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Paralyzing hit, diabetes can’t slow Davis down | Sports

Diabetes News


It’s not that Gavin Davis takes football for granted. He’s been hurt before, suffered stingers and the like.

He’s always known the inherent risks of playing the game. Still, it sometimes takes a direct confrontation with those dangers to develop a true appreciation.

For Davis, that moment came on Sept. 23, 2022, on his home field at Shady Spring. He was running in to make a tackle, as he had done so many times before, when his life took what ended up being a miraculously brief detour.

The final two minutes were winding down on the Tigers’ game against PikeView. Shady was comfortably ahead by three touchdowns, but PikeView was moving the ball, trying to finish on a high note.

Peyton Mounts caught a pass and took it into the red zone, where he was met by Davis from behind with Adam Richmond charging in ahead.

“(Mounts) catches the ball and he’s running to the outside. When he does, he tries to slow down,” Davis said. “I stop and I end up grabbing him from the back. When I do, you can tell he sees Adam coming at him so he’s trying to go down. When he does, I’m going down with him and Adam’s shoulder hits my head. When it does, you can see in the video it kind of jars it and literally just turns my body off and I just fall down.”

Video of the play provides most of what Davis is able to go on, because he has little recollection of the moment.

“I remember grabbing the kid, and after I grabbed the kid I just remember falling down,” Davis said, “and then that’s it.”

But it wasn’t just that Davis was knocked unconscious. With the clock reading a mere 59 seconds, the hit also left Davis paralyzed, setting into motion tense moments for everyone who was there — especially his mom and dad.

“The whole time I’m going down to the field, I’m just praying to God and asking Him to help him be OK,” mom Jennifer said. “Just help everything be OK. And then just seeing him there, obviously that was scary. Then when our family was coming down and they were all crying. I’m having to console them and be the strong one, letting his buddies know he’s OK. That’s just what I kept telling myself. ‘He’s fine. He’s OK. God will take care of him.’”

“I remember when it first happened that everybody in the stands kind of took a gasp, and then it got quiet,” dad Chris said. “I remember thinking he’s knocked unconscious because of the way his body laid.

“I remember the stillness of how quiet it was. It was Coach Phil (Culicerto) who looked at me, and I believe he said, “Get out here.’ So I went out there and by the time I get there to him, the paramedic is trying to communicate with him.”

It was only then that Chris knew exactly how serious the situation was.

“I remember coming to and I was laying there and the paramedic was grabbing my hand, and he said, ‘Hey, hey, hey, hey, hey. Squeeze my hand. Squeeze my hand,’” Gavin said. “I was just very confused (about) what was happening. He was like, ‘Squeeze my hand. Come on, squeeze it!’”

Gavin was not responding, no matter how much he thought he was.

“I just kept hearing him say that and I told him — because I was laying and I couldn’t look down — I was like, ‘I’m squeezing as hard as I can,’” he said. “And I just remember the paramedic saying, ‘No, we have to get him off this field.’”

Gavin was eventually stabilized and placed in an ambulance to be transported to Raleigh General Hospital. Jennifer rode in the ambulance; Chris followed right behind them.

The ambulance actually had to pull over as consideration was given to flying Gavin to either Morgantown or Charleston. He was given a specialized IV and continued to Raleigh General, where his pads and helmet were carefully removed and multiple scans were performed, which confirmed a concussion.

But soon — very soon, considering the circumstances — the miracle happened. Gavin had suffered no injury to his spine, and things were only getting better.

“At that point in time, he’s starting to get feeling back in his extremities,” Chris said. “Within three or four hours, they’re going to let him stand.

“He grabs my arm, stands up and I say, ‘Praise God.’”

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Relying on God for strength and giving Him praise is nothing new for the Davis family. Neither, unfortunately, is battling adversity.

They have plenty of experience with both.

Gavin was diagnosed with diabetes when he was only 7 years old. Immediately, frequent daily finger sticks to monitor his blood glucose level became a regular part of life.

By the time he became interested in sports — a journey that has included youth basketball, football at the middle and high school levels and baseball — just getting ready for a game has been a challenge that has nothing to do with practice and weight room sessions.

Prep can start well over 24 hours prior to game time, and it’s all monitored by his mom.

“Mom’s texting the trainer and saying, ‘OK, he needs a Gatorade,’” Jennifer said with a smile.

“He will drink several Pedialytes in order to try to stack up those electrolytes and calcium and sodium,” Chris said. “And last year his endocrinologist also ordered that he take a bag of IV fluids before every game. That sometimes is difficult to get administered and get that done.”

That order came after Gavin twice was hospitalized when he went into full body cramps and stopped breathing, once after practice and once after a game. That one occurred on the team bus and he had to be carried out by his dad.

“All the muscles seized, from toe to neck,” Chris said.

During games, Chris and Jennifer get regular readings of Gavin’s sugar levels from his continuous glucose monitor that is located in his thigh. He also wears an insulin pump that is protected by a band and a padded arm sleeve.

If his levels are too high, he has to be rehydrated, but with no carbs — usually with a Powerade Zero. If they are too low, he still has to be hydrated but with enough carbs to where he is medically safe enough to compete. That’s where the Gatorade comes in.

Gavin’s glucose level even played a part as he lay motionless on the field that night, not responding to the paramedic’s pleas to squeeze his hand.

“I was afraid he was panicking as well, so the first thing I was trying to get was a blood sugar (reading), because that also determines how he is communicating with us,” Chris said. “If his blood sugar is too high, sometimes his rationale is not there, and if it’s too low his rationale’s not there.”

There is nothing easy about what Gavin goes through, but he keeps it in stride. He even adds a bit of levity to it.

“I get IVs a couple hours before the game. Sometimes, the IV, I have to take it with me on the bus to road games,” he said. “I’ll be sitting on the bus with the pole with my IV hanging off of it and I’ll get off the bus. Normally I go last because I don’t want to bang it or anything. So all these players get off the bus and they have their shoulder pads, and I get off the bus with my little IV.

“I’ve had a couple friends from other schools that are like, ‘Who’s the hospital patient getting off the bus?’ and a bunch of stuff like that.”

“‘This should be an easy game,’” Jennifer quips.

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There are certainly difficulties, like the tingly feeling he gets in his legs when his sugar runs too low.

And, ironically, he confesses to being “very terrified of needles” despite the multiple times he has had to face them.

“It’s definitely gotten easier over the years, just adapting to it and getting used to it,” he said.

Through his strong faith in God and a lot of hard work, Gavin overcomes it all. Amazingly, he only missed one game after the hit. Of course, he was placed in concussion protocol. And conditioning was modified and his practice work was monitored by team trainer Faye Gray.

“She would be like, ‘You sure about this? No headache? You can see? Everything’s good?’” Gavin said. “And I was like, ‘Yep.’ She was like, ‘All right, I guess I’ve got to turn you loose now.’ I was very happy that day, to go back and practice with them.”

He returned against Man on Oct. 7, although some people may have missed it.

“I had to actually wear a different jersey, because they had to cut my jersey off (after the injury),” he said. “So I wore No. 85 instead of 45.”

The rest of the season went well, and he was a member of the basketball team that played in the Class AA state title game for the third straight year.

With his senior year about to start, Gavin stands to play an even bigger role in the Tigers’ plans. Head coach Vince Culicerto said Gavin will start at running back, he and quarterback Brady Green providing a formidable duo.

“He played a lot of receiver last year, ran the ball towards the end of the year a little more. We’ve run him a bunch over the last couple of years, but (he will) run more this year,” Culicerto said. “And boy he can catch the ball when we slip him out and do that kind of stuff.”

No matter his role, he considers every moment on the field a blessing. He was touched and encouraged that both teams came together to pray for him after he was hurt.

