Pancreatic exocrine insufficiency in diabetes mellitus - prevalence and characteristics

BackgroundThe prevalence of pancreatic exocrine insufficiency (PEI) in diabetes mellitus (DM) varies widely between studies, which may be explained by methodological problems. We aimed to establish the prevalence of PEI in DM using the faecal elastase-1 (FE-1) assay as a screening test, and to further investigate these patients by the mixed ¹³C-triglyceride (¹³C-MTG) breath test.MethodsOne hundred and thirty-three consecutive type 1 or type 2 DM patients without known exocrine pancreatic disorders were recruited. Demographic parameters, stool consistency, stool frequency, routine laboratory tests, and the presence of DM complications were registered. An FE-1 value <200 μg/g was used as the screening cut-off for PEI, and patients with FE-1 values below this level were referred for a ¹³C-MTG breath test.ResultsOne hundred and two patients returned faecal samples. The prevalence of PEI as measured by low FE-1 was 13%. Insulin usage, type 1 DM, and DM duration were associated with low FE-1. Stool habits were unaffected by low FE-1. Twelve out of 13 patients with low FE-1 performed the breath test, which was normal in all cases.ConclusionsThe prevalence of PEI defined by FE-1 was low in our mixed cohort of type 1 and 2 DM patients. Furthermore, there was a discrepancy between FE-1 and the breath test. Hence, the role of FE-1 in evaluating pancreatic exocrine function in DM should be evaluated in larger studies in order to clarify the association between low FE-1 and clinically relevant PEI.     

Liver and pancreas: ‘Castor and Pollux’ regarding the relationship between hepatic steatosis and pancreas exocrine insufficiency

BackgroundPancreatic exocrine insufficiency (PEI) is found in 30–50% of diabetes mellitus (DM). Insulin resistance is triggering factor in both DM and nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to investigate frequency of PEI in NAFLD, and relationship of fecal pancreatic elastase (PE) levels with liver histology and pancreatic fat.MethodsNinety-seven biopsy proven NAFLD patients and 50 controls were enrolled. Pancreas exocrine functions were measured by PE. Magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) was used to quantify fat.ResultsNAFLD patients had significantly lower PE levels than controls (297 [204–517] vs. 500 [298–678] μg/g, p < 0.01). PEI (PE < 200 μg/g) ratio of NAFLD patients (22.7%, n = 22) was higher than PEI ratio of controls (6%, n = 3) (p = 0.011). Among diabetic (n = 35) NAFLD patients, 9 (25.7%) exhibited PEI, compared to 13 (21%) of non-diabetics. There was no significant difference in patients with and without DM in terms of PEI (p = 0.592). Among NASH (n = 68) patients 16 (23.5%) exhibited PEI, compared to (20.7%) of non-NASH (p = 0.76). Multiple analysis revealed NAFLD as a predictor of PEI independent of age, sex and DM (OR = 4.892, p = 0,021). Mean pancreas MRI-PDFF was significantly higher in diabetics (13.7% ± 3.6% vs. 8.7% ± 5.1%, p = 0.001). There was no significant pancreas MRI-PDFF difference between NASH and non-NASH (P = 0.95). Mean pancreas MRI-PDFF was significantly higher in patients with PEI (13.7% ± 3.4% vs. 8.9% ± 5.2%, P < 0.01).ConclusionThis is the first study demonstrating the high frequency of PEI in NAFLD independent of DM. Moreover, increasing pancreatic steatosis appears to be associated with higher frequency of PEI in NAFLD.     

Factors associated with sclerostin levels – A calcification inhibitor – In individuals with type 2 diabetes mellitus; Is autonomic neuropathy the missing link?

BackgroundSclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM.MethodsA total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays.ResultsPlasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC.ConclusionPlasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM.     

