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As a result, from type 2 diabetes long term elevated blood glucose levels negatively affect kidney function. The filters in the kidney may become leaky and no longer able to filter waste products as efficiently from the body. Resulting in kidney disease. This image shows the difference between a healthy kidney and kidney with diabetic kidney disease.

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Frequent urination. As blood sugar rises the kidneys try to get rid of excess glucose through urination. Frequent urination can cause dehydration, leading to drinking more fluids. The cycle repeats!

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The focus should be on controlling blood sugar through lifestyles changes and medication. Drinking plenty of water to sat hydrated and avoiding alcohol and caffeine is crucial.

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The Link between Thirst and Diabetes: What You Need to Know

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Oral medication is usually first line of defense. 

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Metformin- lowers glucose production in the liver ($10-$30).

Sulfonylureas- increase insulin production ($15-$25).

GLP-1 Receptor agonists- Lower blood sugar and promote weight loss ($1000-$2000).

Insulin ($300-$400).

These are prices without insurance.

Avoiding use of medications may lead to worsening of the condition, leading to kidney disease, blood vessel damage, extremitiy neuropothay.

Medications may be required for long term use if a patient is not able to lower sugar levels through diet and exercise.

Most insurance plans cover medications for type 2 diabetes.

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Devices like apple watches and Fitbit can be used as a preventive measure. It tracks physical activity and heart rate. It can also track sleep patterns to see if you are getting quality sleep.

Cost can be a negative or limitation.

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a doctor who specializes in hormone related conditions, like diabetes.

They manage complex cases of type 2 diabetes.

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Diabetes can increase the chance of early onset dementia.

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Part 1/2: Dementia and diabetes. What is dementia?

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Type 2 diabetes occurs when the pancreas doesn’t make enough insulin or the body doesn’t know how to regulate it

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Our brain needs sugar! Type 2 diabetes disrupts the way our body uses sugar, which is the primary source of energy for our body. Our brain is the most demanding organ using one-half of all the sugar energy in the body.

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Brain functions such as thinking, memory, and learning are closely linked to glucose levels and how efficiently the brain uses this fuel source. If there isn't enough glucose in the brain, for example, neurotransmitters, the brain's chemical messengers, are not produced and communication between neurons breaks down. In addition, hypoglycemia, a common complication of diabetes caused by low glucose levels in the blood, can lead to loss of energy for brain function and is linked to poor attention and cognitive function.

"The brain is dependent on sugar as its main fuel," says Vera Novak, MD, PhD, an HMS associate professor of medicine at Beth Israel Deaconess Medical Center. "It cannot be without it."

Although the brain needs glucose, too much of this energy source can be a bad thing. A 2012 study in animals by researchers at the University of California at Los Angeles indicated a positive relationship between the consumption of fructose, another form of sugar, and the aging of cells, while a 2009 study, also using an animal model, conducted by a team of scientists at the University of Montreal and Boston College, linked excess glucose consumption to memory and cognitive deficiencies.

The effects of glucose and other forms of sugar on the brain may be the most profound in diabetes, a group of diseases in which high blood glucose levels persist over a prolonged period of time. Type 1 diabetes is a disease in which the immune system destroys the cells in the pancreas that produce insulin, a hormone used by the body to keep blood glucose levels in check. Type 2 diabetes, caused by dietary and other environmental factors, is a condition in which cells become overwhelmed by insulin and fail to properly respond; they become resistant to insulin.

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Brain functions such as thinking, memory, and learning are closely linked to glucose levels and how efficiently the brain uses this fuel source. If there isn't enough glucose in the brain, for example, neurotransmitters, the brain's chemical messengers, are not produced and communication between neurons breaks down.

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Type 2 diabetes can affect different anatomical structures, some being our pancreas, heart, and eyes. Here is a video showing how.

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Pancreas helps with digestion and regulation sugar. The pancreas naturally over produces insulin. But then sometimes it doesn’t make enough.

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Peripheral Neuropathy is the most common symptom affecting 50% of type 2 diabetes patients. High blood sugar levels affect neurons; sensory neurons are the first to be affected. Watch this video up until the 1:30 min mark. After that is goes into other neuropathy symptoms.

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Excess body fat, particularly around the stomach region, increases insulin resistance.

Visceral fat releases hormones that interfere with how insulin works.

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Genetics and access to health care play a role in why ethnic groups are affected by type 2 diabetes.

African Americans and Native Americans used to be very active and hunters.

Fast forward to today many African and Native Americans live in low socio-economic communities, these communities usually only have access to unhealthy foods.

Genetically they both retain body fat longer due to their feast and famine history. Causing that bad visceral fat we spoke about

This video talks about African Americans and Native Americans.

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Why Do Some Ethnicities Have Greater Rates Of Diabetes?

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The main anatomical structures involved in type 2 diabetes include the pancreas, liver, skeletal muscles, adipose (fat) tissue, small intestine, kidneys, and the brain. The pancreas, specifically the β‑cells in the islets of Langerhans, is responsible for producing insulin. In type 2 diabetes, these cells initially compensate for insulin resistance by producing more insulin but eventually become dysfunctional and fail to meet the body’s demand (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], 2022). 

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Anatomical structure of Type 2 diabetes 

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The liver contributes to high blood glucose levels by continuing to produce and release glucose even when it is not needed (Mayo Clinic, 2023). Adipose tissue releases inflammatory cytokines and free fatty acids that worsen systemic insulin resistance (Mayo Clinic, 2023). The small intestine’s enteroendocrine cells, which secrete incretin hormones like GLP‑1 to enhance insulin secretion, often have a blunted response in type 2 diabetes (NIDDK, 2022).

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Third Symptom of Type 2 Diabetes- Fatigue

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Third Symptom of Type 2 Diabetes- Fatigue

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3) Fatigue - The body's inability to properly use glucose for energy can result in tiredness and lack of energy

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image of fatigued individual suffering from type 2 diabetes

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Lifestyle modifications are highly recommended. Participating in regular physical activities, focusing on eating whole foods, prioritizing Mental Health, and a consistent sleep routine are few of the recommended treatment for Type 2 Diabetes.

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Type 2 diabetes is becoming more common in children, often linked to obesity and lack of physical activity. Healthy eating, regular exercise, and early checkups can help prevent or manage this condition.

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Getting the facts right.

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Type 2 Diabetes: Facts and Misconceptions You Should Know | Mass General Brigham

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The Mediterranean diet rich in vegetables, fruits, whole grains, olive oil, nuts and lean proteins, can help lower blood sugar, improve insulin sensitivity, and reduce the risk of type 2 diabetes. Its focus on healthy fats and plant-based foods makes it a heart-friendly choice for diabetes prevention and management.

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Fourth Symptom of Type 2 Diabetes - Weight Gain/Loss

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Fourth Symptom of Type 2 Diabetes - Weight Gain/Loss

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While most healthy individuals experience some weight gain as they age, people with diabetes Type 2 are more likely to gain weight faster. Depending on the individual, some people are known to lose weight instead of maintaining what is considered a healthy Body Mass Index, BMI.

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Symptom of Type 2 Diabetes Weight Gain or Loss

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Type 2 diabetes increases the risk of a heart disease and stroke. High blood sugar can damage blood vessels, leading to Coronary artery disease, heart attacks and stroke.

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Cardiovascular Disease caused by diabetes

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If left untreated, diabetic neuropathy can lead to injuries to the feet and toes. This is because sensory nerves are damaged, individuals with type 2 diabetes may not notice injuries to feet and toes. This can lead to serious injuries like ulcers and infections. Ultimately leading to amputation.

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POORLY MANAGING YOUR BLOOD SUGAR IS ONE OF THINGS LINKED A FASTER PACED LOSS OF MEMORY OR OTHER THINKING SKILLS

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If the cells don’t respond to the insulin the correct way it can increase your blood sugar and this can cause to body to burn fat and muscle for energy

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DIABETES IS LINKED TO INCREASED RISK OF HEART DISEASE AND NARROWED BLOOD VESSELS, WHICHBIS CALLED ATHEROSCLEROSIS

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HEARING ISSUES ARE COMMON IN PEOPLE WITH DIABETES

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Abstract

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.

Keywords: type 2 diabetes mellitus, insulin resistance, β-cell, liver, adipocyte, muscle, cardiovascular disease, pathophysiology

1. Introduction

Type 2 Diabetes Mellitus (T2DM) is one of the most common metabolic disorders worldwide and its development is primarily caused by a combination of two main factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond to insulin [ 1]. Insulin release and action have to precisely meet the metabolic demand; hence, the molecular mechanisms involved in the synthesis and release of insulin, as well as the insulin response in tissues must be tightly regulated. Therefore, defects in any of the mechanisms involved can lead to a metabolic imbalance that leads to the pathogenesis of T2DM.

This review analyses the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism and associations between T2DM and cardiovascular pathophysiology. In this review, we describe the global trends of T2DM, the roles of major risk factors, in particular, obesity, lifestyle factors, genetic predispositions, gut dysbiosis, epigenetics and mitochondrial deregulation. We highlight physiological and molecular mechanisms leading to T2DM and its complications.

