Insulin resistance and type 2 diabetes in youth with obesity 

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Author(s):

	Gianpaolo De Filippo
	Pediatric Endocrinology & Adolescent Medicine Unit, Bicêtre Hospital, Paris 11 University, France
	View Author’s Full Biography

INTRODUCTION  

Insulin is an essential hormone secreted by the pancreas that regulates the homeostasis of glucose, lipids and protein. Insulin stimulates glucose uptake and glycolysis in the muscle; in the liver it decreases endogenous glucose production and stimulates glycogen synthesis.  

Insulin resistance (IR) (i.e., reduced insulin action in skeletal muscle, adipose and hepatic tissues) reflects a combination of factors leading to disturbances of glucose, lipid and protein metabolisms.  IR one of the most common metabolic alterations related to obesity, is  a key element of metabolic syndrome and a pivotal pathophysiological feature of type 2 diabetes mellitus (T2D). Mechanisms linking obesity to IR and diabetes are multiple, sharing molecular and genetic bases (1) in association with an important contribution of environmental and lifestyle factors (2,3). The interaction between genetics and environmental factors is translated into phenotype of T2D that appears complex and heterogeneous (4). 

Even if both obesity and T2D are associated with IR, most obese, insulin-resistant individuals do not develop hyperglycemia. Under normal conditions, pancreatic islet β -cells increase insulin release to sufficient levels to compensate for the reduced efficacy of insulin action, allowing the persistence of normal glucose tolerance. For the clinical onset of T2D to occur, b-cells must be unable to fully compensate for decreased insulin sensitivity (1). 

In the last two decades, T2D , once thought to be a metabolic disorder exclusively affecting  adults, has become increasingly more frequent in adolescents with obesity, reaching about 15 million of all adolescents worldwide vs. 3.5 million for Type 1 Diabetes (T1D). All populations may be affected: while it is still rare in Europe, some ethnic groups (in particular, African Americans, Native Americans, Hispanics), seem to be much more prone to it, reflecting a peculiar genetic background (5). Treatment of overt diabetes is largely inspired by the experience in adults. However, the pediatric form of the disease has some specificities requiring specific investigations and management.  

When compared with adult-onset T2D, youth-onset T2D has a more aggressive clinical course with rapid deterioration in β-cell function. Youth-onset obesity and T2D are associated with an increased risk and earlier onset of serious long-term health complications, such as retinopathy, nephropathy, cardiovascular diseases, and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NASH, non-alcoholic steatohepatitis) (6,7). Since T1D is far more frequent in the young without obesity than T2D, careful screening is required. Similarly, genetic variants called MODY (Maturity Onset Diabetes of the Young) have to be identified.  

PHYSIOPATHOLOGY  

The occurrence of hyperglycemia in T2D always reflects a higher production of glucose by the liver than its use by peripheral tissue in an insulin dependent manner (muscles, heart, bowel, kidney, except the brain) whether or not the level of production is high (see figure 1). Fluctuations in insulin sensitivity occur during the normal life cycle and IR is physiologically observed during puberty (8) and pregnancy (9), but, at any age, obesity phenotype is on average characterized by an increased production of glucose by the liver which precedes a frequent association with IR.  

Figure 1 Progression of β-cell failure in T2D. 

A When blood glucose concentrations rise after a meal, β-cells secrete insulin, which activates peripheral tissues to take up glucose and maintain glucose homeostasis. For example, this process acts by reducing hepatic glucose output and gluconeogenesis (liver), inducing glycogen synthesis (liver and muscle), and increasing glucose uptake (muscle and adipocytes). B, C Metabolic stresses, such as excessive calorie intake, obesity, and physical inactivity, promote the development of insulin resistance, a condition in which peripheral tissues become less responsive to insulin. In response, β-cells produce and secrete an abnormally large amount of insulin (hyperinsulinemia). Sustained metabolic stress exacerbates ER and oxidative stress and mitochondrial dysfunction, which collectively contribute to β-cell failure and the loss of β-cell mass, leading to hyperglycemia. 

Downloaded from Open source: Jinsook Son, Domenico Accili,  Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes. Exp Mol Med. 2023 Aug 1;55(8):1652–1658.  

