The Effects Of Metformin And Diabinese On Female Sex Hormone Of Type 2 Diabetes Mellitus Patients Attending University Of Ilorin Teaching Hospital (UITH), Ilorin, Kwara State.
1.1 Background of Study
Diabetes mellitus is a group of metabolic disorders in which a person has high plasma glucose, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. The high plasma glucose produces the classical symptoms of polyuria, polydipsia and polyphagia (Rother, 2007). Type 2 diabetes mellitus, formerly non-insulin dependent diabetes mellitus or adult onset diabetes, is a metabolic disorder that is characterized by hyperglycemia in the context of insulin resistance and relative insulin deficiency (Vinayet al., 2008). It has been regarded as one of the most common metabolic diseases with the rate of 6.4 % in people aged 20-79 years and one of the leading causes of death all over the world (Burtiset al., 2008; Vinayet al., 2008; Rosen, 2012). Nearly 80% of the type 2 diabetes mellitus patients come from developing countries (Dhindsaet al., 2009).
Many factors, such as genetics, aging and life style, have been involved in the development of type 2 diabetic mellitus, diagnosis of type 2 diabetic mellitus are found to be obese (Ramarao and Kaul, 2009). Over 90% of people with diabetes mellitus are type 2 diabetics and it is reported to be associated with certain endocrine disorders. There have been increasing anti-diabetic drugs such as sulfonylureas, biguanides and dipeptidyl peptidase-4 have been used to control type 2 diabetes mellitus (Murali and Saravanan, 2012; Neeratiet al., 2014). However, most of these anti-diabetic drugs have limited efficacy and many undesirable side effects such as drug resistance, weight gain, dropsy and high rates of secondary failure (Tahraniet al., 2010; Murali and Saravanan, 2012). Therefore, the development of low toxicity, effective and economic anti-diabetic drugs is still needed and has far-reaching significance. Metformin, a class of insulin sensitizers, is commonly used for the treatment of type 2 diabetes. While lowering the blood glucose level, metformin can cause reduction of fat mass and inhabitation of tumor cell proliferation (Kargulewiczet al., 2016; Huoet al., 2017).Diabinese is equally used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (Murali and Saravanan, 2012).
Metformin hydrochloride, a biguanide, is the most popular oral glucose-lowering medication in most countries, widely viewed as ‘foundation therapy’ for individuals with newly diagnosed type 2 diabetes mellitus. This reputation has resulted from its effective glucose-lowering abilities, low cost, weight neutrality, overall good safety profile (especially the lack of hypoglycaemia as an adverse effect), and modest evidence for cardioprotection (Inzucchiet al., 2015). A derivative of guanidine, which was initially, extracted from the plant Galegaofficinalis or French lilac, metformin was first synthesised in 1922 and introduced as a medication in humans in 1957, after the studies of Jean Sterne (Sterne, 2007). Its popularity increased after eventual approval in the USA in 1994, although it was used extensively in Europe and other regions of the world prior to that (Pryor and Cabreiro, 2015). The drug’s efficacy has been demonstrated in monotherapy as well as in combination with other glucose lowering medications for type 2 diabetes mellitus. Based on these important characteristics, there continues to be extensive interest in this compound, even many years after its incorporation into the diabetes pharmacopeia. Interestingly, and despite this popularity, there still remains controversy about the drug’s precise mechanism of action, although most data point to a reduction in hepatic glucose production being predominately involved although, recent data suggests that some of the drug’s effect may involve the stimulation of intestinal release of Incretin hormones (Rena et al., 2017).
Diabinese (chlorpropamide) is an oral blood-glucose-lowering drug of the sulfonylurea class(Inzucchiet al., 2015).It lowers the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which diabinese lowers blood glucose during long-term administration has not been clearly established(Inzucchiet al., 2015). Extra-pancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
At rest, women have greater storage of free Fatty acids than men, but during exercise and conditions of sustained increased demand, women were shown to exert higher oxidation of lipids in relation to carbohydrates. Males instead rely relatively more on glucose and protein metabolism (Mauvais-Jarvis, 2015). During times of food deprivation, females reduce energy expenditure with consequent loss of fat stores contrary to males.
Estrogen can decrease food intake directly by effects in the brain. Tight interacting of leptin, insulin, neuropeptide Y (NPY), and ghrelin seem to play a vital role (Brown et al, 2010). Moreover, estrogen can exert direct effects on fat tissue by enhancing proliferation of pre-adipocytes, especially in females (Anderson et al., 2001), and by up-regulating sc-2A-adrenergic receptors promoting SAT accumulation, notably in premenopausal women (Pedersen et al., 2004). Women display less reduction of insulin sensitivity with increasing body fat and lower resting energy expenditure, which declines more rapidly with ageing compared with men. However, up to now, there is paucity of research that establishes the direct effects of anti-diabetic drugs (metformin and diabinese) on female sex hormone. This study therefore addresses the gap in knowledge of the effects of combine anti-diabetic drugs diabinese and metformin on female sex hormone of patients with type 2 diabetes mellitus.
