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Metabolism www.metabolismjournal.com
Review
Type 1 diabetes, metabolic syndrome and cardiovascular risk Juan J. Chillarón⁎, Juana A. Flores Le-Roux, David Benaiges, Juan Pedro-Botet Department of Endocrinology and Nutrition, Hospital del Mar, Barcelona Institut Municipal d´Investigacions Mèdiques Departament de Medicina, Universitat Autònoma de Barcelona
A R T I C LE I N FO
AB S T R A C T
Article history:
Patients with type 1 diabetes mellitus (T1DM) traditionally had a low body mass index and
Received 22 July 2013
microangiopathic complications were common, while macroangiopathy and the metabolic
Accepted 16 October 2013
syndrome were exceptional. The Diabetes Control and Complications Trial, published in 1993, demonstrated that therapy aimed at maintaining HbA1c levels as close to normal as
Keywords:
feasible reduced the incidence of microangiopathy. Since then, the use of intensive insulin
Type 1 diabetes
therapy to optimize metabolic control became generalized. Improved glycemic control
Chronic complications
resulted in a lower incidence of microangiopathy; however, its side effects included a higher
Metabolic syndrome
rate of severe hypoglycemia and increased weight gain. Approximately 50% of patients with
Cardiovascular risk
T1DM are currently obese or overweight, and between 8% and 40% meet the metabolic syndrome criteria. The components of the metabolic syndrome and insulin resistance have been linked to chronic T1DM complications, and cardiovascular disease is now the leading cause of death in these patients. Therefore, new therapeutic strategies are required in T1DM subjects, not only to intensively lower glycemia, but to control all associated metabolic syndrome traits. © 2014 Elsevier Inc. All rights reserved.
1.
Introduction
Traditionally, patients with type 1 diabetes mellitus (T1DM) suffered microangiopathic complications, especially nephropathy, which had a negative impact on prognosis and quality of life [1]. In 1993, the Diabetes Control and Complications Trial (DCCT) demonstrated that intensive glucose lowering therapy could reduce by 50% the incidence of microangiopathy [2]. The Epidemiology of Diabetes Interventions and Complications trial (EDIC), an extension study of the DCCT, with a mean
follow-up of 17 years, revealed a 57% reduction in the relative risk of non-fatal myocardial infarction, stroke or cardiovascular death in the group that had initially received intensive insulin therapy [3]. Ever since, most therapeutic efforts in T1DM have focused on reducing glycated hemoglobin levels. However, a growing body of evidence underlines the frequent coexistence of metabolic syndrome components in patients with T1DM [4–7], resulting in the so-called "double diabetes" [8] (Fig. 1). This fact, together with the decline in the incidence of microangiopathy, has led to cardiovascular disease now
Abbreviations: ADA, American Diabetes Association; Apo, apolipoprotein; DCCT, Diabetes Control and Complications Trial; EASD, European Association for the Study of Diabetes; EDIC, Epidemiology of Diabetes Interventions and Complications trial; eGDR, estimated glucose disposal rate; HDL, high-density lipoproteins; HOMA-IR, homeostasis model assessment-insulin resistance; LDL, low-density lipoproteins; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. ⁎ Corresponding author. Department of Endocrinology and Nutrition Hospital del Mar Passeig Marítim, 25–29 E-08003 Barcelona, Spain. Tel.: + 34 932483902; fax: + 34 932483337. E-mail address: [email protected] (J.J. Chillarón). 0026-0495/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2013.10.002
Hypertension Dyslipidemia Overweight/ Obesity
Type 2 Diabetes Insulin Resistance
Double Diabetes
Inmune destruction -cell
Type 1 Diabetes
Chronic complcations
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 3 ( 2 0 14 ) 18 1–1 87
HbA1c
182
Fig. 1 – Physiopathologic aspects of type 1 and type 2 diabetes.
being the leading cause of death in T1DM patients over 30 years of age [9]. Although acceptance of the metabolic syndrome has been controversial in certain scientific forums [10], several studies have shown the classic phenotype of the metabolic syndrome to be associated with increased mortality, nearly 10 times higher in those meeting all components [11]. The prevalence of the metabolic syndrome in the general population ranges from 20% to 50% [5,12] but it can reach almost 80% in type 2 diabetes patients (T2DM) [5]. In T1DM patients its prevalence varies between 8% and 40% depending on the study population and the diagnostic criteria (Table 1) [4–7,13–20]. Since all these aspects must be taken into account for therapeutic management, we considered it appropriate to review the main factors associated with the metabolic syndrome in T1DM patients and its relationship with the development of chronic complications and mortality.
glucose disposal rate (eGDR) [21], which is easily applicable and its correlation with the hyperinsulinemic euglycemic clamp is excellent. It should be emphasized that higher eGDR levels indicate greater insulin sensitivity and lower levels greater resistance. Several studies confirm the relationship between insulin resistance and the presence of chronic complications of diabetes, both type 1 and 2[22–28]. Insulin resistance, assessed by eGDR in T1DM patients has been linked to chronic complications, both micro and macrovascular, and increased mortality [6,7,23–28]. A study by our group showed that no patient with eGDR levels exceeding 8.16 mg kg−1 min− 1 had diabetes-related chronic complications. Additionally, an eGDR value less than 8.77 mg kg − 1 min− 1 showed 100% sensitivity and 85.2% specificity for the diagnosis of the metabolic syndrome.
3. 2.
T1DM and insulin resistance
The metabolic syndrome can be considered a surrogate marker for insulin resistance. Therefore, quantification of insulin resistance in this group of patients seems particularly relevant. The reference method for its calculation is the hyperinsulinemic euglycemic clamp; however, being too invasive, time-consuming and expensive, this technique is limited to research purposes. Thus, various formulas for insulin resistance calculation have been devised for its use at population level, with the homeostasis model assessmentinsulin resistance (HOMA-IR) being the most frequently used. However, since insulinemia is included in the formula, this index is not applicable in T1DM patients who receive insulin exogenously. In 2000, Williams et al. validated the estimated
Adiponectin and insulin resistance
Recent studies reported that adiponectin, a fat-derived protein, plays an important role in the regulation of insulin action, glucose and lipid metabolism. In this regard, plasma concentrations of adiponectin are reduced in human obesity and negatively correlated with insulin resistance [29]. Hypoadiponectinemia is independently associated with the metabolic syndrome and with T2DM prevalence and incidence [30]. Paradoxically, adiponectin levels are elevated in T1DM and associated with the presence of microalbuminuria and diabetic nephropathy in cross-sectional data. Furthermore, elevated adiponectin levels predict all-cause mortality and end-stage renal disease in those with diabetic nephropathy [31]. Since levels decrease after renal transplantation, this association may be due to impaired renal clearance of the protein [32]. On the other hand, it could represent a
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Table 1 – Prevalence of metabolic syndrome in patients with type 1 diabetes and risk of associated complications. Reference
n
Metabolic syndrome
Complications
Criteria
Prevalence Women 38% Men 40% Intensive group 45.4%
FinnDiane study [4]
2415
NCEP-ATP III
DCCT study [7]
1337
IDF
Control group 27.2% Reindel et al. [14]
1241
NCEP-ATP III
18.2%
Metascreen study [5]
638
NCEP-ATP III
Women 24.5% Men 43.2%
Pittsburg epidemiology of diabetes complications study [6]
514
IDF
8%
Chillarón et al. [13]
291
WHO NCEP-ATP III NCEP-ATP III
21% 12% 26.8%
Ferreira-Hermosillo et al. [15]
130
NCEP-ATP III
25%
127
IDF WHO NCEP-ATP III IDF WHO NCEP-ATP III NCEP-ATP III WHO
39.4% 44.9% 42.1% 32% 32% 26% 25% 45%
Davis et al. [17]
Santos et al. [18]
Báez et al. [19] Momesso et al. [20]
101
52 45
OR diabetic nephropathy: 3.75 (95% CI: 2.89–4.85) b HR retinopathy: 0.85 (95% CI: 0.61–1.18) HR nephropathy: 0.98 (95% CI: 0.71–1.35) HR macroangiopathy: 1.15 (95% CI: 0.69–1.92) OR PVD: 2.28 (95% CI: 1.38–3.76) b OR CVD: 2.19 (95% CI: 1.24–3.85) b OR nephropathy: 3.0 (p < 0.001) b OR neuropathy: 1.75 (p = 0.021) b OR CVD: 1.72 (ns, p = 0.09) OR main complications a: 2.0 (95% CI: 1.2–3.4) b OR main complications a: 6.5 (95% CI: 4.5–9.4) b OR main complications a: 5.8 (95% CI: 3.9–8.6) b Microangiopathy: 37.9% vs 4.8% (MS vs no MS) Macroangiopathy: 6.9% vs 0% (MS vs no MS) Retinopathy: 70% vs 29% (MS vs. no MS) All-cause mortality, prevalence MS: 62.1% 69.0% 55.2% Microalbuminuria: 50% vs 7.2% (MS vs no MS) Retinopathy: 56.2% vs 26.1% (MS vs no MS)
MS: metabolic syndrome; NCEP-ATPIII: National Cholesterol Education Program-Adult Treatment Panel III; IDF: International Diabetes Federation; WHO: World Health Organization; CVD: cardiovascular disease. a Coronary artery disease, renal failure or death-related diabetes. b Favors patients with metabolic syndrome.
