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{{Diabetes mellitus type 2}}
{{Diabetes mellitus type 2}}
{{CMG}}; {{AE}} [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com]; {{CZ}},{{MehdiP}}
{{CMG}}; {{AE}} [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com]; {{CZ}},{{MehdiP}}{{Anahita}}


==Overview==
==Overview==
The exact pathophysiology of type 2 diabetes mellitus is not fully understood. The underlying pathology is the development of insulin resistance. Contrary to type 1 diabetes, patients with type 2 diabetes sufficiently produce insulin; however, cellular response to the circulating insulin is diminished. The mechanism by which the insulin resistance develops is postulated to be influenced by both genetic and environmental factors. Environmental influences on the pathogenesis of type 2 DM include high glycemic diets, central obesity, older age, male gender, low-fiber diet, and high saturated fat diet.  
The exact [[pathophysiology]] of [[Diabetes mellitus type 2|type 2 diabetes mellitus]] is not fully understood. The underlying [[pathology]] is the development of [[insulin resistance]]. Contrary to [[Diabetes mellitus type 1|type 1 diabetes]], patients with [[Diabetes mellitus type 2|type 2 diabetes]] sufficiently produce [[insulin]]. However, the cellular response to the circulating [[insulin]] is diminished in [[Diabetes mellitus type 2|type 2 DM]]. The mechanism by which the [[insulin resistance]] develops is postulated to be influenced by both [[genetic]] and environmental factors. Environmental influences on the [[pathogenesis]] of [[Diabetes mellitus type 2|type 2 DM]] include high glycemic diets, central [[obesity]], older age, male gender, low-fiber diet, and highly [[saturated fat]] diet.There are some genetic variants and [[Human leukocyte antigen|HLA]] related to [[Diabetes mellitus type 2|type 2 diabetes mellitus]]. [[Diabetes mellitus type 2|Diabetes type 2]] is associated with [[Metabolic disorder|metabolic disorders]], [[sarcopenia]] and [[Liver cancer (patient information)|liver cancer]]. It also has some associated features with [[insulin resistance]]. [[Gross pathology]] of [[pancreas]] shows serrated borders and reduced volume, which is due to [[Beta cell|pancreatic cells]] [[necrosis]]. [[Amyloid]] deposition, [[inflammation]] and [[fibrosis]] are some of the [[microscopic]] changes in [[Diabetes mellitus|diabetic]] [[pancreas]]. 


==Pathophysiology==
==Pathophysiology==
===Pathogenesis===


[[Insulin resistance]] means that body [[cell (biology)|cells]] do not respond appropriately when insulin is present.  
* The development of [[Insulin resistance]] is the underlying [[pathology]]; the [[cell (biology)|cells]] in the body do not respond appropriately when [[insulin]] is present.


Other important contributing factors:
* Other important contributing factors:
* increased hepatic glucose production (e.g., from glycogen degradation), especially at inappropriate times  
** Increased hepatic [[glucose]] production (e.g., from [[glycogen]] degradation), especially at inappropriate times.
* decreased insulin-mediated [[glucose]] transport in (primarily) [[muscle]] and adipose tissues (receptor and post-receptor defects)
** Decreased [[insulin]]-mediated [[glucose]] transport in (primarily) [[muscle]] and [[Adipose|adipose tissues]] ([[Receptor (biochemistry)|receptor]] and post-receptor defects).
* impaired beta-cell function—loss of early phase of insulin release in response to hyperglycemic stimuli
** Impaired [[Beta-cells|beta-cell]] function, loss of early phase of [[insulin]] release in response to [[Hyperglycemia|hyperglycemic]] stimuli.
* Cancer survivors who received allogenic Hematopoeitic Cell Transplantation (HCT) are 3.65 times more likely to report type 2 diabetes than their siblings. Total body irradiation (TBI) is also associated with a higher risk of developing diabetes.
**[[Cancer]] survivors who received [[Allogeneic|allogenic]] [[Hematopoietic stem cell|Hematopoeitic Cell]] [[Organ transplant|Transplantation]] (HCT) are 3.65 times more likely to report [[Diabetes mellitus type 2|type 2 diabetes]] than their siblings. [[Total body irradiation]] ([[Total body irradiation|TBI]]) is also associated with a higher risk of developing [[diabetes]].


This is a more complex problem than type 1, but is sometimes easier to treat, especially in the initial years when insulin is often still being produced internally. Type 2 may go unnoticed for years in a patient before diagnosis, since the symptoms are typically milder (no ketoacidosis) and can be sporadic. However, severe complications can result from unnoticed type 2 diabetes, including [[renal failure]], blindness, wounds that fail to heal, and [[coronary artery disease]]. The onset of the disease is most common in [[middle age]] and [[old age|later life]].  
* This is a more complex problem than [[Diabetes mellitus type 1|type 1 diabetes]], but is sometimes easier to treat, especially in the initial years when [[insulin]] is often still being produced internally.
*[[Diabetes mellitus type 2|Type 2 DM]] may go unnoticed for years in a patient before [[diagnosis]], since the symptoms are typically milder (no [[ketoacidosis]]) and can be sporadic. However, severe [[Complication (medicine)|complications]] can result from unnoticed [[Diabetes mellitus type 2|type 2 diabetes]], including [[renal failure]], [[blindness]], [[Wound|wounds]] that fail to heal, and [[coronary artery disease]]. The onset of the disease is most common in [[middle age]] and [[old age|later life]].