2. Type 2 Diabetes Mellitus: Background and Epidemiology

According to the World Health Organization (WHO) diabetes mellitus is a chronic, metabolic disease characterized by elevated levels of blood glucose, which leads over time to damage to the heart, vasculature, eyes, kidneys and nerves. Over 90% of diabetes mellitus cases are T2DM, a condition marked by deficient insulin secretion by pancreatic islet β-cells, tissue insulin resistance (IR) and an inadequate compensatory insulin secretory response [ 2, 3]. Progression of the disease makes insulin secretion unable to maintain glucose homeostasis, producing hyperglycaemia. Patients with T2DM are mostly characterized by being obese or having a higher body fat percentage, distributed predominantly in the abdominal region. In this condition, adipose tissue promotes IR through various inflammatory mechanisms, including increased free fatty acid (FFA) release and adipokine deregulation. The main drivers of the T2DM epidemic are the global rise in obesity, sedentary lifestyles, high caloric diets and population aging, which have quadrupled the incidence and prevalence of T2DM [ 4, 5].

The organs involved in T2DM development include the pancreas (β-cells and α-cells), liver, skeletal muscle, kidneys, brain, small intestine, and adipose tissue [ 6]. Evolving data suggest a role for adipokine dysregulation, inflammation, and abnormalities in gut microbiota, immune dysregulation, and inflammation have emerged as important pathophysiological factors [ 7].

Epidemiological data show alarming values that predict a worrisome projected future for T2DM. According to the International Diabetes Federation (IDF), in 2019, diabetes caused 4.2 million deaths; and 463 million adults aged between 20 and 79 years old were living with diabetes, a number that will likely rise up to 700 million by 2045. Diabetes was the underlying cause of at least 720 billion USD in health expenditure in 2019. Additionally, the true disease burden of T2DM is likely an underrepresentation as 1 in 3 diabetic people were underdiagnosed, equivalent to 232 million people. The greatest number of people suffering from diabetes are aged between 40 and 59 years old. Incidence and prevalence of T2DM vary according to geographical region, with more than 80% of patients living in low-to-middle-income countries, which poses additional challenges in effective treatment. Patients with T2DM have a 15% increased risk of all-cause mortality compared with people without diabetes with cardiovascular disease (CVD) as the greatest cause of morbidity and mortality associated with T2DM [ 8]. The association of diabetes with increased risk of coronary heart disease (hazard ratio [HR] 2.00; 95% CI 1.83-2.19), ischaemic stroke (HR 2.27; 1.95-2.65), and other vascular disease-related deaths (HR 1.73; 1.51-1.98) has been shown in a meta-analysis [ 9].

Epidemiology of T2DM is affected both by genetics and the environment. Genetic factors exert their effect following exposure to an environment characterized by sedentary behavior and high-calorie intake. Common glycaemic genetic variants for T2DM have been identified by genome-wide association studies, but these only account for 10% of total trait variance, suggesting that rare variants are important [ 10]. People of different ethnic origins may have different specific phenotypes that increase predisposition to clusters of CVD risk factors, including hypertension, insulin resistance, and dyslipidemia [ 11].

3. Risk Factors and Pathophysiology

T2DM risk factors include a complex combination of genetic, metabolic and environmental factors that interact with one another contributing to its prevalence. Although individual predisposition to T2DM due to non-modifiable risk factors (ethnicity and family history/genetic predisposition) has a strong genetic basis, evidence from epidemiological studies suggests that many cases of T2DM can be prevented by improving the main modifiable risk factors (obesity, low physical activity and an unhealthy diet) [ 12, 13].

3.1. Ethnicity and Family History/Genetic Predisposition

Globally, the incidence and prevalence of T2DM are found to vary widely depending on ethnicity and geographical region with Japanese, Hispanics and Native Americans having the highest risks [ 14, 15, 16]. It has been shown higher incidence rates in Asians compared with a White American population [ 17, 18], and white population in the UK, [ 19], where the highest risk is among the black population [ 20]. Whilst no clear reasons have been found, contributing factors such as modern lifestyle factors (which promote obesity), socioeconomic and direct genetic propensity or gene environmental interactions have been postulated.

3.2. Obesity, Low Physical Activity and Unhealthy Diet

Obesity (body-mass index [BMI]≥30 kg/m ²) is the strongest risk factor for T2DM [ 26, 27] and is associated with metabolic abnormalities resulting in IR [ 28]. There exist an inverse linear relationship between BMI and the age at diagnosis of T2DM [ 29]. The exact mechanisms by which obesity induces T2DM and IR remain to be elucidated; however, numerous factors have shown a significant role in the development of this pathological process, which involves both cell-autonomous mechanisms and inter-organ communications.

A sedentary lifestyle is another risk factor for T2DM as shown by the Women's Health Study and in the Kuipio Ischemic Heart Disease Risk Factor Study, which showed a reduction of 34% and 56% reduction of developing T2DM in participants walking 2-3 h a week or at least 40 min a week, respectively [ 30, 31]. There are three primary benefits of physical activity on the delay of T2DM onset. First, the contraction of skeletal muscle cells induces an increase in blood flow into the muscle, enhancing glucose uptake from plasma [ 32]. Second, physical activity reduces the notorious intra-abdominal fat, which is a known risk factor that promotes IR [ 33]. Finally, moderate-intensity exercise has been shown to improve glucose uptake by 40% [ 34]. Physical activity improves glucose uptake and insulin sensitivity but it can also improve or even reverse inflammation and oxidative stress, which are T2DM predisposing factors [ 32].

3.3. Pathophysiology

Regarding the pathophysiology of the disease, a malfunctioning of the feedback loops between insulin action and insulin secretion results in abnormally high glucose levels in blood [ 2]. In the case of β-cell dysfunction, insulin secretion is reduced, limiting the body's capacity to maintain physiological glucose levels. On the other hand, IR contributes to increased glucose production in the liver and decreased glucose uptake both in the muscle, liver and adipose tissue. Even if both processes take place early in the pathogenesis and contribute to the development of the disease, β-cell dysfunction is usually more severe than IR. However, when both β-cell dysfunction and IR are present, hyperglycaemia is amplified leading to the progression of T2DM [ 35, 36].

4. Mechanisms Leading to T2DM and Pathophysiology

4.1. Insulin Secretion: Physiological and Dysfunctional Mechanisms Leading to T2DM

4.1.1. β-Cell Physiology

To safeguard proper β-cell function, cellular integrity must be ensured and the mechanisms and pathways implicated in the physiology of β-cell must be tightly regulated [ 35].

β-cells are responsible for insulin production, which is synthesized as pre-proinsulin. In the maturation process, pre-proinsulin undergoes a conformational modification carried out with the help of several proteins in the endoplasmic reticulum (ER) to yield proinsulin [ 37]. Afterwards, proinsulin is translocated from the ER to the Golgi apparatus (GA), entering into immature secretory vesicles and being cleaved into C-peptide and insulin [ 38, 39].

Once matured, insulin is stored in granules until insulin release is triggered. Insulin release is primarily triggered by a response to high glucose concentrations. It is worth noting that some other factors can also induce insulin release such as amino acids, fatty acids and hormones [ 40]. When circulating glucose levels increase, β-cells take in glucose mainly through the glucose transporter 2 (GLUT2), a solute carrier protein that also works as a glucose sensor for β-cells. Once glucose enters, glucose catabolism is activated, increasing the intracellular ATP/ADP ratio, which induces the closing of ATP-dependant potassium channels in the plasma membrane. This leads to membrane depolarization and opening of the voltage dependant Ca ²⁺ channels, enabling Ca ²⁺ to enter the cell. The rise in the intracellular Ca ²⁺ concentration triggers the priming and fusion of the secretory insulin-containing granules to the plasma membrane, resulting in insulin exocytosis [ 38, 40, 41, 42] ( Figure 1 A).

Figure 1.

Signaling pathways involved in insulin secretion in β-cells in physiological conditions ( A) and mechanisms leading to dysfunction ( B). ( A) Insulin release is primarily triggered by a response to high glucose concentrations and glucose in mainly internalized mainly through GLUT2 transporter. Glucose catabolism increases ATP/ADP ratio, ATP-dependant potassium channels are closed leading to membrane depolarization and opening of the voltage dependant Ca ²⁺ channels. The latter enables Ca ²⁺ influx triggering insulin exocytosis. Additional Ca ²⁺ channels as P2X, P2Y, SERCA and RYR contribute to Ca ²⁺ mobilization and insulin secretion. ( B) hyperglycemia and hyperlipidemia promote oxidative stress leading to ROS generation that inhibits Ca ²⁺ mobilization and activates proapoptotic signals. Additionally, an excess of FFAs and hyperglycemia lead to the activation of the apoptotic unfolded protein response (UPR) pathways and generation of ER stress. Sustained high glucose levels increase proinsulin and IAAP biosynthesis, which generate ROS. GLUT2: glucose transporter 2, P2X: purinergic receptor X; P2Y: purinergic receptor Y; IP2: inositol 1,3-bisphosphate; IP3: inositol 1,4,5-trisphosphate; RYR: ryanodine receptor channel; SERCA: sarco-endoplasmic reticulum Ca ²⁺-ATPase; FFA: free fatty acid, ROS: reactive oxygen species; UPR: unfolded protein response.

