780G Hybrid Closed-Loop Pump as Adjunct to Metreleptin in Lipodystrophy-Associated Diabetes: Three Case Observations

Lipodystrophies (LDs) are rare disorders characterized by partial or generalized loss of functional adipose tissue, ectopic lipid deposition, and leptin deficiency. Severe insulin resistance, extreme hypertriglyceridemia, hepatic steatosis, and premature cardiovascular disease are common and contribute to high morbidity and mortality. The pathophysiology of LD-related diabetes differs from both type 1 and type 2 diabetes, reflecting a unique combination of ectopic fat deposition, adipokine imbalance, and markedly increased hepatic gluconeogenesis.

Metreleptin, by restoring leptin signaling, rapidly improves hyperphagia, hepatic glucose output, and insulin sensitivity, reducing HbA_1c and insulin requirements (1,2). However, glycemic responses are frequently incomplete or transient. Persistent ectopic fat, severe hepatic insulin resistance, and antimetreleptin antibodies limit durable glycemic control (3).

Hybrid closed-loop (HCL) insulin delivery systems integrate continuous glucose monitoring with automated basal modulation and frequent algorithm-driven microboluses that approximate physiologic insulin secretion. They adjust insulin delivery every few minutes, allowing rapid correction of rising glucose and suspension of insulin during impending hypoglycemia. In type 1 diabetes, HCL systems consistently outperform multiple daily injections and conventional pump therapy, improving time in range (TIR) and reducing hypoglycemia (4). However, their performance has never been evaluated in LD, a context characterized by profound insulin resistance and erratic subcutaneous insulin absorption, and this represents a major knowledge gap.

We describe three female patients with generalized or partial LD and refractory insulin-treated diabetes in whom metreleptin produced transient glycemic benefit. Transition to an advanced HCL system (Medtronic 780G) led to sustained improvement in glucose metrics despite persistently high insulin requirements.

Patient 1 was a 61-year-old woman with familial partial LD type 3 who presented with decades of insulin-treated diabetes (5 IU/kg/day), severe hypertriglyceridemia, diabetic nephropathy and neuropathy, and lipoatrophy of the limbs and gluteal region. Metreleptin (5 mg/day) promptly lowered HbA_1c from 10 to 8.7% (after 3 months) and triglycerides from 2,919 to 242 mg/dL, with insulin reduced to 2.2 IU/kg/day. Six months later, glycemia again worsened despite adherence (HbA_1c 9.7%). After 780G initiation, TIR was approximately 60–67% and HbA_1c fell to 6.8%. Although insulin needs later returned to 2.4 IU/kg/day, glycemic variability and hypoglycemia risk remained low and quality of life markedly improved.

Patient 2 was a 42-year-old woman with familial partial LD type 2, recurrent pancreatitis, severe hypertriglyceridemia, hypertension, and multiple miscarriages who had poorly controlled diabetes on 1.5 IU/kg/day of insulin plus metformin. Metreleptin 5 mg/day reduced HbA_1c from 10.1 to 7.8% after 3 months, triglycerides from 3,390 to 267 mg/dL, and insulin to 0.5 IU/kg/day. After 18 months, however, HbA_1c rose to 9.7% and triglycerides to 2,542 mg/dL despite dose escalation. Following 780G initiation at 4 months, TIR increased to 85–86% and glucose management indicator to 6.6%, with coefficient of variation <30%, even as insulin requirements again exceeded 2 IU/kg/day.

Patient 3 was a 29-year-old woman with congenital generalized LD (AGPAT2 mutations) who was diagnosed with diabetes at 14 years old and ultimately required 2.6 units/kg/day insulin (HbA_1c 10.2%). Metreleptin 5 mg/day initially halved insulin needs and lowered HbA_1c to 5.4% after 6 months, but control deteriorated within a year. After 780G initiation, TIR stabilized at 75% and HbA_1c at 6.8% over >2 years, including a successful pregnancy during which metreleptin was safely paused, with postpartum resumption.

These cases confirm metreleptin’s occasionally partial and often short-lived glycemic efficacy (1,2). Diabetes in LD is physiologically distinct. Extreme loss of metabolically active adipose tissue results in rapid postprandial glucose excursions driven by profound hepatic and peripheral insulin resistance. Clinically, this forces the use of unusually large mealtime boluses that increase the risk of delayed and nocturnal hypoglycemia, especially when delivered through traditional multiple daily injections.

HCL systems such as the 780G directly address these challenges and correct the fundamental imbalance in LD, where postprandial insulin needs are extraordinarily high due to severe hepatic and peripheral insulin resistance (4). Frequent, small microboluses stabilize plasma insulin levels, minimize peaks and stacking, and provide automatic corrections for hyperglycemia while suspending insulin to avert hypoglycemia, especially overnight (5). They also more effectively suppress exaggerated hepatic glucose output after meals. Because subcutaneous absorption is erratic in LD, such microbolusing improves pharmacokinetic predictability. This mechanistic advantage allows tighter control despite persistently high insulin requirements.

This is the first report of HCL use as adjunctive therapy in LD-related diabetes. For patients with LD and refractory diabetes, particularly when metreleptin alone is insufficient and subcutaneous injections are problematic, early integration of HCL may improve metabolic outcomes. Larger prospective studies are needed to confirm these findings and to define optimal sequencing of metreleptin and HCL therapy.