Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long-acting dual amylin and calcitonin receptor agonist improves insulin-mediated glycaemic control and controls body weight

Br J Pharmacol. 2024 Jun;181(12):1829-1842. doi: 10.1111/bph.16329. Epub 2024 Feb 20.

Abstract

Background and purpose: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D.

Experimental approach: Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg-1) to induce T1D. Humulin (1 U/200 g·day-1 or 2 U/200 g·day-1) was continuously infused, while half of the rats received additional KBP-336 (4.5 nmol·kg-1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study.

Key results: Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation.

Conclusion and implications: The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits.

Keywords: DACRA; combination therapy; glycaemic control; hyperglucagonomia; insulin sensitivity; insulin sensitizer; type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amylin Receptor Agonists / pharmacology
  • Animals
  • Blood Glucose* / drug effects
  • Blood Glucose* / metabolism
  • Body Weight* / drug effects
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1* / drug therapy
  • Diabetes Mellitus, Type 1* / metabolism
  • Glycemic Control*
  • Hypoglycemic Agents* / administration & dosage
  • Hypoglycemic Agents* / pharmacology
  • Insulin*
  • Islet Amyloid Polypeptide
  • Male
  • Rats
  • Rats, Sprague-Dawley*
  • Receptors, Calcitonin* / agonists
  • Receptors, Calcitonin* / metabolism
  • Streptozocin

Substances

  • Receptors, Calcitonin
  • Insulin
  • Hypoglycemic Agents
  • Blood Glucose
  • Amylin Receptor Agonists
  • Islet Amyloid Polypeptide
  • Streptozocin