How high glucose impairs cognitive function in patients with diabetics

Good news!

"... Patients with type 2 diabetes are nearly three times as likely to develop cognitive impairment, and up to one in five patients over 60 develops dementia. Despite this, the cellular mechanisms linking high blood sugar to cognitive decline have been difficult to isolate.

A new study ... combines patient data with mouse experiments to map a pathway connecting elevated glucose to the death of memory-forming neurons. In a cohort of more than 2000 older adults with type 2 diabetes followed for nearly 5 years, higher levels of lactate, a byproduct of how the body processes glucose, were associated with an increased risk of mild cognitive impairment.

To probe causality, the researchers turned to mice, focusing on neurons from the hippocampus, a region central to learning and memory.

Under high glucose conditions, these neurons overstabilized a protein called Creb3, which, in turn, ramped up production of an enzyme that generates lactate. The excess piled up, overwhelming the cell’s energy systems and disrupting mitochondria, eventually triggering neuronal death.

These changes were then reflected in behavior; in tests like the Morris water maze, which measures spatial learning and memory, diabetic mice performed worse than controls.

Interrupting this pathway with a specially designed peptide reversed the damage. In diabetic mice, the treatment lowered lactate levels, protected hippocampal neurons, and improved performance on memory tests. Because the peptide can cross the blood-brain barrier, it points to a potential strategy for slowing or preventing diabetes-related cognitive decline. ..."

From the editor's summary and abstract:

"Editor’s summary

Cognitive impairment is an unfortunately common complication of diabetes. Xu et al. investigated the underlying mechanisms in mouse models of diabetes.

In hippocampal neurons from these mice, the transcription factor Creb3 was stabilized by O-GlcNAcylation, a modification that is often enhanced by high glucose conditions, leading to greater lactate production through increased expression of the Creb3 target gene Ldha.

High amounts of lactate in the hippocampi of diabetic mice induced neuronal apoptosis and cognitive impairment.

These effects were attenuated by Ldha deficiency or by blocking the O-GlcNAcylation of Creb3 with a small peptide, suggesting that this pathway could be therapeutically targeted to preserve cognitive function in patients with diabetes.  ...

Abstract

The high glucose levels characteristic of diabetes can lead to increases in glucose metabolism through the process of glycolysis, resulting in greater production of lactate and in a monosaccharide-based posttranslational modification called O-GlcNAcylation.

Here, we identified O-GlcNAcylation and lactate production as the molecular mechanisms underlying high glucose–induced cognitive impairment, a prevalent complication of diabetes.

A prospective observational study revealed that elevated plasma concentrations of lactate were an independent risk factor for predicting mild cognitive impairment in patients with diabetes.

High-glucose treatment of mouse hippocampal neurons increased the O-GlcNAcylation of the transcription factor Creb3, which stabilized the protein by preventing its ubiquitination. The increase in Creb3 subsequently up-regulated the expression of the downstream target gene Ldha, which encodes the enzyme lactate dehydrogenase. As a result, lactate production was increased during glycolysis, triggering neuronal apoptosis and cognitive dysfunction in mouse models of type 1 and 2 diabetes.

Expression of a Creb3 mutant that could not be O-GlcNAcylated at Ser325 or competitive blockade of the O-GlcNAcylation of Ser325 in Creb3 with a short peptide alleviated these effects.

This study elucidates a mechanistic link between high glucose–induced Creb3 O-GlcNAcylation and Ldha-mediated lactate production, offering a potential therapeutic strategy for managing diabetes-related cognitive dysfunction."

ScienceAdviser

High glucose impairs cognitive function through Creb3 O-GlcNAcylation and increased lactate production (no public access)

Reprogrammed Human Stomach Organoids Secrete Insulin

Good news! This is about an older research article.

"... differentiated human embryonic stem cells into gastric organoids. They engineered the organoids such that the structures could be reprogrammed into pancreatic beta-like cells upon flipping a genetic switch using appropriate molecular cues.

The researchers then transplanted these organoids into the abdomen of mice and coaxed the organoids to produce insulin-secreting cells. Within three weeks, they observed insulin-producing cells within the organoids, which expressed key markers of pancreatic beta cells. ..."

"Highlights

• Engrafted human gastric organoids (hGOs) model human stomach in vivo

• NPM factor induction converts hGOs into insulin+ β-like cells in vitro and in vivo

•In situ gastric reprogramming offers potential for autologous diabetes cell therapy

Summary

Insulin-dependent diabetes could be treated by supplying patients with primary pancreatic islets or other types of insulin-secreting cells. Functional insulin-secreting cells can be induced in situ from the murine stomach using defined genetic factors, offering a promising method to directly produce autologous insulin-secreting cells.

Here, we modeled whether such gastric insulin-secreting (GINS) cells could be generated in vivo from human stomach tissues. We produced human gastric organoids (hGOs) from human embryonic stem cells engineered with inducible expression of reprogramming factors. The hGOs were stably transplanted for 6 months and showed robust cytodifferentiation resembling the human stomach in structure and cellular composition.

Upon hGO maturation in vivo, we activated the reprogramming factors and observed the formation of insulin+ cells, which secreted insulin into the circulation and ameliorated experimental diabetes. Our modeling indicates that GINS cells can be induced from human stomach tissues in vivo, warranting further therapeutic development for this technology."

Reprogrammed Human Stomach Organoids Secrete Insulin | The Scientist "Transplanting human gastric organoids engineered to release insulin in diabetic mice reduced hyperglycemia, offering a therapeutic avenue for type 1 diabetes."

Modeling in vivo induction of gastric insulin-secreting cells using transplanted human stomach organoids

Figure 1 Generation of hGOs from hESCs with inducible expression of NPM factors

Key enzyme controls both weight gain and cholesterol levels in animal models

Good news!

"... Nitric oxide is a gas molecule with pleiotropic actions in the body. These effects of nitric oxide are carried out through its binding to proteins. Too much or too little nitric oxide binding (to key proteins) causes disease.

