Professor Lu Juming: Improving "insulin resistance" is the root of the treatment of diabetes, and three drugs can "draw from the bottom"

It was edited and compiled by Yimaitong, and reviewed and released
by Professor Lu Juming.

Insulin resistance is the fundamental pathophysiological mechanism of type 2 diabetes mellitus (T2DM), and it is also the common soil for many metabolic disorders such as cardiovascular diseases and fatty liver, and treatment should start
from the source.
So, which drugs are effective in treating insulin resistance?

On October 15, 2022, at the online meeting of the "13th Chongyang Endocrine and Metabolism Summit" hosted by the Endocrinology and Metabolism Branch of the Chinese Geriatrics Association, Professor Lu Juming of the Department of Endocrinology of PLA General Hospital gave a wonderful academic lecture on the topic of "Drug Treatment of Insulin Resistance", and listed three hypoglycemic drugs
that can effectively treat insulin resistance.

Expert presentation

Prof.
Juming Lu

Chief Physician, Department of Endocrinology, PLA General Hospital;

Vice President of Beijing Hypertension Prevention and Control Association;

Former Vice Chairman of the Diabetes Branch of the Chinese Medical Association;

Chairman of the Endocrinology Professional Committee of the PLA Medical Association

"Insulin resistance" - the "common soil" of high blood sugar and many metabolic disorders

Professor Lu Juming pointed out that insulin resistance is caused by genetic and environmental factors caused by the body's responsiveness to the physiological effects of insulin, which is manifested by the decline
in glucose uptake and utilization promoted by insulin.
Evidence suggests that insulin resistance is the underlying pathophysiology of T2DM, the source of β cell failure, and throughout the natural history
.

Fig.
1 Insulin resistance is the fundamental pathophysiological mechanism of T2DM

In addition, insulin resistance is a common ground
for many metabolic disorders such as cardiovascular disease, fatty liver, polycystic ovary syndrome, etc.
Treatment of insulin resistance can address the root causes of these diseases
.

Fig.
2 Insulin resistance is the common soil for hyperglycemia and many metabolic disorders

Treating insulin resistance – three drugs can "draw from the bottom"

At present, the "insulin resistance therapy drugs" available for clinical application mainly include metformin, thiazolidinediones (TZDs) and the new hypoglycemic drug siglitasodium
.

1.
Metformin

In addition to metformin, it has the characteristics of good safety and remarkable hypoglycemic effect, and can also bring benefits
such as improving the body's insulin sensitivity and improving glucose utilization in peripheral tissues.

Fig.
3 Metformin lowers glucose through multiple mechanisms, including improving insulin sensitivity

"Activation of AMPK" is the main mechanism by which metformin increases insulin sensitivity, which can reduce gluconeogenesis and increase insulin sensitivity of the liver in the liver; In muscles, it can increase the uptake
of glucose by muscle tissue.

Fig.
4 Metformin increases insulin sensitivity by activating AMPK

2.
Pioglitazone

TZDs protect islet β cell function by alleviating insulin resistance, primarily by increasing the expression of nucleus-specific receptors, primarily peroxide proliferator-activated receptor r (PPARr), at the gene and molecular levels of enzymes and proteins related to metabolism such as glucose and fat, including muscle and fat cell glycogen synthetase, lipoprotein lipase, glucokinase, and glucose transporters4
.

Fig.
5 TZDs protect islet β cell function by reducing insulin resistance

Pioglitazone, a PPARr and PPARα double agonist, was approved by the FDA in 1999 and is currently the leading international and domestic TZD drug, and evidence suggests that it may include the following drug properties:

➤ Pioglitazone improves islet β cell function: ACT-NOW research suggests that pioglitazone can improve islet β cell function and prevent diabetes
.

➤ Pioglitazone can modulate blood lipid profiles by activating PPARα (compared with rosiglitazone, it can lower triglycerides, lower LDL-C, increase HDL-C).

➤ Pioglitazone can improve lipid metabolism, promote fat redistribution, and reduce visceral fat
.

➤ Pioglitazone Demonstrates Secondary Prevention of Stroke and Myocardial Infarction: A randomized, placebo-controlled, double-blind multicenter study (IRIS) showed that patients without diabetes but with insulin resistance had a 24% reduction in recurrent stroke and cardiovascular (CV) events and a 24%
decrease in insulin resistance index in the pioglitazone group after 4.
8 years of treatment.

➤ Delay the progression of diabetes: Compared with the prevention and delay of disease progression of various hypoglycemic drugs, it was found that pioglitazone can reduce the risk of diabetes by 72%.

➤ Delay β cell failure, delay insulin-dependent therapy: postpone insulin use for more than 3 years, combined with metformin, postpone permanent insulin-dependent therapy for up to 1.
24 years
.

➤ Reduction of microalbuminuria: the urine albumin/creatinine ratio was significantly reduced
in patients with pioglitazone in T2DM.

However, Professor Lu Juming reminds that in clinical application, the side effects of TZD should be taken into account, such as weight gain, sodium and water retention, increased heart failure, fracture risk, etc
.

Pioglitazone in combination with metformin: sensitization effect 1+1>2

The combination of pioglitazone and metformin has been shown to have a synergistic effect, covering more target organs through mechanism complementarity to improve insulin resistance and long-lasting sugar
control.

Fig.
6 The combined application of pioglitazone and metformin exerts synergistic effect

3.
Siglitasodium

Siglitasodium is a PPAR total agonist, which can activate PPAR α, PPARδ and PPARγ in vivo with different functions, which can regulate sugar, lipid and energy metabolism respectively, exert systemic insulin sensitization effect, and improve glycolipid/energy homeostasis
.

Fig.
7 There are three subtypes of PPAR, which act on different target organs

summary

In this lecture, Professor Lu Juming took stock of drugs that can effectively treat insulin resistance from mechanism to efficacy, and once again emphasized the importance of insulin resistance management for the common soil of many metabolic disorders such as hyperglycemia and fatty liver, in order to provide reference
for clinical medication.