PI3Kt/GSK-3β inhibition/Wnt+β-cateni: The Overlooked Circuitry of Diabetes Progression
- Bowie Matteson
- Aug 28
- 20 min read
Updated: Aug 29
When we talk about blood sugar regulation, the conversation usually stops at insulin and glucose. But beneath that surface lies a far more intricate web of signaling pathways — the real machinery that decides whether sugar is burned for energy, stored for later, or left to circulate in the blood. Three of the most important players in this story are the PI3K/Akt pathway, GSK-3β, and Wnt/β-catenin.
I've read about each of these pathways in my years of diabetes research but never fully understood their place in the orchestra of health variables. I had a friend recently share a TikTok video (username: @iammarcmalone) talking about holistic gene management technology to address different chronic diseases. He calls it Triune Restoration. The biggest takeway I had from watching the video (aside from the obvious health implications) was his emphasis on the PI3K signaling pathway. For whatever reason it sent me on a rabbit hole dive into PI3K/Akt dynamics and quickly included the other two pathways covered here.
These pathways aren’t just textbook biochemistry. They are living, dynamic circuits that shape how our bodies respond to food, stress, and inflammation. In health, they work together seamlessly: insulin switches on PI3K/Akt, GSK-3β steps aside to allow glycogen storage, and Wnt/β-catenin maintains the regenerative capacity of beta cells and gut stem cells. But when the terrain of the body begins to shift — through nutrient depletion, oxidative stress, or chronic inflammation — these same pathways begin to falter.
What follows isn’t instant collapse, but a stepwise process of compensation, as different systems of the body take turns carrying the burden. First the pancreas and liver, then the adrenals, then the gut and bone, until finally the kidneys and nervous system are pulled into the struggle. This progressive drift mirrors the experience of diabetes development far more closely than the outdated idea of a sudden autoimmune strike.
In this post, we’ll walk through how these pathways normally regulate blood sugar, what happens when they become disrupted, and how the body adapts stage by stage in an attempt to keep balance. By the end, you’ll see not only the mechanisms of glucose regulation, but also the terrain-wide story of compensation and collapse — and why that story matters for understanding both the development and the healing of diabetes today.
What are they? How do they impact healthy glucose metabolism?
1. PI3K/Akt Pathway (Phosphoinositide 3-kinase + Akt)
Where it starts: Insulin binds to its receptor (IR) on the cell membrane.
Cascade: IR → IRS (insulin receptor substrate) → PI3K → PIP3 → Akt activation.
Healthy functions:
Glucose uptake: Akt signals GLUT4 vesicles in muscle and fat cells to move to the surface, allowing glucose entry.
Glycogen storage: Akt phosphorylates and inhibits GSK-3β, which otherwise blocks glycogen synthase. This allows glycogen synthase to stay active, promoting glycogen storage in liver and muscle.
Cell survival: PI3K/Akt reduces apoptosis (important for beta cell longevity).
Metabolic flexibility: Supports lipid synthesis and suppresses gluconeogenesis (via FOXO1 inhibition).
➡️ Key takeaway: PI3K/Akt is the main insulin-signaling branch ensuring glucose is used, stored, or metabolized efficiently.
2. GSK-3β (Glycogen Synthase Kinase-3 beta)
Baseline role: Despite its name, GSK-3β is more of a “brake” enzyme. It phosphorylates glycogen synthase, making it inactive.
In healthy signaling:
When insulin is present, Akt inhibits GSK-3β, releasing the brake → glycogen synthase becomes active → glucose gets stored as glycogen.
This tight regulation allows the body to store glucose post-meal and prevent excess circulating sugar.
Outside of glycogen: GSK-3β also intersects with transcription factors and the Wnt pathway (see below).
➡️ Key takeaway: GSK-3β is the switch between glucose staying in the blood vs. being stored. Insulin turns it off so glucose can be stored.
3. Wnt/β-catenin Pathway
Where it starts: Wnt ligands bind to Frizzled receptors → Disheveled proteins are activated → GSK-3β is sequestered/inhibited within a “destruction complex.”
Effect: β-catenin stabilizes, accumulates, and translocates to the nucleus → regulates gene transcription.
In glucose metabolism & beta cells:
Supports pancreatic development and beta cell proliferation.
Cross-talks with PI3K/Akt to support cell survival and replication.
Helps regulate metabolic gene expression tied to energy balance, insulin secretion, and mitochondrial function.
In the liver, Wnt/β-catenin is tied to balancing gluconeogenesis vs. glycogen storage.
➡️ Key takeaway: Wnt/β-catenin is more of a long-term regulator — maintaining pancreatic architecture, beta cell mass, and metabolic gene expression — whereas PI3K/Akt handles the immediate insulin response.
How They Interconnect
PI3K/Akt inhibits GSK-3β, leading to both:
Increased glycogen storage (via glycogen synthase activation).
