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Peptides for Insulin Resistance

Insulin resistance is the metabolic fault line beneath type 2 diabetes, metabolic syndrome, PCOS, fatty liver disease, and a growing list of conditions that cost the healthcare system hundreds of billions of dollars each year.

Insulin resistance is the metabolic fault line beneath type 2 diabetes, metabolic syndrome, PCOS, fatty liver disease, and a growing list of conditions that cost the healthcare system hundreds of billions of dollars each year. Your cells gradually stop responding to insulin's signal to take up glucose. The pancreas compensates by producing more insulin. Eventually, it can't keep up — and blood sugar rises.

Standard treatment relies on metformin, lifestyle changes, and eventually insulin itself. These approaches manage the condition. But they don't always address the cellular machinery that broke down in the first place: impaired GLUT4 transporter movement, dysfunctional mitochondria, chronic low-grade inflammation, and broken intracellular signaling cascades.

This is where peptide research gets interesting. Several peptides — from FDA-approved GLP-1 receptor agonists to mitochondrial-derived peptides still in preclinical studies — act on the molecular mechanisms of insulin resistance directly. Some work through AMPK, the same energy-sensing pathway activated by exercise. Others improve insulin signaling through pathways metformin doesn't touch.

Here's what the science shows, what it doesn't, and what it means for you.

Table of Contents

How Insulin Resistance Works at the Cellular Level

To understand how peptides might help, you need to understand what goes wrong.

When you eat, your pancreas releases insulin. Insulin binds to receptors on the surface of your muscle, liver, and fat cells. This triggers a signaling cascade — insulin receptor substrate (IRS-1) activates PI3K, which activates Akt (protein kinase B), which tells GLUT4 glucose transporters to move from inside the cell to the cell membrane. Once GLUT4 reaches the surface, glucose flows in [1].

In insulin resistance, this chain breaks down at multiple points:

The signal weakens. Chronic inflammation (driven by TNF-alpha, IL-6, and other cytokines released by visceral fat) causes serine phosphorylation of IRS-1 instead of the normal tyrosine phosphorylation. This effectively jams the signal — insulin binds to the receptor, but the message doesn't get through [1].

GLUT4 stays stuck inside. Even when some signal gets through, the translocation machinery that moves GLUT4 to the cell surface becomes impaired. Excess membrane cholesterol, disrupted actin cytoskeleton, and faulty Rab-GTPase signaling all contribute to GLUT4 staying trapped in intracellular vesicles [2].

Mitochondria falter. Skeletal muscle mitochondria in insulin-resistant individuals produce less ATP and generate more reactive oxygen species (ROS). This oxidative stress further damages insulin signaling and reduces the cell's capacity to burn both glucose and fat [3].

The liver overproduces glucose. Normally, insulin suppresses hepatic glucose output. When the liver becomes insulin resistant, it keeps pumping glucose into the bloodstream even after a meal — which is why fasting blood sugar rises [1].

Fat tissue becomes inflammatory. As fat cells enlarge and multiply, they attract macrophages and shift their cytokine profile from anti-inflammatory to pro-inflammatory. This visceral fat inflammation is now understood as a primary driver — not just a consequence — of whole-body insulin resistance [4].

The result is a vicious cycle: insulin resistance leads to hyperinsulinemia, which promotes more fat storage, which worsens inflammation, which deepens insulin resistance.

Two Pathways to Fix It: Insulin-Dependent vs. AMPK

Your cells have two major routes for getting glucose inside — and this distinction matters for understanding how different peptides work.

The insulin pathway (PI3K/Akt). This is the one that breaks in insulin resistance. Peptides that work here — like GLP-1 agonists — improve the existing insulin signaling cascade. They make cells more responsive to insulin rather than bypassing it entirely.

