total 43,620 participants. Two, it’s noteworthy that some of the associations already look at least reasonably strong, despite interest in HbA1c variability being a relatively recent phenomenon. Confounding might be an issue, but then again it almost always might be, and to give an example, out of 11 studies analyzing the association between renal disease and HbA1c variability included in the review, ten of them support a link and the only one which does not was a small study on pediatric patients which was almost certainly underpowered to investigate such a link in the first place (the base rate of renal complications is, as mentioned before here on this blog quite recently (link 3), quite low in pediatric samples).

ii. Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study.

(I should perhaps note here that I’m already quite familiar with the context of the DCCT/EDIC study/studies, and although readers may not be, and although background details are included in the paper, I decided not to cover such details here although they would make my coverage of the paper easier to understand. I instead decided to limit my coverage of the paper to a few observations which I myself found to be of interest.)

“During the DCCT, the rates of SH [Severe Hypoglycemia, US], including episodes with seizure or coma, were approximately threefold greater in the intensive treatment group than in the conventional treatment group […] During EDIC, the frequency of SH increased in the former conventional group and decreased in the former intensive group so that the difference in SH event rates between the two groups was no longer significant (36.6 vs. 40.8 episodes per 100 patient-years, respectively […] By the end of DCCT, with an average of 6.5 years of follow-up, 65% of the intensive group versus 35% of the conventional group experienced at least one episode of SH. In contrast, ∼50% of participants within each group reported an episode of SH during the 20 years of EDIC.”

“Of [the] participants reporting episodes of SH, during the DCCT, 54% of the intensive group and 30% of the conventional group experienced four or more episodes, whereas in EDIC, 37% of the intensive group and 33% of the conventional group experienced four or more events […]. Moreover, a subset of participants (14% [99 of 714]) experienced nearly one-half of all SH episodes (1,765 of 3,788) in DCCT, and a subset of 7% (52 of 709) in EDIC experienced almost one-third of all SH episodes (888 of 2,813) […] Fifty-one major accidents occurred during the 6.5 years of DCCT and 143 during the 20 years of EDIC […] The most frequent type of major accident was that involving a motor vehicle […] Hypoglycemia played a role as a possible, probable, or principal cause in 18 of 28 operator-caused motor vehicle accidents (MVAs) during DCCT […] and in 23 of 54 operator-caused MVAs during EDIC”.

“The T1D Exchange Clinic Registry recently reported that 8% of 4,831 adults with T1D living in the U.S. had a seizure or coma event during the 3 months before their most recent annual visit (11). During EDIC, we observed that 27% of the cohort experienced a coma or seizure event over the 20 years of 3-month reporting intervals (∼1.4% per year), a much lower annual risk than in the T1D Exchange Clinic Registry. In part, the open enrollment of patients into the T1D Exchange may be reflected without the exclusion of participants with a history of SH as in the DCCT and other clinical trials. The current data support the clinical perception that a small subset of individuals is more susceptible to SH (7% of patients with 11 or more SH episodes during EDIC, which represents 32% of all SH episodes in EDIC) […] a history of SH during DCCT and lower current HbA1c levels were the two major factors associated with an increased risk of SH during EDIC. Safety concerns were the reason why a history of frequent SH events was an exclusion criterion for enrollment in DCCT. […] Of note, we found that participants who entered the DCCT as adolescents were more likely to experience SH during EDIC.”

“In summary, although event rates in the DCCT/EDIC cohort seem to have fallen and stabilized over time, SH remains an ever-present threat for patients with T1D who use current technology, occurring at a rate of ∼36–41 episodes per 100 patient-years, even among those with longer diabetes duration. Having experienced one or more such prior events is the strongest predictor of a future SH episode.”

I didn’t actually like that summary. If a history of severe hypoglycemia was an exclusion criterion in the DCCT trial, which it was, then the event rate you’d get from this data set is highly likely to provide a biased estimator of the true event rate, as the Exchange Clinic Registry data illustrate. The true population event rate in unselected samples is higher.

Another note which may also be important to add is that many diabetics who do not have a ‘severe event’ during a specific time period might still experience a substantial number of hypoglycemic episodes; ‘severe events’ (which require the assistance of another individual) is a somewhat blunt instrument in particular for assessing quality-of-life aspects of hypoglycemia.

iii. The Presence and Consequence of Nonalbuminuric Chronic Kidney Disease in Patients With Type 1 Diabetes.

