Type II Diabetes:

Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels which come about due to insulin secretion defects, insulin action, or both combined. There are two types of diabetes, type I and type II. For the sake of brevity, I will focus on type II diabetes.

The main characteristic of type ii diabetes is insulin resistance which occurs when the body becomes less sensitive and less responsive to insulin and its action. Glucose uptake is impaired. This begins initially in the muscle, liver, and fat tissues. Since the body is not responding to insulin, the pancrease begins to compensate by producing even more insulin. This initial act does help the body but quickly becomes exhausting. This leads to beta cell dysfunction. The exhausted beta cells, now functioning abnormally, become unable to secrete insulin effectively. This causes insulin deficiency. Insulin deficiency and insulin resistance combined lead to a state called chronic hyperglycemia.

A positive feedback cycle is created: chronic high blood glucose levels and elevated fatty acids damage beta cells further. The organs involved in the development of type II diabetes are the pancreas, liver, skeletal muscle, brain, kidneys, small intestine, and adipose tissue. Pathophysiological hallmarks of this condition include chronic inflammation, adipokine dysregulation, and gut microbiota abnormalities along with immune system dysregulation.

There is a genetic predisposition to developing this condition. It occurs more often in certain ethnic groups as well including Hispanic and native American populations (Galicia-Garcia, et.al.)

The biggest risk factor for the development of type ii diabetes is obesity, specifically having a BMI over 30. Another risk factor is leading a sedentary lifestyle. Exercise decrease the chance of developing type II diabetes through the contraction of skeletal muscle which increases blood flow to the muscle which in turn enhances glucose uptake from plasma. It also decreases intra-abdominal fat storage, a risk factor which promotes the development of insulin resistance, the precursor to type II diabetes development. Exercise also reduces inflammation.

Beta cells in the pancreas are responsible for producing insulin. It synthesizes pre-proinsulin, and undergoes a change with the assistance of proteins in the endoplasmic reticulum to form proinsulin. In the golgi apparatus, proinsulin becomes C-peptide and insulin. At this point insulin is stored in granules and awaits a signal to release insulin. This signal is high glucose levels. Other factors, such as amino acids and hormones, can release insulin as well.

Beta cell dysfunction arises from hyperglycemia and hyperlipidemia, which is high glucose blood levels and high levels of fatty acids. These high levels of both lead to susceptibility to inflammation, metabolic/oxidative stress, and amyloid stress.

There are a number of conditions which change the physiology of the body leading to the development of type II diabetes. The Western diet tends to be highly caloric with high amounts of fats and carbs which elevates blood glucose levels. A high-fat diet contributes also to gut and intestinal dysbiosis which contributes to the development of inflammation and insulin resistance. Dysbiosis affects also production of metabolites which disrupts glucose homeostasis triggering Type II diabetic development.

The diagnostic criteria for type II diabetes is as follows:

A fasting plasma glucose level of 126 mg/dl or higher

A 2hour plasma glucose level of 200mg/dl or higher

A random plasma glucose level of 200mg/dl or higher

It is a complex metabolic condition involving many pathways. Insulin not only promotes glucose uptake but acts also as an inhibitor for hepatic gluconeogenesis and stimulates glycogen, prtein synthesis, and lipogenesis. Insulin is the primary hormone behind the regulation of protein, lipid, and carbohydrate metabolism, and induces transcriptional activation of lipogenic genes.

Plasma, serum, and urine tests in diabetic subjects show that isoleucine, valine, leucine, tyrosine, tryptophan, phenylalanine, and lysine metabolite 2-aminoadipc acid have been positively correlated with type II diabetes. Whether they are cause or effect has not been positively elucidated (Sanches, et.al.) Carbohydrates affected include glucose, hexoses, mannose, and fructose. Other potential biomarkers for type II diabetes includes glucose-6-phosphate and lactate.

Lactate and alanine are considered to be important sources for gluconeogenesis. Glycolysis in muscle tissues releases high amounts of lactate in plasma and is inversely correlated with oxidative activity in mitochondria. Mitochondrial oxidative capacity is lower in type II diabetes compared to healthy individuals. High levels of alanine are found in the liver, blood, and urine I type II diabetic patients. High concentrations of lactate lead to an increase in glucose production which combined with lipid metabolism imbalance leads to insulin resistance (Sanches, et.al.)

References:

Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K.B., Ostolaza, H., Martín, C (2020). Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci:21(17):6275. doi: 10.3390/ijms21176275. PMID: 32872570; PMCID: PMC7503727.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503727/

Sanches, J.M., Zhao, L.N., Salehi, A., Wollheim, C.B. and Kaldis, P. (2023), Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. FEBS J, 290: 620-648. https://doi.org/10.1111/febs.16306