In this article, the author reviews the long-term outcomes and their precursors of type 1 diabetes starting in youth. The author also contrasts the changing incidence of these long-term complications as we have moved from the pre–Diabetes Control and Complications Trial (DCCT) to the post-DCCT standard of care and reviews the emerging data related to complications in youths with type 2 diabetes. Finally, the author reviews the recent understanding related to the effects of diabetes on the brain and cognition.
Key points
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Clinically significant diabetes-related complications are uncommon in children and adolescents, but patients with youth-onset diabetes do develop life-altering complications during their young adult years.
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Retinopathy, nephropathy (microalbuminuria), and neuropathy are associated with glycemic control; current levels of glycemic control seem inadequate to completely prevent these complications.
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Cardiovascular disease (CVD) associated with diabetes starts during adolescence, and vigorous attention to CVD risk factors (dyslipidemia and hypertension) is an important component of caring for children and adolescents with diabetes.
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Type 2 diabetes with its onset in youth is likely associated with more and earlier diabetes-related microvascular and macrovascular complications than type 1 diabetes.
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Recent and emerging data show that hyperglycemia as well as hypoglycemia may have lasting effects on brain function and structure, especially in young children.
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Taken together, these considerations support the need for continuing research into new approaches and technology to improve the long-term overall glycemic control of those with diabetes of all ages, including young children.
The Diabetes Control and Complications Trial (DCCT) and its ongoing longitudinal observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, represent a major turning point in our understanding of the long-term outcomes of type 1 diabetes (T1D). The DCCT clearly demonstrated that intensive therapy for diabetes that lowered hemoglobin A1c (HbA1c) levels by about 2% (9.0%–7.1%) reduced the incidence of onset and progression of diabetic retinopathy (DR), diabetic nephropathy, and diabetic neuropathy by 47% to 54%, 39%, and 60%, respectively, in both young adults (18–39 years old) and adolescents (13–18 years old) with a diabetes duration of 1 to 15 years at the time of enrollment. During the EDIC follow-up study, the benefits on cardiovascular disease (CVD) outcomes also became apparent with a 42% reduction in CVD events after 17 years. The ongoing EDIC study subsequently showed that these benefits not only persisted but indeed widened at 4 and 10 years after the end of the DCCT during a time of equivalent glycemic control between the original conventional and intensive groups in the DCCT; this has been called metabolic memory . The between-group differences in complication rates in DCCT and EDIC and the metabolic memory phenomenon were almost entirely a result of the differences in HbA1c between the groups during the DCCT. Other factors contributed little if any to these differences.
Intensive therapy, as implemented in the DCCT and along with many subsequent pharmacologic and technologic advances, has now become the standard of care for T1D. With this changing standard of care for T1D during the last 2 decades since the release of the DCCT results, the morbidity and mortality associated with the microvascular and macrovascular complication of T1D has been reduced or delayed but not eliminated. Comparing complication rates from about 20 years earlier to those in the DCCT/EDIC cohort after 20 years of follow-up, the cumulative incidence of proliferative DR (PDR) and nephropathy decreased from 50% and 35%, respectively, to 30% and 12%, respectively; the rates of end-stage renal disease (ESRD) requiring dialysis or transplantation have also declined ( Fig. 1 ). The rates of other clinically severe complications also decreased dramatically. There remains no cure or prevention of T1D, and indeed the incidence of T1D and the overall impact of its complications seem to be increasing.
Simultaneous with the changing climate surrounding T1D, and along with the increasing prevalence of childhood obesity not only in the United States but also around much of the developed world, the incidence of type 2 diabetes (T2D) is increasing. T2D now accounts for a substantial portion of new-onset diabetes in youth. Emerging evidence suggests that T2D starting during childhood or adolescence may have worse long-term outcomes than either T1D in youth or T2D presenting during the adult years (see later discussion).