Additionally, Ca ²⁺ signals can be amplified by the RY receptors (RYR) and may play important roles in stimulus- insulin secretion coupling by virtue of their strategic locations within the cell and their ability to mediate Ca ²⁺ induced Ca ²⁺ release (CICR). RYR amplifies Ca ²⁺ signals when the channel is sensitized by messenger molecules generated from the nutrient metabolism or ligand-binding and are involved in the amplification of insulin secretion [ 43] ( Figure 1 A).

Nevertheless, other cell signals can also assist or enhance insulin release from β-cells. Among them, cAMP might be the most important messenger potentiating insulin release. Accumulated evidence suggests that cAMP induces insulin-containing secretory vesicle mobilization by depleting intracellular Ca ²⁺ reservoirs, thereby increasing intracellular Ca ²⁺ concentrations [ 44]. There is also compelling evidence that extracellular ATP is another important regulator of β-cell function. It is well-documented that β-cells release ATP through exocytosis of insulin granules upon glucose stimulation. Purinergic signaling via P2Y and P2X purinergic receptors stimulates Ca ²⁺ mobilization and regulates insulin exocytosis also independently of glucose. P2Y purinoreceptors have been reported to be coupled to G-proteins [ 45, 46] whereas P2X-type receptors are ATP-activated ligand-gated ion channels non-selective for cations [ 47]. In the case of P2Y receptors, it has been proposed that insulin release could be mediated by intracellular Ca ²⁺ mobilization in response to inositol-1,4,5-trisphosphate (IP3) formation that triggers the release of Ca ²⁺ from ER stores, which amplifies the exocytosis-triggering Ca ²⁺ signal [ 48, 49] ( Figure 1 A).

4.1.2. Mechanisms Leading to β-Cell Dysfunction

β-cell dysfunction has been traditionally associated with β-cell death [ 50]. However, recent evidence suggests that the dysfunction of β-cells in T2DM might be due to a more complex network of interactions between the environment and different molecular pathways implicated in cell biology [ 51]. In an excessive nutritional state, similar to that found in obesity, hyperglycemia and hyperlipidemia are often present, favoring IR and chronic inflammation. Under these circumstances, β-cells, due to differences in their genetic susceptibility, are subject to toxic pressures including inflammation, inflammatory stress, ER stress, metabolic/oxidative stress, amyloid stress, with the potential of ultimately leading to a loss of islet integrity [ 50].

An excess of FFAs and hyperglycemia lead to β-cell dysfunction by inducing ER stress through the activation of the apoptotic unfolded protein response (UPR) pathways [ 52]. In fact, lipotoxicity, glucotoxicity and glucolipotoxicity occurring in obesity, induce metabolic and oxidative stress that leads to β-cell damage [ 51]. Stress derived from high levels of saturated FFAs can activate the UPR pathway by several mechanisms including inhibition of the sarco/endoplasmic reticulum Ca ²⁺ ATPase (SERCA) responsible for ER Ca ²⁺ mobilization; activation of IP3 receptors or direct impairment of ER homeostasis. In addition, sustained high glucose levels increase proinsulin biosynthesis and islet amyloid polypeptides (IAAP) in β-cells, leading to the accumulation of misfolded insulin and IAAP and increasing the production of oxidative protein folding-mediated reactive oxygen species (ROS) [ 52]. These effects alter physiological ER Ca ²⁺ mobilization and favor proapoptotic signals, proinsulin mRNA degradation and induce interleukin (IL)-1 β release that recruits macrophages and enhances local islet inflammation [ 51] ( Figure 1 B).

As previously mentioned, insulin secretion has to be finely regulated to precisely meet metabolic demand. For that reason, proper islet integrity must be conserved in order to allow β-cells to respond to metabolic needs. Under pathogenic conditions, the mechanism described above can ultimately lead to disruption of islet integrity/organization, impairing optimal cell-to-cell communication within pancreatic islets, contributing to poor regulation of insulin and glucagon release and ultimately exacerbating the hyperglycemia. Defects in the synthesis of any insulin precursors, or insulin itself, as well as disruption of the secretion mechanism, can lead to insulin secretory dysfunction, the primary driver of β-cell failure, and a foundation of T2DM. For instance, reduced expression in the GLUT2 glucose transporter would affect the downstream signaling pathway [ 53], while failure in the folding of proinsulin is another finding commonly linked to deficient insulin production and diabetes [ 54].

4.1.3. Pathological Conditions Perpetuating T2DM

Figure 2.

Type 2 Diabetes Mellitus (T2DM) risk factors and the pathological changes leading to the perpetuation of insulin dysfunction. Complex combinations of genetic, metabolic and environmental factors that interact with one another constitute both non-modifiable (ethnicity and family history/genetic predisposition) and modifiable risk factors (obesity, low physical activity and an unhealthy diet). These states affect cell function resulting in a complex network of pathological changes that influence mutually and lead to the perpetuation of insulin dysfunction. ROS: reactive oxygen species; ER: endoplasmic reticulum; AGEs: advanced glycation end products; PKC: protein kinase C; LPS: lipopolysaccharide; miRNA: microRNA.

Figure 3.

Mitochondrial dysfunction and contribution to T2DM development. Oxidative stress, defective mitochondrial biogenesis and impaired mitophagy promote mitochondrial dysfunction. Generation of ROS links mitochondrial dysfunction and IR. As a consequence of nutrient overload, electron supply to the mitochondrial ETC increases and the electron excess is transferred to oxygen generating O ₂− and H ₂O ₂. ROS oxidize proteins, damage DNA and membrane lipids. Mitofusin-2 and PGC 1α are downregulated leading to reduced mitochondrial biogenesis. Cellular stress and ROS production contribute to higher mitochondrial fission and impaired mitophagy. PCG 1α: Peroxisome proliferator-activated receptor-gamma coactivator-1.

5. Insulin Resistance

IR refers to a decrease in the metabolic response of insulin-responsive cells to insulin or, at a systemic level, an impaired/lower response to circulating insulin by blood glucose levels [ 153]. There are three broad categories of IR or insulin-deficient conditions: (1) diminished insulin secretion by β-cells; (2) insulin antagonists in the plasma, due either to counter-regulatory hormones or non-hormonal bodies that impair insulin receptors or signaling; and (3) impaired insulin response in target tissues [ 154]. The action of insulin is influenced by the interplay of additional molecules including growth hormone and IGF-1 in the fed state. While fasting, the insulin response is mitigated by glucagon, glucocorticoids and catecholamines in order to prevent insulin-induced hypoglycemia. The ratio of insulin/glucagon plays a major role in this regulation, since it determines the relative degree of phosphorylation of downstream enzymes in the regulatory signaling pathways. While catecholamines promote lipolysis and glycogenolysis, glucocorticoids promote muscle catabolism, gluconeogenesis and lipolysis. Hence, excessive secretion of these hormones may be responsible for inducing IR [ 155, 156]. Regarding the last category, there are three main extra-pancreatic insulin-sensitive organs that play major roles in the aforementioned processes: skeletal muscle, adipose tissue and liver. A defective action of insulin in these tissues often precedes the development of systemic IR, thus progressively leading T2DM.

5.1. Skeletal Muscle

Skeletal muscle IR is considered to be the most important extra-pancreatic factor in the development of T2DM [ 157]. Under physiological conditions, insulin stimulates muscle glycogen synthesis by enhancing glucose uptake from plasma. There are three primary rate-limiting factors implicated in glucose uptake and glycogen synthesis: glycogen synthase, hexokinase and the glucose transporter GLUT4 [ 158]. Upon insulin binding to insulin receptor (INSR) in muscle cells, GLUT4 translocates from intracellular compartments (early endosomes (EE), endosomal recycling compartment (ERC) and trans-Golgi network (TGN)) to the plasma membrane. This process allows glucose uptake and reduces circulating glucose levels [ 159].

5.2. Adipose Tissue

Adipose tissue is a metabolically dynamic tissue capable of synthesizing a wide range of biologically active compounds that regulate metabolic homeostasis at a systemic level [ 163]. Indeed, adipose tissue participates in a broad range of biological processes involving, among others, immunity, coagulation, angiogenesis, fibrinolysis, reproduction, vascular tone control, appetite regulation, body weight homeostasis and glucose and lipid metabolism [ 164].

Insulin acts on adipose tissue in two different ways: (1) stimulating glucose uptake and triglyceride synthesis; and (2) suppressing triglyceride hydrolysis and inducing the uptake of FFA and glycerol from circulation [ 165]. In the fed state, GLUT4 allows uptake of glucose from the bloodstream into adipocytes, activating glycolysis in which glycerol-3-phospate (glycerol-3-P) is produced and incorporated into lipogenic pathways. Glycerol-3-P, along with the fatty acids coming from VLDLs, are esterified, forming triacylglycerol (TGA) that is stored in lipid droplets. During metabolic stress, TGA droplets the adipocyte are depleted, in order to provide FFA to be used as an energy source in other tissues.

An impaired response to insulin stimulation by adipose tissue is known as adipose IR (Adipose-IR). Adipose-IR can lead to impaired suppression of lipolysis, impaired glucose uptake, and enhanced FFA release into plasma even in the presence of high insulin levels [ 166]. Among the signaling elements affected by adipose-IR, we found that defective AKT activation impairs GLUT4 translocation to the membrane and promotes the activation of lipolytic enzymes that aggravate hyperglycemia [ 153]. Adipose-IR, as mentioned before, is associated with glucose intolerance and elevated release of FFA into a plasma that accumulates in other tissues such as muscle or liver. In the case of the liver, FFA accumulation results in impaired insulin signaling that promotes hepatic gluconeogenesis and impairs the glucose-stimulated insulin response, inducing T2DM development.