In a study ... a research team ... discovered a novel enzyme (SCoR2) that removes nitric oxide from proteins controlling fat build up. Removal of nitric oxide turned on fat synthesis, establishing that SCoR2 is needed to make fat.

The team then inhibited SCoR2 genetically and by developing a drug. They found that blocking this nitric oxide-removing enzyme prevented weight gain and liver injury in mouse models. The same drug also lowered bad cholesterol.

"We have a new class of drug that prevents weight gain and lowers cholesterol—a potential therapy for obesity and cardiovascular disease, with additional hepatic benefits," ..."

"... 

• Cleveland research team has discovered a new enzyme that is required to make fat.
• Blocking the enzyme prevented weight gain and lowered cholesterol.
• A three-in-one drug is being developed to treat obesity, fatty liver disease, and cardiovascular disease.

..."

From the editor's summary and abstract:

"Editor’s summary

Hypertrophy of white adipose tissue due to triglyceride storage and steatosis in the liver due to excessive de novo lipogenesis have detrimental metabolic effects. Venetos et al. found that these processes were stimulated by the enzymatic removal of S-nitrosyl (SNO) groups from distinct protein targets in white adipose tissue and liver by the denitrosylase SCoR2.
Mice deficient in SCoR2 or given a SCoR2 inhibitor were metabolically protected from obesogenic diets because of increased fatty acid oxidation in the liver and reduced adipose tissue expansion.
Moreover, SCoR2 mRNA or protein abundance correlated with obesity, adipocyte surface area, or steatotic liver disease in patients. Thus, because SCoR2 activity skews global lipid metabolism toward storage and synthesis, this denitrosylase could be targeted to treat both obesity and hepatic steatosis. ...

Abstract

Lipid homeostasis is subject to control by posttranslational modification machinery, such as sirtuin deacetylases that reverse coenzyme A (CoA)–dependent acetylation.

Here, we showed that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, promoted both fat storage and lipogenesis to impair metabolic health.
In mice, SCoR2 protein abundance correlated with body mass, and deleting or pharmacologically inhibiting SCoR2 prevented both diet-induced obesity and metabolic dysfunction–associated steatotic liver disease (MASLD).
Loss of SCoR2 in adipocytes promoted the S-nitrosylation of the actin cytoskeletal regulator myosin 9, which inhibited the activity of the lipogenesis-promoting transcription factors PPARγ, SREBP1, and CEBPα to prevent fat storage.
In hepatocytes, inhibition of SCoR2-mediated denitrosylation of lipogenic enzymes reduced fat synthesis and induced fat oxidation.
In humans, an obesity-linked polymorphism was associated with increased SCoR2 mRNA expression, and in patient adipose and liver tissues, SCoR2 protein or mRNA abundance directly correlated with adipocyte size or MASLD.
These results indicate that SCoR2 regulates nutrient metabolism, similar to sirtuins, and is a potential drug target for obesity and MASLD."

Key enzyme controls both weight gain and cholesterol levels in animal models

Cleveland Researchers Discover Enzyme That Controls Both Weight Gain and Cholesterol Levels in Animal Models (original news release)

The protein denitrosylase SCoR2 regulates lipogenesis and fat storage (no public access)

Gut microbes use common nutrient choline to fight type 2 diabetes

Good news! Is a choline dietary supplement a good idea?

"... Earlier this year, for example, it was found that an antibiotic primarily used in veterinary medicine was able to convince the microbes in mouse guts to produce colonic acid, a life-extending compound.

Now, a team led by a researcher ... has figured out another powerful way our gut microbes can help us out – this time by tamping down inflammation caused by a fatty diet, keeping our insulin response in check and, in turn, warding off diabetes. ...

The researchers found that one of the chemicals involved in this cascade of negative effects is the immune-system protein IRAK4, which triggers inflammation in the presence of a high-fat diet as a sort of alarm bell. When that protein is expressed for an extended period of time, it leads to insulin resistance and diabetes. ...

Using mice, human cell models, and molecular target-screening, the scientists found that when the nutrient choline hits the gut, microbes convert it into a metabolite called trimethylamine (TMA). TMA, in turn, binds to IRAK4, blocks its activity, reduces inflammation, and restores insulin sensitivity. ..."

"An international research team ... has uncovered a surprising ally in the fight against insulin resistance and type 2 diabetes: a microbial metabolite called trimethylamine (TMA). ... the study reveals that TMA, produced by gut bacteria from dietary choline can block a key immune pathway and improve blood sugar control. ..."

From the abstract:

"The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered.
Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock.
Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets.

Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk."

Gut microbes use common nutrient to fight type 2 diabetes

Microbial molecule offers new hope for diabetes (original news release)

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control (open access)

Fig. 1: Choline supplementation improves glucose homoeostasis and inflammation after 5 months of HFD [high fat diet]. 

Noninvasive imaging could replace finger pricks to accurately measure blood glucose in people with diabetes

Good news!

MIT omitted to provide a link and the title of the underlying research paper! Possibly, this paper is still not published in a journal, but what about a preprint.

"The MIT team used Raman spectroscopy — a technique that reveals the chemical composition of tissues by shining near-infrared or visible light on them — to develop a shoebox-sized device that can measure blood glucose levels without any needles.

In tests in a healthy volunteer, the researchers found that the measurements from their device were similar to those obtained by commercial continuous glucose monitoring sensors that require a wire to be implanted under the skin.

While the device presented in this study is too large to be used as a wearable sensor, the researchers have since developed a wearable version that they are now testing in a small clinical study. ..."

Noninvasive imaging could replace finger pricks for people with diabetes | MIT News | Massachusetts Institute of Technology "MIT engineers show they can accurately measure blood glucose by shining near-infrared light on the skin."

Reprogrammed Human Stomach Organoids Secrete Insulin

Good news!

