**11. Uncommon diseases cause hyperglycemia and DM**

#### **11.1. Endocrine diseases**

more often [223,224]. In addition, the mutations in other genes include glucokinase (GCK), HLA antigens, insulin receptor (INSR), insulin-like growth factor-2 (IGF2), HNF4A, insulin gene (INS-VNTR), plasminogen activator inhibitor 1 (PAI-1), potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11), hepatocyte nuclear factor-4a (HNF4A) and 1α (HNF1A) [224] suggest the susceptibility to increase the risk of GDM in certain patients.

The stimulators or the inducers of IR and phosphorylate insulin receptor substrate (IRS) proteins are activated in uncontrollable method several kinases, including inhibitor of nuclear factor ĸB kinase β (IKK β), c-Jun N-terminal kinase (JNK), mammalian target of rapamycin (mTOR), protein kinase C (PKC) and ribosomal S6 protein kinase (S6K). Substance P is a potent cytokine and is considered one of the crucial activators that contribute in the development of IR by impairment of insulin signaling [225]. The genetic variants in TCF7L2 is the strongest gene associated with GDM risk among other minor alleles of rs7903146 (TCF7L2), rs1225 5372 (TCF7L2), rs1799884 (-30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) significantly associated with a higher risk of GDM. There are 12 SNPs from 10 genes are

The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women [226] and the polymorphism of TCF7L2 (rs7903146 C/T) gene, and the G972R polymorphism of the IRS1 gene, seems to predispose to GDM in Greek women [227]. In women of Han nationality in north China, The defect in sulfonylurea receptor-1 (SUR1) gene (cc and AA) may contribute to insulin hypersecretion, which might be the cause of increased body weight and

In animals but not in human, Galanin inhibits glucose-stimulated insulin release [230]. In the human, the initial postprandial rise of glucose and insulin are suppressed by galanin admin‐ istration [231]. Galanin and IL-6 were found to be significantly associated with IR markers in GDM, thus may play important roles in the regulation of glucose hemostasis [232].The higher

In late pregnancy the relative proinsulin secretion is mainly related to IR and does not necessarily reflect β-cell function. T2DM is not independently associated with hyperproinsu‐ linemia as measured by the proinsulin-to-C-peptide ratio. While, in pregnant women, the increased in IR is associated with decreased proinsulin to C-peptide ratio, independently of

The islet amyloid pancreatic polypeptid hypersecretion is characteristic for pregnancy and might partially decrease hyperinsulinemia in pregnancy by inhibiting insulin secretion [235].

The β- cells dysfunction and IR are the core in the pathogenesis of T2DM and both are mediated by Adiponectin. Therefore, in late pregnancy the Adiponectin is an independent factor

In pregnancy IR and GDM caused by the placental hormones and cytokines such as tumor necrosis factor alpha (TNFα), resisten and leptin. All of these are secreted by placenta inde‐ pendently. The human chorionic somatomammotropin (HCS), cortisol, estrogen, progester‐

decreased IS and genotype cc of SUR1 is connected with severe type of GDM [229].

level of plasma galanin is a novel biomarker for the prediction of GDM [233].

associated GDM [228].

84 Treatment of Type 2 Diabetes

glucose tolerance status [234].

correlated with β- cells dysfunction [236].

Acromegaly and hypercortisolism are frequently associated with IGT and T2DM. It is a recognized finding of occurrence of secondary T2DM with many hormonal diseases (pituitary, adrenal/or thyroid disease). Patients with Acromegaly have IR, both in the liver and in the periphery displaying hyperinsulinemia and increased glucose turnover in the basal postabsorptive states. There is increase in blood glucose level and free fatty acids due to stimulation of gluconeogenesis and lipolysis. Although, insulin growth factor-1(IGF-1) level is increased but it is unable to counteract IR induced by abnormal excess GH level. On the other hand, IS primarily enhanced in the skeletal muscles by increased IGF-1. The excess of the GH and IGF-1 in patients with Acromegaly could be controlled by somatostatin analogues (SSAs) therapy in most of the patients. On the contrast, the overall glucose tolerance might be complicated by the inhibitory effect of SSAs on pancreatic insulin secretion.

