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Type 2 Diabetes & Prediabetes
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In one pass Type 2 diabetes is not simply eating too much sugar. Not this — GLP-1 is a miracle weight-loss shot for everyone — It is meant for people with a BMI (body mass index) of 30 or more, or 27 or more with a related health condition (the STEP-1 trial). Within a year of stopping, about two-thirds of the lost weight comes back (STEP-4).
Educational content, not medical advice — consult a clinician.
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Chapter 1
What type 2 diabetes is
Type 2 diabetes is not simply eating too much sugar. It is the body becoming less and less responsive to insulin, the key that brings blood glucose down.
After a meal, glucose in the blood rises and the pancreas releases insulin. Insulin's job is to knock on the doors of muscle, liver and fat cells and open their glucose channels so sugar can get in and be used for energy. Early in type 2 diabetes, the key and the lock are both still there, but the lock has become sluggish: the same amount of insulin knocks and knocks and the door barely opens. This is called insulin resistance. The body's answer is to cut more keys, making the pancreas produce more insulin to force its way through. That works for a while, but the key-making beta cells of the pancreas slowly wear out, the keys start to run short, and blood glucose builds up and stays high.
This is different from type 1 diabetes. In type 1, the immune system usually destroys the insulin-making cells, so almost no insulin is made. In type 2, the key first stops working well and then gradually runs short, and it usually builds up slowly from excess weight, diet and a metabolism that has drifted out of balance.
If you have thirst and heavy urination together with nausea and vomiting and deep, fast breathing, or cold sweats, shaking and confusion, this may be a diabetic emergency: go to the emergency department right away (see Where you are and what to do).
After a meal, glucose in the blood rises and the pancreas releases insulin. Insulin's job is to knock on the doors of muscle, liver and fat cells and open their glucose channels so sugar can get in and be used for energy. Early in type 2 diabetes, the key and the lock are both still there, but the lock has become sluggish: the same amount of insulin knocks and knocks and the door barely opens. This is called insulin resistance. The body's answer is to cut more keys, making the pancreas produce more insulin to force its way through. That works for a while, but the key-making beta cells of the pancreas slowly wear out, the keys start to run short, and blood glucose builds up and stays high.
This is different from type 1 diabetes. In type 1, the immune system usually destroys the insulin-making cells, so almost no insulin is made. In type 2, the key first stops working well and then gradually runs short, and it usually builds up slowly from excess weight, diet and a metabolism that has drifted out of balance.
If you have thirst and heavy urination together with nausea and vomiting and deep, fast breathing, or cold sweats, shaking and confusion, this may be a diabetic emergency: go to the emergency department right away (see Where you are and what to do).
Clinical · How the lab sheet counts diabetes
Type 2 diabetes () is long-term high blood glucose caused by insulin resistance combined with a relative shortfall in insulin secretion. It differs from type 1 diabetes (T1D), in which the immune system destroys the insulin-making beta cells and insulin is absolutely lacking.How the lab sheet counts diabetes: the diagnostic criteria (the same for the American Diabetes Association, ADA, and the Chinese Diabetes Society) need any one of the following:
≥ 6.5% (glycated hemoglobin, which reflects average blood glucose over roughly the past 3 months)or fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL), on two occasionsor 2-hour glucose ≥ 11.1 mmol/L (200 mg/dL) in an (OGTT)or random glucose ≥ 11.1 mmol/L together with symptoms of high blood glucose
The in-between zone that is not yet diabetes but is already high is called prediabetes:
HbA1c 5.7–6.4%or fasting glucose 5.6–6.9 mmol/L (100–125 mg/dL), called impaired fasting glucose (IFG). These are the ADA cut-offs; the World Health Organization and Chinese guidelines set impaired fasting glucose at 6.1–6.9 mmol/L, so the same lab sheet can read differently depending on which standard is usedor 2-hour OGTT glucose 7.8–11.0 mmol/L, called impaired glucose tolerance (IGT)About 5–10% a year progress to type 2 diabetes; but many people in this zone can also return to the normal range, which makes it the golden window for acting
Numbers · How many people in China have it
The figures for China (Wang 2017, a 2013 national survey of more than 170,000 adults, published in JAMA):Adult diabetes prevalence 10.9% (95% 10.4–11.5)Prediabetes 35.7%, about 388 million adultsMost do not know they have it: only 36.5% of people with diabetes were aware of it, and 32.2% were being treated
What is different in Asian populations:
At the same body mass index (), Asian people have a higher risk of type 2 diabetes than European peopleLean type 2 diabetes: people with a BMI under 25 can still develop the disease, which is why Asian cut-offs for overweight are lower (in China a BMI of 24 or more already counts as overweight; in the West it is 25 or more)The usual explanation: at the same BMI there is more visceral fat, and both insulin resistance and the decline in beta-cell function are more marked
