Jump to content

Biomarkers of diabetes: Difference between revisions

Add links
From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
No edit summary
No edit summary
Line 12: Line 12:




'''Diabetes mellitus (DM):''' is a type of metabolic disease characterized by hyperglycemia. It is caused by either defected insulin secretion or damaged biological function, or both. The high-level blood glucose for a long time will lead to dysfunction of a variety of tissues.
'''Diabetes mellitus (DM):''' is a type of metabolic disease characterized by hyperglycemia. It is caused by either defected insulin secretion or damaged biological function, or both. The high-level blood glucose for a long time will lead to dysfunction of a variety of tissues.<ref>AbuHanoud, Amal, Violet Kasabri, Naiyla Bulayova, Amal Akour, Haidar Bustanji, Nahla Khawaja, Dana Hyasat, Rula Silawi, Yasser Bustanji, and Yusuf Al-Hiari. "Evaluation of Oxytocin (OXT), Endothelin-1 and Nesfatin Plasma Concentrations in Newly-diagnosed Diabetic and Non-diabetic Patients with Metabolic Syndrome." Jordan Journal of Pharmaceutical Sciences 9, (2016): 2-12</ref>


'''Type 2 diabetes:''' is a progressive condition in which the body becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in the pancreas.
'''Type 2 diabetes:''' is a progressive condition in which the body becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in the pancreas.<ref>"Type 2 Diabetes." Diabetes Australia. Accessed December 1, 2018. https://www.diabetesaustralia.com.au/type-2-diabetes.</ref>


'''Pre-diabetes:''' means that your blood sugar level is higher than normal but not yet high enough to be type 2 diabetes.
'''Pre-diabetes:''' means that your blood sugar level is higher than normal but not yet high enough to be type 2 diabetes.<ref>Hess-Fischl, Amy. "Prediabetes." Endocrine Web. July 9, 2018. Accessed December 1, 2018. https://www.endocrineweb.com/conditions/pre-diabetes/pre-diabetes.</ref>


'''Gestational diabetes:''' is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy.
'''Gestational diabetes:''' is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy.<ref>"Gestational Diabetes." Mayo Clinic. April 28, 2017. Accessed December 1, 2018. https://www.mayoclinic.org/diseases-conditions/gestational-diabetes/symptoms-causes/syc-20355339.</ref>


Type 2 diabetes mellitus and prediabetes are associated with changes in levels of metabolic markers, these markers could serve as potential prognostic or therapeutic targets for patients with prediabetes or Type 2 diabetes mellitus.
Type 2 diabetes mellitus and prediabetes are associated with changes in levels of metabolic markers, these markers could serve as potential prognostic or therapeutic targets for patients with prediabetes or Type 2 diabetes mellitus.<ref>Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8</ref>



'''Metabolic markers:
⚫
'''Metabolic markers:<ref>Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8</ref>
'''
'''
* Oxytocin (OXT)
* Oxytocin (OXT)
Line 34: Line 35:




-Biomarkers with insulin-sensitizing properties (irisin, omentin, oxytocin)
-Biomarkers with insulin-sensitizing properties (irisin, omentin, oxytocin)<ref>Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8</ref>


-Biomarkers of metabolic dysfunction (HGF, Nesfatin and Betatrophin)<ref>Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8</ref>
-Biomarkers of metabolic dysfunction (HGF, Nesfatin and Betatrophin)


⚫
=Biomarkers with insulin-sensitizing properties:=




⚫
'''Biomarkers with insulin-sensitizing properties:
'''


'''Oxytocin'''
'''Oxytocin'''


Oxytocin (OXT), a hormone most commonly associated with labor and lactation, may have a wide variety of physiological and pathological functions, which makes Oxytocin and its receptor potential targets for drug therapy.
Oxytocin (OXT), a hormone most commonly associated with labor and lactation, may have a wide variety of physiological and pathological functions, which makes Oxytocin and its receptor potential targets for drug therapy.<ref>Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).</ref>
OXT may have positive metabolic effects; this is based on the change in glucose metabolism, lipid profile, and insulin sensitivity. It may modify glucose uptake and insulin sensitivity both through direct and indirect effects. It may also cause regenerative changes in diabetic pancreatic islet cells. So, the activation of the OXT receptor pathway by infusion of OXT, OXT analogues, or OXT agonists may represent a promising approach for the management of obesity and related metabolic diseases as well as diabetes and its complications.
OXT may have positive metabolic effects; this is based on the change in glucose metabolism, lipid profile, and insulin sensitivity. It may modify glucose uptake and insulin sensitivity both through direct and indirect effects. It may also cause regenerative changes in diabetic pancreatic islet cells. So, the activation of the OXT receptor pathway by infusion of OXT, OXT analogues, or OXT agonists may represent a promising approach for the management of obesity and related metabolic diseases as well as diabetes and its complications.<ref>Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).</ref>




⚫
'''Oxytocin improves insulin sensitivity by:'''<ref>Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).</ref>
'''Oxytocin improves insulin sensitivity by:'''


* Reducing Gluco-toxicity and Lipo-toxicity.
* Reducing Gluco-toxicity and Lipo-toxicity.
Line 55: Line 57:




'''Oxytocin may cause β-cell regeneration by:'''
'''Oxytocin may cause β-cell regeneration by:'''<ref>Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).</ref>