"... Now, researchers ... engineered human stomach organoids to secrete insulin. Transplanting these into diabetic mice reduced hyperglycemia.2 Their findings, published today in Stem Cell Reports, could help develop technologies to engineer a person’s own insulin-secreting cells for diabetes treatment. ..."

From the highlights and abstract:

"Highlights

• Engrafted human gastric organoids (hGOs) model human stomach in vivo

• NPM factor induction converts hGOs into insulin+ β-like cells in vitro and in vivo

• In situ gastric reprogramming offers potential for autologous diabetes cell therapy

Summary

Insulin-dependent diabetes could be treated by supplying patients with primary pancreatic islets or other types of insulin-secreting cells. Functional insulin-secreting cells can be induced in situ from the murine stomach using defined genetic factors, offering a promising method to directly produce autologous insulin-secreting cells.

Here, we modeled whether such gastric insulin-secreting (GINS) cells could be generated in vivo from human stomach tissues. We produced human gastric organoids (hGOs) from human embryonic stem cells engineered with inducible expression of reprogramming factors.

The hGOs were stably transplanted for 6 months and showed robust cytodifferentiation resembling the human stomach in structure and cellular composition.

Upon hGO maturation in vivo, we activated the reprogramming factors and observed the formation of insulin+ cells, which secreted insulin into the circulation and ameliorated experimental diabetes.

Our modeling indicates that GINS cells can be induced from human stomach tissues in vivo, warranting further therapeutic development for this technology."

Reprogrammed Human Stomach Organoids Secrete Insulin | The Scientist

Modeling in vivo induction of gastric insulin-secreting cells using transplanted human stomach organoids

Figure 1 Generation of hGOs from hESCs with inducible expression of NPM factors

India’s Diabetes Epidemic

Bad news!

"India now accounts for a quarter of all global diabetes cases, with ~212 million people living with the disease—8X as many as in 1990, and likely surpassing China and the U.S. combined. 

 

How it happened: A combination of factors created the perfect conditions for diabetes to thrive.  

• The consumption of imported fast foods: Sales of ultra-processed foods in India have risen by ~13% every year since 2011. 
• Genetic traits: People of South Asian heritage are more likely to develop diabetes at a much lower BMI, even within what is considered a healthy weight range. 
• Urbanization: Around 35% of Indians now live in cities, compared to 18% in the 1960s; by 2030, that number is expected to rise to 40%.

"

Global Health NOW: Warfare Over Welfare; Reviving Pediatric Health in Sudan; and India’s Diabetes Epidemic

MIT engineers develop implanted emergency rescue device to combat hypoglycemia

Good news!

"Hypoglycemia – a condition in which low blood glucose levels can cause you to feel dizzy, weak, and shaky – can catch you by surprise. It often occurs due to excess insulin, whether it's produced by your body or if you've injected too much of it. ...

To counteract this condition, a team of engineers ... has developed a coin-sized device that can be safely implanted in the body to automatically deliver a dose of glucagon when a sensor notices blood glucose levels dropping too low – and potentially save the user's life.

The compact device that's designed to be implanted under the skin only weighs 0.07 oz (2 g), and features a tiny reservoir for glucagon, a hormone that stimulates your liver to release glucose into your bloodstream. ...

glucagon in the reservoir is a specially developed powdered version, which remains stable for longer. The reservoir itself is made from a 3D-printed polymer, sealed with a nickel-titanium shape-memory alloy that curls from a flat slab into a U-shape when it's heated up to 104 °F (40 °C).

The tiny implant also includes an antenna that receives a signal from a remote trigger or a system that works with a glucose monitor. ...

"... we’re currently working on establishing what the optimal lifetime is. But then after that, it would need to be replaced." ..."

"A wireless, minimally invasive emergency rescue device is developed for the active burst-release of stable particulate forms of peptide and hormone drugs into subcutaneous sites in mice."

"... After implanting the device in diabetic mice, the researchers used it to trigger glucagon release as the animals’ blood sugar levels were dropping. Within less than 10 minutes of activating the drug release, blood sugar levels began to level off, allowing them to remain within the normal range and avert hypoglycemia.

The researchers also tested the device with a powdered version of epinephrine. They found that within 10 minutes of drug release, epinephrine levels in the bloodstream became elevated and heart rate increased.

In this study, the researchers kept the devices implanted for up to four weeks, but they now plan to see if they can extend that time up to at least a year. ..."

From the abstract:

"Rapidly administered emergency drug therapy represents life-saving treatment for a range of acute conditions including hypoglycaemia, anaphylaxis and cardiac arrest. Devices that automate emergency delivery, such as pumps and automated injectors, are limited by the low stability of liquid formulations.

In contrast, dry particulate formulations of these drugs are stable but are incompatible with drug pumps and require reconstitution before administration. Here we develop a miniaturized (<3 cm3), lightweight (<2 g), minimally invasive, fully wireless emergency rescue device for the storage and active burst-release of indefinitely stable particulate forms of peptide and hormone drugs into subcutaneous sites for direct reconstitution in interstitial biofluids and rapid (<5 min) therapeutic effect.

Importantly, the device delivers drug across fibrotic tissue, which commonly accumulates following in vivo implantation, thereby accelerating systemic delivery. Fully wireless delivery of dry particulate glucagon in vivo is demonstrated, providing emergency hypoglycaemic rescue in diabetic mice.

In addition, triggered delivery of epinephrine is demonstrated in vivo. This work provides a platform for the long-term in vivo closed-loop delivery of emergency rescue drugs."

MIT engineers develop implant to combat hypoglycemia

Implantable device could save diabetes patients from dangerously low blood sugar (original news release) "The new implant carries a reservoir of glucagon that can be stored under the skin and deployed during an emergency — with no injections needed."

Emergency delivery of particulate drugs by active ejection using in vivo wireless devices (no public access)

3D printed pancreas cells the future of diabetes treatment

Good news!

