Prognostic implications of diabetes phenotyping: new concepts for an old disease
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Dr. Daniele: The case record presented here is that of D.S., a woman who is now 35 years. Her case report begins when she was 14 years (1987) at which time she underwent screening for diabetes because of her obesity (weight 95 kg, BMI 36 kg/m2) and her family history of diabetes (mother and maternal grandmother). Based on her fasting glucose level (160 mg/dl), she was diagnosed with diabetes mellitus. At that time, her level of HbA1c was 7.8%. D.S. began treatment with a low calorie diet with which she obtained a moderate weight reduction (about 10–15 kg). During the following years, she has had several weight fluctuations until she reached 67 kg in 1995. Throughout that period, she had several medical visits, but there is no available information regarding her glucose levels. At 22 years of age (1996), she was admitted into the hospital following a hyperglycemic crisis, accompanied by polyuria and polydipsia. This hospitalization resulted in the diagnosis of insulin-dependent diabetes mellitus and subsequently, she began insulin treatment. On that occasion, diabetic retinopathy was found. The following years she saw an improvement in her glucose levels (HbA1c 6.5%) but a worsening of the retinopathy (diffuse microaneurysms, microhemorthages, and hard exudates) that required bilateral laser therapy. Concurrently, she developed a peripheral motor and sensory neuropathy, and then microalbuminuria but with preserved renal function. She continued insulin with four daily injections and maintained good metabolic control (HbA1c < 6.5–7%), although her body weight rose continuously until she again reached 95 kg in 2000. In 2003, her HbA1c levels increased (7.8%) and she gained an additional 5 kg.
Dr. Daniele, Dr. Bianchi: The clinical characteristics of disease at onset and during follow-up, questioned the appropriateness of the initial diagnosis and suggests a different etiology of diabetes. At that time, her β-cell function was tested in fasting and after glucagon stimulus. The results highlighted C-peptide values of 1.24 ng/ml in basal condition, and 1.47 ng/ml 6 min after the stimulus. The studies for the antibodies anti-GAD and anti IA2 were negative.
Dr. Daniele, Dr. Bianchi: The phenotypic characteristics, along with a moderate β-cell function reserve, and the negative antibody results, might be indicative of type 2 diabetes mellitus instead of type 1 diabetes.
Dr. Daniele, Dr. Del Prato, Dr. Miccoli: The case reported here is useful to discuss several aspects regarding both the diagnosis and treatment of diabetes.
The etiologic classification of hyperglycemic syndromes identifies two main types of diabetes, type 1 and type 2 diabetes . Recently, other categories of diabetes have been defined, including type 1a, type 2b, type 1 1/2, LADA (latent autoimmune diabetes of adult), double diabetes, hybrid diabetes, MODY (maturity onset diabetes of the young) and LADY (latent autoimmune disease in youth) [2, 3].
Type 1 diabetes, or immune-mediated, represents 5–10% of all cases of diabetes . It is characterized by β-cellular destruction associated with an autoimmune process, which is evidenced in 85–90% of presenting cases by the presence of the antibodies anti-insula, anti-GAD, anti-IA2, and anti-IA2β. Patients with type 1 diabetes have an elevated risk of other associated autoimmune diseases such as celiac disease, Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, and pernicious anemia. A small percentage of patients (idiopathic type 1b) of African and Asian descent do not present with signs of autoimmune disorders. Although type 1 diabetes can occur at any age, it most frequently develops in childhood and adolescence, usually associated with ketoacidosis. In other patients, it manifests in a slower onset of hyperglycemia and develops into ketoacidosis following an infection or stress trigger. Classic symptoms of the disease are polyuria, polydipsia, asthenia, and weight loss. A distinctive characteristic of type 1 diabetes is in the almost complete absence of C-peptide .
Type 2 diabetes accounts for 90–95% of all cases of diabetes, and manifests primarily in adulthood . It is the result of a combination of insulin-resistance and a relative β-cell failure. The occurrence of hyperglycemia may be occasional, for example in conjunction with a cardiovascular event. The C-peptide levels are normal or elevated with this type of diabetes . Only 10–15% of patients present with antibodies (anti-GAD) that can be seen as a sign of future insulin dependence ; in this case the diabetes is defined as LADA.
New evidence has opened the discussion of a possible common acquisition that would redefine the two distinct pathologies of type 1 and type 2 diabetes. This includes the directly proportional relationship between body weight and the risk of type 1 diabetes, the increase in incidence of type 2 diabetes in adolescents and of diabetes type 1 in children under 5 years of age, and the occasional presence of autoantibodies in patients with type 2 diabetes. Based on these considerations, a hypothesis has been made showing a continuum between type 1 and 2 diabetes with a considerable superimposition for the onset age . According to a recent hypothesis, a complicated interaction between genetic factors (genotype HLA involvement in the immune response) and non-genetic factors (i.e. insulin resistance) is the basic mechanism of the β-cell hyper-stimulation that causes the β-cell to become immunogenic and the target of autoimmune reactions. From this viewpoint, the individual factors accelerate the development of diabetes and therefore the β-cell deficit that would determine the onset age of the disease. Furthermore, the insulin-independence is not an entity of the diagnosis but only a temporary state that will eventually lead to insulin-dependence.