* OXT decreases pancreatic islet hypertrophy.
* OXT decreases pancreatic islet hypertrophy.
Line 65: Line 67:




'''Oxytocin levels:'''<ref>Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8.</ref>
'''Oxytocin levels:'''


* OXT was negatively and significantly correlated with HbA1c, FGF21, HGF and positively correlated with both irisin and gender.
* OXT was negatively and significantly correlated with HbA1c, FGF21, HGF and positively correlated with both irisin and gender.
Line 74: Line 76:
'''Omentin
'''Omentin
'''
'''

⚫
Omentin is an anti-inflammatory adipokine produced preferentially by visceral adipose tissue. Plasma omentin-1 levels are significantly decreased in patients with obesity, insulin resistance and diabetes that contribute to the major components of the metabolic syndrome. Insulin resistance contributes to the changes of cholesterol synthesis and absorption as well. However, nothing is known about the relationship between Omentin and metabolic risk factors. So a study were held in japan comprised 201 Japanese men who underwent annual health check-ups. Plasma Omentin levels were determined by enzyme-linked immunosorbent assay. They divided the subjects into 4 groups according to Omentin levels. A reduction of plasma Omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, Dyslipidemia, high blood pressure and glucose intolerance. They concluded that Circulating Omentin levels are negatively correlated with the multiplicity of metabolic risk factors, suggesting that Omentin acts as a biomarker of metabolic disorders.

⚫
Omentin is an anti-inflammatory adipokine produced preferentially by visceral adipose tissue. Plasma omentin-1 levels are significantly decreased in patients with obesity, insulin resistance and diabetes that contribute to the major components of the metabolic syndrome. Insulin resistance contributes to the changes of cholesterol synthesis and absorption as well. However, nothing is known about the relationship between Omentin and metabolic risk factors. So a study were held in japan comprised 201 Japanese men who underwent annual health check-ups. Plasma Omentin levels were determined by enzyme-linked immunosorbent assay. They divided the subjects into 4 groups according to Omentin levels. A reduction of plasma Omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, Dyslipidemia, high blood pressure and glucose intolerance. They concluded that Circulating Omentin levels are negatively correlated with the multiplicity of metabolic risk factors, suggesting that Omentin acts as a biomarker of metabolic disorders.<ref>AbuHanoud, Amal, Violet Kasabri, Naiyla Bulayova, Amal Akour, Haidar Bustanji, Nahla Khawaja, Dana Hyasat, Rula Silawi, Yasser Bustanji, and Yusuf Al-Hiari. "Evaluation of Oxytocin (OXT), Endothelin-1 and Nesfatin Plasma Concentrations in Newly-diagnosed Diabetic and Non-diabetic Patients with Metabolic Syndrome." Jordan Journal of Pharmaceutical Sciences 9, (2016): 2-12</ref>




Line 80: Line 84:


Irisin, a newly identified hormone, was first reported by Bostromet al. in 2012, is a novel myokine which plays an important role in the homeostasis , metabolism and energy balance. Irisin is reported to be involved in insulin resistance in both humans and animal models. Circulating irisin levels progressively decrease with the worsening of the glucose tolerance.
Irisin, a newly identified hormone, was first reported by Bostromet al. in 2012, is a novel myokine which plays an important role in the homeostasis , metabolism and energy balance. Irisin is reported to be involved in insulin resistance in both humans and animal models. Circulating irisin levels progressively decrease with the worsening of the glucose tolerance.<ref>Hee Park, Kyung, Lesya Zaichenko, Mary Brinkoetter, Bindiya Thakkar, Ayse Sahin-Efe, Kyoung Eun Joung, Michael A. Tsoukas, Eleni V. Geladari, Joo Young Huh, Fadime Dincer, Cynthia R. Davis, Judith A. Crowell, and Christos S. Mantzoros. "Circulating Irisin in Relation to Insulin Resistance and the Metabolic Syndrome." The Journal of Clinical Endocrinology & Metabolism 98, no. 12 (2013): 4899-907</ref>
A recent study conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone Irisin and the established adipokine adiponectin with metabolic syndrome, cardio-metabolic variables and cardiovascular disease risk, and they found out that the baseline irisin levels were significantly higher in subjects with metabolic syndrome than in subjects without metabolic syndrome.
A recent study conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone Irisin and the established adipokine adiponectin with metabolic syndrome, cardio-metabolic variables and cardiovascular disease risk, and they found out that the baseline irisin levels were significantly higher in subjects with metabolic syndrome than in subjects without metabolic syndrome.<ref>Hee Park, Kyung, Lesya Zaichenko, Mary Brinkoetter, Bindiya Thakkar, Ayse Sahin-Efe, Kyoung Eun Joung, Michael A. Tsoukas, Eleni V. Geladari, Joo Young Huh, Fadime Dincer, Cynthia R. Davis, Judith A. Crowell, and Christos S. Mantzoros. "Circulating Irisin in Relation to Insulin Resistance and the Metabolic Syndrome." The Journal of Clinical Endocrinology & Metabolism 98, no. 12 (2013): 4899-907</ref>


'''Biomarkers of metabolic dysfunction:
=Biomarkers of metabolic dysfunction:=

'''



'''Nesfatin-1
'''Nesfatin-1
'''
'''
⚫
Nesfatin-1 is a peptide secreted by peripheral tissues, central and peripheral nervous system. It is involved in the regulation of energy, homeostasis related with food regulation and water intake.
⚫
Nesfatin-1 can pass through the blood-brain barrier in both directions. It suppresses feeding independently from the leptin pathway and increases insulin secretion from pancreatic beta islet cells. this is demonstrated by in-vitro studies that Nesfatin-1 stimulates the Preproinsulin mRNA expression and increases the glucose induced insulin release. That is why nesfatin-1 has drawn attention as a new therapeutic agent, especially for the treatment of obesity and diabetes mellitus.