The AMPK pathway. This is the exercise pathway. When your muscles contract during exercise, or when cellular energy drops (more AMP relative to ATP), AMPK activates. AMPK triggers GLUT4 translocation through a completely separate mechanism — it phosphorylates AS160/TBC1D4 and TBC1D1, plus the newly identified Tmod3 protein, which directly facilitates GLUT4 insertion into the plasma membrane [2].

Here's the critical point: the AMPK pathway remains fully functional in insulin-resistant individuals [2]. This is why exercise works even when insulin doesn't — and it's why peptides that activate AMPK (like MOTS-c) are so interesting for insulin resistance specifically. They don't need the broken insulin signaling machinery to get glucose into cells.

AMPK also suppresses HMGR and SREBP, lowering membrane cholesterol — which itself improves GLUT4 trafficking by restoring the cortical actin structure that hyperinsulinemia disrupts [5].

Semaglutide: Proven Insulin Sensitizer

Semaglutide has the strongest clinical evidence for improving insulin resistance among all peptides currently available. It's an FDA-approved GLP-1 receptor agonist used for type 2 diabetes (Ozempic, Rybelsus) and obesity (Wegovy).

How It Improves Insulin Resistance

Semaglutide works on insulin resistance through several overlapping mechanisms:

  • Glucose-dependent insulin secretion. It amplifies insulin release only when blood sugar is elevated, reducing the burden on beta cells and limiting hyperinsulinemia [6].
  • Glucagon suppression. By reducing inappropriate glucagon secretion, semaglutide decreases hepatic glucose output — addressing liver-level insulin resistance directly [6].
  • Weight loss. Semaglutide produces average weight loss of 15% in clinical trials, and much of this comes from visceral fat — the metabolically active tissue that drives inflammation-mediated insulin resistance [7].
  • Beta-cell protection. A 2025 meta-analysis found that semaglutide improved beta-cell function (HOMA-B) while reducing insulin resistance (HOMA-IR), suggesting it may slow the progressive beta-cell decline that defines the transition from insulin resistance to frank diabetes [8].

Clinical Numbers

The data across multiple populations is consistent:

Adults with type 2 diabetes (SUSTAIN trials). HOMA-IR decreased significantly with semaglutide treatment. Analysis showed that 34% to 94% of the insulin resistance reduction was mediated by weight loss — meaning some improvement occurred independent of weight change [9].

Adults with obesity and prediabetes (STEP trials). HOMA-IR improved significantly compared to placebo (p < 0.01). Among those with prediabetes, 84% achieved normal blood sugar levels by week 68 with semaglutide versus 48% with placebo [10].

Adolescents with obesity (STEP TEENS). HOMA-IR decreased by 38.6% with semaglutide versus 5.8% with placebo — a treatment difference of nearly 35 percentage points [11].

Women with PCOS. In obese women with PCOS who hadn't responded to lifestyle changes, HOMA-IR improved in all treated patients — even those who didn't lose 5% of their body weight. The researchers concluded that semaglutide may improve insulin resistance through a mechanism partially independent of weight loss [12].

Weight-Dependent vs. Weight-Independent Effects

This is an important nuance. Most of semaglutide's insulin-sensitizing effect comes from weight loss. But not all of it. Glucose lowering itself reduces HOMA-IR values, and the direct suppression of glucagon (reducing hepatic glucose output) and improvement of beta-cell function appear to be pharmacological effects of GLP-1 receptor activation rather than downstream consequences of losing weight [9].

An interesting comparison: in a head-to-head trial against dapagliflozin (an SGLT2 inhibitor), dapagliflozin improved fasting insulin resistance (HOMA2-IR) more, while semaglutide improved postprandial insulin sensitivity more. The two drugs address different aspects of insulin resistance through different mechanisms [13].

Tirzepatide: Dual Incretin Approach

Tirzepatide combines GLP-1 receptor activation with GIP (glucose-dependent insulinotropic polypeptide) receptor activation. The dual mechanism produces the most dramatic insulin resistance improvements documented in clinical trials.