compensatory mechanism to reduce oxidative status [33]. Regarding insulin sensitivity in T1DM, higher adiponectin concentrations are associated with a lower prevalence of the metabolic syndrome [34,35].
4.
T1DM and obesity
Obesity is currently considered to be the great epidemic of the century, with a prevalence increasing steadily worldwide over the past 20 years. Besides the known association between obesity and type 2 diabetes, a recent meta-analysis showed the presence of obesity in childhood to be a predictor of subsequent T1DM [36]. As mentioned previously, the DCCT study demonstrated the benefits of tight glycemic control in reducing the incidence of microangiopathy. However, this intensive approach also entailed certain side effects. First, the intensively treated group had a mean of 60 severe hypoglycemias per 100 patients and year to achieve a glycated hemoglobin of 7% [2]. Second,
weight gain in the intensive group was 14 kg on average during follow-up, which caused a 33% increase in the prevalence of overweight [2]. It is remarkable that in the preDCCT era, the body mass index of patients with T1DM was lower than in the general population [37,38]. However, nowadays the percentage of T1DM patients with overweight/ obesity is close to 50% [23], even in children [39,40]. Obesity in these patients has been associated with increased insulin requirements, poor metabolic control [41], greater atherosclerotic burden [42] and increased need for hospitalization due to heart failure [43]. Two meta-analyses on the effect of physical activity in T1DM patients showed very slight reductions in both glycated hemoglobin levels and body mass index [44,45].
5.
T1DM and atherogenic dyslipidemia
Atherogenic dyslipidemia, characterized by decreased concentrations of high-density lipoprotein (HDL) cholesterol,
184
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hypertriglyceridemia and increased levels of small and dense low-density lipoprotein (LDL) particles, is common in patients with coronary heart disease, metabolic syndrome and type 2 diabetes, and is largely responsible for residual macrovascular and microvascular risk [46,47]. One proposed mechanism contributing to low HDL cholesterol levels in diabetic dyslipidemia is reduced liver synthesis of apolipoprotein (apo) A-I [48]. In healthy individuals, insulin causes an increase in apo A-I gene expression, which is decreased in patients with insulin resistance. This would explain why patients with T2DM and those with T1DM and decreased insulin sensitivity maintain low HDL cholesterol levels compared to the general population, even in a normotriglyceridemic situation; however, no specific studies in this group of T1DM patients are available. In a study conducted by our group in a cohort of 291 patients with T1DM, hypoalphalipoproteinemia was present in 17.2% and its presence was associated with macroalbuminuria and polyneuropathy [16]. Other studies found poor metabolic control to be related with lower HDL cholesterol levels [49], which adversely influenced the incidence of micro and macrovascular complications. Conversely, patients with long standing T1DM and high levels of HDL are less likely to develop neuropathy [50]. As for hypertriglyceridemia, its prevalence in T1DM patients ranges from 13% to 31%, depending on the cutoff level used for its definition [16,51–53]. Furthermore, the risk of all microangiopathic complications is two- to three-fold greater for those with higher triglyceride levels [16,51]. It should be noted that although hypertriglyceridemia is the least common lipid abnormality in patients with T1DM, its presence is accompanied by a high rate of microangiopathic complications, even at young ages and without an excessively long diabetes duration [16]. This fact underlines the importance of lipid control and the need to implement therapeutic strategies aimed at correcting these abnormalities.
6.
T1DM and hypertension
Hypertension constitutes one of the most prevalent cardiovascular risk factors worldwide and particularly in patients with diabetes mellitus, both types 1 and 2 [54]. In the general population, an estimated rise of 20 mm Hg from 115 mm Hg in systolic blood pressure or 10 mm Hg over 75 mm Hg in diastolic blood pressure doubles the risk of cardiovascular events [54]. Strict blood pressure control significantly reduces morbidity and mortality in the general population and in patients with T2DM [53,55]. Although hypertension in T1DM patients is clearly associated with diabetic nephropathy, other factors, such as weight gain after insulin therapy [41] and the presence of insulin resistance, play a key role [56]. Studies assessing hypertension prevalence in T1DM show a wide disparity in the criteria used for diagnosis. In this respect, the prevalence varied between 11% and 59% [57–61]. According to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommendations [62,63], approximately 30% of T1DM patients were estimated to have hypertension
Intensive insulin treatment
CVD microangiopathy
severe hypoglycemia Weight MS Prevalence
Insulin dose
InsulinResistance
Fig. 2 – Effects of intensive insulin therapy. CVD: cardiovascular disease; MetS, metabolic syndrome.
[56]. Several studies reported that hypertensive patients with T1DM were older, had longer diabetes duration, lower insulin sensitivity and a higher prevalence of overweight, obesity, and chronic complications, mainly microangiopathy [56,58–60]. Again, the high prevalence of overweight/obesity in these patients and its relationship with both insulin resistance and the presence of cardiovascular risk factors traditionally associated with T2DM are noteworthy.
7.
Therapeutic strategies
Given this scientific evidence, therapeutic strategies aimed at improving insulin resistance in patients with T1DM are mandatory. Among non-pharmacologic strategies, those promoting a healthy lifestyle in order to reduce overweight and obesity must be emphasized, thereby avoiding the insulin resistance vicious circle (Fig. 2). In patients with T2DM, physical exercise improves glycated hemoglobin levels and body mass index regardless of diet and other components [64,65]. In T1DM patients, two metaanalyses assessing the effects of exercise indicated a slight improvement in glycated hemoglobin levels and body mass index [44,45]. Although no trials have assessed the impact of exercise on insulin sensitivity in patients with T1DM, the benefits of exercise on body weight and other risk factors should be stressed. Given the clinical benefits of metformin therapy in patients with T2DM through improved insulin sensitivity in muscle and liver, several clinical studies have been conducted in patients with T1DM to assess the effectiveness of this drug. A recent meta-analysis found metformin use in these patients to be associated with a reduction in insulin requirements of 5– 10 daily units and a non-significant improvement in glycated hemoglobin of 0.28%. A weight loss of 1.7–6 kg and a slight reduction in total and LDL cholesterol were also observed, although there are no long-term data to ascertain the
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influence of these changes on cardiovascular disease [66]. Vella et al. concluded that longer-term studies with a larger sample size are needed to justify metformin treatment in T1DM patients. Nevertheless, these trials did not select patients according to insulin sensitivity and, furthermore, most of the subjects included had poor metabolic control. Thiazolidinediones are another class of drugs that act as insulin sensitizers, of which only pioglitazone is currently available for clinical use. A 6-month trial on T2DM patients showed pioglitazone to be associated with a significant increase in adiponectin levels (+ 10.6 μg/mL) and a reduced hepatic and intramyocellular lipid content [67]. Few clinical trials on this topic have been carried out in patients with T1DM, and the results were controversial. Nevertheless, modest benefits were obtained in glycated hemoglobin (−0.22%) with a slight increase in body mass index (+ 0.3 kg/m2) and without changes in insulin requirements [68,69].
8.