⚫
Nesfatin-1 is a peptide secreted by peripheral tissues, central and peripheral nervous system. It is involved in the regulation of energy, homeostasis related with food regulation and water intake.<ref>Ayada, Toru, and Korkut. "Nesfatin-1 and Its Effects on Different Systems." Hippokratia 19, (2015): 4-10</ref>
⚫
In T2DM patients Nesfatin-1 is elevated and this could possibly be as a result of a resistance. Thus, Nesfatin-1 acts as a potent Anorexigenic factor (anti-obesity) that improves insulin resistance and opposes weight gain.
⚫
Nesfatin-1 can pass through the blood-brain barrier in both directions. It suppresses feeding independently from the leptin pathway and increases insulin secretion from pancreatic beta islet cells. this is demonstrated by in-vitro studies that Nesfatin-1 stimulates the Preproinsulin mRNA expression and increases the glucose induced insulin release. That is why nesfatin-1 has drawn attention as a new therapeutic agent, especially for the treatment of obesity and diabetes mellitus.<ref>Ayada, Toru, and Korkut. "Nesfatin-1 and Its Effects on Different Systems." Hippokratia 19, (2015): 4-10</ref>

⚫
In T2DM patients Nesfatin-1 is elevated and this could possibly be as a result of a resistance. Thus, Nesfatin-1 acts as a potent Anorexigenic factor (anti-obesity) that improves insulin resistance and opposes weight gain.<ref>Ayada, Toru, and Korkut. "Nesfatin-1 and Its Effects on Different Systems." Hippokratia 19, (2015): 4-10</ref>




Line 99: Line 105:
'''
'''


Hepatocyte growth factor (HGF) is a mitogen and insulin tropic agent for the β cell. Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis.
Hepatocyte growth factor (HGF) is a mitogen and insulin tropic agent for the β cell. Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis.<ref>Morishita, Ryuichi, Shigefumi Nakamura, Yoshio Nakamura, Motokuni Aoki, Atsushi Moriguchi, Iwao Kida, Yoshikage Yo, Kunio Matsumoto, Toshikazu Nakamura, Jitsuo Higaki, and Toshio Ogihara. "Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes." American Diabetes Association 46, (1996): 138-42</ref>.<ref>Demirci, Cem, Sara Ernst, Juan C. Alvarez-Perez, Taylor Rosa, Shelley Valle, Varsha Shridhar, Gabriella P. Casinelli, Laura C. Alonso, Rupangi C. Vasavada, and Adolfo García-Ocana. "Loss of HGF/c-Met Signaling in Pancreatic Β Cells Leads to Incomplete Maternal Β-Cell Adaptation and Gestational Diabetes Mellitus." American Diabetes Association (2012)</ref>
It is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. In diabetic patient’s, levels of the hepatocyte growth factor (HGF) were found in high levels, thus independently associated with increased the incidence of diabetes.
It is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. In diabetic patient’s, levels of the hepatocyte growth factor (HGF) were found in high levels, thus independently associated with increased the incidence of diabetes.
There is a study that indicate that HGF/c-Met signalling is essential for maternal β-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus.
There is a study that indicate that HGF/c-Met signalling is essential for maternal β-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus.<ref>Demirci, Cem, Sara Ernst, Juan C. Alvarez-Perez, Taylor Rosa, Shelley Valle, Varsha Shridhar, Gabriella P. Casinelli, Laura C. Alonso, Rupangi C. Vasavada, and Adolfo García-Ocana. "Loss of HGF/c-Met Signaling in Pancreatic Β Cells Leads to Incomplete Maternal Β-Cell Adaptation and Gestational Diabetes Mellitus." American Diabetes Association (2012)</ref>.<ref>Morishita, Ryuichi, Shigefumi Nakamura, Yoshio Nakamura, Motokuni Aoki, Atsushi Moriguchi, Iwao Kida, Yoshikage Yo, Kunio Matsumoto, Toshikazu Nakamura, Jitsuo Higaki, and Toshio Ogihara. "Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes." American Diabetes Association 46, (1996): 138-142</ref>