On the other hand, lifestyle improvements such as increased physical activity (i.e.  resistance exercises alongside aerobic sessions (for a minimum of two to three 60-minutes per week), have a significant positive impact on insulin-sensitivity leading to decreased IR  and are a key therapeutic tool in the management of both obesity, IR or T2D (see below) (10).  

Adipose tissue is nowadays considered as a genuine endocrine organ; it modulates metabolism by releasing Non–Esterified Fatty Acids (NEFAs), glycerol, several hormones (including leptin and adiponectin), and proinflammatory cytokines (11). A growing body of evidence supports the role of inflammatory cytokines, and adipokines in the pathogenesis of T2D (12). 

In obesity, the level of many of these metabolites is increased, inducing a delicate balance between factors that promote and factors that protect from IR. For example, Retinol-Binding-Protein-4 (RBP4) acts not only as a transporter of vitamin A but also as a cytokine involved in IR. RBP4 has been demonstrated to induce IR in muscle and enhance gluconeogenesis in the liver through a retinol-dependent mechanism (13). Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPARγ coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK (14). The impairment of the adiponectin system function has been demonstrated even in young age (15).  

Adipose tissue distribution: the paradox of the metabolically healthy obesity and unhealthy thinness  

 Adipose tissue is associated with IR, but insulin sensitivity also varies markedly in lean individuals because differences in body fat distribution are partly linked  to ethnicity. Even out of an obesity context, lean individuals with a more peripheral, subcutaneous fat distribution are more insulin sensitive than lean subjects with predominant central, visceral fat. Furthermore, liver fat content independently of visceral fat, is a key determinant of  overall IR, which involves liver, muscle, and adipose tissue (16,17). The first study on the MONW (Metabolically Obese of Normal Weight), a phenotype that is characterized by metabolic diseases in people with normal body weight was published in 1981 (18). Since then, no uniform criteria have been established for MONW definition, which has created difficulties in identifying affected individuals. These observations lead to the more recent definition of « TOFI » phenotype (Thin Outside, Fat Inside) as an important risk factor in the pathogenesis of T2D, leading to further onset of MONW. Subjects with this phenotype, despite undersized fatty tissue, have an increased amount of adipose tissue surrounding the internal organs, which increases the risk of IR and T2D (19).  

Other factors such vitamin D deficiency (20) and excess dietary salt intake (20) seem to play a substantial role in the development of IR. Poor vitamin D status is associated with future risk of T2D and metabolic syndrome in obesity. The biological mechanisms by which vitamin D influences glycemic control in obesity are not well understood but are thought to involve enhancement of peripheral/hepatic uptake of glucose, attenuation and/or regulation of insulin synthesis/secretion by pancreatic b-cells. There is evidence that the bone interacts with extra-skeletal organs, including metabolic and cardiovascular systems, through its endocrine functions. These observations support the hypothesis of the implication of vitamin D in the determinism of metabolic disorders (21). 

Genes and environment 

Genetics and heritability play a role in childhood IR and later development of diabetes. Many genes, together with their interactions with the environment, are involved in the development of obesity and diabetes (22). A vast majority of obesity cases is of polygenic origin, including severe cases that mimic monogenic forms. Mutations may cause early onset severe obesity. Up to now, about 30 mutations have been identified, the most frequent one in up to 4% of cases, affects the melanocortin-4 receptor gene (MC4R). Other rare causes include mutations in leptin (LEP) and the leptin receptor (LEPR), prohormone convertase 1 (PC1) and pro-opiomelanocortin (POMC) (22). These genes are associated with obesity but do not seem so far to enhance directly the susceptibility to diabetes. Epigenetics contributes to these differences (23,24,25) and to the susceptibility to T2D in obesity. Over 400 genomic variants associated with T2D and its related quantitative traits are now identified. Genetic scores comprising dozens to millions of associated variants can predict incident T2D. Paradoxically, this complexity represents an interesting issue for future therapeutic strategies, allowing artificial intelligence-based design of drugs and precision medicine.  

Progression from insulin resistance to type 2 diabetes 

T2D onset is progressive and is usually the result of a slow process lasting many years.  In order to maintain glycemia within physiological range, IR is compensated by a proportionate increase in insulin secretion. Defects in β-cell function can be detected at the prediabetes stage (26,27). Decreased insulin output may also impair adipocyte metabolism, resulting in increased lipolysis and elevated NEFA levels. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity (27,28).  

