Endocrinopathies and Insulin Resistance Can Cause Type-2 Diabetes Mellitus.

Soheli Chowdhury1*, Majeedul H. Chowdhury2.

1. Hostos Community College, The City University of New York (CUNY).
2. Touro University, LAS Division, Flatbush Campus, NY 11230.

Introduction:

In 150 AD, the Greek physician Aretaeus described what we now call diabetes as “the melting down of flesh and limbs into urine.” From then on, physicians began to gain a better understanding about diabetes. The first known mention of diabetes symptoms was in 1552 B.C., when Hesy-Ra, an Egyptian African physician, documented frequent urination as a symptom of a mysterious disease that also caused emaciation. The word “mellitus,” meaning honey, was added to the name “diabetes,” meaning siphon. Indian Ayurveda physicians called it madhumeha (‘honey urine’) because it attracted ants. The ancient Indian physician Sushruta, and the surgeon Charaka (400–500 A.D.) were able to identify the two types of Diabetes mellitus, later to be named Type I and Type II diabetes (1).

Diabetes mellitus (DM) is a disease caused by a deficiency in the effects of insulin that leads to the failure of glucose uptake and metabolism in peripheral tissues.

DM is of two types: Type-1 diabetes mellitus (T1DM) and Type-2 diabetes mellitus (T2DM). T1DM is called insulin-dependent diabetes mellitus. The pathogenesis

of the T1DM involves T cell-mediated autoimmune destruction of β-cells of the endocrine pancreas. Consequently, insulin can no longer be synthesized or be secreted into the blood, and it leads to hyperglycemia. T2DM is called non-

insulin-dependent diabetes mellitus, where the primary failure is a loss of insulin sensitivity of the tissues, which is often accompanied by reduced insulin secretion, leading to insulin resistance (IR). T2DM pathogenesis is not well understood but reduced population of islet beta-cells, reduced secretory function of islet beta- cells that survive, and peripheral tissue IR are known to be involved (2). T2DM is characterized by increased glucagon hormone secretion, which is unaffected by, and unresponsive to the concentration of blood glucose. But insulin hormone is still secreted into the blood in response to the blood glucose. As a consequence, hyperglycemia ensues, because glucagon promotes hepatic glucose output by

increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and

glycolysis in a concerted fashion via multiple mechanisms (3).

Beta cells of the pancreatic islets are sensitive to blood sugar levels so that they secrete insulin into the blood in response to high level of glucose, in a fed state, and inhibit secretion of insulin when glucose levels are low, in a fasted state. Insulin

enhances glucose uptake, via glucose transporter or GLUT, and metabolism in the cells, thereby reducing blood sugar level. Alpha cells of the pancreatic islets secrete glucagon into the blood in the opposite manner: increased secretion in

hypoglycemia, and decreased secretion in hyperglycemia. Glucagon increases blood glucose level by stimulating glycogenolysis and gluconeogenesis in the liver. The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis (4, 5).

In this review T2DM has been discussed with reference to the regulation of intermediary metabolism by insulin, signal transduction by insulin, endocrinopathies that can precipitate T2DM, and insulin resistance (IR).

Regulation of intermediary metabolism by insulin: Insulin, an anabolic peptide hormone, is produced by beta cells of the pancreatic islets and encoded in humans by the INS gene. It regulates the intermediary metabolism of biomolecules

by promoting the absorption of glucose from the blood into liver, adipocytes, and skeletal muscle cells. The absorbed glucose is converted into glycogen (liver and muscle) and triglycerides (liver and adipocytes).Circulating insulin also

affects the synthesis of proteins in a wide variety of tissues. This anabolic hormone promotes the conversion of small molecules in the blood into large molecules inside the cells. Gluconeogenesis in the liver cells is strongly inhibited by insulin and proinsulin (16,17). However, low insulin levels or its absence in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat and protein (5, 6).

Signal transduction by insulin: Insulin is a key homeostatic factor that plays a cardinal role in maintaining postprandial normoglycemia. It acts through both the insulin receptor for metabolic regulation, and insulinlike growth facor1receptor (IGF-1R) for normal growth and development. Insulin, proinsulin, and epidermal growth factor (EGF) use high-affinity cell surface receptors, the receptor tyrosine kinases (RTK), for signal transduction mechanism to regulate intracellular activities. The author reported that proinsulin, the prohormone precursor to insulin made in the beta cell of the islets of Langerhans of the pancreas, manifests effects similar to insulin on metabolic pathways, but with much less efficiency. EGF,

on the other hand, counteracted the glycogenic effects of insulin in parenchymal hepatocytes in culture. To understand the signal transduction mechanism, in insulin receptor binding studies, it was noted that proinsulin binds with insulin receptors, albeit less effectively. However, EGF did not share the same subset of RTK receptors, which perhaps explain its counteraction of insulin’s glycogenic effect (16,17). Today approximately 20 different RTK classes have been identified; EGF receptor family belongs to RTK class I whereas insulin receptor family to RTK class II. This difference of RTK class explains their differences in signal transduction mechanism.