“This study investigated the prevalence of nonalbuminuric chronic kidney disease in type 1 diabetes to assess whether it increases the risk of cardiovascular and renal outcomes as well as all-cause mortality. […] This was an observational follow-up of 3,809 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. […] mean age was 37.6 ± 11.8 years and duration of diabetes 21.2 ± 12.1 years. […] During 13 years of median follow-up, 378 developed end-stage renal disease, 415 suffered an incident cardiovascular event, and 406 died. […] At baseline, 78 (2.0%) had nonalbuminuric chronic kidney disease. […] Nonalbuminuric chronic kidney disease did not increase the risk of albuminuria (hazard ratio [HR] 2.0 [95% CI 0.9–4.4]) or end-stage renal disease (HR 6.4 [0.8–53.0]) but did increase the risk of cardiovascular events (HR 2.0 [1.4–3.5]) and all-cause mortality (HR 2.4 [1.4–3.9]). […] ESRD [End-Stage Renal Disease] developed during follow-up in 0.3% of patients with nonalbuminuric non-CKD [CKD: Chronic Kidney Disease], in 1.3% of patients with nonalbuminuric CKD, in 13.9% of patients with albuminuric non-CKD, and in 63.0% of patients with albuminuric CKD (P < 0.001).”

CONCLUSIONS Nonalbuminuric chronic kidney disease is not a frequent finding in patients with type 1 diabetes, but when present, it is associated with an increased risk of cardiovascular morbidity and all-cause mortality but not with renal outcomes.”

iv. Use of an α-Glucosidase Inhibitor and the Risk of Colorectal Cancer in Patients With Diabetes: A Nationwide, Population-Based Cohort Study.

This one relates closely to stuff covered in Horowitz & Samsom’s book about Gastrointestinal Function in Diabetes Mellitus which I just finished (and which I liked very much). Here’s a relevant quote from chapter 7 of that book (which is about ‘Hepato-biliary and Pancreatic Function’):

“Several studies have provided evidence that the risk of pancreatic cancer is increased in patients with type 1 and type 2 diabetes mellitus [136,137]. In fact, diabetes has been associated with an increased risk of several cancers, including those of the pancreas, liver, endometrium and kidney [136]. The pooled relative risk of pancreatic cancer for diabetics vs. non-diabetics in a meta-analysis was 2.1 (95% confidence interval 1.6–2.8). Patients presenting with diabetes mellitus within a period of 12 months of the diagnosis of pancreatic cancer were excluded because in these cases diabetes may be an early presenting sign of pancreatic cancer rather than a risk factor [137]”.

They don’t mention colon cancer there, but it’s obvious from the research which has been done – and which is covered extensively in that book – that diabetes has the potential to cause functional changes in a large number of components of the digestive system (and I hope to cover this kind of stuff in a lot more detail later on) so the fact that some of these changes may lead to neoplastic changes should hardly be surprising. However evaluating causal pathways is more complicated here than it might have been, because e.g. pancreatic diseases may also themselves cause secondary diabetes in some patients. Liver pathologies like hepatitis B and C also display positive associations with diabetes, although again causal pathways here are not completely clear; treatments used may be a contributing factor (interferon-treatment may induce diabetes), but there are also suggestions that diabetes should be considered one of the extrahepatic manifestations of hepatitis. This stuff is complicated.

The drug mentioned in the paper, acarbose, is incidentally a drug also discussed in some detail in the book. It belongs to a group of drugs called alpha glucosidase inhibitors, and it is ‘the first antidiabetic medication designed to act through an influence on intestinal functions.’ Anyway, some quotes from the paper:

“We conducted a nationwide, population-based study using a large cohort with diabetes in the Taiwan National Health Insurance Research Database. Patients with newly diagnosed diabetes (n = 1,343,484) were enrolled between 1998 and 2010. One control subject not using acarbose was randomly selected for each subject using acarbose after matching for age, sex, diabetes onset, and comorbidities. […] There were 1,332 incident cases of colorectal cancer in the cohort with diabetes during the follow-up period of 1,487,136 person-years. The overall incidence rate was 89.6 cases per 100,000 person-years. Patients treated with acarbose had a 27% reduction in the risk of colorectal cancer compared with control subjects. The adjusted HRs were 0.73 (95% CI 0.63–0.83), 0.69 (0.59–0.82), and 0.46 (0.37–0.58) for patients using >0 to <90, 90 to 364, and ≥365 cumulative defined daily doses of acarbose, respectively, compared with subjects who did not use acarbose (P for trend < 0.001).