And he now truly understands why teams are required to watch a film on concussions before the season.

“Nothing’s really changed. I still love playing. I wouldn’t say (I’m) more cautious, but definitely a thought in the back of my mind since it happened,” Gavin said. “Throughout my years of playing, they talk about concussions and getting knocked out, and you don’t really think about it. You just play football. … It is something I look back and reflect on, but it’s part of the game so I’ve kind of accepted it, moved on and played ball.

“Concussions are no joke. I do take them more seriously since that day.”

Chris looks at a photo of Gavin with his neck in a brace, then another of him walking at the hospital that same night.

“You don’t go from that to that without God,” Chris said. “It’s impossible.”


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Ferroptosis and Chinese medicine for type 2 diabetes

Diabetes News



With an aging global population and social lifestyle changes, the diabetes mellitus (DM) prevalence rate continues to increase annually. The most recent data released by the International Diabetes Federation (IDF)1 stated that the DM global prevalence in adults aged 20–79 years was expected to be approximately 10.5% (>500 million people) in 2021. Moreover, the largest increase in DM prevalence by 2045 is expected to occur in middle-income countries. In China, the most recent epidemiological survey2–4 revealed that DM prevalence among adults aged ≥18 years increased from 9.7% in 2007–2008 to 11.2% in 2015–2017, among which type 2 DM (T2DM) accounted for >90% of cases. T2DM is a metabolic disease characterized by elevated blood glucose caused by insulin resistance (IR) combined with a relative decrease in insulin secretion. Long-term carbohydrate metabolism disorders and related fat and protein metabolism impairments can cause chronic progressive damage to the kidney, eye, nerves, heart vessels, bone, and other tissues and organs. T2DM and its complications have become an important public health problem that seriously threatens human life and health and represents an important cause of death and disability.5 The etiology and pathogenesis of T2DM are complex, with genetic, environmental, and gut microbiota factors considered the major causes of T2DM, while oxidative stress, inflammation, endothelial cell damage, apoptosis, and autophagy are closely related to its development.

Ferroptosis, a recently identified form of regulated programmed cell death, is characterized by its iron dependence and lipid peroxidation-induced cellular dysfunction. It has been implicated in various diseases, including tumors and neurodegenerative diseases. In the context of T2DM, studies have explored the association between ferroptosis and its occurrence and development.6 Patients with T2DM often exhibit elevated serum iron concentrations and reactive oxygen species (ROS) levels in pancreatic tissues and cells.7,8 Moreover, pancreatic β cells, responsible for insulin secretion, possess weaker antioxidant defenses and are susceptible to ferroptosis compared to other tissues.9–11 Therefore, ferroptosis may contribute to the dysfunction of pancreatic β cells and the development of T2DM. Traditional Chinese medicine (TCM) has been used to treat DM for a long time and was described in ancient Chinese medicinal texts such as Huangdi Neijing (425–221 BC) regarding obesity and overeating. The TCM theory classifies DM into the category of “xiaoke” or “xiaodan”. With the continuous in-depth understanding and practice related to DM among the doctors of previous dynasties, the clinical TCM theory of T2DM has been gradually enriched. TCM is multi-targeted and multi-component, with anti-inflammatory, immunoregulation, antioxidant stress, and intestinal flora regulation effects, which have unique advantages for preventing and treating T2DM. However, its targets and specific mechanisms of action are still not fully elaborated. Increasing evidence suggests that Chinese herbs and their active ingredients may modulate ferroptosis and thereby exert therapeutic effects on T2DM and its complications.12,13 This review paper explores the concept, mechanism, and regulatory pathways of ferroptosis and its involvement in T2DM development of and develops a search strategy with strict inclusion and exclusion criteria, By summarizing and analyzing the mechanisms underlying TCM’s treatment of T2DM and its complications, this study provides a novel theoretical basis and clinical perspective for the utilization of TCM in the management of T2DM.

Mechanisms of Ferroptosis

Overview of Ferroptosis

In 2012, the Stockwell research team proposed a new form of regulated programmed cell death, termed ferroptosis, which differs from apoptosis, necrosis, and autophagy.14 Under iron-rich and ROS conditions, phospholipids containing polyunsaturated fatty acids (PUFAs) in the cell membranes are prone to peroxidation, resulting in the continuous accumulation of lipid peroxidation products. These products eventually disrupt cell membrane integrity and induce the cell death known as ferroptosis. The main cellular morphological changes associated with ferroptosis are mitochondrial atrophy, which includes the reduction or loss of mitochondrial cristae, outer mitochondrial membrane rupture, and mitochondrial membrane wrinkling. The primary biochemical features include intracellular iron and ROS accumulation, inhibition of the cystine/glutamate antiporter (system Xc), decreased glutathione peroxidase 4 (GPX4) activity, and reduced glutathione (GSH) production.15,16 The production of oxides of phospholipids containing PUFAs (PLOOHs) enforces ferroptosis, and PLOOH accumulation can lead to rapid and irreparable cell membrane damage, causing cellular iron death.

GSH represents the most abundant reducing agent in mammalian cells and is a cofactor of many enzymes (GPX4 and glutathione-S-transferase). System Xc is an important intracellular antioxidant system (a transmembrane protein complex composed of the light chain subunit SLC7A11 and the heavy chain subunit SLC3A2) that regulates GSH synthesis by mediating cystine uptake and glutamate release. GPX4 is a selenoprotein that functions as a key enzyme to catalyze the reduction of PLOOHs to the corresponding alcohols to reduce lipid peroxide production.17–19 From this perspective, ferroptosis is involved in several pathophysiological processes and linked to cellular metabolism through iron, selenium, lipid, and redox reactions. Ferroptosis is associated with disease pathogenesis, including tumors, ischemic organ damage, neurodegenerative lesions, pulmonary fibrosis, and endocrine metabolic diseases. Therefore, targeting ferroptosis potentially represents an effective therapeutic modality for ferroptosis-related diseases by regulating the ferroptosis-related mechanisms.20,21

Regulation of Ferroptosis

Mechanisms Governing Ferroptosis

Essentially, ferroptosis occurs when the cellular antioxidant capacity becomes weakened and catalyzed by ferrous ions, intracellular lipid peroxidation metabolites continuously accumulate, intracellular redox homeostasis is imbalanced, and ferroptosis occurs. These factors cause irreparable cell membrane damage and result in cellular dysfunction.20 Therefore, the core molecular mechanism of ferroptosis is an imbalance of cellular metabolism and redox homeostasis, where the key signals include the accumulation of intracellular iron, ROS, and lipid peroxidation products (Figure 1).16,20,21

Figure 1 Mechanism of ferroptosis occurrence. This figure was created with Figdraw (www.figdraw.com).

Regulation of Ferroptosis-Suppressing Pathways and Suppressors

It is currently believed that three major systems: cyst(e)ine/GSH/GPX4, FSP1/CoQ (ferroptosis suppressor protein 1, ubiquinone), and GCH1/BH4/DHFR (GTP cyclohydrolase 1, tetrahydrobiopterin, dihydrofolate reductase), effectively inhibit lipid peroxidation and thereby counteract the onset of ferroptosis (Figure 2).20–22

Figure 2 Regulation of ferroptosis suppressing pathways and suppressors. This figure was created with Figdraw (www.figdraw.com). Cytoplasmically located GPX4, mitochondrially located GPX4 and DHODH, plasma membrane located FSP1, and GCH1 (“?” indicates that the exact subcellular localization is unknown), together mediating the ferroptosis defense mechanism.