Diabetes as an old person's disease no longer holds:
In the same 2013 national survey, diabetes prevalence was already 5.9% in adults under 40 (12.9% at 40–59 and 20.2% at 60 or older)Type 2 diabetes in children and teenagers is rising clearly as obesity becomes more commonObservational studies show that the earlier the onset, the greater the effect on life expectancy: ERFC 2023 pooled data on more than 1.5 million people in high-income countries, and using US death rates, people diagnosed at 30 died about 14 years earlier on average, and those diagnosed at 50 about 6 years earlier
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Background · One disease, eight organs
Type 2 diabetes is often described as a disease of the pancreas, but DeFronzo 2009, a review, summarizes its underlying problems as eight organs going wrong together: muscle, liver, the beta cells of the pancreas, fat cells, the gut, the alpha cells of the pancreas, the kidneys and the brain. Muscle and fat have trouble taking up glucose, the liver releases glucose when it should not, beta cells secrete too little insulin, the alpha cells' glucose-raising hormone (glucagon) is not held down, the kidneys reabsorb more glucose back into the blood, and the brain responds less to fullness signals.This map is useful in two ways. First, it explains why different drugs act on different organs: metformin mainly holds down glucose release from the liver, inhibitors make the kidneys send glucose into the urine, and drugs act on the pancreas, the stomach and the brain at once, which is why drugs are often combined. Second, it ties type 2 diabetes to several other topics: fat and fructose in the liver (see Fructose vs Glucose Metabolism), how muscle stores glucose as glycogen (see Carbs & Fiber), how sleep apnea affects blood glucose (see Obstructive Sleep Apnea), and the whole set of hormonal changes in metabolic syndrome (see endocrine).
Chapter 2
Why cells stop responding to insulin
Insulin is the key that sends blood glucose into cells. Insulin resistance means the cells have become less responsive to that key, so the body has to make more and more insulin, until the key factory, the beta cells, wears out.
Normally, insulin binds to a receptor on the cell surface, and the signal is passed down a chain of proteins inside the cell. At the end of the chain, muscle and fat cells move the glucose transporter to the cell surface, and only then can glucose get in (DeFronzo 2009). One key relay station in the chain is insulin receptor substrate 1 (IRS-1). In insulin resistance, it gets phosphate groups added at the wrong places (phosphorylation, which is like a switch being flipped the wrong way), and everything downstream weakens together, like a lock that has been tampered with so the key goes in but will not turn.
Who tampered with it? Mainly three upstream forces that reinforce each other: fat stored in the wrong places, inflammation that has flared up, and hormones out of balance. For the full set of changes in metabolic syndrome, see endocrine.
Normally, insulin binds to a receptor on the cell surface, and the signal is passed down a chain of proteins inside the cell. At the end of the chain, muscle and fat cells move the glucose transporter to the cell surface, and only then can glucose get in (DeFronzo 2009). One key relay station in the chain is insulin receptor substrate 1 (IRS-1). In insulin resistance, it gets phosphate groups added at the wrong places (phosphorylation, which is like a switch being flipped the wrong way), and everything downstream weakens together, like a lock that has been tampered with so the key goes in but will not turn.
Who tampered with it? Mainly three upstream forces that reinforce each other: fat stored in the wrong places, inflammation that has flared up, and hormones out of balance. For the full set of changes in metabolic syndrome, see endocrine.
Mechanism · Three upstream forces
So who tampered with the lock? Mainly three upstream forces, and they reinforce one another. After IRS-1, the insulin signal still has to pass two more relay stations, PI3K and Akt, before the glucose transporter () reaches the cell surface; all three forces below do their damage at the IRS-1 station.Fat: visceral fat pours a steady stream of fatty acids into the blood, which pile up as fat where it does not belong, in muscle, liver and beta cells (ectopic fat). Intermediates of that fat, such as diacylglycerol (DAG) and ceramide, activate several kinases (PKCθ and JNK, enzymes that add phosphate groups to other proteins), and these are what damage the IRS-1 lock. The pathway by which fructose is turned into new fat in the liver (de novo lipogenesis) feeds this step from upstream (see Fructose vs Glucose Metabolism).Inflammation: visceral fat also behaves like an inflamed organ. It releases a set of pro-inflammatory signals (tumor necrosis factor , interleukin-6 and others), attracts immune cells called macrophages, and pulls the whole body into low-grade chronic inflammation. Inflammatory signals act through the pathway and also land on IRS-1, making it even less responsive.Hormones: an imbalance in sex hormones adds to the problem. In women with polycystic ovary syndrome, higher androgens worsen insulin resistance (see pcos); in middle-aged men with abdominal obesity, low testosterone and insulin resistance feed each other. A low level of (SHBG) is often a marker of this whole metabolic tangle.