CONCLUSIONS Acarbose use reduced the risk of incident colorectal cancer in patients with diabetes in a dose-dependent manner.”

It’s perhaps worth mentioning that the prevalence of type 1 is relatively low in East Asian populations and that most of the patients included were type 2 (this is also clearly indicated by this observation from the paper: “The median age at the time of the initial diabetes diagnosis was 54.1 years, and the median diabetes duration was 8.9 years.”). Another thing worth mentioning is that colon cancer is a very common type of cancer, and so even moderate risk reductions here at the individual level may translate into a substantial risk reduction at the population level. A third thing, noted in Horowitz & Samsom’s coverage, is that the side effects of acarbose are quite mild, so widespread use of the drug is not out of the question, at least poor tolerance is not likely to be an obstacle; the drug may cause e.g. excessive flatulence and something like 10% of patients may have to stop treatment because of gastrointestinal side effects, but although the side effects are annoying and may be unacceptable to some patients, they are not dangerous; it’s a safe drug which can be used even in patients with renal failure (a context where some of the other oral antidiabetic treatments available are contraindicated).

v. Diabetes, Lower-Extremity Amputation, and Death.

“Worldwide, every 30 s, a limb is lost to diabetes (1,2). Nearly 2 million people living in the U.S. are living with limb loss (1). According to the World Health Organization, lower-extremity amputations (LEAs) are 10 times more common in people with diabetes than in persons who do not have diabetes. In the U.S. Medicare population, the incidence of diabetic foot ulcers is ∼6 per 100 individuals with diabetes per year and the incidence of LEA is 4 per 1,000 persons with diabetes per year (3). LEA in those with diabetes generally carries yearly costs between $30,000 and $60,000 and lifetime costs of half a million dollars (4). In 2012, it was estimated that those with diabetes and lower-extremity wounds in the U.S. Medicare program accounted for $41 billion in cost, which is ∼1.6% of all Medicare health care spending (47). In 2012, in the U.K., it was estimated that the National Health Service spent between £639 and 662 million on foot ulcers and LEA, which was approximately £1 in every £150 spent by the National Health Service (8).”

“LEA does not represent a traditional medical complication of diabetes like myocardial infarction (MI), renal failure, or retinopathy in which organ failure is directly associated with diabetes (2). An LEA occurs because of a disease complication, usually a foot ulcer that is not healing (e.g., organ failure of the skin, failure of the biomechanics of the foot as a unit, nerve sensory loss, and/or impaired arterial vascular supply), but it also occurs at least in part as a consequence of a medical plan to amputate based on a decision between health care providers and patients (9,10). […] 30-day postoperative mortality can approach 10% […]. Previous reports have estimated that the 1-year post-LEA mortality rate in people with diabetes is between 10 and 50%, and the 5-year mortality rate post-LEA is between 30 and 80% (4,1315). More specifically, in the U.S. Medicare population mortality within a year after an incident LEA was 23.1% in 2006, 21.8% in 2007, and 20.6% in 2008 (4). In the U.K., up to 80% will die within 5 years of an LEA (8). In general, those with diabetes with an LEA are two to three times more likely to die at any given time point than those with diabetes who have not had an LEA (5). For perspective, the 5-year death rate after diagnosis of malignancy in the U.S. was 32% in 2010 (16).”

“Evidence on why individuals with diabetes and an LEA die is based on a few mainly small (e.g., <300 subjects) and often single center–based (13,1720) studies or <1 year duration of evaluation (11). In these studies, death is primarily associated with a previous history of cardiovascular disease and renal insufficiency, which are also major complications of diabetes; these complications are also associated with an increased risk of LEA. The goal of our study was to determine whether complications of diabetes well-known to be associated with death in those with diabetes such as cardiovascular disease and renal failure fully explain the higher rate of death in those who have undergone an LEA.”

