Marked Hyperproinsulinemia in Atypical Adult-Onset Diabetes

Dr. Ghassan Taraben, MD, PhD, FAAN

Dr. Tarabein

Abstract

Adult-onset diabetes is clinically heterogeneous, and some patients do not fit neatly within the conventional distinction between insulin resistance and insulin deficiency. We report the case of a 66-year-old man previously managed as having type 2 diabetes mellitus for approximately 13 years, in whom glycemic control improved more reliably with exogenous insulin than with non-insulin therapy alone. Further evaluation showed markedly elevated plasma proinsulin of approximately 27,000 pmol/L (reference range, 3.6–22 pmol/L), preserved C-peptide of 2.7 ng/mL (0.9 nmol/L; reference range, 1.1–4.4 ng/mL [0.37–1.47 nmol/L]), fasting plasma glucose of approximately 220 mg/dL (12.2 mmol/L), hemoglobin A1c of 11.5%, and body mass index of 31.3 kg/m². Serum creatinine was 1.11 mg/dL (98 µmol/L), alanine aminotransferase was 15 U/L, and aspartate aminotransferase was 17 U/L. Triglycerides were approximately 1,800 mg/dL (20.3 mmol/L). Contrast-enhanced computed tomography of the abdomen reportedly showed no pancreatic mass or structural pancreatic abnormality. After transition to insulin therapy delivered by Omnipod together with metformin extended-release, hemoglobin A1c improved from 11.5% to 6.5% over approximately 6 months. Although hyperproinsulinemia is nonspecific and may reflect beta-cell stress, the magnitude of elevation and the therapeutic discordance raise the possibility of impaired endogenous insulin processing. This case highlights the potential value of selective biochemical phenotyping in adults with atypical diabetes.

Key Words

proinsulin; hyperproinsulinemia; diabetes mellitus; beta-cell dysfunction; insulin processing; atypical diabetes

Abbreviations

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CT, computed tomography.

Case Presentation

A 66-year-old man with a prior diagnosis of type 2 diabetes mellitus had been managed for approximately 13 years under the prevailing assumption that insulin resistance was the primary abnormality. His treatment had focused largely on non-insulin glucose-lowering therapy, including metformin and other agents, while endogenous insulin production was presumed to be sufficient.

Over time, however, the patient repeatedly observed that glycemic control improved more reliably with subcutaneous insulin than with strategies directed primarily at insulin sensitization. This recurring response pattern appeared discordant with a model of uncomplicated insulin resistance alone and prompted further evaluation of endogenous insulin biosynthesis.

A plasma proinsulin assay was obtained and was reported as approximately 27,000 pmol/L. This value was dramatically above the cited laboratory reference interval of 3.6–22 pmol/L. Because of concern for pancreatic endocrine pathology, including the possibility of a proinsulin-secreting lesion, contrast-enhanced CT of the abdomen was performed and reportedly showed no pancreatic mass, no pancreatic ductal abnormality, and no radiographic evidence of pancreatic malignancy.

At the time of evaluation, fasting plasma glucose was approximately 220 mg/dL (12.2 mmol/L), hemoglobin A1c was 11.5%, and BMI was 31.3 kg/m². C-peptide was 2.7 ng/mL (0.9 nmol/L; reference range, 1.1–4.4 ng/mL [0.37–1.47 nmol/L]). Serum creatinine was 1.11 mg/dL (98 µmol/L; reference range, 44–106 µmol/L). ALT and AST were 15 U/L and 17 U/L, respectively. Triglycerides were approximately 1,800 mg/dL (20.3 mmol/L). Autoimmune diabetes markers, including glutamic acid decarboxylase 65 antibody, insulinoma-associated antigen-2 antibody, zinc transporter 8 antibody, and islet-cell antibodies, were not obtained. Family history was notable for type 2 diabetes mellitus in the patient’s father.

Key laboratory and imaging findings are summarized in Table 1.

Table 1. Laboratory and Imaging Summary

Parameter	Result	Reference Range	Clinical Interpretation
Fasting plasma glucose	220 mg/dL (12.2 mmol/L)	70–99 mg/dL (3.9–5.5 mmol/L)	Markedly elevated
Hemoglobin A1c	11.5%	Lab dependent	Severe chronic hyperglycemia
Proinsulin	27,000 pmol/L	3.6–22 pmol/L	Markedly elevated
C-peptide	2.7 ng/mL (0.9 nmol/L)	1.1–4.4 ng/mL (0.37–1.47 nmol/L)	Preserved endogenous peptide secretion
Creatinine	1.11 mg/dL (98 µmol/L)	0.5–1.2 mg/dL (44–106 µmol/L)	No clear renal impairment
ALT	15 U/L	Lab dependent	No apparent hepatic injury
AST	17 U/L	Lab dependent	No apparent hepatic injury
Triglycerides	1,800 mg/dL (20.3 mmol/L)	<150 mg/dL (<1.7 mmol/L)	Severe hypertriglyceridemia
Contrast-enhanced CT abdomen	No pancreatic mass or ductal abnormality	Not applicable	No large structural pancreatic lesion identified

Diagnosis and Treatment

Several diagnostic possibilities were considered. The patient may have had conventional type 2 diabetes with advanced beta-cell dysfunction, in which hyperproinsulinemia reflected secretory stress and impaired beta-cell processing rather than a distinct mechanistic subgroup. An atypical or monogenic form of diabetes associated with abnormal proinsulin folding, processing, or secretion was also considered. A pancreatic endocrine neoplasm such as insulinoma or proinsulinoma was considered because marked proinsulin elevation can occur in that setting; however, no pancreatic lesion was identified on initial CT imaging, although small neuroendocrine pathology could not be fully excluded. Pancreatogenic diabetes secondary to structural pancreatic disease was considered less likely because imaging reportedly showed no evidence of chronic pancreatitis, pancreatic atrophy, or other clear pancreatic abnormality. Finally, because the reported proinsulin value was extreme, analytic or preanalytic error should also be considered, and repeat confirmatory testing would strengthen the interpretation.

