Influence of remission and its duration on development of early microvascular complications in young adults with type 1 diabetes

Journal of Diabetes and Its Complications 29 (2015) 1105–1111

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Influence of remission and its duration on development of early microvascular complications in young adults with type 1 diabetes Pawel Niedzwiecki ⁎, Stanislaw Pilacinski, Aleksandra Uruska, Anna Adamska, Dariusz Naskret, Dorota Zozulinska-Ziolkiewicz Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences

a r t i c l e

i n f o

Article history: Received 20 May 2015 Received in revised form 7 August 2015 Accepted 2 September 2015 Available online 5 September 2015 Keywords: Remission Diabetes type 1 Microangiopathy Chronic complications Insulin therapy

a b s t r a c t Introduction: Prevalence of partial remission ranges between 20% and 80% in the initial course of type 1 diabetes. In this phase of the disease, a substantial insulin secretion contributes to good metabolic control. The aim of the study was to determine the association between presence of partial remission and occurrence of microangiopathy complications in type 1 diabetes. Material and Methods: Ninety-eight consecutive patients with newly diagnosed type 1 diabetes were asked to participate in a cohort study. Partial remission was defined as the time in which all of the following criteria were met: HbA1c below 6.5% (48 mmol/mol), daily insulin requirement below 0.3 U/kg body weight and serum Cpeptide concentration above 0.5 ng/ml. Patients were divided into those who were in remission at any time during follow-up (remitters) and non-remitters. After 7 years of follow-up, the occurrence of microangiopathy complications was analyzed. In statistical analysis, Mann–Whitney test, chi2 test and Fisher test were used for analysis between groups. We applied a Cox's multivariate regression model and univariate regression method. P b 0.05 was considered statistically significant. Results: In univariate logistic regression, a significant association was found between absence of remission and occurrence of at least one microvascular complication. In the Cox proportional hazards regression model that included clinically significant parameters at diagnosis (presence of ketoacidosis, cigarette smoking and HbA1c value) as covariates, absence of remission was associated with occurrence of chronic complications of diabetes at 7 years [HR: 3.65 (95% CI 1.23–4.56), p = 0.04]. In non-remitters, higher incidence of at least one microvascular complication (46.4% vs. 7.6%), higher incidence of retinopathy (42.8% vs. 5.7%), and neuropathy (21.4% vs. 1.9%) was found. Conclusions: Occurrence of partial remission of diabetes is associated with a reduced risk of chronic microvascular complications at 7-year follow-up. © 2015 Elsevier Inc. All rights reserved.

1. Introduction The natural course of type 1 diabetes mellitus involves a gradual reduction in beta cell mass within islets of Langerhans in the pancreas (Sherry, Tsai, & Herold, 2005). Symptoms of diabetes appear when the mass of insulin-producing cells reaches a point where the insulin concentration does not suffice to maintain proper glycemia. In many patients, beta cells regenerate shortly after the diagnosis of diabetes and initiation of insulin therapy. This phenomenon is called a remission. The prevalence of remission is estimated between 20% and 80% in a group of patients with type 1 diabetes (Abdul-Rasoul, Habib, & Al-Khouly, 2006; Chloot et al., 2007; Hramiak, Dupre, & Finegood, Conflict of interest: The authors declare no conflict of interest. ⁎ Corresponding author at: Mickiewicza 2, 60-834 Poznan, Poland. Tel.: +48 61 847 45 79. E-mail address: [email protected] (P. Niedzwiecki). http://dx.doi.org/10.1016/j.jdiacomp.2015.09.002 1056-8727/© 2015 Elsevier Inc. All rights reserved.

1993; Martin et al., 1992). It usually appears within 3–6 months from the diagnosis (Abdul-Rasoul et al., 2006; Bonfati, Bognetti, Meschi, Brunelli, & Riva, 1998; Hramiak et al., 1993). It is characterized by a low demand for exogenous insulin to maintain normoglycemia. Remission may be total or partial. In the former case, it is possible to temporarily discontinue insulin treatment, while in the latter case, a daily insulin dose may be significantly reduced. However, complete cessation of insulin therapy usually leads to rapid depletion of beta cell insulin-producing ability, and it is not the recommended therapeutic option (DCCT, 1998; Scholin, Berne, Schvarcz, Karlsson, & Bjork, 1999). Most criteria for remission take into consideration the following parameters: glycated hemoglobin level (HbA1c), demand for exogenous insulin (number of units/kg body weight/day), and serum C-peptide concentration (Abdul-Rasoul et al., 2006; Bonfati et al., 1998; Chase, MacKenzie, Burdick, Fiallo-Scharer, & Walravens, 2004; Chloot et al., 2007; Couper, Hudson, Werther, Warne, & Court, 1991; Scholin et al., 1999, 2004). It is known that maintaining residual