Clinical characteristics of type 1, type 2 and monogenic diabetes
Type 1 diabetes
Type 2 diabetes
Often postpubertal except MODY2 and neonatal diabetes
Most often acute, rapid
Reflects the background risk
Reflects the background risk
Rare (1/3 of newly diagnosed adolescent)
Rare in MODY common in neonatal diabetes
Based on the recent guidelines from America Diabetes Association (ADA) , patients with diabetes type 2, like the patient presented here, should be treated at the time of diagnosis with a low-calorie diet and metformin when the HbA1c is above 7%. The level of HbA1c should be used to guide future treatment decisions taking into consideration the most effective agent or insulin therapy if the HbA1c is at or above 8.5% or if secondary symptoms to hyperglycemia are present .
After approximately 10 years of what was likely inadequate treatment, acute metabolic complications and chronic microvascular complications appeared in our patient. The last decade has shown an increase in the presence of type 2 diabetes in childhood through adolescence that runs parallel to an increase in the prevalence of obesity in the same age group. Further review of epidemiological studies has shown that the onset of type 2 diabetes in adolescence can be associated with a higher morbidity and mortality . In fact, in these subjects microvascular complications (retinopathy, nephropathy, and neuropathy) may be present at the time of diagnosis , and are qualitatively similar but rapidly progressive in comparison with these symptoms in adolescents with type 1 diabetes. Moreover, obesity, hypertension, dyslipidemia, and NAFLD (non-alcoholic fatty liver disease) can be associated with a higher cardiovascular risk although the data to prove this is lacking. In any case, type 2 diabetes must be quickly diagnosed to prevent subsequent β-cell failure  and the development of micro-macrovascular complications by reducing insulin resistance through weight loss and antidiabetic drugs.
Clinical recommendations for bariatric surgery in type 2 diabetes
Level of evidence
Bariatric surgery should be considered for adults with BMI 35 kg/m2 and type 2 diabetes, especially if the diabetes is difficult to control with lifestyle and pharmacologic therapy
Patients with type 2 diabetes who have undergone bariatric surgery need lifelong lifestyle support and medical monitoring
Although small trials have shown glycemic benefit of bariatric surgery in patients with type 2 diabetes and BMI of 30–35 kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI 35 kg/m2 outside of a research protocol
The long-term benefits, costeffectiveness, and risks of bariatric surgery in individuals with type 2 diabetes should be studied in well-designed randomized controlled trials with optimal medical and lifestyle therapy as the comparator
Bariatric surgery is emerging as a prominent form of treatment for obesity and, more recently, for diabetes. An elevated percentage of diabetic subjects are overweight or morbidly obese. The obesity also represents an important risk factor for cardiovascular disease, and is often associated with type 2 diabetes, dyslipidemia, hypertension, non-alcoholic hepatopathy steatosis, subclinical inflammation, and endothelial dysfunction. Several studies on surgical interventions have shown that treatment of obesity, especially that of grade III, can improve diabetes and other metabolic conditions. The reduction of caloric intake mediates anatomical modifications of the intestine that represents the main effect of bariatric surgery . Restrictive surgery, like gastroplastic, gastric banding, the combination of the previous two operations, and vertical gastrectomy (sleeve) slow the gastric emptying process by creating a reservoir. Gastric bypass Roux-en-Y and the biliopancreatic diversion with duodenal switch are usually completed in combination with restrictive vertical gastrectomy to reduce food absorption by excluding a large part of the intestine.
In a meta-analysis involving 136 studies encompassing a total of 22,094 diabetic patients, bariatric surgery led to complete remission of diabetes in 48% of patients after gastric banding, 84% of patients after gastric bypass Roux-en-Y and in 95% after biliopancreatic diversion . Furthermore, in the case of the malabsorptive procedures, the diabetic remission was verified in the weeks following the surgery, which suggests a metabolic effect independent of weight modification. It is possible that the duodenum and the proximal part of the ileum have a role in the physiopathology of diabetes through the regulation of the incretin system in order to maintain glucose homeostasis . A recent hypothesis proposes that there is an imbalance towards the anti-incretinic system with a reduction of insulin secretion and action, and β-cell growth in patients with type 2 diabetes. In bypassing the duodenum and portions of the ileum through malabsorptive bariatric surgery, the balance between these systems is restored by the exaggerated contact between nutrients and the distal regions of the ileum and colon. The β-cell function, unlike BMI, should represent a predictive factor of bypass surgery for the treatment of diabetes. In our patient, the positive outcome of gastric banding surgery has permitted a rapid weight reduction (around 30 kg), better control of diabetes (HbA1c −1%) and a significant reduction in insulin need.
In conclusion, the phenotypic characteristics are important tools to the correct etiological diagnoses of diabetes, and allow the correct formulation of prognosis and treatment. The early onset of type 2 diabetes in adolescence is related to an increased risk of severe and premature microvascular complications, and therefore an early screening for retinopathy, nephropathy, and other co-morbidities should be performed from the time of the diabetes diagnosis, as well as to permit an accurate, follow-up. At diagnosis, the intensive life style approach should be the first intervention unless other metabolic abnormalities are present. Metformin is useful in controlling glucose-metabolism. Finally, bariatric surgery, when indicated, can be an effective alternative approach for the treatment of obesity and diabetes.
Dr. Di Cianni: In January 2007, D.S. underwent her first pregnancy. A strict home blood glucose monitoring allowed her to reach HbA1c values of less than 6%, with a weight gain of 10 kg by the end of the pregnancy. During the 36th week she had a rise in blood pressure and edema in the lower limbs which were associated with thrombocytopenia and a worsening of albuminuria. These elements all suggested pre-eclampsia and D.S. was admitted to the obstetric ward. Finally, she delivered a normal baby boy weighing 3.2 kg, after induced labor.
Conflict of interest statement
The authors declare that they have no conflict of interest related to the publication of this manuscript.
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