Diabetes mellitus type 2; The incretin effect and interaction with the autonomic nervous system

Bakgrunn: Inkretineffekten er kroppens evne til økt insulinsekresjon når glukose inntas peroralt sammenliknet med administrert intravenøst, utløst av spesifikke hormoner fra tarmen. En redusert inkretineffekt leder til forhøyet blodsukker etter måltid, og er et tidlig fenomen ved diabetes type 2, også påvist i forstadier til diabetes, såkalt prediabetes, og ved fedme. En bevart inkretineffekt ser delvis ut til å være avhengig av et intakt autonomt nervesystem. Autonom nevropati har vært betraktet som en sen komplikasjon til diabetes mellitus, men det er økende evidens for at nevropati også kan oppstå tidlig i forløpet. Kjennskap til disse faktorene ledet oss til en hypotese om at tidlig autonom nevropati kan bidra til den reduserte inkretineffekten ved diabetes type 2. Mål: Vårt primære mål var å undersøke om det var assosiasjon mellom inkretineffekt og grad av autonom nevropati. Sekundære mål var å se på inkretineffekten relatert til grad av hyperglykemi og varighet av diabetes, og sammenlikne en ny test som innebærer ballongdilatasjon i rektum, som mål for tarmens sensitivitet og videre signaloverføring, med mer etablerte tester for nevropati. Et siste sekundærmål var å undersøke gjennomførbarheten av en norsk versjon av spørreskjemaet, «Composite Autonomic Symptom Score» (COMPASS) 31, som kan påvise mulige symptomer fra autonom dysfunksjon, og vi testet om dette var assosiert med øvrige nerveundersøkelser. Metode: Tre grupper ble inkludert; en gruppe med diabetes type 2 varighet >10 år, en gruppe med nyoppdaget type 2 diabetes siste året, uten behov for medikamentell behandling, og en kontrollgruppe matchet for alder, kjønn og kroppsmasseindeks. Inkretineffekten ble kalkulert fra c-peptid (areal under kurven) ved oral glukosebelastning sammenliknet med intravenøs isoglykemisk glukose infusjon. Gastrointestinal glukose-håndtering (GIGD) ble kalkulert fra glukose gitt oralt sammenliknet med glukose tilført intravenøst. Tester for nevropati inkluderte kardiovaskulære reflekstester, hjertefrekvensvariabilitet, svettefunksjon, nerveledningshastighet i nervus suralis og monofilament test. Som mål på gastrointestinal visceral nervefunksjon utførte vi rektal ballongdilatasjon med registrering av trykk for første følelse av dilatasjon og ubehagelig følelse av dilatasjon. Evokerte hjernepotensial ble målt som respons på ballongdilatasjon ved gjentatte stimuli av nevnte trykk. Spørreskjemaet COMPASS 31 ble besvart digitalt. Resultat: Deltakerne med diabetes trengte høyere trykk for å oppnå første følelse av ballongdilatasjon i rektum, uavhengig av diabetesvarighet. Økt behov for trykk korrelerte med nedsatt GIGD, men ikke med inkretineffekt. Økt behov for trykk korrelerte også med nedsatt følelse på monofilament test. GIGD og inkretineffekt korrelerte signifikant med både grad av hyperglykemi og diabetesvarighet. Det ble funnet få tilfeller av nevropati totalt sett, og få forskjeller mellom gruppene. Det var en tendens til at lenger latenstid og mindre amplituder på evokerte hjernepotensial var assosiert med lavere hjertefrekvensvariabilitet og kardiovaskulære reflekstester, sural nerveledning og monofilament test, men ikke statistisk signifikant etter korreksjon for multippel testing. Høyere score på COMPASS 31 ble funnet hos dem med langvarig diabetes og hos kvinner, med best sensitivitet og negativ prediktiv verdi for score <10. Konklusjon: Vi fant rektal hyposensitivitet både ved langvarig og tidlig type 2 diabetes og dette var assosiert med redusert GIGD, men ikke med redusert inkretineffekt. Dette kan tyde på at adekvat nervefunksjon i tarmen er viktig for andre faktorer enn inkretineffekten i håndteringen av glukose. Redusert GIGD og inkretineffekt er assosiert med økende hyperglykemi og varighet av diabetes, som viser et kontinuum i tarmens glukosehåndtering fra normo- til hyperglykemi. Vi fant klinisk plausible tegn på at sentral nerveledning er assosiert med perifer nervefunksjon, men resultatene må tolkes med forsiktighet, gitt multippel testing. Rektal ballongdilatasjon med måling av sensitivitet og evokerte hjernepotensial synes å være en lovende metode for undersøkelse av nervefunksjon i tarmen, også når øvrige autonome tester er normale. Til sist finner vi spørreskjemaet COMPASS 31 lovende til bruk både i forskning, men også i den kliniske hverdag, hvor autonome symptomer ofte er neglisjert. I