"An international team of scientists has 3D printed human islet – the insulin-producing cell clusters in the pancreas – in what they claim is “a critical step toward personalised, implantable therapies for diabetes. ...

The durable, high density islet structures are designed to be implanted just under the skin. They have been shown to remain alive and functional, maintaining a strong insulin-producing response to glucose (sugar) for up to 3 weeks in laboratory experiments. ...

The resulting porous structures were designed to enhance the flow of oxygen and nutrients to the islet cells and to promote the formation of blood vessels.

These factors are critical to the long-term survival and function of grafts after transplantation.

The researchers report that their approach reduced the physical stress on the islets and helped keep their natural shape, solving a major problem that had held back earlier bioprinting attempts.

The bioprinted islets remained alive and healthy with cell survival at more than 90%. After 3 weeks, they showed significantly higher insulin response to glucose levels compared to free islets. ..."

"... “This is one of the first studies to use real human islets instead of animal cells in bio-printing, and the results are incredibly promising,” study leader Quentin Perrier of Wake Forest University School of Medicine in North Carolina said in a statement. ..."

From the abstract:

"OBJECTIVE

This study aimed to evaluate the impact of islet transplantation (IT) on diabetes complications, death, and cancer incidence.

RESEARCH DESIGN AND METHODS

This retrospective, multicenter, cohort study included patients from three IT clinical trials (intervention group) and from the French health insurance claims database Système National des Données de Santé (SNDS) (control group). Two cohorts of IT recipients were analyzed: IT recipients after kidney transplantation (IAK) and IT recipients alone (ITA). They were matched with patients living with type 1 diabetes (T1D) from the SNDS using a propensity score. The primary outcome was a composite criterion including death, dialysis, amputation, nonfatal stroke, nonfatal myocardial infarction, and transient ischemic attack. The secondary outcome was cancer. Hazard ratio (HRs) and P values were obtained using Cox proportional hazards analysis and log-rank test, respectively.

RESULTS

The study included 61 ITA recipients matched to 610 T1D control patients and 45 IAK recipients matched to 45 T1D control patients over a median follow-up period >10 years. Compared with T1D control patients, ITA and IAK recipients had a lower composite outcome risk (HR 0.39 [95% CI 0.21–0.71; P = 0.002] and 0.52 [0.30–0.88; P = 0.014], respectively) that seemed driven by reduced mortality (0.22 [0.09–0.54]; P < 0.001) for ITA and reduced dialysis (0.19 [0.07–0.50]; P < 0.001) for IAK. Both groups showed no significant changes in cancer risk.

CONCLUSIONS

This study suggests long-term benefits of IT on diabetes-related outcomes. Furthermore, despite the use of immunosuppressive drugs following IT, we observed no significant increase in the risk of cancer. Altogether, these findings highlight a favorable risk-benefit ratio of IT in treating patients with unstable T1D."

3D printed pancreas cells the future of diabetes treatment

Health Rounds: 3D printed insulin-producing cells show promise for type 1 diabetes in lab tests (Reuters news 7/2/2025)

Impact of Islet Transplantation on Diabetes Complications and Mortality in Patients Living With Type 1 Diabetes (open access, but I am not sure this is the correct article)

Graphical abstract

10 patients With Severe Diabetes Are Cured in Small clinical Trial of a New Drug

Good news! This could be a breakthrough!

Two deaths occurred among the 14 selected patients, but these death were apparently unrelated to the treatment.

"A single infusion of a stem cell-based treatment may have cured 10 out of 12 people with the most severe form of type 1 diabetes. One year later, these 10 patients no longer need insulin. The other two patients need much lower doses.

The experimental treatment, called zimislecel and made by Vertex Pharmaceuticals of Boston, involves stem cells that scientists prodded to turn into pancreatic islet cells, which regulate blood glucose levels. The new islet cells were infused and reached the liver, where they took up residence. ..."

"... – All 12 patients with at least one year of follow-up who received a full dose of zimislecel as a single infusion achieved ADA-recommended target HbA1c levels <7% and >70% time-in-range (70-180 mg/dL), and 10/12 patients were insulin free – ..."

From the abstract:

"Background

Zimislecel is an allogeneic stem cell–derived islet-cell therapy. Data on the safety and efficacy of zimislecel in persons with type 1 diabetes are needed.

Methods

We conducted a phase 1–2 study of zimislecel in persons with type 1 diabetes.

In part A, participants received a half dose of zimislecel (0.4×109 cells) as a single infusion into the portal vein, with an option for a second half dose within 2 years. In parts B and C, participants received a full dose of zimislecel (0.8×109 cells) as a single infusion.

All the participants also received glucocorticoid-free immunosuppressive therapy.

The primary end point in part A was safety. The primary end point in part C was freedom from severe hypoglycemic events during days 90 through 365, with a glycated hemoglobin level of less than 7% or a decrease of at least 1 percentage point from baseline in the glycated hemoglobin level at one or more time points between days 180 and 365.

Secondary end points in part C included safety and insulin independence between days 180 and 365.

Assessment of the primary and secondary end points in part C involved the participants who received the full dose of zimislecel as a single infusion in part B or C. 

Detection of serum C-peptide during a 4-hour mixed-meal tolerance test was used to assess engraftment and islet function. All the analyses were interim and not prespecified.

Results

A total of 14 participants (2 in part A and 12 in parts B and C) completed at least 12 months of follow-up and were included in the analyses.

C-peptide was undetectable at baseline in all 14 participants.

After zimislecel infusion, all the participants had engraftment and islet function, as evidenced by the detection of C-peptide.

Neutropenia was the most common serious adverse event, occurring in 3 participants.

Two deaths occurred — one caused by cryptococcal meningitis and one by severe dementia with agitation owing to the progression of preexisting neurocognitive impairment.

All 12 participants in parts B and C were free of severe hypoglycemic events and had a glycated hemoglobin level of less than 7%; these participants spent more than 70% of the time in the target glucose range (70 to 180 mg per deciliter).