Line 107: Line 113:
'''
'''


is a novel protein predominantly expressed in human liver and adipose tissues. Increasing evidence has revealed an association between betatrophin expression and serum lipid profiles, particularly in patients with obesity or diabetes, Thus betatrophin is closely related to diabetes treatment, it promotes greatly the proliferation of pancreatic beta cells, plays an important role in modulating glycolipid metabolism, and maybe replaces insulin in the effective treatment of diabetes.
is a novel protein predominantly expressed in human liver and adipose tissues. Increasing evidence has revealed an association between betatrophin expression and serum lipid profiles, particularly in patients with obesity or diabetes, Thus betatrophin is closely related to diabetes treatment, it promotes greatly the proliferation of pancreatic beta cells, plays an important role in modulating glycolipid metabolism, and maybe replaces insulin in the effective treatment of diabetes.<ref>Yue, Song, Jingyang Wu, Jiahua Zhang, Lei Liu, and Lei Chen. "The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis." Hindawi 2016, (2016): 1-8</ref>
studies showed that betatrophin could increase the quantity of cells that produce insulin in mice quickly. Others showed that the circulating level of betatrophin in T2DM patient blood was higher than that in control groups.
studies showed that betatrophin could increase the quantity of cells that produce insulin in mice quickly. Others showed that the circulating level of betatrophin in T2DM patient blood was higher than that in control groups.<ref>Yue, Song, Jingyang Wu, Jiahua Zhang, Lei Liu, and Lei Chen. "The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis." Hindawi 2016, (2016): 1-8</ref>
Expression of betatrophin correlates with β cell proliferation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.
Expression of betatrophin correlates with β cell proliferation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.<ref>Yue, Song, Jingyang Wu, Jiahua Zhang, Lei Liu, and Lei Chen. "The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis." Hindawi 2016, (2016): 1-8</ref>


=Others:=
=Others:=
Line 117: Line 123:
'''
'''


Is a vasoconstrictor peptide released from vascular endothelial cells. At the cellular level, the balance between vasodilator (Nitric oxide) and vasoconstrictor (ET-1) actions determines the vascular response to insulin. So, high levels of ET-1, which achieved in insulin resistance states that includes patients that have T2DM or metabolic syndromes or they are obese, have inhibitory effect on nitric oxide production which results in low nitric oxide and heightened levels of ET-1.
Is a vasoconstrictor peptide released from vascular endothelial cells. At the cellular level, the balance between vasodilator (Nitric oxide) and vasoconstrictor (ET-1) actions determines the vascular response to insulin. So, high levels of ET-1, which achieved in insulin resistance states that includes patients that have T2DM or metabolic syndromes or they are obese, have inhibitory effect on nitric oxide production which results in low nitric oxide and heightened levels of ET-1.<ref>Takahashi, Ghatei, Lam, H a l l o r a n, and B l o o m. "Elevated Plasma Endothelin in Patients with Diabetes Mellitus." Diabetologia 33, (1990): 306-10.</ref>
ET-1 activity is also enhanced secondary to abnormalities in vascular insulin signalling, In addition to its direct vasoconstrictor effects. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome.
ET-1 activity is also enhanced secondary to abnormalities in vascular insulin signalling, In addition to its direct vasoconstrictor effects. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome.<ref>Takahashi, Ghatei, Lam, H a l l o r a n, and B l o o m. "Elevated Plasma Endothelin in Patients with Diabetes Mellitus." Diabetologia 33, (1990): 306-10.</ref>




PVAT AND ET-1:
PVAT AND ET-1:


ET-1 In addition to its direct vasoconstrictor effects, it causes changes in visceral and perivascular adipose tissue (PVAT), and may contribute to the pathogenesis of both insulin resistance and vascular dysfunction/damage. Perivascular adipose tissue seems to have anti contractile effect and this dilator effect was lost in obese patients.
ET-1 In addition to its direct vasoconstrictor effects, it causes changes in visceral and perivascular adipose tissue (PVAT), and may contribute to the pathogenesis of both insulin resistance and vascular dysfunction/damage. Perivascular adipose tissue seems to have anti contractile effect and this dilator effect was lost in obese patients.<ref>...</ref>
secondary to obesity, ET-1 high level changes on PVAT will lead to PVAT hypertrophy which will be associated with reduced partial oxygen pressure, an increase in the production of inflammatory cytokines such as TNF-α and IL-6, and elevation of reactive oxygen species. Thus, oxidative stress and hypoxia may promote imbalance in the production of vasoactive compounds and may affect vascular homeostasis by activating the ET-1 system.
secondary to obesity, ET-1 high level changes on PVAT will lead to PVAT hypertrophy which will be associated with reduced partial oxygen pressure, an increase in the production of inflammatory cytokines such as TNF-α and IL-6, and elevation of reactive oxygen species. Thus, oxidative stress and hypoxia may promote imbalance in the production of vasoactive compounds and may affect vascular homeostasis by activating the ET-1 system.<ref>Morishita, Ryuichi, Shigefumi Nakamura, Yoshio Nakamura, Motokuni Aoki, Atsushi Moriguchi, Iwao Kida, Yoshikage Yo, Kunio Matsumoto, Toshikazu Nakamura, Jitsuo Higaki, and Toshio Ogihara. "Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes." American Diabetes Association 46, (1996): 138-142</ref>




Line 133: Line 139:




fibroblast growth factor (FGF-21) has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents.
fibroblast growth factor (FGF-21) has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents.<ref>Kharitonenkov, Alexei, Victor J. Wroblewski, Anja Koester, Yun-Fei Chen, Cathleen K. Clutinger, Xenia T. Tigno, Barbara C. Hansen, Armen B. Shanafelt, and Garret J. Etgen. "The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21." Endocrinology 148, no. 2 (2007): 774-81</ref>