Stabilization of β-catenin, since GSK-3β normally tags β-catenin for degradation.
Wnt signaling also inhibits GSK-3β, further stabilizing β-catenin.
Together, this creates a reinforcing loop:
Insulin → PI3K/Akt → GSK-3β off → glycogen synthesis + β-catenin stability.
Wnt → GSK-3β off → β-catenin stability → gene programs supporting insulin secretion and metabolic health.
In Healthy Glucose Regulation
After a meal, insulin activates PI3K/Akt → GLUT4 moves to the membrane → glucose uptake.
Akt shuts off GSK-3β → glycogen is stored in liver and muscle.
Wnt/β-catenin signaling maintains healthy beta cell mass and transcriptional programs, ensuring long-term insulin availability.
Together, these pathways:
Short term: Get glucose out of the blood and into cells.
Medium term: Store glucose as glycogen and suppress gluconeogenesis.
Long term: Protect beta cells, promote regeneration, and sustain insulin signaling capacity.
✨ So in essence:
PI3K/Akt = immediate insulin action
GSK-3β inhibition = gatekeeper for glycogen storage + β-catenin signaling
Inhibiting this allows for beta cell action, glycogen storage to preserve blood sugar stability
Wnt/β-catenin = long-term beta cell and metabolic health
What are the materials, nutrients and infrastructure that make up these pathways?
1. PI3K/Akt Pathway
Materials & Nutrients Needed:
Phospholipids (for PIP2 → PIP3 conversion):
Phosphatidylinositol requires inositol, choline, and PUFAs.
Magnesium: cofactor for kinases (PI3K, Akt).
ATP: phosphorylation requires abundant cellular energy.
Zinc: cofactor for insulin receptor activity.
Chromium: enhances insulin receptor signaling efficiency.
Amino acids (esp. leucine): modulate mTOR/Akt balance.
Infrastructure:
Cell membrane integrity (PUFA balance, cholesterol, phospholipids).
Insulin receptor sensitivity (liver, muscle, adipose tissue).
Mitochondrial ATP supply to fuel phosphorylation steps.
Feeding systems:
Liver (synthesizes phospholipids, maintains glucose balance).
Pancreas (insulin production).
Gut (absorbs inositol, minerals, fatty acids).
2. GSK-3β (Brake on Glycogen Storage & β-catenin)
Materials & Nutrients Needed:
Magnesium + manganese: required for kinase activity.
Insulin signaling nutrients (see above) to keep GSK-3β inhibited at the right time.
Glycogen synthase substrates: glucose, UDP-glucose (requires magnesium, phosphate, vitamin B6).
Infrastructure:
Liver and muscle glycogen stores: the “storage tanks” that GSK-3β regulates.
Healthy circadian signaling (glycogen storage varies across the day).
Feeding systems:
Liver: central glycogen storage and release.
Muscle: glucose sink, activity-dependent.
Endocrine system: cortisol, epinephrine counterbalance insulin.
3. Wnt/β-catenin Pathway
Materials & Nutrients Needed:
Wnt proteins: require palmitoleic acid (a monounsaturated fatty acid) for post-translational modification.
Glycosylation capacity: depends on zinc, manganese, and proper sugar handling.
Minerals influencing β-catenin signaling:
Lithium (direct GSK-3β inhibitor → stabilizes β-catenin).
Magnesium (again, kinase activity).
Iron & copper (influence ROS and transcription factor binding).
Vitamin D: interacts with Wnt/β-catenin in regulating calcium and insulin secretion.
Infrastructure:
Nuclear transcription machinery (DNA integrity, histones, methylation balance).
Stem cell and beta cell niche: pancreas and intestinal crypts are Wnt-rich tissues.
Feeding systems:
Pancreas: beta cell mass maintenance.
Bone: Wnt/β-catenin is central in bone turnover (reflects systemic mineral balance).
Gut: Wnt maintains intestinal stem cells → indirectly affects nutrient absorption.
Cross-System Inputs (Common Denominators)
Mineral Economy
Magnesium: universal kinase cofactor (PI3K, Akt, GSK-3β).
Zinc: insulin receptor + gene transcription.
Manganese: kinases + glycosylation.
Lithium: GSK-3β regulation, stabilizes β-catenin.
Chromium: insulin sensitivity.
Iron & copper: mitochondrial redox signaling, but can tip to ROS overload.
Energy Substrate Flow
ATP (mitochondria must be healthy → fueled by B-vitamins, CoQ10, carnitine).
NADPH (pentose phosphate pathway, fueled by glucose-6-phosphate dehydrogenase, requires thiamine and riboflavin).
Membrane Composition & Integrity
PUFA balance, cholesterol, phosphatidylinositol → define receptor activity and vesicle movement (GLUT4 translocation).