Even mild impairments of insulin release may have central effects on metabolic homeostasis. Insulin acts in the hypothalamus to regulate appetite and impaired insulin signaling is associated with changes in food intake and body weight. 

Dysregulation in other hormonal (glucagon, incretins) and metabolic (adipose tissue dysfunction, chronic inflammation) pathways also contributes to the pathogenesis of youth-onset prediabetes and T2D. Elevated glucagon concentrations in youth with obesity and impaired glucose regulation have been linked to adiposity and IR. Hyperglucagonemia is suspected to be an early event in the pathogenesis of dysglycemia with a longitudinal decline in glucose tolerance over a short period of observation although this occurs independently of β-cell dysfunction (29).  

Some studies have described trajectories in plasma glucose, insulin sensitivity, β cell function, and subclinical inflammation related to diabetes before the disease is evidenced. Population-level growth curves contribute to etiological and pathophysiological understanding but may somewhat oversimplify the complex and heterogeneous disease mechanisms responsible for T2D. 

Given that -cell function is decreased by about 75% when fasting hyperglycemia is present, assessment of -cell function in individuals at risk of developing diabetes has been of interest to better understand the physiopathology of diabetes progression. Even when the glucose level is still within the normal range, -β cell function decreases progressively with a corresponding increase of fasting glucose. First-degree relatives of individuals with T2D, who are genetically at increased risk, also have impaired -cell function, even though they may still have normal glucose tolerance. Data from groups of first-degree relatives with different ethnic backgrounds suggest that common processes underlie the development of T2D— namely, IR and β-cell dysfunction — and that the degree of abnormality of insulin release is the dominant determinant of differences in glucose tolerance between individuals (30). 

Even if children and young people with impaired glucose tolerance (IGT) (or newly diagnosed T2D) had significantly higher C-peptide and insulin-levels than adults with the same condition, b-cell function declined faster than in adult-onset T2D (31).  

DIAGNOSIS AND THERAPEUTIC MANAGEMENT: EVALUATION OF INSULIN-SENSITIVITY AND IDENTIFICATION OF INSULIN-RESISTANCE 

Identification and diagnosis of IR usually rely on clinical and biochemical criteria. A systematic screening of all patients is not indicated in daily practice since the work-up doesn’t change in absence of overt diabetes (see below). Screening for T2D or prediabetes in asymptomatic children and adolescents in a clinical setting should be risk-based (see below table 2) (32). 

Acanthosis nigricans (AN) (see figure 2) is so closely linked with IR that is considered as a clinical surrogate for laboratory-determined hyperinsulinemia. AN is characterized by the presence of visible posterolateral neck pigment and/or texture and visible axillary pigment and/or texture (33). Considering that the onset of hyperglycemia is usually slow and symptoms such as polyuria, nycturia and polydipsia are often subtle and may go unrecognized by the patient, the presence of AN, in an obesity context, can be the unique clinical sign of incipient (or overt) T2D).  

Figure 2 : visible acanthosis nigricans on the neck of a Caucasian (a), a North-African (b), and a Black-African subject (c) 

Biochemical criteria 

The gold standard method to measure insulin sensitivity, the hyperinsulinemic euglycemic clamp, described in 1979 by the Fronzo et al. (34) is very labor- and time-intensive and thus not feasible either in epidemiological research nor in daily practice. Thus, several surrogate indices have been developed and validated in order to perform the diagnosis in a clinical setting, whether in or even in outpatients, (35). 

The fasting insulin level and the homeostasis model assessment to quantify insulin resistance (HOMA-IR,  is largely used among others as a surrogate marker for screening in adults.  Since  the HOMA-IR varies among populations, there is no agreement on HOMA-IR cutoffs, and several studies proposed specific cut-offs for prepubescent and pubescent subjects (36). 

For example, in the IDEFICS study (37), dealing with a large European population of prepubescent children, the 5th and 95th percentiles of insulin levels in 3 to < 3.5-year-old were 4.2 and 49.3 pmol/L, respectively, in girls, and 3.5 and 41.0 pmol/L, respectively, in boys. In 10.5 to < 11-year-old, the 5th and 95th percentiles were 25.7 and 100.7 pmol/L, respectively, in girls and 19.4 and 88.2 pmol/L respectively, in boys. 