Erythropoietin response to anemia and its association with autonomic neuropathy in type 2 diabetic patients without advanced renal failure

AimWe aim to investigate erythropoietin (EPO) response to anemia and its association with autonomic neuropathy in type 2 diabetic patients without advanced renal failure.MethodsA cross-sectional study was conducted on 211 type 2 diabetes mellitus patients without advanced renal failure [estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m²]. The response of EPO to anemia of type 2 diabetic patients without advanced renal failure was compared with those of nondiabetic control subjects. Autonomic nerve function was assessed using three cardiovascular tests (deep breathing, the Valsalva maneuver, and lying-to-standing). The results of each test were scored as 0 if normal, 1 if borderline, and 2 if abnormal. Autonomic neuropathy was diagnosed when a total score of the tests was 2 or more.ResultsFifty-eight patients were anemic; compared with nonanemic patients, they had a longer duration of diabetes (16.69±10.11 vs. 10.67±8.41 years, P<.001), lower eGFR (66.43±16.30 vs. 81.74±19.49 ml/min/1.73 m², P<.001), and higher cardiovascular autonomic neuropathy score (3.17±1.95 vs. 1.79±1.72, P<.001). Serum EPO level was weakly correlated with hemoglobin (Hb) level (r=?.085, P<.001). However, the slopes of regression lines between EPO and Hb levels differed significantly between type 2 diabetic patients and nondiabetic control subjects (?0.0085 vs. ?0.255, P=.008). Multiple linear regression analysis revealed that cardiovascular autonomic neuropathy score was independently related to Hb (P<.001) or EPO level (P=.052).ConclusionsAutonomic neuropathy is associated with a blunted EPO response to anemia in type 2 diabetic patients without advanced renal failure.     

Pancreatic exocrine insufficiency following pancreatoduodenectomy: A prospective bi-center study

Background/objectivesPancreatic exocrine insufficiency (PEI) is a common complication following pancreatoduodenectomy (PD) leading to malnutrition. The course of PEI and related symptoms and vitamin deficiencies is unknown. This study aimed to assess the (long-term) incidence of PEI and vitamin deficiencies after PD.MethodsA bi-centre prospective observational cohort study was performed, including patients who underwent PD for mainly pancreatic and periampullary (pre)malignancies (2014–2018). Two cohorts were formed to evaluate short and long-term results. Patients were followed for 18 months and clinical symptoms were evaluated by questionnaire. PEI was based on faecal elastase-1 (FE-1) levels and/or clinical symptoms.ResultsIn total, 95 patients were included. After three months, all but three patients had developed PEI and 27/29 (93%) patients of whom stool samples were available showed abnormal FE-1 levels, which did not improve during follow-up. After six months, all patients had developed PEI. During follow-up, symptoms resolved in 35%–70% of patients. Vitamin D and K deficiencies were observed in 48%–79% of patients, depending on the moment of follow-up; 0%–50% of the patients with deficiencies received vitamin supplementation.DiscussionThis prospective study found a high incidence of PEI after PD with persisting symptoms in one-to two thirds of all patients. Limited attention was paid to vitamin deficiencies. Improved screening and treatment strategies for PEI and vitamins need to be designed.     

Transforming growth factor beta 1 as a biomarker of diabetic peripheral neuropathy: cross-sectional study

BackgroundSimple and efficient screening methods are lacking for diabetic peripheral neuropathy (DPN), the most common and most difficult to treat of the long-term diabetic complications. Increased levels of transforming growth factor beta 1 (TGFβ1) in type 2 diabetic patients (T2DM) plays an immunomodulatory role in diabetic nephropathy and, possibly, in atherosclerotic evolution. Since preliminary interrelationships between experimental DPN and TGFβ1 have been observed, we sought to assess whether TGFβ1 could be a biomarker molecule for human DPN.Materials and MethodsCross-sectional cohort study focused on the assessment of the interrelationships between TGFβ1 levels, cardiovascular disease (CVD), diabetic nephropathy (DNF), and neuropathy (DPN) in a group of T2DM patients (N=180; male 117, female 63) randomly selected from the North Catalonia Diabetes Study. DPN was diagnosed using clinical and neurophysiology evaluation. Incipient DNF was assessed by microalbuminuria (MAU). Total TGFβ1 (without acidification) was measured by immunoassay by ELISA (Promega).ResultsDPN correlated with age, time of diabetes duration, MAU, CVD, and TGFβ1 (P<.0001). Log-transformed TGFβ1 (logTGβ1) was significantly higher in patients with DPN than in those without (P<.0005). LogTGFβ1 (OR=7.5; P=.006), age (OR=1.1; P<.0005), and logMAU (OR=2.0; P=.016) appear as significant estimators of the occurrence of DPN in our series. The integrated ROC curve evaluation with these three parameters expressed an important sensitivity (78.1%), specificity (76.0%), positive predictive value (79.2%), and negative predictive value (70.3%) in relation to DPN presence.DiscussionTGFβ1 stands as an important biomarker molecule for DFN and DPN screening in our series. Further prospective studies are warranted.     

