Double-diabetes in a real-world sample of 2711 individuals: associated with insulin treatment or part of the heterogeneity of type 1 diabetes?

This post was originally published on this site

In this paper, we have studied a large sample of individuals with type 1 diabetes. About one third of this real-world sample was overweight/obese. Diabetes duration and intensity of insulin treatment were not related to weight excess. Insulin dose was inversely related to BMI status.

In univariate analysis, individuals with less than 5 years of diabetes duration were more obese, younger, and had lower HDL when compared to individuals with more than 5 years of diabetes duration. This finding could possibly be related to higher beta-cell residual function, since 5 years of diabetes duration could be regarded as a maximum time limit for its presence in type 1 diabetes [15]. Although the findings of obesity and lower HDL could be related to genetic predisposition for IR, this group had a lower frequency of type 2 diabetes in family history. This finding is compatible with the lower age range in this group, since there might be not enough time for older generations in the families to manifest type 2 diabetes.

In the group with higher diabetes duration, obese individuals had lower insulin doses per body weight. Nephropathy could influence insulin doses by decreasing its renal excretion. On the other hand, IR wouldn’t be higher in lean individuals (who had higher insulin doses) and our composite endpoint of nephropathy comprehends many individuals with mild or no renal disfunction. This lower insulin dose can be explained also by clinical inertia or fear of hypoglycaemia by both attending physicians and patients, since in this group HbA1c levels are far from recommended goals, although heterogeneity in the progression of beta-cell failure cannot be excluded given the findings of multivariable analysis. Longitudinal studies have previously demonstrated that C-peptide levels are higher at onset of type 1 diabetes in individuals with higher weight, although in a short term follow up of recently diagnosed patients [16].

Overweight and obesity were present in 31 % of our sample. Data about overweight and type 1 diabetes are very heterogeneous in literature, partly owing to different clinical criteria by which this clinical outcome is assessed. In a sample from Colorado, 16 % of youths with type 1 diabetes had BMIs above the 85th percentile for age (i.e., equivalent to both overweight and obese groups in our sample) upon diagnosis [17]. In 115 Spanish individuals with type 1 diabetes on intensive therapy, with a mean age of 12 years old and a mean diabetes duration of 5 years, about 30 % were overweight and 20 % were obese [18]. In a sample of American youths from 0 to 17 years old with diabetes, 16.3 % were obese and were classified as obese-indeterminate diabetes. They had significantly older age of onset and frequency of hypertension than type 1 diabetes [19].

Data for adults are not as widely available, and frequently analyzed jointly with data about children and adolescents. Both adolescents (mean age 15 years old) and adults (mean age 38 years old) gained weight after 1 year of follow up in the DCCT [20]. In the completed trial, after 6.5 years of follow up, there was approximately 13 % of adolescents in a sample with mean age around 27 years old [14]. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), in a group of patients diagnosed before age 30 and followed for 4 years, weight variation went from losing 0.6 to gaining 3.4 kg in different quartiles [13]. Besides age range, recruitment criteria highly influence these numbers. In DCCT, individuals with more than 130 % of ideal body weight were excluded, making obesity upon diagnosis virtually non-existent in this sample and consequently in all follow-up studies [6].

As expected, insulin doses were higher in the group with longer disease duration, a finding compatible with the natural history of progressive insulin deficiency. Nevertheless, they were lower in obese than in normal weight individuals. Age could be a source of bias, since groups divided by diabetes duration had different ages and therefore different ages at diagnosis. Age at diagnosis is known to influence progression of beta-cell failure [21], with individuals diagnosed after 18 years old having higher baseline residual beta-cell function and less pronounced decay after several years of follow-up, when compared to individuals diagnosed in childhood. Since multivariable models have been corrected for body surface and age, this source of bias can be circumvented. Moreover, body surface was not significantly associated with insulin dose. Data from a Spanish group of individuals with type 1 diabetes and aged on average 17 years old showed that insulin dose per body surface but not with dose per kg of body weight was higher in individuals with metabolic syndrome. No combined analysis of both parameters has been performed, though. Insulin dose was moderately correlated with HbA1c and BMI [22]. In the initial pilot of the DCCT, insulin dose per body weight was higher in adolescents (0.94 U/kg) than in adults (0.65 U/kg), suggesting puberty-associated IR or clinical heterogeneity of late-onset type 1 diabetes rather than progression of beta-cell failure as an explanation for this variability [6]. Another possible hypothesis is that obesity could have different effects on insulin sensitivity in type 1 and type 2 diabetes.