FGF21 can function as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagonlike peptide1analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid .A study of The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21 showed that when FGF-21 administered daily for 6 weeks to diabetic rhesus monkeys ,FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin and glucagon. In a significant point during the study FGF-21 administration also led to significant improvements in lipoprotein profiles and a beneficial changes in the circulating levels of several cardiovascular risk markers. And the induction of a small but significant weight loss. These data support the development of FGF-21 for the treatment of diabetes and other metabolic diseases.
FGF21 can function as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagonlike peptide1analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid .A study of The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21 showed that when FGF-21 administered daily for 6 weeks to diabetic rhesus monkeys ,FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin and glucagon. In a significant point during the study FGF-21 administration also led to significant improvements in lipoprotein profiles and a beneficial changes in the circulating levels of several cardiovascular risk markers. And the induction of a small but significant weight loss. These data support the development of FGF-21 for the treatment of diabetes and other metabolic diseases.<ref>Kharitonenkov, Alexei, Victor J. Wroblewski, Anja Koester, Yun-Fei Chen, Cathleen K. Clutinger, Xenia T. Tigno, Barbara C. Hansen, Armen B. Shanafelt, and Garret J. Etgen. "The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21." Endocrinology 148, no. 2 (2007): 774-81</ref>




Line 141: Line 147:
==References ==
==References ==


<references />
AbuHanoud, Amal, Violet Kasabri, Naiyla Bulayova, Amal Akour, Haidar Bustanji, Nahla Khawaja, Dana Hyasat, Rula Silawi, Yasser Bustanji, and Yusuf Al-Hiari. "Evaluation of Oxytocin (OXT), Endothelin-1 and Nesfatin Plasma Concentrations in Newly-diagnosed Diabetic and Non-diabetic Patients with Metabolic Syndrome." Jordan Journal of Pharmaceutical Sciences 9, (2016): 2-12.<ref>[http://www.example.org Link text], additional text.</ref>
⚫
Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8.<ref>[http://www.example.org Link text], additional text.</ref>

Ayada, Toru, and Korkut. "Nesfatin-1 and Its Effects on Different Systems." Hippokratia 19, (2015): 4-10.<ref>[http://www.example.org Link text], additional text.</ref>

Demirci, Cem, Sara Ernst, Juan C. Alvarez-Perez, Taylor Rosa, Shelley Valle, Varsha Shridhar, Gabriella P. Casinelli, Laura C. Alonso, Rupangi C. Vasavada, and Adolfo García-Ocana. "Loss of HGF/c-Met Signaling in Pancreatic Β Cells Leads to Incomplete Maternal Β-Cell Adaptation and Gestational Diabetes Mellitus." American Diabetes Association (2012).<ref>[http://www.example.org Link text], additional text.</ref>

⚫
Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).<ref>[http://www.example.org Link text], additional text.</ref>

Hee Park, Kyung, Lesya Zaichenko, Mary Brinkoetter, Bindiya Thakkar, Ayse Sahin-Efe, Kyoung Eun Joung, Michael A. Tsoukas, Eleni V. Geladari, Joo Young Huh, Fadime Dincer, Cynthia R. Davis, Judith A. Crowell, and Christos S. Mantzoros. "Circulating Irisin in Relation to Insulin Resistance and the Metabolic Syndrome." The Journal of Clinical Endocrinology & Metabolism 98, no. 12 (2013): 4899-907.<ref>[http://www.example.org Link text], additional text.</ref>

Hess-Fischl, Amy. "Prediabetes." Endocrine Web. July 9, 2018. Accessed December 1, 2018. https://www.endocrineweb.com/conditions/pre-diabetes/pre-diabetes.<ref>[http://www.example.org Link text], additional text.</ref>

Kharitonenkov, Alexei, Victor J. Wroblewski, Anja Koester, Yun-Fei Chen, Cathleen K. Clutinger, Xenia T. Tigno, Barbara C. Hansen, Armen B. Shanafelt, and Garret J. Etgen. "The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21." Endocrinology 148, no. 2 (2007): 774-81.<ref>[http://www.example.org Link text], additional text.</ref>

Morishita, Ryuichi, Shigefumi Nakamura, Yoshio Nakamura, Motokuni Aoki, Atsushi Moriguchi, Iwao Kida, Yoshikage Yo, Kunio Matsumoto, Toshikazu Nakamura, Jitsuo Higaki, and Toshio Ogihara. "Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes." American Diabetes Association 46, (1996): 138-42.<ref>[http://www.example.org Link text], additional text.</ref>

Takahashi, Ghatei, Lam, H a l l o r a n, and B l o o m. "Elevated Plasma Endothelin in Patients with Diabetes Mellitus." Diabetologia 33, (1990): 306-10.<ref>[http://www.example.org Link text], additional text.</ref>

"Type 2 Diabetes." Diabetes Australia. Accessed December 1, 2018. https://www.diabetesaustralia.com.au/type-2-diabetes.<ref>[http://www.example.org Link text], additional text.</ref>

Yue, Song, Jingyang Wu, Jiahua Zhang, Lei Liu, and Lei Chen. "The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis." Hindawi 2016, (2016): 1-8.<ref name="test">[http://www.example.org Link text]</ref>

Revision as of 18:03, 16 December 2018

Biomarkers of Diabetes

Introduction


Diabetes mellitus (DM): is a type of metabolic disease characterized by hyperglycemia. It is caused by either defected insulin secretion or damaged biological function, or both. The high-level blood glucose for a long time will lead to dysfunction of a variety of tissues.[1]

Type 2 diabetes: is a progressive condition in which the body becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in the pancreas.[2]