Figure 4.

Insulin stimulation effects on healthy and hypertrophic adipose tissue. In healthy adipose tissue insulin stimulates glucose uptake and TG synthesis, induces FFA uptake and diminishes macrophage-mediated inflammation. Hypertrophic adipose tissue leads to diminished glucose uptake, TG synthesis and enhances FFA release, hypoxia and macrophage-mediated inflammation. FFA: free fatty acid.

5.3. Liver

In the liver, insulin does not only regulate glucose production/utilization but also affects lipid metabolism more broadly. When circulating glucose levels increase and insulin is secreted by pancreatic β-cells, insulin binding to liver INSR induces autophosphorylation of the receptor. Consequently, insulin receptor substrates (IRSs) are recruited and phosphorylated. In turn, IRSs activate PI3K, which phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2), generating phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 then activates PDK1, which phosphorylates AKT. In addition, AKT is phosphorylated by mTORC2. Once AKT is fully activated, it participates in several downstream pathways that regulate multiple metabolic processes including glycogen synthesis, gluconeogenesis, glycolysis and lipid synthesis [ 169].

In physiological states, the combined action of glucagon and insulin allows the precise regulation of hepatic glucose output. While glucagon induces hepatic glucose production, insulin acts as a potent inhibitor of glucose production when its concentration in the blood is elevated [ 170]. The effect of insulin on hepatic glucose production is due to both direct and indirect mechanisms. However, the relative importance of each of these mechanisms remains unclear [ 171].

Figure 5.

Signaling pathways involved in insulin signaling in hepatocytes. Binding of insulin to INSR induces IRSs recruitment and phosphorylation. Phosphorylated IRSs activate PI3K, generating PIP3 which activates PDK resulting in AKT phosphorylation. AKT is fully activated by further mTORC2 phosphorylation and participates in several downstream pathways that regulate multiple metabolic processes including glycogen synthesis, gluconeogenesis, glycolysis and lipid synthesis. INSR: insulin receptor; PIP2: inositol 1,3-bisphosphate; PIP3: inositol 1,4,5-trisphosphate; IRS1: insulin receptor substrate 1; PI3K: phosphoinositide 3 kinase; mTORC2: mammalian target of rapamycin complex 2; PDK1: Phosphoinositide-dependent kinase-1; AKT: protein kinase B; AS160: Akt substrate of 160 kDa; GLUT4: glucose transporter 4; GSk3β: Glycogen Synthase Kinase 3 Beta; GS: Glycogen synthase; FOXO1: Forkhead box protein O1; G6pc:Glucose 6 phosphate; Pck1: Phosphoenolpyruvate Carboxykinase 1.

Similar to the case in insulin-sensitive tissues, in states of IR, physiologic levels of circulating insulin are insufficient to elicit the appropriate insulin response in hepatic cells [ 176]. In the liver, IR impairs glycogen synthesis, fails to suppress glucose production, enhances lipogenesis, and increases the synthesis of proteins such as the proinflammatory CRP. In fact, the abnormal production of proinflammatory proteins such as adipocytokines and cytokines, combined with conditions such as oxidative stress, can lead to an inflammatory state responsible for altered insulin response by the liver [ 175].

6. T2DM Outcomes/Complications: Cardiovascular Risk

As described in the previous sections, T2DM is a multisystem disease with a strong correlation with CVD development [ 177]. T2DM leads to a two- to four-fold increase in the mortality rate of adults from heart disease and stroke and is associated with both micro- and macro-vascular complications, the latter consisting of accelerated atherosclerosis leading to severe peripheral vascular disease, premature coronary artery disease (CAD) and increased risk of cerebrovascular diseases [ 178, 179, 180]. These factors lead to T2DM being considered a significant risk factor for CVD [ 181], likely through the involvement of several molecular mechanisms and pathological pathways. These include the role of IR in atherosclerosis, vascular function, oxidative stress, hypertension, macrophage accumulation and inflammation [ 182, 183, 184, 185]. The following sections describe in detail the main factors implicated in cardiovascular risk outcomes from T2DM and the interactions between them ( Figure 6).

Figure 6.

Factors implicated in cardiovascular risk outcomes from T2DM and the interactions between them. T2DM derived hyperglycemia, hyperinsulinemia and IR causes endothelial dysfunction, diabetic dyslipidemia and inflammation leading to CVD. The flowchart illustrates the multiple interactions among the implicated factors.

6.1. Diabetic Dyslipidaemia and Atherosclerosis Development

Dyslipidaemia is a common feature of T2DM, and increases the incidence of atherosclerosis and mortality of diabetic patients [ 186]. The hallmark of diabetic dyslipidemia is a characteristic dyslipidaemic profile consisting of elevated TG, TG-rich lipoproteins (TRLs), small dense LDLs (sdLDL), and reduced HDL levels [ 187, 188, 189]. Although the pathophysiology of dyslipidemia in T2DM is not completely characterized, several factors such as hyperglycemia, insulin resistance, hyperinsulinemia, abnormalities in adipokines and adipocytokines have been implicated [ 190]. Epidemiological studies indicate that TG-rich lipoproteins and their remnants contribute to atherogenesis and CVD risk [ 191, 192, 193, 194, 195] and experimental studies indicated a connection between cholesterol deposition and inflammation as a result of TRLs entry into the artery wall [ 196, 197]. TRLs consist of a great variety of nascent and metabolically modified lipoprotein particles including intestine-derived apoB48 (chylomicrons and chylomicron remnants) and liver-derived apoB100 (VLDL and its remnants). TRLs are highly heterogeneous in size, density, and apolipoprotein composition [ 198].

Figure 7.

Diabetic dyslipidemia: mechanisms leading to T2DM dyslipidemia and lipoprotein clearance in physiological an IR conditions. ( A) IR leads to an impaired adipose tissue fat storage, resulting in constitutive FFA release from the intracellular TG stores of adipocytes. The released FFAs are taken up by hepatocytes, where they can be directed to the mitochondria and undergo β-oxidation; be re-assimilated into TG to assemble new VLDL particles; shifted to gluconeogenesis resulting in a worsening of hyperglycemia; or stored as TG leading to hepatic steatosis. ( B) Under physiological conditions, VLDL particles incorporate apo-CII and apoE from HDL allowing VLDL to be progressively lipolyzed leading to the generation of smaller VLDL particles (upper panel). T2DM and IR impair metabolism and clearance of chylomicrons and VLDLs. Activation of CETP promotes an exchange of TG out of RLPs and incorporates CE from HDL and LDL particles leading to reduced levels of circulating HDL-C and an increase in the more atherogenic sdLDL particles (lower panel). TG: triglyceride; FFA: free fatty acid, LPL: lipoprotein Lipase; CR: chylomicron remnants; HL: hepatic lipase; CETP: Cholesteryl Ester Transfer Protein; ApoE: apolopoprotein E; ApoC-II: apolipoprotein CII; apoC-III: apolipoprotein CIII; VLDL: very low-density lipoprotein; sdLDL: small dense lipoprotein.

Mechanisms Leading to T2DM Dyslipidemia and Atherosclerosis

Increased hepatic TG content present in T2DM patients leads to elevated hepatic production of VLDL and normal or slightly elevated LDL-C levels, most commonly sdLDLs enriched in TG [ 189, 201]. One of the primary abnormalities in IR is impaired adipose tissue fat storage, resulting from insulin's inability to inhibit hormone-sensitive lipase (HSL). This results in constitutive FFA release from the intracellular TG stores of adipocytes. The released FFAs are taken up by hepatocytes, where they can be directed to the mitochondria and undergo β-oxidation; be re-assimilated into TG to assemble new VLDL particles; shifted to gluconeogenesis resulting in a worsening of hyperglycemia; or stored as TG leading to hepatic steatosis.

The dominant feature of diabetic dyslipidemia is the increased production rate of VLDL-apoB100 by the liver, mainly VLDL1, which is related to insulin sensitivity indices [ 202]. This highlights the role of insulin on VLDL assembly and secretion by hepatocytes [ 203]. Insulin plays a role in almost all the steps of VLDL assembly and secretion. It is known that insulin inhibits the transcription of Mttp, the gene coding for the microsomal transfer protein (MTP), the protein responsible for assembling TG with apoB100 [ 204]. MTP facilitates concerted lipid transfer and apoB100 folding as it enters the ER lumen and lipidation determines the amount of the active pool of apoB100 [ 205]. Lipidation of apoB100 is a co-translational event and a rate-limiting step of apoB100 mRNA stability thus low availability of TG leads to apoB100 degradation. The addition of TG to apoB100 generates nascent VLDL particles that are transported to the GA by Sar2/COPII-containing vesicles. Within the GA, VLDL maturation occurs in a process promoted by the phospholipase D1 (PLD1) [ 203]. Therefore, in insulin-resistant condition, MTP expression and activity is increased thus contributing to raising apoB100 lipidation and to its rescue from degradation. Indeed, IR leads to a loss of the acute insulin-mediated inhibition of apoB100 secretion [ 205].