Endocrine & Nervous System Integration
Insulin, cortisol, thyroid hormones, and autonomic balance all tune signaling pathways.
Circadian Rhythm Entrainment
PI3K/Akt and Wnt/β-catenin are strongly circadian → light, sleep, meal timing matter.
In a state of disease (emphasis on T1D), what changes occur regarding these pathways? What are the possible sources of those changes based on what we know about their energy sources and material infrastructure?
1. PI3K/Akt Pathway in T1D
Healthy role: mediates insulin receptor signaling → glucose uptake (GLUT4), glycogen storage, survival signals for beta cells.
Disease changes:
Loss of insulin signaling: Without sufficient endogenous insulin, PI3K/Akt activation is blunted in muscle, fat, and liver.
GLUT4 trafficking impaired → reduced glucose uptake into cells, higher blood glucose.
Beta cell survival signals fail → Akt normally defends against apoptosis, but with low activity, beta cells are more vulnerable.
Possible sources of these changes:
Material deficits:
Magnesium deficiency (common in T1D, worsened by glycosuria) → kinases lose efficiency.
Chromium, zinc depletion → impair insulin receptor activity.
Energy deficits: mitochondrial dysfunction (less ATP for phosphorylation).
Infrastructure breakdown: chronic hyperglycemia damages membranes (lipid peroxidation, AGE accumulation), impairing insulin receptor signaling.
2. GSK-3β in T1D
Healthy role: turned OFF by insulin/Akt → allows glycogen storage + β-catenin stabilization.
Disease changes:
Hyperactive GSK-3β:
With little insulin → Akt does not inhibit GSK-3β.
GSK-3β remains chronically active → blocks glycogen synthase → reduced glycogen storage.
Promotes β-catenin degradation → transcriptional programs for beta cell survival and proliferation are lost.
Inflammation connection: Active GSK-3β amplifies NF-κB and pro-inflammatory cytokine production, worsening autoimmune attack.
Possible sources of these changes:
Mineral drivers: Loss of lithium (a natural GSK-3β inhibitor, already found to be deficient in neurodegenerative and metabolic disease).
Energy/material drivers: hyperglycemia-induced ROS (iron-driven Fenton chemistry, mitochondrial overload) feed into GSK-3β–NF-κB inflammatory signaling.
Infrastructure: liver glycogen storage dysregulated → metabolic inflexibility (no buffer for blood sugar swings).
3. Wnt/β-catenin in T1D
Healthy role: stabilizes β-catenin (via GSK-3β inhibition) → supports beta cell proliferation, gut stem cell health, bone turnover, and long-term metabolic gene expression.
Disease changes:
Suppressed Wnt/β-catenin signaling:
With GSK-3β hyperactivity, β-catenin is degraded.
Reduced β-catenin → fewer survival/growth programs in beta cells.
Pancreatic development and regeneration blunted: loss of proliferative drive.
Gut integrity compromised: Wnt is essential for intestinal stem cells → imbalance may contribute to leaky gut + antigen exposure fueling autoimmunity.
Possible sources of these changes:
Material deficits:
Palmitoleic acid (needed for Wnt ligand modification) may be reduced by altered fat metabolism.
Zinc/manganese deficiency → impaired glycosylation of Wnt proteins.
Vitamin D deficiency (commonly seen in T1D onset) → weakens synergy with Wnt/β-catenin.
Infrastructure breakdown:
Pancreas loses regenerative signaling.
Bone turnover disrupted (osteopenia in T1D is common).
Cross-Pathway Terrain Changes in T1D
Let’s pull out the themes across these pathways:
Energy system breakdown
Mitochondria overloaded by ROS → less ATP, poor phosphorylation.
Iron overload + Fenton reaction → chronic ROS → damages insulin signaling machinery.
PPP (pentose phosphate pathway) under-fueled (due to thiamine/riboflavin deficits) → poor NADPH → weak redox buffering.
Mineral economy collapse
Magnesium loss through urine → kinase efficiency drops everywhere.
Zinc depletion → weaker insulin receptor activity, reduced gene transcription stability.
Chromium deficiency → poor insulin sensitivity.
Lithium deficiency → unchecked GSK-3β.
Membrane + receptor dysfunction
Glycation and lipid peroxidation → phosphatidylinositol pools (needed for PI3K/PIP3) are compromised.
PUFA imbalance → alters membrane fluidity, receptor clustering, and GLUT4 vesicle fusion.
Endocrine + immune miscoordination
Lack of insulin → PI3K/Akt silent, GSK-3β hyperactive.
Cortisol and catecholamines dominate → blood sugar rises further.
Immune cytokines (IL-1β, TNF-α) directly push GSK-3β activity → pro-inflammatory loop.
Big Picture
PI3K/Akt goes dark → glucose not used properly, beta cells not protected.