Cyst(e)ine/GSH/GPX4: The classical ferroptosis-suppressing pathway. Located in the cytoplasm and mitochondria, GPX4 converts reduced GSH into oxidized GSH (glutathione disulfide, GSSG), which is converted to GSH by glutathione reductase (GSR) through the action of electrons donated by nicotinamide adenine dinucleotide phosphate (NADPH), thereby enabling GSSG recycling.20,22,23 CoQ10/FSP1: Located primarily in the plasma membrane, FSP1 inhibits ferroptosis by preventing lipid peroxide accumulation by reducing CoQ to ubiquinol (CoQH2) via NADPH and by acting on α-tocopherol (α-TOH).20–22,24,25 GCH1/BH4/DHFR: GCH1 (exact subcellular localization unknown) is a GPX4-independent ferroptosis suppressor gene identified using the CRISPR/dCas9 screening technique.26,27 GCH1 inhibits ferroptosis through its metabolites BH4 and dihydrobiopterin (BH2).21,26,27

Dihydroorotate dehydrogenase (DHODH) is a recently identified ferroptosis suppressor that is primarily located in the mitochondria.28 DHODH inhibits ferroptosis in the mitochondria by reducing CoQ to CoQH2 in concert with mitochondrial GPX4.21,29

The GPX4 in the cytoplasm, GPX4 and DHODH in the mitochondria, and FSP1 in the plasma membrane form a triad within the cell and together mediate the ferroptosis defense mechanism.29

Ferroptosis and the Pathogenesis of T2DM and Its Related Complications

Ferroptosis and T2DM Pathogenesis

Pancreatic β cell dysfunction and IR are the two main links in T2DM pathogenesis, T2DM occurs when β cells lose compensation to IR. The etiology of pancreatic β cell injury and the pathogenesis of T2DM are closely related to iron overload and ROS accumulation. Pancreatic β-cells are sensitive to ferroptosis. Iron overload7 and increased ROS8 are often present in the pancreatic tissues and cells of patients with T2DM. Compared with other tissues, the pancreas has the weaker antioxidant defense, pancreatic tissues have lower expression and activity of antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], GPX), and pancreatic β cells are susceptible to ROS-induced oxidative stress damage.9–11 When human pancreatic islet β cells were treated with the ferroptosis inducer erastin in vitro, the glucose-stimulated insulin secretion (GSIS) capacity was significantly reduced, whereas treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) or the iron-chelating agent deferoxamine (DFO) rescued GSIS injury.30 These findings suggested that ferroptosis may be involved in T2DM occurrence and development by affecting the insulin secretion capacity of pancreatic β cells.

Environmental factors, such as long-term arsenic exposure and excessive iron intake, are also important factors in T2DM development.31–34 Wei et al35 constructed pancreatic dysfunction models both in vivo and in vitro using NaAsO2-induced Sprague-Dawley rats and MIN6 cells, respectively. They reported that ferroptosis was present in the pancreatic islet β cell injury models both in vivo and in vitro. The NaAsO2-induced mitochondrial damage produced excess mitochondrial ROS (MtROS), increased intracellular free iron levels and MtROS-dependent autophagy, and resulted in imbalanced iron homeostasis. These changes ultimately led to ferroptosis and insulin secretion dysfunction in pancreatic cells, whereas inhibiting the MtROS–autophagy–ferritin pathway improved the insulin secretion capacity of pancreatic β cells. In another study,36 iron stores were associated with the risk of developing DM. Iron regulatory genes, ferritin heavy chain (FTH1), and ferritin light chain (FTL) were highly expressed in islet tissues derived from diabetic patients and high-glucose-cultured INS-1 cells, heme oxygenase-1 (HO-1) and the inhibitor of differentiation proteins (ID1, ID3) may serve as potential endogenous antioxidants for pancreatic β cells against ROS and iron-overload, thereby protecting pancreatic β cells from oxidative stress and ferroptosis in T2DM patients.36

Ferroptosis and the Pathogenesis of T2DM Microangiopathy

Diabetic microvascular complications can affect various tissues and systems throughout the body and are associated with a variety of factors including microcirculatory disorders, inflammatory damage, and oxidative stress, among which nephropathy and retinopathy are the most common. Diabetic kidney disease (DKD) is a common chronic kidney disease and is thought to represent a major cause of end-stage renal disease (ESRD), which is responsible for approximately 30% to 50% of ESRD worldwide.37 Recent studies demonstrated that iron overload, ROS, and lipid peroxidation products accumulated in both mouse models of DKD and human renal tubular epithelial cells (HK-2) cultured under high glucose. The use of DFO or Fer-1 reduced renal iron accumulation and injury.38,39 Kim et al40 reported that renal biopsy samples derived from DKD patients had lower SLC7A11 and GPX4 mRNA expression compared to that from non-diabetic patients. They used streptozotocin (STZ)-induced DKD mice and transforming growth factor-β-1-stimulated proximal tubular epithelial cells in vivo and in vitro experiments, respectively, and found that the concentration of GSH was reduced, total iron levels and malondialdehyde (MDA, a lipid peroxidation product) were increased, SLC7A11 and GPX4 protein and mRNA expression levels were lower than in controls, and lipid peroxidation was enhanced. Fer-1 treatment alleviated these changes and significantly improved kidney damage and proteinuria caused by DM.40 It is suggested that ferroptosis is associated with the development of DKD and that inhibiting or attenuating ferroptosis may improve renal function in DKD.

Diabetic retinopathy (DR) is another common microvascular complication of T2DM. DR is a major cause of blindness in diabetic patients and is closely related to endothelial dysfunction and increased retinal capillary permeability.41 The current main DR treatment modalities include anti-angiogenic drug therapy and laser or surgical treatment.42 However, the benefits of these treatments for patients are also associated with adverse drug reactions or surgical risks. Zhang et al43 reported that human retinal vascular endothelial cell death induced by high-glucose treatment was associated with ferroptosis. Further investigation revealed that the high-glucose treatment upregulated TRIM46 (a member of the E3 ubiquitin ligase family TRIM), facilitated GPX4 ubiquitination, and induced ferroptosis in the cells. It was suggested that inhibiting ferroptosis by targeting TRIM46 and GPX4 represents a potential mechanism for effective DR treatment.

Ferroptosis and the Pathogenesis of T2DM Cardiovascular Complications

Patients with T2DM often have risk factors, such as obesity, abnormal lipid metabolism, and hypertension. Compared with the non-diabetic population, diabetic patients have a substantially increased risk of atherosclerotic vascular disease, which is one of the main causes of death in patients with T2DM.44–46 Diabetic cardiovascular complications can affect the heart, large blood vessels, and myocardial tissue, causing coronary atherosclerotic heart disease, diabetic cardiomyopathy, and other cardiac lesions.

The disorders of lipid and glucose metabolism are closely related to atherosclerosis development.47,48 The pathogenesis of diabetic atherosclerotic vasculopathy may be related to iron accumulation and lipid peroxidation.49–51 Using gene microarray technology (mRNA expression profiling) and bioinformatics analysis, Meng et al identified ferroptosis and HO-1 as important factors in diabetic atherosclerotic vascular disease.52 In vitro and in vivo diabetic atherosclerosis models were constructed using ApoE knockout mice and human umbilical vein endothelial cells (HUVECs), respectively. The results confirmed that Fer-1 reduced ROS production, attenuated high-glucose- and high-fat-induced lipid peroxidation, and reduced diabetic atherosclerosis formation. Similarly, knockout of the HO-1 gene reduced iron content, ROS production, lipid peroxidation, and ferroptosis in the HUVECs under a high-glucose environment. These findings suggested that ferroptosis is involved in diabetic atherosclerosis formation and that HO-1 may be a potential target for the treatment or drug development of diabetic atherosclerotic vascular disease.