The visceral obesity and IR are induced by hypercortisolemia. It also leads to hyperglycemia and reduced glucose tolerance, determines IR and stimulates hepatic gluconeogenesis and glycogenolysis. The hyperglycemia is due to decreased insulin secretion in patients with neuroendocrine tumors (NETs), patients with pancreatic surgery and in those with pheochro‐ mocytoma. While in somatostatinoma or gluconoma the hyperglycemia is related to alteration in the counterbalance between these hormones. In the symptomatic treatment of NETs, the SSAs represent a valid therapeutic choice and it may have a significant impact on the preva‐ lence of glucose metabolism imbalance.

Hyperthyroidism is the principally cause of hyperglycemia among thyroid disorders [241]. IR is associated positively with abnormal increase in the thyroid hormone levels [242]. The uncontrolled diabetes in patient with diabetes developing thyrotoxicosis is related to the stimulation of hepatic glucose production by thyroid hormones acting via a sympathetic pathway from the hypothalamus and FT3 influenced the transcriptional regulators of meta‐ bolic and mitochondrial genes may contribute to the development of IR. In contrast, hypo‐ thyroidism is linked to decreased IS. The thyroid hormones have insulin antagonistic effects at the liver that lead to an increase in glucose hepatic output, via an enhanced rate of gluco‐ neogenesis and glycogenolysis. Lipid metabolism (lipogenesis and lipolysis) are stimulated by FT3 further aggravating the dysregulation of liver glucose and lipid metabolism predispose to IR There are several genes are involved in gluconeogenesis, glycogen metabolism, insulin signaling and many hepatic glucogenic enzymes are regulated by thyroid hormones. The thyroid hormones also could cause an increase in hepatic glucose output, through increased hepatic expression of the glucose transporter GLUT2 [243].

#### **11.2. Polycystic ovary syndrome**

The features of PCOS are hyperinsulinemia, IR and hyperandrogenesim. The later present‐ ed in those patients with hirsutism, acne, irregular periods and reproductive disorders. These features are more marked and severe in obese females and the combination of both (these features with obesity) have a synergistic effect on increased insulin secretion by βcells and development of compensatory hyperinsulinemia. Subsequently, with the decline of the β-cell compensatory response a relative or absolute insulin secretion and produc‐ tion insufficiency develops which may lead to dysglycemia (IFG, IGT and T2DM). There‐ fore, it is well-known that PCOS and IR are considered risk factors for GDM [244]. This risk is increased in obese females, presence of family history of T2DM and to the severity of high androgenic activity. Therefore, the dysglycemia could occur in earlier age group than normal population. It could be in the 3rd or 4th decade of life and it is approximately 5 to 10 folds higher than normal population. No doubt, it is higher compared with age and weight matched control age group [245].

#### **11.3. Pancreatic damage or β-cell damage of the pancreas**

Chronic alcoholism and tropical calcified pancreatitis are most commonly associated with diabetes [247]. Pancreatic exocrine disease associated with hyperglycemia or DM has a unique clinical and metabolic form. It is painless occasionally and malabsorption occurs after clinical hyperglycemia or DM following failure or impairment of endocrine and exocrine pancreatic function of both α and β cells [246]

#### **11.4. Hereditary hemochromatosis**

Iron overload and excessive tissues deposition of iron including the pancreas. It is an autosomal recessive genetic disorder caused by a mutation in the HFE gene located on the short arm of chromosome 6. Approximately 50% of patients diagnosed with hemochromatosis will have either type 1 or T2DM [248].

#### **11.5. Cystic fibrosis**

Diabetes Mellitus is the most common morbidity in patients with cystic fibrosis (CF). It occurs in about 20% of adolescent and 40-50% of adults with this disease. CF primarily caused by insulin insufficiency. However, there is a role for IR in acute and chronic stages of this disease due to fluctuation level of insulin. DM has a unique distinct entity in patient with CF because it has mixed features of TIDM and T2DM [249].

**Other causes** of damage of the pancreas are toxins like alcohol, surgical resection of the pancreas and pancreatic cancer.