Mechanism · How beta cells are worn down
Beta-cell decompensation (when they can no longer keep up):Early: beta cells compensate by secreting 2–3 times more insulin, keeping blood glucose in the normal range; but by now insulin in the blood is already highMiddle: beta-cell function declines and cell numbers fall, glucose tolerance worsens, and prediabetes sets inLate: beta-cell function drops below 50% of normal, diabetes develops, and some people need insulin injections
Key points:
Diabetes is just eating too much sugar is an oversimplification: the real cause is fat, inflammation and hormones stacking up into a whole-body metabolic imbalance that finally pushes the beta cells past what they can handle is a result, not a cause: it is a measure that reflects blood glucose, not the same thing as the heart attacks, strokes and kidney failure people actually want to avoid. Watching HbA1c alone is not enough; look upstream too: weight, visceral fat, free fatty acids in the blood, and inflammationEarly on there is a chance to reverse it: in people who have had the disease for a short time and whose blood glucose is not yet very high (early here roughly means an HbA1c still below 7.5%; the DiRECT trial enrolled people diagnosed within 6 years), remission was more common with a weight loss of 10–15 kg (see Weight loss can put it into remission)
Clinical · How to read the lab tests
(glycated hemoglobin):Reflects average blood glucose over the past 8–12 weeks (set by how long red blood cells live)Advantages: no fasting needed, a single blood draw, stableLimits: conditions that shorten red-cell life (hemolytic anemia, recent blood loss) and some abnormal hemoglobins (thalassemia, sickle cell disease) can make it falsely lowIron deficiency and vitamin B12 deficiency: can make it falsely highChronic kidney disease: unreliable
Fasting plasma glucose (FPG):
After at least 8 hours without foodReflects glucose output from the liver plus baseline insulin resistanceThe dawn phenomenon: cortisol and growth hormone rise in the early morning, the liver releases more glucose, and the fasting reading comes out higher
(oral glucose tolerance test):
Fast, drink 75 g of glucose, and have blood glucose measured again at 2 hoursThe most sensitive test: it can catch early insulin resistance (sharp rises in blood glucose after a meal)Some people have normal HbA1c and fasting glucose but an abnormal OGTT, which is an important early signalScreening: the ADA suggests starting screening at age 35 (earlier for people with overweight and other risk factors), and repeating it at least every 3 years if results are normal
Insulin and C-peptide:
Fasting insulin above 12 µ/mL is sometimes taken as a sign of insulin resistance (Reaven 1988); there is no standard cut-off, and insulin assays differ between labs, so treat it only as a reference = (fasting insulin × fasting glucose) / 22.5; 2.5 or higher is a commonly used rough cut-off for insulin resistance, but different population studies use different valuesC-peptide reflects the insulin the beta cells make themselves; in people already treated with insulin it can show how much function remains
(continuous glucose monitoring):
Measures glucose in the fluid under the skin continuously for 24 hoursA normal HbA1c with clear peaks in blood glucose after meals is often a clue to early insulin resistancePeople vary enormously: the same banana with milk produces completely different glucose responses in different peopleFor healthy people, 1–2 weeks of CGM can help show how they respond to their own foods
A self-check list (priority from age 35):
Once a year: HbA1c, fasting glucose, waist, blood lipids and (a liver enzyme)If anything is abnormal, add an OGTT, insulin and C-peptideA normal check-up this year does not mean next year will be normal too: early type 2 diabetes often takes shape quietly over 5–10 years
Chapter 3
Weight loss can put it into remission
Many people believe that once you have diabetes, it can only get worse every year. A randomized trial gave a different answer: people early in the disease who genuinely lost weight brought their blood glucose back below the diabetes threshold, without medication.
The trial is DiRECT (Lean 2018, published in The Lancet), run in UK primary-care practices. After one year, 46% of the intervention group were in remission: still below 6.5% at least two months after stopping all glucose-lowering drugs. Be clear about what it measured: remission is a lab measure, not a such as heart attack, stroke or death, and the trial did not answer whether weight loss reduces those outcomes.
The leading explanation is the twin-cycle hypothesis: excess weight stores fat in the liver and pancreas, where it suppresses the insulin-making beta cells and pushes up the liver's glucose output. With large weight loss this fat is cleared first, and both organs recover. A study of 11 people on a very-low-calorie diet for 8 weeks (Lim 2011) supports this explanation. When the disease is fairly recent (within roughly 6–8 years), the process can be reversed; after many years, too many beta cells have been lost and it becomes hard.
The trial is DiRECT (Lean 2018, published in The Lancet), run in UK primary-care practices. After one year, 46% of the intervention group were in remission: still below 6.5% at least two months after stopping all glucose-lowering drugs. Be clear about what it measured: remission is a lab measure, not a such as heart attack, stroke or death, and the trial did not answer whether weight loss reduces those outcomes.