Gabapentin therapy improves heart rate variability in diabetic patients with peripheral neuropathy

PurposeDiabetic cardiac neuropathy, which is characterized by reduced heart rate variability (HRV), frequently coexists with peripheral neuropathy. Gabapentin has been used for the treatment of diabetic neuropathy. We aimed to evaluate the possible effect of gabapentin treatment on autonomic function in patients with type 2 diabetes via HRV.MethodsThirty patients with type 2 diabetes mellitus and peripheral neuropathy and 28 age- and sex-matched healthy controls were consecutively registered. Each patient underwent HRV measurements, and diabetic patients were administered gabapentin. After 3 months of gabapentin therapy, HRV parameters were measured again.ResultsBaseline HRV parameters were blunted in patients with diabetes mellitus according to the controls [standard deviation of all NN intervals (SDNN, ms): 106.3±29.9 vs. 148.8±36.5, P=.001; power spectrum of the high-frequency band (HF, ms²): 133.6±98.3 to 231.4±197.6, P=.02; power spectrum of the low-frequency band (LF, ms²): 341.8±247.8 to 511.5±409.4, P=.048; LF/HF ratio: 3.3±2.4 to 2.6±1.5, P=.33]. After 3 months of treatment with gabapentin, some HRV parameters showed some improvement. SDNN (106.2±29.8 to 119.4 ± 25, P=.016) and HF (133.6±98.3 to 167.6±118.3, P=.021) increased significantly. LF/HF ratio decreased (from 3.3±2.4 to 2.3±1.9, P=.039) and LF remained unchanged (341.8±247.8 to 352.3±228.9, P=.88).ConclusionsTherapeutic doses of gabapentin not only alleviate neuropathic symptoms but also improve cardiac autonomic function in diabetic patients with peripheral neuropathy.     

TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy

Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case–control association study and a genotype–phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P = 0.003, P = 0.004 and P = 0.012) and at allelic level (P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy.     

Cardiovascular Autonomic Neuropathy Is Associated With Macrovascular Risk Factors in Type 2 Diabetes: New Technology Used for Routine Large-Scale Screening Adds New Insight

Background:The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN.Methods:The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed.Results:The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025).Conclusion:In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.     

Burning mouth syndrome and peripheral neuropathy in patients with type 1 diabetes mellitus

ObjectiveBurning mouth syndrome (BMS) has been attributed secondarily to diabetes, poor glycemic control, and diabetic neuropathy. The prevalence and predictor factors of BMS were compared in type 1 diabetes mellitus (T1DM) and nondiabetic subjects.Study designAn assessment of 371 adult T1DM subjects and 261 control subjects participating in a cross-sectional epidemiological study of oral health complications of diabetes was performed. Subjects were participants of the Pittsburgh Epidemiology of Diabetes Complications study. Prevalence of BMS was determined by response to the following questions: “Do you now or in the last month had any persistent uncomfortable sensations in your mouth or tongue? If yes, would you describe the feeling as tingling, burning, sore, numb, or other?”ResultsBurning mouth syndrome symptoms were reported by 28 T1DM and control subjects (4.6%). Eleven had oral pathologies that might explain the BMS, including atrophy of the tongue papillae, fissured tongue, denture stomatitis, and candidiasis. The prevalence of BMS within the two groups with no pathologies was similar; 12/371 (3.2%) vs. 5/233 (2.1%). Multivariate analyses of the 12 T1DM subjects with BMS found significant associations for female gender (P=.042) and a diagnosis of diabetic peripheral neuropathy (P=.024).ConclusionsIn this T1DM population, BMS or related discomforts occurred slightly more frequently than in the control group. Symptomatic T1DM subjects were more likely to be female who had also developed peripheral neuropathy. These findings and other similarities between BMS and diabetic peripheral neuropathy suggest that a neuropathic process may be an underlying source of BMS in some patients who have no apparent oral abnormality.     