Pre-diabetes: means that your blood sugar level is higher than normal but not yet high enough to be type 2 diabetes.[3]

Gestational diabetes: is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy.[4]

Type 2 diabetes mellitus and prediabetes are associated with changes in levels of metabolic markers, these markers could serve as potential prognostic or therapeutic targets for patients with prediabetes or Type 2 diabetes mellitus.[5]


Metabolic markers:[6]

  • Oxytocin (OXT)
  • Omentin
  • Endothelin-1
  • Nesfatin-1
  • Irisin
  • Betatrophin
  • Hepatocyte growth factor (HGF)
  • Fibroblast growth factor


-Biomarkers with insulin-sensitizing properties (irisin, omentin, oxytocin)[7]

-Biomarkers of metabolic dysfunction (HGF, Nesfatin and Betatrophin)[8]


Biomarkers with insulin-sensitizing properties:

Oxytocin

Oxytocin (OXT), a hormone most commonly associated with labor and lactation, may have a wide variety of physiological and pathological functions, which makes Oxytocin and its receptor potential targets for drug therapy.[9] OXT may have positive metabolic effects; this is based on the change in glucose metabolism, lipid profile, and insulin sensitivity. It may modify glucose uptake and insulin sensitivity both through direct and indirect effects. It may also cause regenerative changes in diabetic pancreatic islet cells. So, the activation of the OXT receptor pathway by infusion of OXT, OXT analogues, or OXT agonists may represent a promising approach for the management of obesity and related metabolic diseases as well as diabetes and its complications.[10]


Oxytocin improves insulin sensitivity by:[11]

  • Reducing Gluco-toxicity and Lipo-toxicity.
  • Regulating cytokines like leptin and adiponectin.
  • OXT decreased fat mass, resulting in reduction in leptin level.


Oxytocin may cause β-cell regeneration by:[12]

  • OXT decreases pancreatic islet hypertrophy.
  • OXT has antioxidant and anti-inflammatory effects.
  • Pancreatic islet inflammation is an important factor in the pathogenesis of diabetes. The protection of β-cells from death is considered as a new therapeutic target.
  • The hypoglycaemic effect, stimulatory effect on insulin secretion and sensitivity, and improvement of pancreatic islet cells after OXT administration, strongly suggested that OXT might be a therapeutic target for treating diabetes
  • Deficits in OXT or its receptor developed hyperleptinemia and late-onset obesity with increases in abdominal fats and fasting plasma triglycerides
  • The balance of leptin and adiponectin in diabetic patients can be used as a predictor of insulin resistance and a useful indicator for the choice of drug to treat diabetes mellitus


Oxytocin levels:[13]

  • OXT was negatively and significantly correlated with HbA1c, FGF21, HGF and positively correlated with both irisin and gender.
  • OXT levels higher in normoglycemic as compared to pre-DM/T2DM patients.
  • OXT are reduced in paitent with pre-DM/Type2 DM.


Omentin


Omentin is an anti-inflammatory adipokine produced preferentially by visceral adipose tissue. Plasma omentin-1 levels are significantly decreased in patients with obesity, insulin resistance and diabetes that contribute to the major components of the metabolic syndrome. Insulin resistance contributes to the changes of cholesterol synthesis and absorption as well. However, nothing is known about the relationship between Omentin and metabolic risk factors. So a study were held in japan comprised 201 Japanese men who underwent annual health check-ups. Plasma Omentin levels were determined by enzyme-linked immunosorbent assay. They divided the subjects into 4 groups according to Omentin levels. A reduction of plasma Omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, Dyslipidemia, high blood pressure and glucose intolerance. They concluded that Circulating Omentin levels are negatively correlated with the multiplicity of metabolic risk factors, suggesting that Omentin acts as a biomarker of metabolic disorders.[14]


Irisin


Irisin, a newly identified hormone, was first reported by Bostromet al. in 2012, is a novel myokine which plays an important role in the homeostasis , metabolism and energy balance. Irisin is reported to be involved in insulin resistance in both humans and animal models. Circulating irisin levels progressively decrease with the worsening of the glucose tolerance.[15] A recent study conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone Irisin and the established adipokine adiponectin with metabolic syndrome, cardio-metabolic variables and cardiovascular disease risk, and they found out that the baseline irisin levels were significantly higher in subjects with metabolic syndrome than in subjects without metabolic syndrome.[16]


Biomarkers of metabolic dysfunction:

Nesfatin-1

Nesfatin-1 is a peptide secreted by peripheral tissues, central and peripheral nervous system. It is involved in the regulation of energy, homeostasis related with food regulation and water intake.[17] Nesfatin-1 can pass through the blood-brain barrier in both directions. It suppresses feeding independently from the leptin pathway and increases insulin secretion from pancreatic beta islet cells. this is demonstrated by in-vitro studies that Nesfatin-1 stimulates the Preproinsulin mRNA expression and increases the glucose induced insulin release. That is why nesfatin-1 has drawn attention as a new therapeutic agent, especially for the treatment of obesity and diabetes mellitus.[18]

In T2DM patients Nesfatin-1 is elevated and this could possibly be as a result of a resistance. Thus, Nesfatin-1 acts as a potent Anorexigenic factor (anti-obesity) that improves insulin resistance and opposes weight gain.[19]


Hepatocyte growth factor (HGF)

