# Metabolomics/Hormones/Insulin
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    Metabolites

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    Glucagon

## Introduction
### The three dimensional dtructure of insulin

Insulin is a small protein with two polypeptide chains joined by two disulfide bonds. It is synthesized in the pancreas as an inactive single chain precursor, preproinsulin, with an maison terminal signal sequence that directs its passage into secretory vesicles.
Insulin (Latin insula, "island", as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary effector in carbohydrate homeostasis, it also has a substantial effect on small vessel muscle tone, controls storage and release of fat (triglycerides) and cellular uptake of both amino acids and some electrolytes. In this last sense, it has anabolic properties. Its concentration (more or less, presence or absence) has extremely widespread effects throughout the body.
Insulin is used medically in some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on exogenous insulin (injected subcutaneously) for their survival because of an absolute deficiency of the hormone; patients with Type 2 diabetes mellitus have either relatively low insulin production or insulin resistance or both, and a non-trivial fraction of Type 2 diabetics eventually require insulin administration when other medications become inadequate in controlling blood glucose levels. Insulin structure varies slightly between species. Its carbohydrate metabolism regulatory function strength in humans also varies. Pig insulin is particularly close to the human one.
The exact sequence of amino acids comprising the insulin molecule, the so-called primary structure, was determined by British molecular biologist Frederick Sanger. It was the first protein the structure of which was completely determined. For this he was awarded the Nobel Prize in Chemistry in 1958. In 1967, after decades of work, Dorothy Crowfoot Hodgkin determined the spatial conformation of the molecule, by means of X-ray diffraction studies. She also was awarded a Nobel Prize.

### Insulin secretion location
#### Control of insulin secretion

Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This makes sense because insulin is "in charge" of facilitating glucose entry into cells. Some neural stimuli (e.g. sight and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion.
Glucose is transported into the beta cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the beta cell. Elevated concentrations of glucose within the beta cell ultimately leads to membrane depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules. The mechanisms by which elevated glucose levels within the beta cell cause depolarization is not clearly established, but seems to result from metabolism of glucose and other fuel molecules within the cell, perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in membrane conductance. Increased levels of glucose within beta cells also appears to activate calcium-independent pathways that participate in insulin secretion.

### General overview

Throughout body it regulates blood glucose levels, increases storage of glycogen, and facilitates glucose intake by body cells. Proteolytic removal of the signal sequence and formation of three disulfide bonds produces proinsulin, which is stored in secretory granules in pancreatic beta cells. When elevated blood glucose triggers insulin secretion, proinsulin is converted to active insulin by specific proteases, which cleave two peptide bonds to form the mature insulin molecule.

### Insulin process from precursor

The effect of insulin is to favor the conversion of excess blood glucose to two storage forms glycogen (in the liver and muscle), and triacylglycerol (in adipose tissue)
Proinsulin is synthesized in the pancreatic beta cells as a 9390 mw polypeptide of 86 amino acids.
Proinsulin is subsequently cleaved enzymatically, releasing insulin into the circulation along with a residual 3000 mw fragment called C-peptide, so-named because it connects the A and B chains of insulin within the proinsulin molecule.
Proinsulin, which has relatively low biological activity (approximately 10% of insulin potency), is the major storage form of insulin. Normally, only small amounts (~3% of the amount of insulin, on a molar basis) of proinsulin enter the circulation. Because the hepatic clearance of proinsulin is only 25% of insulin clearance, the half-life of proinsulin is two- to threefold longer and concentrations in the fasting state are approximately 10% to 15% of insulin concentrations.

## References

* Elaine Marieb, Anatomy & Physiology 3rd Ed. McGraw Hill, 2007
* Nelson, David L. and Cox, Micheal M. Lehninger Principles of Biochemistry, 4th Ed. New York: W. H. Freeman and Company, 2005.

## Website sources

Association of Adiposity, Cardiorespiratory Fitness and Exercise Practice with the Prevalence of Type 2 Diabetes in Brazilian Elderly Women
http://www.medsci.org/v04p0288.htm

### General overview

The incidences of diabetes in age increasing women are substantially growing in alarming rate. Therefore it is important to keep close research on this topic to reduce the growing communities in type 2 diabetes. In order to analyze the effects, adiposity, cardio respiratory fitness, and exercise practice in T2D in Brazilian elderly women are put to several exercises to measure their health conditions.
The general and central adiposity were directly associated with T2D, whereas cardio respiratory fitness was inversely related with T2D. The joint effect of exercise practice and central adiposity showed that inactive women had higher rate of odd in facing T2D when compared with active women.
The researchers were able to determine the association of general and central adiposity as well as an inverse relation with CRF (cardio respiratory fitness) and exercise practice side by side with T2D. Elderly women practicing regular exercise had lower odds of acquiring T2D than the inactive group of women. By having proper exercise, the exercise will reduce the body fatness and possibly benefiting from reducing the prevalence of T2D in old aging group.