1.3 Aim of Study
The study aims at evaluating the effects of metformin and diabinese on female sex hormone of type 2 diabetes mellitus patients attending University of Ilorin Teaching Hospital (UITH), Ilorin, Kwara State.
1.4 Specific Objectives
The specific objectives of this study include:
- To determine the levels of oestrogen and progesterone in patients with type 2 diabetes mellitus on metformin and diabinese therapy.
- To determine the level of oestrogen and progesterone in apparently non-diabetic age matched volunteer female individual.
- To compare the result of one and two above in order to make inference on the status of oestrogen and progesterone in type 2 diabetes mellitus patients
- To assess the association between the level of Oestrogen and progesterone and the duration of the diabetes.
1.5 Research Hypothesis
- Ho: Anti-diabetic drugs does not have direct effect on female sex hormone of patients with type 2 diabetes mellitus.
- H1: An anti-diabetic drug have direct effect on female sex hormone of patients with type 2 diabetes mellitus.
1.6 Scope of the Study
Patients for this study will be recruited from University of Ilorin Teaching Hospital (UITH), Ilorin in order to analyse the estrogen and progesterone in serum of patients with type 2 diabetes mellitus on metformin and diabinese and compare values with control subjects.
1.7 Research Design
This is a Randomized cross sectional case-control study.
Type 2 diabetes mellitus, formerly known as non-insulin dependent diabetes mellitus or adult onset diabetes, is a metabolic disorder that is characterized by hyperglycemia in the context of insulin resistance and relative insulin deficiency (Vinayet al., 2008). Sex differences and the role of gonadal hormones in modulating insulin sensitivity and glucose tolerance are of increasing interest and importance because of the increasing prevalence of type 2 diabetes mellitus and the metabolic abnormalities associated with aging. Body composition is closely associated with insulin sensitivity, and increased body fat, particularly in the visceral compartment, is a risk factor for developing type 2 diabetes mellitus. Sex differences in body composition and/or insulin sensitivity are evident in humans throughout the lifespan.
In this study female sex hormone was assayed in patients on antidiabetic drugs (metformin and diabinese), observable data shows the mean age of the diabetic patients and the control to be 57.43±1.31 and 43.30±2.67respectively and this was different and statistically significant (p˂0.05). The educational status of the diabetic patients and non-diabetic control subjects were tertiary 27(45%); secondary 3(5%); Primary 9(15%) and none 21(35%) and non-diabetic control subjects were tertiary31(77.5%); primary 1(2.5%); none education 8(20%) and none has secondary education and this was statistically significant. The significant differences recorded in the mean age, marital status and educational status of the diabetic patients compare with the control may be attributed to a product of chance. However Campagnoliet al. (2012) reported no significant difference in the mean age and other demographic indices of patients treated with metformin and other antidiabetic agents.
Also, the anthropometric indices between diabetic patients using antidiabetic drugs (Metformin and Diabinese) and non-diabetic patients (control) depicts a significantly (p˂0.05) increased mean height in the diabetic patients (170.78±0.62) compare to control (168.4±0.816). The mean weight and BMI of the diabetic patients compare with the control were however not statistically significant (p>0.05). This finding was consistent with the previous work of Shahghebiet al. (2013)that recorded a higher BMI in diabetic patients compare with that of the control. Also, another author documented the treatment with metformin to be associatedwith less hypoglycaemic events and less or no weight gain when compared to insulin and sulfonylurea treatment (Eriksson1 and Nystrom, 2015). Also studies by Onalanet al. indicated that treatment with metformin increases insulin sensitivity and reduce weight and body mass index (BMI), blood pressure, and cholesterol levels (Onalanet al., 2005). However Campagnoliet al. (2012) reported no significant difference in the mean height, weight and BMI of patients treated with metformin and other antidiabetic agents.