The 5th and 95th percentiles of HOMA-IR in 3 to < 3.5-year-olds were 0.1 and 1.5, respectively, in girls and 0.1 and 1.3, respectively, in boys. In 10.5 to < 11-year-olds, the 5th and 95th percentile HOMA-IR values were 0.8 and 3.4, respectively, in girls and 0.6 and 3.0, respectively, in boys. From a practical point of view, it is reasonable to state that HOMA value > 3.5 indicates a state of non-physiological IR at any age.  

Table 1:  Some indexes of IR and IS derived from fasting blood samples (from 35) 

HOMA – IR : homeostasis model assessment for insulin resistance 

QUICKI : quantitative insulin-sensitivity check index 

IGR : fasting glucose-to-insulin ratio 

In : fasting insulin 

TG : triglycerides  

*the cut-off can change according to age and ethnicity 

Several tools for calculating the various indices are available for free online. For example:  

https://codingace.net/medical/insulin sensitivity.html 

Diagnosis of Prediabetes and Diabetes 

The onset of T2D in adolescents’ obesity is a slow process the initial clinical manifestations of which are in most cases difficult to detect. This scenario deeply contrasts with the dramatic onset of the classical form of T1D of the young, always clinically evident and as a consequence, a high proportion of cases of T2D, appear to be initially undiagnosed. 

A pitfall should be kept in mind: a rapid weight loss in an obese adolescent (who may be pleased by this unexpected situation and try to hide the polyuro-polydipsia) is in some cases the first alarming feature of incipient ketoacidosis and later diabetic coma. T1D should not be ruled out a priori in obese children and adolescents although T2D is the commonest form associated to obesity. In some cases, it may seem difficult to differentiate in presence of obesity T2D from genuine T1D or even some of the rare familiar Maturity Onset Diabetes of the Young (MODY) of genetic origin. Table 4 sums up the mains differences. In any case, T2D is not associated to circulating auto antibodies.  

Table 2 : Risk-based screening for type 2 diabetes or prediabetes in  

asymptomatic children and adolescents in a clinical setting (from 32) 

Screening should be considered in youth with overweight (≥85th percentile of BMI) or obesity (≥95th percentile of BMI) and who have one or more additional risk factors: 

• Maternal history of diabetes or GDMduring the child’s gestation 
• Family history ofT2Din first- or second-degree relative  
• High-risk ethnicity, and ancestry 
• Signs ofIRor conditions associated with IR (acanthosis  

nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, large- or small-for-  

gestational-age birth weight) 

GDM: gestational diabetes mellitus  

Table 3 : Diagnostic criteria for prediabetes and diabetes (from 32) 

FPG : fasting plasma glucose, OGTT : oral glucose tolerance test, HbA1c : glycated haemogloblin, IGT : impaired glucose tolerance. 

Table 4: Differential diagnosis criteria between T2D and T1D 

A specific type of diabetes, MODY (maturity-onset diabetes of the young), particularly in its type 2 form, can be mistaken for type 2 diabetes.  

MODY is a type of diabetes known as “monogenic,” meaning that it is caused by pathogenic variants in a single gene, most often involved in insulin secretion and/or pancreatic development. It accounts for 2 to 3% of all diabetes cases.  MODY-type monogenic diabetes is characterized by early onset (before the age of 35–40) and autosomal dominant inheritance. They differ from type T1D and T2D by the absence of autoimmunity and of ketoacidosis at diagnosis, as well as a by a BMI within the normal range of the general population. Pathogenic variants in the genes encoding glucokinase (MODYGCK or “MODY2”), the HNF1A transcription factor (MODY-HNF1A, or “MODY3”), and the HNF4A transcription factor (MODY-HNF4A, or “MODY1”), are responsible for the majority of MODY diabetes cases (38). 