Diabetes mellitus type 2 is presently of unknown [[etiology]] (i.e., origin). Diabetes mellitus with a known etiology, such as secondary to other diseases, known gene defects, trauma or surgery, or the effects of drugs, is more appropriately called secondary diabetes mellitus. Examples include diabetes mellitus caused by [[hemochromatosis]], pancreatic insufficiency, or certain types of medications (e.g. long-term [[steroid]] use).  
* Although primary [[Diabetes mellitus type 2]] is presently of unknown [[etiology]], there are some known etiologies responsible for the secondary [[diabetes mellitus]]. These known etiologies are known [[gene]] defects, [[Physical trauma|trauma]], [[surgery]], [[hemochromatosis]], [[pancreatic insufficiency]], or certain types of [[Medication|medications]] (e.g. long-term [[steroid]] use).
* 23 years follow up in a study showed that enough level of [[tocopherol]] has been linked to lower risk of [[Diabetes mellitus type 2|type 2 diabetes]] development.<ref name="MontonenKnekt2004">{{cite journal|last1=Montonen|first1=J.|last2=Knekt|first2=P.|last3=Jarvinen|first3=R.|last4=Reunanen|first4=A.|title=Dietary Antioxidant Intake and Risk of Type 2 Diabetes|journal=Diabetes Care|volume=27|issue=2|year=2004|pages=362–366|issn=0149-5992|doi=10.2337/diacare.27.2.362}}</ref> Furthermore low level of [[vitamin E]] is related to increased risk of [[diabetes mellitus]].<ref name="van der SchaftSchoufour2019">{{cite journal|last1=van der Schaft|first1=Niels|last2=Schoufour|first2=Josje D.|last3=Nano|first3=Jana|last4=Kiefte-de Jong|first4=Jessica C.|last5=Muka|first5=Taulant|last6=Sijbrands|first6=Eric J. G.|last7=Ikram|first7=M. Arfan|last8=Franco|first8=Oscar H.|last9=Voortman|first9=Trudy|title=Dietary antioxidant capacity and risk of type 2 diabetes mellitus, prediabetes and insulin resistance: the Rotterdam Study|journal=European Journal of Epidemiology|volume=34|issue=9|year=2019|pages=853–861|issn=0393-2990|doi=10.1007/s10654-019-00548-9}}</ref> These data are suggestive of the role of dietary [[antioxidant]] and decreased risk of [[diabetes mellitus]]. Moreover [[animal model]]<nowiki/>s suggested the role of dietary [[Antioxidant|antioxidants]] in suppressing the [[beta cell]] [[apoptosis]] due to [[oxidative stress]].<ref name="KanetoKajimoto1999">{{cite journal|last1=Kaneto|first1=H.|last2=Kajimoto|first2=Y.|last3=Miyagawa|first3=J.|last4=Matsuoka|first4=T.|last5=Fujitani|first5=Y.|last6=Umayahara|first6=Y.|last7=Hanafusa|first7=T.|last8=Matsuzawa|first8=Y.|last9=Yamasaki|first9=Y.|last10=Hori|first10=M.|title=Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity|journal=Diabetes|volume=48|issue=12|year=1999|pages=2398–2406|issn=0012-1797|doi=10.2337/diabetes.48.12.2398}}</ref>


==== Beta-cell function ====


Diabetes mellitus type 2 is often associated with [[obesity]] and [[hypertension]] and elevated [[cholesterol]] ([[combined hyperlipidemia]]), and with the condition [[Metabolic syndrome]] (also known as Syndrome X, Reavan's syndrome, or CHAOS).  It is also associated with [[acromegaly]], [[Cushing's syndrome]] and a number of other[[endocrinology|endocrinological]] disorders. Additional factors found to increase risk of type 2 diabetes include aging<ref>Jack, L., Jr., Boseman, L. & Vinicor, F. Aging Americans and diabetes. A public health and clinical response. ''Geriatrics'' '''2004''', 59, 14-17.</ref>, high-fat diets<ref>Lovejoy, J. C. The influence of dietary fat on insulin resistance. ''Curr Diab Rep'' '''2002''', 2,435-440.</ref> and a less active lifestyle<ref>Hu, F. B. Sedentary lifestyle and risk of obesity and type 2 diabetes. Lipids 2003, 38,103-108.</ref>.
* [[Insulin]] production is more or less constant within the [[Beta cell|beta cells]].


* It is stored within [[vacuoles]] pending release, via [[exocytosis]], which is triggered by increased [[Blood sugar|blood glucose]] levels.


* [[Insulin]] production is more or less constant within the beta cells.  
*[[Insulin]] is the principal [[hormone]] that regulates uptake of [[glucose]] from the blood into most cells (primarily [[muscle]] and [[Adipose tissue|fat cells]], but not [[central nervous system]] cells). Therefore deficiency of [[insulin]] or the insensitivity of its [[Receptor (biochemistry)|receptors]] plays a central role in all forms of [[diabetes mellitus]].


* It is stored within [[vacuoles]] pending release, via [[exocytosis]], which is triggered by increased blood glucose levels.
* Much of the [[carbohydrate]] in food is converted within a few hours to the [[monosaccharide]] [[glucose]], the principal [[carbohydrate]] found in blood and used by the body as fuel.


* Insulin is the principal hormone that regulates uptake of [[glucose]] from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore deficiency of insulin or the insensitivity of its [[Receptor (biochemistry)|receptors]] plays a central role in all forms of diabetes mellitus.
* Some [[Carbohydrate|carbohydrates]] are not converted e.g fruit sugar ([[fructose]]) is usable as cellular fuel but it is not converted to glucose, and it therefore does not participate in the [[insulin]]/[[glucose]] metabolic regulatory mechanism.


* Much of the carbohydrate in food is converted within a few hours to the [[monosaccharide]] glucose, the principal carbohydrate found in blood and used by the body as fuel.  
* Additionally, the [[carbohydrate]] [[cellulose]] (though it is actually many [[glucose]] molecules in long chains) is not converted to [[glucose]], as humans and many animals have no [[Digestive system|digestive]] pathway capable of breaking up [[cellulose]].


* Some carbohydrates are not so converted for e.g. fruit sugar ([[fructose]]), usable as cellular fuel but it is not converted o glucose, and which therefore does not participate in the insulin/glucose metabolic regulatory mechanism.  
*[[Insulin]] is released into the blood by [[beta cells]] ([[Beta cell|β-cells]]), found in the [[Islets of Langerhans]] in the [[pancreas]], in response to rising levels of blood [[glucose]] after eating.


* Additionally, the carbohydrate [[cellulose]] (though it is actually many glucose molecules in long chains) is not converted to glucose, as humans and many animals have no digestive pathway capable of breaking up cellulose.
*[[Insulin]] is used by about two-thirds of the body's cells to absorb [[glucose]] from the blood for use as fuel, for conversion to other needed [[Molecule|molecules]], or for storage.


* Insulin is released into the blood by [[beta cells]] (β-cells), found in the [[Islets of Langerhans]] in the [[pancreas]], in response to rising levels of blood glucose after eating.  
*[[Insulin]] is also the principal control signal for conversion of [[glucose]] to [[glycogen]] for internal storage in [[liver]] and [[muscle]] cells.


* Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage.  
* Lowered [[glucose]] levels result both in the reduced release of [[insulin]] from the [[beta cells]] and in the reverse conversion of [[glycogen]] to [[glucose]] when [[glucose]] levels fall. This is mainly controlled by[[glucagon]] which acts in an opposite manner to [[insulin]]. [[Glucose]] thus recovered by the [[liver]] and re-enters the bloodstream; [[muscle]] cells lack the necessary export mechanism.


* Insulin is also the principal control signal for conversion of [[glucose]] to [[glycogen]] for internal storage in liver and muscle cells.
* Higher [[insulin]] levels increase some [[anabolism|anabolic]] processes such as [[cell growth]] and duplication, [[protein biosynthesis|protein synthesis]], and [[lipid|fat]] storage. [[Insulin]] (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a [[catabolism|catabolic]] to an [[Anabolism|anabolic]] direction, and vice versa. In particular, a low [[insulin]] level is the trigger for entering or leaving [[ketosis]] (the [[fat]] burning metabolic phase).


* Lowered glucose levels result both in the reduced release of insulin from the [[beta cells]] and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the hormone [[glucagon]] which acts in an opposite manner to insulin. Glucose thus recovered by the liver re-enters the bloodstream; muscle cells lack the necessary export mechanism.
* If the amount of [[insulin]] available is insufficient, if cells respond poorly to the effects of [[insulin]] ([[insulin]] insensitivity or [[insulin resistance|resistance]]), or if the [[insulin]] itself is defective, then [[glucose]] will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the [[liver]] and muscles. The net effect is persistent high levels of [[Blood sugar|blood glucose]], poor [[protein synthesis]], and other metabolic derangement, such as [[acidosis]].


* Higher insulin levels increase some [[anabolism|anabolic]] ("building up") processes such as cell growth and duplication, [[protein biosynthesis|protein synthesis]], and [[lipid|fat]] storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a [[catabolism|catabolic]] to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving [[ketosis]] (the fat burning metabolic phase).
[[Image:Glucose-insulin-release.png|center|500px|Mechanism of insulin release in normal pancreatic beta cells]]
 
* If the amount of [[insulin]] available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or [[insulin resistance|resistance]]), or if the insulin itself is defective, then glucose will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as [[acidosis]].


[[Image:Glucose-insulin-release.png|center|500px|Mechanism of insulin release in normal pancreatic beta cells]]
==== Inflammation and Diabetes ====


=== Inflammation and Diabetes ===
* In 1923, when Banting and Bests were awarded the [[Nobel Prize]] for [[insulin]] discovery, most researchers believed that this had led to a cure for [[diabetes]]. However, despite the advances in the [[Blood sugar|blood glucose]] management, there is no cure for [[diabetes]] or for the prevention of its major [[Complication (medicine)|complications]].  
In 1923, when Banting and Bests were awarded the Nobel Prize for [[insulin]] discovery, most researchers believed that this had led to a cure for [[diabetes]]. However, despite the advances in the blood glucose management, there is no cure for diabetes or for the prevention of its major complications. Scientists have observed that people with [[type 2 diabetes]] have overly active, and sometimes dysfunctional immune systems, which are linked to these complications. In current times, diabetes is seen as the disease of high blood [[glucose]], or lack of insulin, however chronic inflammatory states and the overabundance of [[reactive oxygen species]] (ROS) also play a part in the disease process.<ref name="pmid14679177">{{cite journal| author=Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al.| title=Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. | journal=J Clin Invest | year= 2003 | volume= 112 | issue= 12 | pages= 1821-30 | pmid=14679177 | doi=10.1172/JCI19451 | pmc=PMC296998 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14679177  }} </ref>.[[Inflammation]] is part of a healthy immune response, an orchestrated onslaught of cells and chemicals that heal injury and fight [[infection]]. [[Chronic inflammation]] is a process which occurs throughout the body when a trigger activates the immune system. This inflammation results in the cascade of reactive oxygen species and further damage to tissue.  <ref name="pmid14679177">{{cite journal| author=Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al.| title=Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. | journal=J Clin Invest | year= 2003 | volume= 112 | issue= 12 | pages= 1821-30 | pmid=14679177 | doi=10.1172/JCI19451 | pmc=PMC296998 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14679177  }} </ref> <ref name="pmid22252015">{{cite journal| author=Calle MC, Fernandez ML| title=Inflammation and type 2 diabetes. | journal=Diabetes Metab | year= 2012 | volume= 38 | issue= 3 | pages= 183-91 | pmid=22252015 | doi=10.1016/j.diabet.2011.11.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22252015  }} </ref>. In 1993, scientists showed that the [[tumor necrosis factor α]] (TNF-α) expression was up-regulated in the adipose tissue of obese mice with type 2 diabetes <ref name="pmid7678183">{{cite journal| author=Hotamisligil GS, Shargill NS, Spiegelman BM| title=Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. | journal=Science | year= 1993 | volume= 259 | issue= 5091 | pages= 87-91 | pmid=7678183 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7678183  }} </ref>. When mice deficient in TNF-α were bred, diabetes did not develop. It appeared that inflammation preceded diabetes, long before diagnosis.
* Scientists have observed that people with [[type 2 diabetes]] have overly active, and sometimes dysfunctional [[immune system]]<nowiki/>s, which are linked to some [[Complication (medicine)|complications]]. In current times, [[diabetes]] is seen as the disease of high blood [[glucose]], or lack of [[insulin]], however chronic [[Inflammation|inflammatory]] states and the overabundance of [[reactive oxygen species]] ([[Reactive oxygen species|ROS]]) also play a part in the disease process.<ref name="pmid14679177">{{cite journal| author=Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al.| title=Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. | journal=J Clin Invest | year= 2003 | volume= 112 | issue= 12 | pages= 1821-30 | pmid=14679177 | doi=10.1172/JCI19451 | pmc=PMC296998 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14679177  }} </ref>.
* [[Inflammation]] is part of a healthy immune response, an orchestrated onslaught of cells and chemicals that heal injury and fight [[infection]]. [[Chronic inflammation]] is a process which occurs throughout the body when a trigger activates the [[immune system]]. This inflammation results in the cascade of [[reactive oxygen species]] and further damage to tissue.  <ref name="pmid14679177">{{cite journal| author=Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al.| title=Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. | journal=J Clin Invest | year= 2003 | volume= 112 | issue= 12 | pages= 1821-30 | pmid=14679177 | doi=10.1172/JCI19451 | pmc=PMC296998 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14679177  }} </ref> <ref name="pmid22252015">{{cite journal| author=Calle MC, Fernandez ML| title=Inflammation and type 2 diabetes. | journal=Diabetes Metab | year= 2012 | volume= 38 | issue= 3 | pages= 183-91 | pmid=22252015 | doi=10.1016/j.diabet.2011.11.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22252015  }} </ref>.
* In 1993, scientists showed that the [[Tumour necrosis factor|tumor necrosis factor α]] ([[Tumor necrosis factor-alpha|TNF-α]]) expression was up-regulated in the [[adipose tissue]] of [[Obesity|obese]] mice with [[Diabetes mellitus type 2|type 2 diabetes]] <ref name="pmid7678183">{{cite journal| author=Hotamisligil GS, Shargill NS, Spiegelman BM| title=Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. | journal=Science | year= 1993 | volume= 259 | issue= 5091 | pages= 87-91 | pmid=7678183 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7678183  }} </ref>. When mice deficient in [[Tumor necrosis factor-alpha|TNF-α]] were bred, [[diabetes]] did not develop. It appeared that [[inflammation]] preceded diabetes, long before [[diagnosis]].