Ten of the 12 participants (83%) had insulin independence and were not using exogenous insulin at day 365.

Conclusions

The results of this small, short-term study involving persons with type 1 diabetes support the hypothesis that zimislecel can restore physiologic islet function, warranting further clinical investigation. ..."

People With Severe Diabetes Are Cured in Small Trial of New Drug - The New York Times

Vertex Presents Positive Data for Zimislecel in Type 1 Diabetes at the American Diabetes Association 85th Scientific Sessions (original news release)

Stem Cell–Derived, Fully Differentiated Islets for Type 1 Diabetes (no public access)

Spleen-based islet transplantation restores glycemic control in type 1 diabetes without full immunosuppression

Good news! However, this early stage approach seems very technically involved and complicated.

"... researchers have reimagined the spleen as a viable site for islet transplantation, enabling long-term diabetes control without the burden of full immunosuppression. Nanoparticle-driven spleen remodeling allowed transplanted mouse, rat, and human islets to restore normal blood sugar in diabetic rodents and cynomolgus macaques. ...

In the study ... researchers engineered spleens with glucomannan-coated silica nanoparticles to create a vascularized, immunosuppressive environment for transplanted islets. ..."

From the editor's summary and abstract:

"Editor’s summary

Pancreatic islet transplantation is a promising approach for treating type 1 diabetes mellitus (T1DM) but can be beset by problems with engraftment or immunogenicity. Liu et al. used injection of immunomodulatory nanoparticles to remodel the extrahepatic spleens of T1DM mice into a more hospitable transplant site that supported the engraftment, vascularization, and function of transplanted allo- and xenogeneic islets. Proof-of-concept transplants of human islets into macaques on different degrees of immunosuppression further advocated for the feasibility of the approach. This study supports further safety and efficacy testing of the remodeled spleen as an islet transplant site for ameliorating insulin-deficient diabetes.

Abstract

Islet transplantation is a promising therapy for insulin-dependent diabetes. However, immune rejection and insufficient vascularization hinder the survival and function of transplanted islets.

Here, we show effective engraftment of vascularized and functional mouse and rat islets transplanted into biomaterial-remodeled spleens of nonimmunosuppressed rodents and human islets transplanted into the remodeled spleens of nonhuman primates (NHPs) on varying degrees of immunosuppression.

We found evidence that konjac glucomannan–modified silica nanoparticles (KSiNPs) remodeled the spleen into an extracellular matrix (ECM)–rich, immunosuppressive niche to support the survival of syngeneic or xenogeneic islets. Transplanted islets in the remodeled spleens showed improved engraftment, neovascularization, and functionality and restored normoglycemia in streptozotocin (STZ)–induced type 1 diabetic models in the mice and macaques, with stable insulin and C-peptide secretion in mice for 90 days and macaques for 28 days. KSiNP injection and islet transplantation into macaque spleens under B-ultrasound guidance were preclinically feasible.

These findings highlight the safety and effectiveness of spleen tissue remodeling in supporting the survival and function of transplanted islets, providing a promising strategy for treating type 1 diabetes mellitus (T1DM)."

Spleen-based islet transplantation restores glycemic control in type 1 diabetes without full immunosuppression

Islet transplantation in immunomodulatory nanoparticle–remodeled spleens (no public access)

Human islets grown in the immune-remodeled spleen of macaques.

Australia on the verge of diabetes treatment breakthrough

Good news!

"Australian researchers are taking the final steps towards being the first in the world to take pancreatic islet cells from genetically modified pigs and transplant them into human patients. Their goal: to cure type 1 diabetes (T1D).

The culmination of decades of work ...

“We’ve got animals surviving out past 2 years post-transplant, with no hyperacute rejection, no rejection, and with cured diabetes in that pre-clinical model. ..."

Australia on the verge of diabetes breakthrough

Human islets (red) sourced from a cadaveric human pancreas donor.

Study reveals glucose’s surprising role as master manipulator of tissue maturation

Amazing stuff!

"... [Glucose] by binding in its intact form to proteins that control which genes in the genome are made into proteins and when.

The discovery of glucose’s undercover double life was so surprising the researchers spent several years confirming their findings before publishing their results.

“At first we just didn’t believe it,” ... “But the results of extensive follow-up experiments were clear: Glucose interacts with hundreds of proteins throughout the cell and modulates their function to promote differentiation.” ...

They found that human skin organoids – engineered skin tissue grown in liquid that mimic the cellular composition and organization of native skin – were unable to differentiate properly when glucose levels were lower than normal. A closer look found that the expression of over 3,000 genes in the cells was affected by the low glucose levels; many of these genes encoded proteins known to be involved in skin differentiation. ...

found that glucose levels increase due to a boost in production of a protein that transports glucose from the outside of the cell to its interior. Once inside, glucose binds to hundreds of proteins, including one called IRF6, that increase the expression of many genes involved in differentiation. When glucose binds to IRF6, it causes the protein to change its conformation in a way that changes its ability to influence gene expression and drive differentiation. ..."

From the highlights and abstract:

"Highlights

• Intracellular free glucose accumulates during differentiation

• Elevation of free glucose is essential for epidermal differentiation

• Glucose physically associates with numerous proteins, including the IRF6 TF

• Glucose enables IRF6 dimerization, genomic localization, and target gene induction

Summary

Non-energetic roles for glucose are largely unclear, as is the interplay between transcription factors (TFs) and ubiquitous biomolecules. Metabolomic analyses uncovered elevation of intracellular glucose during differentiation of diverse cell types. Human and mouse tissue engineered with glucose sensors detected a glucose gradient that peaked in the outermost differentiated layers of the epidermis. Free glucose accumulation was essential for epidermal differentiation and required the SGLT1 glucose transporter. Glucose affinity chromatography uncovered glucose binding to diverse regulatory proteins, including the IRF6 TF. Direct glucose binding enabled IRF6 dimerization, DNA binding, genomic localization, and induction of IRF6 target genes, including essential pro-differentiation TFs GRHL1, GRHL3, HOPX, and PRDM1. These data identify a role for glucose as a gradient morphogen that modulates protein multimerization in cellular differentiation."