Future research areas
Evidence suggests that common polymorphisms of the adiponectin gene are associated with microangiopathic complications in patients with T2DM [70]. However, few studies have been conducted in T1DM patients and the results were inconclusive [71]. Given the importance of the interaction of genetic and environmental factors in the clinical phenotype of the disease, better understanding of the genetic influence of adiponectin could explain the paradoxical results obtained in T1DM and T2DM. Little information is available on the potential effects of diet on insulin resistance and other metabolic parameters in patients with T1DM. In one small crossover study on the effects of a low-fat, isocaloric diet in 10 individuals with T1DM, a reduction in insulin resistance was found without improvement in glycemic control [72]. Thus, larger intervention trials on the effects of calorie-reduced diets must be conducted to further explore the benefits of a healthy diet in T1DM patients. As for pharmacologic strategies, the potential of metformin to attenuate insulin resistance in T1DM subjects should be further evaluated in specifically designed clinical trials. Moreover, recent studies suggest that the use of metformin might reduce the risk of cancer in patients with T2D [73]. This possible additional benefit of metformin use should be specifically tested in T1D. Multiple mechanisms can be responsible for insulin resistance in patients with T1DM. Improved understanding of the implicated pathophysiologic mechanisms could lead to the identification of potential molecular targets for the development of new therapeutic strategies aimed at reducing morbidity and mortality in these subjects.
9.
Conclusions
The presence of metabolic syndrome components in T1DM patients is frequent and is associated with an increased incidence of chronic complications and mortality. eGDR, a surrogate marker of the metabolic syndrome, is useful in T1DM patients as it correlates with the presence of compli-
185
Table 2 – Type 1 diabetes mellitus and metabolic syndrome: Key messages. The prevalence of the metabolic syndrome in T1DM is increasing in our societies. Metabolic syndrome components in T1DM patients: Overweight/obesity 50% Low HDL cholesterol levels 20% Hypertriglyceridemia 13%–30% Hypertension 11%–59% Each of the components of metabolic syndrome has been associated with the onset of chronic complications. Metabolic syndrome and insulin resistance in T1DM are related with all chronic complications and mortality. Treatment with metformin or pioglitazone in T1DM has shown a modest impact in some parameters of the metabolic syndrome. New trials specifically designed for T1DM patients with insulin resistance should assess further benefits of these interventions. Improved understanding of the pathophysiologic mechanisms of insulin-resistance could lead to the development of new therapeutic strategies. T1DM: type 1 diabetes mellitus; HDL: high-density lipoproteins.
cations and mortality. Thus, patients with T1DM and metabolic syndrome traits should be identified as early as possible and treated appropriately. In this respect, pharmacologic and non-pharmacologic strategies to improve insulin sensitivity must be considered in the clinical management of these patients (Table 2). Juan J. Chillarón and Juan Pedro-Botet performed a review of the literature and elaborated the draft of the manuscript. Juana A. Flores and David Benaiges contributed to the review of the literature. All authors read and approved the final manuscript.
Acknowledgments We thank Miss Christine O’Hara for review of the English version of the manuscript.
Conflict of interest The authors have nothing to disclose. REFERENCES
[1] Chillarón JJ, Goday A, Pedro-Botet J. Metabolic syndrome, type 1 diabetes mellitus and insulin resistance. Med Clin (Barc) 2008;130:466–71. [2] The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329: 977–86. [3] The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53. [4] Thorn LM, Forsblom C, Fagerudd J, et al. Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and
186
[5]
[6]
[7]
[8] [9]
[10] [11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 3 ( 2 0 14 ) 18 1–1 87
glycemic control (the FinnDiane study). Diabetes Care 2005;28:2019–24. The Metascreen Writing Committee. The metabolic syndrome is a risk indicator of microvascular and macrovascular complications in diabetes: results from Metascreen, a multicenter diabetes clinic-based survey. Diabetes Care 2006;29:2701–7. Pambianco G, Costacou T, Orchard TJ. The prediction of major outcomes of type 1 diabetes: a 12 year prospective evaluation of three separate definitions of the metabolic syndrome, and their components and estimated glucose disposal rate: the Pittsburg Epidemiology of Diabetes Complications Study experience. Diabetes Care 2007;30:1248–54. Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and complications risk in type 1 diabetes: “double diabetes” in the Diabetes Complications Trial. Diabetes Care 2007;30:707–12. Teupe B, Bergis K. Epidemiological evidence for “double diabetes”. Lancet 1991;337:361–2. Laing SP, Swerdlow AJ, Slater SD, et al. The British Diabetic Association Cohort Study II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabet Med 1999;16:466–71. Reaven GM. The metabolic syndrome: requiescat in pace. Clin Chem 2005;51:931–8. Mäkinen VP, Forsblom C, Thorn LM, et al. Metabolic phenotypes, vascular complications, and premature deaths in a population of 4,197 patients with type 1 diabetes. Diabetes 2008;57:2480–7. Park YW, Zhu S, Palaniappan L, et al. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 2003;163:427–36. Chillarón JJ, Flores-Le-Roux JA, Goday A, et al. Metabolic syndrome and type 1 diabetes mellitus: prevalence and associated factors. Rev Esp Cardiol 2010;63:423–9. Reindel J, Zander E, Heinke P, et al. The metabolic syndrome in patients with type 1 diabetes mellitus. Associations with cardiovascular risk factors and cardiovascular morbidity. Herz 2004;29:463–9. Ferreira-Hermosillo A, Vargas-Ortega G, González-Virla B, et al. Prevalence of metabolic syndrome (MS) in patients with type 1 diabetes (DM1). Gac Med Mex 2012;148:137–43. Chillarón JJ, Sales MP, Flores Le-Roux JA, et al. Atherogenic dyslipidemia in patients with type 1 diabetes mellitus. Med Clin (Barc) 2013. http://dx.doi.org/10.1016/j.medcli.2013.03.016. Davis TM, Bruce DG, Davis WA. Prevalence and prognostic implications of the metabolic syndrome in community-based patients with type 1 diabetes: the Fremantle Diabetes Study. Diabetes Res Clin Pract 2007;78:412–7. Santos CE, Schrank Y, Kupfer R. Critical analysis of WHO, IDF and NCEP criteria for metabolic syndrome among patients with type 1 diabetes mellitus. Arq Bras Endocrinol Metabol 2009;53:1096–102. Báez MS, Novik AV, Alegría GF, et al. Presence of metabolic syndrome among patients with type 1 diabetes mellitus. Rev Med Chil 2009;137:888–93. Momesso DP, Bussade I, Lima GA, et al. Body composition, metabolic syndrome and insulin resistance in type 1 diabetes mellitus. Arq Bras Endocrinol Metabol 2011;55:189–93. Williams K, Erbey J, Becker D, et al. Can clinical factors estimate insulin resistance in type 1 diabetes? Diabetes 2000;49:626–32. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002;25:1135–41.