Here, the author reviews the outcomes of diabetes starting during childhood and adolescence with particular focus on the long-term complications of diabetes (retinopathy, nephropathy, neuropathy, macrovascular disease) and their precursors in T1D starting in youth as well as the emerging, though still inadequate, data related to complications in youths with T2D. Also, the author reviews the recent understanding related to the effects of diabetes on the brain and cognition. This subject warrants important consideration in developing the best targets for managing diabetes in children and adolescents.
Overview of diabetes-related complications
The outcomes of diabetes in youth include short-term and long-term complications ( Box 1 ). Although the long-term complications rarely have clinically important manifestations during the years that youths are under the care of their pediatrician or pediatric endocrinologist, youths with T1D are at risk for the short-term complications every day.
Short-term Complications
Diabetic ketoacidosis
Hypoglycemia
Visual
Psychosocial
Long-term Complications
Microvascular
Retinopathy
Nephropathy
Neuropathy
Peripheral
Autonomic
Macrovascular
Coronary artery disease
Cerebrovascular disease
Peripheral vascular disease
Overview of diabetes-related complications
The outcomes of diabetes in youth include short-term and long-term complications ( Box 1 ). Although the long-term complications rarely have clinically important manifestations during the years that youths are under the care of their pediatrician or pediatric endocrinologist, youths with T1D are at risk for the short-term complications every day.
Short-term Complications
Diabetic ketoacidosis
Hypoglycemia
Visual
Psychosocial
Long-term Complications
Microvascular
Retinopathy
Nephropathy
Neuropathy
Peripheral
Autonomic
Macrovascular
Coronary artery disease
Cerebrovascular disease
Peripheral vascular disease
Short-term complications of type 1 diabetes
Diabetic ketoacidosis is dealt by Jefferies et al. elsewhere in this volume and will not be addressed here.
Some hypoglycemia is unavoidable in most individuals who are insulin treated. Hypoglycemia is best considered an adverse effect of insulin therapy (and potentially sulfonylurea therapy as well) instead of a complication of diabetes. Hypoglycemia can cause a myriad of symptoms and signs that are generally divided into neurogenic/autonomic and neuroglycopenic. Neurogenic symptoms are the result of low blood glucose triggering an autonomic response with adrenergic and cholinergic symptoms, including shakiness or tremor, diaphoresis, tachycardia or palpitations, hunger, or irritability. Neuroglycopenic symptoms are the result of reduced availability of glucose to the brain and include sleepiness or lethargy, confusion, loss of consciousness, seizure, coma, and even death. Mild hypoglycemia is generally defined as hypoglycemia that patients recognize because of neurogenic/autonomic symptoms and self-treat with recovery before neuroglycopenic signs or symptoms. Mild hypoglycemia is largely unavoidable in well-managed insulin-treated patients with T1D using currently available treatment modalities. However, see the discussion on “Brain and Cognitive Effects of Diabetes” later.
Severe hypoglycemia, generally defined using the DCCT criteria as hypoglycemia resulting in neuroglycopenic symptoms or signs that render patients unable to treat themselves, represents a more significant concern. Severe hypoglycemia can result in injury (to self or others), seizure, coma, or death. In addition, severe hypoglycemia, especially in young children, may contribute to subsequent neurocognitive deficits and altered regional brain anatomy. Severe hypoglycemia is a complication of diabetes management that should be avoided, and goals of treatment and education should include prevention of severe hypoglycemia.
Short-term visual effects of T1D are not uncommon. Blurred vision may be an acute symptom of hypoglycemia in some patients. More commonly, those with high or rapidly fluctuating blood glucose report blurred vision. This effect is usually transient and resolves once the blood glucoses are stable for a while. It is thought that this is caused by changes in the osmotic characteristics of the lens. Refractive error may change acutely with wide fluctuation of blood glucose, and many ophthalmologists and optometrists recommend postponing refraction for the purpose of prescribing glasses or contact lenses until the blood glucose has been stable. In rare cases, cataracts can develop at or soon after the diagnosis of T1D, even in children and teenagers. If the visual disturbances do not clear within a couple of months after the onset of diabetes treatment, examination by an eye doctor should be strongly considered.