Effect of cardiovascular autonomic neuropathy (CAN) on left ventricular function in normotensive type 1 diabetic patients: A study by pulsed wave tissue Doppler echocardiography

Background and aimPatients with diabetes mellitus are at increased risk for cardiovascular diseases. Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes, as it can contribute in the pathogenesis of diabetic cardiomyopathy (DCM) and has been weakly linked with left ventricular diastolic dysfunction. Our aim was to investigate the effect of presence or absence of cardiovascular autonomic neuropathy (CAN) on systolic and diastolic LV function in normotensive type 1 diabetic patients by using both conventional and tissue Doppler echocardiography.Subjects and methodsFifty two type 1 diabetic patients entered this study. They were divided into two groups. The first group included 24 patients with evidence of cardiovascular autonomic neuropathy. The second group included 28 patients without evidence of cardiovascular autonomic neuropathy. In addition to 18 healthy normal weights non diabetic subjects as a control group. Complete clinical examination, routine laboratory investigations, lipid profile, urinary albumin excretion, HbA1c and 12 leads ECG were done to all participants. Conventional and tissue Doppler indices of systolic and diastolic left ventricular function were recorded.ResultsHeart rate was significantly higher in diabetic patients with CAN compared to both diabetic patients without CAN and normal control subjects (P < 0.001, <0.001, respectively). Glycemic control as assessed by HbA1c was more worse in diabetic patients with CAN compare to diabetic patients without CAN (P < 0.001). As regard conventional echo-Doppler, there were a significant difference in A wave velocity and E/A ratio in diabetic patients with or without CAN compared to control (P < 0.001, <0.001, <0.001, <0.001, respectively). Tissue Doppler indices show a significant difference at the lateral annular side in Em and Am velocity and Em/Am ratio in diabetic patients with or without CAN vs. control (P < 0.001, <0.001, <0.001, <0.05, <0.05, <0.01, respectively) and also, between diabetic patients with CAN vs. diabetic patients without CAN (P < 0.001, <0.05, <0.01, respectively). Also, tissue Doppler indices show a significant difference at the septal annular side in Em and Am velocity and Em/Am ratio in diabetic patients with or without CAN vs. control (P < 0.001, <0.001, <0.001, <0.01, <0.05, <0.05, respectively) and also, between diabetic patients with CAN vs. diabetic patients without CAN (P < 0.001, <0.05, <0.01, respectively). Contrary to that, no significant differences were found in LV systolic function parameters measured by either conventional or tissue Doppler imaging among the three groups.ConclusionOur results demonstrated that, LV diastolic function was impaired in normotensive type 1 diabetic patients and, the presence of CAN is associated with more deterioration in diastolic function. Systolic function is seems to be unaffected. TDI should be the preferred modality in evaluation of LV function as it can detect minimal changes in diastolic function much earlier than conventional echo-Doppler.     

Impaired gastric emptying and altered intragastric meal distribution in diabetes mellitus related to autonomic neuropathy?