Recently, several studies confirmed that diabetic cardiomyopathy development is associated with ferroptosis.53–55 Both DM myocardial ischemia-reperfusion injury model rats and a high-glucose hypoxia-reoxygenation cardiomyocyte model exhibited increased levels of iron ion concentration, ROS, SOD, MDA, and myocardial injury markers (serum creatine kinase MB and lactate dehydrogenase), ferroptosis, endoplasmic reticulum stress (ERS), and myocardial functional impairment. The ferroptosis inducer erastin or the inhibitor Fer-1 aggravated or reduced myocardial cell injury, respectively. Moreover, inhibiting endothelial network stress reduced ferroptosis and cell injury.54 Therefore, these findings indicated that ferroptosis is involved in DM myocardial ischemia–reperfusion-induced cardiomyocyte injury and is associated with ERS.

Endothelial cell injury is another important pathological mechanism in DM and diabetic cardiovascular disease.56 Luo et al57 reported that in HUVECs treated with high glucose and interleukin 1β, cell viability decreased, lipid ROS increased, and GSH and GPX4 concentrations decreased, and after treatment with ferroptosis inhibitors DFO and Fer-1, ROS levels in HUVECs decreased significantly and cell viability and GPX4 concentrations increased compared to pre-treatment. Further, transient transfection of HUVECs using p53 small interfering ribonucleic acid revealed that p53 small interfering ribonucleic acid attenuated the decrease in xCT (the light chain subunit of system Xc, also known as SLC7A11) and GSH and the increase in ROS induced by HG and IL-1β. In addition, in the aortic endothelium of db/db mice, p53 mRNA was up-regulated, xCT mRNA was down-regulated, and de-endothelialization areas were also observed. These findings suggested that ferroptosis may be involved in the pathogenesis of diabetic vascular endothelial cell dysfunction through the p53-xCT-GSH axis.57

Together, the aforementioned studies suggested that ferroptosis is involved in the pathogenesis of diabetic cardiovascular complications and that inhibiting the ferroptosis-related mechanisms represents a potential therapeutic target for diabetic cardiovascular disease.58

Ferroptosis and the Pathogenesis of Abnormal Bone Metabolism in T2DM

In patients with T2DM, chronic hyperglycemia leads to the accumulation of advanced glycation end-products (AGEs) in the bone matrix, triggering non-enzymatic glycosylation reactions that result in decreased bone quality, increased bone fragility, and a heightened risk of osteoporosis (OP) and fractures.59,60 Recently, Ge et al investigated the role of AGEs in diabetes-related OP and reported that the serum AGEs levels and bone mineral density in patients with OP were positively and negatively correlated with fasting glucose, respectively, and that AGEs and serum from patients with OP and T2DM could promote the development of ferroptosis in hFOB1.19 osteoblast, which was reversed by the ferroptosis inhibitor DFO. The results suggest that AGEs may promote OP by disrupting osteoblast function.61 The loss of osteocyte viability is another important factor in the development of diabetic osteoporosis. Another recent study62 reported that osteocytes cultured in a diabetic microenvironment had increased lipid peroxidation, iron overload, ferroptosis pathway activation, and significant upregulation of HO-1 expression. Moreover, targeting ferroptosis or HO-1 rescued osteocyte death and improved bone structural degeneration in the diabetic OP. These studies suggested that ferroptosis is involved in the development of diabetic OP and that targeting ferroptosis may represent an effective mechanism-based strategy for OP treatment.

Application of Ferroptosis in TCM Treatment of T2DM and Its Related Complications

Search Strategy

We searched PubMed, Web of Science, the Cochrane Library, the Chinese National Knowledge Infrastructure database (CNKI), the Chinese Biomedical Literature database (CBM), the Chinese Scientific Journal database (VIP), and the Wan Fang database for articles published from January 1, 2012, to March 27, 2022. No language restrictions were imposed. The medical subject headings and main keywords used for the search were (“Diabetes Mellitus” OR diabet* OR glucose) AND (“Ferroptosis” OR ferropto* OR “iron death” OR (iron AND “cell death”)). The full search strategy used is shown in the Supplemental Appendix. The supplemental literature was searched manually.

Selection Criteria

Inclusion criteria: (1) study type: clinical trials or basic experimental studies; (2) study object: patients with T2DM or its related complications, animal or cell models; (3) interventions: active ingredients, monomers, or compound preparation of TCM; (4) mechanism of action: ferroptosis. Correspondence, comments, editorials, reviews, meta-analyses, and conference abstracts were excluded.

Data Extraction

Two investigators independently reviewed the full text of the studies that met the selection criteria and extracted the following data: first author’s name, year of publication, disease type, study object, ferroptosis regulation mechanism, and characteristics of action (Table 1). When there was disagreement between the two investigators, a third researcher was consulted to make the final decision.

Table 1 The Role of Ferroptosis in the Therapeutic Use of TCM for T2DM and Its Related Complications


Figure 3 illustrates the inclusion screening process employed in this study. A comprehensive database search yielded a total of 726 potentially relevant studies. Additionally, two articles were manually searched, bringing the cumulative number of potentially relevant studies to 728. Subsequently, eliminating 205 duplicate articles and 502 articles that were deemed not relevant after reading the titles and abstracts, 21 articles were entered in the full-text review. After a critical evaluation of the complete texts according to the predetermined inclusion and exclusion criteria, eight articles were excluded. Ultimately, a total of 13 eligible studies were included in the final analysis.

Figure 3 Flow chart of the literature retrieval and screening process.

These 13 studies primarily consisted of basic experimental investigations conducted on animal or cell models. Among them, five studies were relevant to T2DM, four to DKD, three to diabetic cardiomyopathy, and one addressed DR. Notably, no study exploring the treatment of diabetes-related OP through TCM via the modulation of ferroptosis was identified. Table 1 provides an overview of the main characteristics of the studies included in this review.


Application of Ferroptosis in TCM Treatment of T2DM

Diabetic patients have elevated ROS levels8 and dietary iron intake is associated with the risk of developing T2DM.76,77 Iron overload tends to lead to cellular oxidative damage, promoting the occurrence of ferroptosis, causing pancreatic β cell dysfunction, and thereby participating in T2DM occurrence and development.78 Recent studies64,79–81 indicate that natural polyphenolic compounds possess iron-chelating properties in addition to their well-known antioxidant, anti-inflammatory, and anti-tumor effects, enabling them to regulate ferroptosis and reduce blood glucose levels.

Curcumin, derived from the rhizomes of turmeric (Curcuma longa L.) and other ginger family plants, (-)-Epigallocatechin-3-gallate (EGCG) found in tea, especially green tea, and grapeseed procyanidin extract (GSPE) abundant in various plants, particularly grape seeds, all containing polyphenols, have been studied. Treatment with these polyphenolic compounds, such as curcumin, EGCG, and GSPE, has shown an increase in cell viability and a decrease in iron accumulation, depletion of GSH, inactivation of GPX4, levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation in mouse pancreatic MIN6 cells when compared to control cells exposed to erastin alone.63,64 Consistent with these findings, diabetic rats exhibited decreased iron content, increased GSH activity in pancreatic tissue, alleviation of ferroptosis and pancreatic damage, increased insulin levels, and reduced blood glucose levels.65 These effects may be associated with the activation of Nrf2-related signaling pathways.63,64

Quercetin, a flavonoid found widely in various plants,82–84 has been found to potentially regulate ferroptosis.66 Compared to the control group, quercetin reduced the iron content in the T2DM mice pancreas, increased the expression of GSH and GPX4, and reduced oxidative stress in pancreatic tissues. Furthermore, quercetin demonstrated the viability to restore the viability of pancreatic β cells under high-glucose stimulation, suggesting its potential beneficial effects on T2DM by inhibiting pancreatic iron accumulation and ferroptosis in pancreatic β cells.