The leading explanation is the twin-cycle hypothesis: excess weight stores fat in the liver and pancreas, where it suppresses the insulin-making beta cells and pushes up the liver's glucose output. With large weight loss this fat is cleared first, and both organs recover. A study of 11 people on a very-low-calorie diet for 8 weeks (Lim 2011) supports this explanation. When the disease is fairly recent (within roughly 6–8 years), the process can be reversed; after many years, too many beta cells have been lost and it becomes hard.
Evidence · How DiRECT was run
Design:49 primary-care practices in Scotland and the Tyneside region of England, randomized by practice (cluster randomization)298 people with type 2 diabetes in the analysis (diagnosed within 6 years, 27–45, not using insulin)The comparison: a very-low-calorie diet (VLCD) program versus best-practice usual care following guidelines
The VLCD program:
At the start, glucose-lowering and blood-pressure drugs were stopped under a doctor's supervision3–5 months: 825–853 kcal a day of formula meal replacements (protein shakes plus vitamins)Food reintroduction: solid food brought back gradually over 2–8 weeksLong-term maintenance: regular dietitian follow-up, once a month, with strategies for keeping the weight off
Numbers · After one, two and five years
Results at 12 months (Lean 2018):46% remission in the intervention group ( < 6.5%, off glucose-lowering drugs)4% remission in the usual-care groupAverage weight loss of 10 kg in the intervention group, versus 1 kg in the control groupBy amount of weight lost (both groups counted together): 86% remission among people who lost 15 kg or more, and 57% among those who lost 10–15 kg
Results at 2 years (Lean 2019):
36% still in remission (3% in the usual-care group)People still in remission were not taking glucose-lowering drugs, which is part of how remission is defined
Results at 5 years (a 2024 extension study):
The 85 people who kept receiving low-intensity support were still 6.1 kg lighter than at the start on average, and 11 of them (13%) were in remission, a clear drop from 36% at 2 years; regaining weight was the main reason for relapseThis stretch is no longer a randomized comparison but an extended observation
The message of these figures: DiRECT shows that remission is possible, not that it is a one-time fix. Remission is judged by HbA1c and medication, which are measures; the trial did not answer whether weight loss reduces heart attacks, strokes and similar outcomes.
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In practice · Not dieting at home on your own
How it is put into practice:Since 2020 the UK's NHS has rolled out the DiRECT program as one option for early type 2 diabetesSome hospitals in China run similar programs, but insurance coverage and the supply of dietitians are still the bottlenecksNote: this is not dieting. It is structured medical nutrition therapy with long-term follow-up; losing weight on your own at home is not the same as doing DiRECT
Mediterranean diet and exercise:
PREDIMED (the version republished in 2018) was a primary-prevention trial in adults at high cardiovascular risk: a Mediterranean diet with added olive oil or nuts cut major cardiovascular events by about 30% compared with a low-fat control diet. It measured cardiovascular outcomes, not diabetes remissionLook AHEAD (2013) put overweight people with type 2 diabetes on an intensive lifestyle program: they lost weight, but cardiovascular events did not fallWeight loss on these diets is slower than on a VLCD, but many people find them easier to stick with, which suits people who cannot do a VLCD
Conclusion: in people early in the disease who lose enough weight, type 2 diabetes can go into remission; but it comes back when the weight returns, so the accurate description is remission is possible, not fixed for good.
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In practice · China's guide: 3–5% loss already helps
Not everyone can lose weight on the scale of DiRECT, and not everyone needs to. China's National Health Commission guideline, *Dietary Guidelines for Adults with Diabetes (2023 edition)*, sets a bar far lower than most people assume:For people with type 2 diabetes who are overweight or obese, losing just 3–5% of body weight already brings clinically meaningful health benefits.The suggested pace is 1–2 kg a month, adding up to 5–10% over 3–6 months; faster is not better.The healthy body mass index () range for Chinese adults is 18.5–23.9; adults over 65 may appropriately carry more weight (in that age group the direction of risk reverses; see sarcopenia).
The share of energy from each macronutrient:
Protein 15–20%, carbohydrate 45–60%, fat 20–35%
The staple-food rule is the most concrete and the easiest to follow: whole grains, mixed beans and other foods with a low glycemic index () should make up at least 1/3 of staple foods; vegetables 500 g a day, more than half of them dark-colored.
Remember that 3–5%, because it changes the mindset: a person weighing 80 kg is already in the benefit range after losing 3 kg. The hardest part of losing weight was never the first 3 kg; it is believing the first 3 kg is worth it.