====Obesity as the Link Between Diabetes and Inflammation====
====Obesity as the Link Between Diabetes and Inflammation====
[[Leukocytes]] and innate immunity is the main source of [[inflammation]] in humans In animal species, adipose tissue is the mediator of innate immunity. In insects, [[adipocytes]] have a receptor for the cell wall of [[bacteria]] and [[fungi]], called toll like receptor. It is responsible for nuclear factor 1 β (NF1β) activation which induces the secretion of antibacterial peptides and other defense mechanisms. This induces the inflammatory cascades. [[Fat tissue]] also manages the storage of lipids in the liver <ref name="pmid12881560">{{cite journal| author=Rolff J, Siva-Jothy MT| title=Invertebrate ecological immunology. | journal=Science | year= 2003 | volume= 301 | issue= 5632 | pages= 472-5 | pmid=12881560 | doi=10.1126/science.1080623 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12881560  }} </ref>.However some aspects of [[innate immunity]] are still preserved in the adipocytes. Moreover adipose tissue is populated with tissue resident [[macrophages]], which is significantly increased by diet induced [[weight gain]] <ref name="pmid15890981">{{cite journal| author=Berg AH, Scherer PE| title=Adipose tissue, inflammation, and cardiovascular disease. | journal=Circ Res | year= 2005 | volume= 96 | issue= 9 | pages= 939-49 | pmid=15890981 | doi=10.1161/01.RES.0000163635.62927.34 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15890981  }} </ref>.


The first theory in regards to fat tissue being the source of [[inflammation]] and diabetes, is that there is an overabundance of energy in the form of glucose and lipid in obesity. This leads to [[mitochondrial]] dysfunction and reactive oxygen species (ROS) production from the adipocytes. ROS can activate the immunity by inducing the NF1β and hence secretion of the inflammatory cytokines <ref name="pmid15890981">{{cite journal| author=Berg AH, Scherer PE| title=Adipose tissue, inflammation, and cardiovascular disease. | journal=Circ Res | year= 2005 | volume= 96 | issue= 9 | pages= 939-49 | pmid=15890981 | doi=10.1161/01.RES.0000163635.62927.34 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15890981  }} </ref>.  The second theory is the hypoxia theory reported by Trayhurn and Wood <ref name="pmid15469638">{{cite journal| author=Trayhurn P, Wood IS| title=Adipokines: inflammation and the pleiotropic role of white adipose tissue. | journal=Br J Nutr | year= 2004 | volume= 92 | issue= 3 | pages= 347-55 | pmid=15469638 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15469638  }} </ref>. The fat cells expand when a person gains weight. These fat cells sometimes do not get enough oxygen. In response to hypoxia; they induce [[cytokines]], which activate the [[angiogenesis]], [[metabolism]] and cellular stress. These cytokines induce [[insulin resistance]] and hence result into diabetes. The adipose tissue is not usually considered as an immune or inflammatory organ, however these observations provide evidence for the link between obesity and inflammation.
* [[Leukocytes]] and [[Innate immune system|innate immunity]] is the main source of [[inflammation]] in humans. In animal species, [[adipose tissue]] is the mediator of [[Innate immune system|innate immunity]]. In insects, [[adipocytes]] have a [[Receptor (biochemistry)|receptor]] for the cell wall of [[bacteria]] and [[fungi]], called [[TLR 1|toll like receptor]]. It is responsible for nuclear factor 1 β (NF1β) activation which induces the secretion of [[Antiseptic|antibacterial]] [[Peptide|peptides]] and other defense mechanisms. This induces the [[Inflammation|inflammatory]] cascades. [[Fat tissue]] also manages the storage of [[Lipid|lipids]] in the [[liver]] <ref name="pmid12881560">{{cite journal| author=Rolff J, Siva-Jothy MT| title=Invertebrate ecological immunology. | journal=Science | year= 2003 | volume= 301 | issue= 5632 | pages= 472-5 | pmid=12881560 | doi=10.1126/science.1080623 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12881560  }} </ref>.However some aspects of [[innate immunity]] are still preserved in the [[Adipocyte|adipocytes]]. Moreover [[adipose tissue]] is populated with tissue resident [[macrophages]], which is significantly increased by diet induced [[weight gain]] <ref name="pmid15890981">{{cite journal| author=Berg AH, Scherer PE| title=Adipose tissue, inflammation, and cardiovascular disease. | journal=Circ Res | year= 2005 | volume= 96 | issue= 9 | pages= 939-49 | pmid=15890981 | doi=10.1161/01.RES.0000163635.62927.34 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15890981  }} </ref>.
 