Additionally, studies focused on mulberry (Morus alba L.) leaf extract, a Chinese herbal medicine, revealed its potential mechanism to regulate abnormalities in glycolipid metabolism.85–87 Cryptochlorogenic acid,67 the primary active substance in mulberry leaves, ameliorated islet damage in diabetic rats by inhibiting ferroptosis, reducing iron overload and accumulation of lipid peroxides, and lowering blood glucose levels. The mechanism underlying these effects involves the activation of the cystine/Xc/GPX4/Nrf2 pathway and the inhibition of nuclear receptor coactivator 4 (NCOA4).67

Taken together, these findings underscore the potential of TCM Taken together, these findings underscore the potential of Chinese herbal medicine to elevate GSH and GPX4 levels in mice with T2DM by modulating ferroptosis in pancreatic tissues or cells, possibly involving the cystine/ Xc/GPX4/Nrf2 pathway.

Application of Ferroptosis in TCM Treatment of T2DM Microangiopathy

TCM has demonstrated significant efficacy in ameliorating kidney damage and preserving kidney function and is widely used in DKD treatment in some countries, including China. Numerous studies have elucidated that the therapeutic protective effects of TCM on DKD are closely intertwined with its regulation of glucose/lipid metabolism, antioxidant activity, anti-inflammatory response, anti-fibrotic properties, and protection of podocytes.88 Recent reports have highlighted the pivotal role of ferroptosis in the TCM treatment of DKD. Notably, TCM rhubarb (Rheum palmatum L.) has shown remarkable efficacy in improving lipid metabolism in DKD patients.89 Ding et al68 reported that sennoside A, an active compound found in rhubarb, reduced MDA levels, downregulated the expression of HO-1 and PTGS2, and increased GSH concentration to inhibit ferroptosis in DKD mice, thereby improving oxidative stress and renal injury in DKD. Another active compound, berberine, extracted from the rhizome of Coptis chinensis Franch (known as Huanglian in Chinese), has been found to effectively reduce ROS, PTGS2, and ACSL4 levels while upregulating the expression of Nrf2, HO-1, and GPX4 to improve ferroptosis in high-glucose-induced podocytes.69 These effects were achieved through the regulation of the Nrf2/HO-1/GPX4 pathway, thus providing a new theoretical foundation for the application of berberine in DKD treatment. Additionally, a study70 investigating the mechanism of action of umbelliferone, a coumarin derivative found in traditional herbal components such as Cnidium monnieri (L.) Cuss, Angelica dahurica (Fisch. ex Hoffm) Benth. et Hook. f., and Peucedanum praeruptorum Dunn, revealed that it protected against DKD. Umbelliferone treatment decreased ROS accumulation, downregulated ACSL4, and upregulated GPX4, Nrf2, and HO-1 expression, resulting in the alleviation of ferroptosis and renal pathological damage in db/db DKD mice.70 Knockdown of Nrf2 blocked the inhibitory effect of umbelliferone on ferroptosis in DKD model cells. Moreover, platycodin D, a triterpene saponin derived from the dried root of Platycodon grandiflorum (Jacq.) A. DC., exhibited various pharmacological effects, including anti-tumor, anti-inflammatory, and neuroprotective properties.90–92 In a recent study utilizing high-glucose-induced HK-2 cells as an in vitro DKD model, platycodin D treatment inhibited high-glucose-induced ferroptosis, upregulated GPX4, FTH-1, and SLC7A11 expression, and downregulated ACSL4 and TFR1 expression. These effects led to increased cell viability and reduced cellular damage.71 Collectively, these studies indicate that TCM may exert therapeutic effects on DKD by inhibiting ferroptosis through the regulation of Nrf2/HO-1-related pathways.

Astragaloside IV, an active ingredient of the TCM Astragalus membranaceus (Fisch.) Bge., exhibits anti-inflammatory, antioxidative stress, and immunomodulatory effects. Astragaloside IV has been used in the treatment of various diseases, including tumors, DM, and autoimmune diseases.93–95 Recent findings have also demonstrated its effective inhibition of retinal endothelial cell death and amelioration of pathological damage associated with DR.96,97 In an in vitro model of DR utilizing a high-glucose culture of ARPE-19 cells, Tang et al reported that astragaloside IV attenuated the decrease of Sirt1 and Nrf2 levels induced by high glucose in retinal pigment epithelial cells. It increased the levels of GPX4, glutamate cysteine ligase (GCLM), and glutamate cysteine ligase catalytic subunit (GCLC), leading to the reduction of ferroptosis, increased cell viability, and enhanced antioxidant capacity. These effects may be associated with the inhibition of miR-138-5p expression and activation of the Sirt1/Nrf2 pathway.75

In conclusion, TCM demonstrates a beneficial role in the management of T2DM microangiopathy, including DKD and DR, through the regulation of ferroptosis. The underlying mechanism is likely associated with the modulation of Nrf2-related pathways.

Application of Ferroptosis in TCM Treatment of T2DM Cardiovascular Complications

Resveratrol, a natural polyphenolic compound found in various Chinese herbal medicine plants such as Veratrum nigrum L. and Polygonum cuspidatum Sieb. et Zucc., exhibits varied pharmacological effects including anti-inflammatory and antioxidative stress properties. It is commonly used in the prevention and treatment of tumors, cardiovascular diseases, and DM.98–100 In an in vitro model of diabetic myocardial injury utilizing H9c2 cells cultured in a high-glucose environment, resveratrol demonstrated significant effects. It notably increased cell viability, SOD activity, and protein levels of HSF1, GPX4, and SLC7A11, while decreasing MDA levels and iron ion content in H9c2 cells. These findings indicate that resveratrol may improve high-glucose-induced cardiomyocyte injury by inhibiting ferroptosis through the upregulation of HSF1 expression.72

Previous studies have confirmed the positive effects of puerarin, the main active flavonoid in Pueraria lobata (Willd.) Ohwi, on improving cardiac function in rats with heart failure by reducing lipid peroxidation and ferroptosis.101 Similarly, baicalein, the active ingredient of Scutellaria baicalensis Georgi, has shown a neuroprotective role as a natural ferroptosis inhibitor.102 Building upon this knowledge, Yu et al observed the effects of Gegen Qinlian decoction, a Chinese herbal compound preparation composed mainly of P. lobata (Willd.) Ohwi and S. baicalensis Georgi, on the cardiac diastolic function of diabetic mice with the damp-heat syndrome.73 The study revealed that Gegen Qinlian decoction upregulated GPX4 and SLC7A11 levels, while downregulating ACSL4 and PTGS2 levels. It also reduced MDA content and alleviated damp-heat symptoms, such as elevated blood glucose, reduced diet, and urination. Furthermore, Gegen Qinlian decoction mitigated lipid peroxidation in myocardial tissue, improved cardiac diastolic function, and reversed myocardial remodeling in the mice. These findings demonstrated that Gegen Qinlian decoction’s beneficial effects on cardiac remodeling and diastolic function in diabetic mice with the damp-heat syndrome may be associated with the inhibition of ferroptosis in cardiomyocytes.

Prolonged elevated blood glucose levels in T2DM contribute to significant production and accumulation of AGEs in the body, particularly in the extracellular matrix of the heart., AGEs are an important feature of diabetic cardiomyopathy (DCM) pathogenesis. Sulforaphane, an isothiocyanate widely found in plants like broccoli, possesses anti-tumor and antioxidant effects. It has been shown to alleviate diabetes-induced oxidative stress and cardiac functional impairment.103,104 Further studies74 have revealed that sulforaphane alleviated ferroptosis and lipid peroxidation through AMPK-mediated activation of Nrf2, leading to amelioration of cardiac injury in mice with AGE-induced DCM and enhancing the cardioprotective effect.