Study reveals glucose’s surprising role as master manipulator of tissue maturation | Stanford Report "The discovery, based on extensive Stanford Medicine research, has implications for the treatment of diabetes and cancers."

Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation 

Graphical abstract:

Type 1 diabetes reversed by new cell transplantation technique

Good news!

"Transplanting insulin-producing cells along with engineered blood-vessel-forming cells has successfully reversed type 1 diabetes, according to a new preclinical study. With further testing, the novel approach could one day cure the as-yet incurable condition. ...

Now, researchers ... a study where they transplanted islets along with engineered blood-vessel-forming cells – successfully reversing diabetes in mice.

“This work lays the foundation for subcutaneous [under the skin] islet transplants as a relatively safe and durable treatment option for type 1 diabetes,” ..."

"... A substantial majority of diabetic mice transplanted with islets-plus-R-VECs regained normal body weight and showed normal blood glucose control even after 20 weeks—a period that for this mouse model of diabetes suggests an effectively permanent islet engraftment. Mice that received islets but no R-VECs fared much less well. ..."

From the abstract:

"Tissue-specific endothelial cells (ECs) are critical for the homeostasis of pancreatic islets and most other tissues. In vitro recapitulation of islet biology and therapeutic islet transplantation both require adequate vascularization, which remains a challenge.

Using human reprogrammed vascular ECs (R-VECs), human islets were functionally vascularized in vitro, demonstrating responsive, dynamic glucose-stimulated insulin secretion and Ca2+ influx.

Subcutaneous transplantation of islets with R-VECs reversed hyperglycemia in diabetic mice, with high levels of human insulin detected within recipient serum and relapses of hyperglycemia following graft removal. Examination of retrieved grafts demonstrated that engrafted human islets were mainly vascularized by the cotransplanted R-VECs, which had anastomosed with the host microcirculation. Notably, single-cell RNA-sequencing revealed that R-VECs, when cocultured with islets, acquired islet EC-specific characteristics. Together, R-VECs establish an adaptable vascular niche that supports islet homeostasis both in vitro and in vivo."

Type 1 diabetes reversed by new cell transplantation technique

Islet Transplantation with Blood Vessel Cells Shows Promise to Treat Type 1 Diabetes (original news release)

Vascularization of human islets by adaptable endothelium for durable and functional subcutaneous engraftment (open access)

Fig. 1. R-VECs form perfusable blood vessels in microchambers and TransWells.

Gene edited Insulin-producing beta cells avoid immune attack in treatment of type 1 diabetes over extended period

Good news!

"Gene-edited insulin-producing beta cells have survived for a month after being injected into a man with type 1 diabetes. These tweaked cells have a protein called CD47 on their surface, which tells the immune system not to destroy them. Only a small number of cells were injected into the man’s arm, but they have produced insulin and avoided his immune system’s crosshairs so far, suggesting that they could become an effective treatment for diabetes."

Nature Briefing: Translational Research

Gene-edited cells that evade rejection show promise in type 1 diabetes "Insulin-producing cells injected into a man with type 1 diabetes have survived for a month so far without the need for immune suppression"

Sana Biotechnology Announces Positive Clinical Results from Type 1 Diabetes Study of Islet Cell Transplantation Without Immunosuppression (original 

Researchers discover a way to make fat cells skinny or larger fat cells drive obesity

Good news! However, the news release and the research article are horribly written!

"Scientists ... have discovered a key biological reason why obesity increases the risk of Type 2 diabetes, and it boils down to size — specifically the size of fat cells. ..."

"Key takeaways

• Fat tissue stores energy from food and is crucial for maintaining normal glucose metabolism, but doesn’t function properly in obesity when fat cells become enlarged.
• Scientists ... have pinpointed at a molecular level how obesity causes fat cells to become enlarged. The answer lies in fat stem cells that don’t produce essential cellular building blocks called ribosomal factors, preventing the cells’ ability to make new fat cells. 
• Restoring ribosomal factors triggers the fat stem cells to differentiate to produce new, better and smaller fat cells, improving glucose metabolism and Type 2 diabetes symptoms.

...

The findings ... establishing for the first time that obesity limits the body’s ability to produce crucial cellular building blocks called ribosomal factors.

Without sufficient ribosomal factors, fat stem cells lack the machinery to differentiate to produce functioning fat cells. Instead, energy gets trapped and they become enlarged. ...

When obese, diabetic mice — whose fat cells were four to five times larger than those found in lean mice — were given a drug called rosiglitazone, their ribosomal factors increased to normal levels, which triggered their fat stem cells to differentiate to produce new, smaller fat cells. The fat tissue, in turn, was then able to function properly in storing energy and generating key hormones that regulate metabolism. ...

Rosiglitazone is currently being used to treat Type 2 diabetes, but what hasn’t been clear, until now, is what the drug is doing on a molecular level to improve glucose metabolism. ..."

From the highlights and abstract (not easy to understand unless you are a specialist in the field):

"Highlights

• Single-cell RNA sequencing reveals reprogramming of adipocyte precursors

• PPARγ agonist stimulates ribosomal gene expression in adipocyte precursors in obesity

• Polysome profiling of adipocytes shows translational selectivity of mRNAs

• Inhibition of translation with eIF4A inhibitor blocks adipogenesis

Summary

Adipose tissue regulates energy homeostasis and metabolic function, but its adaptability is impaired in obesity. In this study, we investigate the impact of acute PPARγ agonist treatment in obese mice and find significant transcriptional remodeling of cells in the stromal vascular fraction (SVF). Using single-cell RNA sequencing, we profile the SVF of inguinal and epididymal adipose tissue of obese mice following rosiglitazone treatment and find an induction of ribosomal factors in both progenitor and preadipocyte populations, while expression of ribosomal factors is reduced with obesity. Notably, the expression of a subset of ribosomal factors is directly regulated by PPARγ. Polysome profiling of the epididymal SVF shows that rosiglitazone promotes translational selectivity of mRNAs that encode pathways involved in adipogenesis and lipid metabolism. Inhibition of translation using a eukaryotic translation initiation factor 4A (eIF4A) inhibitor is sufficient in blocking adipogenesis. Our findings shed light on how PPARγ agonists promote adipose tissue plasticity in obesity."