GSK-3β goes into overdrive → no glycogen storage, pro-inflammatory signaling, β-catenin degraded.
Wnt/β-catenin silenced → loss of regenerative and survival pathways in pancreas, gut, and bone.
➡️ And all of this traces back to terrain-level breakdowns:
mineral insufficiency,
mitochondrial exhaustion,
membrane/rhythm dysregulation,
and immune stress feeding back on signaling pathways.
✨ If you think about it visually:
In health: Insulin → PI3K → GSK-3β off → glycogen + β-catenin up → storage + survival
In T1D: Without insulin + with depleted materials → PI3K silent, GSK-3β on, β-catenin degraded → chaos.
Let's operate under the assumption that these pathways are being altered over time, without an acute "triggering event". As the body senses these terrain changes progressing how does it compensate? What systems bear the weight of these efforts to adapt?
1. Early Terrain Drift — Insulin Signaling Weakening (PI3K/Akt)
What happens:
Reduced magnesium, zinc, chromium → insulin receptor efficiency falters.
PI3K/Akt activation weakens → less GLUT4 translocation, poor glycogen storage.
Body’s compensation:
Pancreas increases insulin output (hyperinsulinemia, early beta cell stress).
Liver ramps glycogenolysis + gluconeogenesis to buffer swings.
Muscles increase fatty acid oxidation (shifting away from glucose).
Systems bearing the weight:
Pancreas (beta cell overdrive).
Liver (glucose buffering).
Skeletal muscle (picking up energetic slack).
2. Intermediate Drift — GSK-3β Overactivity
What happens:
Less Akt inhibition → GSK-3β remains active.
Glycogen synthase suppressed → glycogen stores don’t refill well.
GSK-3β amplifies NF-κB → pro-inflammatory cytokines increase.
Body’s compensation:
Cortisol and catecholamines rise to mobilize glucose directly (stress-axis dominance).
Adipose tissue lipolysis → free fatty acids as backup fuel.
Immune system signaling intensifies (NF-κB, IL-1β, TNF-α) — inflammation as an adaptive attempt to “clear threats” but actually worsening beta cell terrain.
Systems bearing the weight:
Adrenals (cortisol/epinephrine drive).
Adipose tissue (fuel mobilization, FFA spillover → lipotoxicity).
Immune system (pro-inflammatory tone ramps up).
3. Advanced Drift — Wnt/β-catenin Suppression
What happens:
GSK-3β activity degrades β-catenin.
Loss of Wnt/β-catenin transcription → pancreatic regeneration slows, gut lining stem cells weaken, bone mineralization suffers.
Body’s compensation:
Immune tolerance breaks down → with gut barrier stress, more antigens leak, immune cells stay hypervigilant.
Bone resorption increases (secondary mineral mobilization — the skeleton acting as a buffer to terrain collapse).
Magnesium loss, Calcium and Vitamin D dynamics breakdown
Thymus and lymphatic systems pick up the role of “re-educating” immunity, but with nutrient/mineral insufficiency, their efficiency drops.
Systems bearing the weight:
Gut (leaky barrier, microbiome shifts).
Bone (sacrificed to release minerals for buffering).
Stem cell generation (rebuilding/repair) and iron utilization (ROS control) suffers
Immune system (chronically over-engaged, losing tolerance).
Thymus/lymph (exhausted in the re-education effort).
4. Late Terrain Collapse — Beta Cell Vulnerability
What happens:
Without PI3K/Akt survival signals + without Wnt-driven proliferation, beta cells can’t regenerate.
ROS accumulation and GSK-3β–NF-κB inflammation amplify ER stress and apoptosis.
Autoantibodies emerge as markers of the failed compensations (not initiators).
Body’s last-ditch compensations:
Alpha cells release glucagon excessively → worsening hyperglycemia.
Kidneys increase glucose excretion (glycosuria, osmotic diuresis).
Adrenal stress system maxed out — eventually burning out.
Systems bearing the weight:
Pancreas (beta cell death, alpha cell dysregulation).
Kidneys (glucose dumping, electrolyte loss).
Whole HPA axis (running on adrenaline/cortisol to maintain fuel flow).
The Terrain-Wide Picture
Instead of a rogue immune attack, we see:
Pancreas overworks → insulin resistance precedes beta cell exhaustion.
Adrenals and liver step in to manage glucose swings → stress hormones dominate.
Immune system ramps up inflammation to manage misfolded proteins, oxidized lipids, and leaky barriers.
Bone and gut serve as sacrificial terrain — giving up minerals and barrier integrity to keep the blood environment viable.
Kidneys become the final safety valve when all else fails.
✨ In this framing:
T1D isn’t a single event; it’s the collapse of a layered compensation ladder.
Each system takes a turn bearing the weight: pancreas → liver → adrenals → immune/gut → bone → kidneys.
