The picture of a skinny young person with newly diagnosed T1 diabetes does not have to be typical at a time when obesity in young people is not unusual. Today, there are young people who get T1 diabetes and who are obese, as well as those who get T2 diabetes. They always represent a challenge – in determining the correct diagnosis and treatment. These young people should not be identified with the adults with T2 diabetes.
Myth 1: Young people with type 1 diabetes develop vascular complications solely due to hyperglycemia caused by beta cell insufficiency.
Does insulin resistance and obesity play a role in this process? The study included healthy young, obese young people, young with T1 and normal weight, young with T1 who are obese and young people with T2 diabetes, aged 12-19 years. They all had the same HbA1c, but were different in body mass index.
It has been established that insulin resistance at the muscle level also exists in young people with T1 diabetes and normal body weight. This was unknown before! It occurs due to mitochondrial dysfunction in muscle fibers, and not due to the presence of fat in muscle tissue. Insulin resistance in muscles of young people with T1 diabetes is worse than in obese, “healthy” young people. Muscular resistance worsens with weight gain in young people with T1 diabetes. Of course, insulin resistance at the muscle level is greatest in young people with T2 diabetes. However, insulin resistance at the muscle level in young obese T1 is the same as in young people with type 2 diabetes.
What does all this tell us? The only cure for insulin resistance at the muscle level is physical activity! Physical activity improves the action of insulin and the utilization of glucose in the muscles.
Along with the existence of insulin resistance at the level of muscles in young people with T1 and T2 diabetes, there is also a vascular dysfunction, i.e. endothelial dysfunction. Venous plethysmography revealed lower vascular flow through the muscles of young people with T1 and T2 diabetes. Of course, vascular dysfunction is more pronounced in young people with T2 diabetes. An examination of physical condition discovered that young people with diabetes have poorer physical condition, even compared to obese peers. Of course, physical fitness is lower in obese T2 than in obese T1 adolescents. It is unknown to what extent the presence of vascular dysfunction affects the occurrence of hypertension.
In young adolescents with T1 diabetes, even when they have a normal body weight, there is insulin resistance at the level of adipose tissue. Glycerol and free fatty acids are released from adipose tissue. A large dose of insulin is needed to stop this lipolysis. It is possible that puberty contributes to this phenomenon, and not just obesity. Of course, insulin resistance at the level of adipose tissue is more pronounced in obese T1 and T2 adolescents. It is unknown whether the unstoppable release of free fatty acids contributes to the onset of cardiovascular disease.
The presence of visceral and intrahepatic fat in young people with T1 and T2 diabetes was analyzed by nuclear magnetic resonance. It is established that young people with T2 diabetes have more visceral and hepatic fats and that it correlates with hepatic insulin resistance. Young people with T1 diabetes also have insulin resistance at the liver level, which is lower than young people with T2, but higher than healthy young people. Hepatic insulin resistance does not correlate with the amount of hepatic or visceral fat in T1 youth. Then why isn’t the hepatic glucose production stopped in young people with T1 diabetes, with insulin?
In people with T1 diabetes, there is no passage of insulin from the pancreas to the liver through the portal circulation. This reduces the secretion of insulin-like growth factor 1 (IGF-1) in the liver. Decreased IGF-1 stimulates the secretion of growth hormone. Increased secretion of growth hormone stimulates the liver to produce hepatic glucose in young people with T1 diabetes.
Adolescents with T2 diabetes have all the components of metabolic syndrome. These include: low adiponectin, low HDL cholesterol, high transaminases and high triglycerides. Metabolic syndrome in young people with T2 diabetes correlates with the amount of hepatic, muscle and visceral fat. In obese people with T1 diabetes, the components of metabolic syndrome are not present, although there is insulin resistance at the level of the liver, muscles and adipose tissue.
The components of metabolic syndrome may worsen with weight gain in young people with T1 diabetes, but a typical picture of metabolic syndrome is missing. The reason is in the different pathogenetic mechanism of the tissue insulin resistance in T1 diabetes.
However, with weight gain, cardiovascular parameters worsen in young people with T1 diabetes. Arterial pressure rises, the pulse speeds up, the circulation in the muscles worsens, the blood vessels become harder and physical fitness decreases. This indicates that obese young people with T1 diabetes represent a special phenotypic population where much can be done with physical activity.
Myth 2: All cardiovascular disorders in young people with T1 diabetes can be corrected with insulin, which reduces hyperglycemia and glucose variability.
In light of the presence of insulin resistance in young people with T1 diabetes, it is obvious that all disorders cannot be corrected solely by insulin. It is especially important to explain this to young people who exercise in gyms and who think that insulin is an anabolic, which will improve their physical fitness. They give themselves higher doses of insulin and fall into hypoglycemia.