Table 5. Factors suggesting MODY diabetes 

• Moderate fasting hyperglycemia, stable over the long term, with strong familial penetrance 

• Gestational diabetes in the absence of classic risk factors 

• Phenotype suggestive of T1D but without ketosis and without autoantibodies (GAD, IA-2, ZnT8) 

• Phenotype suggestive of T1D that is unusually stable and easily controlled in the long term 

• Non-insulin-dependent diabetes without overweight or markers of insulin resistance 

• Diabetes that is unusually responsive to low doses of sulfonylureas or glinides 

• Strong family history of early-onset diabetes in normal-weight individuals 

• Presence of extrapancreatic symptoms (kidney, liver, genital tract, etc.);  

• Syndromic diabetes 

• Family history of diabetes or hyperinsulinism with onset in the neonatal period or early childhood 

(Adapted from https://www.sfdiabete.org/files/files/JNDES/2019/12_mced95_timsit.pdf 

PREVENTION, MANAGEMENT AND MEDICATIONS 

The onset of T2D, requires a complex management in patients under 18 years of age based on a combination of healthy lifestyle changes and pharmacological intervention. Recent advances in the treatment of T2D, which have also benefited the approach of obesity, should not distract attention from the essential need for a prevention policy, where pharmacological or surgical therapy could be seen as an easy shortcut. The risk of diabetes can significantly be reduced even in genetically predisposed subject by lifestyle modifications. At the prediabetes stage, physical activity has even been shown to be more effective than metformin (though this is no longer the case once diabetes has developed) (39). 

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) and Restoring Insulin Secretion (RISE) trials highlighted the need for improved treatments in patients with youth-onset T2D. The TODAY trial demonstrated that metformin only provided effective glycaemic control in half of the participants, while in neither trial were metformin nor insulin able to effectively slow the accelerated decline in β-cell function (40). 

Insulin resistance and prediabetes  

 A systematic pharmacological treatment of a metabolic disturbance without presence of overt diabetes is no recommended (see below, section “therapeutics”); thus, changing lifestyle is the basis of primary and/or secondary prevention. Moreover, the efficacy of interventions for primary T2D prevention (i.e., preventing shift from prediabetes to T2D ) has been demonstrated mainly among individuals with prediabetes who have impaired glucose tolerance (IGT) with or without elevated fasting glucose, not for individuals with isolated impaired fasting glucose (IFG) or for those with prediabetes defined by HA1c levels  (41).  

Lifestyle modification is a pivotal element of IR management and T2D prevention (39). The recommended intervention includes weight loss (typically 7-10 % of body weight in adults), regular physical activity and behavioral support that includes especially in pediatric age, the familial environment. However, extrapolating data from adults to the paediatric and adolescent population is still difficult. 

Nutritional Recommendations 

Dietary pattern selection should be individualized according to the metabolic phenotype, comorbidities, and adherence potential (42) 

Reducing nutrient-poor carbohydrates intake by reducing (or excluding) consumption of highly refined cereals  and added sugars and eliminating sweet beverages is recommended.  

Low-carbohydrate (<26% of daily energy intakes) dietary programs have been quite successful in preventing and treating diabetes in adults. Even if metanalysis do not bring convincing evidence in favour of the prescription of these dietary changes in youth, the negative impact of a unhealthy dietary pattern is undeniable. In clinical trials requiring significant sustained changes to typical eating, investigators report challenging feasibility and acceptability. 

A dietary pattern that emphasizes plant-based foods with high fiber content (vegetables, fruits, whole grains, nuts), lean sources of protein (poultry, fish, legumes), and mono and polyunsaturated fats and limits sugary beverages and highly processed foods is associated with optimal glycaemic and cardiometabolic risk profiles (43). 

Physical Activity Recommendations 

Lifestyle interventions, particularly regular exercise, are acknowledged as the cornerstone of prevention and treatment of T2D. Abundant evidence indicates that exercise can effectively improve insulin sensitivity, reduce blood glucose, and provide broad metabolic benefits (39). 

Physical activity, independent of weight loss, decreases insulin resistance and is associated with lower HbA1c, BMI, and CVD risk factors in youth with T2D (42). Moderate-to-vigorous physical activity totalling at least 60 min daily and limitation of sedentary time are strongly recommended (44,45). Despite the introduction of new medications into the therapeutic arsenal of the paediatric diabetologist, focusing the efforts on lifestyle’s changes should be the primary objective, the aim being to deprescribe while positive health outcomes are reached, as proposed in adults (46). 