The Incretin Problem in Insulin Resistance

In healthy people, eating a meal triggers the incretin effect — GLP-1 and GIP from the gut amplify insulin secretion by 50–70% beyond what glucose alone would produce. In type 2 diabetes, this incretin effect drops to 20–30%. It's one of the earliest measurable defects in the progression from insulin resistance to diabetes [14].

Tirzepatide works to restore this impaired incretin response by activating both incretin receptors simultaneously. The GIP component adds effects that GLP-1 alone doesn't provide, including direct improvements in adipose tissue function and complementary effects on lipid metabolism [14].

Clinical Results on Insulin Resistance

In the SURPASS trials, tirzepatide produced HbA1c reductions of 1.9% to 2.6% — the largest sustained improvements in glycemic control reported for any single agent in type 2 diabetes trials [15]. The 15 mg dose reduced HbA1c from an average of approximately 8.5% to below 6.0% in many participants, effectively normalizing blood sugar.

A post hoc analysis specifically examined the effect on metabolic syndrome criteria: the proportion of patients meeting metabolic syndrome diagnostic criteria decreased significantly with tirzepatide treatment across all SURPASS trials [15].

Body weight reductions ranged from 6.6% to 13.9% depending on dose and trial duration, with reductions continuing beyond the week 40–52 primary endpoints [15]. In the SURMOUNT program (obesity without diabetes), tirzepatide 15 mg produced approximately 20% weight loss sustained over three years [16].

Liver Fat: A Marker of Hepatic Insulin Resistance

The SURPASS-3 sub-study provided a direct measure of hepatic insulin resistance: tirzepatide reduced liver fat content by 8.09% compared to 3.38% with insulin degludec [16]. Liver fat accumulation is both a consequence and a cause of hepatic insulin resistance — reducing it improves the liver's ability to respond to insulin and suppress glucose output.

Liraglutide: Rapid Effects Independent of Weight Loss

Liraglutide was the first widely used GLP-1 receptor agonist for type 2 diabetes (Victoza) and obesity (Saxenda). A 2024 study from Vanderbilt University produced a finding that changed how researchers think about GLP-1 agonists and insulin resistance.

The Vanderbilt Discovery

Eighty-eight individuals with obesity and prediabetes were randomized to liraglutide, sitagliptin (a DPP-4 inhibitor that raises endogenous GLP-1), or a calorie-restricted diet. The results after just two weeks [17]:

  • Liraglutide improved insulin sensitivity (measured by HOMA-IR, HOMA2, and the Matsuda index) within two weeks — before any weight loss occurred
  • Diet-induced weight loss improved HOMA-IR and HOMA2 but not the Matsuda index, and did not decrease glucose levels
  • Sitagliptin increased endogenous GLP-1 levels but did not alter insulin sensitivity or fasting glucose at all

This finding carries two important implications. First, GLP-1 receptor agonists improve insulin resistance through a rapid pharmacological mechanism that's separate from — and additive to — weight loss. Second, simply raising endogenous GLP-1 levels (as DPP-4 inhibitors do) isn't enough. The pharmacological activation of the GLP-1 receptor at supraphysiological levels appears to be what drives the insulin-sensitizing effect [17].

Broader Clinical Evidence

In the LEAD-3 monotherapy trial, liraglutide reduced insulin resistance by 0.65–1.35% versus an increase of 0.85% with the sulfonylurea glimepiride [18]. The SCALE trial showed improvement in both insulin resistance and beta-cell function, with concurrent reductions in cardiometabolic risk factors [19].

In patients with coronary artery disease and newly diagnosed type 2 diabetes, adding liraglutide to metformin reduced ambient insulin levels, improved insulin sensitivity and insulin clearance — measured during a physiologic meal test — within a real-world clinical context [20].