### New terms
#### Adiposity

    loose connective tissue composed of adipocyte, which is derived from lipoblasts and their maine role is to store energy in the form of fat

#### CRF (Cardio respiratory fitness)

    refers to the ability of the circulatory and respiratory systems to supply oxygen to skeletal muscles during sustained physical activity.

#### Type 2 diabetes (T2D)

    common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin.

### Course relevance

       Analysis of prevalence of diabetes and poor glycemic control
       Metabolic control; this was measured by reduced insulin resistance and inflammation in study subjects
       Biochemical measure method

### References

* Bassett MT. Diabetes is Epidemic. Am J Publ Health. 2005;95:1496
* Mokdad AH, Ford ES, Bowman BA. et al. Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001. JAMA. 2003;289:76-79
* Sullivan PW, Morrato EH, Ghushchyan V, Wyatt H, Hill JO. Obesity, Inactivity, and the Prevalence of Diabetes and Diabetes-Related Cardiovascular Comorbidities in the U.S, 2000-2002. Diabetes Care. 2005;28:1599-1603
* Nasri F. Diabetes Mellitus no Idoso. In: (ed.) Freitas EV. et al. Tratado de Geriatria e Gerontologia. Guanabara Koogan. 2002:496-501
* Elaine Marieb, Anatomy & Physiology 3rd Ed. McGraw Hill, 2007
* Nelson, David L. and Cox, Micheal M. Lehninger Principles of Biochemistry, 4th Ed. New York: W. H. Freeman and Company, 2005.

## Website #2

Insulin secretion location http://www.clarian.org/ADAM/doc/graphics/images/en/19200.jpg
General Overview
       Throughout body it regulates blood glucose levels, increases storage of glycogen, and facilitates glucose intake by body cells. Proteolytic removal of the signal sequence and formation of three disulfide bonds produces proinsulin, which is stored in secretory granules in pancreatic beta cells. When elevated blood glucose triggers insulin secretion, proinsulin is converted to active insulin by specific proteases, which cleave two peptide bonds to form the mature insulin molecule.
       Insulin process from precursor
       The effect of insulin is to favor the conversion of excess blood glucose to two storage forms: glycogen (in the liver and muscle), and triacylglycerol (in adipose tissue)
References
       Elaine Marieb, Anatomy & Physiology 3rd Ed. McGraw Hill, 2007
       Nelson, David L. and Cox, Micheal M. Lehninger Principles of Biochemistry, 4th Ed. New York: W. H. Freeman and Company, 2005.

## Website #3

Strength training improves muscle quality and insulin sensitivity in Hispanic older adults with type 2 diabetes
http://www.medsci.org/v04p0019.htm

### General overview

       Type 2 diabetes is a chronic disease characterized by hyperglycemia and disturbances of carbohydrate,fat and protein metabolism. Diet, exercise and weight loss are cornerstones of diabetes management to improve glycemic control, reduce muscle wasting and mortality. Targeted interventions are needed to improve long-term diabetes control in high risk groups,like Hispanic older adults for whom diabetes and poor glycemic control are prevalent.
       The inflammatory response is correlated with multiple metabolic markers of insulin resistance. We measured CRP, a systemic marker of low-grade systemic inflammation. It has recently been shown that ten months of aerobic exercise reduced CRP levels in elderly subjects and aerobic exercise training combined with a dietary intervention in diabetic men reduced their CRP levels. The decrease in CRP levels we observed in the present study suggests that the reduction in the inflammatory state of diabetes may be an important factor leading to improved insulin sensitivity and better metabolic control. Furthermore, since adiponectin has anti-inflammatory actions and we showed a significant increase in this adipokine, the reduction in inflammation may be related to this increase.
       In conclusion, the findings of the present study suggest that 16 weeks of strength training results in improved muscle quality, skeletal muscle fiber hypertrophy, accompanied by concomitant changes in biochemical markers known that contribute to whole-body insulin sensitivity; namely, reduced HOMA-IR, increased adiponectin levels and decreased FFA and CRP levels. Further studies are needed to establish the mechanisms associated with these relationships. However, these data show that strength training is an exercise modality worth considering as an adjunct of standard of care for high risk populations with diabetes.