* The first theory in regards to [[Adipose tissue|fat tissue]] being the source of [[inflammation]] and [[diabetes]], is that there is an overabundance of energy in the form of [[glucose]] and [[lipid]] in [[obesity]]. This leads to [[mitochondrial]] dysfunction and [[reactive oxygen species]] ([[Reactive oxygen species|ROS]]) production from the [[Adipocyte|adipocytes]]. [[Reactive oxygen species|ROS]] can activate the immunity by inducing the NF1β and hence secretion of the inflammatory [[Cytokine|cytokines]] <ref name="pmid15890981">{{cite journal| author=Berg AH, Scherer PE| title=Adipose tissue, inflammation, and cardiovascular disease. | journal=Circ Res | year= 2005 | volume= 96 | issue= 9 | pages= 939-49 | pmid=15890981 | doi=10.1161/01.RES.0000163635.62927.34 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15890981  }} </ref>.  The second [[theory]] is the [[Hypoxia (medical)|hypoxia]] theory reported by Trayhurn and Wood <ref name="pmid15469638">{{cite journal| author=Trayhurn P, Wood IS| title=Adipokines: inflammation and the pleiotropic role of white adipose tissue. | journal=Br J Nutr | year= 2004 | volume= 92 | issue= 3 | pages= 347-55 | pmid=15469638 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15469638  }} </ref>. The [[fat]] cells expand when a person gains weight. These [[fat]] cells sometimes do not get enough [[oxygen]]. In response to [[Hypoxia (medical)|hypoxia]]; they induce [[cytokines]], which activate the [[angiogenesis]], [[metabolism]] and cellular stress. These [[Cytokine|cytokines]] induce [[insulin resistance]] and hence lead to [[diabetes]].
* The [[adipose tissue]] is not usually considered as an immune or inflammatory organ, however these observations provide evidence for the link between [[obesity]] and [[inflammation]].


====Systemic Inflammation in Diabetes====
====Systemic Inflammation in Diabetes====
A growing body of evidence demonstrates that adipose tissue [[inflammation]] eventually results in systemic inflammation<ref name="pmid22252015">{{cite journal| author=Calle MC, Fernandez ML| title=Inflammation and type 2 diabetes. | journal=Diabetes Metab | year= 2012 | volume= 38 | issue= 3 | pages= 183-91 | pmid=22252015 | doi=10.1016/j.diabet.2011.11.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22252015  }} </ref>. [[C-reactive protein|C reactive protein]] (CRP) is an inflammatory marker produced by the liver in response to [[TNFα]] and [[Interleukin 6|Interleukin-6]]. [[CRP]] has been shown to precede diabetes years before diagnosis. Elevated CRP levels are unquestionably associated with [[obesity]] and increased risk of cardiovascular disorders. Patients with a high CRP levels are at a higher mortality risk from heart disease. Other inflammatory markers are also disproportionately elevated in diabetes which results into systemic inflammation. The systemic inflammation result into [[insulin resistance]] and insulin resistance results into [[obesity]]. Hence both diabetes and [[inflammation]] reinforce each other via a positive feedback <ref name="pmid22252015">{{cite journal| author=Calle MC, Fernandez ML| title=Inflammation and type 2 diabetes. | journal=Diabetes Metab | year= 2012 | volume= 38 | issue= 3 | pages= 183-91 | pmid=22252015 | doi=10.1016/j.diabet.2011.11.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22252015  }} </ref>.
 
* A growing body of evidence demonstrates that [[adipose tissue]] [[inflammation]] eventually results in systemic [[inflammation]]<ref name="pmid22252015">{{cite journal| author=Calle MC, Fernandez ML| title=Inflammation and type 2 diabetes. | journal=Diabetes Metab | year= 2012 | volume= 38 | issue= 3 | pages= 183-91 | pmid=22252015 | doi=10.1016/j.diabet.2011.11.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22252015  }} </ref>. [[C-reactive protein|C reactive protein]] ([[C-reactive protein|CRP]]) is an inflammatory marker produced by the [[liver]] in response to [[TNFα]] and [[Interleukin 6|Interleukin-6]].
* [[CRP]] has been shown to precede [[diabetes]] years before diagnosis. Elevated [[C-reactive protein|CRP]] levels are unquestionably associated with [[obesity]] and increased risk of [[cardiovascular]] disorders. Patients with a high [[C-reactive protein|CRP]] levels are at a higher [[Mortality rate|mortality risk]] from [[heart]] disease.  
* Other inflammatory markers are also disproportionately elevated in [[diabetes]] which results into systemic [[inflammation]]. The systemic [[inflammation]] result into [[insulin resistance]] and [[insulin resistance]] results into [[obesity]]. Hence both [[diabetes]] and [[inflammation]] reinforce each other via a positive feedback <ref name="pmid22252015">{{cite journal| author=Calle MC, Fernandez ML| title=Inflammation and type 2 diabetes. | journal=Diabetes Metab | year= 2012 | volume= 38 | issue= 3 | pages= 183-91 | pmid=22252015 | doi=10.1016/j.diabet.2011.11.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22252015  }} </ref>.
 