Hepatocyte growth factor (HGF) is a mitogen and insulin tropic agent for the β cell. Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis.[20].[21] It is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. In diabetic patient’s, levels of the hepatocyte growth factor (HGF) were found in high levels, thus independently associated with increased the incidence of diabetes. There is a study that indicate that HGF/c-Met signalling is essential for maternal β-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus.[22].[23]


Betatrophin:

is a novel protein predominantly expressed in human liver and adipose tissues. Increasing evidence has revealed an association between betatrophin expression and serum lipid profiles, particularly in patients with obesity or diabetes, Thus betatrophin is closely related to diabetes treatment, it promotes greatly the proliferation of pancreatic beta cells, plays an important role in modulating glycolipid metabolism, and maybe replaces insulin in the effective treatment of diabetes.[24] studies showed that betatrophin could increase the quantity of cells that produce insulin in mice quickly. Others showed that the circulating level of betatrophin in T2DM patient blood was higher than that in control groups.[25] Expression of betatrophin correlates with β cell proliferation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.[26]

Others:

Endothelin-1(ET-1)

Is a vasoconstrictor peptide released from vascular endothelial cells. At the cellular level, the balance between vasodilator (Nitric oxide) and vasoconstrictor (ET-1) actions determines the vascular response to insulin. So, high levels of ET-1, which achieved in insulin resistance states that includes patients that have T2DM or metabolic syndromes or they are obese, have inhibitory effect on nitric oxide production which results in low nitric oxide and heightened levels of ET-1.[27] ET-1 activity is also enhanced secondary to abnormalities in vascular insulin signalling, In addition to its direct vasoconstrictor effects. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome.[28]


PVAT AND ET-1:

ET-1 In addition to its direct vasoconstrictor effects, it causes changes in visceral and perivascular adipose tissue (PVAT), and may contribute to the pathogenesis of both insulin resistance and vascular dysfunction/damage. Perivascular adipose tissue seems to have anti contractile effect and this dilator effect was lost in obese patients.[29] secondary to obesity, ET-1 high level changes on PVAT will lead to PVAT hypertrophy which will be associated with reduced partial oxygen pressure, an increase in the production of inflammatory cytokines such as TNF-α and IL-6, and elevation of reactive oxygen species. Thus, oxidative stress and hypoxia may promote imbalance in the production of vasoactive compounds and may affect vascular homeostasis by activating the ET-1 system.[30]



Fibroblast growth factor:


fibroblast growth factor (FGF-21) has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents.[31]

FGF21 can function as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagonlike peptide1analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid .A study of The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21 showed that when FGF-21 administered daily for 6 weeks to diabetic rhesus monkeys ,FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin and glucagon. In a significant point during the study FGF-21 administration also led to significant improvements in lipoprotein profiles and a beneficial changes in the circulating levels of several cardiovascular risk markers. And the induction of a small but significant weight loss. These data support the development of FGF-21 for the treatment of diabetes and other metabolic diseases.[32]