Autoimmunity appears as the final chapter — the immune system cleaning up damaged terrain after years of strain.
Now that we can visualize and identify the stages of compensation the body goes through we have a clearer picture of what needs our attention. Knowing the specific systems being challenged, altered and drained of their resources, what do we do about it? How do these compensations alter the raw materials needed to stay functional?
And once we can identify what they need, we need to know how the body communicates its needs in the external. How might the body express the need for these raw materials (nutrition, cravings, vitamins/minerals, symptoms etc)? Are there any outward "symptoms" a person can look for to determine how their body is compensating and what they can do to address the need?
Stage 1: Early Drift (Weak PI3K/Akt → Pancreas, Liver, Muscle Compensation)
What’s drained?
Magnesium (kinase activity, ATP handling) → lost in urine with mild glycosuria.
Zinc & Chromium (insulin receptor signaling).
B-vitamins (esp. B1 thiamine & B3 niacin for glycolysis + PPP).
Phospholipids (inositol, choline) for insulin receptor membrane signaling.
How the body signals it:
Cravings for carbs/sweets → cells aren’t getting glucose in, so the body drives intake.
Frequent urination/thirst → magnesium and other electrolytes being dumped.
Fatigue after meals → PI3K/Akt not shuttling glucose efficiently.
Early hypoglycemia swings → poor glycogen storage → unstable blood sugar.
Actionable focus:
Replenish magnesium (glycinate, malate), chromium, zinc.
Support B-vitamin sufficiency (esp. thiamine).
Emphasize membrane health (phosphatidylcholine, omega-3s, inositol).
Stage 2: Intermediate Drift (GSK-3β Overactivity → Adrenals, Adipose, Immune Compensation)
What’s drained?
Vitamin C (adrenal stress).
B5 (pantothenic acid) (cortisol synthesis).
Electrolytes (sodium, potassium, magnesium) → lost with stress diuresis.
Amino acids (muscle breakdown → gluconeogenesis fuel).
PUFAs and stored fats mobilized from adipose → can create lipotoxicity.
How the body signals it:
Salt cravings → adrenal effort to balance electrolytes.
Caffeine/stimulant reliance → energy demand + adrenal strain.
Abdominal weight gain or fat redistribution (cortisol dominance).
Inflammatory flares → joint pain, skin outbreaks, chronic infections (immune system overactive).
Anxiety or “wired but tired” feeling → stress hormones in control.
Actionable focus:
Adrenal support: Vitamin C, B5, electrolytes, adaptogens (ashwagandha, rhodiola).
Anti-inflammatory nutrients: omega-3s, curcumin, quercetin.
Balance energy substrates: don’t over-rely on stimulants → balanced protein + fat intake.
Stage 3: Advanced Drift (Wnt/β-catenin Suppressed → Gut, Bone, Thymus/Lymph Compensation)
What’s drained?
Vitamin D & K2 (bone + immune tolerance).
Calcium & magnesium (bone buffering, immune cell signaling).
Zinc & manganese (Wnt glycosylation, immune defense).
Amino acids (glutamine, glycine, serine) → gut lining fuel.
Lithium (trace) → natural GSK-3β brake, stabilizes β-catenin.
How the body signals it:
Digestive distress → bloating, food sensitivities, constipation/diarrhea (gut lining thinning).
Frequent infections or allergies → immune tolerance waning.
Bone/joint aches, fractures, tooth enamel changes → minerals pulled from bone.
Mood shifts (depression/irritability) → lithium/zinc depletion, gut-brain stress.
Autoimmune markers appear → not cause, but reflection of terrain collapse.
Actionable focus:
Rebuild gut lining: glutamine, collagen, mucilaginous herbs (aloe, slippery elm, marshmallow root).
Support bone-immune axis: vitamin D3 + K2, magnesium, trace lithium (orotate), zinc.
Encourage microbiome diversity → fiber variety, polyphenols.
Stage 4: Late Collapse (Beta Cell Failure → Pancreas, Kidneys, HPA Axis Compensation)
What’s drained?
Electrolytes (potassium, sodium, magnesium) → glycosuria.
Water-soluble vitamins (C, B vitamins) → lost in urine.
Mitochondrial cofactors (CoQ10, lipoic acid, carnitine) → burned out in oxidative stress.
Antioxidants (glutathione, catalase, SOD) → overwhelmed by chronic ROS.
Iron and copper balance → iron sequestered in inflammation, copper/ceruloplasmin imbalanced.
How the body signals it:
Extreme thirst/urination → kidneys maxing out.
Electrolyte symptoms → muscle cramps, heart palpitations, dizziness.
Chronic fatigue → mitochondrial insufficiency.
Visual changes, neuropathy, kidney distress → late-stage microvascular damage.
Emotional collapse (burnout, depression, apathy) → HPA exhaustion.