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Chapter 4
The three main drug groups
Type 2 diabetes is now treated mainly with three groups of drugs: metformin as the base, with receptor agonists and inhibitors taking over next. Beyond lowering glucose, the last two reduced cardiovascular events in large trials and bring extra protection to the heart and kidneys, which has been the biggest shift in thinking of recent years.
Metformin is the first-line choice for almost everyone. It came to market in 1957 and has more than sixty years of safety data. It mainly holds down the liver's glucose output and improves insulin resistance, lowering by 1–2%. In China it costs only a few yuan to a little over ten yuan a month, and it is available worldwide. The trade-off is that about a quarter of people get gut side effects (switching to an extended-release tablet helps), and long-term use lowers vitamin B12 (see Vitamin B12), so people taking metformin should have their B12 checked regularly, commonly once a year.
Metformin is the first-line choice for almost everyone. It came to market in 1957 and has more than sixty years of safety data. It mainly holds down the liver's glucose output and improves insulin resistance, lowering by 1–2%. In China it costs only a few yuan to a little over ten yuan a month, and it is available worldwide. The trade-off is that about a quarter of people get gut side effects (switching to an extended-release tablet helps), and long-term use lowers vitamin B12 (see Vitamin B12), so people taking metformin should have their B12 checked regularly, commonly once a year.
Clinical · The group that cuts weight most
receptor agonists (liraglutide, semaglutide sold as Ozempic, tirzepatide sold as Mounjaro, and others) are the standout second-line group. They do several things at once: slow stomach emptying, make the brain feel full sooner, prompt beta cells to release insulin, and hold glucagon down. Over 12–24 months they can lower by 1–2% and body weight by 10–20%.More important are the hard outcomes: cardiovascular outcome trials such as SUSTAIN-6 show that they reduce major cardiovascular events (heart attack, stroke, cardiovascular death). There is also evidence of kidney protection, while the evidence on heart failure is still building. The main side effects are gut symptoms such as nausea and vomiting (20–40%), and pancreatitis is rare. They are expensive: in China about ¥800–1500 a month, partly covered by health insurance.
Clinical · The group that sends sugar out in urine
inhibitors (empagliflozin, dapagliflozin and others) take a different route: they block the kidneys from reabsorbing glucose, so sugar leaves in the urine, and along the way they reduce weight and protect the heart and kidneys. They lower by 0.7–1.0% and weight by 2–3 kg. Trials such as EMPA-REG show that they reduce hospital admissions for heart failure and slow the progression of chronic kidney disease; that is why they are now used even in people with heart failure or chronic kidney disease () who do not have diabetes. The main side effects are urinary and genital infections, and ketoacidosis is rare.The other drugs each have a place but are no longer the leads: sulfonylureas easily cause low blood sugar and are gradually fading out; DPP-4 inhibitors are moderately effective and fairly safe; pioglitazone reduces fat in the liver but raises body weight; acarbose mainly handles blood glucose after meals; insulin comes later in the sequence.
Clinical · From lowering glucose to protecting organs
To spell out the shift in thinking: receptor agonists and inhibitors have moved from glucose-lowering drugs to combined protectors of the heart, kidneys and metabolism, and more and more evidence supports using them in people with obesity, heart failure or chronic kidney disease who do not have diabetes. The open questions are long-term safety, the muscle loss that comes with GLP-1 drugs, price, and weight regain after stopping.As for influencers promoting berberine as nature's Ozempic: in small trials berberine's weight loss is small, while GLP-1 drugs work on a different scale in large trials (semaglutide 14.9% vs 2.4% on placebo at 68 weeks in STEP-1; tirzepatide 15.0–20.9% at 72 weeks in SURMOUNT-1). At most it is a stand-in for metformin, not for a GLP-1 drug (see berberine). In DiRECT, the lifestyle group lost 10 kg on average in a year and about a quarter lost 15 kg or more: the same order of magnitude as the drugs, only with more effort.
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Chapter 5
Where you are and what to do
🚩 Safety first · when to get emergency care now
Diabetes has several emergencies. If any of the following happens, go to the emergency department now — do not wait:
Diabetic ketoacidosis (DKA): thirst and passing a lot of urine + nausea and vomiting + abdominal pain + deep, rapid breathing or breath that smells of rotten apples + confusionSevere hypoglycemia: cold sweat, shaking hands, a pounding heart, altered consciousness, seizures — if the person is awake and can swallow, take 15 g of fast-acting sugar right away; if it does not improve or they are not fully conscious, call an ambulance immediatelyHyperosmolar hyperglycemic state (HHS): extreme thirst + passing large amounts of urine + drowsiness and altered consciousness (more common in older people)
The safety floor for medicines and diet: talk to your doctor before any adding, reducing or stopping of medication; a very-low-calorie diet (such as DiRECT's ~825 kcal) must be done under a doctor's and a dietitian's supervision — it can put early patients into remission, but it is not a plan to start casually on your own at home.