Availability of TGs within hepatocytes is important for VLDL synthesis [ 206] and the liver uses both de novo synthesized FAs and extra-hepatic FFAs as a substrate for TG synthesis [ 207]. De novo lipogenesis occurs primarily in the fed state in which the expression of lipogenic genes is regulated by the sterol regulatory element-binding protein (SREBP). The SREBP-1c isoform up-regulates almost all the enzymes involved in FA synthesis as well as enzymes that supply acetyl-CoA units and reducing equivalents to the pathway [ 208]. Insulin regulates SREBP-1c, which explains the lipogenic effect of chronic hyperinsulinemia [ 208]. FFAs derived from adipose tissue is also a major source of liver TGs and VLDL production. As mentioned above, T2DM is characterized by increased production of FFAs by adipose tissue [ 207]. Therefore, in IR, an increase in TG lipolysis in adipose tissue and FFA influx serves as another source of lipid to the liver [ 207].

The lower HDL concentration and modified composition of HDL have an important impact in diminishing the particle capacity of inducing cholesterol efflux from the cells, which is the first step in reverse cholesterol transport (RCT) [ 218]. The impaired RCT activity has been associated with increased risk of CAD [ 219] and with flow-mediated vasodilation in T2DM patients [ 220].

Atherosclerosis is accelerated by the increased permeability of sdLDL into the subendothelial space ( Figure 7) [ 221, 222]. SdLDL particles are characterized by a lower affinity for LDLR due to conformational rearrangements occurring in apoB100 as the particle decreases in volume and size [ 223]. Furthermore, sdLDL particles are more susceptible to oxidation and thus avidly scavenged by activated macrophages in the subendothelial space, giving rise to foam cells [ 224]. In addition, sdLDL particles show increased proteoglycan binding and facilitated entry into the arterial wall, increased arterial retention, and a longer half-life [ 225]. sdLDL particles are also more likely to be glycated, more resistant to breakdown, and more susceptible to oxidation by free radicals [ 226].

There is an insulin response element in the gene for apoA-I, the primary apolipoprotein constituent of HDL particles [ 227, 228]. As the liver becomes more insulin resistant, less apoA-I is produced and there is less HDL biogenesis. Adipocytes express the ATP-binding membrane cassette transport protein A1 (ABCA1). IR downregulates the expression of ABCA1 on the surface of adipocytes and reduces HDL formation by these cells [ 229, 230, 231]. Chylomicrons are enriched with apoA-I. IR reduces the release of this apoA-I into the serum by inhibiting LPL. In addition, within the milieu of IR of diabetes, HDL particle concentrations are not only quantitatively reduced, but also tend to be dysfunctional and unable to perform their primary functions, including reversal of cholesterol transport and inhibition of oxidative and inflammatory phenomena [ 232].

Diabetic dyslipidemia acts in concert with other metabolic and vascular abnormalities to further compound vascular risk. Chronic hyperglycemia induces endothelial dysfunction through a variety of mechanisms such as by reducing vasodilation, increasing vasoconstriction, increasing exposure to free radicals and impairing endothelial cell function, with a net effect of facilitating pro-atherogenic conditions [ 238]. Increased activity of the renin-angiotensin axis has also been found to further increase oxidative stress [ 239].

6.2. Impaired Endothelial Function and Atherosclerosis Development

Endothelium plays an important role in the regulation of vascular tone and structure through a balanced release of endothelial-derived relaxing and contracting factors. This balance is altered in T2DM leading to alteration of the physicochemical properties of the vascular wall via endothelial dysfunction, oxidative stress, platelet hyperreactivity, and inflammation [ 240, 241]. These abnormalities lead to enhanced vasoconstriction, development of atherosclerosis, and favored thrombus formation [ 179, 180].

6.2.1. Mechanisms Leading to Endothelial Dysfunction in T2DM

Vascular endothelial cells are particularly susceptible to developing intracellular hyperglycemia because glucose diffuses passively through their plasma membrane. In T2DM, the excess of glucose can be metabolized in the sorbitol pathway to sorbitol and fructose by aldose reductase, which activates the aldose reductase secondary metabolic pathway, with concomitant oxidation of NADPH to NADP⁺ and reduction of NAD⁺ to NADH. NADPH depletion and an increased NADH/NAD⁺ cytosolic ratio leads to a change in redox potential that accelerates glycolysis and increases de novo synthesis of DAG [ 242]. As a result, protein kinase C (PKC) is activated, nitric oxide (NO) is reduced. These effects cause vascular permeability and increase contractility. Simultaneously, the increased NADH/NAD⁺ ratio also results in higher production of O ₂−, LDL oxidation, cytotoxic effects on endothelial cells and reduced NO availability, leading to endothelial dysfunction [ 241, 242].

The overproduction of aldoses by the sorbitol pathway promotes protein glycosylation that yields the formation of the stable Amadori products (such as glycosylated hemoglobin) and AGEs. AGEs are associated with several molecules that augment oxidant activity and consequently the production of ROS, which increases oxidative stress and prevents the release of NO, resulting in vascular lesions. AGEs may also reduce endothelium-derived NO bioavailability and activity, further compromising vascular activity [ 243]. In addition, AGEs can trigger an inflammatory and pro-coagulant state and can cause endothelial activation through the induction of receptor-mediated gene transcription. AGE binding to the RAGE-receptor, nuclear transcription factor NF-κB [ 242, 243] is activated leading to transcription of endothelin-1, VCAM-1, ICAM-1, E-selectin, thrombomodulin, TF, vascular endothelial growth factor (VEGF), IL-1, IL-6, and TNF-α [ 242, 244]. Increased expression of inflammatory and adhesion molecules amplifies the inflammatory response and aggravates diabetic vascular complications. These pro-inflammatory cytokines stimulate the expression and release of pro-coagulant molecules and inhibit the expression of anti-coagulant molecules by endothelial cells [ 245]. This leads to a pro-coagulant state in the surface of the endothelium and increases growth factor production resulting in a thickening of the basement membrane, thus favoring protein and lipid deposition and impairing vasodilation [ 242, 246].

6.2.2. Endothelial Dysfunction in T2DM and Atherosclerosis Development

6.3. Diabetes-Associated Chronic Inflammation and Atherosclerosis Progression

A critical component of T2DM is a chronic low-grade inflammatory state, referred to as "metaflammation" [ 250]. This chronic condition involves the same cellular and molecular players of acute inflammatory responses and has been suggested as an underlying cause of the progression of atherosclerosis in T2DM. Hyperglycaemia can increase circulating cytokines that can lead to chronic inflammation in T2DM [ 250]. Among them, patients with T2DM have higher levels of IL-1b, IL-6, IL-8, MCP-1, and other major cytokines in both monocytes and macrophages [ 130]. The underlying mechanisms involved in this process are ROS-mediated activation of p38 and other proinflammatory kinases, upregulation of NF-kB induction, oxidative stress, and activation of the AGE-RAGE pathway [ 129, 130]. In addition, exposure to high glucose levels impairs the phagocytic activity of macrophages, which partially explains the increased incidence of chronic infection among T2DM patients [ 251]. Indeed, T2DM is associated with increased activity of the inflammasome, upregulation of the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), increased levels of IL-1β and IL-18 [ 252, 253, 254]. These events trigger neutrophil extracellular trap activation, or NETosis, a characteristic cell death of macrophages causing chronic inflammation [ 255]. High levels of these markers have been found in T2DM patients [ 256], which are enhanced in hyperglycaemic conditions [ 257].

6.4. Adipokine Balance and CVD Risk

Adipose tissue dysfunction as a result of T2DM can result in an imbalance between pro-inflammatory and anti-inflammatory adipokines, and is one of the mechanisms of T2DM complications. Several studies indicate that adipokines are related to IR, and can result in endothelial dysfunction, and pro-inflammatory and pro-atherogenic states [ 258, 259].

Adiponectin is a well-described insulin-sensitizing hormone and its expression and circulating levels are inversely proportional to the extent of adiposity. Adiponectin has insulin-sensitizing properties [ 260, 261]. Adiponectin acts through ADIPOR1 and ADIPOR2 receptors [ 262] and the peroxisome proliferator-activated receptor α (PPARα) pathway, leading to decreased hepatic gluconeogenesis, increased liver and skeletal muscle fatty acid oxidation, increased glucose uptake in skeletal muscle and white adipose tissue, and decreased white adipose tissue inflammation [ 263]. In addition, adiponectin ameliorates β-cell death by neutralizing inflammatory and lipotoxic ceramides and DAGs [ 264] and shows strong anti-inflammatory effects on other cell types such as macrophages and fibrogenic cells [ 263, 265, 266]. Low concentrations of adiponectin have been found in T2DM patients and are correlated with increased risk of developing premature arteriosclerosis, and are thus considered an additional CVD risk factor [ 267]. Notably, adiponectin deficiency is associated with coronary artery disease, hypertension, endothelial dysfunction and greater carotid intima-media thickness [ 268, 269, 270, 271]. Low concentrations of adiponectin lead to an increased expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, promotes differentiation of macrophages into foam cells and enhances the proliferation and migration of smooth muscle cells [ 272].

