Participants are being asked to be in a research study. Scientists do research to answer important questions which might help change or improve treatment of participants disease in the future.

In patients with Type 1 Diabetes (T1D), Dapagliflozin a Selective Glucose Transporter 2 Inhibitor (SGLT2i) is known to increase production of glucose in the liver, increase breakdown of fats (lipolysis), and increase production of ketones (ketogenesis). Ketones are chemicals produced by the liver when the body breaks down fat for energy instead of glucose. When the level of ketones in the body becomes too high, a condition called ketoacidosis develops. In this study, the study team will investigate whether adding pioglitazone (a medication commonly used to treat type 2 diabetes), can reduce the Dapagliflozin - induced liver glucose production, fat break down (lipolysis) and ketone body production (ketogenesis) in patients with Type 1 Diabetes (T1D).

The purpose of this research study is to investigate the effects of Dapagliflozin and Pioglitazone in the body - specifically, on liver glucose production, breakdown of fat, and ketone production in Type 1 Diabetic patients treated with insulin. Subjects with type 1 diabetes mellitus (T1DM) can't make insulin because their pancreas doesn't work properly. This means they need insulin injections to control their blood sugar. But using insulin can sometimes cause low blood sugar and weight gain, making it harder for insulin to work and requiring higher doses. Finding other medicines that can help lower blood sugar in people with T1DM and can be used along with insulin would make it easier to manage their blood sugar.

Dapagliflozin is in a class of drugs known as Selective Glucose Cotransporter 2 inhibitors (SGLT2i) and has been shown to effectively lower blood sugar concentration in type 1 diabetes mellitus (T1DM) patients. These drugs lower blood glucose levels by preventing or reducing the re-absorption of glucose in the kidneys. This results in the release of glucose into the urine. At the same time, Selective Glucose Transporter 2 Inhibitor (SGLT2i) drugs stimulate glucose production by the liver, which helps compensate for the loss of glucose into the urine. Also, the use of dapagliflozin in patients with type 1 diabetes was associated with increased risk of ketoacidosis. Ketoacidosis is a serious condition that occurs when the body produces high levels of ketones, leading to increased acidity in the blood. Pioglitazone is in a class of thiazolidinediones and is commonly used to treat high blood sugar levels caused by type 2 diabetes. The investigators believe that the addition of pioglitazone, to dapagliflozin will prevent the risk of ketoacidosis associated with dapagliflozin, and will cause a large reduction in plasma glucose concentration in type 1 diabetes (T1DM) patients.

Inclusion Criteria:

1. Age >18 years
2. T1DM
3. Other than diabetes, subjects must be in good general health as determined by physical exam, medical history, Chem 20, CBC, TSH, urinalysis, and EKG.
4. Fasting C-peptide concentration <0.7 ng/ml
5. Poor glycemic control (HbA1c=7.0-11.0%)
6. Treatment with multiple daily insulin injections (basal plus prandial) or insulin pump
7. Total daily insulin dose ≥0.6 U/kg per day
8. Stable insulin dose (±4 units) in the preceding three months.
9. eGFR≥60 ml/min
10. Weight stable over the preceding 3 months (± 3 pounds) and who do not participate in an excessively heavy exercise program

Exclusion Criteria:

1. T2DM
2. Daily insulin dose <0.6 U/kg per day
3. Fasting C-peptide >0.7 ng/ml
4. HbA1c <7.0% or >11.0%
5. eGFR<60 ml/min
6. Hematuria in urine analysis
7. Pregnancy, lactating, positive pregnancy test or planning to become pregnant in the following year. Women of child-bearing potential will be requested to use at least two barrier methods before being enrolled in the study.
8. Major organ system disease which includes: (i) malignancy or history of malignancy including bladder cancer; (ii) Congestive heart failure or history of coronary heart disease or any other cardiac disease; (iii) chronic liver disease or LFT >3 times the upper normal level; (iv) History of alcohol or drug abuse; (v) History of chronic lung disease (e.g., COPD, asthma); (vi) history of rheumatic disease; (vii) History of chronic pancreatitis or pancreatic surgery; (viii) History of CVA or TIA (ix) Planned surgery during the study; (x) history of HIV infection or other immune compromised disease; and history of organ transplantation; (xi) patients who take medications, other than insulin, known to affect glucose metabolism, e.g., prednisone.
9. Evidence of proliferative diabetic retinopathy
10. Patients enrolled in a heavy exercise program
11. Patients on ketogenic diet
12. History of hospitalization for DKA, hypoglycemia or uncontrolled hyperglycemia in the preceding 6 month.
13. Presence of symptoms of poor glycemic control, e.g. polydipsia or polyurea
14. History of hypersensitivity to dapagliflozin or pioglitazone

Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the Diabetes division at UT Health. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by Diabetes division at UT Health research staff will be secured, and password protected. At the end of the study, all study databases will be de-identified and archived at the Diabetes division at UT Health.

At the end of the study, after data analysis is complete.

At week 16, subjects will be randomized to receive in a double-blinded fashion pioglitazone or placebo for 16 weeks.