UCLA researchers discover a way to make fat cells skinny | UCLA

PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity (open access)

Graphical abstract

Adult Diabetes cases Reach New global record in 2022 of almost 830 million, an increase of 630 million compared to 1990

Bad news! How much is due to lack of individual responsibility for your own health?

I have a strong hunch that the reference number for 1990 is incorrect or something else is wrong. An increase of almost 630 million cases or from 200 million to 830 million within 32 years seems extraordinary!

"The number of adults globally living with diabetes has soared 4X since 1990—surpassing 800 million, finds a new Lancet study released on World Diabetes Day, per the WHO.

Extra troubling: 445+ million people with diabetes—59% of the global total—are not receiving treatment ...

The problem is most acute in LMICs, where treatment rates are as low as 10%, ... India, Pakistan, and Indonesia have especially high rates of untreated diabetes. 

Behind the rise: The “alarming” uptick stems from factors including a lack of physical activity, unhealthy food marketing, and economic hardship ..."

From the abstract:

"Summary

Background

Diabetes can be detected at the primary health-care level, and effective treatments lower the risk of complications. There are insufficient data on the coverage of treatment for diabetes and how it has changed. We estimated trends from 1990 to 2022 in diabetes prevalence and treatment for 200 countries and territories.

Methods

We used data from 1108 population-representative studies with 141 million participants aged 18 years and older with measurements of fasting glucose and glycated haemoglobin (HbA1c), and information on diabetes treatment. We defined diabetes as having a fasting plasma glucose (FPG) of 7·0 mmol/L or higher, having an HbA1c of 6·5% or higher, or taking medication for diabetes. We defined diabetes treatment as the proportion of people with diabetes who were taking medication for diabetes. We analysed the data in a Bayesian hierarchical meta-regression model to estimate diabetes prevalence and treatment.

Findings

In 2022, an estimated 828 million (95% credible interval [CrI] 757–908) adults (those aged 18 years and older) had diabetes, an increase of 630 million (554–713) from 1990. From 1990 to 2022, the age-standardised prevalence of diabetes increased in 131 countries for women and in 155 countries for men with a posterior probability of more than 0·80. The largest increases were in low-income and middle-income countries in southeast Asia (eg, Malaysia), south Asia (eg, Pakistan), the Middle East and north Africa (eg, Egypt), and Latin America and the Caribbean (eg, Jamaica, Trinidad and Tobago, and Costa Rica). Age-standardised prevalence neither increased nor decreased with a posterior probability of more than 0·80 in some countries in western and central Europe, sub-Saharan Africa, east Asia and the Pacific, Canada, and some Pacific island nations where prevalence was already high in 1990; it decreased with a posterior probability of more than 0·80 in women in Japan, Spain, and France, and in men in Nauru. The lowest prevalence in the world in 2022 was in western Europe and east Africa for both sexes, and in Japan and Canada for women, and the highest prevalence in the world in 2022 was in countries in Polynesia and Micronesia, some countries in the Caribbean and the Middle East and north Africa, as well as Pakistan and Malaysia. In 2022, 445 million (95% CrI 401–496) adults aged 30 years or older with diabetes did not receive treatment (59% of adults aged 30 years or older with diabetes), 3·5 times the number in 1990. From 1990 to 2022, diabetes treatment coverage increased in 118 countries for women and 98 countries for men with a posterior probability of more than 0·80. The largest improvement in treatment coverage was in some countries from central and western Europe and Latin America (Mexico, Colombia, Chile, and Costa Rica), Canada, South Korea, Russia, Seychelles, and Jordan. There was no increase in treatment coverage in most countries in sub-Saharan Africa; the Caribbean; Pacific island nations; and south, southeast, and central Asia. In 2022, age-standardised treatment coverage was lowest in countries in sub-Saharan Africa and south Asia, and treatment coverage was less than 10% in some African countries. Treatment coverage was 55% or higher in South Korea, many high-income western countries, and some countries in central and eastern Europe (eg, Poland, Czechia, and Russia), Latin America (eg, Costa Rica, Chile, and Mexico), and the Middle East and north Africa (eg, Jordan, Qatar, and Kuwait).

Interpretation

In most countries, especially in low-income and middle-income countries, diabetes treatment has not increased at all or has not increased sufficiently in comparison with the rise in prevalence. The burden of diabetes and untreated diabetes is increasingly borne by low-income and middle-income countries. The expansion of health insurance and primary health care should be accompanied with diabetes programmes that realign and resource health services to enhance the early detection and effective treatment of diabetes."

Global Health NOW: Rising Resistance Threatens a Key Malaria Drug; Uncontrolled Diabetes Reaches New Heights; and Fun, Games—and Fame

Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants (open access)

Figure 2 Age-standardised diabetes prevalence and treatment coverage in 2022 and change from 1990 to 2022

"Functional cure" for diabetes restores insulin production with stem cells

Good news! Almost a miracle! Unfortunately, only one patient so far.

"... Now, early results from a phase I clinical trial suggest that replacing those lost insulin-producing cells with new ones could be a viable treatment. The first patient to receive this kind of transplant has now been insulin-independent for over a year, the team says. ...

For the trial, the scientists isolated stem cells from her adipose tissue, and induced them to return to an earlier state of development, from which they could differentiate into almost any cell type. Then, they were coaxed to become pancreatic islet cells, which were cultivated and transplanted into her abdominal muscles. ...