== Genetics ==
 
* Variants in 11 [[genes]] have been related to [[Diabetes mellitus type 2|type 2 diabetes mellitus]] development. these genes include:<ref name="LyssenkoJonsson2008">{{cite journal|last1=Lyssenko|first1=Valeriya|last2=Jonsson|first2=Anna|last3=Almgren|first3=Peter|last4=Pulizzi|first4=Nicoló|last5=Isomaa|first5=Bo|last6=Tuomi|first6=Tiinamaija|last7=Berglund|first7=Göran|last8=Altshuler|first8=David|last9=Nilsson|first9=Peter|last10=Groop|first10=Leif|title=Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes|journal=New England Journal of Medicine|volume=359|issue=21|year=2008|pages=2220–2232|issn=0028-4793|doi=10.1056/NEJMoa0801869}}</ref>
**''[[TCF7L2]]''
** ''[[PPARG]],''
** ''[[FTO gene|FTO]],''
** ''KCNJ11,''
** ''[[NOTCH2]],''
** ''[[WFS1]],''
** ''[[CDKAL1]],''
** ''[[IGF2BP2]],''
** ''[[SLC30A8]],''
** ''[[JAZF1]],''
** ''[[HHEX]]''
* 8 variants of these [[genes]] are related to [[beta cell]] dysfunction.<ref name="LyssenkoJonsson20082">{{cite journal|last1=Lyssenko|first1=Valeriya|last2=Jonsson|first2=Anna|last3=Almgren|first3=Peter|last4=Pulizzi|first4=Nicoló|last5=Isomaa|first5=Bo|last6=Tuomi|first6=Tiinamaija|last7=Berglund|first7=Göran|last8=Altshuler|first8=David|last9=Nilsson|first9=Peter|last10=Groop|first10=Leif|title=Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes|journal=New England Journal of Medicine|volume=359|issue=21|year=2008|pages=2220–2232|issn=0028-4793|doi=10.1056/NEJMoa0801869}}</ref>
*Carriers of the ''[[PPARG]]'' P12/P12 and ''[[CAPN10]]'' SNP43/44 GG/TT [[Genotype|genotypes]], who also had [[obesity]] and elevated [[Blood sugar|fasting plasma glucose]] (FPG), showed 21.2 –fold increased risk for [[Diabetes mellitus type 2|type 2 diabetes]] development.<ref name="pmid16892160">{{cite journal| author=Das SK, Elbein SC| title=The Genetic Basis of Type 2 Diabetes. | journal=Cellscience | year= 2006 | volume= 2 | issue= 4 | pages= 100-131 | pmid=16892160 | doi=10.1901/jaba.2006.2-100 | pmc=1526773 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16892160  }}</ref>
*[[HLA-DR4]] or [[HLA-DR3]]/DR4 [[frequency]] has been increased in [[Diabetes mellitus type 2|diabetes type 2]], compared to normal population. Even though these findings were limited to patients with [[insulin]] deficiency or [[Islets of Langerhans|islet cell]] [[antibodies]] ([[ICA1|ICAs]]) and/or  [[Glutamate decarboxylase|Glutamic Acid Decarboxylase]] [[Antibodies]] (GADAs).<ref name="Tuomi2005">{{cite journal|last1=Tuomi|first1=T.|title=Type 1 and Type 2 Diabetes: What Do They Have in Common?|journal=Diabetes|volume=54|issue=Supplement 2|year=2005|pages=S40–S45|issn=0012-1797|doi=10.2337/diabetes.54.suppl_2.S40}}</ref>
*[[Variable number tandem repeat]] ([[Variable number tandem repeat|VNTR]]) [[polymorphism]] in the [[promoter region]] of [[insulin]] [[gene]] on [[chromosome]] 11p15 has been detected in both [[Diabetes mellitus type 1|type 1]] and [[Diabetes mellitus type 2|type 2 diabetes mellitus]]. A follow-up study in a population from the U.K. showed that class III homozygosity was related to higher risk for [[Diabetes mellitus type 2|type 2 diabetes]] in women, but not in men.<ref name="pmid15562019">{{cite journal| author=Meigs JB, Dupuis J, Herbert AG, Liu C, Wilson PW, Cupples LA| title=The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women. | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 2 | pages= 1137-43 | pmid=15562019 | doi=10.1210/jc.2004-1212 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15562019  }}</ref><ref name="Tuomi20052">{{cite journal|last1=Tuomi|first1=T.|title=Type 1 and Type 2 Diabetes: What Do They Have in Common?|journal=Diabetes|volume=54|issue=Supplement 2|year=2005|pages=S40–S45|issn=0012-1797|doi=10.2337/diabetes.54.suppl_2.S40}}</ref>
 
== Associated Conditions ==
 
* [[Diabetes mellitus type 2]] is often associated with [[obesity]] and [[hypertension]] and elevated [[cholesterol]] ([[combined hyperlipidemia]]), and with the condition [[Metabolic syndrome]]. It is also associated with [[acromegaly]], [[Cushing's syndrome]], [[Non-alcoholic fatty liver disease|Nonalcoholic steatohepatitis]]([[Non-alcoholic fatty liver disease|NASH]]) and a number of other [[endocrinology|endocrinological]] disorders.<ref name="YounossiGolabi2019">{{cite journal|last1=Younossi|first1=Zobair M.|last2=Golabi|first2=Pegah|last3=de Avila|first3=Leyla|last4=Paik|first4=James Minhui|last5=Srishord|first5=Manirath|last6=Fukui|first6=Natsu|last7=Qiu|first7=Ying|last8=Burns|first8=Leah|last9=Afendy|first9=Arian|last10=Nader|first10=Fatema|title=The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis|journal=Journal of Hepatology|volume=71|issue=4|year=2019|pages=793–801|issn=01688278|doi=10.1016/j.jhep.2019.06.021}}</ref>
 
*Additional factors found to increase risk of [[Diabetes mellitus type 2|type 2 diabetes]] include [[Ageing|aging]]<ref>Jack, L., Jr., Boseman, L. & Vinicor, F. Aging Americans and diabetes. A public health and clinical response. ''Geriatrics'' '''2004''', 59, 14-17.</ref>, high-[[fat]] diets<ref>Lovejoy, J. C. The influence of dietary fat on insulin resistance. ''Curr Diab Rep'' '''2002''', 2,435-440.</ref> and a less active lifestyle<ref>Hu, F. B. Sedentary lifestyle and risk of obesity and type 2 diabetes. Lipids 2003, 38,103-108.</ref>.
* There is a bidirectional relationship between [[Diabetes mellitus]] and [[sarcopenia]]. Numerous factors like accumulation of [[Advanced glycation endproduct|advanced glycation end-product]], [[inflammation]], [[insulin resistance]], vascular [[Complication (medicine)|complications]] and [[Oxidative stress|oxidative injury]] can interfere with muscle health. This impaired muscle health can eventually lead to [[Diabetes mellitus type 2|type 2 diabetes]].<ref name="pmid31372016">{{cite journal| author=Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D| title=Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship. | journal=Diabetes Metab Syndr Obes | year= 2019 | volume= 12 | issue=  | pages= 1057-1072 | pmid=31372016 | doi=10.2147/DMSO.S186600 | pmc=6630094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31372016  }}</ref>
*Based on a review study using data from years 1990 to 2017, [[diabetes]] is linked to higher mortality from primary [[Liver cancer (patient information)|liver cancers]]. This study suggests [[diabetes]] as a significant [[risk factor]] for primary liver cancers.<ref name="GeDu2020">{{cite journal|last1=Ge|first1=Xiao-Jun|last2=Du|first2=Yu-Xuan|last3=Zheng|first3=Li-Mei|last4=Wang|first4=Mei|last5=Jiang|first5=Jun-Yao|title=Mortality trends of liver cancer among patients with type 2 diabetes at the global and national level|journal=Journal of Diabetes and its Complications|volume=34|issue=8|year=2020|pages=107612|issn=10568727|doi=10.1016/j.jdiacomp.2020.107612}}</ref>
*Diabetic patients have higher concentration of [[bile acid]] in feeding state, compared to normal population. This change in [[bile acid]] level also showed some correlations with higher [[triglyceride]] level, [[insulin resistance]] index, [[blood pressure]], and [[Body mass index|BMI]].<ref name="WuZhou2020">{{cite journal|last1=Wu|first1=Yingjie|last2=Zhou|first2=An|last3=Tang|first3=Li|last4=Lei|first4=Yuanyuan|last5=Tang|first5=Bo|last6=Zhang|first6=Linjing|title=Bile Acids: Key Regulators and Novel Treatment Targets for Type 2 Diabetes|journal=Journal of Diabetes Research|volume=2020|year=2020|pages=1–11|issn=2314-6745|doi=10.1155/2020/6138438}}</ref>
 
