Obesity and Insulin Resistance in Type 1 Diabetes Mellitus: From Bariatric Surgery to Pancreas Transplantation

DISCUSSION

Although insulin deficiency is the defining feature of type 1 diabetes mellitus, insulin resistance is increasingly recognized in this population.¹ Patients with type 1 diabetes mellitus who have a family history of diabetes mellitus, exhibit features of type 2 diabetes mellitus such as obesity and metabolic syndrome, and develop insulin resistance are described as having double diabetes, hybrid diabetes, or type 1.5 diabetes.⁶ This symptom overlap suggests that type 1 and type 2 diabetes mellitus are on a spectrum of the same disease rather than 2 distinct entities.⁶ Patients with type 1 diabetes mellitus who develop insulin resistance are at increased risk of diabetic complications and mortality, independent of their average glucose control or HbA1c level, likely because of the microvascular burden.^7,8

The pathogenesis of insulin resistance in type 1 diabetes mellitus is not well understood but appears to be multifactorial and to involve lifestyle factors, genetic predisposition, repeated hypoglycemia, and the nonphysiologic nature of subcutaneous insulin administration.⁹ Attempts to achieve optimal glycemic control by intensifying insulin therapy in obese patients with type 1 diabetes mellitus may trigger a cycle of hypoglycemia, compensatory carbohydrate intake, rebound hyperglycemia, and escalating insulin doses—ultimately worsening weight gain and insulin resistance.^4,9 Additional mechanisms that may contribute to weight gain include increased sympathetic nervous system activity, altered protein turnover, changes in substrate transport, alterations in the gut microbiome, and an increase in the size of metabolically active organs.^1,2

Management of insulin resistance in obese patients with type 1 diabetes mellitus is challenging. The traditional strategies of insulin optimization, nutrition, exercise, and lifestyle modifications often fail to achieve adequate glycemic control. Medications used to treat insulin resistance in patients with type 2 diabetes mellitus (metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors) may reduce weight, improve hyperglycemia, and have beneficial cardiovascular effects, but concerns about diabetic ketoacidosis, hypoglycemia, costs, off-label use, and minimal long-term efficacy limit their routine use in patients with type 1 diabetes mellitus.^1,2

Bariatric surgery outcomes in patients with type 1 diabetes mellitus have not been evaluated in randomized controlled trials, but experience in several cohorts of patients with type 1 diabetes mellitus has been reported. In a 2020 review, Korakas et al summarize the effects of bariatric surgery on weight loss, daily insulin requirements, and HbA1c in obese patients with type 1 diabetes mellitus.⁵ In 189 patients from 20 studies who had obesity and type 1 diabetes mellitus and underwent bariatric surgery—Roux-en-Y gastric bypass, sleeve gastrectomy, adjustable gastric band, or biliopancreatic diversion—mean BMI reductions ranged from 8.3 to 23 kg/m². Although insulin requirements decreased, the effect on glucose control and HbA1c was modest or nonexistent.⁵ In a 2019 review, Yeung et al reported beneficial effects of bariatric surgery on insulin requirements and HbA1c reduction but limited improvement of daily glucose control.¹⁰ These mixed results highlight the metabolic heterogeneity across the diabetes types.

Reports describe minimal major complications after bariatric surgery.^5,10,11 Notably, in patients with type 1 diabetes mellitus, bariatric surgery was associated with increased rates of diabetic ketoacidosis and hypoglycemia.¹¹ Rapid carbohydrate delivery to the jejunum after Roux-en-Y gastric bypass combined with improved insulin sensitivity may create a mismatch between glucose absorption and exogenous insulin action, contributing to severe hypoglycemia. For that reason, sleeve gastrectomy may be a more appropriate option for patients with type 1 diabetes mellitus.¹⁰

Pancreas transplantation is the most effective intervention for restoring glucose homeostasis and preventing progression of complications. However, organ scarcity, surgical risk, and lifelong immunosuppression limit transplantation.¹² Additionally, pancreas transplantation is generally restricted to patients with a BMI <30 kg/m², so substantial weight loss is necessary for obese candidates to qualify.¹³

Data on pancreas transplantation outcomes after bariatric surgery are limited. Porubsky et al reported on 4 morbidly obese patients (BMI of 38 to 59.8 kg/m²) with type 1 diabetes mellitus and severe recurrent hypoglycemia who underwent bariatric surgery (3 Roux-en-Y gastric bypass and 1 sleeve gastrectomy) followed by pancreas transplantation 1.7 to 7.6 years later.¹³ All patients had an unremarkable postoperative course and achieved stable glucose control and resolution of hypoglycemia.¹³ Matar et al identified 17 patients who received a pancreas transplant after bariatric surgery (1.1% of 1,542 total pancreas transplant patients); the outcomes of the patients who had undergone bariatric surgery were comparable to the outcomes of the patients who did not undergo bariatric surgery.¹⁴ Matar et al noted transplant challenges because of the altered anatomy after bariatric surgery and used a side-to-side jejunal anastomosis technique.¹⁴ In our case, we used a duodenoduodenostomy to provide more physiologic drainage and to facilitate postoperative management.

Islet transplantation is an alternative to whole pancreas transplantation in patients with type 1 diabetes mellitus and preserved renal function. However, inferior long-term outcomes, the need for more than one islet infusion in approximately 70% of cases, and the fact that few medical centers offer this therapy limit the application of islet transplantation.¹⁵