Actionable focus:
Aggressive electrolyte + hydration support.
Mitochondrial nutrients: CoQ10, ALA, carnitine, NAC, glutathione precursors.
Gentle adrenal recovery: rest, circadian entrainment, adaptogens.
Support iron handling: copper, retinol, zinc to restore balance.
The Symptom Compass
Each stage produces body “asks”:
Cravings (carbs → Stage 1, salt → Stage 2).
Digestive flags (Stage 3).
Energy + hydration crises (Stage 4).
Subtle lab clues: falling magnesium, zinc, lithium, and B-vitamin sufficiency across stages.
✨ Takeaway:
As terrain drifts, the body burns through minerals and vitamins in a predictable sequence. Each stage hands off to the next, and symptoms/cravings are messages about which raw materials the compensation machinery is running low on.
Stage | Compensating Systems | Raw Materials Drained | Body Signals & Symptoms | Supportive Actions |
1. Early Drift (Weak PI3K/Akt) | Pancreas, Liver, Muscle | Magnesium, Zinc Chromium B1 (Thiamine) B3 (Niacin) Phospholipids (inositol, choline) | - Cravings for carbs/sweets - Fatigue after meals - Frequent urination/thirst - Early hypoglycemia swings | - Replete Mg, Zn, Cr - Support B vitamins - Phosphatidylcholine, omega-3s, inositol for membranes |
2. Intermediate Drift (GSK-3β Overactivity) | Adrenals, Adipose, Immune | Vitamin C B5 (Pantothenic acid) Electrolytes (Na, K, Mg) Amino acids Stored fats (PUFAs) | - Salt cravings - “Wired but tired” (anxiety, poor sleep) - Abdominal fat gain - Skin/joint inflammation - Stimulant reliance | - Vit C + B5 for adrenals - Electrolytes (Na, K, Mg) - Adaptogens (ashwagandha, rhodiola) - Anti-inflammatory nutrients (omega-3s, curcumin) |
3. Advanced Drift (Wnt/β-catenin Suppressed) | Gut, Bone, Thymus/Lymph | Vitamin D3 + K2, Calcium, Magnesium, Zinc, Manganese, Trace Lithium, Amino acids (glutamine, glycine, serine) | - Digestive distress (bloating, food sensitivities) - Frequent infections/allergies - Bone/joint pain, fractures, weak enamel - Mood shifts (depression, irritability) - Autoimmune markers appear | - Gut lining support (glutamine, collagen, mucilaginous herbs: aloe, slippery elm, marshmallow) - Bone-immune axis nutrients (D3+K2, Mg, Zn, Li orotate) - Fiber + polyphenols for microbiome |
4. Late Collapse (Beta Cell Failure) | Pancreas, Kidneys, HPA Axis | Electrolytes (Na, K, Mg) Water-soluble vitamins (C, Bs) Mitochondrial cofactors (CoQ10, ALA, carnitine) Antioxidants (GSH, NAC, catalase) Copper/Retinol (iron balance) | - Extreme thirst/urination - Muscle cramps, heart palpitations - Chronic fatigue, energy crashes - Visual changes, neuropathy, kidney distress - Emotional burnout/apathy | - Electrolytes + hydration - Mitochondrial nutrients (CoQ10, ALA, carnitine, NAC) - Adrenal recovery (rest, circadian rhythm, adaptogens) - Iron handling support (copper, retinol, zinc) |
Now that we a shopping list, so to speak, now we need some context. How can we best transpose what we've learned here over our unique healing situation?
If you're still here reading (thank you!) you may be eager to get started. Yet, if you're like me, you've probably seen a few different areas that you could focus on. And identifying the compensation is only half the equation. Can we elaborate on exactly what undoing these compensations looks like? There are obviously confounding factors and crossover in feedback loops: - Iron retention impacting ROS production, bone resorption and stem cell production - ROS coming from multiple sources - Is there a leak that's more important to patch than others? (Do we want the chicken or the egg?) - Is precise supplementation more beneficial for certain systems or symptoms? Or is clean, whole food ideal?
Undoing the Ladder of Compensation in T1D Terrain Drift
Healing is not a straight line — it’s more like peeling back layers of adaptation the body built to survive. Each stage has its own bottlenecks and feedback loops. Progress is possible, but it unfolds gradually, like soil regenerating after years of depletion.
Stage 1 Recovery — Restoring Insulin Signaling Foundations
Undoing compensation:
Replenishing magnesium, zinc, chromium, and B-vitamins → insulin receptors regain sensitivity.
GLUT4 translocation improves, so glucose uptake becomes more efficient.
Pancreas reduces its “overdrive” output → insulin and amylin stress decreases.
Timeline:
Weeks to months: cravings soften, energy after meals steadies, urination/thirst normalize.
Labs: improved fasting glucose, lower postprandial spikes, better Mg/Zn status.