Diabetes has several emergencies. If any of the following happens, go to the emergency department now — do not wait:
Diabetic ketoacidosis (DKA): thirst and passing a lot of urine + nausea and vomiting + abdominal pain + deep, rapid breathing or breath that smells of rotten apples + confusionSevere hypoglycemia: cold sweat, shaking hands, a pounding heart, altered consciousness, seizures — if the person is awake and can swallow, take 15 g of fast-acting sugar right away; if it does not improve or they are not fully conscious, call an ambulance immediatelyHyperosmolar hyperglycemic state (HHS): extreme thirst + passing large amounts of urine + drowsiness and altered consciousness (more common in older people)
The safety floor for medicines and diet: talk to your doctor before any adding, reducing or stopping of medication; a very-low-calorie diet (such as DiRECT's ~825 kcal) must be done under a doctor's and a dietitian's supervision — it can put early patients into remission, but it is not a plan to start casually on your own at home.
In practice · Which stage you are in, and your goal
I have prediabetes or type 2 diabetes — what do I do? The stages below are a rough guide to help you place yourself, not the formal staging of any guideline.Question 1: What stage are you in?
5.7–6.4%: prediabetes, the golden window; the focus is lifestyleHbA1c 6.5–7.5%, diabetes for less than 6 years: early type 2 diabetes; DiRECT-style remission is worth consideringHbA1c 7.5–9%, diabetes for 5–10 years: middle stage; lifestyle plus medication (starting with metformin)HbA1c above 9%, or diabetes for more than 10 years with serious complications: several drugs in combination, possibly insulin
Question 2: What is your goal?
Remission (off medication): for early patients, losing 10–15 kg is the most powerful interventionControl (keeping HbA1c below 7%): for most patients, medication and lifestyle togetherFewer complications and a longer life: the focus is protecting the heart and blood vessels, the kidneys and the retina
In practice · How much you can lose, which drug
Question 3: Your weight and how much you can lose?You can lose weight strictly (you have the time and resources): the DiRECT program, plus a dietitian and long-term supportModerate weight loss (a 5–10% target): a Mediterranean diet, strength training and walkingLosing weight is very hard (for psychological reasons, lack of time, or appetite): consider a drug (when it is indicated)
Question 4: Which drug?
First line: metformin (unless there is a reason not to use it)Second line, with cardiovascular disease, heart failure or chronic kidney disease: a GLP-1 receptor agonist or an inhibitor (with trial evidence of fewer hard cardiovascular and kidney outcomes)Second line, when weight loss is the main aim: a GLP-1 receptor agonistSecond line, when blood glucose after meals is high: acarbose or an SGLT2 inhibitorThird line: several drugs combined, plus insulinNote (ADA 2024/2025): if atherosclerotic cardiovascular disease (), heart failure or chronic kidney disease is already present, a GLP-1 receptor agonist or SGLT2 inhibitor with proven heart and kidney benefit should be started early, and metformin does not have to come first; for these conditions, the order of drugs is no longer decided by the level or by starting with metformin (type 2 diabetes without these conditions still starts with metformin)
Clinical · GLP-1 drugs: mechanism and trials
After 2015, diabetes treatment took a major turn: two groups of glucose-lowering drugs brought hard cardiovascular and kidney benefits in large trials at the same time, and the order of treatment changed. drugs first.GLP-1 receptor agonists (glucagon-like peptide-1 receptor agonists):
Semaglutide (Ozempic, Wegovy): weekly injection, also available as a tabletLiraglutide (Victoza): daily injectionDulaglutide (Trulicity): weekly injectionTirzepatide (Mounjaro, Zepbound): activates both the GLP-1 and the GIP receptors, weekly injection, on the market in China since 2024
Mechanism (five routes):
Pancreatic beta cells: insulin release is boosted in proportion to blood glucose (the effect is weak when glucose is not high, so the risk of low blood sugar is very low when the drug is used alone)Pancreatic alpha cells: less glucagonStomach: slower emptying, a smoother rise in glucose after meals, and stronger fullnessHypothalamus: appetite is turned downHeart, blood vessels and kidneys: direct protection (not explained by glucose lowering alone)
Key randomized trials:
LEADER (liraglutide): major adverse cardiovascular events () down 13% in relative terms, cardiovascular death down 22%, death from any cause down 15%SUSTAIN-6 (semaglutide): MACE down 26% in relative termsSTEP-1 (semaglutide 2.4 mg for weight loss): body weight down 14.9% at 68 weeks (the basis for Wegovy's weight-loss approval)SURMOUNT-1 (tirzepatide): body weight down 22.5% at 72 weeks (the highest-dose group)SELECT (semaglutide in adults with overweight or obesity and existing cardiovascular disease, without diabetes): MACE down 20% in relative terms (6.5% vs 8.0%), which moved GLP-1 drugs into the group of drugs for cardiovascular disease
Side effects:
