Vey Low-Energy Ketogenic Therapy in Adults With Type 1 Diabetes and Obesity on Intensive Insulin Therapy Using Advanded Hybrid Closed Loop System

Official title

Applying Very Low Calorie Ketogenic Diet to the Treatment of Obesity in People With Type 1 Diabetes on Intensive Insulin Therapy Using Automated Insulin Delivery System

Overview

Overweight and obesity are frequent in adults with type 1 diabetes (T1D), with prevalence exceeding 50% in recent studies. Excess weight in T1D is associated with higher cardiometabolic risk and therapeutic challenges, while effective and safe weight management strategies are still limited. This single-center, single-arm feasibility study will evaluate the efficacy and safety of a Very Low-Energy Ketogenic Therapy (VLEKT; 600-800 kcal/day) in adults with T1D and obesity treated with Advanced Hybrid Closed Loop (AHCL) insulin delivery systems. Participants will follow a structured 4-week program with commercial very-low-carbohydrate, high-protein meal replacements, under close medical supervision. The primary endpoint is change in body weight at 4 weeks. Secondary outcomes include body composition, muscle strength, glucose metrics, insulin requirements, biochemical parameters, and patient-reported outcomes. Safety will be assessed through hypoglycemia incidence, ketone monitoring, and occurrence of diabetic ketoacidosis (DKA). The study will enroll 14 participants. It is expected that VLEKT will achieve \~5% weight loss within one month while maintaining glycemic safety under AHCL technology.

Detailed description

Excess weight in type 1 diabetes (T1D) is increasingly recognized as a critical clinical problem. Factors contributing to weight gain include intensive insulin therapy, compensatory intake of high-energy foods to prevent hypoglycemia, reduced physical activity due to fear of hypoglycemia, and pathophysiological mechanisms such as adipose tissue dysfunction and insulin resistance. Current therapeutic options for weight management in T1D are limited compared with type 2 diabetes, and novel approaches are urgently needed.

Ketogenic and very low-carbohydrate diets are effective in obesity and type 2 diabetes but have traditionally been discouraged in T1D because of risks of hypoglycemia, dyslipidemia, poor adherence, and diabetic ketoacidosis (DKA). The introduction of Advanced Hybrid Closed Loop (AHCL) systems, which combine continuous glucose monitoring with automated insulin delivery, provides a safer framework to test structured dietary interventions that were previously considered unsuitable in this population.

This feasibility study investigates a Very Low-Energy Ketogenic Therapy (VLEKT) for 4 weeks in adults with T1D and obesity using AHCL technology. The intervention will consist of commercially available meal replacements (600-800 kcal/day, \<30 g/day carbohydrates, adequate protein supply) with strict monitoring of capillary ketones and insulin adjustments.

Baseline assessments include anthropometry, bioimpedance-derived body composition, handgrip strength, biochemical testing, continuous glucose monitoring metrics, and validated questionnaires (SF-12, IPAQ, PSQI, FH-15). Participants will attend weekly visits for clinical review, adherence reinforcement, safety checks, and repeat assessments. At study completion, a gradual reintroduction of conventional meals will be initiated.

The primary endpoint is absolute weight change after 4 weeks. Secondary endpoints include proportion achieving ≥5% weight loss, changes in body composition and muscle strength, glucose control (TIR, TAR, TBR, CV, GMI, GRI, TITR), insulin requirements, lipid and liver function markers, and patient-reported outcomes. Safety evaluation will focus on hypoglycemia incidence and DKA events.

Sample size calculation determined that 14 participants are required to detect a clinically relevant mean weight reduction of \~5%. The results will provide initial evidence on the feasibility, metabolic impact, and safety of VLEKT in this specific population, laying the groundwork for larger randomized controlled trials.

Interventions

• Dietary supplement VLEKT
  Participants will follow a Very Low-Energy Ketogenic Therapy (VLEKT) providing 600-800 kcal/day for 4 weeks. The intervention consists of meal replacements (solid or liquid, ready-to-use or reconstituted) with very low carbohydrate content, high-quality proteins (milk, whey, pea, soy), and fiber (inulin, FOS). Gluten-free, lactose-free, and vegan options are available. Meal replacements are provided by Therascience or Penta at discounted prices. Participants will self-monitor capillary ketonemia

Primary outcome measures

• Change in body weight from baseline to end of 4-week Very Low-Energy Ketogenic Therapy [Time frame: Baseline and Week 4]

Eligibility criteria

Inclusion criteria

Age ≥ 18 years

Diagnosis of type 1 diabetes or autoimmune diabetes for ≥ 12 months

BMI ≥ 30 kg/m²

HbA1c < 9%

Knowledge and use of carbohydrate counting

Use of an Advanced Hybrid Closed Loop (AHCL) system for ≥ 3 months and willingness to maintain it during the study