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insulin secretion facilitates good metabolic control of diabetes and decreases the risk of hypoglycemia (Ali & Dayan, 2009; Fukuda et al., 1988). The question remains whether occurrence of remission decreases the risk of chronic complications of diabetes. Chronic complications of diabetes significantly influence the quality of life. In type 1 diabetic patients, microvascular lesions of the kidney and eye lead to increased morbidity and mortality (Parving, Osterby, & Ritz, 2000). Retinopathy is the most common microvascular complication. It is one of the main causes of blindness (The Eye Diseases Prevalence Research Group, 2004). It is diagnosed after 20 years in nearly 90% of patients with type 1 diabetes (Frank, 2004; Karnafel, 2000). In the course of type 1 diabetes, nephropathy develops in 35–40% of patients (Karnafel, 2000). Diabetic nephropathy is believed to be the cause for almost 30% of cases of the end-stage renal failure (American Diabetes Association, 2002). Prevention of microangiopathy is one of the main long-term goals of diabetes treatment. Many factors play a role in the pathogenesis of diabetic micro- and macroangiopathy. Some of them may be modified (control of glycemia, arterial hypertension, dyslipidemia, smoking), while some are non-modifiable (age at diagnosis, duration of diabetes, genetic factors). Clinical trials aiming at improved glycemic control have shown a beneficial effect on the development and progression of diabetic kidney and eye complications (DCCT Research Group, 1994; Wang, Lau, & Chalmers, 1993). There are reasons to believe that occurrence and duration of remission may be associated with a reduced risk of chronic complications of diabetes. The Diabetes Control and Complications Trial (DCCT) showed that microangiopathic complications were less common in a group of patients with higher serum C-peptide levels at the time of enrollment (Steffes, Sibley, Jackson, & Thomas, 2003). However, data on the association between remission of type 1 diabetes and development of chronic complications are lacking. 2. Aim The aim of this study is to assess the association between occurrence and duration of partial remission and the development of microangiopathic complications among young adults with type 1 diabetes. 3. Material and methods 3.1. Study population The study included 98 consecutive patients, 34 women and 64 men hospitalized at the Department of Internal Medicine and Diabetology of the Poznan University of Medical Sciences between 2006 and 2007 due to newly diagnosed type 1 diabetes. The study included patients who met the following selection criteria: 1. Newly diagnosed type 1 diabetes according to ADA (American Diabetes Association) 1997 criteria 2. Age of 18–35 years 3. Patient education in the intensive functional insulin therapy at the time of diagnosis 4. Patient's consent to participate in the study 5. Presence of islet cell antibodies (ICA) or antibodies against glutamic acid decarboxylase (GADA) orinsulinoma antigen-2 (IA-2A) autoantibodies. Exclusion criteria were as follows: 1. Acute inflammation (serum C-reactive protein concentration (hsCRP) N 10 mg/L, white blood cell count (WBC) N 15 × 10 9/L, erythrocyte sedimentation rate (ESR) N 30 mm/1 h) 2. Laboratory signs of liver damage: alanine and aspartate aminotransferase levels are 2-fold higher than the upper limit of the normal range.