Gut symptoms: nausea (30–40% when starting), vomiting, constipation and diarrhea; managed by raising the dose gradually and giving the body time to adaptMedullary thyroid cancer warning (from rat data, not confirmed in humans): not to be used by people with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN2)Pancreatitis: a slightly higher , with a low absolute riskGallstones: linked to rapid weight lossMuscle loss: about 20–40% of the weight lost is lean mass (lean mass is not all muscle; it also includes water and organs) (see sarcopenia)
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Clinical · SGLT2 inhibitors and the order of drugs
inhibitors (sodium-glucose co-transporter 2 inhibitors):Dapagliflozin (Farxiga)Empagliflozin (Jardiance)Canagliflozin (Invokana)
Mechanism: they block glucose reabsorption in the proximal tubule of the kidney, so about 80–100 g of glucose leaves in the urine each day. Blood glucose falls, and about 300 kcal a day of energy is lost along with it
Unexpected benefits: protection in heart failure and for the kidneys (not explained by glucose lowering alone)
Key randomized trials:
EMPA-REG (empagliflozin): cardiovascular death down 38% in relative terms, hospital admission for heart failure down 35%DAPA-HF (dapagliflozin in heart failure, enrolling patients with and without diabetes): worsening heart failure or cardiovascular death down 26%, which made SGLT2 inhibitors a heart-failure drug tooDAPA-CKD: progression of chronic kidney disease down 39%, which made SGLT2 inhibitors a kidney drug too
Side effects:
Genital yeast infections (more sugar in the urine): 10–20% of women and 2–5% of menUrinary tract infections: slightly more commonKetoacidosis (DKA): rare; people with type 1 diabetes and people on very-low-carbohydrate diets need to watch for itAmputation risk (canagliflozin, in the CANVAS trial): slightly raised, with later evidence closer to neutral
The order of drugs in type 2 diabetes (ADA 2024):
First line: metformin (unless there is a reason not to use it)Second line (with cardiovascular disease, kidney disease or heart failure): a receptor agonist or an SGLT2 inhibitor (chosen according to the condition, no longer by alone)Second line (when weight loss is the main need): a GLP-1 receptor agonist (especially semaglutide or tirzepatide)Third line: several drugs combined, possibly with insulin later
In practice · Price, access and rebound after stopping
Price and access (China, 2024–2025):Semaglutide: ¥800–1200 a month in China, partly covered by national health insurance since 2024Tirzepatide: launched in 2024, not yet covered by insurance, ¥1500–3000 a monthChinese-made inhibitors: much cheaper, ¥30–100 a month, covered by insurance
The risks hidden under the miracle weight-loss drug label:
Regain after stopping: in the off-treatment extension of STEP 1, one year after all treatment stopped, about two-thirds of the weight that had been lost had come backMuscle loss: about 25% of the weight lost is lean mass (studies range from 20–40%), so the drugs usually need to be combined with strength training and enough proteinLong-term (10 years or more) safety data are still building upThe risks of buying through influencers or informal online resellers: counterfeit drugs, wrong doses and no medical supervision; avoid this route entirely
wilding-2022-step1-extension
In practice · What to do at any stage
The core list (do these at any stage):Cut out sugary drinks and milk tea30 minutes of aerobic exercise a day, and strength training 2–3 times a weekAt each meal, eat vegetables and protein first and carbohydrates last (Shukla 2015: a small crossover trial of 11 people with type 2 diabetes taking metformin, which looked only at blood glucose in the 2 hours after one meal)Try not to eat after 10 p.m., and get 7–8 hours of sleepStop smoking and limit alcohol (alcohol worsens fatty liver, and drinking on an empty stomach while using insulin or some glucose-lowering drugs can cause low blood sugar)Monitor B12 (yearly if you take metformin)
Mental health and diabetes:
A commonly quoted figure is that 30–40% of people with type 2 diabetes also have depressionDiabetes distress: the burden of treatment, self-blame and anxietyThis is not a lack of self-discipline; it is the psychological load that comes with a chronic illness, and it deserves dedicated psychological support
Self-management tools:
Continuous glucose monitoring (): 1–2 weeks of use can help you learn how your blood glucose responds to different foodsPhone apps: choose ones with food logging that can connect to a glucose meterCommunity support: patient groups, dietitians and endocrinologists
Background · How it connects to other topics
How it connects to other topics:The full set of reversible changes in metabolic syndrome: see endocrineHow muscle takes up glucose using (the transporter that carries glucose into cells) and insulin signaling: see Carbs & FiberDietary drivers: fructose being turned into fat in the liver (see Fructose vs Glucose Metabolism), plus Ultra-processed Foods (UPF) and Alcohol MetabolismSleep drivers: sleep apnea (see Obstructive Sleep Apnea), plus insomnia and Shift WorkOther hormonal conditions that often come with it: polycystic ovary syndrome (see pcos), plus hashimotoExercise, protein and strength training: keeping muscle (see sarcopenia)
Type 2 diabetes is not a fate sealed by the label diabetes; it is a metabolic state, and in many people at an early or middle stage it can improve with intervention. Understanding the mechanism and the evidence is meant to help you make sense of your own metabolism and decide together with your doctor. This is health education, not medical advice; follow your doctor's guidance.