#### **11.6. Smoking**

neogenesis and glycogenolysis. Lipid metabolism (lipogenesis and lipolysis) are stimulated by FT3 further aggravating the dysregulation of liver glucose and lipid metabolism predispose to IR There are several genes are involved in gluconeogenesis, glycogen metabolism, insulin signaling and many hepatic glucogenic enzymes are regulated by thyroid hormones. The thyroid hormones also could cause an increase in hepatic glucose output, through increased

The features of PCOS are hyperinsulinemia, IR and hyperandrogenesim. The later present‐ ed in those patients with hirsutism, acne, irregular periods and reproductive disorders. These features are more marked and severe in obese females and the combination of both (these features with obesity) have a synergistic effect on increased insulin secretion by βcells and development of compensatory hyperinsulinemia. Subsequently, with the decline of the β-cell compensatory response a relative or absolute insulin secretion and produc‐ tion insufficiency develops which may lead to dysglycemia (IFG, IGT and T2DM). There‐ fore, it is well-known that PCOS and IR are considered risk factors for GDM [244]. This risk is increased in obese females, presence of family history of T2DM and to the severity of high androgenic activity. Therefore, the dysglycemia could occur in earlier age group than normal population. It could be in the 3rd or 4th decade of life and it is approximately 5 to 10 folds higher than normal population. No doubt, it is higher compared with age and

Chronic alcoholism and tropical calcified pancreatitis are most commonly associated with diabetes [247]. Pancreatic exocrine disease associated with hyperglycemia or DM has a unique clinical and metabolic form. It is painless occasionally and malabsorption occurs after clinical hyperglycemia or DM following failure or impairment of endocrine and exocrine pancreatic

Iron overload and excessive tissues deposition of iron including the pancreas. It is an autosomal recessive genetic disorder caused by a mutation in the HFE gene located on the short arm of chromosome 6. Approximately 50% of patients diagnosed with hemochromatosis will have

Diabetes Mellitus is the most common morbidity in patients with cystic fibrosis (CF). It occurs in about 20% of adolescent and 40-50% of adults with this disease. CF primarily caused by insulin insufficiency. However, there is a role for IR in acute and chronic stages of this disease due to fluctuation level of insulin. DM has a unique distinct entity in patient with CF because

hepatic expression of the glucose transporter GLUT2 [243].

**11.2. Polycystic ovary syndrome**

86 Treatment of Type 2 Diabetes

weight matched control age group [245].

function of both α and β cells [246]

**11.4. Hereditary hemochromatosis**

it has mixed features of TIDM and T2DM [249].

either type 1 or T2DM [248].

**11.5. Cystic fibrosis**

**11.3. Pancreatic damage or β-cell damage of the pancreas**

There are several studies suggestive of smoking is a risk factor for T2DM, it is an independent and modifiable risk. The early weight gain following smoking cessation is far more beneficial compared with the long term effect of smoking. This weight gain could increase the risk of diabetes [250-252]. Smoking deteriorates glucose metabolism and it is considered a possible a risk factor for development of IR and subsequently T2DM [253]. Smoking is also through a body mass index independent mechanism increasing the risk of T2DM [254, 255]. Pancreatic damage by toxic agents cause insufficient insulin secretion and development of the disease. Tobacco is one of the toxic agent to the human body and organ damage; on the pancreas it is also considered a risk factor of pancreatic cancer and chronic pancreatitis [256].

#### **11.7. Prematurity and birth weight**

Hofman PL in 2004 reported an association between low birth weight, commonly a reflection of an adverse in utero environment, and the subsequent development of diseases such as T2DM and hypertension in later life is now generally accepted as is an association between an adverse perinatal environment and a permanent reduction in IS [257, 258].This concept was changed in other report by the evidence has accumulated that small for gestational age children have long-term adult health consequences including obesity, T2DM, hypertension, coronary artery disease and stroke. This increased risk of later adult disease is likely a consequence of an early, persistent reduction in IS [259]. Reduced fetal growth is associated with increased risk of diabetes and suggested a specific association with thinness at birth [260]. Prevalence of T2DM and IGT depended on the synergic effect of thin body size at birth and obesity during adulthood [261]. IGT and T2DM are early signs and indications of growth retardation in early life. The raise in plasma levels of 32-33 split proinsulin is closely related to growth retardation and reflects the β-cells dysfunction [262]. A review and analysis of 14 studies low birth weight (<2,500 g), as compared with a birth weight of >/=2,500 g, was associated with increased risk of T2DM. The risk is the same in high birth weight (>4,000 g), as compared with a birth weight of (</=4,000 g) [263]. The two strongest predictor factors for development of T2DM in adult life are low birth weight and abdominal obesity. The risk of T2DM in Chinese adults is inversely correlated to birth weight. Subjects with high risk of developing hypertension and abdominal obesity are those with the lowest or highest birth weight [264].