Can insulin resistance be improved by metformin? In a clinical trial where metformin was given to young people with T1 diabetes during 3 months, this was found: reduction of body weight, body fat and insulin dose, reduction of muscle insulin resistance, improvement of vascular flow, improvement of fitness and reduction of glomerular hyperfiltration.
Dopamine is a hormone that contributes to unexplained morning hyperglycemia, which cannot be overcome by basal insulin. A short clinical trial showed that bromocriptine helps young people with T1 diabetes with a pronounced dawn phenomenon.
Certainly, the near future will show that all metabolic, cardiovascular and kidney problems in young people with T1 diabetes cannot be solved with insulin alone.
Myth 3: Young people with newly diagnosed T2 diabetes can be treated like adults with T2 diabetes.
Since metabolic syndrome is present in young people with T2 diabetes treatment with metformin, insulin glargine and glitazone was tried. What were the results?
Type 2 diabetes occurs more often in young girls, precisely because of less physical activity. It is not only to blame the earlier appearance of puberty and hormonal disturbances. Girls and young ladies move less, have fewer steps per day than boys and are less involved in sports. Hence, T2 in young people is more related to the female sex, unlike T2 in adults, where no such difference exists. Physical activity in young people would prevent the onset of T2 diabetes.
Glitazones improve insulin resistance at the level of adipose tissue and muscles. They are good medications for adults with T2 diabetes. On the other hand, in young people with newly diagnosed T2 diabetes, glitazones (in our country it is pioglitazone) increase visceral and subcutaneous adipose tissue, and do not decrease it! Hence, glitazones should not be used in young people with T2 diabetes, although short use of glitazone in girls improves glycoregulation and reduces HbA1c, better than in boys. In boys, the best HbA1c reduction is achieved by a combination of physical activity and metformin.
If T2 diabetes does not achieve remission, best with a change in lifestyle, proper diet, weight loss and physical activity, the first cardiovascular and renal consequences can be seen, as early as after 10 years. 25% of young people with T2 diabetes have hypertension after 10 years. Increased glomerular filtration and albuminuria are even more common. Changes are also found on ultrasound of the heart. How to treat a young patient with T2 if he/she does not want to maintain physical fitness?
Oral GTT with insulinemia is usually tested in young people with prediabetes or newly diagnosed T2 diabetes. It is always found that young people (persons aged 10-26) have hyperinsulinemia, which speaks for insulin resistance. However, there is also a high response of c-peptide, which speaks for hypersecretion of insulin in response to insulin resistance, from the beta cell. This differs from the response to oGTT of adults (26-60 years) with prediabetes. They usually have only hyperinsulinemia, with a more normal beta cell secretory response (a more normal c-peptide response).
In young and adults with prediabetes, or newly diagnosed T2 diabetes, metformin leads to a decrease in HbA1c and body weight during 12 months. The effect is already lost in young people after 6 months! This means that metabolic disorders cannot be corrected with metformin in young people with prediabetes.
Insulin glargine treatment given for the first 3 months and then continued with metformin alone resulted in HbA1c reduction in both groups, but the effect was less pronounced in young people with T2 diabetes. For the same reduction in HbA1c, the dose of insulin glargine in young people was twice as high as the dose required in adults. Adult people with prediabetes or newly diagnosed with T2 diabetes responded well to this therapy; it did not lead to weight gain and kept HbA1c low. However, the effect was completely opposite in young people. After the initial HbA1c reduction, nothing favorable happened further, even when insulin was discontinued and treatment was continued with metformin. Insulin led to a large gain in kilograms. That weight could not be reduced for 12 months, on metformin.
Metformin has no effect on T2 prevention in young people with prediabetes. Practically, for this group, there is no other solution than regular and persistent physical activity. Insulin resistance due to obesity and physical inactivity cannot be solved by metformin, insulin, or glitazones! Over time, it leads to beta cell depletion, due to hypersecretion of insulin. Rising morning hyperglycemia is bad prognostic parameter in young people with prediabetes.
Bariatric surgery in extremely obese young people with T2 diabetes has shown excellent results. New medications from the group of SGLT2 inhibitors and GLP-1RA have not been studied in this population, which does not mean that their use is contraindicated and will not give good results.
Physical activity and movement are the only good medications for young people! They have excellent metabolic, psychological and social effects.
The free mobile app OTVORI PLAVI KRUG (open blue circle) is a big help!
For all the doctors who wish to read more about this topic, I suggest the following literature:
San S, Edelstein S et al and Nadeau K for the RISE consortium. Baseline predictors of glycemic worsening in youth and adults with impaired glucose tolerance or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. Diabetes Care 2021;44:1-10.
Kahn S, Mother K et al and Edelstein S for the RISE consortium. Hyperglucagonemia does not explain the beta cell hyperresponsiveness and insulin resistance in dysglycemic youth compared with adults; lessons from the RISE study. Diabetes Care 2021;44:1-9.