Insulin and IGF-1 acting via specific tyrosine kinase receptors propagate signals via two main branches: the PI3K-PDK-1-Akt and the Grb2-SOS-Ras- MAPK pathways that control proliferation, differentiation, and survival at the cellular level, and growth and metabolism in organisms (PI3K: Phosphoinositide

1. kinase; PDK-1:3-phosphoinositide-dependent protein kinase; Akt: Protein kinase B; Grb2: Growth Factor Receptor-bound protein 2; SOS: son-of-sevenless protein, a guanine nucleotide exchange factor for Ras activation; Ras: from “Rat sarcoma virus”, Ras proteins, called small GTPase, function as binary molecular switches controlling intracellular signaling networks; MAPK: mitogen-activated protein kinase). Identifying new molecules that impact insulin-signaling and new levels

of control, as well as better understanding the causes and mechanisms leading to insulin resistance (IR), will be essential for a more effective treatment of type-2 diabetes and associated diseases (19).

Role of endocrinopathies in the genesis of T2DM: Many metabolic hormones and their interactions help maintain normoglycemia. Blood glucose concentration is increased by glucagon, catecholamines, growth hormone and glucocorticoids, without insulin. They affect two metabolic pathways: Glycogenolysis is facilitated by glucagon, catecholamines and growth hormone; and gluconeogenesis is increased by glucagon, catecholamines and glucocorticoids.

Endocrinopathies can cause insulin resistance, leading to the genesis of hyperglycemia, and can precipitate T2DM.

Growth hormone: Acromegaly is an endocrinopathy when there is an excessive amount of growth hormone (GH) that causes hyperglycemia, through

gluconeogenesis in liver and its decreased utilization in peripheral tissues. This is probably due to disturbances in the production and action of a second messenger in the insulin receptor. In addition, GH increases lipolysis of adipose tissue, and an increased concentration and oxidation of fatty acids enhances IR (7, 8).

Prolactin: Hyperprolactinaemia is a condition where an excessive amount of prolactin hormone being produced, and it can cause IR (9). The chemical

structure of prolactin is similar to the structure of growth hormone and placental lactogen hormone. Together, they form the “prolactin/growth hormone/placental lactogen” family. All hormonesin this family derive from a common ancestral gene. Prolactin’s structure being very similar to that of GH, both resistance and carbohydrate disorders will be present under such conditions. Hyperprolactinaemia also cause hypogonadism, and the anti-dopaminergic effect of hyperprolactinaemia promote weight gain and the occurrence of the atherogenic lipid profile (7, 10).

Glucocorticosteroids: Glucocorticoids (GCs) is a very large class of hormones, and an excessive amount of them can lead to IR, abdominal obesity, increased accumulation of body fat, higher blood pressure, lipid disorders, glucose

intolerance, or diabetes. The mechanisms underlying the relationship between GCs and diabetes are not fully understood. What remains clear is that GCs are capable of regulating aspects of glucose homeostasis in each target organ by antagonizing the effects of insulin either directly or indirectly (11). In hypercortisolism, glucocorticoids cause insulin resistance by affecting the activation of the liver enzyme phosphoenolpyruvate carboxykinase (PEPCK),

increasing proteolysis in skeletal muscle and lipolysis in adipose tissue, which ultimately provides more substrate for gluconeogenesis, leading to hyperglycemia. Enhanced lipolysis leads to the development of reduced insulin sensitivity. Insulin resistance induced by hypercortisolism has a post-receptor nature. Cortisol also reduces expression of the adiponectin gene, which reflects good insulin sensitivity (7). All of this can lead to hyperglycemia.