Eight patients were excluded from the study due to exclusion criteria. Ultimately, 90 patients were prospectively observed. From that group, 81 patients completed observation and were evaluated for presence of chronic complications. During the prospective observation, loss to follow-up was the same for remitters (4 patients) and non-remitters (5 patients). 3.2. Study design The first stage of the study encompassed the hospitalization at the time of diagnosis. During this stage we assessed the following: anthropometric factors, 7-point glycemic profile, HbA1c, serum C-peptide concentration, lipid profile, parameters of acid-base homeostasis, inflammatory markers, thyroid-stimulating hormone (TSH), complete blood count, urinalysis and presence of ICA, GADA and IA-2A autoantibodies. During hospitalization at diagnosis of diabetes, all patients undertook a 5-day instruction course in intensive functional insulin therapy, conducted according to WHO criteria. In the course of hospitalization, patients learned about principles of self-monitoring and adjusting doses of short acting insulin or rapid acting insulin analogue, which are administered before meals depending on the level of blood glucose, amount of ingested carbohydrates or planned physical activity. Presence of remission was determined at 3 months following diagnosis. According to presence of remission in the third month after diagnosis of diabetes, patients were divided into two groups – those with partial remission (remitters) and without remission (non-remitters). The duration of remission was counted from the time of diagnosis. The end of remission was considered as the time-point half way between a visit when the patient met the criteria for remission and the next visit when a patient no longer met such criteria. If remission was observed later than after 3 months of observation, the patient was not shifted to another group. Remitters and non-remitters were followed-up in regular three-month visits. During follow-up we regularly checked: HbA1c level, C-peptide, daily insulin dose, body mass index and blood pressure. Nine patients were excluded during prospective observation (5 patients changed their place of living and 4 withdrew their consent to participate in the study). After a period of no less than 5 years, during hospitalization, we checked the presence of chronic microangiopathic complications of diabetes. During this stage we assessed the following: anthropometric factors, 7-point glycemic profile, HbA1c, serum C-peptide concentration, daily dose of insulin, lipid profile, blood pressure and inflammatory markers. The study design is shown in Fig. 1. 3.3. Definition of partial remission Partial remission of type 1 diabetes was defined as all three of the following: (1) dose of exogenous insulin less than or equal to 0.3 U/kg/ 24 h, (2) HbA1c value below 6.5% (48 mmol/mol) and (3) a random serum C-peptide concentration above0.5 ng/ml. 3.4. Laboratory tests The same assays have been used for laboratory assessments at different points of the study. Venous plasma glucose was determined using enzymatic amperometric measurement (EBIO compact, Eppendorf). HbA1c was determined using high-performance liquid chromatography [normal reference range 4.1–6.4% (21–46 mmol/ml)]. Serum C-peptide concentration was determined using an enzyme immunoassay (IMMULITE, DPC, Los Angeles, CA, USA; normal range: 1.1–5.0 ng/ml). C-peptide stimulation test was performed 40 minutes after a standard mixed meal (50 grams of carbohydrates). High sensitivity C-reactive protein (hs-CRP) was measured by the turbidimetric immunoassay method (Roche/Hitachi, Cobas, normal range below 5.0 mg/L). Serum cholesterol, LDL-cholesterol, HDL-cholesterol and

P. Niedzwiecki et al. / Journal of Diabetes and Its Complications 29 (2015) 1105–1111 98 patients hospitalized with newly diagnosed type 1 diabetes

Excluded from the study due to exclusion criteria (N=8) 3 months following diagnosis presence of remission was determined

Follow-up with regular visits in Outpatient Diabetology Clinic

Loosed during follow-up (N=9)

Non-Remitters (N=28)

Remitters (N=53)

Analysis of presence of microangiopathy

Fig. 1. Study design.

triglycerides were measured after an overnight fast using the enzymatic method (BioMerieux, Lyon, France). Post prandial glycemia was calculated as mean glycemia 2 hours after breakfast on 5 consecutive days. Islet cell antibodies were detected using indirect immunofluorescence tests on cryostat sections of human pancreas of the donor with blood group O. Antibody titers were determined by sera dilution and expressed as Juvenile Diabetes Foundation (JDF) units based on a reference sample of 80 JDF collected as a gift from the laboratory at Saint Vincent de Paul Hospital in Paris, France. Positivity was defined as N 5 JDF units. Autoantibodies against glutamic acid decarboxylase (GADA) and antibodies to insulinoma antigen-2 (IA-2A) were measured by commercial enzyme-linked immunosorbent assay kits, anti-GAD assay (IgG) (positivity: N10 U⁄ml) and Anti-IA-2A Assay (IgG) (positivity: N20 U⁄ml), respectively (EUROIMMUN GmbH, Lubeck, Germany). Autoantibody analysis was performed in the Immunopathology Laboratory at the Department of Pediatrics, Medical University of Lodz, Poland, which is a reference laboratory for the measurement of islet antibodies.