Overall, these findings suggest that TCM may improve AGE accumulation and reduce lipid peroxidation in T2DM cardiovascular complications by regulating ferroptosis, thereby enhancing the cardioprotective effect on the heart.


Through the above-detailed analysis of the therapeutic effects of TCM and its active ingredients on T2DM,63–67 as well as related complications such as DKD,68–71 DR75 and DCM,72–74 we found that Chinese herbs and their main active ingredients exerted therapeutic or protective effects by inhibiting ferroptosis, and the specific mechanisms are summarized in Figure 4.

Figure 4 Mechanism in the treatment of T2DM and its complications with TCM by inhibiting ferroptosis. This figure was created with Figdraw (www.figdraw.com).


Ferroptosis is a recently proposed new cell death model and is closely related to the occurrence and development of various diseases (tumors, ischemia-reperfusion injury, neurological diseases, and metabolic diseases).6,20 Recent studies have confirmed that, in addition to oxidative stress, the inflammatory response, endothelial cell damage, apoptosis, and autophagy, iron-overload, ROS, and lipid peroxide accumulation are also important pathogenic mechanisms of T2DM and the related complications, and blocking the iron-dependent death pathways with ferroptosis inhibitors or iron-chelating agents can treat or delay the progression of T2DM and its related complications.105

TCM has a long history of use for treating T2DM, being multi-component, multi-target, systematic, and basing treatment on syndrome differentiation (different conditions of each patient), and is highly effective in the clinical treatment and early prevention of disease progression of T2DM. With progressive research on the relationship between the mechanism of TCM and ferroptosis, several studies have confirmed that TCM exerts therapeutic effects on T2DM and its complications by regulating the ferroptosis-related pathways.102,106–108 In this paper, the concept, mechanism of occurrence, regulatory pathways of ferroptosis, and its correlation with T2DM and its related complications were described. The application of ferroptosis to related studies of TCM for treating T2DM and its complications was summarized and analyzed for the first time. In this review, we identified the existence of ferroptosis in T2DM and its related complications, Chinese herbs or their active ingredients (quercetin, curcumin, cryptochlorogenic acid, resveratrol, platycodin D, astragaloside IV) exert beneficial effects on T2DM and its complications by inhibiting ferroptosis. These TCMs all exert their therapeutic effects by inhibiting ferroptosis, with different regulatory mechanisms. However, the number of related studies is relatively small, and all of them are basic experiments. Therefore, future studies should continue to target ferroptosis, explore the mechanism of T2DM occurrence and progression, further clarify the exact mechanism by which different TCMs and their active ingredients mediate their therapeutic effects, and actively explore the relevant regulatory signaling pathways and specific molecular markers. The elucidation of these mechanisms will provide a new theoretical basis for TCM treatment of T2DM and will be crucial in leveraging the knowledge of ferroptosis for the clinical therapeutic benefit.21

Despite the comprehensive and systematic literature search, our review has several limitations. First, the studies included in this review were all basic experimental studies and no published clinical trials were retrieved. Moreover, given the wide variation in animal and in vitro conditions, the generalization of the experimental results to humans requires careful evaluation in rigorous clinical trials. Second, as all experiments included studies that were conducted in China, there may be geographical bias. Third, most of the Chinese herbal medicines used in the included studies were active ingredients of TCM or herbal monomers, and there is a need to increase the study of ferroptosis-related mechanisms of single herbs or TCM compound preparations. Finally, there were only a small number of studies on ferroptosis for TCM treatment of T2DM and its related complications, and TCM treatments for the common complications of T2DM (diabetic neuropathy and abnormal bone metabolism) were not retrieved.

Conclusion and Prospects

TCM treatment of T2DM and its related complications is an effective treatment modality. T2DM is closely associated with ferroptosis and lipid peroxidation, and TCM interventions may play a therapeutic or beneficial role by inhibiting ferroptosis, and the specific mechanism may be relevant to Nrf2-related pathways. Currently, research efforts focusing on the mechanism of ferroptosis in TCM treatment of T2DM primarily concentrate on TCM extracts. However, future studies should delve into the mechanism of ferroptosis in the treatment of T2DM using single herbs and Chinese herbal compounds. This will contribute to the development of new theoretical foundations and potential therapeutic strategies for T2DM and its complications using TCM.


ACSL4, acyl-CoA synthetase long-chain family member 4; AMPK, AMP-activated protein kinase; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; CoQ10, Coenzyme Q10; CoQ10H2, ubiquinol; DCM, diabetic cardiomyopathy; DHFR, dihydrofolate reductase; DHODH, dihydroorotate dehydrogenase; DKD, diabetic kidney disease; DR, diabetic retinopathy; FSP1, ferroptosis suppressor protein 1; FTH-1, ferritin heavy chain 1; GCH1, GTP cyclohydrolase 1; GCLC, glutamate cysteine ligase catalytic subunit; GCLM, glutamate cysteine ligase; GPX4, glutathione peroxidase 4; GSH, glutathione; HO-1, heme oxygenase-1; HSF1, heat shock factor 1; MDA, malondialdehyde; NADPH, nicotinamide adenine dinucleotide phosphate; NCOA4, nuclear receptor coactivator 4; Nrf2, nuclear factor erythroid 2-related factor 2; PLOOHs, phospholipid hydroperoxides; PTGS2, prostaglandin-endoperoxide synthase 2; PUFA, polyunsaturated fatty acid; PUFA-PL, phospholipid containing PUFA chain; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; TCM, traditional Chinese medicine; T2DM, type 2 diabetes mellitus; TFR1, transferrin receptor 1.


This work was supported by grants from the National Natural Science Foundation of China [grant numbers 82174334 and 81870622], the Changsha Municipal Natural Science Foundation [grant number kq2014251], Hunan Provincial Innovation Foundation for Postgraduate [grant number CX20210372], Scientific Research Project of Hunan Provincial Health Commission [grant number 202112070631], and the Research Projects in the Health Industry of Hainan Province [grant number 22A200053].


All authors declare that they have no conflicts of interest in this work.


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Volunteers for Diabetes providing support services for diabetics | Hancock County Journal-Pilot

Diabetes News


In 1987, the Hancock County Volunteers for Diabetes was formed in an effort to provide a variety of support services to diabetics living in Hancock County. The volunteers have been able to provide a limited amount of financial support for diabetes medications or supplies, lab work, eye or dental exams, nutrition counseling or other special needs. Over the years, the Volunteers for Diabetes have also planned the Annual Diabetes Spotlight, a day-long educational event, typically held in November. This event is particularly beneficial for diabetics and their families, as there are presentations on diabetes topics and educational information distributed by exhibitors. Years ago the volunteers sponsored a Diabetes Support group. The volunteers are hopeful to begin offering a Diabetes Support Group to diabetics and their families in the near future.


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Lions Clubs grants provide diabetes education for 10,000 school nurses and school personnel

Diabetes News


Diabetes in youth, both type 1 and type 2, are on the rise, and as studies show this trend is expected to continue. School nurses and school staff, alike, need to be aware of the needs of children with diabetes and be prepared to meet those needs in the education environment. Laws governing this are set by both the federal government and the Code of Virginia.

The Virginia Code requires that training be offered to school staff who care for students with diabetes. It was recognized that not all schools had access to quality training due to geographic location or limited resources. Changes in diabetic treatment/regimens as well as advancing new technologies make it especially important that quality training be made available.

