MÓDULO FORMATIVO 3

In 1889 two German scientists, von Miring and Oskar Minkowski noted, from their studies on animals, which after total pancreatectomy animals developed severe diabetes. They theorised that there was a substance secreted by the pancreatic cells responsible for the glycaemic control. The hypothesis was later refined by others, recognising diabetes to be associated with the destruction of the islets of Langerhans. Minkowski and Zuelzer in Germany, as well as Scott in the USA and the Romanian Paulesco, attempted to isolate and administer the missing pancreatic islet substance (Karamitsos, 2011). Belgian scientist de Meyer in 1909 suggested the name “insulin”; this name has also been proposed by the British researcher Schaefer later in 1916 (De Meyts Pierre, 2014).

In 1921, insulin was isolated, purified and became available in a form for therapeutic administration. In May 1921, a young orthopaedic surgeon called Banting, assisted by his medical student Best, and under the supervision of McLeod, head of the physiology department at Toronto University began experiments in dogs. They infused saline extracts of pancreas intravenously to

deliberately diabetic dogs (by pancreatectomy) and observed the lowering effect of the insulin on the blood glucose (Rosenfeld, 2002). Collip, who was a

biochemist, joined McLeod’s experimental team in Toronto and demonstrated that this extract lowered sugar excretion in urine and established that the deficiency in insulin secretion was the cause of diabetes (Lakhtakia, 2013). In January 1922, the first human experiments began on a 14-year-old boy with diabetes. He was clinically symptomatic; his biochemical deviations were

reversed by the administration of the pancreatic isolate (Rosenfeld, 2002). In May 1922, the pancreatic extract had been named insulin, and the results of these experiments were presented to the Association of American Physicians. Eli Lilly began production of porcine insulin, enhancing purification and the production of commercial quantities in early 1923. Subsequently, Banting and McLeod were awarded the 1923 Nobel prize (Quianzon and Cheikh, 2012).

Insulin receptors signalling cascade

T2DM is increasing worldwide; a primary focus of research is understanding the signalling pathways influencing this disease. Insulin signalling regulates glucose homeostasis, lipid, and energy production, mostly via their action on the adipose tissue, liver, and skeletal muscle. Accurate control of this pathway is crucial for adaptation as the situation moves from feeding to a fasting state. Positive and negative receptor signals work at different stages of the signalling pathway, as well as the variety of protein isoform interfacing to ensure an appropriate and synchronised Insulin biological action in various tissues. Insulin controls a wide range of biological processes by acting on two closely related tyrosine kinase receptors. Activation of insulin receptors by their binding molecules starts a sequence of phosphorylation events that lead to the activation of proteins that controls metabolism and growth (Bononi et al., 2011). Insulin receptor signalling consists of several points of regulatory steps. These steps are controlled both negatively and positively, to ensure proper signal intensity and duration. Dysfunctions in these signalling pathways can lead to IR (Boucher et al., 2014).

(Pearson Education, https://goo.gl/images/Bb97nG)

Insulin action

Dysfunction of any glucose homeostasis pathway would disturb metabolic regulation and promote the development of pre-diabetes and eventually, if not corrected, to T2DM.

Defect in Insulin signalling

As mentioned before, skeletal muscle is the primary site of insulin-mediated glucose clearance and play a significant role in decreasing glucose uptake, as in states of IR. Dysfunction in the early insulin-signalling pathway leading to the reduction of glucose uptake plays a primary role in the development of IR.

A substantial body evidence supports that insulin-signalling pathway dysfunction contributes to IR in tissues like the skeletal muscle and human as general. For example, in patients with T2DM or obesity, several investigators have shown decreased phosphorylation of the insulin receptors, decreased PI3K activation and decrease IRS-1 tyrosine phosphorylation (Bandyopadhyay et al., 2005). Scientific evidence that a reduction in the insulin receptor kinase itself can add to the development of IR is increasing (Chiu and Cline, 2010). However, it is

indefinite whether these changes in insulin receptor role represent a primary defect that causes IR or whether they occur secondary to hyperglycaemia or hyperinsulinemia. Even if the defect at the level of the insulin receptor can cause these physiological behaviours, whether decreased insulin receptor function can account for the insulin-resistant pathophysiology present in the general patient population is doubtful (American Diabetes, 2009).

Impaired β cell function

Some studies were conducted during the late 80s and early 90s on

normoglycaemic participants with a genetic predisposition for T2DM from vulnerable ethnic groups such as African American, Mexican American, and Pacific Islands populations, demonstrating IR as the predictor and precursor for T2DM. Other studies suggested that β cell dysfunction is the primary defect in type2 diabetes (Doria et al., 2008). In 1979, DeFronzo introduced the euglycemic and hyperglycaemic clamp technique and later, this technique was used by

Pimenta, to conclude that an insulin secretion defect is the major factor for T2DM (Pimenta et al., 1995, Tam et al., 2012). Furthermore, Van Haeften et.al.

compared the importance of β cell dysfunction to IR, concluding that impaired β cell function has a predisposed genetic predisposition in T2DM patients (Van Haeften et al., 2000).

progressive dysfunction of β cells as the leading factor in the development of hyperglycaemia (Halban et al., 2014).