Other studies have been done before with similar promising results, but this new trial differs in a few key ways. For one, the stem cells are induced chemically rather than genetically, and come from a different source within the patient’s body. ..."

From the highlights and abstract:

"Highlights

• Patient-derived islets were generated with chemically induced pluripotent stem cells

• Transplantation of these islets to an abdominal site led to engraftment in one patient

• Exogenous insulin-independent glycemic control was restored in the patient

• All safety and efficacy clinical endpoints were met at 1-year follow-up of the patient

Summary

We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial ... assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient’s time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted."

"Functional cure" for diabetes restores insulin production with stem cells

NKU Research Team Publishes Breakthrough in Type 1 Diabetes Treatment in Cell (original news release)

Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient (open access)

Graphical abstract

Diabetes risk soars for adults whose mums ate a high-sugar diet during pregnancy, but only during rationing of sugar

The original title of the article is kind of lame! Do not almost all kids have a sweet tooth at some point?

This seems to be a typical article to use an obscure study to demonize sugar!

This article also uses the terrible, ideological expression "pregnant people"!

From the abstract:

"We examined the impact of sugar exposure within 1000 days since conception on diabetes and hypertension, leveraging quasi-experimental variation from the end of the United Kingdom’s sugar rationing in September 1953. Rationing restricted sugar intake to levels within current dietary guidelines, yet consumption nearly doubled immediately post-rationing. Using an event study design with UK Biobank data comparing adults conceived just before or after rationing ended, we found that early-life rationing reduced diabetes and hypertension risk by about 35% and 20%, respectively, and delayed disease onset by 4 and 2 years. Protection was evident with in-utero exposure and increased with postnatal sugar restriction, especially after six months when solid foods likely began. In-utero sugar rationing alone accounted for about one third of the risk reduction."

Diabetes risk soars for adults who had a sweet tooth as kids "Study of 1950s sugar rationing in the United Kingdom also suggests risk to babies whose mums ate a high-sugar diet during pregnancy."

Exposure to sugar rationing in the first 1000 days of life protected against chronic disease (no public access)

New type 2 diabetes treatment could mean an end to insulin shots

Good news! What a relief to so many! Unfortunately, the number of participants in this study was very low. A very interesting approach for treatment!

"86% of type 2 diabetes patients treated with a new procedure no longer needed insulin throughout the two-year-long study they participated in. That procedure could be a real game changer for nearly half a billion people currently estimated to be living with the condition worldwide. ...

It was conducted with a small group of 14 participants aged between 28 and 75 years, who were monitored over the course of 24 months. ...

In this new study ... carried out a procedure called Recellularization via Electroporation Therapy, or ReCET.

Electroporation is an endoscopic operation that applies controlled electric pulses to "create small, irreversible holes in the cell membranes," and is typically used to facilitate DNA delivery into cells. Here, it's being used to improve the body’s sensitivity to its own insulin. ...

At the 6- and 12-month follow-ups, 12 out of 14 participants no longer required insulin therapy. They didn't need it at the 24-month mark either.  ...

"Unlike drug therapy, which requires daily medication adherence, ReCET is compliance-free, addressing the critical issue of ongoing patient adherence in the management of type 2 diabetes," she continued. "In addition, the treatment is disease-modifying: it improves the patient's sensitivity to their own (endogenous) insulin, tackling the root cause of the disease, as opposed to currently available drug therapies, that are at best disease-controlling." ..."

From the abstract:

"Background and Aims

Studies have shown that hydrothermal duodenal mucosal ablation results in improved glycemic control. Recellularization via electroporation therapy (ReCET) is a novel endoscopic procedure that uses electroporation to induce cellular apoptosis and subsequent reepithelization. In this study, we aimed to eliminate exogenous insulin treatment in type 2 diabetes (T2D) patients through a single ReCET procedure combined with a glucagon-like peptide 1 receptor agonist. Feasibility, safety, and (dose) efficacy of ReCET were assessed.

Methods

This first-in-human study included patients with T2D on basal insulin (age, 28-75 years; body mass index, 24-40 kg/m2; glycosylated hemoglobin, ≤64 mmol/mol; C-peptide, ≥0.2 nmol/L). The electroporation dose was optimized during the study, starting with single 600 V and ending with double 750 V treatments. All patients underwent ReCET, after which insulin was discontinued and semaglutide (glucagon-like peptide-1 receptor agonist) was initiated. The primary endpoints were feasibility (procedure time [from catheter in to catheter out], technical success rate), safety, and efficacy (patients off insulin at 6 months; HbA1c, ≤58 mmol/mol).

Results

Fourteen patients underwent endoscopic ReCET. The median procedure time was 58 (interquartile range, 49-73) minutes. ReCET demonstrated a technical success rate of 100%. No device-related severe adverse events or severe hypoglycemic events were observed. At the 12-month follow-up, 12 (86%) patients remained off exogenous insulin therapy, with significant improvements in glycemic control and metabolic parameters. The 2 patients in whom insulin therapy was reintroduced both received ReCET at the lowest voltage (single 600 V).

Conclusion

These results suggest that ReCET is feasible and safe. In combination with semaglutide, ReCET may be a promising therapeutic option to replace insulin therapy in selected T2D patients while improving glycemic control and metabolic health."

New type 2 diabetes treatment could mean an end to insulin shots

Novel procedure combined with semaglutide may eliminate insulin dependency in type 2 diabetes (original news release) "Groundbreaking research presented today at UEG Week 2024 reveals a promising new treatment strategy for type 2 diabetes (T2D) that could significantly reduce or even eliminate the need for insulin therapy."

Recellularization via electroporation therapy of the duodenum combined with glucagon-like peptide 1 receptor agonist to replace insulin therapy in patients with type 2 diabetes: 12-month results of a first-in-human study (no public access; I believe this is the underlying study, both sources above to not reference any related research paper for some odd reason)