en liknende populasjon som vår vil en score på 10 poeng eller mindre nærmest utelukke kardiovaskulær autonom nevropati.Background: The incretin effect refers to the amplified insulin response when glucose is administered orally compared to intravenously. A reduced incretin effect is found at early stages of type 2 diabetes, even in prediabetes and obesity, but the mechanisms behind are unknown. Evidence suggests that part of the effect of incretin hormones are mediated through vagal nerve transmission. Diabetic autonomic neuropathy is considered a late complication of diabetes mellitus, but there is an increasing awareness that neuropathy can exist in both prediabetes and early stages of diabetes. This led us to the hypothesis that the incretin effect could be affected by early autonomic neuropathy because of a reduced transmission of signals. Aims: Our main objective was to explore whether a reduced incretin effect could be associated with autonomic neuropathy. Secondarily, we aimed to explore the incretin effect in relation to degree of dysglycemia and the duration of diabetes. Other secondary objectives were to explore a novel test of gut visceral sensitivity and central transmission of peripheral signals, and to compare it with established tests for diabetic neuropathy, including assessment of symptoms using the Composite Autonomic Symptom Score (COMPASS) 31. Methods: This was case-control study including three groups of participants: People with type 2 diabetes for >10 years (longstanding), people with newly discovered type 2 diabetes within the last year, without the need for antidiabetic medication (early), and a group of matched controls in age, sex, and body mass index. An oral glucose tolerance test followed by an intravenous isoglycemic glucose infusion were performed to calculate the incretin effect (from c-peptide area under the curve). Gastrointestinal-mediated glucose disposal (GIGD) was calculated as an estimate of the body’s ability to cope with the challenge of a carbohydrate ingestion. Neuropathy tests included cardiovascular reflex tests, heart rate variability, sudomotor function, sural nerve, and the monofilament test. Rapid rectal balloon distention measuring visceral sensitivity and evoked potentials was performed as a proxy for gut autonomic nerve function. The COMPASS 31 questionnaire was distributed and answered online. Results: Both groups of diabetes were hyposensitive to first sensation performing rapid rectal balloon distention. Also, those with reduced sensation performing the monofilament test showed hyposensitivity. A correlation was found between rectal hyposensitivity at the first sensation and reduced GIGD, but not with the incretin effect. Both GIGD and the incretin effect were found to correlate with degree of dysglycaemia and duration of diabetes, and were comparable to previous studies. Overall, few cases of confirmed neuropathy were detected, and there were few differences between groups regarding established neuropathy tests. Longer evoked potential latencies and smaller amplitudes plausibly correlated with lower heart rate variability and cardiovascular reflex test score, reduced parameters in the sural nerve test and monofilament sensation, but not statistically significant considering multiple testing. Higher scores in COMPASS 31 were correlated with longstanding diabetes and female sex. We found an acceptable negative predictive value for cardiovascular autonomic neuropathy at a 10-point cut-off . Conclusions: Rectal hyposensitivity may be an early manifestation of type 2 diabetes, and associated with GIGD, but not with the incretin effect. GIGD and the incretin effect are associated with degree of dysglycemia and duration of diabetes, indicating a continuum in the diminished effect. Central neuronal signal processing appears to be affected in parallel with peripheral neuronal function, but the results must be interpreted with caution. In general, we found that investigating evoked potentials following rapid rectal balloon distention may be a useful research tool for evaluating gut autonomic neuropathy, also when other autonomic neuropathy tests are normal. The Norwegian version of COMPASS 31 was easy to use and for assessing autonomic neuropathy in diabetes, and we suggest a cut off at ten points for screening purposes. Symptoms of autonomic neuropathy seems to be more frequent in people with longstanding diabetes and in women.Doktorgradsavhandlin