Mechanism of β cell dysfunction

Failure of the β cells to maintain an adequate amount of insulin secretion in response to blood glucose level is the main and final pathway in the pathogenesis of T2DM. The integrity of β cells is crucial. The islets of Langerhans are affected by several elements including obesity, consumption of saturated fat and FFA and cytokine-induced inflammation (Cerf, 2013).

Hypothetically, the β cells decompensation process can develop in five stages. These stages are based on experimental evidence and clinical observation. Stage 1 is indicated by adequate adaptation to the increase in blood glucose level, to overcome IR which is usually present in individuals with a predisposition to T2DM. At this stage, there will be an increase in β cells mass and normal or sometimes higher insulin level. Stage 2 is characterized by early signs of decompensation, β cells secretory action will start to regress, and this stage shows increase blood glucose up to 6.6 mmol/l (120 mg/dl). By the time fasting blood glucose reaches up to 6.1 mmol/l (110 mg/dl), the condition will be called prediabetes.

In Stage 3, progressive β cell dysfunction and apparent decompensation is eminent. This phase demonstrates the rise of blood glucose to a diabetes threshold. Glucose-induced Insulin secretion is entirely impaired. Other non- glucose insulin responses may still be in action but significantly compromised. Stage 4 is characterized by chronic functional decompensation with structural changes characteristics of T2DM. These consist of Amyloid deposition in the pancreas and the presence of lipid droplets; fibrosis; apoptosis; degeneration and glycogen deposits. Stage 5 is the last stage of diabetes, there will be severe loss of β cell function. Patients at this stage will depend on external insulin to survive,

otherwise, will develop fatal diabetic ketosis. This stage is typically present in type 1 diabetes (Weir and Bonner-Weir, 2004, Curran et al., 2016).

It is accepted that T2DM is a genetically predetermined failure of the β cell (DeFronzo and Abdul-Ghani, 2011). However, according to recent diabetes studies, decreased insulin receptor function, particularly in skeletal muscles, can account for the insulin-resistant pathophysiology present in the general patient population, and the hypothesis of pooled defects in insulin secretion and insulin sensitivity appear to be more accepted (Taylor, 2012). Polonsky and co-workers suggested that T2DM is a genetically programmed failure of the β cell to

compensate for IR (Polonsky et al., 1996). Further, Miyazaki and co-workers and Rendell et. al. share a similar interpretation where it has been proposed that abdominal obesity, which is believed to be genetically inherited, is associated with fat deposits in pancreatic cells, muscles, and liver, can suggest the common explanation for defects in insulin secretion and insulin sensitivity (Miyazaki et al., 2002, Rendell et al., 2001).

The genes predisposing to T2DM and the metabolic syndrome are energy-saving thrifty genes that helped our ancestors to survive by storing energy in the form of fat (Genné-Bacon, 2014). This perhaps clarifies the fact of the high prevalence of T2DM among Pima Indians, Pacific Islanders, and Native Australian. Similarly, it may explain the recent massive epidemic in several developing countries like Arabian Peninsula (Acton et al., 2002, Sherif and Sumpio, 2015).

The challenging hypothesis of relative superiorities in the defective insulin

secretion or IR is still a debatable issue (Cernea and Dobreanu, 2013). Highlighting the importance of IR is the fact of the frequent initial finding of hyperinsulinemia in the early stages of T2DM (Roberts et al., 2013).

Higher insulin response to glucose may be prominent during progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT). The second phase of increased insulin secretion is noticeable in patients with prediabetes for

Hence, it is possible to assume that both factors are equally liable for the

pathogenesis of T2DM. So far, it is accepted to say that whichever comes first the other follows (Cerf, 2013). Recently, the roles of incretin, leptin, renal tubular glucose resorption and hypothalamic nuclei in homeostasis have been

emphasised (DeFronzo et al., 2014).

An innovative study with the hypothesis that high caloric intake will increase the deposition of fatty liver and high content of TG in the liver, leading to decrease in hepatic insulin sensitivity, furthermore, the fat content in the pancreatic cell will increase, leading to the increase of ATP production and insensitivity to glucose. This condition will lead to the prognosis of T2DM. The study showed that low caloric intake with significant weight loss was able to cause a substantial fall in fasting plasma glucose. This was the first study to show that β cells are inhibited rather than permanently damaged in T2DM (Taylor, 2013).