Omentin is an adipokine secreted from white adipose tissue and is involved in glucose homeostasis [ 273, 274]. Omentin circulates in the blood [ 275, 276], and is associated with reduced levels in T2DM patients [ 277, 278]. In vitro studies have shown that omentin enhances insulin-stimulated glucose uptake in human adipocytes by AKT signaling pathway activation [ 273]. In humans, an inverse correlation between omentin levels and IR is seen, both at the protein and mRNA levels [ 277, 279, 280]. Additional studies show that omentin has anti-inflammatory properties, diminishes cytokine expression [ 281, 282], and is negatively associated with systemic inflammatory markers such as TNF and IL-6 [ 283].

Vaspin (visceral adipose tissue-derived serine protease inhibitor) is an adipokine that inhibits proteases responsible for IR and protects against atherosclerosis and plaque development [ 284, 285]. It has been shown that T2DM patients have higher serum vaspin levels than healthy controls. Higher vaspin levels are associated with a 1.7-fold increased risk of CVD [ 70]. High vaspin is also associated with increased severity of coronary artery disease [ 286].

7. Conclusions

The importance of research in the fields of glucose homeostasis, insulin and diabetes has not faded. In fact, due to rapid globalization and the normalization of a sedentary lifestyle, along with increased obesity, diabetes and their consequent co-morbidities, research in this topic must continue to grow. Understanding the mechanisms implicated in every step in the development and complications of T2DM is crucial in order to prevent, control, treat or revert the pathophysiology of T2DM its complications. Although quality outcomes for patients are optimized by early detection of T2DM through screening and intensive patient-centered management, research efforts are needed to define causative factors accounting for correlations among different demographic subsets and the corresponding variable risks for T2DM as well as the drivers of increased risk in individuals of low socioeconomic status. Being the pathophysiology and underlying mechanisms of T2DM increasingly understood, precision medicine should be implemented and treatments individualized and targeted appropriately with the help of molecular genetic tools by identifying specific variants contributing to disease development as well as by searching biomarkers to assess progression and response to therapeutic interventions. Additional research is needed to determine a direct causal role of the intestinal microbiota in pathogenesis of T2DM and response to therapies needs to be determined.

Taking everything in this review into consideration, it is clear that there is still a long way until we fully understand each of the many stakeholders in glucose homeostasis.

Author Contributions

U.G.-C., A.B.-V., S.J., A.L.-S., H.S., K.B.U., H.O. and C.M. have contributed to the writing of the manuscript. U.G.-G. and C.M. conceptualized the review. A.B.-V. and C.M. drawn the images. H.S. edited language. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Basque Government (Grupos Consolidados IT-1264-19). U.G-G. was supported by Fundación Biofísica Bizkaia. A.B.-V. was supported by Programa de especializaci.n de Personal Investigador Doctor en la UPV/EHU (2019) 2019-2020. S.J. and A.L-S. were supported by a grant PIF (2017-2018) and (2019-2020), Gobierno Vasco, respectively. A.L.-S. was partially supported by Fundación Biofísica Bizkaia.

Conflicts of Interest

The authors declare no conflict of interest.

References

89. Simmons D. Epigenetic Influences and Disease. Nat. Educ. 2008;1:6. [Google Scholar]

Articles from International Journal of Molecular Sciences are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

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Pathophysiology of Type 2 Diabetes Mellitus

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Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately ...

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Read more on the warning signs, symptoms of diabetes, prediabetes, type 1 & 2 symptoms, type 2 risk test, different ways diabetes is diagnosed.

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Long term complications of type 2 diabetes

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Diagnosis

Type 2 diabetes is usually diagnosed using the glycated hemoglobin (A1C) test. This blood test indicates your average blood sugar level for the past two to three months. Results are interpreted as follows:

Below 5.7% is normal.

5.7% to 6.4% is diagnosed as prediabetes.

6.5% or higher on two separate tests indicates diabetes.

If the A1C test isn't available, or if you have certain conditions that interfere with an A1C test, your health care provider may use the following tests to diagnose diabetes:

Random blood sugar test. Blood sugar values are expressed in milligrams of sugar per deciliter ( mg/dL) or millimoles of sugar per liter ( mmol/L) of blood. Regardless of when you last ate, a level of 200 mg/dL (11.1 mmol/L) or higher suggests diabetes, especially if you also have symptoms of diabetes, such as frequent urination and extreme thirst.

Fasting blood sugar test. A blood sample is taken after you haven't eaten overnight. Results are interpreted as follows:

Less than 100 mg/dL (5.6 mmol/L) is considered healthy.

100 to 125 mg/dL (5.6 to 6.9 mmol/L) is diagnosed as prediabetes.

126 mg/dL (7 mmol/L) or higher on two separate tests is diagnosed as diabetes.

Oral glucose tolerance test. This test is less commonly used than the others, except during pregnancy. You'll need to not eat for a certain amount of time and then drink a sugary liquid at your health care provider's office. Blood sugar levels then are tested periodically for two hours. Results are interpreted as follows:

Less than 140 mg/dL (7.8 mmol/L) after two hours is considered healthy.

140 to 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) is diagnosed as prediabetes.

200 mg/dL (11.1 mmol/L) or higher after two hours suggests diabetes.

Screening. The American Diabetes Association recommends routine screening with diagnostic tests for type 2 diabetes in all adults age 35 or older and in the following groups:

After a diagnosis

If you're diagnosed with diabetes, your health care provider may do other tests to distinguish between type 1 and type 2 diabetes because the two conditions often require different treatments.

Your health care provider will test A1C levels at least two times a year and when there are any changes in treatment. Target A1C goals vary depending on age and other factors. For most people, the American Diabetes Association recommends an A1C level below 7%.

You also receive tests to screen for complications of diabetes and other medical conditions.

Treatment

Management of type 2 diabetes includes:

Healthy eating.

Regular exercise.

Weight loss.

Possibly, diabetes medication or insulin therapy.

Blood sugar monitoring.

These steps make it more likely that blood sugar will stay in a healthy range. And they may help to delay or prevent complications.

Healthy eating

There's no specific diabetes diet. However, it's important to center your diet around:

A regular schedule for meals and healthy snacks.

Smaller portion sizes.

More high-fiber foods, such as fruits, nonstarchy vegetables and whole grains.

Fewer refined grains, starchy vegetables and sweets.

Modest servings of low-fat dairy, low-fat meats and fish.

Healthy cooking oils, such as olive oil or canola oil.

Fewer calories.

Your health care provider may recommend seeing a registered dietitian, who can help you:

Physical activity

Exercise is important for losing weight or maintaining a healthy weight. It also helps with managing blood sugar. Talk to your health care provider before starting or changing your exercise program to ensure that activities are safe for you.

Aerobic exercise. Choose an aerobic exercise that you enjoy, such as walking, swimming, biking or running. Adults should aim for 30 minutes or more of moderate aerobic exercise on most days of the week, or at least 150 minutes a week.

Resistance exercise. Resistance exercise increases your strength, balance and ability to perform activities of daily living more easily. Resistance training includes weightlifting, yoga and calisthenics. Adults living with type 2 diabetes should aim for 2 to 3 sessions of resistance exercise each week.

Limit inactivity. Breaking up long periods of inactivity, such as sitting at the computer, can help control blood sugar levels. Take a few minutes to stand, walk around or do some light activity every 30 minutes.

Weight loss

Weight loss results in better control of blood sugar levels, cholesterol, triglycerides and blood pressure. If you're overweight, you may begin to see improvements in these factors after losing as little as 5% of your body weight. However, the more weight you lose, the greater the benefit to your health. In some cases, losing up to 15% of body weight may be recommended.

Your health care provider or dietitian can help you set appropriate weight-loss goals and encourage lifestyle changes to help you achieve them.

Monitoring your blood sugar

Your health care provider will advise you on how often to check your blood sugar level to make sure you remain within your target range. You may, for example, need to check it once a day and before or after exercise. If you take insulin, you may need to check your blood sugar multiple times a day.

Monitoring is usually done with a small, at-home device called a blood glucose meter, which measures the amount of sugar in a drop of blood. Keep a record of your measurements to share with your health care team.

Continuous glucose monitoring is an electronic system that records glucose levels every few minutes from a sensor placed under the skin. Information can be transmitted to a mobile device such as a phone, and the system can send alerts when levels are too high or too low.

Diabetes medications

If you can't maintain your target blood sugar level with diet and exercise, your health care provider may prescribe diabetes medications that help lower glucose levels, or your provider may suggest insulin therapy. Medicines for type 2 diabetes include the following.

Metformin (Fortamet, Glumetza, others) is generally the first medicine prescribed for type 2 diabetes. It works mainly by lowering glucose production in the liver and improving the body's sensitivity to insulin so it uses insulin more effectively.

