Kidney disease has long been recognized as one of the leading causes of morbidity and mortality in people with diabetes. But while all diabetes-related kidney disease (DKD) may look the same clinically, histopathologic, molecular, and genetic features appear to suggest important differences in kidney disease in type 1 diabetes and type 2 diabetes that could influence risk, progression, and treatment choices.

What is known of the natural history of diabetes is based largely on type 1 diabetes studies, said Viji Nair, PhD, MS, Bioinformatics Team Leader, George M. O’Brien Kidney Translational Core Center, University of Michigan. Serial biopsies suggest that type 2 diabetes follows different trends and patterns in terms of progression, complications, and comorbidities.

Dr. Nair opened Diabetes Kidney Disease in Type 1 and Type 2 Diabetes—The Same Disease? on Sunday morning. The session can be viewed by registered meeting participants at ADA2023.org. If you haven’t registered for the 83rd Scientific Sessions, register today to access the valuable meeting content through August 28.

The differences between type 1 diabetes and type 2 diabetes are particularly pronounced in youth, Dr. Nair said. Compared to youth with type 1 diabetes, youth with type 2 diabetes have a higher prevalence of DKD and more rapid progression of albuminuria. At the same time, youth-onset type 2 diabetes carries a higher risk of end-stage kidney disease and all-cause mortality versus older-onset diabetes at any age.

Morphometric analysis of kidney biopsies from youth-onset type 1 diabetes and type 2 diabetes shows distinct differences. Glomerular tuft area and glomerular volume are both increased in youth-onset type 2 diabetes versus type 1 diabetes, as are mesangial matrix area and mesangial volume.

Single-cell sequencing shows shared and specific transcriptional alterations in both type 1 diabetes and type 2 diabetes compared to healthy controls, but gene expression patterns are distinctly different between the two types.

“We are looking into molecular pathways and planning direct comparisons between type 1 diabetes and type 2 diabetes to find altered mechanisms,” Dr. Nair said.

The Kidney Precision Medicine Project (KPMP) is using kidney biopsies to redefine and reclassify common kidney diseases by combining deep molecular phenotyping of kidney biopsies with clinical characteristics, innovative digital pathology, and clinical outcomes. Early work is revealing significant histologic differences between individuals who have lived with diabetes for over 25 years who do not have chronic kidney disease (CKD) and those who do.

“There are clear histologic differences between CKD patients and diabetes mellitus resilient (DMR) patients when examining glomerular, tubulointerstitial, and vascular compartments,” said Sylvia Rosas, MD, MSCE, Associate Professor of Medicine, Joslin Diabetes Center. “Histopathologic lesions are significantly associated with estimated glomerular filtration rate (eGFR), and proteinuria and chronic histopathologic lesions are associated with kidney disease progression.”

Single-cell ribonucleic acid (RNA) sequencing shows distinct cell types for DMR and DKD patients, she added, although the clinical implications are not yet clear.

There are also distinct treatment approaches for type 1 diabetes and type 2 diabetes for mainstays angiotensin II receptor blockers (ARB) and angiotensin-converting enzyme (ACE) inhibitors, as well as for newer agents such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (nsMRA), and glucagon-like peptide-1 (GLP-1) receptor agonists.

“Intensive glycemic control helps in type 1 diabetes, but it is not enough,” said Anand Srivastava, MD, MPH, Associate Professor of Nephrology, University of Illinois Chicago. “A quarter of patients still develop microalbuminuria, and intensive glycemic control is associated with weight gain, worsening insulin resistance, central obesity, dyslipidemia, higher blood pressure, and worse inflammation.”

The temptation is to use the same agents in type 1 diabetes that offer renal protection in type 2 diabetes, he added. Some agents translate well, while others may not.

ARB trials in type 2 diabetes show up to 20% reduction in the risk of doubling serum creatinine, end-stage kidney disease (ESKD), or death. ACE inhibitor trials in type 1 diabetes show even better results, up to 50% reduction in doubling of serum creatinine, death, dialysis, or kidney transplant.

SGLT2 inhibitors have similar effects on eGFR and albuminuria in type 1 diabetes and type 2 diabetes, Dr. Srivastava added. The class also carries a similar risk of diabetic ketoacidosis in both types.

Data are scarce and contradictory for nsMRA and GLP-1 receptor agonists in type 1 diabetes. Both classes offer clear kidney benefits in type 2 diabetes, but the benefits are less clear-cut for type 1 diabetes. “More trials are needed that target reduction of adverse kidney outcomes in type 2 diabetes and type 1 diabetes,” Dr. Srivastava concluded.