3.5. Definition of endpoints 3.5.1. Diagnosis of retinopathy Eye fundus examination by a specialist was done [dilated pupil, photographic documentation – pictures of both eyes taken with a 450-pixel digital camera, 9 pictures of each eye (optic disc + 2 pictures of each quadrant of a retina)]. Diabetic retinopathy was diagnosed if at least one microaneurysm was present in both eyes. A diabetic retinopathy classification according to the American Academy of Ophthalmology was applied: nonproliferative diabetic retinopathy, pre-proliferative retinopathy and more advanced stages – proliferative diabetic retinopathy and diabetic maculopathy (American Academy of Ophthalmology, 2003).

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3.5.2. Diagnosis of diabetic nephropathy Assessment of the renal function (serum creatinine concentration, glomerular filtration rate [GFR] calculation using Modification of Diet in Renal Disease [MDRD] formula (Levey et al., 2007), assessment of urinary albumin). Diabetic nephropathy was defined as albuminuria or overt proteinuria. Albuminuria was defined (according to the guidelines of the Polish Diabetes Association) as: (1) excretion of 20–200 μg albumin/min in 24-hour urine collection and (2) abnormal albumin/creatinine ratio (30– 299 μg albumin/mg of creatinine in a random urine sample). Albuminuria was diagnosed when two out of three tests performed within 3 months were positive. Advancement of diabetic nephropathy was determined based on the GFR value according to the National Kidney Foundation Disease Outcomes Quality Initiative classification (KDOQI, 2007). 3.5.3. Diagnosis of diabetic neuropathy a) Evaluation of peripheral neuropathy: assessment of touch sensation using a 10-g Semmes-Weinstein monofilament, vibratory sensation using a 128-Hz tuning fork and a neurothesiometer (Horwell Neurothesiometer), temperature sensation using a cylinder with a metal and plastic tip (Tip-Therm) and ankle reflex assessment. Diabetic peripheral neuropathy was diagnosed based on the presence of two or more of four components: symptoms of neuropathy, absence of the ankle reflex, disruption of touch and/or vibratory and/or temperature sensation. b) Evaluation of autonomic neuropathy of the cardiovascular system was performed based on medical history, physical examination and additional tests: - heart rate variability tests (assessment at rest, deep breathing test, Valsalva maneuver, orthostatic test) using ProSciCard III® apparatus (CPS GmbH) - assessment of a systolic or diastolic blood pressure change in an orthostatic test. Diagnosis of diabetic autonomic neuropathy was defined based on the presence of three of five above-mentioned components and based on typical features in medical history: gastroparesis, diarrhea or constipation, erectile dysfunction, neuropathic bladder, thermoregulatory dysfunction, and sweating dysfunction. 3.6. Statistical analysis Statistical analysis of results was performed using Statistica PL v. 8.0 software. Normal distribution of results was tested using Kolmogorov– Smirnov test with Lilliefors correction. Analyzed parameters did not have normal distributions; therefore, non-parametric tests were used for further analyses. Results are presented as numbers and percentages as well as medians and interquartile ranges (IQR). In case of numerical variables, differences between subgroups were analyzed using Mann– Whitney test. Differences with regard to qualitative data were assessed with a Chi2 test (Mendenhall, Beaver, & Beaver, 2003). Fisher test was used for analysis of groups of small size in a nominal scale. To assess the influence of remission and selected parameters for diagnosis of diabetes on development of chronic complications, we applied a Cox's multivariate regression model (Collet, 2003; Cox, 1972). We used stepwise multiple regression for selection parameters for the Cox regression. In the analysis we considered parameters at diagnosis: body mass index, glucose level, triglycerides level and total cholesterol level, dose of insulin and C-peptide level, presence of DKA, smoking before diagnosis of diabetes, absence of remission in the third month after diagnosis, mean HbA1c from follow-up. In a stepwise regression model we received 4 important factors: presence of DKA, HbA1c level, smoking and absence of remission. We used a univariate regression method to analyze the correlation between selected parameters and occurrence of chronic complications. p b 0.05 was considered statistically significant. All patients participating in the study were informed of its aim and gave their written consent. The work schedule was presented to and

