A Study to Determine Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Type 1 Diabetes

Insulin resistance (IR) is consistently found in patients with type 1 diabetes (T1DM) and pathophysiologically links T1DM with atherosclerotic disease. IR and nascent atherosclerosis, as characterized by endothelial dysfunction, are present early in T1DM. Although atherosclerosis leads to cardiovascular disease (CVD)-the predominant cause of death in T1DM-the early cardiometabolic processes driving atherosclerosis are not currently well-characterized. My overarching hypothesis is that IR and endothelial dysfunction in T1DM are, in part, iatrogenic, occurring as a function of nonphysiologic insulin delivery.

Previous research shows IR in T1DM is closely related to iatrogenic hyperinsulinemia. Iatrogenic hyperinsulinemia in T1DM results from injecting insulin into subcutaneous tissue rather than delivering insulin more physiologically into the hepatic portal vein. Hyperinsulinemia, per se, is closely linked with IR and independently predicts CVD in diabetic and nondiabetic populations. Thus, peripheral insulin delivery brings about unintended adverse cardiometabolic consequences in T1DM. The investigators propose a practical intervention to diminish iatrogenic hyperinsulinemia and thereby mitigate CVD risk. The investigators hypothesize that a reduction in iatrogenic hyperinsulinemia brought about by a low carbohydrate diet (LCD) will independently correlate with improved insulin sensitivity (Aim 1) and endothelial function (Aim 2).

In this pilot study, the investigators will mechanistically dissect the contribution of iatrogenic hyperinsulinemia to IR and endothelial dysfunction in 8 adults with T1DM using a crossover study of LCD vs. standard carbohydrate diet (SCD) to experimentally modify hyperinsulinemia. The investigators will quantify insulin sensitivity using hyperinsulinemic, euglycemic clamps and measure endothelium-dependent flow mediated vasodilation using high-resolution ultrasound.

Inclusion criteria

• Age: 18-60
• HbA1c: 5.6-9.0%
• Insulin delivery: must be on an insulin pump
• Glucose Monitor: must use a continuous glucose monitor (CGM)
• BMI 18-33 kg/m^2
• Body Mass >/= 50 kg ( 110 lbs)

Exclusion criteria

• severe hypoglycemia : >/= 1 episode in the past 3 months
• diabetes comorbidities (>= 1 trip to emergency department for poor glucose control in the past 6 months,
• New York Heart Association Class II-IV cardiac functional status
• SBP > 140 and DBP > 100 mmHg,
• eGFR by MDRD equation of <60 mL/min/1.73m^2
• AST or ALT > 2.5 times the upper limit of normal
• HCT <35%

medications

• any antioxidant vitamin supplement (<2 weeks before STUDY visit)
• any systemic glucocorticoid
• any antipsychotic
• atenolol, metoprolol, propranolol
• niacin
• any thiazide diuretic
• any OCP with > 35 mcg ethinyl estradiol,
• growth hormone
• any immunosuppressant
• any antihypertensive
• any antihyperlipidemic

other:

• pregnancy
• Tanner stage < 5
• peri or postmenopausal woman
• active smoker
• gluten-free diet requirement

Additional exclusion criteria for T1DM subjects

• any diabetes medication except insulin