Acute Metabolic Effects of Tirzepatide in Type 1 Diabetes

This study will examine the effects of Tirzepatide (TZP), a glucagon-like peptide 1 (GLP1) - gastric inhibitory peptide (GIP) co-agonist, on metabolism in type 1 diabetes (T1D). Research participants with T1D will undergo measures of insulin sensitivity, and hormone levels post-meal, post-hypoglycemia and during the overnight period. These measures will be performed prior to, and after 4 weeks of treatment with TZP. These measures will also be compared to a group of adults without diabetes (who will not receive treatment with TZP) to assess how metabolism of energy and nutrients is different in T1D compared to people without diabetes.

TIRTLE2 is a phase 2 double-blinded placebo-controlled mechanistic clinical trial that extends upon the findings of TIRTLE1, a phase 2 double-blinded placebo-controlled trial (TZP 5.0mg vs placebo over 12 weeks) in T1D (trial registration: ACTRN12624000111572).

TIRTLE2 is a designed to 1) demonstrate that T1D is associated with insulin resistance, increased lipolysis and excessive growth hormone and prandial glucagon secretion; 2) determine whether TZP can improve whole body insulin sensitivity (main aim) and adipose insulin sensitivity, while reducing growth homrone and prandial glucagon secretion, before significant weight loss (indicating a role for TZP beyond weight management in T1D); 3) determine if TZP can maintain the glucagon response to hypoglycemia.

To address these research aims, a single comprehensive clinical trial will be performed in 20 participants with T1D, who will receive a weekly injection of TZP 2.5mg or placebo for 4 weeks. A short treatment duration was chosen to assess if TZP offers T1D-specific benefits prior to significant weight loss. Dynamic tests will also be performed in 10 participants without diabetes in a baseline only cross-sectional study (participants without diabetes will not receive treatment in the main clinical trial).

TIRTLE2 will employ the 'gold standard' hyperinsulinemic-euglycemic and hypoglycemic clamps, in conjunction with complementary analyses of the effects of TZP on metabolism across multiple physiological states. This mechanistic study will define mechanisms by which GLP1-GIP co-agonism may uniquely provide clinical benefits in T1D during the fasting and fed states, and during hypoglycemia.

Eligibility Criteria:
Inclusion Criteria:

* age 18-55 years
* BMI ≥ 27 kg/m2
* HbA1c ≤ 9.0%
* insulin delivery using an automated insulin delivery system
* at least 2 years since diagnosis of type 1 diabetes

Exclusion Criteria:

* TZP or GLP-1 receptor agonist in last 3 months; metformin or sodium glucose co-transporter 2 (SGLT2) inhibitor in the last 6 weeks; steroids, antipsychotics, immunosuppressants in the last 6 weeks.
* Hypoglycemic unawareness or severe hypoglycemia last 6 months.
* History of seizure disorder.
* History of weight loss surgery.
* eGFR \<60 mL/min/1.73 m2.
* Liver disease (known cirrhosis, LFTs \> 3x upper limit of normal).
* Active malignancy.
* Pregnant, breastfeeding, planning pregnancy within 6 months, or not using adequate contraception.
* History of cardiovascular disease, or coronary event or stroke in last 3 months
* Hemoglobin level \< 13.5 g/dL