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Table 1 Clinical characteristics of the study group at diagnosis of diabetes and at the end of follow-up. Rated variables

Characteristics of the study group at the diagnosis of diabetes

Characteristics of the study group during the evaluation of microangiopathy

p

N Age [years] Duration of diabetes [years] Smoking [n] (%) Duration of remission [days] Body weight [kg] BMI [kg/m2] SBP [mmHg] DBP [mmHg] Daily insulin dose [U/kg body weight/day] HbA1c [%] HbA1c [mmol/mol] HbA1c-median from observation period [%] HbA1c-median from observation period [mmol/mol] FPG [mmol/l] PPG [mmol/l] Fasting C-peptide [ng/ml] hsCRP [mg/l] TCH [mmol/l] TG [mmol/l] LDL cholesterol [mmol/l] HDL cholesterol [mmol/l] GFR (MDRD) [ml/min/1.73 m2]

90 26 (22–31) 0 26 (28.9) – 67.5 (58.7–75.6) 21.5 (19.8–23.5) 120 (110–120) 80 (70–80) 0.2 (0.1–0.3) 10.6 (9.7–12.0) 92 (83–108) – – 7.0 (6.1–8.8) 9.3 (7.8–12.0) 0.79 (0.54–1.15) 1.2 (0.4–2.4) 4.5 (4.1–5.2) 1.2 (0.8–1.7) 3.1 (2.4–3.5) 1.1 (0.9–1.3) 107 (94–136)

81 33 (29–38) 7 (6–8) 26 (32) 286 (0–502) 78 (67.0–88.5) 25 (22–27) 125 (115–135) 80 (70–85) 0.4 (0.3–0.6) 7.0 (6.3–7.9) 53 (45 – 63) 6.9 (6.6–8.2) 52 (49–66) 8.3 (6.2–10.0) 9.1 (8.0–10.2) 0.03 (0–0.4) 0.8 (0.4–1.8) 4.8 (4.2–5.6) 0.8 (0.6–1.1) 2.9 (2.5–3.5) 1.7 (1.4–2.6) 100 (90–111)

– b0.0001 – 0.78 – b0.0001 b0.0001 0.09 0.87 b0.0001 b0.0001 – – 0.02 0.11 b0.0001 0.28 0.003 b0.0001 0.85 b0.0001 b0.0001

Mann–Whitney and Chi2 test. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HbA1c: glycated haemoglobin; FPG: fasting glycaemia; PPG: 2-hour postprandial glycaemia; hsCRP: high-sensitive C-reactive protein; TCH: total cholesterol; TG: triglycerides; LDL: low density lipoproteins; HDL-high density lipoproteins; GFR: glomerular filtration rate estimated using Modification of Diet in Renal Disease (MDRD) study equation. Median (IQR), n (%).

approved by the Bioethical Committee of the Poznan University of Medical Sciences (no. 498/12). 4. Results Statistical analysis was performed on a group of 81 patients, including 24 women and 57 men, with median age of 33 (IQR 29–38) years and mean diabetes duration of 7 (IQR 6–8) years (which was equal to follow-up time). Remission was noted in 53 patients (66% of the study group), of which7 patients (9%) fulfilled the criteria for remission during hospitalization when assessing chronic complications of diabetes. Remission was not observed in 28 patients (35% of the study group). Clinical characteristics of the study group at the diagnosis and during the evaluation of chronic complications are shown in Table 1. In the studied group of patients with type 1 diabetes, diabetic retinopathy was diagnosed in 15 subjects (18.5%), and it was nonproliferative retinopathy in all cases. One patient was diagnosed with diabetic nephropathy (1.2%), and 7 patients (8.6%) were diagnosed with diabetic neuropathy. Microangiopathy defined as presence of at least one of the above complications was diagnosed in 17 patients (21%). In the group where remission had not occurred we noted a greater prevalence of microangiopathic complications (46.4% vs. 7.6%; p = 0.00009), more frequent occurrence of retinopathy (42.8% vs. 5.7%; p = 0.00004) and neuropathy (21.4% vs. 1.9%; p = 0.006). Only one patient diagnosed with diabetic nephropathy belonged to the group with a history of remission, although it was relatively short lasting (230 days) (Fig. 2). In univariate logistic regression, a significant association was found between absence of remission and occurrence of at least one microvascular complication (OR: 10.6, 95% CI: 2.94–38.22, p = 0.002). We did not observe any association of C-peptide at diagnosis and C-peptide during observation with development of chronic complications (OR: 1.17 CI: 0.30–4.45; p = 0.80 and OR: 1.42 CI: 0.53–3.82, p = 0.47, respectively). A Cox proportional hazard regression model, which took into consideration clinically important parameters assessed at the time of