Some people experience B-12 deficiency and may need to take supplements. Other possible side effects, which may improve over time, include:

Sulfonylureas help the body secrete more insulin. Examples include glyburide (DiaBeta, Glynase), glipizide (Glucotrol XL) and glimepiride (Amaryl). Possible side effects include:

Glinides stimulate the pancreas to secrete more insulin. They're faster acting than sulfonylureas. But their effect in the body is shorter. Examples include repaglinide and nateglinide. Possible side effects include:

Thiazolidinediones make the body's tissues more sensitive to insulin. An example of this medicine is pioglitazone (Actos). Possible side effects include:

DPP-4 inhibitors help reduce blood sugar levels but tend to have a very modest effect. Examples include sitagliptin (Januvia), saxagliptin (Onglyza) and linagliptin (Tradjenta). Possible side effects include:

GLP-1 receptor agonists are injectable medications that slow digestion and help lower blood sugar levels. Their use is often associated with weight loss, and some may reduce the risk of heart attack and stroke. Examples include exenatide (Byetta, Bydureon Bcise), liraglutide (Saxenda, Victoza) and semaglutide (Rybelsus, Ozempic, Wegovy). Possible side effects include:

SGLT2 inhibitors affect the blood-filtering functions in the kidneys by blocking the return of glucose to the bloodstream. As a result, glucose is removed in the urine. These medicines may reduce the risk of heart attack and stroke in people with a high risk of those conditions. Examples include canagliflozin (Invokana), dapagliflozin (Farxiga) and empagliflozin (Jardiance). Possible side effects include:

Vaginal yeast infections.

Urinary tract infections.

Low blood pressure.

High cholesterol.

Risk of gangrene.

Risk of bone fractures (canagliflozin).

Risk of amputation (canagliflozin).

Other medicines your health care provider might prescribe in addition to diabetes medications include blood pressure and cholesterol-lowering medicines, as well as low-dose aspirin, to help prevent heart and blood vessel disease.

Insulin therapy

Some people who have type 2 diabetes need insulin therapy. In the past, insulin therapy was used as a last resort, but today it may be prescribed sooner if blood sugar targets aren't met with lifestyle changes and other medicines.

Different types of insulin vary on how quickly they begin to work and how long they have an effect. Long-acting insulin, for example, is designed to work overnight or throughout the day to keep blood sugar levels stable. Short-acting insulin generally is used at mealtime.

Your health care provider will determine what type of insulin is right for you and when you should take it. Your insulin type, dosage and schedule may change depending on how stable your blood sugar levels are. Most types of insulin are taken by injection.

Side effects of insulin include the risk of low blood sugar - a condition called hypoglycemia - diabetic ketoacidosis and high triglycerides.

Weight-loss surgery

Weight-loss surgery changes the shape and function of the digestive system. This surgery may help you lose weight and manage type 2 diabetes and other conditions related to obesity. There are several surgical procedures. All of them help people lose weight by limiting how much food they can eat. Some procedures also limit the amount of nutrients the body can absorb.

Weight-loss surgery is only one part of an overall treatment plan. Treatment also includes diet and nutritional supplement guidelines, exercise and mental health care.

Generally, weight-loss surgery may be an option for adults living with type 2 diabetes who have a body mass index (BMI) of 35 or higher. BMI is a formula that uses weight and height to estimate body fat. Depending on the severity of diabetes or the presence of other medical conditions, surgery may be an option for someone with a BMI lower than 35.

Weight-loss surgery requires a lifelong commitment to lifestyle changes. Long-term side effects may include nutritional deficiencies and osteoporosis.

Pregnancy

People living with type 2 diabetes often need to change their treatment plan during pregnancy and follow a diet that controls carbohydrates. Many people need insulin therapy during pregnancy. They also may need to stop other treatments, such as blood pressure medicines.

There is an increased risk during pregnancy of developing a condition that affects the eyes called diabetic retinopathy. In some cases, this condition may get worse during pregnancy. If you are pregnant, visit an ophthalmologist during each trimester of your pregnancy and one year after you give birth. Or as often as your health care provider suggests.

Signs of trouble

Regularly monitoring your blood sugar levels is important to avoid severe complications. Also, be aware of symptoms that may suggest irregular blood sugar levels and the need for immediate care:

High blood sugar. This condition also is called hyperglycemia. Eating certain foods or too much food, being sick, or not taking medications at the right time can cause high blood sugar. Symptoms include:

Hyperglycemic hyperosmolar nonketotic syndrome (HHNS). This life-threatening condition includes a blood sugar reading higher than 600 mg/dL (33.3 mmol/L). HHNS may be more likely if you have an infection, are not taking medicines as prescribed, or take certain steroids or drugs that cause frequent urination. Symptoms include:

Diabetic ketoacidosis. Diabetic ketoacidosis occurs when a lack of insulin results in the body breaking down fat for fuel rather than sugar. This results in a buildup of acids called ketones in the bloodstream. Triggers of diabetic ketoacidosis include certain illnesses, pregnancy, trauma and medicines - including the diabetes medicines called SGLT2 inhibitors.

The toxicity of the acids made by diabetic ketoacidosis can be life-threatening. In addition to the symptoms of hyperglycemia, such as frequent urination and increased thirst, ketoacidosis may cause:

Nausea.

Vomiting.

Abdominal pain.

Shortness of breath.

Fruity-smelling breath.

Low blood sugar. If your blood sugar level drops below your target range, it's known as low blood sugar. This condition also is called hypoglycemia. Your blood sugar level can drop for many reasons, including skipping a meal, unintentionally taking more medication than usual or being more physically active than usual. Symptoms include:

If you have symptoms of low blood sugar, drink or eat something that will quickly raise your blood sugar level. Examples include fruit juice, glucose tablets, hard candy or another source of sugar. Retest your blood in 15 minutes. If levels are not at your target, eat or drink another source of sugar. Eat a meal after your blood sugar level returns to normal.

If you lose consciousness, you need to be given an emergency injection of glucagon, a hormone that stimulates the release of sugar into the blood.

More Information

Show more related information

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Careful management of type 2 diabetes can reduce the risk of serious - even life-threatening - complications. Consider these tips:

Commit to managing your diabetes. Learn all you can about type 2 diabetes. Make healthy eating and physical activity part of your daily routine.

Work with your team. Establish a relationship with a certified diabetes education specialist, and ask your diabetes treatment team for help when you need it.

Identify yourself. Wear a necklace or bracelet that says you are living with diabetes, especially if you take insulin or other blood sugar-lowering medicine.

Schedule a yearly physical exam and regular eye exams. Your diabetes checkups aren't meant to replace regular physicals or routine eye exams.

Keep your vaccinations up to date. High blood sugar can weaken your immune system. Get a flu shot every year. Your health care provider also may recommend the pneumonia vaccine. The Centers for Disease Control and Prevention (CDC) also recommends the hepatitis B vaccination if you haven't previously received this vaccine and you're 19 to 59 years old. Talk to your health care provider about other vaccinations you may need.

Take care of your teeth. Diabetes may leave you prone to more-serious gum infections. Brush and floss your teeth regularly and schedule recommended dental exams. Contact your dentist right away if your gums bleed or look red or swollen.

Pay attention to your feet. Wash your feet daily in lukewarm water, dry them gently, especially between the toes, and moisturize them with lotion. Check your feet every day for blisters, cuts, sores, redness and swelling. Contact your health care provider if you have a sore or other foot problem that isn't healing.

Keep your blood pressure and cholesterol under control. Eating healthy foods and exercising regularly can go a long way toward controlling high blood pressure and cholesterol. Take medication as prescribed.

If you smoke or use other types of tobacco, ask your health care provider to help you quit. Smoking increases your risk of diabetes complications. Talk to your health care provider about ways to stop using tobacco.

Use alcohol sparingly. Depending on the type of drink, alcohol may lower or raise blood sugar levels. If you choose to drink alcohol, only do so with a meal. The recommendation is no more than one drink daily for women and no more than two drinks daily for men. Check your blood sugar frequently after drinking alcohol.

Make healthy sleep a priority. Many people with type 2 diabetes have sleep problems. And not getting enough sleep may make it harder to keep blood sugar levels in a healthy range. If you have trouble sleeping, talk to your health care provider about treatment options.

Alternative medicine

Many alternative medicine treatments claim to help people living with diabetes. According to the National Center for Complementary and Integrative Health, studies haven't provided enough evidence to recommend any alternative therapies for blood sugar management. Research has shown the following results about popular supplements for type 2 diabetes:

Chromium supplements have been shown to have few or no benefits. Large doses can result in kidney damage, muscle problems and skin reactions.

Magnesium supplements have shown benefits for blood sugar control in some but not all studies. Side effects include diarrhea and cramping. Very large doses - more than 5,000 mg a day - can be fatal.

Cinnamon, in some studies, has lowered fasting glucose levels but not A1C levels. Therefore, there's no evidence of overall improved glucose management.

Talk to your health care provider before starting a dietary supplement or natural remedy. Do not replace your prescribed diabetes medicines with alternative medicines.

Coping and support

Type 2 diabetes is a serious disease, and following your diabetes treatment plan takes commitment. To effectively manage diabetes, you may need a good support network.

Anxiety and depression are common in people living with diabetes. Talking to a counselor or therapist may help you cope with the lifestyle changes and stress that come with a type 2 diabetes diagnosis.

Support groups can be good sources of diabetes education, emotional support and helpful information, such as how to find local resources or where to find carbohydrate counts for a favorite restaurant. If you're interested, your health care provider may be able to recommend a group in your area.

You can visit the American Diabetes Association website to check out local activities and support groups for people living with type 2 diabetes. The American Diabetes Association also offers online information and online forums where you can chat with others who are living with diabetes. You also can call the organization at 800-DIABETES (800-342-2383).