In this study the comparison of biochemical parameters (estrogen, progesterone and fasting blood sugar)in diabetes patient using antidiabeticdrugs (metformin and diabinese) and non-diabetic control patients shows a significantly (p˂0.05) reduced level of Estrogen(35.5 ±3.988) and Progesterone (0.78 ±0.0 06) in the diabetic patients using antidiabetic drugs compared with the non-diabetic control patients (58.72 ±12.31 and 2.49 ±0.64 respectively). However, the diabetic patients on antidiabetic drugs recorded a significantly (p˂0.05) elevated fasting blood sugar level (9.11 ±0.39) compared with the non-diabetic control patients (5.07 ±0.85). The decrease in estrogen and progesterone recorded in the diabetic patients may be associated with the effects of antidiabetic drugs on these hormones levels. Metformin has been documented to reduce sex hormone (Hankinson and Eliassen, 2007; Farhatet al., 2011). This findings correlates with the report of Campagnoliet al. (2012) in which metformin was reported to decrease circulating androgen and estrogen levels in non-diabetic women with breast cancer. Estrogen and progesterone are hormones produces and released by the ovaries, adrenal gland and the placental during pregnancy. They are also kept in reserve in the adipose tissue and have been documented to affect how cells respond to insulin. A fluctuation in progesterone, estrogen and other hormones has been documented to exacerbate diabetic symptoms. With the aforementioned, the lowering effects of antidiabetic drugs may directly reduce the level of these hormones as demonstrated by this present study.
Also, estrogen and progesterone has been implicated in the activation of the constitutive androstane receptor (CAR) is an orphan nuclear receptor. It was originally characterized as a nuclear receptor that can activate an empirical set of retinoic acid response elements without retinoic acid (Baeset al. 1994, Choi et al. 1997), and can be activated in response to xenochemical exposure, including phenobarbital (PB)-stimulated activation of a response element, NR1, found in the human cytochrome p450 2B (CYP2B) genes (Honkakoskiet al. 2008, Sueyoshiet al. 2009). Metformin on the other hand act in an antagonistic manner, this mechanism may equally explain the lower level of estrogen and progesterone recorded in this study. Although to the best of our knowledge, till date there is no documentation on the direct effect of metformin on estrogen and progesterone.
Another mechanism of the reduced estrogen and progesterone recorded in this study may be the indirect reduction of estrogen by the action of metformin on testosterone which invariably reduces estrogen level (Key et al., 2011).
The increase in mean fasting blood sugar level recorded in the patients on anti-diabetic drugs compare with the control subjects may be attributed to the fact that the test subjects are known and confirmed diabetic patients. This observation correlate with the findings of various authors, who documented the increase in fasting blood sugars in patients with type 2 diabetes mellitus compare to normal control (Campagnoliet al., 2013; Shahghebiet al., 2013). However, Kazerooniet al. (2010) performed a study in Shiraz and found no significant change in blood sugar of diabetic patients after metformin administration over a period of 3 months and 6 months. However the difference in the level of fasting blood sugar recorded in these various studies might be attributed to the doses of metformin and other anti-diabetic agents used.
In the present study, the comparison of biochemical parameters (Estrogen, Progesterone and Fasting blood sugar) between diabetic patient on Metformin only and diabetic patients on combined metformin with other drugs (glimepiride) shows an insignificant (p>0.05) increased in the level of estrogen (36.15 ±4.33), progesterone (0.78 ±0.61) and fasting blood sugar (9.22 ±0.42) of patients using metformin alone compare with patients using metformin with other drugs (29.20 ±3.85; 0.74 ±0.17 and 7.80 ±1.16 respectively). This finding is in agreement with the previous works of Eriksson and Nystrom (2015), in which various antidiabetic agents were documented to reduce fasting blood sugar. Various studies confirm the positive effect of metformin on most metabolic functions such as better blood glucose control, lipid profile improvement, and decrease in cystic inflammation (Yu Ng et al., 2001; Onalanet al., 2005; Banaszewskaet al., 2006). More so the action of these antidiabetic agents may directly affect the levels of estrogen and progesterone which may account for the insignificant differences observed in patients using metformin and patients combining metformin and other drugs.
In this study the correlation of duration of diabetes and BMI with biochemical parameters (estrogen, progesterone and fasting blood sugar) in diabetic patients using antidiabeticdrugs (metformin and diabinese) indicated a significant correlation between biochemical parameters and duration of diabetes. Estrogen and duration of illness (rValue 0.778; p <0.037); progesterone (rValue 0.97; p <0.004) and fasting blood sugar (rValue0.773;p<0.038). However, data indicated no significant correlation between biochemical parameters and body mass index of the patients. This finding is in agreement with the report of Vermaet al. (2006) who reported a significant correlation between the duration of ailment and fasting blood sugar.
This study has established that antidiabetic drugs metformin and diabinese have a lowering effect on female sex hormone (estrogen and progesterone).
It is therefore recommended that Physicians be conscious of the secondary effects of antidiabetic drugs on other organs of the body. Also, these effects of antidiabetic drugs on other biochemical analytes should be performed probably on a larger population.
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