[23] Chillarón JJ, Goday A, Flores-Le-Roux JA, et al. Estimated glucose disposal rate in assessment of the metabolic syndrome and microvascular complications in patients with type 1 diabetes. J Clin Endocrinol Metab 2009;94:3530–4. [24] Girgis CM, Scalley BD, Park KE. Utility of the estimated glucose disposal rate as a marker of microvascular complications in young adults with type 1 diabetes. Diabetes Res Clin Pract 2012;96:e70–2. [25] Orchard TJ, Olson JC, Erbey JR, et al. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 2003;26:1374–9. [26] Olson JC, Erbey JR, Forrest KY, et al. Glycemia (or, in women, estimated glucose disposal rate) predict lower extremity arterial disease events in type 1 diabetes. Metabolism 2002;51: 248–54. [27] Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti G. Insulin resistance in insulin-dependent diabetic patients with microalbuminuria. Lancet 1993;342:883–7. [28] Olson JC, Erbey JR, Williams KV, et al. Subclinical atherosclerosis and estimated glucose disposal rate as predictors of mortality in type 1 diabetes. Ann Epidemiol 2002;12:331–7. [29] Yatagai T, Nagasaka S, Taniguchi A, et al. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism 2003;52:1274–8. [30] Ryo M, Nakamura T, Kihara S, et al. Adiponectin as a biomarker of the metabolic syndrome. Circ J 2004;68:975–81. [31] Jorsal A, Tarnow L, Frystyk J, et al. Serum adiponectin predicts all-cause mortality and end stage renal disease in patients with type 1 diabetes and diabetic nephropathy. Kidney Int 2008;74:649–54. [32] Chudeck J, Adamczak M, Karkoszka H, et al. Plasma adiponectin concentration before and after successful kidney transplantation. Transplant Proc 2003;35:2186–9. [33] Prior SL, Tang TS, Gill GV, Bain SC, Stephens JW. Adiponectin, total antioxidant status, and urine albumin excretion in the low-risk “Golden Years” type 1 diabetes mellitus cohort. Metabolism 2011;60:173–9. [34] Pereira RI, Snell-Bergeon JK, Erickson C, et al. Adiponectin dysregulation and insulin resistance in type 1 diabetes. J Clin Endocrinol Metab 2012;97:E642–7. [35] Blaslov K, Bulum T, Zibar K, Duvnjak L. Relationship between adiponectin level, insulin sensitivity, and metabolic syndrome in type 1 diabetic patients. Int J Endocrinol 2013;2013:535906. http://dx.doi.org/10.1155/2013/535906. [36] Verbeeten KC, Elks CE, Daneman D, Ong KK. Association between childhood obesity and subsequent type 1 diabetes: a systematic review and meta-analysis. Diabet Med 2011;28: 10–8. [37] Conway B, Miller RG, Costacou T, et al. Temporal patterns in overweight and obesity in type 1 diabetes. Diabet Med 2010;27:398–404. [38] Ogden C, Yanovski SZ, Carroll MD, et al. The epidemiology of obesity. Gastroenterology 2007;132:2087–102. [39] van Vliet M, Van der Heyden JC, Diamant M, et al. Overweight is highly prevalent in children with type 1 diabetes and associates with cardiometabolic risk. J Pediatr 2010;156:923–9. [40] Miguel-Soca PE, Corella-del Toro I. Risk lipoprotein profile in patients with type 1 diabetes mellitus. An Pediatr (Barc) 2013. http://dx.doi.org/10.1016/j.anpedi.2013. 02.002. [41] Melin EO, Thunander M, Svensson R, Landin-Olsson M, Thulesius HO. Depression, obesity, and smoking were independently associated with inadequate glycemic control in patients with type 1 diabetes. Eur J Endocrinol 2013;168: 861–9. [42] Purnell JQ, Zinman B, Brunzell JD, et al. The effect of excess weight gain with intensive diabetes mellitus treatment on
M ET ABOL I SM CL IN I CA L A N D EX PE RI ME N TA L 6 3 ( 2 0 14 ) 18 1–1 8 7
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51] [52]
[53]
[54]
[55]
[56]
[57]
cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study. Circulation 2013;127:180–7. Vestberg D, Rosengren A, Olsson M, Gudbjörnsdottir S, Svensson AM, Lind M. Relationship between overweight and obesity with hospitalization for heart failure in 20,985 patients with type 1 diabetes: a population-based study from the Swedish national diabetes registry. Diabetes Care 2013;36: 2857–61. Nielsen PJ, Hafdahl AR, Conn VS, et al. Meta-analysis of the effect of exercise interventions on fitness outcomes among adults with type 1 and type 2 diabetes. Diabetes Res Clin Pract 2006;74:111–20. Conn VS, Hafdahl AR, Lemaster JW, et al. Meta-analysis of health behavior change interventions in type 1 diabetes. Am J Health Behav 2008;32:315–29. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:1512–24. Millán Núñez-Cortés J, Pedro-Botet Montoya J, Pintó Sala X. Residual vascular risk: recommendations of the Spanish Initiative for the Reduction of Residual Risk. Med Clin (Barc) 2010;135:165–71. Mooradian AD, Haas MJ, Wong NC. Transcriptional control of apolipoprotein A-I gene expression in diabetes. Diabetes 2004;53:513–20. Pérez A, Wägner AM, Carreras G, et al. Prevalence and phenotypic distribution of dyslipidemia in type 1 diabetes mellitus: effect of glycemic control. Arch Intern Med 2000;160:2756–62. Molitch ME, Rupp D, Carnethon M. Higher levels of HDL cholesterol are associated with a decreased likelihood of albuminuria in patients with long-standing type 1 diabetes. Diabetes Care 2006;29:78–82. Vergès B. Lipid disorders in type 1 diabetes. Diabetes Metab 2009;35:353–60. Sosenko JM, Breslow JL, Miettinen OS, et al. Hyperglycemia and plasma lipid levels: a prospective study of young insulin-dependent diabetic patients. N Engl J Med 1980;302:650–4. The DCCT Research Group. Lipid and lipoprotein levels in patients with IDDM: Diabetes Control and Complications Trial experience. Diabetes Care 1992;15:886–94. The seventh report of the Joint National Committee in Prevention: Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, US Dept of Health and Human Services; 2004. Arauz-Pacheco C, Parrott MA, Raskin P. The treatment of hypertension in adult patients with diabetes. Diabetes Care 2002;25:134–47. Chillarón JJ, Sales MP, Flores-Le-Roux JA, et al. Insulin resistance and hypertension in patients with type 1 diabetes. J Diabetes Complications 2011;25:232–6. Maahs DM, Kinney GL, Wadwa P, et al. Hypertension prevalence, awareness, treatment, and control in an adult
[58]
[59]
[60] [61]
[62] [63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
187
type 1 diabetes population and a comparable general population. Diabetes Care 2005;28:301–6. Collado-Mesa F, Colhoun HM, Stevens LK, et al. Prevalence and management of hypertension in type 1 diabetes mellitus in Europe: the EURODIAB IDDM Complications Study. Diabet Med 1999;16:41–8. Soedamah-Muthu SS, Colhoun HM, Abrahamian H, et al. Trends in hypertension management in type I diabetes across Europe, 1989/1990–1997/1999. Diabetologia 2002;45: 1362–71. Estudio DIAMANTE. Renal involvement in type 1 (IDDM) diabetes in Spain. Diabetes Res Clin Pract 1997;38:129–37. De Pablos-Velasco PL, Martínez-Martín F, Aguilar JA. Prevalence of hypertension in IDDM patients in the Northern Grand Canary Island, according to the WHO/ISH and JNC-V/ADA criteria. Diabetes Res Clin Pract 1997;38:191–7. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care 2013;36(Suppl 1):S11–66. The Task Force on Diabetes and Cardiovascular Disease of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, prediabetes and cardiovascular diseases: executive summary. Eur Heart J 2007;28:88–136. Pehmøller C, Brandt N, Birk JB, et al. Exercise alleviates lipid-induced insulin resistance in human skeletal musclesignaling interaction at the level of TBC1 domain family member 4. Diabetes 2012;61:2743–52. Mackenzie R, Maxwell N, Castle P, et al. Intermittent exercise with and without hypoxia improves insulin sensitivity in individuals with type 2 diabetes. J Clin Endocrinol Metab 2012;97:E546–55. Vella S, Buetow L, Royle P, et al. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010;53:809–20. Teranishi T, Ohara T, Maeda K, et al. Effects of pioglitazone and metformin on intracellular content in liver and skeletal muscle of individuals with type 2 diabetes mellitus. Metabolism 2007;56:1418–24. Bhat R, Bhansali A, Bhadada S, et al. Effect of pioglitazone therapy in lean type 1 diabetes mellitus. Diabetes Res Clin Pract 2007;78:349–54. Zdravkovic V, Hamilton JK, Daneman D, et al. Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes. J Pediatr 2006;149:845–9. Choe EY, Wang HJ, Kwon O, et al. Variants of the adiponectin gene and diabetic microvascular complications in patients with type 2 diabetes. Metabolism 2013;62:677–85. Ma J, Mollsten A, Falhammar H, et al. Genetic association analysis of the adiponectin polymorphism in type 1 diabetes with and without diabetic nephropathy. J Diabetes Complications 2007;21:28–33. Rosenfalck AM, Almdal T, Viggers L, Madsbad S, Hilsted J. A low-fat diet improves peripheral insulin sensitivity in patients with type 1 diabetes. Diabet Med 2006;23: 384–392. Leone A, Di Gennaro E, Bruzzese F, Avallone A, Budillon A. New perspective for an old antidiabetic drug: Metformin as anticancer agent. Cancer Treat Res 2014;159:355–76.