MOTS-c: The Exercise Mimetic From Your Mitochondria

MOTS-c may be the most mechanistically interesting peptide for insulin resistance. It's a 16-amino-acid peptide encoded in the mitochondrial genome — one of only a handful of biologically active peptides produced by mitochondrial DNA rather than nuclear DNA.

Why It Matters for Insulin Resistance

MOTS-c activates AMPK — the same energy-sensing kinase that exercise activates [21]. As discussed earlier, the AMPK pathway is the one that still works in insulin-resistant individuals. By turning on AMPK, MOTS-c triggers glucose uptake in skeletal muscle through GLUT4 translocation via an insulin-independent route.

In practical terms: MOTS-c does molecularly what exercise does physically. It switches cells from energy-storage mode to energy-burning mode, bypassing the broken insulin signaling cascade entirely.

Animal Evidence

The landmark 2015 study in Cell Metabolism showed that MOTS-c treatment prevented both age-dependent and high-fat-diet-induced insulin resistance in mice. It also prevented diet-induced obesity and improved glucose tolerance in already-obese animals [21].

The mechanism starts with inhibition of the folate cycle and de novo purine biosynthesis. This metabolic disruption activates AMPK, which then:

  • Increases glucose uptake in skeletal muscle
  • Improves insulin sensitivity at the tissue level
  • Promotes fatty acid oxidation
  • Reduces hepatic glucose output

A 2025 study published in Experimental & Molecular Medicine revealed another piece of the puzzle: MOTS-c levels decline with aging in pancreatic islet cells, and treating aged islets with MOTS-c reduced cellular senescence and improved glucose intolerance in diabetic mouse models [22]. A separate 2025 paper showed that MOTS-c restores mitochondrial respiration in the type 2 diabetic heart — linking mitochondrial dysfunction, insulin resistance, and cardiovascular damage [23].

Human Correlations

Circulating MOTS-c levels are consistently lower in people with type 2 diabetes compared to healthy controls. The same pattern holds in gestational diabetes, in obese children and adolescents, and in people with coronary endothelial dysfunction [24]. The peptide appears to decline in exactly the populations where insulin resistance is most pronounced.

Clinical Development

MOTS-c is the first mitochondrial-encoded peptide to enter human clinical trials, with studies examining its effects on insulin resistance in obese individuals and frailty in older adults. However, the peptide faces delivery challenges — short half-life, low bioavailability, and a tendency to persist at the injection site rather than reaching target tissues [24].

The next-generation analog CB411 was engineered for a longer half-life and greater potency. Preclinical data suggest it may offer superior metabolic benefits and is under investigation for NASH and obesity [24].

MOTS-c vs. Metformin

Both MOTS-c and metformin activate AMPK, which invites comparison. The key difference: metformin's primary site of action is the liver, where it suppresses hepatic glucose production. MOTS-c primarily acts on skeletal muscle, where it promotes glucose uptake. Since muscle is the largest glucose disposal organ in the body (accounting for approximately 80% of insulin-stimulated glucose uptake), MOTS-c targets the tissue most directly responsible for insulin resistance [21].

BPC-157: The Gut-Inflammation-Insulin Axis

BPC-157 is a 15-amino-acid peptide from human gastric juice. Its connection to insulin resistance runs through two pathways: inflammation and gut health.

Inflammation and Insulin Resistance

Chronic low-grade inflammation is now recognized as a primary driver of insulin resistance, not just an accompanying symptom. TNF-alpha and IL-6 from visceral fat tissue directly impair insulin signaling by promoting serine phosphorylation of IRS-1 and activating inflammatory pathways (NF-kB, JNK) that interfere with GLUT4 translocation [4].

BPC-157 reduces inflammatory cytokine production and modulates the nitric oxide system in animal models. It interacts with the gut-brain axis and influences systemic cytokine profiles — potentially addressing the inflammatory root of insulin resistance rather than its downstream effects [25].

