Study of Arginine and Nitric Oxide in Patients With Diabetes

This study will test the effect of citrulline versus placebo supplementation in ketosis-prone diabetes (KPD) patients on arginine and nitric oxide production and on glucose- and arginine-stimulated insulin secretion and arterial flow-mediated dilation.

Both arginine and its derivative nitric oxide (NO) have been implicated in the regulation of glucose homeostasis. Arginine is a β cell secretagogue, potentiating glucose stimulated insulin secretion. Further, it has been shown that glucose can stimulate NO production in primary β cells, and NO then enhances insulin secretion. On the other hand, because the only known fate of citrulline is its conversion to arginine, citrulline supplementation could be a more efficient and safe way to increase intracellular arginine. Compared to enteral arginine, citrulline administration to healthy humans elicited a greater increase in plasma arginine and NO products, suggesting a greater increase in cellular arginine availability for NO synthesis. Therefore dietary citrulline supplementation will result in greater arginine availability and NO synthesis than arginine supplementation per se in KPD patients. In addition, because the consequences of diminished NO production in usual type 2 diabetes includes vascular dysfunction, an overall increase in NO production in response to citrulline supplementation will result in an improvement in vascular function assessed by arterial flow-mediated dilation

In this arm, 10 ketosis prone diabetes patients will be randomly assigned to receive 34.2 mmol/d of dietary citrulline for 20 days. Citrulline will be in the form of 2.85 mmol capsules and patients will be instructed to consume 4 capsules with each of their 3 main meals. The citrulline will be provided in a double-blind fashion by a designated unblinded investigator who will not come in direct contact with the subjects.

In this arm, 10 ketosis prone diabetes patients will be randomly assigned to receive 34.2 mmol/d of dietary alanine for 20 days. Alanine will be in the form of 2.85 mmol capsules and patients will be instructed to consume 4 capsules with each of their 3 main meals. The alanine will be provided in a double-blind fashion by a designated unblinded investigator who will not come in direct contact with the subjects.

Ketosis prone diabetes patients (n=10) will be randomly assigned to receive either dietary supplement of citrulline or alanine as placebo. They will then cross over to the other supplement.

Ketosis prone diabetes patients (n=10) will be randomly assigned to receive either dietary supplement of citrulline or alanine as placebo. They will then cross over to the other supplement.

The change in the amount of arginine produced from baseline in response to supplements of citrulline versus alanine (placebo) will be assessed by stable isotope tracers after 3 weeks of supplementation.

The change in the amount of nitric oxide produced produced from baseline in response to supplements of citrulline versus alanine (placebo) will be assessed by stable isotope tracers after 3 weeks of supplementation.

The change in in arterial function (assessed by endopat) from baseline in response to supplements of citrulline versus alanine placebo will be assessed after 3 weeks of supplementation.

The change in glucose stimulated insulin secretion from baseline in response to supplements of citrulline versus alanine placebo will be assessed after 3 weeks of supplementation.

Inclusion Criteria: New onset (defined as receiving a diagnosis within the past 1 year) diagnosis of unprovoked" A-β+ ketosis-prone diabetes Aged 20-65 years In good health except for diabetes without clinical evidence of micro- or macrovascular complications by history, physical exam and blood chemistries Exclusion Criteria: Chronic or acute illness History of myocardial infarction or coronary artery disease or stroke, Renal insufficiency (eGFR <90mL/min/1.73m2; <30 mg albumin / g creatinine in urine) Abnormal liver, thyroid, gonadal or adrenal functions On medications other than metformin, On any hormonal replacement therapy Pregnancy