“This is the largest and longest evaluation of the risk of death among those with diabetes and LEA […] Between 2003 and 2012, 416,434 individuals met the entrance criteria for the study. This cohort accrued an average of 9.0 years of follow-up and a total of 3.7 million diabetes person-years of follow-up. During this period of time, 6,566 (1.6%) patients had an LEA and 77,215 patients died (18.5%). […] The percentage of individuals who died within 30 days, 1 year, and by year 5 of their initial code for an LEA was 1.0%, 9.9%, and 27.2%, respectively. For those >65 years of age, the rates were 12.2% and 31.7%, respectively. For the full cohort of those with diabetes, the rate of death was 2.0% after 1 year of follow up and 7.3% after 5 years of follow up. In general, those with an LEA were more than three times more likely to die during a year of follow-up than an individual with diabetes who had not had an LEA. […] In any given year, >5% of those with diabetes and an LEA will die.”

“From 2003 to 2012, the HR [hazard rate, US] for death after an LEA was 3.02 (95% CI 2.90, 3.14). […] our a priori assumption was that the HR associating LEA with death would be fully diminished (i.e., it would become 1) when adjusted for the other risk factor variables. However, the fully adjusted LEA HR was diminished only ∼22% to 2.37 (95% CI 2.27, 2.48). With the exception of age >65 years, individual risk factors, in general, had minimal effect (<10%) on the HR of the association between LEA and death […] We conducted sensitivity analyses to determine the general statistical parameters of an unmeasured risk factor that could remove the association of LEA with death. We found that even if there existed a very strong risk factor with an HR of death of three, a prevalence of 10% in the general diabetes population, and a prevalence of 60% in those who had an LEA, LEA would still be associated with a statistically significant and clinically important risk of 1.30. These findings are describing a variable that would seem to be so common and so highly associated with death that it should already be clinically apparent. […] In summary, individuals with diabetes and an LEA are more likely to die at any given point in time than those who have diabetes but no LEA. While some of this variation can be explained by other known complications of diabetes, the amount that can be explained is small. Based on the results of this study, including a sensitivity analysis, it is highly unlikely that a “new” major risk factor for death exists. […] LEA is often performed because of an end-stage disease process like chronic nonhealing foot ulcer. By the time a patient has a foot ulcer and an LEA is offered, they are likely suffering from the end-stage consequence of diabetes. […] We would […] suggest that patients who have had an LEA require […] vigilant follow-up and evaluation to assure that their medical care is optimized. It is also important that GPs communicate to their patients about the risk of death to assure that patients have proper expectations about the severity of their disease.”

vi. Trends in Health Care Expenditure in U.S. Adults With Diabetes: 2002–2011.

Before quoting from the paper, I’ll remind people reading along here that ‘total medical expenditures’ != ‘total medical costs’. Lots of relevant medical costs are not included when you focus only on direct medical expenditures (sick days, early retirement, premature mortality and productivity losses associated therewith, etc., etc.). With that out of the way…

“This study examines trends in health care expenditures by expenditure category in U.S. adults with diabetes between 2002 and 2011. […] We analyzed 10 years of data representing a weighted population of 189,013,514 U.S. adults aged ≥18 years from the Medical Expenditure Panel Survey. […] Relative to individuals without diabetes ($5,058 [95% CI 4,949–5,166]), individuals with diabetes ($12,180 [11,775–12,586]) had more than double the unadjusted mean direct expenditures over the 10-year period. After adjustment for confounders, individuals with diabetes had $2,558 (2,266–2,849) significantly higher direct incremental expenditures compared with those without diabetes. For individuals with diabetes, inpatient expenditures rose initially from $4,014 in 2002/2003 to $4,183 in 2004/2005 and then decreased continuously to $3,443 in 2010/2011, while rising steadily for individuals without diabetes. The estimated unadjusted total direct expenditures for individuals with diabetes were $218.6 billion/year and adjusted total incremental expenditures were approximately $46 billion/year. […] in the U.S., direct medical costs associated with diabetes were $176 billion in 2012 (1,3). This is almost double to eight times the direct medical cost of other chronic diseases: $32 billion for COPD in 2010 (10), $93 billion for all cancers in 2008 (11), $21 billion for heart failure in 2012 (12), and $43 billion for hypertension in 2010 (13). In the U.S., total economic cost of diabetes rose by 41% from 2007 to 2012 (2). […] Our findings show that compared with individuals without diabetes, individuals with diabetes had significantly higher health expenditures from 2002 to 2011 and the bulk of the expenditures came from hospital inpatient and prescription expenditures.”


August 10, 2017 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Economics, Epidemiology, Gastroenterology, Health Economics, Medicine, Nephrology, Pharmacology | Leave a comment