diagnosis (presence of ketoacidosis, HbA1c, smoking at diagnosis) as well as occurrence and duration of remission, showed a significant correlation between absence of remission and development of chronic complications of diabetes [HR: 3.65 (95% CI 1.23–4.56); p = 0.04] (Fig. 3). Duration of remission in the Cox regression model had no influence on microangiopathy [HR: 0.99 (95% CI 0.10–1.31); p = 0.68] (Fig. 4). Comparison of remitters and non-remitters revealed significant changes in the daily dose of insulin [0.3 (0.3–0.4) vs. 0.6 (0.4–0.7) U/kg; p b 0.0001], median HbA1c from observation [6.6 (6.2–7.2) vs. 7.7 (7.1– 9.3)%; p = 0.005], fasting plasma glucose [139 (111–163) vs. 180 (133– 204) mg/dl; p = 0.009], fasting C-peptide level [0.04 (0–0.4) vs. 0 (0–0.1) ng/ml; p = 0.01], C-peptide after stimulation [0.13 (0.02–0.86) vs. 0.02 (0–0.2) ng/ml; p = 0.02], triglycerides [0.8 (0.6–1.0) vs. 1.0 (0.7–1.3) mmol/l; p = 0.02] and smoking[50% vs. 22%; p = 0.006]. Comparison of remitters and non-remitters is shown in Table 2.

5. Discussion Presence of clinical remission in type 1 diabetes has several health benefits. According to the results of the study, the remission period could decrease the risk of microangiopathy. Remission is connected with better good metabolic control parameters such as HbA1c, FPG and triglycerides levels and a low daily insulin requirement. It is difficult to determine precisely the frequency of remission in various populations as different criteria are applied. In many publications, criteria include insulin demand below 0.5 unit per kg body weight and HbA1c level (depending on a study) between 6.0 and 7.5% (42–58 mmol/mol) (Abdul-Rasoul et al., 2006; Chase et al., 2004; Couper et al., 1991; Muhammad, Swift, Raymond, & Botha, 1999). In the study of Scholin et al., in which remission criteria were a daily insulin requirement below 0.4 U/kg body weight/day and HbA1c level below 6.5% (48 mmol/mol), the frequency of remission was 61% (Scholin et al., 1999). In our own studies on a comparable age group, remission was identified in 66% of patients with newly diagnosed type 1 diabetes.

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Fig. 2. Comparison of occurrence of diabetes microangiopathic complications in the group with and without remission (%).

At the time of assessment of chronic complications performed after 7 years of disease duration on average, 10% of patients still fulfilled the criteria for remission, which is rarely observed in other publications (Dinccag, Satman, Ozer, Karsidag, & Yilmaz, 1998; Martin et al., 1992). The literature refers to remission as long lasting when it persists for over one year. In 2006 studies by Abdul-Rasoul, remission lasted for over one year in 10% of patients only (Abdul-Rasoul et al., 2006). In our study, a long remission period (above one year) was observed as frequently as in every third patient. Occurrence of chronic complications in our study is comparable with that reported in other publications with a similar follow-up time, for the whole study population (Donaghue et al., 2005). While analyzing the prevalence of chronic complications and remission period, a question arises regarding the proportion of patients with remission who developed complications. In our study, microangiopathic complications were 6 times more common in the group without remission, with a higher prevalence of retinopathy and neuropathy. There are currently no data in the literature to compare more frequent occurrence of complications in a group without remission. It is interesting to note that in a group with a remission period, presence of microangiopathy was lower than in non-remitters. In univariate regression analysis, absence of the remission period was associated with a 10-fold higher risk of microangiopathy. A Cox proportional hazard regression model showed a significant influence

