**10. Gestational Diabetes Mellitus**

**Drugs Mechanisms Notes**

causes hypoglycemia [192].

absorption of glucose.

Causes hyperglycemia.

Stimulation of insulin secretion by inhibition of pancreatic beta-cell K(ATP) channels

Gatifloxacin was withdrawn from the market because of this effect [193]. Levofloxacin has a small effect. [192].

It is an early phase of hyperglycemia and disappeared after few days of treatment.

The incidence of new onset DM was 14 to 16% augmented in the first post-

transplantation year, declining thereafter to an annual incidence of 4 to 6%, similar to the pre-transplantation baseline rate [205,

The cumulative incidence of new onset DM was 24% at 3 yr after transplantation [205].

There is a synergetic effect of cyclosporine

Thalidomide, withdrawn for teratogenicity and was reintroduced in 1997 as an immunomodulator to treat erythema

Among all adults who use natural products, more than 37% report taking fish

Sustained virological responses reduce the risk of developing glucose abnormalities, especially in patients with normal glucose

to induce DM if given with other diabetogenic drug [207].

nodosum leprosum.

oil or omega-3s.

[210].

baseline.

This effect in rat [194].

206].

It may also cause hyperglycemia. [193].

Impair the function β-cells by impairing insulin gene expression [195-197].

Impair insulin-mediated suppression of hepatic glucose production [202]. May cause ectopic triglyceride deposition,

The above aggravated by many modifiable and non-modifiable risk factors [201].

Decreases insulin-stimulated peripheral glucose uptake by 31% (increased insulin

Decreases glycogen synthesis by 48%.

PUFAs may affect glucose metabolism through increased IS, but studies to date

Risk of hyperglycemia only in patient with

have been inconclusive [209].

chronic hepatitis C infection.

Direct β-cells toxicity [198-200].

Decreases in IS [201].

leading to IR [203, 204].

resistance)

Possibly by augmenting intestinal

Gatifloxacin Temafloxacin Levofloxacin

82 Treatment of Type 2 Diabetes

**Rifampicin** [191].

**Tetracyclines** Tetracycline chlortetracycline

Cyclosporine

Sirolimus Tacrolimus Cyclosporine

**Thalidomide** [208].

**Fish oil**

or Omega -3 polyunsaturated

fatty acids (PUFAs).

**Interferon α** [211].

**\Calcineurin inhibitors**

Gestational diabetes mellitus (GDM) is a heterogeneous pathogenic condition affecting 2-5% of all pregnant women during pregnancy [223, 224] in other data is 5-6% [225]. GDM and T2DM share a common pathophysiological background, including β-cell dysfunction and IR [226, 227]. In addition, women with GDM are at increased risk of developing T2DM later in life [226]. The pancreatic β- cells failure and impairment is the primary characteristic of GDM. In this group of patients with diabetes, there is a genetic predisposition triggered by increased IR during pregnancy leading to malfunction of the pancreatic β-cells [224]. The clustering of the GDM within family members suggestive of genetic predisposition to the development of this disease. Furthermore, women with MODY gene mutations are reported to have GDM 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 associated GDM [228].

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

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

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 glucose tolerance status [234].

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 correlated with β- cells dysfunction [236].

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‐ one, and human placental growth hormone (hPGH) are important placental hormones. Severe IR produced by overexpression of hPGH and the increase of the HCS throughout pregnancy stimulates maternal pancreatic insulin release [237].

The fall of IS during pregnancy is counteracted by increase maternal insulin secretion to maintain glucose control [238]. The insufficient insulin secretion to counteract the pregnancyrelated decrease in IS is contributing in development of DM [239]. Women at high risk of GDM should have a prior conception plan to prevent DM by normalize body weight, regular physical exercise, reducing excess intake of animal protein and soft drinks, planning of pregnancy in younger ages, avoiding pollutant exposition and smoking cessation [240].