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Metabolism www.metabolismjournal.com
Review
Type 1 diabetes, metabolic syndrome and cardiovascular risk Juan J. Chillarón⁎, Juana A. Flores Le-Roux, David Benaiges, Juan Pedro-Botet Department of Endocrinology and Nutrition, Hospital del Mar, Barcelona Institut Municipal d´Investigacions Mèdiques Departament de Medicina, Universitat Autònoma de Barcelona
A R T I C LE I N FO
AB S T R A C T
Article history:
Patients with type 1 diabetes mellitus (T1DM) traditionally had a low body mass index and
Received 22 July 2013
microangiopathic complications were common, while macroangiopathy and the metabolic
Accepted 16 October 2013
syndrome were exceptional. The Diabetes Control and Complications Trial, published in 1993, demonstrated that therapy aimed at maintaining HbA1c levels as close to normal as
Keywords:
feasible reduced the incidence of microangiopathy. Since then, the use of intensive insulin
Type 1 diabetes
therapy to optimize metabolic control became generalized. Improved glycemic control
Chronic complications
resulted in a lower incidence of microangiopathy; however, its side effects included a higher
Metabolic syndrome
rate of severe hypoglycemia and increased weight gain. Approximately 50% of patients with
Cardiovascular risk
T1DM are currently obese or overweight, and between 8% and 40% meet the metabolic syndrome criteria. The components of the metabolic syndrome and insulin resistance have been linked to chronic T1DM complications, and cardiovascular disease is now the leading cause of death in these patients. Therefore, new therapeutic strategies are required in T1DM subjects, not only to intensively lower glycemia, but to control all associated metabolic syndrome traits. © 2014 Elsevier Inc. All rights reserved.
1.
Introduction
Traditionally, patients with type 1 diabetes mellitus (T1DM) suffered microangiopathic complications, especially nephropathy, which had a negative impact on prognosis and quality of life [1]. In 1993, the Diabetes Control and Complications Trial (DCCT) demonstrated that intensive glucose lowering therapy could reduce by 50% the incidence of microangiopathy [2]. The Epidemiology of Diabetes Interventions and Complications trial (EDIC), an extension study of the DCCT, with a mean
follow-up of 17 years, revealed a 57% reduction in the relative risk of non-fatal myocardial infarction, stroke or cardiovascular death in the group that had initially received intensive insulin therapy [3]. Ever since, most therapeutic efforts in T1DM have focused on reducing glycated hemoglobin levels. However, a growing body of evidence underlines the frequent coexistence of metabolic syndrome components in patients with T1DM [4–7], resulting in the so-called "double diabetes" [8] (Fig. 1). This fact, together with the decline in the incidence of microangiopathy, has led to cardiovascular disease now
Abbreviations: ADA, American Diabetes Association; Apo, apolipoprotein; DCCT, Diabetes Control and Complications Trial; EASD, European Association for the Study of Diabetes; EDIC, Epidemiology of Diabetes Interventions and Complications trial; eGDR, estimated glucose disposal rate; HDL, high-density lipoproteins; HOMA-IR, homeostasis model assessment-insulin resistance; LDL, low-density lipoproteins; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. ⁎ Corresponding author. Department of Endocrinology and Nutrition Hospital del Mar Passeig Marítim, 25–29 E-08003 Barcelona, Spain. Tel.: + 34 932483902; fax: + 34 932483337. E-mail address: [email protected] (J.J. Chillarón). 0026-0495/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2013.10.002
Hypertension Dyslipidemia Overweight/ Obesity
Type 2 Diabetes Insulin Resistance
Double Diabetes
Inmune destruction -cell
Type 1 Diabetes
Chronic complcations
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 3 ( 2 0 14 ) 18 1–1 87
HbA1c
182
Fig. 1 – Physiopathologic aspects of type 1 and type 2 diabetes.
being the leading cause of death in T1DM patients over 30 years of age [9]. Although acceptance of the metabolic syndrome has been controversial in certain scientific forums [10], several studies have shown the classic phenotype of the metabolic syndrome to be associated with increased mortality, nearly 10 times higher in those meeting all components [11]. The prevalence of the metabolic syndrome in the general population ranges from 20% to 50% [5,12] but it can reach almost 80% in type 2 diabetes patients (T2DM) [5]. In T1DM patients its prevalence varies between 8% and 40% depending on the study population and the diagnostic criteria (Table 1) [4–7,13–20]. Since all these aspects must be taken into account for therapeutic management, we considered it appropriate to review the main factors associated with the metabolic syndrome in T1DM patients and its relationship with the development of chronic complications and mortality.
glucose disposal rate (eGDR) [21], which is easily applicable and its correlation with the hyperinsulinemic euglycemic clamp is excellent. It should be emphasized that higher eGDR levels indicate greater insulin sensitivity and lower levels greater resistance. Several studies confirm the relationship between insulin resistance and the presence of chronic complications of diabetes, both type 1 and 2[22–28]. Insulin resistance, assessed by eGDR in T1DM patients has been linked to chronic complications, both micro and macrovascular, and increased mortality [6,7,23–28]. A study by our group showed that no patient with eGDR levels exceeding 8.16 mg kg−1 min− 1 had diabetes-related chronic complications. Additionally, an eGDR value less than 8.77 mg kg − 1 min− 1 showed 100% sensitivity and 85.2% specificity for the diagnosis of the metabolic syndrome.
3. 2.
T1DM and insulin resistance
The metabolic syndrome can be considered a surrogate marker for insulin resistance. Therefore, quantification of insulin resistance in this group of patients seems particularly relevant. The reference method for its calculation is the hyperinsulinemic euglycemic clamp; however, being too invasive, time-consuming and expensive, this technique is limited to research purposes. Thus, various formulas for insulin resistance calculation have been devised for its use at population level, with the homeostasis model assessmentinsulin resistance (HOMA-IR) being the most frequently used. However, since insulinemia is included in the formula, this index is not applicable in T1DM patients who receive insulin exogenously. In 2000, Williams et al. validated the estimated
Adiponectin and insulin resistance
Recent studies reported that adiponectin, a fat-derived protein, plays an important role in the regulation of insulin action, glucose and lipid metabolism. In this regard, plasma concentrations of adiponectin are reduced in human obesity and negatively correlated with insulin resistance [29]. Hypoadiponectinemia is independently associated with the metabolic syndrome and with T2DM prevalence and incidence [30]. Paradoxically, adiponectin levels are elevated in T1DM and associated with the presence of microalbuminuria and diabetic nephropathy in cross-sectional data. Furthermore, elevated adiponectin levels predict all-cause mortality and end-stage renal disease in those with diabetic nephropathy [31]. Since levels decrease after renal transplantation, this association may be due to impaired renal clearance of the protein [32]. On the other hand, it could represent a
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183
Table 1 – Prevalence of metabolic syndrome in patients with type 1 diabetes and risk of associated complications. Reference
n
Metabolic syndrome
Complications
Criteria
Prevalence Women 38% Men 40% Intensive group 45.4%
FinnDiane study [4]
2415
NCEP-ATP III
DCCT study [7]
1337
IDF
Control group 27.2% Reindel et al. [14]
1241
NCEP-ATP III
18.2%
Metascreen study [5]
638
NCEP-ATP III
Women 24.5% Men 43.2%
Pittsburg epidemiology of diabetes complications study [6]
514
IDF
8%
Chillarón et al. [13]
291
WHO NCEP-ATP III NCEP-ATP III
21% 12% 26.8%
Ferreira-Hermosillo et al. [15]
130
NCEP-ATP III
25%
127
IDF WHO NCEP-ATP III IDF WHO NCEP-ATP III NCEP-ATP III WHO
39.4% 44.9% 42.1% 32% 32% 26% 25% 45%
Davis et al. [17]
Santos et al. [18]
Báez et al. [19] Momesso et al. [20]
101
52 45
OR diabetic nephropathy: 3.75 (95% CI: 2.89–4.85) b HR retinopathy: 0.85 (95% CI: 0.61–1.18) HR nephropathy: 0.98 (95% CI: 0.71–1.35) HR macroangiopathy: 1.15 (95% CI: 0.69–1.92) OR PVD: 2.28 (95% CI: 1.38–3.76) b OR CVD: 2.19 (95% CI: 1.24–3.85) b OR nephropathy: 3.0 (p < 0.001) b OR neuropathy: 1.75 (p = 0.021) b OR CVD: 1.72 (ns, p = 0.09) OR main complications a: 2.0 (95% CI: 1.2–3.4) b OR main complications a: 6.5 (95% CI: 4.5–9.4) b OR main complications a: 5.8 (95% CI: 3.9–8.6) b Microangiopathy: 37.9% vs 4.8% (MS vs no MS) Macroangiopathy: 6.9% vs 0% (MS vs no MS) Retinopathy: 70% vs 29% (MS vs. no MS) All-cause mortality, prevalence MS: 62.1% 69.0% 55.2% Microalbuminuria: 50% vs 7.2% (MS vs no MS) Retinopathy: 56.2% vs 26.1% (MS vs no MS)
MS: metabolic syndrome; NCEP-ATPIII: National Cholesterol Education Program-Adult Treatment Panel III; IDF: International Diabetes Federation; WHO: World Health Organization; CVD: cardiovascular disease. a Coronary artery disease, renal failure or death-related diabetes. b Favors patients with metabolic syndrome.
compensatory mechanism to reduce oxidative status [33]. Regarding insulin sensitivity in T1DM, higher adiponectin concentrations are associated with a lower prevalence of the metabolic syndrome [34,35].