Pharmacological treatment 

Until recently, the major challenge in the management of youth onset T2D was the lack of treatment options; for nearly 20 years treatment was limited to metformin and insulin (47). In 2000, metformin was approved for use in patients aged 10 years or older by the Food and Drug Administration (FDA) as a first-line oral antidiabetic therapy, with add-on insulin therapy initiated when glycaemic targets were not met (48). New therapeutic agents across different drug classes have been now approved for the treatment of youth-onset T2D in the United States and Europe, including the injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide, exenatide, dulaglutide, and the orally active sodium–glucose cotransporter-2 (SGLT-2) inhibitors, dapagliflozin and empagliflozin . Despite multiple phase 3 studies assessing the efficacy and safety of these new therapies in patients with youth-onset T2D, challenges in patients’ recruitment make performing such trials extremely difficult (50). 

In addition, much of the enthusiasm for this type of treatment stems from its demonstrated cardiovascular and nephroprotective benefits. However, this kind of evidence is difficult to establish in the paediatric population, while cardiovascular complications are still silent, and would require much longer-term studies in order to be evidenced. 

Prediabetes  

The aim of the therapy at the stage of prediabetes should be to avoid the progression to overt diabetes. Pharmacotherapy in youth with prediabetes (metformin or rosiglitazone) has been tested in a few studies which were relatively small and of short duration. In the RISE study investigators tested treatment of 91 youth with either IGT or recently diagnosed T2D, with metformin for 12 months or insulin glargine for 3 months followed by metformin for 9 months. Neither of these strategies was effective for preventing the deterioration in β-cell function during or after the treatment period. Following medication withdrawal, both fasting and 2-h OGTT glucose worsened from baseline, associated with the decline in β-cell function (51). These results indicate that, to date, the medication strategies have not been effective for preventing the progressive b-cell dysfunction that underlies the transition from prediabetes to T2D. 

Nevertheless; new therapeutic agents such as that GLP-1 agonists may be considered for selected adolescents and young individuals with severe obesity or obesity accompanied by comorbidities to prevent or delay progression to T2D (52). 

T2D with stable metabolic state at onset 

The excellent safety profile of metformin makes it the gold standard for initial treatment of T2D in adults and youth. Youth with presumptive T2D who present in a stable metabolic state and with HbA1c <8.5% can receive metformin as initial therapy. The initial  dose of metformin is 500–1,000 mg/day, titrated weekly as tolerated, to the recommended therapeutic dose of 1,000 mg twice a day (53). 

Treatment in presence of more severe hyperglycemia or ketoacidosis 

In youth with symptomatic hyperglycemia (i.e. polyuria, nycturia, polydipsia), but without acidosis a treatment with basal insulin should be introduced while concurrently initiating and titrating metformin. 

In patients with ketosis/ketoacidosis at diagnosis, subcutaneous or intravenous insulin should be initiated in order to treat  the metabolic decompensation. Once acidosis is resolved and the diagnosis of T2D confirmed, metformin can be initiated while insulin therapy is weaned as tolerated (53). 

New pharmacological agents  

GLP-1 receptor agonists 

GLP-1 receptor agonists (GLP-1RA) target multiple processes including improvement in glucose mediated insulin secretion (incretin effect), inhibition of glucagon production, delay in gastric emptying, and promotion of satiety (54). In a first phase, three GLP-1RA have received the U.S. Food and Drug Administration (FDA) approval for use in children and adolescents aged 10-17 years with T2D, based on efficacy data from clinical trials focused on exenatide, liraglutide and dulaglutide, the latter well studied in a young T2D population (52). Semaglutide as well as the double antagonist tirzepatide are actually approved for the treatment of obesity but not of T2D in subjects younger than 18 years. However, caution is required in considering the efficacy of these medications in youth with T2D requiring insulin therapy. Moreover, the long-term efficacy and adverse effects are still unknown. For example, semaglutide therapy is also associated with concerning adverse effects such as acute pancreatitis, anaesthetic risks (pulmonary aspiration of residual gastric content), acute kidney injury, acute gallbladder injury, non-arteritic anterior ischemic optic neuropathy and diabetic retinopathy (55). 

Gliflozines  

Gliflozines are sodium-glucose transport inhibitors-2 (SGLT-2 inhibitors) that decrease post prandial glycemia by inhibiting SGLT-2 transporters in the proximal convoluted tubule of the kidney leading to an increased glycosuria and decreased glycaemia.  

