Patients with pathogenic variants of the insulin receptor (INSR) gene may present with an unusual metabolic profile characterized by marked insulin resistance and very high insulin concentrations that coexist with episodes of hypoglycemia, normal or low triglyceride concentrations, and ketonemia. Recognition of this pattern, as described by Brazilian researchers, may help endocrinologists identify a rare genetic disorder earlier and avoid prolonged investigations of more common causes of hyperinsulinemic hypoglycemia, such as insulinoma.

A study led by Ramon Marcelino do Nascimento, MD, of the University of São Paulo School of Medicine and the State University of Campinas, both in São Paulo, Brazil, published in Frontiers in Endocrinology, described five unrelated families with pathogenic or likely pathogenic INSR variants.

Genetic testing identified 23 carriers among the family members. Of these, 18 had documented hypoglycemia during at least one metabolic test, and five had already been diagnosed with diabetes at the time of their initial evaluation.

Speaking with Medscape’s Portuguese edition, Nascimento said,“The principal contribution of this study is that these patients have a highly characteristic metabolic phenotype — a metabolic signature that can be recognized during the initial clinical evaluation using simple, readily available tests.”

“This pattern should alert endocrinologists to a primary defect in insulin signaling — that is, an INSR receptor disorder that may have a genetic cause. Recognizing this metabolic signature allows earlier molecular investigation, avoiding repeated testing, prolonged hospitalizations, and, most importantly, invasive procedures such as extensive investigations for insulinoma in patients whose clinical presentation is not typical of that disease,” he added.

From Hypoglycemia to Genetic Diagnosis

Hyperinsulinemic hypoglycemia is a rare and heterogeneous disorder characterized by inappropriate insulin secretion despite falling blood glucose concentration. Well-recognized causes include sporadic or hereditary insulinoma, autoimmune hypoglycemia, congenital hyperinsulinism, postbariatric hypoglycemia, and the exogenous use of insulin or insulin secretagogues.

Less commonly, hyperinsulinemic hypoglycemia may result from pathogenic INSR variants. Alterations in this gene have traditionally been associated with several clinical syndromes, including type A insulin resistance, familial hyperinsulinemic hypoglycemia type 5, Rabson-Mendenhall syndrome, and Donohue syndrome.

Despite this recognized clinical spectrum, systematic studies evaluating the glycemic, insulinemic, and ketotic profiles of patients with hypoglycemia associated with insulin receptor abnormalities remain limited. In addition, most reported cases of familial hyperinsulinemic hypoglycemia type 5 have been confined to isolated case reports or small families.

The researchers evaluated a cohort of 94 individuals assessed between January 2020 and January 2025. Eligible participants had a BMI < 25, clinical suspicion of hypoglycemia, and evidence of insulin resistance, such as acanthosis nigricans, with or without polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS).

Individuals with a history of gastrointestinal surgery, autoimmune hypoglycemia, insulinoma, insulinomatosis, noninsulinoma pancreatogenous hypoglycemia syndrome, or factitious hypoglycemia were excluded.

Five index cases, the first affected individuals identified within each family, met the criteria for molecular evaluation. Three were referred primarily because of hypoglycemic episodes, one belonged to a family with PMOS and type A insulin resistance syndrome, and the fifth had Rabson-Mendenhall syndrome and diabetes preceded by a history of hypoglycemia.

The median age at diagnosis of index cases was 22 years. All patients had marked insulin resistance and a BMI < 25.

The participants underwent three metabolic evaluations: a prolonged fasting test, a mixed meal test, and a 75-g oral glucose tolerance test. Whole-exome sequencing was performed in all five index cases, and the variants identified were subsequently evaluated in at-risk relatives using Sanger sequencing.

Genetic testing of 32 family members identified 23 carriers and nine relatives without the variants. Five different INSR variants were identified: four heterozygous variants in families 1 through 4 and one homozygous variant in family 5.

Postprandial Hypoglycemia Predominated Among Carriers

Among women who carried INSR variants, nine of 15 (60%) had PMOS. Metabolic assessment showed similar glucose responses in carriers and relatives without variants during the oral glucose tolerance test. However, insulin concentrations were significantly higher in carriers at all time points.

Despite marked insulin resistance, only four of the 23 carriers (17.4%) had acanthosis nigricans. According to researchers, this finding underscores the low sensitivity of this clinical sign for identifying insulin resistance in these patients.

Among the 17 heterozygous carriers evaluated in the cohort, 53% experienced both postprandial and fasting hypoglycemia, whereas 47% exclusively had postprandial hypoglycemia.

The literature review conducted by researchers supports this pattern. Among the 56 patients with heterozygous pathogenic INSR variants reported to date, including those in this study, 57% had isolated postprandial hypoglycemia, and 22% had both postprandial and fasting hypoglycemia. Only 7% of patients experienced hypoglycemia exclusively in the fasting state. Among the 11 patients with biallelic INSR variants identified in the study and the literature review, eight (73%) had predominantly fasting hypoglycemia.

Ketonemia Distinguishes INSR Disorders From Insulinoma

One of the study’s most important findings emerged from the comparison between the five index cases with INSR variants and a previously published cohort of 103 patients with insulinoma. The metabolic profiles of the index cases were compared with those of the insulinoma cohort.

The five index cases were younger, had a lower BMI, and tolerated substantially longer fasting periods before developing hypoglycemia. The median fasting time to hypoglycemia was 22 hours in patients with INSR variants compared with 6 hours in the insulinoma cohort.

The minimum blood glucose concentration during fasting also differed between the groups. The median value was 55 mg/dL in the index cases with INSR variants compared with 31 mg/dL in the insulinoma cohort.