Previous studies in diabetic patients suggested a relationship between delayed gastric emptying and increased ingesta retention in either proximal or distal stomach, but the determinants underlying these abnormalities remained obscure. We aimed at assessing the impact of cardiovascular autonomic neuropathy, blood glucose concentration, long-term glycemic control, and other factors in 34 type I and 43 type II diabetic patients (ages 21–67 and 34–81 years, respectively). Emptying was slower (P < 0.04) in type I diabetic patients than in 20 healthy control subjects (ages 23–63 years). Patients with autonomic neuropathy (N = 45) had slower gastric emptying (P < 0.02) and retained more in the distal stomach (P < 0.0001) than patients without neuropathy (N = 32). Multiple regression analyses revealed that slow emptying and increased distal retention were significantly associated with autonomic neuropathy (P < 0.043, P < 0.0002), whereas blood glucose, glycemic control, diabetes duration, age, and other factors had no discernible influence. Thus, both slow emptying and increased distal ingesta retention seem primarily referable to autonomic neuropathy.     

Autonomic neuropathy and transcutaneous oxymetry in diabetic lower extremities

Summary Transcutaneous oxygen tension is a useful method with which to assess the functional status of skin blood flow. The reduced values observed in diabetic patients have been interpreted as a consequence of peripheral vascular disease. However, diabetic patients show lower transcutaneous oxygen tension values than control subjects with equivalent degrees of peripheral vascular disease, suggesting that additional factors are involved. Since the autonomic nervous system influences peripheral circulation, we studied the relationship between autonomic neuropathy and foot transcutaneous oxymetry in non-insulin-dependent diabetic (NIDDM) patients without peripheral vascular disease. The following age-matched patients were selected and evaluated: control subjects, C, (n=20), NIDDM patients without autonomic neuropathy, D, (n=16) and with autonomic neuropathy, DN, (n=20). All diabetic patients showed lower transcutaneous oxygen tension values than control subjects, while no differences were observed between the diabetic patients with and without autonomic neuropathy. In addition the saturation index that increases in the presence of autonomic neuropathy does not correlate with foot TcPO₂. In conclusion autonomic neuropathy does not influence foot TcPO₂ and therefore it is unlikely that it contributes to development of foot lesions during induction of foot skin ischaemia.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - TcPO₂ transcutaneous oxymetry - A-V arterio-venous shunts - PVD peripheral vascular disease - HbA_1c glycated haemoglobin - SI saturation index     

Quantification of pancreatic exocrine function of chronic pancreatitis with secretin-enhanced MRCP

AIM:To obtain reference values for pancreatic flow output rate(PFR)and peak time(PT)in healthy volunteers and chronic pancreatitis(CP);to correlate quantification of secretin enhanced magnetic resonance cholangiopancreatography(SMRCP)of pancreatic fluid output following secretin with fecal elastase-1(FE-1)tests.METHODS:The present study includes 53 subjects comprised of 17 healthy individuals and 36 patients with CP from April 2011 to January 2013.The 36 patients with CP were divided into three groups of mild CP(n=14),moderate CP(n=19)and advanced CP(n=3)by M-ANNHEIM classification for CP..Fifty-three cases underwent FE-1 test and magnetic resonance imaging using 3.0 T-device(Signa EXCITE,GE Healthcare).Coronal T2-weighted single-shot turbo spin-echo,spiratory triggered,covering the papillae,duodenum and small bowel.MRCP was performed with a heavily T2-weighted fat-suppressed long TE HASTE sequence (thick slab 2D MRCP sequence),repeated every 2 min up to 11 min after 0.1 mL/kg secretin injection(Secrelux,Sanochemia,Germany).FE-1 test used sandwich enzyme-linked immunosorbent assay(ELISA)test(ScheBo.Tech,Germany).RESULTS:A good linear correlation showed between the calculated volume and the actual volume by Phantom experiments.Fifty-three paired Quantification of secretin enhanced magnetic resonance cholangiopancreatography(MRCPQ)and FE-1 data sets were analyzed.The mean FE-1 of 53 cases was 525.41±94.44μg/g for 17 healthy volunteers,464.95±136.13μg/g for mild CP,301.55±181.55μg/g for moderate CP,229.30±146.60μg/g for advanced CP.Also,there was statistically significant difference in FE-1(P=0.0001)between health and CP.The mean values of PFR and PT were 8.18±1.11 mL/min,5.76±1.71 min for normal;7.27±2.04 mL/min,7.71±2.55 min for mild CP;4.98±2.57 mL/min,9.10±3.00 min for moderate CP;4.13±1.83 mL/min,12.33±1.55 min for advanced CP.Further,statistically significant difference in PFR(P=0.0001)and PT(P=0.0001)was observed between health and CP.Besides,there was correlation(r=0.79)and consistency(K=0.6     

