Pathophysiology of Diabetes Type 2

Pathophysiology of Diabetes Type 2

Diabetes mellitus type II is formerly known as Adult-onset diabetes or Non-insulin dependent diabetes mellitus. This condition arises from the inefficient use of an endogenously secreted hormone, called insulin. It has become a global epidemic affecting 370 million people worldwide. It is characterized by a classic triad of symptoms namely, polydipsia, polyuria and polyphagia. Most of the time, these symptoms are barely noticed by the patient causing a delay in consult and diagnosisfor several years, unless severe complications overtly manifest.

Previously, this was common among adults, but recent epidemiological data show the rising incidence among the younger population. Several risk factors that increase the propensity in developing this condition areethnicity, family history of diabetes, previous history of gestational diabetes combined with advanced age, obesity, unhealthy diet, smoking and physical inactivity.

Pathophysiology

Insulin secretion and metabolism

The homeostasis of glucose is maintained by a balance of hepatic glucose production and peripheral glucose uptake and utilization. Glucose is the key regulator of insulin secretion by the pancreatic beta cell. Other metabolic end products such as ketones, amino acids, enteric peptides and neurotransmitter also influence insulin release.

Insulin is secreted in a pulsatile pattern with small secretory bursts every 10 minutes superimposed upon greater amplitude oscillations of about 80-150 minutes. After a meal, bursts of insulin secretion usually last for two to three hours prior to returning to baseline levels.

Insulin secretion and metabolismOnce insulin is released into the portal venous system, the liver degrades half of the secreted insulin. The remaining insulin enters the systemic circulation to reach the target binding sites. Activation of insulin receptors induces synthesis of glycogen, synthesis of proteins, lipogenesis and regulation of various genes in insulin-responsive cells.

There are three pathophysiologic mechanisms, which are central to the development of Type II diabetes mellitus: impaired insulin secretion, peripheral insulin resistance, and excessive hepatic glucose production. In the early phase of this disease, despite the presence of insulin resistance, blood glucose may remain normal due to compensatory increase in insulin secretion by the remaining beta cells. Once this compensatory mechanism is exhausted, derangements in blood glucose concentrations become evident.

Insulin Resistance

The decreased ability of insulin to act efficiently on its target tissues, such as the muscles and liver, is a prominent feature of Type II diabetes. This results from a synergistic effect of genetic susceptibility and obesity. Insulin resistance occurs when the body does not exert sufficient action in proportion to its blood concentration. The metabolic sequalae is impaired glucose utilization by insulin-sensitive tissues thereby increasing hepatic glucose output causing hyperglycemia.

Persistent hyperglycemia may impair both the insulin secretory response to glucose as well as tissue sensitivity to insulin, causing resistance.  Insulin resistance is mostly seen in type II diabetic patients who are obese. Molecular investigations elucidate the synergistic effect of environmental, genetic susceptibility and obesity in this condition. Polymorphisms of IRS-1 gene, thrifty genes (Beta 3 adrenergic receptor gene, uncoupling protein gene) when present with visceral obesity are found to promote insulin resistance. This is clinically manifested by an impaired glucose tolerance test, while hyperglycemia is due to a decline in beta cell function.

There are two insulin resistance syndromes that have been described. Type A insulin resistance syndrome affects young women and is characterized by severe hyperinsulinemia, features of hyperandrogenism and obesity. They are postulated to have a defect in the insulin-signaling pathway. Type B insulin resistance syndrome affects middle-aged women characterized by severe hyperinsulinemia, features of hyperandrogenism and autoimmune disorders. They have autoimmune antibodies against the insulin receptor. These autoantibodies may block insulin binding or stimulate the insulin receptor leading to intermittent hypoglycemia.

Impaired Insulin Secretion

Impaired sensitivity and insulin secretion are interrelated. Early in the course of the disease of type II diabetes mellitus, insulin secretion initially increases as a compensatory mechanism to maintain a normal glucose concentration. As the disease progress, this results in mild impairment of insulin secretion. Chronically, the secretory defect worsens to grossly inadequate levels resulting in sustained hyperglycemia. The net effect of this event to target tissues are glucose toxicity and lipotoxicity. In animal experimental models, toxicity to glucose and lipid result in a depletion of beta cell function. Although the precise reason for the depletion of the secretory capacity of the beta cells in humans remain obscure.

Impaired Insulin SecretionIn patients with long-standing disease, islet amyloid polypeptide or amylin is co-secreted by the beta cell and likely forms an amyloid fibrillar deposit found in the beta cells. Whether this is a primary or a secondary event, is unclear. This is said to be related to beta cell apoptosis causing a further impairment in insulin secretion.

Increase hepatic Glucose Production

In type II diabetes mellitus, insulin resistance in the liver reflects the failure of hyperinsulinemia to suppress gluconeogenesis. This results in fasting hyperglycemia and decreased glycogen storage by the liver in the post-prandial state. Increased hepatic glucose production occurs early in the disease course of diabetes, likely after the onset of insulin secretory abnormalities and insulin resistance in the skeletal muscle.

Hepatic glucose production is regulated by two rate-limiting enzymes namely, glucose 6-phosphatase catalytic subunit, encoded byG6PC and phosphoenolpyruvatecarboxykinase, encoded by PCK1 and PCK2. As the expression of these enzymes is suppressed by insulin, it has been widely held that patients with type II diabetes would have increased expression of G6PC and PCK, due to hepatic insulin resistance.

Systemic and Islet cell inflammation

Obesity is frequently characterized by systemic inflammation. Cumulatively, both of these contribute to beta cell dysfunction. Research data show that systemic inflammatory markers such as C-reactive protein and its up-regulator, interleukin-6 are directly related to insulin sensitivity and beta cell function. Increased adiposity is associated with increased expression of pro-inflammatory genes, which may impair insulin signaling.  Other pro-inflammatory markers such as cytokines,are released into the circulation where they can act at distant sites such as liver and skeletal muscle to worsen insulin resistance.

References:

  • Global Report on Diabetes 2016 (pp. 1-84, Rep.). (2016). Geneva, Appia: World Health Organization.
  • Haeusler, R. A., Camastra, S., Astiarraga, B., Nannipieri, M., Anselmino, M., &Ferrannini, E. (2015). Decreased expression of hepatic glucokinase in type 2 diabetes.Molecular Metabolism,4(3), 222-226.doi:10.1016/j.molmet.2014.12.007
  • Kahn, S. E., Cooper, M. E., & Prato, S. D. (2014). Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. The Lancet,383(9922), 1068-1083.doi:10.1016/s0140-6736(13)62154-6
  • Kaku, K. (2010). Pathophysiology of Type 2 Diabetes and Its Treatment Policy.Japan Medical Association Journal,53(1), 41-46.
  • Magnusson, I., Rothman, D. L., Katz, L. D., Shulman, R. G., & Shulman, G. I. (1992). Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. Journal of Clinical Investigation J. Clin. Invest.,90(4), 1323-1327. doi:10.1172/jci115997
  • Ozougwu, O. (2013). The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus.J. Physiol. Pathophysiol. Journal of Physiology and Pathophysiology,4(4), 46-57.doi:10.5897/jpap2013.0001
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