At least 1 diabetology follow-up visit in the last 12 months (including telemedicine)

Willingness to purchase meal replacements for the entire study duration

Exclusion criteria

Ketoacidosis, severe hypoglycemia with seizures/coma, or severe hyperglycemia requiring hospitalization in the last 6 months

Febrile illness within the last 2 weeks

Dietary restrictions or intolerances incompatible with study food supplies

Celiac disease, gastroparesis, food allergies

Intense physical exercise >2 hours on >3 days per week

History or risk of eating disorder, or other psychiatric disorders

Recreational drug use or excessive alcohol consumption

Chronic kidney disease (eGFR <60 ml/min)

Gallstones

Liver failure

Heart failure (NYHA III-IV), unstable angina, cardiac arrhythmia, myocardial infarction, or stroke within the last 12 months

Respiratory failure

Severe or active infections

Planned elective surgery

Rare metabolic diseases (porphyria, CPT2 deficiency, mitochondrial fatty acid oxidation defect, pyruvate carboxylase defect)

Pregnancy (current or actively trying to conceive)

Breastfeeding

Current glucocorticoid therapy (except stable low-dose, inhaled, or replacement for adrenal insufficiency)

Other serious medical conditions that might interfere with participation or study completion in the investigator's judgment

Participant judged unable or unwilling to complete the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• University Hospital Policlinico Consorziale — Bari

Publications

• Barrea L, Caprio M, Grassi D, Cicero AFG, Bagnato C, Paolini B, Muscogiuri G. A New Nomenclature for the Very Low-Calorie Ketogenic Diet (VLCKD): Very Low-Energy Ketogenic Therapy (VLEKT). Ketodiets and Nutraceuticals Expert Panels: "KetoNut", Italian Society of Nutraceuticals (SINut) and the Italian Association of Dietetics and Clinical Nutrition (ADI). Curr Nutr Rep. 2024 Sep;13(3):552-556. doi: PMID 39039372
• Phillip M, Nimri R, Bergenstal RM, Barnard-Kelly K, Danne T, Hovorka R, Kovatchev BP, Messer LH, Parkin CG, Ambler-Osborn L, Amiel SA, Bally L, Beck RW, Biester S, Biester T, Blanchette JE, Bosi E, Boughton CK, Breton MD, Brown SA, Buckingham BA, Cai A, Carlson AL, Castle JR, Choudhary P, Close KL, Cobelli C, Criego AB, Davis E, de Beaufort C, de Bock MI, DeSalvo DJ, DeVries JH, Dovc K, Doyle FJ, PMID 36066457
• Guerci B, Sauvanet JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability. Diabetes Metab. 2005 Sep;31(4 Pt 2):4S7-4S24. doi: 10.1016/s1262-3636(05)88263-1. PMID 16389894
• McAuley SA, Horsburgh JC, Ward GM, La Gerche A, Gooley JL, Jenkins AJ, MacIsaac RJ, O'Neal DN. Insulin pump basal adjustment for exercise in type 1 diabetes: a randomised crossover study. Diabetologia. 2016 Aug;59(8):1636-44. doi: 10.1007/s00125-016-3981-9. Epub 2016 May 11. PMID 27168135
• Paldus B, Morrison D, Zaharieva DP, Lee MH, Jones H, Obeyesekere V, Lu J, Vogrin S, La Gerche A, McAuley SA, MacIsaac RJ, Jenkins AJ, Ward GM, Colman P, Smart CEM, Seckold R, King BR, Riddell MC, O'Neal DN. A Randomized Crossover Trial Comparing Glucose Control During Moderate-Intensity, High-Intensity, and Resistance Exercise With Hybrid Closed-Loop Insulin Delivery While Profiling Potential Addi PMID 34789504
• Mallad A, Hinshaw L, Schiavon M, Dalla Man C, Dadlani V, Basu R, Lingineni R, Cobelli C, Johnson ML, Carter R, Kudva YC, Basu A. Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach. Am J Physiol Endocrinol Metab. 2015 Jun 15;308(12):E1106-15. doi: 10.1152/ajpendo.00014.2015. Epub 2015 Apr 21. PMID 25898950
• Buehler LA, Noe D, Knapp S, Isaacs D, Pantalone KM. Ketogenic diets in the management of type 1 diabetes: Safe or safety concern? Cleve Clin J Med. 2021 Oct 1;88(10):547-555. doi: 10.3949/ccjm.88a.20121. PMID 34598919
• Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group; Nathan DM, Zinman B, Cleary PA, Backlund JY, Genuth S, Miller R, Orchard TJ. Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh PMID 19636033

Identifiers

NCT: NCT07185555 · 1835/CEL

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