Psychosocial and behavioral issues are common among children with diabetes and their families. Discussion of these complications and outcomes is beyond the scope of this article; but it should be noted that regardless of whether the disorder or problem predated the onset or presented only after the onset of the diabetes, psychological, behavioral, or emotional problems both interfere with successful management and contribute to worse outcomes associated with poor glycemic control.
Long-term complications of type 1 diabetes
Overview
The long-term complications of diabetes are generally divided into microvascular and macrovascular. The microvascular complications include DR, diabetic nephropathy, and diabetic neuropathy. The initial detectable lesions of DR are termed background DR (BDR) and include microaneurysms, exudates, and hemorrhages. BDR is generally benign and does not impact on vision. However, it does represent the first readily detectable ocular finding of diabetes in most patients. More sensitive and invasive tests, such as 7-field stereo fundus photography, fluorescein angiography, or vitreous fluorophotometry, are generally not considered the standard of care until retinal lesions are identified and treatment is being considered but are often used as part of interventional or epidemiologic research studies. Swelling of the macula (clinically significant macular edema [CSME]) represents an advanced form of retinopathy that will impact vision if not treated.
Proliferative DR (PDR) represents more advanced disease with neovascularization, vitreous or preretinal hemorrhages, retinal detachment, and other vision-impacting lesions. PDR and CSME warrant evaluation and close follow-up by an experienced ophthalmologist. Laser photocoagulation or other specialized forms of therapy may be necessary to preserve vision. DR is a leading cause of new-onset blindness in adults. However, clinically significant or vision-threatening retinopathy is rarely detected during the years of pediatric follow-up.
The earliest manifestation of renal involvement of T1D in children and adolescents, as well as adults, is hyperfiltration and an elevated renal plasma flow (RPF). Laborde and colleagues found in 45 diabetic children (aged 12.5 ± 4.0 years; duration 4.9 ± 3.5 years) that both the glomerular filtration rate (GFR) (171 ± 31 mL/min/1.73 m 2 and 124 ± 18 mL/min/1.73 m 2 , respectively) and RPF (778 ± 172 mL/min/1.73 m 2 and 631 ± 128 mL/min/1.73 m 2 respectively) were higher in those with T1D than in control nondiabetic children. Studies report that hyperfiltration was associated with an increased risk of developing microalbuminuria (MA). Both nephromegaly and higher ambulatory blood pressure precede MA in diabetic children. Nephropathy typically progresses from MA (urinary albumin ≥30 mg/d or ≥30 mg per gram of creatinine) to macroalbuminuria (urinary albumin ≥300 mg/d or ≥300 mg per gram of creatinine) to decreasing GFR and ESRD. Without intervention, diabetic nephropathy may progress to ESRD requiring dialysis or renal transplantation. Diabetic nephropathy is a leading cause of ESRD in adults. However, although MA during adolescence is not uncommon, and it may be transient and/or intermittent, it is a predictor of possible future diabetic nephropathy. Macroalbuminuria, hematuria, or renal insufficiency secondary to diabetes are rare during the pediatric years ; if present, strong consideration should be given to referral to a renal specialist.
Diabetic neuropathy can be manifest as peripheral neuropathy or autonomic neuropathy. Peripheral neuropathy most frequently presents with symptoms and findings in the feet but can occur in any area of the body. Peripheral diabetic neuropathy is most often manifest with symptoms of numbness, tingling, or burning and signs of reduced or absent reflexes and vibratory or temperature perception. Although the definitive diagnosis of diabetic neuropathy usually requires evaluation by a neurologist and/or a nerve conduction velocity study, screening using the Michigan Neuropathy Screening Instrument has good sensitivity and specificity for the diagnosis of diabetic neuropathy; the use of the 10-g monofilament has good sensitivity for predicting the development of morbidity, such as foot ulcer, infection, or amputation. Peripheral neuropathy, along with poor circulation and wound healing, is a leading cause of nontraumatic amputation in adults.