### New terms
#### Type 2 diabetes

    a chronic disease characterized by hyperglycemia and disturbances of carbohydrate, fat, and protein metabolism

#### Muscle quality

    maximal force prodection per unit of muscle mass, better indicator of muscle function

#### Adipokines

    soluble proteins released from adipocytes in response to metabolic signals and are
involved in insulin resistance and inflammation

#### Adiponectin levels

    decrease with increasing fat mass and higher levels of plasma adiponectin are independently associated with
reduced risk of type 2 diabetes in healthy individuals

#### CRP

    carbon reactive protein

#### ST

    strength training with standard care group

#### CON

    control group standard care alone

#### FFA

    free fatty acid

#### HOMA IR

    metabolic control including insulin resistance (Homeostasis Model Assessment)

## Insulin regulation
### Grb14

Interactions between the Grb14 molecular adapter and the autophosphorylated insulin receptor (IR) have been identified. As an IR interacting partner, Grb14 has been identified in insulin sensitive tissues as a selective inhibitor for IR catalytic activity. Enhanced insulin signaling has been identified in adult male Grb14 knockout (KO) mice. However, researchers had been unsure if this phenotype was a result of compensatory action that occurred during growth development. Therefore, in order to determine the exact physiological role of Grb14, small interfering RNAs (siRNA) were used in primary cultured hepatocytes. Grb14 knock-down resulted in improvement of insulin signaling pathways. However, results from another RNA sequence indicated that these observations could not be a consequence of unspecific siRNA action. The resultant Grb14 depletion suggested that Grb14 activity had a second role, in addition to its function as an IR catalytic inhibitor. Experimental results indicated that, under acute modulation of its level of expression, the prevailing effect of Grb14 was more distal.
The assumed inhibitory role of Grb14 was supported by a sustained increase in Akt phosphorylation of Grb14-depleted hepatocytes. This was observed to be in direct response to insulin stimulation. Increased phosphorylation of Akt substrates resulted in an increase of downstream kinases, which accompanied the Grb14 insulin stimulation response. Grb14 knock-down has also been discovered to reduce the impact of insulin. Specifically, Grb14 has been observed to decrease the expression of SREBP-1c, Insig1, GK and FAS, in addition to inhibiting glycogen synthesis.
Link to article:
http://www.ncbi.nlm.nih.gov/pubmed/18339716?ordinalpos=157&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

### Synaptotagmin

Synaptotagmin-7 mutant mice have been proven to undergo a reduction in insulin secretion, which in turn results in higher glucose tolerance. The reduction of insulin secretion had been believed to be a result of a Ca$^{2+}$ defect in insulin-containing granule exocytosis, because there had been no observed abnormalities in steps that lead to increased [Ca$^{2+}$]$_I$, or peripheral insulin sensitivity. These observations also supported the capacity of the synaptotagmin-7 calcium sensor as an insulin secretion regulator.
There have been a minimum of fifteen synaptotagmin isoforms identified in brain and peripheral tissues. However, synaptotagmin-1, -2, and -9 are the only established Ca$^{2+}$ sensors for fast neurotransmitter release. Synaptotagmin-7 is one of the most proliferate Ca$^{2+}$ sensors with different affinities, and has been proven to have an exceedingly higher Ca$^{2+}$ affinity than synaptotagmin-1 and -2, in addition to having insulin secretion regulatory capabilities. When compared with a control, synaptotagmin-7 mutant mice had reduced insulin secretion and impaired glucose tolerance.
As a major anabolic hormone, insulin promotes lipid synthesis while inhibiting lipolysis. In support of this activity, lower plasma insulin levels in synaptotagmin-7 mutant mice were discovered to experience significant reductions of body fat content. Furthermore, exogenous insulin administration was proven to suppress plasma glucose more effectively in synaptotagmin-7 mutant mice than in the controls. It was speculated that, under usual conditions and with high insulin sensitivity, a low level of insulin would be sufficient to maintain blood glucose homeostasis.
It was discovered that synaptotagmin-7 mutant mice had lower insulin levels from birth. Research has indicated that liver insulin receptor mRNA regulation was increased, in these mice. This implied an adaptation to insulin sensitivity. Furthermore, glucose intolerance in the synaptotagmin-7 mice was believed to be a result of insulin secretion dysfunction in beta-cells, instead of peripheral insulin resistance.
Link to article:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18308938#id2619994

## References

       Nasri F. Diabetes Mellitus no Idoso. In(ed.) Freitas EV. et al. Tratado de Geriatria e Gerontologia. Guanabara Koogan. 2002,496-501
       Elaine Marieb, Anatomy & Physiology 3rd Ed. McGraw Hill, 2007
       Nelson, David L. and Cox, Micheal M. Lehninger Principles of Biochemistry, 4th Ed. New York: W. H. Freeman and Company, 2005.

## Further reading

Causes of early-onset type 1 diabetes: toward data-driven environmental approaches
The Journal of Experimental Medicine, Vol. 205, No. 13