Annie Hasib

Type 2 diabetes mellitus (T2DM) is characterised by progressive insulin resistance and pancreatic β-cell dysfunction, ultimately resulting in impaired glucose homeostasis. While metabolic and genetic factors are central to disease development, increasing evidence indicates that disruption of the pancreatic islet extracellular matrix (ECM) may be an important contributor to β-cell failure. The islet ECM is not merely a structural scaffold but a dynamic signalling network that regulates β-cell adhesion, survival, proliferation and insulin secretion through integrin-mediated signalling and mechanotransduction pathways. In healthy islets, a tightly organised ECM composed of collagens, laminins, fibronectin and glycosaminoglycans maintains basement membrane integrity, vascular support and coordinated cell-matrix communication. In T2DM, chronic hyperglycaemia, inflammation and oxidative stress are associated with pathological ECM remodelling and are thought to contribute to alterations in islet ECM composition characterised by fibrosis, altered matrix composition, dysregulated proteolysis and excessive ECM protein deposition. These changes are potentially associated with impaired integrin signalling, altered mechanotransduction and compromised β-cell function and viability in experimental models. ECM remodelling may also promote islet stiffening, vascular dysfunction, amyloid deposition and inflammatory signalling, further amplifying β-cell decline. This review synthesises current understanding of islet ECM composition, cell-matrix interactions and the molecular mechanisms linking metabolic stress to ECM remodelling. It also highlights emerging preclinical evidence that incretin-based therapies, including semaglutide and tirzepatide, are associated with changes in ECM-related pathways, while emphasising that these effects may be secondary to improved metabolic control and that direct ECM-targeting effects have yet to be established. Finally, we discuss emerging therapeutic strategies targeting fibrosis, mechanotransduction and matrix signalling pathways, and identify key knowledge gaps regarding the causal contribution of ECM remodelling to β-cell dysfunction and loss in T2DM.

The ever-increasing prevalence of obesity and Type 2 diabetes has necessitated the development of newer and more effective approaches for achieving efficient glycemic control and weight loss. Conventional treatment methods often result in weight gain, further deteriorating the already impaired metabolic control in people with obesity/Type 2 diabetes. Alleviation of obesity and diabetes achieved after bariatric surgeries highlight the therapeutic importance of gut-brain axis and entails development of more patient-friendly approaches replicating the positive metabolic effects of bariatric surgery. Given the potential involvement of several gut hormones in the success of bariatric surgery, the therapeutic importance of synergistic interaction between these hormones for improved metabolism cannot be ignored. Many unimolecular multiagonist peptides are in preclinical and clinical trials as they maximize the combinatorial metabolic efficacy by concurrent activation of multiple gut hormone receptors. This review summarizes the ongoing developments of multiagonist peptides as novel therapeutic approaches against obesity-diabetes.

Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.

Background: Therapeutic benefits of peptide‐based drugs is limited by rapid renal elimination.Methods: Therefore, to prolong the biological action profile of the recently characterized triple‐acting hybrid peptide, exendin‐4/gastrin/xenin‐8‐Gln, a fatty acid (C‐16) has been covalently attached, creating exendin‐4(Lys²⁷PAL)/gastrin/xenin‐8‐Gln. Exendin‐4/gastrin and liraglutide/gastrin/xenin‐8‐Gln were also synthesized as direct comparator peptides.Results: All hybrid peptides evoked significant concentration‐dependent increases of insulin secretion from isolated murine islets and BRIN‐BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin‐4(Lys²⁷PAL)/gastrin/xenin‐8‐Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin‐4/gastrin/xenin‐8‐Gln, exendin‐4/gastrin, and exendin‐4(Lys²⁷PAL)/gastrin/xenin‐8‐Gln were then progressed to a 31‐day twice‐daily treatment regimen in obese‐diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA_1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin‐4/gastrin and exendin‐4/gastrin/xenin‐8‐Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin‐4(Lys²⁷PAL)/gastrin/xenin‐8‐Gln augmented glucose‐induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose‐dependent insulinotropic polypeptide (GIP) and the glucose‐lowering actions of insulin.Conclusion: This study emphasizes the therapeutic promise of long‐acting, multi‐targeting hybrid gut peptides for type 2 diabetes.

Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla²)GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla²)GIP and xenin-8-Gln. Methods Following confirmation of enzymatic stability, insulin secretory activity of (DAla²)GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla²)GIP/xenin-8-Gln was determined in high-fat-fed mice. Results All peptides significantly (p < 0.05 to p < 0.001) enhanced in vitro insulin secretion from pancreatic clonal BRIN-BD11 cells, with xenin (and particularly GIP)-related signalling pathways, being important for this action. Administration of (DAla²)GIP or (DAla²)GIP/xenin-8-Gln in combination with glucose significantly (p < 0.05) lowered blood glucose and increased plasma insulin in mice, with a protracted response of up to 4 h. All treatments elicited appetite-suppressive effects (p < 0.05), particularly (DAla²)GIP/xenin-8-Gln and xenin-8-Gln at elevated doses of 250 nmol/kg. Twice-daily administration of (DAla²)GIP/xenin-8-Gln or (DAla²)GIP for 21 days to high-fat-fed mice returned circulating blood glucose to lean control levels. In addition, (DAla²)GIP/xenin-8-Gln treatment significantly (p < 0.05) reduced glycaemic levels during a 24 h glucose profile assessment. Neither of the treatment regimens had an effect on body weight, energy intake or circulating insulin concentrations. However, insulin sensitivity was significantly (p < 0.001) improved by both treatments. Interestingly, GIP-mediated glucose-lowering (p < 0.05) and insulin-releasing (p < 0.05 to p < 0.01) effects were substantially improved by (DAla²)GIP and (DAla²)GIP/xenin-8-Gln treatment. Pancreatic islet and beta cell area (p < 0.001), as well as pancreatic insulin content (p < 0.05), were augmented in (DAla²)GIP/xenin-8-Gln-treated mice, related to enhanced proliferation and decreased apoptosis of beta cells, whereas (DAla²)GIP evoked increases (p < 0.05 to p < 0.01) in islet number. Conclusions/interpretation These studies highlight the clear potential of GIP/xenin hybrids for the treatment of type 2 diabetes.

Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18–25 and xenin 18–25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18–25 and xenin 18–25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18–25 or xenin 18–25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18–25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18–25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18–25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18–25 Gln, have potential therapeutic utility for type 2 diabetes.