Treatment of Type 2 Diabetes Mellitus in Youth

Educational Objectives

The goal of this program is to improve management of type 2 diabetes mellitus (DM) in youth. After hearing and assimilating this program, the clinician will be better able to:

1. Cite evidence assessing insulin resistance in pubertal patients with type 1 DM.
2. Diagnose DM in youth using 2-hr glucose and hemoglobin A_1C levels.
3. Use insulin for the management of DM.

Summary

Glucose homeostasis: is regulated by insulin and glucagon; when blood glucose levels drop, the pancreas releases glucagon (releases glucose from the liver) and suppresses insulin; conversely, when glucose levels rise, the pancreas increases insulin secretion (facilitates glucose uptake by tissues) and suppresses glucagon; the relationship between insulin sensitivity (action) and insulin response follows a hyperbolic curve; in states of low insulin sensitivity (eg, pregnancy, puberty), insulin secretion increases; in states of high insulin sensitivity (eg, exercise), insulin secretion decreases

Diabetes mellitus (DM): results from an imbalance between insulin action (sensitivity) and secretion; type 2 DM (T2DM) is initially characterized by a loss of insulin action compensated by increased insulin secretion; T2DM manifests when insulin secretion falls, leading to insufficient insulin; individuals with normal glucose tolerance stay on the hyperbolic curve even in states of insulin resistance; the product of insulin sensitivity and secretion (disposition index [DI]) declines even before impaired glucose tolerance or T2DM

Insulin action in youth: puberty causes transient insulin resistance; Amiel et al (1980) found that insulin sensitivity decreases during puberty in type 1 DM (T1DM) and nondiabetic youth compared with adults; another study found that changes in insulin sensitivity parallel changes in growth hormone (GH) levels; as GH levels fall at the end of puberty, insulin sensitivity normalizes; a longitudinal study showed that DI decreases during puberty in children with obesity and healthy children, affecting glucose homeostasis; although youth with obesity are 3-fold more insulin-resistant, most have excellent compensatory insulin secretion, with no difference in the trajectory of insulin sensitivity over time

Landscape of T2DM in youth: T2DM children are increasingly diagnosed through screening, though ≈11% present with diabetic ketoacidosis (DKA) and 2% with a hyperosmolar state at diagnosis; ≈67% of patients are female patients, unlike the slight male predominance in adults; almost all affected children have a family history of DM, with ≈60% having it within their nuclear family, and many have been exposed to gestational diabetes; T2DM typically emerges around puberty and is rising among youth, particularly in American Indian, Hispanic, and Black individuals; from 2001 to 2017, the prevalence doubled, mainly affecting late adolescent girls and ethnic minority groups; despite high obesity rates, T2DM incidence in youth remains low at 1 to 3 cases per 100,000/yr, affecting ≈0.034% of adolescents; many at-risk youths do not develop diabetes early, for reasons that are still unclear

T1DM and T2DM: in the TODAY study, 10% of children thought to have T2DM had autoantibodies indicating T1DM; although children with autoantibodies had lower triglycerides, higher high-density lipoprotein, lower blood pressure, and higher glycated hemoglobin A_1C (HbA1c) compared with those with T2DM, insulin production was significant, with elevated body mass index Z-scores; checking for autoimmunity is important

Diagnosis of DM: a 2-hr glucose level of 200 mg/dL during an oral glucose tolerance test, fasting glucose of ≥126 mg/dL, HbA1c level of ≥6.5% (commonly used), or a random glucose level of 200 mg/dL with symptoms of DM; a confirmatory test is usually necessary

Treatment of DM: the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes recommend starting metformin if HbA1c level is <8.5% and ketoacidosis is absent; metformin is highly effective (≈90% of youth initially on insulin can be weaned off); if HbA1c is >8.5% or in the presence of acidosis or ketosis, insulin therapy is recommended (start with basal insulin of 0.5 units/kg per day and titrate every 2-3 days); treat DKA or hyperosmolar state; test for antibodies (if negative, wean off insulin)

TODAY trial: the largest trial on T2DM in youth; compared 3 treatments, ie, metformin alone, metformin plus lifestyle changes, and metformin plus rosiglitazone (no longer available; pioglitazone is currently used); metformin plus rosiglitazone showed slightly better results; ≈50% of participants needed insulin ≤2 yr, reflecting a faster decline in β cell function in youth compared with adults; the prevalence of comorbid conditions (eg, dyslipidemia, hypertension, sleep apnea, and nonalcoholic fatty liver disease) was high; youth with T2DM who became pregnant were at high risk for complications; the addition of insulin for glycemic failure had limited success owing to barriers in insulin administration; HbA1c of 6.3% over 3 mo of metformin monotherapy predicted glycemic failure, suggesting the need for more aggressive treatment in youth; complications — included hypertension, kidney disease, dyslipidemia, and neuropathy; by 9 yr, ≈50% of participants developed microvascular complications (cumulative incidence, 80% at 15 yr); pregnancy complications — included high rates of preterm births, large for gestational age, and small for gestational age; 20% of pregnancies had major congenital anomalies; serious cardiovascular events were recorded