The Virginia Diabetes Council Schools Committee recognized this need and in partnership with like-interest community groups has successfully launched a diabetes e-learning program, “Lions Empowering and Aiding Regional Nurses in Schools,” that is now being used by school divisions throughout the commonwealth. With financial grant support of the Lions Club International and Lions Club 24L, the pilot program began in the 2019–20 school year. Initially, Lions Club enrolled 2,872 participants and as of October 2022 has enrolled 10,000 participants. Nine hundred seventy-five schools are enrolled in the program with 70 school districts participating, as well as private and parochial schools.

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This training program offers current information about diabetes and best practices for the care of students living with diabetes. Salus Education’s “Diabetes Care at School: Bridging the Gap” is a comprehensive program that addresses basic diabetes awareness information for the school staff, as well as in-depth, technical information directed to those who have responsibility of the child during school activities. Continuing education credits for nurses and school personnel are available. The training has been approved by the Virginia Board of Nursing.

Those completing the training include administrators, nurses, bus drivers, cafeteria workers, athletic directors, trainers, coaches, choir and band directors, teachers and office staff. Some schools have adopted the program and include it as part of their orientation. Some make the training mandatory annually.

The program has been successful even beyond the walls of the schools. Participants have said they have a better understanding of their own diabetes, and their family members and are very glad they took the training.

Providing feedback about the program, a user responded, “I think this was very useful and designed with the learner in mind. Because something like diabetes is life threatening the subject can be scary to ask questions or to take the time to really understand. This self-paced computer program lowered my level of stress while allowing me to review and study at a pace comfortable to me.”

VDC partners include Lions Club International, Lions Club District 24L, Virginia Department of Education, Virginia Department of Health and the Virginia Coordinating Body of Diabetes Care.


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Implementation and delivery of group consultations for young people with diabetes in socioeconomically deprived, ethnically diverse settings | BMC Medicine

Diabetes News


Developing good value and life-stage oriented care

Introducing group consultations to the diabetes service in the two hospital implementation sites was not straightforward and required careful local experimentation. The appropriate balance between clinical and educational content became a matter of debate, as clinicians were concerned that the typical group consultations format (with standard one-to-one consultations in a group context) would alienate young people who already had low levels of engagement. Instead, they opted for a flexible approach primarily prioritising group interaction on clinically relevant topics, with individual needs addressed indirectly as part of group discussion, rather than replicating one-to-one consultations in the group setting. This also meant that group consultations were not implemented as a substitute to individual clinics but were used purposefully to augment and re-distribute care; when discussing with peers, young people opened up more than they would with clinicians, which resulted in better recognition of their needs and changed the focus of subsequent one-to-one consultations:

‘…they kind of open up. And they may for the first time accept that they’ve not been taking insulin as recommended, or as advised’ (Interview 25 Diabetes consultant)

Experienced diabetes specialist nurses and other members of the implementation team worked closely with a youth worker, whose contribution was instrumental to developing age- and life-stage appropriate, relationship-based group consultations. The youth worker participated actively in sessions, for example delivering ‘icebreakers’ as a group formation activity and contributing to discussions in a way that would level power dynamics, signifying that group consultations focused on young people’s priorities, rather than purely meeting service or cost-efficiency targets. Clinicians valued youth worker support which allowed them to focus on clinical management without juggling multiple roles for which (in many cases) they had never been trained for (such as facilitating groups of young people).

A typical clinic would start with introductions and an ice-breaker, followed by setting ground rules (see Table 2). Depending on the focus of the session, one or more specialists would join, such as diabetes consultants, dietitians, or psychologists. Topics included healthy eating, blood glucose sensors and measurements, exercise, psychology, sex and healthy relationships, hypos and blood tests, diabetic eye screening and annual review information sessions, sex and healthy relationships, and women’s health, among others.

Although clinicians originally intended for young people to be allocated to specific groups meeting repeatedly and developing long-term relationships throughout the programme, in practice, this proved difficult to sustain and group composition became more fluid. Regular attendees particularly welcomed new participants joining the clinics so they could keep learning from different experiences, but groups also benefited from a certain level of consistency to increase connections between members. The youth worker helped in building affinity quickly between young people who had never met each other so they would open up in discussions and feel supported. At the end of each clinic, participants provided feedback and suggestions for improvement in sessions facilitated by the researcher or the youth worker after clinicians had left the room; this was important for ongoing service co-production (alongside dedicated co-design sessions described elsewhere [30]) to continue meeting patient needs and providing young people with a sense of ownership over this new model of care.

Key challenges in the implementation and delivery of group consultations: staff experiences

Delivering group clinics involved working with uncertainty and managing multiple interdependencies across diabetes care pathways. It was not simply a matter of providing individual care to multiple people at the same time. Group consultations required a different degree, mode and depth of preparation, and engagement by clinicians and young people alike. The transition was gradual and required changes in established practices but also surfaced and challenged deeply embedded ways of thinking about patient-centred care provision.

Table 4 provides examples of how complexity underpinned the work required to deliver group consultations, including the challenges staff encountered. There was little scope for standardising the processes followed, especially at the beginning, when diabetes specialist nurses were learning through trial and error. Yet, the need to manage uncertainty continued throughout the programme; each session had to be treated as unique and required comprehensive preparation to meet changing patient needs and address all eventualities (unpredictable participation, parents attending, etc.).

Table 4 Complexity principles underpinning group clinic delivery, including examples from the study and supporting quotes

Self-organisation underpinned efforts to informally co-ordinate between different clinicians providing one-to-one and group care to young people, in terms of selecting participants for group clinics, understanding their needs, inviting the right experts to contribute, and managing interdependencies with other care processes (e.g. diabetes education, individual appointments) (Q3). In-depth clinical and relational knowledge about young people mattered when deciding how to bring them together and facilitate the sessions so they would benefit most; this knowledge needed to be collectively accumulated and negotiated between different clinicians involved and drawn out of medical records. Informal, improvised, and spontaneous interactions between clinicians enabled ongoing co-ordination, largely driven by the efforts of the diabetes specialist nurses, but also other staff involved (e.g. diabetes consultants, research officer). Other practical and logistical challenges ensued, such as securing seminar rooms, adjusting booking processes, and maintaining continuity with the rest of the diabetes service (Q5).

Formal and informal opportunities were needed for reflection and sense-making, and to support learning within and across implementation sites (e.g. implementation and project meetings, co-design, training sessions). Development of adaptive capability became important for clinicians who were delivering a new model of care highly dependent on human relationships. Group clinics involved the dual challenge of delivering good clinical care and education, while facilitating a group of young people. In some cases, it was important for clinicians to engage in emotional work to support groups where conflict and competition emerged and to ensure outcomes remained positive (Q12). Health professionals drew on their skills consulting with young people, but also attended group facilitation training, held regular debriefs between implementation and clinical teams for ongoing adjustment of the model, and derived significant learning from on-the-job trial and error.

Attendance and young people’s motivations

Despite significant effort, mean attendance was relatively low at 32% for site A and 33% for site B—a challenge already familiar to those delivering young adult services. Local teams had to work creatively to make sessions worthwhile regardless of how many young people ended up attending. Despite suggestions that a ‘good’ session should include 6–8 patients, in practice, the ‘right’ number largely depended on the focus and facilitation mode of each session (e.g. more young people could meaningfully participate in a session about exercise compared to psychology). Larger groups did not always guarantee high levels of contribution; there were successful groups with as many as 4 young people who identified with each other and shared openly.