Confounding loops:
Iron overload or persistent inflammation may still keep PI3K/Akt muted, even if nutrients are repleted.
Circadian rhythm realignment is often needed for the pathway to truly “wake up.”
Stage 2 Recovery — Calming the Stress Axis (Adrenals/Immune/Adipose)
Undoing compensation:
Repleting Vitamin C, B5, and electrolytes reduces adrenal overfiring.
Cortisol rhythm begins to normalize → less “wired but tired.”
Fat metabolism shifts away from chronic lipolysis toward balanced glucose-fat usage.
Immune inflammation quiets as GSK-3β inhibition (via nutrients, sleep, lithium trace support) reduces NF-κB signaling.
Timeline:
3–6 months: improved sleep quality, reduced anxiety, fewer inflammatory flares.
1–2 years: body fat redistributes, adrenal fatigue symptoms (salt cravings, afternoon crashes) lift.
Confounding loops:
Chronic infections or stealth pathogens (EBV, coxsackievirus) may keep immune signaling high, slowing adrenal recalibration.
Persistent iron retention will keep NF-κB active unless mineral handling is addressed.
Copper, zinc, magnesium, fat soluble vitamins, blood donations etc.
Stage 3 Recovery — Rebuilding Gut, Bone, and Immune Tolerance
Undoing compensation:
Gut lining repaired (glutamine, mucilaginous herbs, microbiome support) → antigen load decreases, immune system less triggered.
Bone stops over-resorbing → minerals (Ca, Mg, Zn, Li) spared for signaling.
Wnt/β-catenin signaling can stabilize again → stem cell renewal and beta cell regenerative signals return.
Autoantibody titers may plateau or even decrease as immune tolerance is restored.
Timeline:
6–12 months: digestive symptoms stabilize, fewer food sensitivities, stronger immunity (fewer colds).
2–4 years: bone density improves, fractures/joint issues decrease, systemic autoimmune signals may quiet.
Confounding loops:
If circadian rhythms and nervous system regulation aren’t rebuilt, gut permeability may persist.
Iron overload, if unaddressed, continues to feed ROS → damaging stem cells and bone marrow balance.
Stage 4 Recovery — Protecting Beta Cells, Kidneys, and Mitochondria
Undoing compensation:
Electrolyte stability restored → kidneys less stressed.
Mitochondrial cofactors (CoQ10, ALA, carnitine, NAC) improve ATP and redox balance → less apoptosis in beta cells.
Adrenal recovery reduces reliance on cortisol for blood sugar.
Iron-copper-retinol balance recalibrated → ROS pressure on beta cells decreases.
Timeline:
6–18 months: improved hydration tolerance, less extreme fatigue, more resilient blood sugar swings.
3–5 years: mitochondrial stamina returns, complications (neuropathy, retinopathy) may stabilize or regress.
Confounding loops:
Beta cell regeneration is possible but only if the microenvironment (iron balance, mitochondrial health, immune tolerance) is restored.
Some damage (e.g., nephron loss in kidneys) may be permanent, but function can be preserved long-term if terrain is stabilized.
The Honesty + Encouragement Balance
Short-term (weeks–months): cravings ease, hydration normalizes, energy steadies → these are early wins that build trust in the process.
Medium-term (months–2 years): adrenal rhythm, immune flares, digestive tolerance → these take longer but provide a tangible sense of “terrain softening".
Long-term (3–5 years): bone density, autoantibody modulation, mitochondrial stamina, potential beta cell regeneration → these require persistence but show that healing and restoration are possible beyond just management.
✨ Big picture: Undoing compensation isn’t about “fixing” one organ at a time — it’s about lifting the weight off each system sequentially so it can hand the baton back gracefully, instead of collapsing.
The PI3K/Akt, GSK-3β, and Wnt/β-catenin pathways are not abstract biochemistry — they are the core circuitry through which the body regulates blood sugar, balances fuel storage, and sustains beta cell resilience. In a healthy state, insulin signaling through PI3K/Akt turns off GSK-3β, allowing glucose to be stored as glycogen and stabilizing β-catenin to support long-term beta cell survival. At the same time, Wnt/β-catenin ensures regenerative capacity across the pancreas, gut, and bone, reinforcing the body’s ability to adapt and thrive.
What’s striking is how clearly this framework mirrors the lived progression of diabetes today. As these pathways become disrupted — whether from nutrient depletion, mitochondrial overload, chronic inflammation, or mineral imbalance — the body compensates step by step. First the pancreas and liver, then the adrenals and immune system, then the gut and bone, and finally the kidneys and nervous system all take turns carrying the weight. The result is not an overnight collapse, but a gradual sequence of adaptations that eventually unravel into the condition we call type 1 diabetes.