4.
T1DM and obesity
Obesity is currently considered to be the great epidemic of the century, with a prevalence increasing steadily worldwide over the past 20 years. Besides the known association between obesity and type 2 diabetes, a recent meta-analysis showed the presence of obesity in childhood to be a predictor of subsequent T1DM [36]. As mentioned previously, the DCCT study demonstrated the benefits of tight glycemic control in reducing the incidence of microangiopathy. However, this intensive approach also entailed certain side effects. First, the intensively treated group had a mean of 60 severe hypoglycemias per 100 patients and year to achieve a glycated hemoglobin of 7% [2]. Second,
weight gain in the intensive group was 14 kg on average during follow-up, which caused a 33% increase in the prevalence of overweight [2]. It is remarkable that in the preDCCT era, the body mass index of patients with T1DM was lower than in the general population [37,38]. However, nowadays the percentage of T1DM patients with overweight/ obesity is close to 50% [23], even in children [39,40]. Obesity in these patients has been associated with increased insulin requirements, poor metabolic control [41], greater atherosclerotic burden [42] and increased need for hospitalization due to heart failure [43]. Two meta-analyses on the effect of physical activity in T1DM patients showed very slight reductions in both glycated hemoglobin levels and body mass index [44,45].
5.
T1DM and atherogenic dyslipidemia
Atherogenic dyslipidemia, characterized by decreased concentrations of high-density lipoprotein (HDL) cholesterol,
184
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hypertriglyceridemia and increased levels of small and dense low-density lipoprotein (LDL) particles, is common in patients with coronary heart disease, metabolic syndrome and type 2 diabetes, and is largely responsible for residual macrovascular and microvascular risk [46,47]. One proposed mechanism contributing to low HDL cholesterol levels in diabetic dyslipidemia is reduced liver synthesis of apolipoprotein (apo) A-I [48]. In healthy individuals, insulin causes an increase in apo A-I gene expression, which is decreased in patients with insulin resistance. This would explain why patients with T2DM and those with T1DM and decreased insulin sensitivity maintain low HDL cholesterol levels compared to the general population, even in a normotriglyceridemic situation; however, no specific studies in this group of T1DM patients are available. In a study conducted by our group in a cohort of 291 patients with T1DM, hypoalphalipoproteinemia was present in 17.2% and its presence was associated with macroalbuminuria and polyneuropathy [16]. Other studies found poor metabolic control to be related with lower HDL cholesterol levels [49], which adversely influenced the incidence of micro and macrovascular complications. Conversely, patients with long standing T1DM and high levels of HDL are less likely to develop neuropathy [50]. As for hypertriglyceridemia, its prevalence in T1DM patients ranges from 13% to 31%, depending on the cutoff level used for its definition [16,51–53]. Furthermore, the risk of all microangiopathic complications is two- to three-fold greater for those with higher triglyceride levels [16,51]. It should be noted that although hypertriglyceridemia is the least common lipid abnormality in patients with T1DM, its presence is accompanied by a high rate of microangiopathic complications, even at young ages and without an excessively long diabetes duration [16]. This fact underlines the importance of lipid control and the need to implement therapeutic strategies aimed at correcting these abnormalities.
6.
T1DM and hypertension
Hypertension constitutes one of the most prevalent cardiovascular risk factors worldwide and particularly in patients with diabetes mellitus, both types 1 and 2 [54]. In the general population, an estimated rise of 20 mm Hg from 115 mm Hg in systolic blood pressure or 10 mm Hg over 75 mm Hg in diastolic blood pressure doubles the risk of cardiovascular events [54]. Strict blood pressure control significantly reduces morbidity and mortality in the general population and in patients with T2DM [53,55]. Although hypertension in T1DM patients is clearly associated with diabetic nephropathy, other factors, such as weight gain after insulin therapy [41] and the presence of insulin resistance, play a key role [56]. Studies assessing hypertension prevalence in T1DM show a wide disparity in the criteria used for diagnosis. In this respect, the prevalence varied between 11% and 59% [57–61]. According to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommendations [62,63], approximately 30% of T1DM patients were estimated to have hypertension
Intensive insulin treatment
CVD microangiopathy
severe hypoglycemia Weight MS Prevalence
Insulin dose
InsulinResistance
Fig. 2 – Effects of intensive insulin therapy. CVD: cardiovascular disease; MetS, metabolic syndrome.
[56]. Several studies reported that hypertensive patients with T1DM were older, had longer diabetes duration, lower insulin sensitivity and a higher prevalence of overweight, obesity, and chronic complications, mainly microangiopathy [56,58–60]. Again, the high prevalence of overweight/obesity in these patients and its relationship with both insulin resistance and the presence of cardiovascular risk factors traditionally associated with T2DM are noteworthy.
7.
Therapeutic strategies
Given this scientific evidence, therapeutic strategies aimed at improving insulin resistance in patients with T1DM are mandatory. Among non-pharmacologic strategies, those promoting a healthy lifestyle in order to reduce overweight and obesity must be emphasized, thereby avoiding the insulin resistance vicious circle (Fig. 2). In patients with T2DM, physical exercise improves glycated hemoglobin levels and body mass index regardless of diet and other components [64,65]. In T1DM patients, two metaanalyses assessing the effects of exercise indicated a slight improvement in glycated hemoglobin levels and body mass index [44,45]. Although no trials have assessed the impact of exercise on insulin sensitivity in patients with T1DM, the benefits of exercise on body weight and other risk factors should be stressed. Given the clinical benefits of metformin therapy in patients with T2DM through improved insulin sensitivity in muscle and liver, several clinical studies have been conducted in patients with T1DM to assess the effectiveness of this drug. A recent meta-analysis found metformin use in these patients to be associated with a reduction in insulin requirements of 5– 10 daily units and a non-significant improvement in glycated hemoglobin of 0.28%. A weight loss of 1.7–6 kg and a slight reduction in total and LDL cholesterol were also observed, although there are no long-term data to ascertain the
M ET ABOL I SM CL IN I CA L A N D EX PE RI ME N TA L 6 3 ( 2 0 14 ) 18 1–1 8 7
influence of these changes on cardiovascular disease [66]. Vella et al. concluded that longer-term studies with a larger sample size are needed to justify metformin treatment in T1DM patients. Nevertheless, these trials did not select patients according to insulin sensitivity and, furthermore, most of the subjects included had poor metabolic control. Thiazolidinediones are another class of drugs that act as insulin sensitizers, of which only pioglitazone is currently available for clinical use. A 6-month trial on T2DM patients showed pioglitazone to be associated with a significant increase in adiponectin levels (+ 10.6 μg/mL) and a reduced hepatic and intramyocellular lipid content [67]. Few clinical trials on this topic have been carried out in patients with T1DM, and the results were controversial. Nevertheless, modest benefits were obtained in glycated hemoglobin (−0.22%) with a slight increase in body mass index (+ 0.3 kg/m2) and without changes in insulin requirements [68,69].
8.