Direct Metabolic Effects in Animals

In animal studies, BPC-157 has shown:

  • Improved insulin sensitivity in models of insulin resistance [25]
  • Protection against insulin overdose — treated rats maintained blood glucose, liver glycogen, and hepatocyte integrity while untreated animals developed seizures, brain lesions, and fatty liver [26]
  • Reduced hepatic steatosis — a direct marker of hepatic insulin resistance [25]
  • Antioxidant upregulation — increased superoxide dismutase (SOD), one of the main intracellular antioxidant enzymes [25]

The Gut Connection

The gut plays an underappreciated role in insulin resistance. Intestinal barrier breakdown ("leaky gut") allows bacterial endotoxins to enter the bloodstream, triggering systemic inflammation and worsening insulin resistance. The gut microbiome composition itself influences glucose metabolism and insulin sensitivity.

BPC-157 is a gastric peptide with well-documented gut-protective effects. If part of what drives insulin resistance is gut-origin inflammation, then a peptide that repairs gut integrity and modulates intestinal immune function could address a root cause that metformin, GLP-1 agonists, and even exercise don't directly target [25].

Limitations

All of this is animal data. No human clinical trials have tested BPC-157 for insulin resistance endpoints (HOMA-IR, glucose clamp studies, or HbA1c). The peptide is not FDA-approved. The mechanistic story is plausible, but unvalidated in humans.

CJC-1295 and Ipamorelin: Growth Hormone and Insulin Sensitivity

CJC-1295 and ipamorelin stimulate growth hormone (GH) release from the pituitary gland through different receptor pathways. They're often combined because the pairing produces 3–5 times more GH release than either alone.

The Growth Hormone–Insulin Paradox

Growth hormone has a complicated relationship with insulin sensitivity. Long-term GH deficiency leads to increased visceral fat, decreased lean mass, and worsened insulin resistance — essentially, metabolic syndrome. Restoring GH levels improves body composition and, over time, insulin sensitivity [27].

But in the short term, GH directly antagonizes insulin action. It shifts fuel use from glucose to fat, temporarily raising blood sugar. GH activates lipolysis and releases free fatty acids, which themselves impair insulin signaling in muscle [27].

This creates a timing paradox: growth hormone secretagogues may worsen insulin sensitivity in the first weeks of treatment before the body composition improvements (less visceral fat, more muscle) generate net metabolic benefit. For someone who already has significant insulin resistance, this initial worsening can be clinically relevant.

What CJC-1295 Does

A single injection of CJC-1295 increases plasma GH levels by 2- to 10-fold for 6 or more days and IGF-1 by 1.5- to 3-fold for 9 to 11 days [28]. The IGF-1 increase is relevant because IGF-1 has its own insulin-sensitizing effects — it promotes glucose uptake in muscle through the IGF-1 receptor, partially independent of the insulin receptor [27].

Who Should Be Cautious

People with existing diabetes, prediabetes, or high fasting insulin levels need close monitoring if using growth hormone secretagogues. Signs of GH-related insulin resistance include worsening fasting glucose, increased HbA1c, or rising HOMA-IR despite fat loss. Dose reduction or discontinuation may be necessary [27].

Evidence Level

Neither CJC-1295 nor ipamorelin is FDA-approved. No clinical trials have specifically measured their effects on insulin resistance using gold-standard methods (hyperinsulinemic-euglycemic clamp). The metabolic rationale is based on growth hormone physiology rather than controlled insulin resistance studies.

Emerging Peptides Targeting Insulin Resistance

PATAS. A new first-in-class peptide developed by a multinational research team that targets the adipocyte (fat cell) directly. In animal models, PATAS restored glucose uptake in fat cells, reduced whole-body insulin resistance, improved glucose intolerance, and reversed liver steatosis and fibrosis. The researchers describe it as targeting the adipocyte to "ameliorate insulin resistance and its associated comorbidities" [29].