Haemodynamic changes during graded exercise in patients with diabetic autonomic neuropathy

Summary Haemodynamic variables were measured during supine rest and during ergometer cycle exercise at two work loads (50 W and 100 W) in normal subjects (n = 7), in insulin-dependent diabetic subjects without neuropathy (n = 8), in insulin-dependent diabetic subjects with slight autonomic neuropathy (decreased beat-to-beat variation in heart rate, which is considered due to a cardiac parasympathetic defect; n = 8), and in insulin-dependent diabetic subjects with severe autonomic neuropathy, including orthostatic hypotension (n = 7). Compared with normal subjects, cardiac stroke volume was lower in the diabetic subjects with autonomic neuropathy, both at rest and during exercise (p < 0.025), whereas intermediate values were found in the diabetic subjects without neuropathy. The increase in cardiac output in response to exercise was smaller (p < 0.05) in both diabetic groups with autonomic neuropathy compared with the normal and diabetic subjects without autonomic neuropathy. The increase in hepato-splanchnic vascular resistance was smaller in the diabetic subjects with severe autonomic neuropathy than in the normal subjects and the diabetic subjects without autonomic neuropathy (p < 0.025), whereas intermediate values were found in the diabetic subjects with slight autonomic neuropathy. We conclude that, in diabetic patients with severe autonomic neuropathy, the responses of the heart and the splanchnic resistance vessels to exercise are impaired. While sympathetic neuropathy may be responsible for impaired function of splanchnic resistance vessels, both cardiac sympathetic neuropathy and diabetic cardiomyopathy may be involved in the impaired cardiac response to exercise in diabetic subjects with autonomic neuropathy.     

Modified orthostatic load for spectral analysis of short-term heart rate variability improves the sensitivity of autonomic dysfunction assessment

AimTo evaluate the impact of orthostatic load for sensitivity of short-term spectral analysis of heart rate variability (HRV) assessment of potential early autonomic dysfunction in diabetes mellitus.MethodsComparison of results of short-term time- and frequency-domain analysis of HRV during single positions and during modified orthostatic load (supine 1–standing–supine 2, each position 300 s) in diabetic subjects with good glycemic control (n=80, age 38±14, diabetes duration 16±10 years) and without autonomic neuropathy as assessed by a standard bedside reflex test battery, and in nondiabetic controls (n=150, age 40±13 years).ResultsNone of the short-term frequency-domain parameters [absolute and logarithmic (LN) values of spectral powers in total- (TF), low- (LF), and high-frequency (HF) bands and its centroid frequencies] as obtained in single positions “supine” or “standing” revealed a significant difference between well-controlled patients and healthy controls (P>.3). However, during modified orthostatic load, significant differences in ΔLN TF_{(supine 1–supine 2)} and in ΔLN LF_{(supine 1–supine 2)} as well as in ΔLN LF_{(standing–supine 2)} values between diabetic and healthy subjects were recorded [?0.2±0.5 vs. ?0.1±0.4 LN (ms²), P=.05; ?0.3±0.8 vs. 0.1±0.7 LN (ms²), P=.001 and 0.2±1.0 vs. 0.4±0.9 LN (ms²), P=.05, respectively] with insignificant intergroup differences in related centroid frequencies. This finding suggests a delayed recovery of LF spectral power in diabetic subjects after orthostatic challenge.ConclusionsWhen compared with single position measurements, the modified orthostatic load protocol improves the sensitivity of short-term HRV examination. In well-controlled diabetic subjects without cardiovascular autonomic neuropathy (as excluded by standard cardiovascular reflex testing), the delayed recovery of LF band spectral power after orthostatic load with standing up indicates diminished parasympathetic activation.     