== Gross Pathology ==
 
* Based on a study, the following [[Pancreas|pancreatic]] changes have been reported in patients with [[Diabetes mellitus type 2|type 2 diabetes]], compared to the [[Scientific control|control group]]: <ref name="pmid25950180">{{cite journal| author=Macauley M, Percival K, Thelwall PE, Hollingsworth KG, Taylor R| title=Altered volume, morphology and composition of the pancreas in type 2 diabetes. | journal=PLoS One | year= 2015 | volume= 10 | issue= 5 | pages= e0126825 | pmid=25950180 | doi=10.1371/journal.pone.0126825 | pmc=4423920 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25950180  }}</ref>
** 33% reduction in The [[mean]] [[Pancreas|pancreatic]] volume
** 23% elevation in [[triglyceride]] content
** Serrated borders
** Involution of [[pancreas]]
 
== Microscopic Pathology ==
 
* The following [[Pancreas|pancreatic]] [[microscopic]] changes have been found in [[Diabetes mellitus type 2|diabetes type 2]] patients, compared to the normal population: <ref name="pmid259501802">{{cite journal| author=Macauley M, Percival K, Thelwall PE, Hollingsworth KG, Taylor R| title=Altered volume, morphology and composition of the pancreas in type 2 diabetes. | journal=PLoS One | year= 2015 | volume= 10 | issue= 5 | pages= e0126825 | pmid=25950180 | doi=10.1371/journal.pone.0126825 | pmc=4423920 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25950180  }}</ref><ref name="DonathSchumann2008">{{cite journal|last1=Donath|first1=M. Y.|last2=Schumann|first2=D. M.|last3=Faulenbach|first3=M.|last4=Ellingsgaard|first4=H.|last5=Perren|first5=A.|last6=Ehses|first6=J. A.|title=Islet Inflammation in Type 2 Diabetes: From metabolic stress to therapy|journal=Diabetes Care|volume=31|issue=Supplement 2|year=2008|pages=S161–S164|issn=0149-5992|doi=10.2337/dc08-s243}}</ref><ref name="TomovaStoyanov2020">{{cite journal|last1=Tomova|first1=Irina|last2=Stoyanov|first2=George S|last3=Dzhenkov|first3=Deyan L|last4=Petkova|first4=Lilyana|title=Late Pathomorphological Features of the Endocrine Pancreas in Patients With Type 2 Diabetes Mellitus|journal=Cureus|year=2020|issn=2168-8184|doi=10.7759/cureus.8777}}</ref>
**[[Amyloid]] deposition
***Can be detected as a positive [[congo red]] deposition of pink, amorphous material in the [[extracellular matrix]].
**[[Fibrosis]]
**[[Lipomatosis]]
**[[Apoptosis|Apoptotic]] or [[Necrosis|necrotic]] cells
**Increased numbers of [[Macrophage|macrophages]]
**Increased numbers and activity of [[Monocyte|mononuclear cells]]
**Increased [[IL-1|IL-1β]] [[Messenger RNA|mRNA]] expression
***


==References==
==References==

Latest revision as of 11:24, 21 October 2020

Diabetes mellitus main page

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3],Seyedmahdi Pahlavani, M.D. [4]Anahita Deylamsalehi, M.D.[5]

Overview

The exact pathophysiology of type 2 diabetes mellitus is not fully understood. The underlying pathology is the development of insulin resistance. Contrary to type 1 diabetes, patients with type 2 diabetes sufficiently produce insulin. However, the cellular response to the circulating insulin is diminished in type 2 DM. The mechanism by which the insulin resistance develops is postulated to be influenced by both genetic and environmental factors. Environmental influences on the pathogenesis of type 2 DM include high glycemic diets, central obesity, older age, male gender, low-fiber diet, and highly saturated fat diet.There are some genetic variants and HLA related to type 2 diabetes mellitus. Diabetes type 2 is associated with metabolic disorders, sarcopenia and liver cancer. It also has some associated features with insulin resistance. Gross pathology of pancreas shows serrated borders and reduced volume, which is due to pancreatic cells necrosis. Amyloid deposition, inflammation and fibrosis are some of the microscopic changes in diabetic pancreas.

Pathophysiology

Pathogenesis

Beta-cell function

  • Some carbohydrates are not converted e.g fruit sugar (fructose) is usable as cellular fuel but it is not converted to glucose, and it therefore does not participate in the insulin/glucose metabolic regulatory mechanism.
  • Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage.
  • If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangement, such as acidosis.
Mechanism of insulin release in normal pancreatic beta cells
Mechanism of insulin release in normal pancreatic beta cells