PEPITEM. This peptide decreased pancreatic islet cell enlargement and reduced white blood cell infiltration in visceral fat when given to mice on a high-fat diet. Researchers noted that if safely administered in humans, it could benefit people with obesity-related insulin resistance and inflammatory conditions [30].

Catestatin (CST). A naturally occurring peptide that improved glucose and insulin tolerance in obese mice by inhibiting macrophage recruitment to the liver. It normalized blood sugar and insulin levels while reducing fatty liver — hitting several nodes of the insulin resistance pathway simultaneously [31].

Lactoferrin-derived peptides. The peptide RER-EtBn, derived from lactoferrin, stimulated AKT serine phosphorylation, inhibited GSK-3beta phosphorylation, and promoted GLUT4 translocation to the cell membrane — directly repairing the insulin signaling cascade that breaks in insulin resistance [32].

Retatrutide. The first triple hormone receptor agonist (GLP-1, GIP, and glucagon), retatrutide achieved 24.2% weight loss in a phase 2 trial — a level of weight reduction that profoundly reverses insulin resistance across all tissues [33].

Peptide Comparison Table

PeptidePrimary Mechanism for Insulin ResistanceHOMA-IR ImprovementEvidence LevelFDA Status
SemaglutideGLP-1R agonism, weight loss, glucagon suppression18–39% reductionLarge RCTs across multiple populationsApproved (diabetes, obesity)
TirzepatideDual GLP-1/GIP agonism, body composition remodelingSignificant (HbA1c -2.6%)Large RCTsApproved (diabetes, obesity)
LiraglutideGLP-1R agonism, weight-independent insulin sensitizationImproved within 2 weeks pre-weight lossLarge RCTs + mechanistic studiesApproved (diabetes, obesity)
MOTS-cAMPK activation (insulin-independent GLUT4 translocation)Prevented IR in animal modelsPreclinical + early human trialsNot approved
BPC-157Anti-inflammatory, gut barrier repairImproved in animal modelsPreclinical onlyNot approved
CJC-1295 / IpamorelinGH secretion, body composition changeMay worsen short-termSmall PK studiesNot approved
PATASDirect adipocyte glucose uptake restorationReduced in animal modelsPreclinicalNot approved
CatestatinHepatic macrophage inhibitionNormalized in micePreclinicalNot approved

What the Research Doesn't Tell Us Yet

Optimal timing. Insulin resistance is a spectrum. At what point along the progression — from normal insulin sensitivity to prediabetes to type 2 diabetes — do different peptides provide the most benefit? Early intervention with MOTS-c might prevent the cascade from starting. GLP-1 agonists clearly work across the spectrum. But the clinical trials weren't designed to identify the ideal intervention window.

Combination approaches. Could combining a GLP-1 agonist (which improves the insulin signaling pathway) with a MOTS-c analog (which activates the parallel AMPK pathway) produce additive benefits? The biology suggests yes. The clinical data doesn't exist. The peptide stacking guide covers general principles of combination protocols, but insulin resistance-specific combinations haven't been studied.

Tissue-specific responses. Insulin resistance doesn't affect all tissues equally. Muscle, liver, and fat tissue become resistant at different rates and through partially different mechanisms. Semaglutide may address hepatic insulin resistance more through glucagon suppression, while MOTS-c targets muscle. No study has mapped which peptides work best for which tissue compartment.

Sex-based differences. Insulin resistance presents differently in men and women. Women with PCOS have a distinct insulin resistance phenotype. Semaglutide data in PCOS is encouraging [12], but most other peptides haven't been studied in sex-specific populations.

Long-term durability. When you stop taking semaglutide, insulin resistance often returns as weight comes back [7]. Does this mean lifelong therapy? Or could shorter courses of peptide treatment produce lasting metabolic changes? These questions remain open.

Frequently Asked Questions

What is the best peptide for insulin resistance?