The magic of healing now lies in auditing our unique circumstances. How does my health experience overlap with the stages of compensation? What are my imbalances and compensations? In analyzing my symptoms, what systems are carrying the load in keeping my health afloat?
Recognizing this overlap matters. It reframes diabetes not as a sudden, unexplainable attack, but as the end result of terrain-level imbalances that strain these pathways over time. It also opens the door to new hope: if disruption is progressive and layered, so too can healing be. By understanding the raw materials and systemic supports that PI3K/Akt, GSK-3β, and Wnt/β-catenin depend on, we can begin to rebuild them — not just managing blood sugar in the short term, but addressing the deeper architecture of glucose regulation itself.
With this knowledge, we can begin meaningful experimentation peeling back the layers our body has built up to maintain function. What interventions, alternative therapies, foods, nutrients and lifestyle choices can I make? How can I help and how can I tune my awareness to interpret the feedback my body is giving me?
Supporting the Channel
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Additional resources (nutrition guide, supplement guide, exercise) https://bowie1.gumroad.com
📚 Recommended Readings
Insulin Signaling and PI3K/Akt Pathway
Saltiel, A. R., & Kahn, C. R. (2001). Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 414(6865), 799–806. https://doi.org/10.1038/414799a
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006). Critical nodes in signalling pathways: insights into insulin action. Nature Reviews Molecular Cell Biology, 7(2), 85–96. https://doi.org/10.1038/nrm1837
GSK-3β and Glucose Metabolism
Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 378(6559), 785–789. https://doi.org/10.1038/378785a0
Rayasam, G. V., Tulasi, V. K., Sodhi, R., Davis, J. A., & Ray, A. (2009). Glycogen synthase kinase 3: more than a namesake. British Journal of Pharmacology, 156(6), 885–898. https://doi.org/10.1111/j.1476-5381.2008.00085.x
Wnt/β-catenin Pathway and Beta Cell Biology
Rulifson, I. C., Karnik, S. K., Heiser, P. W., ten Berge, D., Chen, H., Gu, X., ... & Kim, S. K. (2007). Wnt signaling regulates pancreatic β cell proliferation. Proceedings of the National Academy of Sciences, 104(15), 6247–6252. https://doi.org/10.1073/pnas.0701509104
Schinner, S., Ulgen, F., Papewalis, C., Schott, M., Woelk, A., & Scherbaum, W. A. (2008). Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules. Diabetologia, 51(1), 147–154. https://doi.org/10.1007/s00125-007-0840-2
Pathway Cross-Talk and Diabetes Development
Liu, Z., Habener, J. F., & Kulkarni, R. N. (2010). Wnt signaling in pancreatic islets: new connections between β-catenin, incretin hormones, and insulin secretion. Trends in Endocrinology & Metabolism, 21(12), 699–707. https://doi.org/10.1016/j.tem.2010.08.005
Sutherland, C. (2011). What are the bona fide GSK3 substrates? International Journal of Alzheimer's Disease, 2011, 505607. https://doi.org/10.4061/2011/505607
Tzivion, G., Dobson, M., & Ramakrishnan, G. (2011). FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1813(11), 1938–1945. https://doi.org/10.1016/j.bbamcr.2011.06.002
Nutrient and Mineral Influences on Pathways
Gröber, U., Schmidt, J., & Kisters, K. (2015). Magnesium in prevention and therapy. Nutrients, 7(9), 8199–8226. https://doi.org/10.3390/nu7095388
Chu, C., Lu, J., Kong, D., & Chen, X. (2016). The role of chromium in diabetes and metabolic syndrome. Nutrients, 8(11), 602. https://doi.org/10.3390/nu8110602
O’Neill, E. C., & Raftery, M. J. (2013). The role of zinc in the pathogenesis of diabetes and its complications. BioMetals, 26(5), 913–927. https://doi.org/10.1007/s10534-013-9662-x
Machado-Vieira, R., Manji, H. K., & Zarate, C. A. Jr. (2009). The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic and neuroprotective effects. Neuropsychopharmacology, 34(8), 1743–1756. (Relevance: lithium as natural GSK-3β inhibitor).
Systemic Compensation in Diabetes Progression
Atkinson, M. A., Eisenbarth, G. S., & Michels, A. W. (2014). Type 1 diabetes. The Lancet, 383(9911), 69–82. https://doi.org/10.1016/S0140-6736(13)60591-7
Chatterjee, S., Khunti, K., & Davies, M. J. (2017). Type 2 diabetes. The Lancet, 389(10085), 2239–2251. https://doi.org/10.1016/S0140-6736(17)30058-2
Wang, P., Alvarez-Perez, J. C., Felsenfeld, D. P., Liu, H., Sivendran, S., Bender, A., ... & Garcia-Ocaña, A. (2015). A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nature Medicine, 21(4), 383–388. https://doi.org/10.1038/nm.3820
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