Future research areas
Evidence suggests that common polymorphisms of the adiponectin gene are associated with microangiopathic complications in patients with T2DM [70]. However, few studies have been conducted in T1DM patients and the results were inconclusive [71]. Given the importance of the interaction of genetic and environmental factors in the clinical phenotype of the disease, better understanding of the genetic influence of adiponectin could explain the paradoxical results obtained in T1DM and T2DM. Little information is available on the potential effects of diet on insulin resistance and other metabolic parameters in patients with T1DM. In one small crossover study on the effects of a low-fat, isocaloric diet in 10 individuals with T1DM, a reduction in insulin resistance was found without improvement in glycemic control [72]. Thus, larger intervention trials on the effects of calorie-reduced diets must be conducted to further explore the benefits of a healthy diet in T1DM patients. As for pharmacologic strategies, the potential of metformin to attenuate insulin resistance in T1DM subjects should be further evaluated in specifically designed clinical trials. Moreover, recent studies suggest that the use of metformin might reduce the risk of cancer in patients with T2D [73]. This possible additional benefit of metformin use should be specifically tested in T1D. Multiple mechanisms can be responsible for insulin resistance in patients with T1DM. Improved understanding of the implicated pathophysiologic mechanisms could lead to the identification of potential molecular targets for the development of new therapeutic strategies aimed at reducing morbidity and mortality in these subjects.
9.
Conclusions
The presence of metabolic syndrome components in T1DM patients is frequent and is associated with an increased incidence of chronic complications and mortality. eGDR, a surrogate marker of the metabolic syndrome, is useful in T1DM patients as it correlates with the presence of compli-
185
Table 2 – Type 1 diabetes mellitus and metabolic syndrome: Key messages. The prevalence of the metabolic syndrome in T1DM is increasing in our societies. Metabolic syndrome components in T1DM patients: Overweight/obesity 50% Low HDL cholesterol levels 20% Hypertriglyceridemia 13%–30% Hypertension 11%–59% Each of the components of metabolic syndrome has been associated with the onset of chronic complications. Metabolic syndrome and insulin resistance in T1DM are related with all chronic complications and mortality. Treatment with metformin or pioglitazone in T1DM has shown a modest impact in some parameters of the metabolic syndrome. New trials specifically designed for T1DM patients with insulin resistance should assess further benefits of these interventions. Improved understanding of the pathophysiologic mechanisms of insulin-resistance could lead to the development of new therapeutic strategies. T1DM: type 1 diabetes mellitus; HDL: high-density lipoproteins.
cations and mortality. Thus, patients with T1DM and metabolic syndrome traits should be identified as early as possible and treated appropriately. In this respect, pharmacologic and non-pharmacologic strategies to improve insulin sensitivity must be considered in the clinical management of these patients (Table 2). Juan J. Chillarón and Juan Pedro-Botet performed a review of the literature and elaborated the draft of the manuscript. Juana A. Flores and David Benaiges contributed to the review of the literature. All authors read and approved the final manuscript.
Acknowledgments We thank Miss Christine O’Hara for review of the English version of the manuscript.
Conflict of interest The authors have nothing to disclose. REFERENCES
[1] Chillarón JJ, Goday A, Pedro-Botet J. Metabolic syndrome, type 1 diabetes mellitus and insulin resistance. Med Clin (Barc) 2008;130:466–71. [2] The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329: 977–86. [3] The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53. [4] Thorn LM, Forsblom C, Fagerudd J, et al. Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and
186
[5]
[6]
[7]
[8] [9]
[10] [11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 3 ( 2 0 14 ) 18 1–1 87
glycemic control (the FinnDiane study). Diabetes Care 2005;28:2019–24. The Metascreen Writing Committee. The metabolic syndrome is a risk indicator of microvascular and macrovascular complications in diabetes: results from Metascreen, a multicenter diabetes clinic-based survey. Diabetes Care 2006;29:2701–7. Pambianco G, Costacou T, Orchard TJ. The prediction of major outcomes of type 1 diabetes: a 12 year prospective evaluation of three separate definitions of the metabolic syndrome, and their components and estimated glucose disposal rate: the Pittsburg Epidemiology of Diabetes Complications Study experience. Diabetes Care 2007;30:1248–54. Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and complications risk in type 1 diabetes: “double diabetes” in the Diabetes Complications Trial. Diabetes Care 2007;30:707–12. Teupe B, Bergis K. Epidemiological evidence for “double diabetes”. Lancet 1991;337:361–2. Laing SP, Swerdlow AJ, Slater SD, et al. The British Diabetic Association Cohort Study II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabet Med 1999;16:466–71. Reaven GM. The metabolic syndrome: requiescat in pace. Clin Chem 2005;51:931–8. Mäkinen VP, Forsblom C, Thorn LM, et al. Metabolic phenotypes, vascular complications, and premature deaths in a population of 4,197 patients with type 1 diabetes. Diabetes 2008;57:2480–7. Park YW, Zhu S, Palaniappan L, et al. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 2003;163:427–36. Chillarón JJ, Flores-Le-Roux JA, Goday A, et al. Metabolic syndrome and type 1 diabetes mellitus: prevalence and associated factors. Rev Esp Cardiol 2010;63:423–9. Reindel J, Zander E, Heinke P, et al. The metabolic syndrome in patients with type 1 diabetes mellitus. Associations with cardiovascular risk factors and cardiovascular morbidity. Herz 2004;29:463–9. Ferreira-Hermosillo A, Vargas-Ortega G, González-Virla B, et al. Prevalence of metabolic syndrome (MS) in patients with type 1 diabetes (DM1). Gac Med Mex 2012;148:137–43. Chillarón JJ, Sales MP, Flores Le-Roux JA, et al. Atherogenic dyslipidemia in patients with type 1 diabetes mellitus. Med Clin (Barc) 2013. http://dx.doi.org/10.1016/j.medcli.2013.03.016. Davis TM, Bruce DG, Davis WA. Prevalence and prognostic implications of the metabolic syndrome in community-based patients with type 1 diabetes: the Fremantle Diabetes Study. Diabetes Res Clin Pract 2007;78:412–7. Santos CE, Schrank Y, Kupfer R. Critical analysis of WHO, IDF and NCEP criteria for metabolic syndrome among patients with type 1 diabetes mellitus. Arq Bras Endocrinol Metabol 2009;53:1096–102. Báez MS, Novik AV, Alegría GF, et al. Presence of metabolic syndrome among patients with type 1 diabetes mellitus. Rev Med Chil 2009;137:888–93. Momesso DP, Bussade I, Lima GA, et al. Body composition, metabolic syndrome and insulin resistance in type 1 diabetes mellitus. Arq Bras Endocrinol Metabol 2011;55:189–93. Williams K, Erbey J, Becker D, et al. Can clinical factors estimate insulin resistance in type 1 diabetes? Diabetes 2000;49:626–32. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002;25:1135–41.