Diabetic autonomic neuropathy has multiple manifestations, including orthostatic hypotension, gastroparesis, pupillary dysfunction, bowel and bladder dysfunction, cardiac autonomic neuropathy with resting tachycardia and abnormal heart response to breathing and Valsalva, and erectile dysfunction.
Complications affecting the larger blood vessels, macrovascular complications, include coronary artery disease resulting in myocardial infarction, cerebrovascular disease resulting in stroke, and peripheral vascular disease causing poor limb circulation resulting in claudication, infection or gangrene, and amputation. Although these disorders are rarely if ever seen during the time of pediatric follow-up, the CVD risk factors (hypertension and dyslipidemia) and subclinical vascular abnormalities (intimal media thickening, stiffening of blood vessels, atherosclerotic plaque formation) certainly start during the adolescent years.
Screening for diabetes complications in youths
Both the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) have guidelines for screening youths with both T1D and T2D for complications (summarized in Table 1 ).
| ADA Recommendations | ISPAD Recommendations | |
|---|---|---|
| Retinopathy | Annual dilated fundoscopic examination by an eye doctor at or after puberty or at 10 y and 3–5 y of diabetes | Annual fundus photography after 11 y of age and 2 y of diabetes or at 9 y of age and 5 y of diabetes |
| Nephropathy | Annual urine albumin/creatinine ratio after 5 y of diabetes and after 10 y of age or puberty | Annual urine albumin/creatinine ratio or first morning albumin after 5 y of diabetes and after 10 y of age or puberty |
| Neuropathy | No specific guidelines in children | No specific guidelines in children |
| Macrovascular/CVD | Blood pressure annually Lipid profile at 2 y of age with a + family history or 10 y of age or puberty without a + family history; if normal, repeat every 5 y | Blood pressure annually Lipid profile every 5 y starting at 12 y of age |
Comparison of outcomes in the pre– and post–diabetes control and complications trial eras
During the pre-DCCT era (before the publication of the results of the DCCT in 1993), the prevalence of retinopathy was reported to occur in 27% to 89% of patients with T1D mellitus (TIDM) for 19 to 30 years ( Table 2 ). The prevalence of MA was reported to be 19% to 28% and macroalbuminuria 16% to 20% after about 15 years’ duration ( Table 3 ); the prevalence of ESRD was 2.2% and 7.8%, respectively, at 20 and 30 years’ duration. Diabetic neuropathy, an outcome that is more difficult to document with certainty, was reported to occur in up to 60% of persons with the onset of T1D during childhood and adolescence ( Table 4 ).