Hypo- and Hyperthyroidism: The presence of disorders of carbohydrate metabolism has been demonstrated in thyroid disease involving either overt hyperthyroidism or overt hypothyroidism. The severity of the disease is proportional to the severity of these disorders. The possible influence of subclinical forms of both hyperthyroidism and hypothyroidism on carbohydrate disorders is still under discussion. Thyroid hormones have a significant effect on glucose metabolism and the development of insulin resistance (IR). In

hyperthyroidism, impaired glucose tolerance may be the result of mainly hepatic insulin resistance, whereas in hypothyroidism the available data suggests

that the insulin resistance of peripheral tissues prevails (12). Hyperglycemia in hyperthyroidism is mainly due to endogenous glucose production by gluconeogenesis. Studies examining insulin-stimulated glucose metabolism in skeletal muscle suggest that, in the hyperthyroid state, it may be of primary importance to increase the rates of glycolysis and lactate formation relative to glucose oxidation in muscle in order to provide substrate for gluconeogenesis

(increase Cori cycle activity). This effect will be achieved primarily by a decrease in glycogen synthesis and an increase in glycogenolysis. In addition to lactate, increased rates of gluconeogenesis in hyperthyroidism can also be sustained by increased plasma concentrations of amino acids (mostly glutamine and alanine) and glycerol (13). Hypothyrodism, on the other hand, causes weight gain, atherogenic lipid profile, an increase in blood pressure, and also an increased blood concentration of free fatty acids. The latter reduces the tissue uptake of glucose, and its enhanced oxidation. Hypothyroidism leads to an increased production of counter-regulating hormones with potentially diabetogenic properties such as cortisol, catecholamines, and glucagon. Hypothyroidism leads to insulin resistance due to triiodothyronine (T3) action at the tissue leads to activation of AMP-kinase, which is responsible for increased glucose utilization, reduced lipolysis, and gluconeogenesis (7).

Insulin Resistance (IR) in T2DM: A cardinal feature of T2DM is IR. This occurs primarily at the level of insulin-sensitive tissues, viz., liver, muscle, and fat, and

can be caused by multiple mechanisms, such as hyperglycemia, hyperinsulinemia, lipotoxicity, inflammation, genetic mutation, mitochondrial dysfunction, and endoplasmic reticulum stress (19). IR is a pathophysiological state related to the decreased response of peripheral tissues to the insulin action, hyperinsulinemia and raised blood glucose levels caused by increased hepatic glucose outflow. All the above precede the onset of full-blown type 2 diabetes. Two major putative mediators that cause IR are ceramides and diacylglycerols. Accumulation of these two intramuscular lipids is proposed to be involved in the induction of IR (14).

Diacylglycerol (DAG) is an important lipid that serves both as an intermediate in lipid biosynthetic pathways and can act as a signaling molecule by activating protein kinase C (PKC). The mechanism of action of DAG-mediated IR is as follows: DAG activates PKC isoforms, and activation of the ε isoform (PKCε) is most consistently observed in insulin-resistant (IR) liver. PKCε phosphorylates insulin receptor (INSR) Thr1160, resulting in inhibition of INSR tyrosine kinase activity. All downstream arms of hepatocellular insulin signaling, including stimulation of net glycogen synthesis, transcriptional upregulation of de

novo lipogenic genes, and transcriptional downregulation of gluconeogenic genes, are predicted to be affected by this mechanism (15).

Another strong causation for IR is the sphingolipid ceramide. However, it causes IR by a mechanism very different from that of DAG. Ceramide can block insulin in two ways. One is that the ceramide activation of protein kinase C (PKC) impairs

the translocation of protein kinase B (PKB), a serine/threonine kinase, to the plasma membrane, preventing PKB from being able to function in insulin action. PKB

is a key regulator of insulin signaling and glucose homeostasis. Impaired PKB function leads to insulin resistance and diabetes mellitus. The other way ceramide blocks insulin is that the ceramide activation of protein phosphatase 2A leads to dephosphorylation and inactivation on PKB (15).

Conclusion: In this article the role of insulin resistance and endocrinopathies in the development of T2DM has been addressed. The basic aspects of T2DM have been discussed, viz., the causative factors, role of pancreatic islets hormones, insulin

and glucagon, in maintaining glucose homeostasis and regulation of intermediary metabolism, role of endocrinopathies that cause hyperglycemia leading to T2DM, and insulin resistance that precede the development of T2DM. T2DM treatment could be achieved with 3Ds: Diet (low sugar, balanced diet), Discipline

(physical exercise), & Drug (medication to lower sugar). Comprehensive diabetes management can delay the progression of complication and maximize the quality of life. Acquiring knowledge about T2DM is an essential part of diabetes management, and even more important is to make the patient aware of this chronic disease. “For a diabetic patient, knowledge and understanding are not a part of treatment--they are the treatment” (18).

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