References · 9
- American Diabetes Association. (2024). Standards of Medical Care in Diabetes — 2024. Diabetes Care, 47(Suppl. 1). diabetesjournals.org/care/issue/47/Supplement_1
- Wang, L., Gao, P., Zhang, M., Huang, Z., Zhang, D., Deng, Q., et al. (2017). Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA, 317(24), 2515-2523. Nationally representative cross-sectional survey of 170,287 adults in mainland China in 2013, ADA 2010 criteria: standardized prevalence of total diabetes 10.9% (10.4-11.5), diagnosed diabetes 4.0%, prediabetes 35.7% (34.1-37.4). Of people with diabetes, 36.5% were aware, 32.2% treated, and 49.2% of the treated had HbA1c < 7.0%. Full text: about 388.1 million adults had prediabetes in 2013, vs a projected 493.4 million (50.1%) from the 2010 survey; total diabetes by age was 5.9% under 40, 12.9% at 40-59 and 20.2% at 60 or older (Table). No cost figures (abstract, PMID 28655017; full text, PMC5815077). 10.1001/jama.2017.7596
- DeFronzo, R. A. (2009). From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes, 58(4), 773-795. Insulin acts via insulin receptor → IRS-1 → PI3K → Akt → GLUT4 translocation in muscle/adipose; suppresses hepatic gluconeogenesis; T2DM involves defects in 8 organs (muscle, liver, beta-cell, fat cell, gut, alpha-cell, kidney, brain). 10.2337/db09-9028
- Rosmond, R. (2005). Role of stress in the pathogenesis of the metabolic syndrome. Psychoneuroendocrinology, 30(1), 1-10. 10.1016/j.psyneuen.2004.05.007
- Lean, M. E. J., Leslie, W. S., Barnes, A. C., et al. (2018). Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The Lancet, 391(10120), 541-551. 49 UK practices, 306 adults aged 20-65 diagnosed within the past 6 years, BMI 27-45, not on insulin. Intervention: withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal/day formula for 3-5 months), stepped food reintroduction (2-8 weeks), then maintenance support. Remission = HbA1c < 6.5% after ≥ 2 months off all antidiabetic drugs. At 12 months: remission 46% (68/149) vs 4% (6/149) in controls, OR 19.7; ≥ 15 kg loss in 24% vs 0; mean loss 10.0 vs 1.0 kg. Remission tracked weight loss: 0% of those who gained, 7% at 0-5 kg, 34% at 5-10 kg, 57% at 10-15 kg, 86% at ≥ 15 kg (abstract, PMID 29221645). 10.1016/S0140-6736(17)33102-1
- Lim, E. L., Hollingsworth, K. G., Aribisala, B. S., Chen, M. J., Mathers, J. C., & Taylor, R. (2011). Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia, 54(10), 2506-2514. 10.1007/s00125-011-2204-7
- Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A., et al. (2016). Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). New England Journal of Medicine, 375(19), 1834-1844. 10.1056/NEJMoa1607141
- Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., et al. (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG OUTCOME). New England Journal of Medicine, 373(22), 2117-2128. 7020 people with type 2 diabetes at high cardiovascular risk, median 3.1 years: primary outcome 10.5% vs 12.1%, HR 0.86 (0.74-0.99); no significant difference in myocardial infarction or stroke; cardiovascular death 3.7% vs 5.9%, heart-failure hospitalisation 2.7% vs 4.1%, death from any cause 5.7% vs 8.3%; more genital infections (abstract, PMID 26378978). 10.1056/NEJMoa1504720
- Shukla, A. P., Iliescu, R. G., Thomas, C. E., & Aronne, L. J. (2015). Food order has a significant impact on postprandial glucose and insulin levels. Diabetes Care, 38(7), e98-e99. Pilot letter: 11 adults with metformin-treated type 2 diabetes, within-subject crossover (the letter does not say the order was randomised), the same 628 kcal meal on 2 days a week apart. Eating vegetables and protein before carbohydrate lowered glucose by 28.6%, 36.7% and 16.8% at 30, 60 and 120 min and glucose iAUC by 73% vs the reverse order (full text, PMC4876745). 10.2337/dc15-0429