of the lack of remission on the development of chronic complications of diabetes. Absence of remission increases the risk of microangiopathy after 7 years of disease duration over 3-fold. No significant influence of remission duration on development of chronic complications of the disease was demonstrated. It may be related to a small number of patients with remission and microangiopathy (4 cases only). Probably a long duration of remission will prevent microangiopathy. A small sample size hinders reliable assessment. Further observation of our study group is needed to establish the association between the duration of remission and the development of chronic complications. There are no data addressing the relationship between the remission period and chronic complications of type 1 diabetes, to which we could relate our observations, we analyzed publications on the influence of residual insulin secretion on the development of chronic complications. Sberna et al. did not confirm the relationship between fasting and stimulated C-peptide and retinopathy (Sberna et al., 1986). However, after publishing the results of the DCCT, it was suggested that retinopathy and nephropathy are less frequently observed in a group of patients with residual insulin secretion (Steffes et al., 2003). Subhan et al. analyzed C-peptide level and presence of complications after about 8 years of diabetes duration. He reported significantly lower C-peptide levels in a group that developed microangiopathy (Subhan et al., 2007). C-peptide may be considered not only as an indicator of preserved residual insulin secretion, but also as a metabolically active molecule.

Microangiopathy complications Microangiopathy complications

p=0.04 p=0.68

hazard ratio hazard ratio Fig. 3. The risk of development of microangiopathy in adult patients with type 1 diabetes associated with absence of remission, smoking, ketoacidosis at diagnosis of diabetes and HbA1c level on development of microangiopathy in adult patients with type 1 diabetes [Cox proportional hazards regression].

Fig. 4. The risk of microangiopathy in adult patients with type 1 diabetes associated with duration of remission, smoking, ketoacidosis at diagnosis of diabetes and HbA1c level [Cox proportional hazards regression].

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Table 2 Comparison of remitters and non-remitters. Rated variables

Remitters

Non-remitters

p

N Males/Females [n] (%) Age [years] Duration of diabetes [years] Smoking [n] (%) Body weight [kg] BMI [kg/m2] SBP [mmHg] DBP [mmHg] Daily dose of insulin (U/kg) HbA1c-median from observation period [%] HbA1c-median from observation period [mmol/mol] FPG [mmol/l] PPG [mmol/l] Fasting C-peptide [ng/ml] C-peptide after stimulation [ng/ml] WBC [103/μl] hsCRP [mg/l] TCH [mmol/l] TG [mmol/l] LDL cholesterol [mmol/l] HDL cholesterol [mmol/l] GFR (MDRD) [ml/min/1.73 m2]

53 38 (72)/15 (28) 33.3 (30.4–38.7) 7.1 (6.5–7.6) 12 (22) 80 (67–91) 24.7 (22.3–27.5) 125 (117–135) 79 (70–85) 0.3 (0.3–0.4) 6.8 (6.5–7.6) 51 (48–60) 7.7 (6.1–9.1) 8.7 (7.9–9.7) 0.04 (0–0.4) 0.13 (0.02–0.86) 5.8 (5.2–6.7) 0.9 (0.4–1.8) 4.9 (4.2–5.5) 0.8 (0.6–1.0) 2.9 (2.4–3.3) 1.7 (1.4–1.9) 98 (88–110)

28 9 (32)/19 (68) 34.1 (28.4–37.3) 7.4 (7.0–8.3) 14 (50) 73.7 (63.5–85.2) 24.8 (21.6–27.0) 126 (112–136) 80 (73–85) 0.6 (0.4–0.7) 9.4 (8.4–9.9) 79 (68–85) 10 (7.4–11.3) 9.4 (8.1–11.2) 0. (0–0.1) 0.02 (0–0.2) 5.9 (5.3–7.3) 0.8 (0.3–1.7) 4.8 (4.6–5.8) 1.0 (0.7–1.3) 3.0 (2.5–3.6) 1.7 (1.2–2.0) 95 (85–123)

– 0.71 0.78 0.06 0.006 0.22 0.58 0.82 0.25 b0.0001 0.005 0.005 0.009 0.18 0.01 0.02 0.38 0.73 0.34 0.02 0.40 0.65 0.10

Mann–Whitney and Chi2 test. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HbA1c: glycated haemoglobin; FPG: fasting glycaemia; PPG: 2-hour postprandial glycaemia; WBC-white blood count; hsCRP: high-sensitive C-reactive protein; TCH: total cholesterol; TG: triglycerides; LDL: low density lipoproteins; HDL-high density lipoproteins; GFR: glomerular filtration rate estimated using Modification of Diet in Renal Disease (MDRD) study equation. Parameters analyzed at endpoint analysis. Median (IQR), n (%).