Interestingly, intensity of insulin treatment, as measured by total number of insulin applications, showed no difference either among different BMI strata or diabetes duration subgroups. In spite of our cross-sectional design, this finding strongly suggests weight excess to be unrelated to intensity of insulin treatment. Moreover, owing to marked social and economic differences observed in our country which have been previously described [23], this sample has a particularly high number of individuals on conventional therapy (i.e., one or two insulin injections per day). This feature is especially suitable to assess the role of intense insulin therapy in this sample.

HbA1c didn’t show a clear trend of association with diabetes duration. This could be due to clinical heterogeneity or limitations of the cross-sectional design, since HbA1c is highly variable during follow-up, thus a single value could be misleading in this setting. The large variability in HbA1c levels could also be explained by factors related to residual pancreatic function and glucose/lipotoxicity, which were not directly evaluated in this study. There was a significant interaction between diabetes duration and familial history of type 2 diabetes, though, which could be related to clinical heterogeneity, partly explaining the irregular pattern of association between HbA1c and other variables. In literature, HbA1c was not correlated with BMI status in children and adolescents [18]. It showed no solid correlation with coronary artery disease (CAD), either [24].

Non-HDL-cholesterol was associated with weight excess in the predicted way. Obese individuals had higher non-HDL cholesterol than lean patients. Besides, interaction between gender and familial history of type 2 diabetes suggests this relationship is probably due to hereditary traits related to IR. Weight gain has been hypothesised to trigger genetic factors related to IR [25]. In this aspect, our sample is different from literature in exhibiting worse HDL in obese individuals. In the DCCT, all metabolic parameters worsened following weight gain, except for HDL, which remained stable [4]. This difference could point to a contribution of individuals obese upon diagnosis for our results, since these have not been excluded from our series. Interestingly, there was no difference in obesity, lipids, and familial history of type 2 diabetes in a substudy of DCCT/EDIC, when comparing individuals with negative and positive islet antibodies [25]. Other studies have also assessed the difficulty of utilising traditional clinical criteria to differentiate between type 2 diabetes and obese type 1 diabetes, with diabetic ketoacidosis being seen in 62 % of type 1 diabetes and 40 % of type 2. Despite the significant statistical difference, accuracy is extremely low [19].

Obese Spanish children and adolescents with type 1 diabetes had lower HDL and higher LDL than lean ones [18]. When assessing association of dyslipidaemia and CAD, individuals with type 1 diabetes and CAD had lower HDL and higher total cholesterol-to-HDL ratio than those without CAD [24]. Type 1 diabetes is classically associated with high HDL levels [2]. Nevertheless, obesity apparently is able to diminish this advantage [5]. Regarding risk of cardiovascular end points, the number of recorded CV events is too small to reach any valid conclusions in our sample. Besides, this analysis is beyond the scope of this study.

Blood pressure did not show a significant correlation with BMI in our sample. Hypertension has been previously shown to be more frequent in youths with type 2 and obese with indeterminate diabetes type than in type 1 diabetes [19]. Blood pressure is higher in individuals with type 1 diabetes with nephropathy or CAD than on complication-free subjects [24]. The presence of individuals in all age ranges with a low frequency of CAD and clinical nephropathy in our sample could be a possible explanation for these differences.

Given the study design, data must be further investigate in a prospective manner in order to confirm causal relationship among studied variables. External validity of the data must also be confirmed by studies from other populations, particularly in the adult age range, for which medical literature is still incipient in double diabetes.

Some limitations of the study should be addressed. The most important is the cross-sectional design. No causal relationship can be established with our data. Nevertheless, we feel the large sample and the fact patients have been unselected regarding BMI at diagnosis give a more realistic perspective of double diabetes in the heterogeneous scenario of type 1 diabetes. Another limitation is the absence of pancreatic autoantibodies in the diagnosis of type 1 diabetes. Although they at first could potentially contribute to differential diagnosis between type 1 diabetes and other subtypes of diabetes, there was no difference between lean and obese subjects regarding islet antibodies in the DCCT-EDIC [25]. Besides, even utilising this diagnostic tool, differential diagnosis can be difficult in a significant proportion of patients, as demonstrated in Finnish individuals [9, 10]. Moreover, although we hypothesised that clinical variability of residual beta-cell function as an explanation for the lower insulin dose in obese than in lean individuals, no direct measurements of C-peptide or other pancreatic function estimate were available in our sample. There is some evidence in literature showing residual beta-cell function to be higher in DD than in classical type 1 diabetes, though [26]. Furthermore, as seen by HbA1c levels far from the recommended goals, we can infer insulin treatment was not fully optimised in this sample. Nevertheless, multivariable models have been corrected for HbA1c, potentially tapering down the effects of metabolic decompensation on our main finding.