[…] it seemed to be around sort of three, four, five we were getting [to attend], even though you know, we invited more than twenty patients, within a good amount of time. So I think just trying to make sure a lot of people, or as many people as possible would attend, was the biggest challenge. (Interview 29, Diabetes Specialist Nurse)

An average of 4–5 young people attended each group consultation at both sites. Higher attendance rates were recorded when a small group of selected young people were invited for a specific care-focused intervention, such as flash glucose monitoring follow-up (range of 83–100% in three sessions). Variable attendance rates were observed at broader educational and self-management sessions (e.g. psychological health, healthy eating), especially when there was an open invite to all young people recruited at each site (range of 0–60% in 25 sessions). As group clinics continued, attendance was mostly from those who had attended previous sessions, suggesting group consultations appealed to and continued to attract a specific set of young people (5–6 young people attended 5–10 sessions in site A and 3–4 in site B), but the majority only attended a small number of sessions.

Some young people expressed feeling motivated to participate in group consultations, mainly to meet others with diabetes in their age group. However, others were unable to fit group consultations alongside standard, individual diabetes care and other responsibilities (such as family, education, employment, social life). They also expressed feeling ambivalent or in ‘two minds’ about this new service model as they did not know what to expect or did not feel ready to engage with their condition; some overcame initial fears although others chose not to participate at all.

But yeah, it’s like having a group clinic is so much nicer, in order to meet people. But then on the other hand, I think because you don’t really know them, you don’t have that personal connection with them, you don’t really want to voice out everything that you’re going through. Do you get that? I’m a quiet person, like I wouldn’t tell people what I’m going through if I don’t really know them. So I was in like two minds. (Interview 12, Patient 7—never attended)

If I’m being honest, at the beginning, I didn’t want to come. I did, but I didn’t. I just like – oh, when is it going to be, is it going to be really long, I might not like it. But I still came. And I liked it. I was like ‘okay, this isn’t what I was expecting’. I was not expecting it to be so laid back. I don’t know. It was really comfortable, the setting. (Interview 10, Patient 5—regular attendee).

Not all young people had disclosed their diabetes in their communities and they were unsure how to share deeply personal experiences. There was also an underlying resistance to supporting a new consultation mode if this would mean reducing individual appointments for cost efficiency.

Differences between attenders and non-attenders in implementation sites

In Tables 5 and 6, we present baseline characteristics of the 73 young people recruited in the two implementation settings, comparing those who attended one or more group clinics to those who did not attend any group clinics at each site (further comparisons with participants recruited in control sites are available in the detailed project report [30]).

Table 5 Participant baseline characteristics by attendance group and site
Table 6 Baseline clinical characteristics and questionnaire scores by attendance group and site

At site A, comparing participants who did (N = 23) and did not (N = 27) attend any group clinics, there were no significant differences in sex, ethnicity, deprivation, speaking English as a first language, type of diabetes, or use of technology within the last year (Table 5). Those who attended were on average diagnosed at a younger age (11 vs. 16 years) and more likely to have attended group education sessions in the past (39% vs 7%), with borderline statistical significance (p = 0.033 and 0.053 respectively). There were no statistically significant differences in these variables when comparing attenders (n = 14) and non-attenders (n = 9) at site B.

Comparison of attenders and non-attenders at site A showed no statistically significant differences between these groups when comparing baseline clinical characteristics and questionnaire scores (Table 6). In contrast, attenders at site B had better glycaemic control (mean HbA1C 68 vs. 98 mmol/mol, p = 0.023) and had attended 80 vs. 50% of planned appointments within the previous year (p = 0.009).

Young people’s experiences in group clinics

Young people who attended group clinics (especially repeat attenders) discussed their experiences as predominantly positive: they felt better understood and supported, learnt new things from peers and clinicians, and were better able to normalise diabetes self-care. Only in a few instances did young patients express (initial) reluctance to share clinical details or found peer comparison challenging; in these cases, internal dynamics required careful management by clinicians.

Group clinics provided the opportunity to discuss emotions and frustrations with others going through similar challenges. Young people found peers could understand and identify with their experiences, which made them feel less isolated. They felt better able to engage in open discussion as they gained encouragement from each other when they started to realise how all were struggling to follow clinical recommendations:

F1: How, I just want to ask generally, how are you guys, like those on type 1, how are you guys finding carb counting? How do you get round it, how do you start all up? F2: I’m not going to lie I haven’t been really carb counting. F1: OK I’m glad to [have asked], I mean it’s a bad thing but it’s like I’ve been struggling so much I’m just like I’ve given up with it totally. Are you the same like? F2: (indicates agreement) (Site A, exchange between female patients in Clinic 2)

Being able to explore emotional challenges of living with diabetes was repeatedly mentioned as a key aspect of positive experiences in group clinics, compared to individual appointments, where young people expressed reluctance to voice their difficulties:

The one-to-one is more personalised, scientific. […] Where [the group clinic] is more lifestyle based. It’s more about how to live with your diabetes, rather than just manage it […] With the doctor, I kind of want to just get it over and done with really quickly, and then just go. So I wouldn’t, I don’t try to ask as many questions or I just forget. (Interview 27, Patient 16)

One of the young people with type 2 diabetes did express feeling alienated initially, in a clinic where everyone else had type 1 diabetes, but then explained: ‘it was [a] very welcome [environment] so, feelings of being left out didn’t last too long to be honest’ (Interview 24, Patient 15)

Another participant suggested that they felt less comfortable with individual appointments because they perceived them as ‘professional’—which at their life stage seemed alienating, as they were unsure how to navigate the rules of engagement and match them with their own priorities.

Social and situated learning emerged through a combination of patient input and clinical advice (e.g. on alternating injection sites, ketone testing or avoiding hypos), carefully facilitated by the diabetes specialist nurses who ensured young people gained insight without feeling judged or criticised. Learning emerged both for those newly diagnosed and for those diagnosed at a younger age, who had been looked after by their families and were only just beginning to learn how to care for themselves independently. Clinicians were surprised that young people had not already acquired this learning through individual appointments on similar topics.

Patient participants talked about how group discussions with peers helped them think about their diabetes differently and normalise their experiences through getting to know how others approached their self-care. This even resulted in some feeling more confident and comfortable with their condition to the extent they started disclosing to their workplace and friends:

[…] within the workplace I would never tell people that I’ve got diabetes, and stuff like that. Now, the other day I was speaking to my friend about where I should be injecting, where I shouldn’t be injecting. Feel like now I’m a bit more confident and comfortable with it. (Interview 13, Patient 8)

There was, however, some reluctance to share clinical details considered private (e.g. glucose levels) or have test results displayed on the computer screen for discussion. Others were not always prepared to discuss self-care aspects they were struggling with or to manage a group discussion that might have led to sharing beyond what they were comfortable with, so chose to control their contributions. For those newly diagnosed, comparison with peers was not always motivating, especially when they were comparing themselves with others doing worse:

And so what I was thinking is that would it get to a stage where it’s going to be hard for me to manage my diabetes. Yeah, it definitely did freak me out a bit, yeah. (Interview 14, Patient 9)

Costs of group consultations and health care

The average staff costs for setting-up and delivering group consultations were similar across the two implementation sites (£572 for site A and £545 for site B) (Additional file 1: Tables 1a and 1b). The average cost of clinic per participant was marginally higher in site A (£158) compared to site B (£127), due to poorer attendance in the former (average number of participants was 3.7 for site A versus 4.5 for site B) (Additional file 1: Table 2). The study participants attended on average 3.6 out of 5.9 scheduled appointments per year, including consultations with a diabetes doctor, diabetes specialist nurse, dietician, and psychologist. The average annual cost of scheduled care was £723 per patient per year. The study participants had on average 3.9 unscheduled contacts per year including A&E visits, hospital admissions, and contacts with general practitioners and diabetes specialist nurses. The average annual cost of unscheduled care was £2566 per patient (Additional file 1: Table 3).


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