Based on published clinical evidence, semaglutide and tirzepatide have the strongest data for reducing insulin resistance, measured by HOMA-IR improvement, HbA1c reduction, and reversal of prediabetes. Liraglutide has a unique evidence base showing insulin sensitization within two weeks, independent of weight loss. Among experimental peptides, MOTS-c has the most compelling mechanism because it activates the AMPK pathway that remains functional even in insulin-resistant cells.

Can peptides reverse insulin resistance completely?

In clinical trials, 84% of people with prediabetes who took semaglutide achieved normal blood sugar levels by week 68 [10]. Tirzepatide normalizes HbA1c in a significant proportion of patients. However, insulin resistance often returns if the peptide is stopped and weight rebounds. Whether peptide treatment can produce lasting metabolic changes that persist after discontinuation is an unanswered question.

How do peptides for insulin resistance compare to metformin?

Metformin primarily works in the liver, suppressing excess glucose production via AMPK activation. GLP-1 agonists work through appetite suppression, weight loss, glucagon suppression, and improved beta-cell function — affecting more components of insulin resistance simultaneously. GLP-1 agonists produce larger improvements in HOMA-IR and HbA1c than metformin. However, metformin is inexpensive, available as an oral tablet, and has decades of safety data. Many clinicians use both together. For a broader view of metabolic peptide therapy, see the peptides for metabolic syndrome guide.

Is MOTS-c better than exercise for insulin resistance?

No. MOTS-c mimics some of exercise's molecular effects — specifically AMPK activation in skeletal muscle — but exercise does far more: it improves cardiovascular fitness, builds muscle mass, reduces stress hormones, improves sleep, and activates dozens of metabolic pathways beyond AMPK. MOTS-c is being studied as a potential adjunct, especially for people who can't exercise due to frailty, injury, or disability. It is not a replacement for physical activity.

Are there food-derived peptides that help insulin resistance?

Yes, though the evidence is largely preclinical. Soy-derived peptides (IAVPGEVA, IAVPTGVA, LPYP) activated GLUT4 translocation through both Akt and AMPK pathways in cell cultures. Whey protein hydrolysate improved GLUT4 translocation in rat muscle through Akt phosphorylation. Egg white hydrolysate restored glucose uptake impaired by TNF-alpha in muscle cells [34]. These findings are interesting but have not been validated in human clinical trials at the scale needed to make dietary recommendations.

Do I need a prescription for insulin resistance peptides?

Semaglutide, tirzepatide, and liraglutide require prescriptions and are dispensed through regular pharmacies. Other peptides discussed here — MOTS-c, BPC-157, CJC-1295, ipamorelin — are not FDA-approved for insulin resistance or any indication. Their legal status and availability vary. For related information, see the guides on peptides for diabetes management and best peptides for fat loss.

The Bottom Line

Insulin resistance is not one broken thing. It's a web of broken things — impaired signaling, stuck transporters, failing mitochondria, inflammatory fat tissue, and an overactive liver. The most effective approaches tackle multiple nodes of this web simultaneously.

GLP-1 receptor agonists (semaglutide, tirzepatide, liraglutide) do this best right now. They improve insulin sensitivity through weight loss, glucagon suppression, beta-cell protection, and at least one weight-independent mechanism we're only beginning to understand. The clinical data is deep, replicated, and covers multiple populations.

Behind them, MOTS-c represents a genuinely different approach — going through the AMPK pathway that stays intact when insulin signaling breaks down. If clinical development succeeds, it could complement GLP-1 agonists by targeting the pathway they don't reach.

BPC-157 and growth hormone secretagogues add useful pieces (gut inflammation, body composition) but carry thinner evidence. The emerging peptides — PATAS, catestatin, PEPITEM — offer intriguing mechanisms that may eventually expand the toolkit.

Talk to your doctor about where you are on the insulin resistance spectrum and which evidence-based options fit your situation. Also see the related guides on peptides for NAFLD/NASH, peptides for obesity, and best peptides for cardiovascular health.

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