Preparing for your appointment

At your annual wellness visit, your health care provider can screen for diabetes and monitor and treat conditions that increase your risk of diabetes, such as high blood pressure, high cholesterol or a high BMI.

If you are seeing your health care provider because of symptoms that may be related to diabetes, you can prepare for your appointment by being ready to answer the following questions:

When did your symptoms begin?

Does anything improve the symptoms or worsen the symptoms?

What medicines do you take regularly, including dietary supplements and herbal remedies?

What are your typical daily meals? Do you eat between meals or before bedtime?

How much alcohol do you drink?

How much daily exercise do you get?

Is there a history of diabetes in your family?

If you are diagnosed with diabetes, your health care provider may begin a treatment plan. Or you may be referred to a doctor who specializes in hormonal disorders, called an endocrinologist. Your care team also may include the following specialists:

Talk to your health care provider about referrals to other specialists who may be providing care.

Questions for ongoing appointments

Before any appointment with a member of your treatment team, make sure you know whether there are any restrictions, such as not eating or drinking before taking a test. Questions that you should regularly talk about with your health care provider or other members of the team include:

How often do I need to monitor my blood sugar, and what is my target range?

What changes in my diet would help me better manage my blood sugar?

What is the right dosage for prescribed medications?

When do I take the medications? Do I take them with food?

How does management of diabetes affect treatment for other conditions? How can I better coordinate treatments or care?

When do I need to make a follow-up appointment?

Under what conditions should I call you or seek emergency care?

Are there brochures or online sources you recommend?

Are there resources available if I'm having trouble paying for diabetes supplies?

What to expect from your doctor

Your health care provider is likely to ask you questions at your appointments. Those questions may include:

Do you understand your treatment plan and feel confident you can follow it?

How are you coping with diabetes?

Have you had any low blood sugar?

Do you know what to do if your blood sugar is too low or too high?

What's a typical day's diet like?

Are you exercising? If so, what type of exercise? How often?

Do you sit for long periods of time?

What challenges are you experiencing in managing your diabetes?

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High blood sugar levels are the main problem in diabetes. Learn about lifestyle changes to lower the risk and treatments to manage type 2 diabetes.

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Certified diabetes care and education specialist

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Certified diabetes care and education specialist

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they help patients understand how to use insulin, adjust doses, monitor blood sugar

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Association of Diabetes Care & Education Specialists

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4 Key Times to See a Diabetes Care and Education Specialist

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Exercising helps with weight loss, lowers blood sugar, improves blood flow and blood pressure, and helps with stress.

This treatment can be done at little to no cost with little research. Walking, running, swimming, you can exercise anywhere. Gyms memberships can cost from $10-$100 a month.

Those unable to exercise on their own or need assistance may need assistance from a physical therapist (PT) $50-$350 per session without insurance $20-$75 with.

Insurance will cover cost of physical therapy only if deemed medically necessary since exercising can be done without the help of a physical therapist, usually.

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Cognitive- behavioral therapy (CBT), is a form of psychotherapy that aims to reduce symptoms of various mental health conditions.

CBT can be used to help treat depression, anxiety and diabetes distress.

Medical professionals- Clinical Psychologist, Psychiatrist, licensed mental health counselor.

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Support groups are a great way to treat symptoms of type 2 diabetes.

Symptoms that can be treated through these groups include, isolation and stress. Also promotes shared learning.

Medical professionals that can facilitate these groups are clinical social workers, therapist, nurse, nurse practitioner.

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Physical Therapy (PT):
PT is typically considered a short-term intervention, as it is often focused on achieving specific rehabilitation goals (e.g., improving balance, strength, and gait) within a defined time frame. Once the patient meets their mobility or pain-reduction goals, they may transition to a home exercise program for maintenance (American Physical Therapy Association, 2023).

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The Role of Physiotherapy Management for Diabetes 💪 Physiotherapy Strategies @FitterflyWellnessDTx

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Occupational therapist helping her patient with a walker. 

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Occupational rehab helps perform daily tasks safely and efficiently.

Foot and hand functional support may be need for patients with T2D. Peripheral neuropathy causes loss of grip strength, along with limited joint mobility.

This treatment would be provided by an Occupational Therapist (OT).

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We know that type 2 diabetes affects our kidney function. There are several ways to check kidney function. Blood/urine test, imaging, and biopsies.

Blood test-GFR, this test how well kidneys are filtering blood. BUN test measures the amount of nitrogen in blood.

Urine- Albumin to creatinine ratio. Albumin in the urine can be an early sign of kidney disease.

Imaging- Ultrasound, CT scans, or MRI can help visualize structural damage or blockages.

Biopsy- By taking tissue from the kidneys it can be examined under a microscope. This is usually done when other test are inconclusive.

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Correcting bad diet habits is important for those with type 2 diabetes. Fewer sweets accompanied with high fiber; low fat meats is a good place to start.

A dietitian can help with meal planning and to help with understanding what foods to eat. The Affordable Care Act (ACA) requires plans to cover nutrition counseling as a preventive medical service.

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Regular doctor visits are very important! Diabetes can affect your body in many ways. Heart, kidney, nervous system, and eyes are all at risk. Early detection makes it easier to prevent serious health issues.

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Risk of T2D increases after the age of 45. As we age metabolism slows, muscle mass is harder to retain, and usually we become less active.

Key barriers to physical activity include muscle and joint pain that comes with aging.

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Children With a Family History of Diabetes

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Children With a Family History of Diabetes

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Having a parent with T2D increases the chance of their children developing it.

Reason being is because children may inherit genes that makes their body insulin resistance or problems with insulin production. Also, poor eating habits may be passed down to children from parents.

Barriers for children include access to healthy food, cultural factors, and lack of awareness.

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Tobacco use promotes insulin resistance which raises diabetes risk.

As with alcohol, Tabacco is also highly addictive and can be hard to quit.

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This device delivers insulin, improving blood sugar when it gets too low. Insulin pumps are used as a treatment.

If not covered by insurance, for some reason these pumps can be expensive. Other complications include technical issues, uncomfortable or inconvenient, and learning how to troubleshoot when the device is not working properly.

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60-Second Risk Test for Type 2 Diabetes| ADA

There are many tests one can find online like the one provided.

This is a preventative measure.

These tests estimate type 2 diabetes risk based on medical history and lifestyle.

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60-Second Risk Test for Type 2 Diabetes| ADA

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Take our free, online 60-second Type 2 Diabetes Risk Test and learn your risk today.

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In case of a hypoglycemia emergency, medical alert bracelets will alert first responders. This is a treatment measure.

Potential drawbacks or limitations to these devices include battery dependency, cost and accessibility and compliance to wearing the bracelet daily.

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sugar sweetened beverages : policies that bulk up the price of sugary drinks to discourage consumption, with one goal in mind reducing type 2 diabetes and overweightness.

Target:policy/individual

Implementation challenges: pushback from beverage companies

School- Based Nutrition and Physical Education programs: programs in school setting to educate kids on healthy eating habits and promote movement daily.

Target: individual

Implementation challenges: Budget constraints sc

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school base nutrition and physical education programs

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A common diagnostic test to determine if someone has type 2 diabetes is the A1C blood test. This test measures the amount of sugar in your blood for the past couple months. The test can be done by a finger prick, will get results in minutes. Or you can get a blood draw that will be sent off to a lab for testing, this is the most common.

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Treatment looks like a healthy lifestyle by managing your diabetes, medication, and addressing the insulin resistance issue. And certain medicines have been associated with a reduced risk of dementia.

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Regular physical activity such as walking, swimming, or cycling can improve blood glucose control, enhance muscle strength, and reduce the risk of neuropathy and other complications. Patients cite lack of time, fatigue, pain from neuropathy as some of the barriers to achieving exercise goals. The difficulty of achieving the above is rated at 7/10 on a scale of 1-10. It is recommended that patients seek support from a certified diabetes care, education Specialist (CDCES), a Physical Therapist or exercise Physiologist to guide them through this lifestyle change.

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swimming exercise for type 2 diabetes patients

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Drinking in moderation to avoid weight gain and spikes in blood sugar.

Challenge to this is alcohol can be addictive and a hard habit to break.

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structured lifestyle programs to individuals at high risk for type 2 diabetes improve weight, diet, physical activity.

Target: individuals

Implementation challenges: low participation due to people lacking awareness and motivation.

ACTIVE LIVING

Designing neighborhoods with safe sidewalks, parks, and riding paths to promote movement

Target:Enivornment

Implementation challenges: displacement concerns in low income areas

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A chronic condition where the body doesn't use insulin properly, leading to high blood sugar levels

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During pregnancy hormones from the placenta makes the mother body more resistant to insulin, this is called gestational diabetes that is temporary but can lead to long term T2D.

50% of women of develop gestational diabetes will develop T2D 5-10 years after giving birth given that no preventions are taken.

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Preventing T2D is difficult because the widespread of unhealthy diets and sedentary lifestyle.  A lot people go without being diagnosed because of the lack of preventative care.Treatments require important lifestyle changes, that can be challenging to maintain.

Also medication can become pricey.  Some of these institutions lack the resources, education  in diabetes, and diabetic specialists. Care sometimes is limited based on the area you live in .