Insulin concentrations were similar in both groups. However, the index cases had lower C-peptide concentrations and higher insulin-to-C-peptide ratios. According to the authors, an elevated ratio may reflect reduced hepatic insulin clearance, resulting in disproportionately high circulating insulin concentrations.

The most striking difference was the production of ketone bodies. The median ketonemia concentration was 1.1 mmol/L in the index cases with INSR variants compared with 0.1 mmol/L in the insulinoma cohort.

This finding contrasts with the expected pattern in classic hyperinsulinemic hypoglycemia. Under normal physiologic conditions, elevated insulin concentrations suppress lipolysis and hepatic ketone body production.

“In patients with pathogenic INSR variants, however, peripheral insulin resistance reduces insulin’s ability to suppress lipolysis and hepatic ketone body production despite very high circulating insulin concentrations,” said Nascimento. “As a result, hyperinsulinemia, hypoglycemia, and ketonemia coexist, creating a pathophysiologic profile that is quite different from that observed in insulinoma.”

Nascimento said that this finding has important implications for interpreting diagnostic tests.

“The presence of ketones during an episode of hyperinsulinemic hypoglycemia should not automatically exclude the diagnosis of hyperinsulinism. On the contrary, when ketonemia occurs together with evidence of insulin resistance, it may represent an important clue to an insulin receptor defect and justify genetic testing.”

However, he cautioned that the mechanism responsible for ketonemia has not yet been fully established.

“One hypothesis is that systemic hypoglycemia partially reduces pancreatic insulin secretion and, consequently, insulin concentrations in the portal circulation,” he said.

With impaired insulin receptor signaling, the residual hepatic action of insulin may be insufficient to completely suppress ketogenesis despite peripheral hyperinsulinemia, which is further amplified by reduced hepatic insulin clearance.

Another component of the metabolic signature observed in the index cases was low triglyceride concentration. Despite severe insulin resistance, the median fasting triglyceride concentration after 12 hours was 47 mg/dL. This profile contrasts with the hypertriglyceridemia commonly seen in more prevalent forms of insulin resistance, such as type 2 diabetes, and may provide another clue for identifying INSR-related disorders.

Disease Spectrum Rather Than Distinct Syndromes

Analysis of the five families revealed considerable clinical variability, even among individuals carrying the same INSR variant. In one family, clinical manifestations occurred in both heterozygous individuals and those with biallelic variants, supporting the possibility of semidominant inheritance.

These findings support a semidominant inheritance model for INSR-related disorders. In this model, heterozygous individuals may develop clinically significant manifestations, whereas biallelic variants generally produce more severe phenotypes.

“Traditionally, these conditions have been considered distinct clinical entities. Our findings suggest that they represent different manifestations of the same spectrum of insulin receptor-related disorders, with the clinical phenotype determined primarily by the functional impact of the genetic variant,” Nascimento said.

According to Nascimento, this shift in perspective also has important implications for genetic counseling.

“Family members considered merely ‘carriers’ may, in fact, have subtle metabolic abnormalities that warrant clinical and laboratory evaluation. Identifying an INSR variant should therefore prompt cascade screening of family members and longitudinal follow-up, enabling earlier diagnosis and individualized management,” he said.

When Should Genetic Testing Be Considered?

According to Nascimento, INSR testing should be considered earlier in the diagnostic evaluation when the clinical presentation is inconsistent with the classic insulinoma profile.

Clinical features that should raise suspicion include a combination of hyperinsulinemic hypoglycemia and marked insulin resistance, normal or low triglyceride concentrations, ketonemia during hypoglycemia, a suggestive family history, and the absence of pancreatic lesions in imaging studies.

“In these situations, INSR testing can establish the diagnosis much earlier and completely change the course of management. In addition to avoiding invasive procedures and unnecessary surgery, molecular diagnosis facilitates appropriate treatment planning, genetic counseling, and identification of potentially affected relatives before more obvious clinical manifestations develop,” Nascimento said.

According to Nascimento, some patients with pathogenic INSR variants initially present with hypoglycemia but later develop pancreatic beta-cell failure and overt diabetes as the disease progresses.

“These patients require long term follow-up. Early diagnosis and treatment may alter the clinical course of the disease and help preserve pancreatic function,” he said.

Limitations and Next Steps

The authors acknowledged several limitations, including the absence of functional in vitro studies to directly evaluate the effects of the identified variants, incomplete triglyceride and adiponectin measurements among family members carrying the variants, and lack of simultaneous insulin and C-peptide measurements during all metabolic challenge tests.

The retrospective, single-center design and small number of families studied, although expected given the rarity of INSR-related disorders, should be considered when interpreting the findings. In addition, the primary comparison between five index cases and a cohort of 103 patients with insulinoma involved significantly different sample sizes, and the two cohorts were not recruited concurrently, limiting the statistical strength of the comparison.

Nevertheless, the use of standardized metabolic protocols, genetic testing of family members, and integrated analysis of clinical phenotypes and inheritance patterns have enabled researchers to identify distinctive characteristics that may be clinically useful. According to the authors, this represents the largest single-center series reported to date of patients with pathogenic INSR variants presenting with hypoglycemia.

The authors concluded that confirmation of these findings in independent cohorts could refine the criteria for INSR sequencing, improve genetic counseling, and guide long-term monitoring of affected individuals. Nascimento added that future studies should determine whether earlier diagnosis and intervention can improve metabolic outcomes and delay progression to diabetes.

Daniela Barros is a journalist from Brazil, specializing in social journalism at the Pontifical Catholic University of São Paulo and a master’s student in the Department of Social Medicine at the Ribeirão Preto Medical School in Ribeirão Preto, Brazil. She has been involved in medicine for 23 years and has contributed to several specialized publications.

This story was translated from Medscape’s Portuguese edition.