[23] Chillarón JJ, Goday A, Flores-Le-Roux JA, et al. Estimated glucose disposal rate in assessment of the metabolic syndrome and microvascular complications in patients with type 1 diabetes. J Clin Endocrinol Metab 2009;94:3530–4. [24] Girgis CM, Scalley BD, Park KE. Utility of the estimated glucose disposal rate as a marker of microvascular complications in young adults with type 1 diabetes. Diabetes Res Clin Pract 2012;96:e70–2. [25] Orchard TJ, Olson JC, Erbey JR, et al. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 2003;26:1374–9. [26] Olson JC, Erbey JR, Forrest KY, et al. Glycemia (or, in women, estimated glucose disposal rate) predict lower extremity arterial disease events in type 1 diabetes. Metabolism 2002;51: 248–54. [27] Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti G. Insulin resistance in insulin-dependent diabetic patients with microalbuminuria. Lancet 1993;342:883–7. [28] Olson JC, Erbey JR, Williams KV, et al. Subclinical atherosclerosis and estimated glucose disposal rate as predictors of mortality in type 1 diabetes. Ann Epidemiol 2002;12:331–7. [29] Yatagai T, Nagasaka S, Taniguchi A, et al. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism 2003;52:1274–8. [30] Ryo M, Nakamura T, Kihara S, et al. Adiponectin as a biomarker of the metabolic syndrome. Circ J 2004;68:975–81. [31] Jorsal A, Tarnow L, Frystyk J, et al. Serum adiponectin predicts all-cause mortality and end stage renal disease in patients with type 1 diabetes and diabetic nephropathy. Kidney Int 2008;74:649–54. [32] Chudeck J, Adamczak M, Karkoszka H, et al. Plasma adiponectin concentration before and after successful kidney transplantation. Transplant Proc 2003;35:2186–9. [33] Prior SL, Tang TS, Gill GV, Bain SC, Stephens JW. Adiponectin, total antioxidant status, and urine albumin excretion in the low-risk “Golden Years” type 1 diabetes mellitus cohort. Metabolism 2011;60:173–9. [34] Pereira RI, Snell-Bergeon JK, Erickson C, et al. Adiponectin dysregulation and insulin resistance in type 1 diabetes. J Clin Endocrinol Metab 2012;97:E642–7. [35] Blaslov K, Bulum T, Zibar K, Duvnjak L. Relationship between adiponectin level, insulin sensitivity, and metabolic syndrome in type 1 diabetic patients. Int J Endocrinol 2013;2013:535906. http://dx.doi.org/10.1155/2013/535906. [36] Verbeeten KC, Elks CE, Daneman D, Ong KK. Association between childhood obesity and subsequent type 1 diabetes: a systematic review and meta-analysis. Diabet Med 2011;28: 10–8. [37] Conway B, Miller RG, Costacou T, et al. Temporal patterns in overweight and obesity in type 1 diabetes. Diabet Med 2010;27:398–404. [38] Ogden C, Yanovski SZ, Carroll MD, et al. The epidemiology of obesity. Gastroenterology 2007;132:2087–102. [39] van Vliet M, Van der Heyden JC, Diamant M, et al. Overweight is highly prevalent in children with type 1 diabetes and associates with cardiometabolic risk. J Pediatr 2010;156:923–9. [40] Miguel-Soca PE, Corella-del Toro I. Risk lipoprotein profile in patients with type 1 diabetes mellitus. An Pediatr (Barc) 2013. http://dx.doi.org/10.1016/j.anpedi.2013. 02.002. [41] Melin EO, Thunander M, Svensson R, Landin-Olsson M, Thulesius HO. Depression, obesity, and smoking were independently associated with inadequate glycemic control in patients with type 1 diabetes. Eur J Endocrinol 2013;168: 861–9. [42] Purnell JQ, Zinman B, Brunzell JD, et al. The effect of excess weight gain with intensive diabetes mellitus treatment on
M ET ABOL I SM CL IN I CA L A N D EX PE RI ME N TA L 6 3 ( 2 0 14 ) 18 1–1 8 7
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51] [52]
[53]
[54]
[55]
[56]
[57]
cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study. Circulation 2013;127:180–7. Vestberg D, Rosengren A, Olsson M, Gudbjörnsdottir S, Svensson AM, Lind M. Relationship between overweight and obesity with hospitalization for heart failure in 20,985 patients with type 1 diabetes: a population-based study from the Swedish national diabetes registry. Diabetes Care 2013;36: 2857–61. Nielsen PJ, Hafdahl AR, Conn VS, et al. Meta-analysis of the effect of exercise interventions on fitness outcomes among adults with type 1 and type 2 diabetes. Diabetes Res Clin Pract 2006;74:111–20. Conn VS, Hafdahl AR, Lemaster JW, et al. Meta-analysis of health behavior change interventions in type 1 diabetes. Am J Health Behav 2008;32:315–29. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:1512–24. Millán Núñez-Cortés J, Pedro-Botet Montoya J, Pintó Sala X. Residual vascular risk: recommendations of the Spanish Initiative for the Reduction of Residual Risk. Med Clin (Barc) 2010;135:165–71. Mooradian AD, Haas MJ, Wong NC. Transcriptional control of apolipoprotein A-I gene expression in diabetes. Diabetes 2004;53:513–20. Pérez A, Wägner AM, Carreras G, et al. Prevalence and phenotypic distribution of dyslipidemia in type 1 diabetes mellitus: effect of glycemic control. Arch Intern Med 2000;160:2756–62. Molitch ME, Rupp D, Carnethon M. Higher levels of HDL cholesterol are associated with a decreased likelihood of albuminuria in patients with long-standing type 1 diabetes. Diabetes Care 2006;29:78–82. Vergès B. Lipid disorders in type 1 diabetes. Diabetes Metab 2009;35:353–60. Sosenko JM, Breslow JL, Miettinen OS, et al. Hyperglycemia and plasma lipid levels: a prospective study of young insulin-dependent diabetic patients. N Engl J Med 1980;302:650–4. The DCCT Research Group. Lipid and lipoprotein levels in patients with IDDM: Diabetes Control and Complications Trial experience. Diabetes Care 1992;15:886–94. The seventh report of the Joint National Committee in Prevention: Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, US Dept of Health and Human Services; 2004. Arauz-Pacheco C, Parrott MA, Raskin P. The treatment of hypertension in adult patients with diabetes. Diabetes Care 2002;25:134–47. Chillarón JJ, Sales MP, Flores-Le-Roux JA, et al. Insulin resistance and hypertension in patients with type 1 diabetes. J Diabetes Complications 2011;25:232–6. Maahs DM, Kinney GL, Wadwa P, et al. Hypertension prevalence, awareness, treatment, and control in an adult
[58]
[59]
[60] [61]
[62] [63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
187
type 1 diabetes population and a comparable general population. Diabetes Care 2005;28:301–6. Collado-Mesa F, Colhoun HM, Stevens LK, et al. Prevalence and management of hypertension in type 1 diabetes mellitus in Europe: the EURODIAB IDDM Complications Study. Diabet Med 1999;16:41–8. Soedamah-Muthu SS, Colhoun HM, Abrahamian H, et al. Trends in hypertension management in type I diabetes across Europe, 1989/1990–1997/1999. Diabetologia 2002;45: 1362–71. Estudio DIAMANTE. Renal involvement in type 1 (IDDM) diabetes in Spain. Diabetes Res Clin Pract 1997;38:129–37. De Pablos-Velasco PL, Martínez-Martín F, Aguilar JA. Prevalence of hypertension in IDDM patients in the Northern Grand Canary Island, according to the WHO/ISH and JNC-V/ADA criteria. Diabetes Res Clin Pract 1997;38:191–7. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care 2013;36(Suppl 1):S11–66. The Task Force on Diabetes and Cardiovascular Disease of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, prediabetes and cardiovascular diseases: executive summary. Eur Heart J 2007;28:88–136. Pehmøller C, Brandt N, Birk JB, et al. Exercise alleviates lipid-induced insulin resistance in human skeletal musclesignaling interaction at the level of TBC1 domain family member 4. Diabetes 2012;61:2743–52. Mackenzie R, Maxwell N, Castle P, et al. Intermittent exercise with and without hypoxia improves insulin sensitivity in individuals with type 2 diabetes. J Clin Endocrinol Metab 2012;97:E546–55. Vella S, Buetow L, Royle P, et al. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010;53:809–20. Teranishi T, Ohara T, Maeda K, et al. Effects of pioglitazone and metformin on intracellular content in liver and skeletal muscle of individuals with type 2 diabetes mellitus. Metabolism 2007;56:1418–24. Bhat R, Bhansali A, Bhadada S, et al. Effect of pioglitazone therapy in lean type 1 diabetes mellitus. Diabetes Res Clin Pract 2007;78:349–54. Zdravkovic V, Hamilton JK, Daneman D, et al. Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes. J Pediatr 2006;149:845–9. Choe EY, Wang HJ, Kwon O, et al. Variants of the adiponectin gene and diabetic microvascular complications in patients with type 2 diabetes. Metabolism 2013;62:677–85. Ma J, Mollsten A, Falhammar H, et al. Genetic association analysis of the adiponectin polymorphism in type 1 diabetes with and without diabetic nephropathy. J Diabetes Complications 2007;21:28–33. Rosenfalck AM, Almdal T, Viggers L, Madsbad S, Hilsted J. A low-fat diet improves peripheral insulin sensitivity in patients with type 1 diabetes. Diabet Med 2006;23: 384–392. Leone A, Di Gennaro E, Bruzzese F, Avallone A, Budillon A. New perspective for an old antidiabetic drug: Metformin as anticancer agent. Cancer Treat Res 2014;159:355–76.