A study by Frost et al. demonstrated a beneficial effect of C-peptide on vascular endothelium and, indirectly, on microangiopathic complications (Forst et al., 2000). Chakrabarti et al. emphasized the value of C-peptide in the prevention of diabetic retinopathy (Chakrabarti, Khan, Cukiernik, Zhang, & Sima, 2004). C-peptide seems to influence retinal circulation and decrease the risk of proliferative retinopathy, which indirectly explains the differences in prevalence of proliferative retinopathy between type 1 and type 2 diabetes (Keen et al., 2001). Use of exogenous C-peptide molecule is even considered in a group of patients devoid of residual insulin secretion for prevention of microangiopathic complications. The DCCT (Diabetes Control and Complications Trial) clearly indicated the predominant role of hyperglycemia in the development and progression of complications of type 1 diabetes (The DCCT Research Group, 1995). Moreover, it showed that the average HbA1c from the time of observation, combined with HbA1c variation, have a stronger association with the occurrence of retinopathy and CChN than a single HbA1c measurement (Kilpatrick, Rigby, & Atkin, 2008). In the study group, significantly lower median glycated hemoglobin in the observation period was reported in patients who had experienced a remission period. Fasting glucose levels were also lower in this subgroup. Chronic hyperglycemia is a well-known determinant of the onset and progression of microvascular complications (Kilpatrick et al., 2008). Also acute hyperglycemic states may accelerate development of chronic complications (Chiarelli & Marcovecchio, 2013; Marcovecchio, Lucantoni, & Chiarell, 2011). One of the explanations of these is the “hyperglycemic memory” phenomenon (Ceriello, 2008; Genuth, 2006). Intensive glucose control from the time of diagnosis and prompt initiation of optimal treatment, in order to achieve therapeutic purposes, seems to be an effective measure to decrease the risk of chronic complications of diabetes.Our study did not compare the results of intensive insulin therapy with other methods because the superiority of intensive treatment in reduction of the microangiopathy risk has already been proven in other cohorts. For instance, the EDIC study (Epidemiology of Diabetes Interventions and Complications) showed that after 15 years of diabetes, despite similar

HbA1c values, the group previously treated in the intensive arm still had a lower risk of development and progression of chronic complications (Albers et al., 2010). In the group in which the remission had not occurred, we noted a higher daily dose of insulin in each stage of the observation. The association between the insulin dose at diagnosis of diabetes, and the occurrence of remission was described in previous studies (Piłaciński, Zozulińska, Uruska, Sporna, Uruski, 2007; Scholin et al., 2004). Despite the end of remission, the majority of patients who experienced it still demonstrate a lower exogenous insulin requirement. Another important risk factor for the development of microvascular and macrovascular disease is cigarette smoking. Cigarette smoking is associated with worse glycemic control, more frequent episodes of hypoglycemia, an increased risk of ketoacidosis, and the increased frequency of development of microvascular complications, compared with people who do not smoke (Chaturvedi, Stephenson, & Fuller, 1995; Haroun et al., 2003; Moy et al., 1990). In our study, remitters were less often smokers than non-remitters. We may conclude that many factors influence the course of diabetes and development of its chronic complications. Occurrence of remission is a clinically significant state that may be associated with a reduced risk of microangiopathy, the finding that has not been reported before. The main limiting factor in this study is a relatively small cohort analyzed and a small number of patients with history of remission who developed microangiopathy. Another limiting factor in this study is a relatively short follow-up. For the assessment of chronic complications in type 1 diabetes, a prolonged observation time seems to be necessary and will be implemented. 6. Conclusions It is possible to achieve partial disease remission in as much as 70% of young adults with newly diagnosed type 1 diabetes. In a patient with newly diagnosed type 1 diabetes, occurrence of partial remission is associated with a decreased risk of microangiopathic complications at 7 years.

P. Niedzwiecki et al. / Journal of Diabetes and Its Complications 29 (2015) 1105–1111

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