The Composite Autonomic Symptom Score 31 Questionnaire: A Sensitive Test to Detect Risk for Autonomic Neuropathy

Background and Aims. Autonomic neuropathy is a common but often neglected complication of diabetes, prediabetes, and even in individuals with an elevated risk of diabetes. The Composite Autonomic Symptom Score (COMPASS) 31 is a validated and easy-to-use questionnaire regarding autonomic symptoms. We aimed to use a digitally, Norwegian version of the COMPASS 31 in people with different durations of diabetes and healthy controls to consider feasibility and to investigate if scores could discriminate between positive and negative outcomes for established tests for diabetic neuropathy, including cardiovascular autonomic neuropathy (CAN) and a novel method of examining the gastrointestinal visceral sensitivity. Method. We included 21 participants with longstanding type 2 diabetes, 15 with early type 2 diabetes, and 30 matched controls. The mean age for all groups was 69 years. Participants were phenotyped by cardiovascular autonomic reflex tests, electrical skin conductance, sural nerve electrophysiology, and the monofilament test. As a proxy for gastrointestinal visceral and autonomic nerve function, evoked potentials were measured following rapid rectal balloon distention. Results. Participants with longstanding diabetes scored a median (IQR) of 14.9 (10.8-28.7) points, early diabetes of 7.3 (1.6-15.2), and matched controls of 8.6 (4.1-21.6), p=0.04. Women and men scored 14.4 (5.5-28.7) and 7.8 (3.6-14.6) points, respectively, p=0.01. Participants with definite or borderline CAN scored 14.3 (10.4-31.9) points, compared to participants with no CAN, 8.3 (3.2-21.5), p=0.04. Lowering the diagnostic cut-off from 16 to 10 points increased the sensitivity from 0.33 to 0.83, with a decreased specificity from 0.68 to 0.55. Conclusion. We successfully used COMPASS 31 in Norwegian. Thus, following the guidelines, we suggest clinical implementation for the assessment of autonomic neuropathy. Participants with longstanding diabetes had an increased likelihood of symptoms and signs of autonomic neuropathy. For screening purposes, the sensitivity was improved by lowering the cut-off to 10 points, with a lower score nearly excluding the diagnosis

Rectal sensitivity correlated with gastrointestinal-mediated glucose disposal, but not the incretin effect

OBJECTIVE: The mechanisms behind the diminished incretin effect in type 2 diabetes are uncertain, but impaired vagal transmission has been suggested. We aimed to investigate the association between the incretin effect and autonomic neuropathy, and the degree of dysglycaemia and duration of diabetes.DESIGN AND METHODS: For a cross-sectional study, we included participants with either longstanding type 2 diabetes, recent onset, untreated diabetes and controls without diabetes matched for age, sex and body mass index. Autonomic nerve function was assessed with cardiovascular reflex tests, heart rate variability and sudomotor function. Visceral afferent nerves in the gut were tested performing rapid rectal balloon distention. An oral glucose tolerance test and an intravenous isoglycaemic glucose infusion were performed to calculate the incretin effect and gastrointestinal-mediated glucose disposal (GIGD).RESULTS: Sixty-five participants were recruited. Participants with diabetes had rectal hyposensitivity for earliest sensation (3.7 ± 1.1 kPa in longstanding, 4.0 ± 1.3 in early), compared to controls (3.0 ± 0.9 kPa), p = .005. Rectal hyposensitivity for earliest sensation was not associated with the incretin effect (rho = -0.204, p = .106), but an association was found with GIGD (rho -0.341, p = .005). Incretin effect and GIGD were correlated with all glucose values, HbA1c and duration of diabetes.CONCLUSIONS: Rectal hyposensitivity was uncovered in both longstanding and early type 2 diabetes, and was not associated with the incretin effect, but with GIGD, implying a potential link between visceral neuropathy and gastrointestinal handling of glucose. Both the incretin effect and GIGD were associated with the degree of dysglycaemia and the duration of diabetes.PREVIOUSLY PUBLISHED: Some of the data have previously been published and presented as a poster on the American Diabetes Association 83rd Scientific Sessions: Meling et al; 1658-P: Rectal Hyposensitivity, a Potential Marker of Enteric Autonomic Nerve Dysfunction, Is Significantly Associated with Gastrointestinally Mediated Glucose Disposal in Persons with Type 2 Diabetes. Diabetes 20 June 2023; 72 (Supplement_1): 1658-P. https://doi.org/10.2337/db23-1658-P.</p