The patient had initially been treated with metformin and other non-insulin agents. Because the clinical response to injectable insulin appeared consistently more favorable, insulin therapy delivered through an Omnipod device was initiated in combination with metformin extended-release. Over approximately 6 months, glycemic control improved substantially, with hemoglobin A1c decreasing from 11.5% to 6.5%.

During follow-up from October 1, 2025, through April 1, 2026, the patient remained on insulin-based therapy in combination with metformin extended-release 1,000 mg twice daily. No pancreatic structural lesion was identified on the available imaging study. This treatment response does not establish mechanism, but it is consistent with the practical possibility that exogenous mature insulin addressed a defect not fully corrected by insulin-sensitizing therapy alone.

Discussion

This case is notable for the discordance between the patient’s long-standing clinical classification and the subsequent biochemical and therapeutic findings. He had been treated primarily under an insulin-resistance model; however, the repeated favorable response to exogenous insulin, together with marked hyperproinsulinemia, suggests that the underlying abnormality may not have been fully explained by insulin resistance alone.

One biologically plausible interpretation is that the pancreas was secreting substantial amounts of insulin precursor but was inadequately generating or releasing fully mature, biologically effective insulin. In such a scenario, a patient may appear clinically similar to one with type 2 diabetes while also exhibiting a partial state of functional insulin deficiency because endogenous peptide output is qualitatively abnormal.

This interpretation should be made cautiously. Hyperproinsulinemia is not specific. It may occur in conventional type 2 diabetes, rare disorders of insulin biosynthesis, and pancreatic endocrine tumors. A single case cannot establish a new diabetes subtype. Nevertheless, the present case raises a hypothesis-generating possibility: among some adults labeled as having type 2 diabetes, there may be a subgroup with disproportionate proinsulin secretion and relative deficiency of effective mature insulin.

The principal value of this report is clinical rather than taxonomic. In selected atypical patients, especially those with discordant biochemical and therapeutic patterns, deeper phenotyping may be warranted. Such evaluation may include simultaneous measurement of glucose, insulin, C-peptide, and proinsulin, together with standard classification studies and pancreatic imaging when clinically indicated.

This report also has important limitations. Repeat proinsulin testing was not available, autoimmune marker testing was not performed, and genetic evaluation was not undertaken. The absence of a pancreatic lesion on CT does not completely exclude small neuroendocrine disease. Accordingly, this case should be presented as an observation that suggests, rather than proves, impaired endogenous insulin processing.

In summary, this case illustrates a clinically important mismatch between presumed type 2 diabetes and subsequent biochemical and therapeutic observations. Marked hyperproinsulinemia, preserved C-peptide, and reproducible improvement with exogenous insulin suggest that, in selected adults, endogenous insulin production may be qualitatively abnormal rather than simply quantitatively reduced. The principal implication is not the proposal of a new diabetes category, but rather a diagnostic caution: patients with presumed type 2 diabetes who show discordant biochemical findings or disproportionate benefit from insulin may warrant deeper phenotyping, including paired measurement of glucose, insulin, C-peptide, and proinsulin when clinically appropriate. This report should be viewed as hypothesis-generating and as support for more precise classification of atypical adult-onset diabetes.

Disclosure Statement

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Patient Consent

Written informed consent for publication of this case report was obtained from the patient.

Author Contributions

Ghassan Tarabein conceived the report, collected and interpreted the clinical data, drafted the manuscript, and approved the final version.

Data Availability

Data sharing is not applicable to this article because no data sets were generated or analyzed beyond the single-patient clinical information described in the manuscript.

Acknowledgments

This report was prepared in good faith with the aim of contributing to the medical literature and supporting the advancement of patient care.

References

1. American Diabetes Association Professional Practice Committee. Diagnosis and classification of diabetes: Standards of Care in Diabetes—2025. Diabetes Care. 2025;48(Suppl 1):S27-S49.

2. Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ, Porte D Jr. Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia. 1987;30(9):698-702.

3. Ahrén B. Type 2 diabetes, insulin secretion and beta-cell mass. Current Molecular Medicine. 2005;5(3):275-286.

4. Nishi M, Steiner DF. Insulin gene mutations and diabetes: from genetics and beta-cell biology to clinical disease. Molecular Aspects of Medicine. 2013;34(1):59-77.

5. Wang J, Takeuchi T, Tanaka S, et al. Proinsulin maturation disorder is a contributor to the defect in peptide hormone secretion in diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(32):13030-13035.

6. Edwards K, de La Portilla L, Mirza FS, Luthra P. Proinsulin-predominant pancreatic neuroendocrine tumor-induced hypoglycemia after Roux-en-Y gastric bypass surgery. AACE Clinical Case Reports. 2019;5(6):e339-e343.