References

  1. ^ AbuHanoud, Amal, Violet Kasabri, Naiyla Bulayova, Amal Akour, Haidar Bustanji, Nahla Khawaja, Dana Hyasat, Rula Silawi, Yasser Bustanji, and Yusuf Al-Hiari. "Evaluation of Oxytocin (OXT), Endothelin-1 and Nesfatin Plasma Concentrations in Newly-diagnosed Diabetic and Non-diabetic Patients with Metabolic Syndrome." Jordan Journal of Pharmaceutical Sciences 9, (2016): 2-12
  2. ^ "Type 2 Diabetes." Diabetes Australia. Accessed December 1, 2018. https://www.diabetesaustralia.com.au/type-2-diabetes.
  3. ^ Hess-Fischl, Amy. "Prediabetes." Endocrine Web. July 9, 2018. Accessed December 1, 2018. https://www.endocrineweb.com/conditions/pre-diabetes/pre-diabetes.
  4. ^ "Gestational Diabetes." Mayo Clinic. April 28, 2017. Accessed December 1, 2018. https://www.mayoclinic.org/diseases-conditions/gestational-diabetes/symptoms-causes/syc-20355339.
  5. ^ Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8
  6. ^ Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8
  7. ^ Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8
  8. ^ Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8
  9. ^ Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).
  10. ^ Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).
  11. ^ Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).
  12. ^ Elabd, Seham, and Ismail Sabry. "Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis." Front Endocrinol (Lausanne) 121, (2015).
  13. ^ Akour, Amal, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, and Munther Momani. "Levels of Metabolic Markers in Drug-naive Prediabetic and Type 2 Diabetic Patients." Crossmark (2016): 1-8.
  14. ^ AbuHanoud, Amal, Violet Kasabri, Naiyla Bulayova, Amal Akour, Haidar Bustanji, Nahla Khawaja, Dana Hyasat, Rula Silawi, Yasser Bustanji, and Yusuf Al-Hiari. "Evaluation of Oxytocin (OXT), Endothelin-1 and Nesfatin Plasma Concentrations in Newly-diagnosed Diabetic and Non-diabetic Patients with Metabolic Syndrome." Jordan Journal of Pharmaceutical Sciences 9, (2016): 2-12
  15. ^ Hee Park, Kyung, Lesya Zaichenko, Mary Brinkoetter, Bindiya Thakkar, Ayse Sahin-Efe, Kyoung Eun Joung, Michael A. Tsoukas, Eleni V. Geladari, Joo Young Huh, Fadime Dincer, Cynthia R. Davis, Judith A. Crowell, and Christos S. Mantzoros. "Circulating Irisin in Relation to Insulin Resistance and the Metabolic Syndrome." The Journal of Clinical Endocrinology & Metabolism 98, no. 12 (2013): 4899-907
  16. ^ Hee Park, Kyung, Lesya Zaichenko, Mary Brinkoetter, Bindiya Thakkar, Ayse Sahin-Efe, Kyoung Eun Joung, Michael A. Tsoukas, Eleni V. Geladari, Joo Young Huh, Fadime Dincer, Cynthia R. Davis, Judith A. Crowell, and Christos S. Mantzoros. "Circulating Irisin in Relation to Insulin Resistance and the Metabolic Syndrome." The Journal of Clinical Endocrinology & Metabolism 98, no. 12 (2013): 4899-907
  17. ^ Ayada, Toru, and Korkut. "Nesfatin-1 and Its Effects on Different Systems." Hippokratia 19, (2015): 4-10
  18. ^ Ayada, Toru, and Korkut. "Nesfatin-1 and Its Effects on Different Systems." Hippokratia 19, (2015): 4-10
  19. ^ Ayada, Toru, and Korkut. "Nesfatin-1 and Its Effects on Different Systems." Hippokratia 19, (2015): 4-10
  20. ^ Morishita, Ryuichi, Shigefumi Nakamura, Yoshio Nakamura, Motokuni Aoki, Atsushi Moriguchi, Iwao Kida, Yoshikage Yo, Kunio Matsumoto, Toshikazu Nakamura, Jitsuo Higaki, and Toshio Ogihara. "Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes." American Diabetes Association 46, (1996): 138-42
  21. ^ Demirci, Cem, Sara Ernst, Juan C. Alvarez-Perez, Taylor Rosa, Shelley Valle, Varsha Shridhar, Gabriella P. Casinelli, Laura C. Alonso, Rupangi C. Vasavada, and Adolfo García-Ocana. "Loss of HGF/c-Met Signaling in Pancreatic Β Cells Leads to Incomplete Maternal Β-Cell Adaptation and Gestational Diabetes Mellitus." American Diabetes Association (2012)
  22. ^ Demirci, Cem, Sara Ernst, Juan C. Alvarez-Perez, Taylor Rosa, Shelley Valle, Varsha Shridhar, Gabriella P. Casinelli, Laura C. Alonso, Rupangi C. Vasavada, and Adolfo García-Ocana. "Loss of HGF/c-Met Signaling in Pancreatic Β Cells Leads to Incomplete Maternal Β-Cell Adaptation and Gestational Diabetes Mellitus." American Diabetes Association (2012)
  23. ^ Morishita, Ryuichi, Shigefumi Nakamura, Yoshio Nakamura, Motokuni Aoki, Atsushi Moriguchi, Iwao Kida, Yoshikage Yo, Kunio Matsumoto, Toshikazu Nakamura, Jitsuo Higaki, and Toshio Ogihara. "Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes." American Diabetes Association 46, (1996): 138-142
  24. ^ Yue, Song, Jingyang Wu, Jiahua Zhang, Lei Liu, and Lei Chen. "The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis." Hindawi 2016, (2016): 1-8
  25. ^ Yue, Song, Jingyang Wu, Jiahua Zhang, Lei Liu, and Lei Chen. "The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis." Hindawi 2016, (2016): 1-8
  26. ^ Yue, Song, Jingyang Wu, Jiahua Zhang, Lei Liu, and Lei Chen. "The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis." Hindawi 2016, (2016): 1-8
  27. ^ Takahashi, Ghatei, Lam, H a l l o r a n, and B l o o m. "Elevated Plasma Endothelin in Patients with Diabetes Mellitus." Diabetologia 33, (1990): 306-10.
  28. ^ Takahashi, Ghatei, Lam, H a l l o r a n, and B l o o m. "Elevated Plasma Endothelin in Patients with Diabetes Mellitus." Diabetologia 33, (1990): 306-10.
  29. ^ ...
  30. ^ Morishita, Ryuichi, Shigefumi Nakamura, Yoshio Nakamura, Motokuni Aoki, Atsushi Moriguchi, Iwao Kida, Yoshikage Yo, Kunio Matsumoto, Toshikazu Nakamura, Jitsuo Higaki, and Toshio Ogihara. "Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes." American Diabetes Association 46, (1996): 138-142
  31. ^ Kharitonenkov, Alexei, Victor J. Wroblewski, Anja Koester, Yun-Fei Chen, Cathleen K. Clutinger, Xenia T. Tigno, Barbara C. Hansen, Armen B. Shanafelt, and Garret J. Etgen. "The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21." Endocrinology 148, no. 2 (2007): 774-81
  32. ^ Kharitonenkov, Alexei, Victor J. Wroblewski, Anja Koester, Yun-Fei Chen, Cathleen K. Clutinger, Xenia T. Tigno, Barbara C. Hansen, Armen B. Shanafelt, and Garret J. Etgen. "The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21." Endocrinology 148, no. 2 (2007): 774-81
Retrieved from "https://en.wikipedia.org/w/index.php?title=Biomarkers_of_diabetes&oldid=874029413"