Advancement in treatment of DM: thiazolidinediones are beneficial as add-ons to metformin, especially for women; newer agents improve glycemic control, promote weight loss, and enhance cardiovascular and renal outcomes; bariatric surgery shows promise in adolescents

Thiazolidinediones: improve peripheral insulin sensitivity, reduce inflammation, and decrease liver fibrosis; they are administered once a day and are backed by evidence in youth; they improve HbA1c control (1%-2%) and metabolic dysfunction-associated steatohepatitis; adverse events (AEs) include weight gain and edema, particularly in patients with cardiac disease; however, no adverse cardiac effects were seen in youth; the risk for osteopenia is increased in postmenopausal women; the onset of action is delayed (2 wk; 2 mo to reach full effect)

Glucagon-like peptide 1 receptor agonists (GLP-1 RA): semaglutide is administered once weekly; GLP-1 RA approved for the treatment of youth include liraglutide (eg, Victoza) and dulaglutide (eg, Trulicity); GLP-1 RA increase insulin secretion and β cell mass, slow gastric emptying (improving satiety), decrease hunger, and indirectly improve insulin sensitivity through weight loss; administered weekly (preferable) or once daily and have an additive effect on HbA1c, with cardiovascular benefits; expensive; GLP-1 RA carries a slight but unproven risk for thyroid cancer and pancreatitis

Sodium-glucose cotransporter-2 inhibitors: lower blood glucose by decreasing the renal threshold for glucose excretion; administered once daily; promote moderate weight loss (≈5%), with cardiovascular (improving heart failure) and renal benefits; AEs include increased risk for urinary tract infections or yeast infections (particularly in women), euglycemic DKA (in adults), and fractures (in older adults)

Psychosocial factors: are key in treating youth with T2DM, as many have experienced trauma or difficult life circumstances; assess social context and address diabetes distress and mental health (eg, depression, disordered eating); offer personalized treatment to improve adherence; preconceptual counseling should begin at puberty, with a focus on long-acting contraception to reduce pregnancy-related complications

Glycemic target for T2DM: recommendations include an HbA1c <7%; a more aggressive target (<6.5%) may be possible (hypoglycemia is rare in youth); self-monitoring of blood glucose should be individualized; coverage of continuous glucose monitoring is expanding

Questions and Answers

Acanthosis nigricans (AN): not all patients with T2DM have AN (a sign of insulin resistance [IR]); AN does not correspond with the degree of IR; some patients with severe IR never develop DM; genetic predisposition to diabetes is more closely linked to β cell failure

Lifestyle changes in youth: when managing DM in youth, it is important to focus on a few manageable lifestyle changes; using motivational interviewing can help identify the most effective changes; keep in mind that lifestyle changes are hard due to the body's natural tendency to maintain weight

Insulin dosing and check: the typical starting dose of insulin for youth with T2DM is 0.5 units/kg; some may need higher doses, as shown in studies where even prediabetic youth required ≤1 unit/kg per day due to high insulin resistance during puberty; routine insulin level checks are not recommended for screening insulin resistance or DM in obese children; insulin levels can vary widely and do not provide useful information about β cell function, making them unreliable for screening

Readings

Abu-Nejem R, Hannon TS. Insulin dynamics and pathophysiology in youth-onset type 2 diabetes. J Clin Endocrinol Metabol. 2024:109(10):2411-2421; Amiel SA, Sherwin RS, Simonson DC, et al. Impaired insulin action in puberty. N Engl J Med. 1986;315:215-219; Fonseca-Correa JI, Correa-Rotter R. Sodium-glucose cotransporter 2 inhibitors mechanisms of action: A review. Front Med. 2021;8:777861; McGuire DK, Inzucchi SE. New drugs for the treatment of diabetes mellitus: part I: Thiazolidinediones and their evolving cardiovascular implications. Circulation. 2008;117:440-449; Singhal S, Kumar S. Current perspectives on management of type 2 diabetes in youth. Children. 2021;8(1):37; Suryasa IW, Rodríguez-Gámez M, Koldoris T. Health and treatment of diabetes mellitus. Int J Health Sci. 2021;5(1):1-5; Zeitler P, Arslanian S, Fu J, et al. ISPAD clinical practice consensus guidelines 2018: Type 2 diabetes mellitus in youth. Pediatr Diabetes. 2018; 27:28-46.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Kelsey was recorded at Pediatrics in the Islands: Clinical Pearls 2024, held on October 28, 2024, in Waikoloa, HI, and presented by Children’s Hospital Los Angeles Medical Group. For more information about upcoming CME activities from this presenter, please visit https://www.chla.org/chla-medical-group/cme-conferences. Audio Digest thanks the speakers and Children’s Hospital Los Angeles Medical Group for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

PD704002

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.