At least three pivotal studies assessed the efficacy and safety of SGLT-2 inhibitors in the treatment of youth-onset T2D (DINAMO, T2NOW, T2GO). DINAMO assessed empagliflozin and T2NOW and T2GO dapagliflozin. Furthermore, the first two used DPP-4 inhibitors, another class of oral agents used in adults, as active comparator. Finally, DPP-4 inhibitors have demonstrated a limited or lack of efficacy and have not been approved for the treatment of youth-onset T2D (56). So far, the orally active SGLT-2 inhibitors dapagliflozin and empagliflozin have been approved for the treatment of youth-onset T2D by both the EMA and FDA. The two molecules showed statistically significant and clinically relevant improvements in glycemic control compared with placebo. Of interest, in contrast to previous studies of SGLT-2 inhibitors in adults with T2D, treatment with dapagliflozin and empagliflozin did not result in significant reductions in body weight in patients with youth-onset T2D (56). 

Issues about safety are altogether reassuring, but observations are limited to small numbers of treated patients. For example, secondary effects in surgical context (absence of total gastric emptying with GLP-1a (56), euglycemic ketoacidosis by SGLT-2 inhibitors (56) should be taken in account even in young patients. 

Finally, the pharmacologic treatment of T2D of youth faces several caveats. All studies demonstrate that genetic factors are essential for the development of overt diabetes. The paradox is that ethnic subgroups that are more prone to diabetes are often underrepresented in phase 3 trials, so that conclusions of many studies are not representative of populations primarily impacted by T2D. Social determinants of health (SDOH) are nonmedical factors that influence health outcomes, including birth and life environment, ethnicity, age, education, work and lifestyle. A patient’s SDOH may present a major challenge in the management of youth-onset T2D, impacting both the access to medication and adherence to treatment. As such, SDOH can greatly affect the likelihood of a patient achieving treatment goals (58).  

Bariatric surgery  

Bariatric surgery, also defined as metabolic and bariatric surgery (MBS) in pediatric patients, is increasingly acknowledged as an essential part of the management of obesity in combination with medication, nutrition, behavioral training, and physical activity. Bariatric surgery in adolescents meeting criteria of  severe obesity should be considered, especially in case of complications such as poor quality of life, orthopedic pathology, idiopathic intracranial hypertension, T2D, obstructive sleep apnea or increased  cardiovascular risk. Early intervention may result in improved long-term outcomes, and referral for MBS should not be conditionally based on of pubertal stage of development (Tanner staging), bone age or prior weight loss attempts. 

MBS results in significant decrease in weight and changes in body composition, along with glucose homeostasis improvement and T2D resolution. Studies dealing with metabolic issues show an improvement in glucose metabolism, in insulin-resistant as well as in diabetic patients. In a study comparing 30 adolescents with severe obesity and T2D who underwent bariatric surgery (Teen–Longitudinal Assessment of Bariatric Surgery cohort) with 63 participants from the TODAY study, BMI decreased by 29.0% in the surgery cohort vs. a 3.7% increase in TODAY participants, while HbA1c decreased from 6.8% to 5.5% in Teen-LABS and increased from 6.4% to 7.8% in TODAY participants. Remission rates 5 years post-surgery were approximately 86% for T2D and 68% for hypertension. Most postsurgical complications were mild, but up to 8% of adolescents faced major perioperative complications (59). In addition to improvement in insulin sensitivity related to weight loss, metabolic improvement in response to metabolic surgery can be related to several mechanisms including improvement in incretins, changes in the microbiome and increase in bile acids (60). New hypotheses are arising from recent studies on signaling pathways impacted by anatomic configuration induced by bariatric surgery (61). 

As for the pharmacological treatment, the best response is observed in the first year, with subsequent stabilization (62). The introduction of new medications with expanded indications for pediatric use has led to a decrease in bariatric surgeries among adolescents, confirming a trend already observed in recent years (63) whereas  their use in the treatment of T2D remains tightly limited and must be evaluated on a case-by-case basis. 

CONCLUSION 

The pathophysiological mechanisms underlying IR and progression to T2D are becoming increasingly well understood. There are significant differences between adult and pediatric pathology, which are only apparently similar. This high level of knowledge allows to develop new therapeutic strategies, including the use of new and targeted drugs, but it should above all lead to implement appropriate prevention strategies, based on the early diagnosis of unfavorable metabolic dynamics in younger subjects.  

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