The impact of canagliflozin on the risk of neuropathy events: A post-hoc exploratory analysis of the CREDENCE trial

AimCanagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy.MethodsThe CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100 mg daily or placebo. Neuropathy events were defined post-hoc as any reported adverse event consistent with a peripheral or autonomic neuropathy event. The effect of canagliflozin and predictors of neuropathy events were estimated using Cox regression analysis. In sensitivity analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, and non-autonomic neuropathy events.ResultsAlmost half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years of follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). Independent factors associated with higher risk of experiencing neuropathy events were non-white race, younger age, higher glycated haemoglobin and lower estimated glomerular filtration rate. The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, P = 0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, P = 0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, P = 0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, P = 0.77). The lack of effect on neuropathy events was consistent in subgroup analyses.ConclusionCanagliflozin did not affect the risk of neuropathy events in the CREDENCE trial. Future large randomized studies with prespecified neuropathy endpoints are required to determine the impact of sodium glucose cotransporter 2 inhibitors on diabetic neuropathy.     

Insulin resistance is independently associated with peripheral and autonomic neuropathy in Korean type 2 diabetic patients

In addition to chronic hyperglycemia, insulin resistance itself has been proposed to cause a diabetic neuropathy. We evaluated the role of insulin resistance in the pathogenesis of peripheral and autonomic neuropathy in patients with type 2 diabetes. Eighty-six patients with type 2 diabetes were evaluated for the anthropometric and biochemical profiles, and Kitt value was calculated from insulin tolerance test to assess the insulin resistance. Various autonomic function tests, nerve conduction velocity, and quantitative sensory tests were performed to assess autonomic and peripheral neuropathy. In univariate analysis, both autonomic and peripheral neuropathy were significantly associated with glycemic exposure index (GE index), HDL-cholesterol, duration of DM, and Kitt value. In stepwise linear regression analysis, GE index was an independent predictor of autonomic and peripheral neuropathy (β = 0.643, P < 0.001; β = 0.207, P = 0.013, respectively), and Kitt value was also an independent factor for the autonomic and peripheral neuropathy (β = − 0.306, P < 0.001; β = − 0.329, P < 0.001, respectively). Low HDL-cholesterol increased the odds ratio for peripheral neuropathy. Insulin resistance is independently associated with peripheral and autonomic neuropathy in Korean Type 2 diabetic patients along with hyperglycemia and HDL-cholesterol.     

The association of diabetic microvascular and macrovascular disease with cutaneous circulation in patients with type 2 diabetes mellitus

Aims

To study the impact of diabetic neuropathy, both peripheral sensorimotor (DPN) and cardiac autonomic neuropathy (CAN), on transcutaneous oxygen tension (TcPO₂) in patients with type 2 diabetes mellitus (T2DM).

Potential for Screening for Pancreatic Exocrine Insufficiency Using the Fecal Elastase-1 Test

The early diagnosis of pancreatic exocrine insufficiency (PEI) is hindered because many of the functional diagnostic techniques used are expensive and require specialized facilities, which prevent their widespread availability. We have reviewed current evidence in order to compare the utility of these functional diagnostic techniques with the fecal elastase-1 (FE-1) test in the following three scenarios: screening for PEI in patients presenting with symptoms suggestive of pancreatic disease, such as abdominal pain or diarrhea; determining the presence of PEI in patients with an established diagnosis of pancreatic disease, such as chronic pancreatitis or cystic fibrosis; determining exocrine status in disorders not commonly tested for PEI, but which have a known association with this disorder. Evidence suggests the FE-1 test is reliable for the evaluation of pancreatic function in many pancreatic and non-pancreatic disorders. It is non-invasive, is less time-consuming, and is unaffected by pancreatic enzyme replacement therapy. Although it cannot be considered the gold-standard method for the functional diagnosis of PEI, the advantages of the FE-1 test make it a very appropriate test for screening patients who may be at risk of this disorder.