Inflammation and Diabetes

Obesity as the Link Between Diabetes and Inflammation

Systemic Inflammation in Diabetes

Genetics

Associated Conditions

Gross Pathology

Microscopic Pathology

References

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  2. van der Schaft, Niels; Schoufour, Josje D.; Nano, Jana; Kiefte-de Jong, Jessica C.; Muka, Taulant; Sijbrands, Eric J. G.; Ikram, M. Arfan; Franco, Oscar H.; Voortman, Trudy (2019). "Dietary antioxidant capacity and risk of type 2 diabetes mellitus, prediabetes and insulin resistance: the Rotterdam Study". European Journal of Epidemiology. 34 (9): 853–861. doi:10.1007/s10654-019-00548-9. ISSN 0393-2990.
  3. Kaneto, H.; Kajimoto, Y.; Miyagawa, J.; Matsuoka, T.; Fujitani, Y.; Umayahara, Y.; Hanafusa, T.; Matsuzawa, Y.; Yamasaki, Y.; Hori, M. (1999). "Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity". Diabetes. 48 (12): 2398–2406. doi:10.2337/diabetes.48.12.2398. ISSN 0012-1797.
  4. 4.0 4.1 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ; et al. (2003). "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance". J Clin Invest. 112 (12): 1821–30. doi:10.1172/JCI19451. PMC 296998. PMID 14679177.
  5. 5.0 5.1 5.2 Calle MC, Fernandez ML (2012). "Inflammation and type 2 diabetes". Diabetes Metab. 38 (3): 183–91. doi:10.1016/j.diabet.2011.11.006. PMID 22252015.
  6. Hotamisligil GS, Shargill NS, Spiegelman BM (1993). "Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance". Science. 259 (5091): 87–91. PMID 7678183.
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  8. 8.0 8.1 Berg AH, Scherer PE (2005). "Adipose tissue, inflammation, and cardiovascular disease". Circ Res. 96 (9): 939–49. doi:10.1161/01.RES.0000163635.62927.34. PMID 15890981.
  9. Trayhurn P, Wood IS (2004). "Adipokines: inflammation and the pleiotropic role of white adipose tissue". Br J Nutr. 92 (3): 347–55. PMID 15469638.
  10. Lyssenko, Valeriya; Jonsson, Anna; Almgren, Peter; Pulizzi, Nicoló; Isomaa, Bo; Tuomi, Tiinamaija; Berglund, Göran; Altshuler, David; Nilsson, Peter; Groop, Leif (2008). "Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes". New England Journal of Medicine. 359 (21): 2220–2232. doi:10.1056/NEJMoa0801869. ISSN 0028-4793.
  11. Lyssenko, Valeriya; Jonsson, Anna; Almgren, Peter; Pulizzi, Nicoló; Isomaa, Bo; Tuomi, Tiinamaija; Berglund, Göran; Altshuler, David; Nilsson, Peter; Groop, Leif (2008). "Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes". New England Journal of Medicine. 359 (21): 2220–2232. doi:10.1056/NEJMoa0801869. ISSN 0028-4793.
  12. Das SK, Elbein SC (2006). "The Genetic Basis of Type 2 Diabetes". Cellscience. 2 (4): 100–131. doi:10.1901/jaba.2006.2-100. PMC 1526773. PMID 16892160.
  13. Tuomi, T. (2005). "Type 1 and Type 2 Diabetes: What Do They Have in Common?". Diabetes. 54 (Supplement 2): S40–S45. doi:10.2337/diabetes.54.suppl_2.S40. ISSN 0012-1797.
  14. Meigs JB, Dupuis J, Herbert AG, Liu C, Wilson PW, Cupples LA (2005). "The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women". J Clin Endocrinol Metab. 90 (2): 1137–43. doi:10.1210/jc.2004-1212. PMID 15562019.
  15. Tuomi, T. (2005). "Type 1 and Type 2 Diabetes: What Do They Have in Common?". Diabetes. 54 (Supplement 2): S40–S45. doi:10.2337/diabetes.54.suppl_2.S40. ISSN 0012-1797.
  16. Younossi, Zobair M.; Golabi, Pegah; de Avila, Leyla; Paik, James Minhui; Srishord, Manirath; Fukui, Natsu; Qiu, Ying; Burns, Leah; Afendy, Arian; Nader, Fatema (2019). "The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis". Journal of Hepatology. 71 (4): 793–801. doi:10.1016/j.jhep.2019.06.021. ISSN 0168-8278.
  17. Jack, L., Jr., Boseman, L. & Vinicor, F. Aging Americans and diabetes. A public health and clinical response. Geriatrics 2004, 59, 14-17.
  18. Lovejoy, J. C. The influence of dietary fat on insulin resistance. Curr Diab Rep 2002, 2,435-440.
  19. Hu, F. B. Sedentary lifestyle and risk of obesity and type 2 diabetes. Lipids 2003, 38,103-108.
  20. Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D (2019). "Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship". Diabetes Metab Syndr Obes. 12: 1057–1072. doi:10.2147/DMSO.S186600. PMC 6630094 Check |pmc= value (help). PMID 31372016.
  21. Ge, Xiao-Jun; Du, Yu-Xuan; Zheng, Li-Mei; Wang, Mei; Jiang, Jun-Yao (2020). "Mortality trends of liver cancer among patients with type 2 diabetes at the global and national level". Journal of Diabetes and its Complications. 34 (8): 107612. doi:10.1016/j.jdiacomp.2020.107612. ISSN 1056-8727.
  22. Wu, Yingjie; Zhou, An; Tang, Li; Lei, Yuanyuan; Tang, Bo; Zhang, Linjing (2020). "Bile Acids: Key Regulators and Novel Treatment Targets for Type 2 Diabetes". Journal of Diabetes Research. 2020: 1–11. doi:10.1155/2020/6138438. ISSN 2314-6745.
  23. Macauley M, Percival K, Thelwall PE, Hollingsworth KG, Taylor R (2015). "Altered volume, morphology and composition of the pancreas in type 2 diabetes". PLoS One. 10 (5): e0126825. doi:10.1371/journal.pone.0126825. PMC 4423920. PMID 25950180.
  24. Macauley M, Percival K, Thelwall PE, Hollingsworth KG, Taylor R (2015). "Altered volume, morphology and composition of the pancreas in type 2 diabetes". PLoS One. 10 (5): e0126825. doi:10.1371/journal.pone.0126825. PMC 4423920. PMID 25950180.
  25. Donath, M. Y.; Schumann, D. M.; Faulenbach, M.; Ellingsgaard, H.; Perren, A.; Ehses, J. A. (2008). "Islet Inflammation in Type 2 Diabetes: From metabolic stress to therapy". Diabetes Care. 31 (Supplement 2): S161–S164. doi:10.2337/dc08-s243. ISSN 0149-5992.
  26. Tomova, Irina; Stoyanov, George S; Dzhenkov, Deyan L; Petkova, Lilyana (2020). "Late Pathomorphological Features of the Endocrine Pancreas in Patients With Type 2 Diabetes Mellitus". Cureus. doi:10.7759/cureus.8777. ISSN 2168-8184.


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