| Reference, Authors, Year | Number of Subjects | Age at Onset (y) Mean (Range) | Duration (y) Mean (Range) | Percent with DR |
|---|---|---|---|---|
| Malone et al, 1984 | 74 | Youth | 4.9 ± 3.3 (1–13) | BDR: 50.0 PDR: 14.0 |
| Verrotti et al, 1994 | 55 | Children & adolescent | 6.9 ± 3.1 (4.8–10) | BDR: 16.4 |
| Kernell et al, 1997 | 557 | 14.6 | 8.0 | 14.5 |
| d’Annunzio et al, 1997 | 100 | 8.3 ± 3.5 (1.2–16.4) | 10.4 ± 1.9 (7.3–14.3) | 28.0 |
| Bognetti et al, 1997 | 317 | — | — | 22.7 |
| Holl et al, 1998 | 441 | Children | 7.6 ± 6.3 | 16.3 |
| Olsen et al, 1999, 2000 | 339 | Children & adolescent | 13.2 | 60.0 |
| Skrivarhaug et al, 2006 | 294 | <15 | 24.3 (19.3–29.9) | BDP: 89.1 PDR: 10.9 |
| Nordwall et al, 2006 | 80 | (7–21) | >13.0 | 27.0 |
| Majaliwa et al, 2007 | 99 | (5–18) | 4.76 ± 3.58 | 22.7 |
| Nordwall et al, 2009 | 269 | 8.6 ± 3.8 | 25.2 ± 7.6 | BDR: 49.6 PDR: 26.1 |
| Mayer-Davis et al, 2012, SEARCH | 222 | <20 | 6.8 ± 1.0 | 17.0 |
| Salardi et al, 2012 | 105 | (16–40) | 19.7 | 56.2 |
| White et al, 2010, DCCT/EDIC | 156 | 13–18 | ∼10 | Severe BDR: 16.1 PDR: 9.7 CSME: 1.7 |
| ∼16 | Severe BDR: 19.5 PDR: 18.2 CSME: 6.9 |
| Reference, Authors, Year of Report | Number of Subjects | Age of Onset (y) Mean (Range) | Duration (y) Mean (Range) | Percent with MA/MacroA |
|---|---|---|---|---|
| Joner et al, 1992 | 371 | — | 10.5 (6.2–17.3) | 12.5 |
| Rudberg et al, 1993 | 156 | <20 | 6.9 ± 4.5 | 24.2 |
| Janner et al, 1994 | 164 | Children & Adolescents | — | 19.5 |
| Bognetti et al, 1997 | 317 | — | — | 11.0 |
| Jones et al, 1998 | 233 | 7.7 (median) | 8.5 | 14.5 |
| Schultz et al, 1999 | 514 | <16.0 | 5.0 | 12.8 |
| Holl et al, 1999 | 447 | Children | 10.0 13.0 | 5.0 10.0 |
| Olsen et al, 1999, 2000 | 339 | Children & adolescent | 13.2 | Micro: 9.0 Macro: 3.7 |
| Moore et al, 2000 | 1007 | <20.0 | 7.8 (median) (1.7–15.9) | 9.7 |
| Levy-Marchal et al, 2000 | 702 | Children & Adolescents | 7.6 ± 3.1 | 5.1 |
| Dahlquist et al, 2001 | 60 | 5.7 ± 3.0 | 29.0 ± 3.0 | Micro: 28.0 Macro: 12.0 |
| Amin et al, 2005 | 308 | 9.8 (0.3–15.9) | 10.9 (6.0–17.8) | 11.4 |
| Nordwall et al, 2006 | 80 | (7–21) | >13.0 | 5.0 |
| Skrivarhaug et al, 2006 | 299 | <15.0 | 24.0 (19.3–29.9) | 14.9 |
| Gallego et al, 2006 | 950 | <16.0 | 7.6 | 13.4 |
| Amin et al, 2009 | 527 | <16.0 | 10.0 | 20.9 |
| Raile et al, 2007 | 27,805 | 12.9 | 8.3 | Micro: 3.0 Macro: 0.2 |
| Maahs et al, 2007, SEARCH | 3259 | <20.0 | (0–5) | 9.2 |
| Chiarelli et al, 2008 | 340 | <18.0 | 16.0 | 9.4 |
| Dart et al, 2012 | T1D: 1011 T2D: 342 | (1–18) | — | 13.5 27.1 |
| Reference, Authors, Year of Publication | Number of Subjects | Age at Onset (y) Mean (Range) | Duration (y) Mean (Range) | Percent with a Finding Compatible with Diabetic Neuropathy |
|---|---|---|---|---|
| Bognetti et al, 1997 | 317 | — | — | 18.5 |
| Olsen et al, 1999, 2000 | 339 | <20 | 13.2 | 62.5 |
| Bao et al, 1999 | 38 | <20 | 7.2 | 68.4 |
| Nordwall et al, 2006 | 80 | (7–21) | >13 | 59.0 |
| Jaiswal et al, 2013, SEARCH | 329 | <20 | 6.2 ± 0.9 | 8.2 |
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