5) ARTICLE - insulin & reward pathway [2012.01.09]

Insulin & reward pathway
Insulin functions between metabolism and neuroscience
Diabetes, dopamine, insulin, insulin-resistance,
reward pathway, metabolic syndrome.

Diabetes, one of the most diffused pathologies in the world (according to the most recent statistics of the World Health Organization 366.000.000 people in the world are affected; 5.374.000 in Italy, corresponding to about 10% of the population [1]), has in insulin-resistance the founding element. Even if the action of the hormone insulin is mostly peripheral, recent studies show that the central nervous system is actually a key-target of insulin function, and particularly the VTA, a mesencephalic anterior area. Therefore diabetes, previously considered mostly an endocrine system pathology, has now been shown to follow neuro-scientiphic logic in its pathogenesis and also generally in each manifestation. This idea, proved by much scientific research [2-5], permits a new way of seeing the diabetic pathology in itself and every therapeutic consequence, from a more global perspective that is also more centered on each patient at the same time.
Diabetes mellitus is a group of metabolic pathologies having in common hyper-glycaemia.
After a certain level (100 mg/dL) has been exceeded, glucose normally enters into the cells throughout transmembrane proteins-transport channel GLUT4. This entrance permits a lowering of glycaemia and the utilization of glucose especially in skeletal muscle tissue and in the liver (where it becomes glycogen) and in adipose tissue (where it becomes triglycerides). Anabolism consists in the formation of new molecules starting from glucose, with parallel tissue heightening. The anabolic function is fostered by insulin, produced by the beta-cells of the pancreas insulae.
Insulin is a proteic hormone characterized by two chains linked by two bridge disolfuro: chain A of 21 aminoacids and chain B of 30 aminoacids. It is secreted after a metabolic-cellular pathway: hyper-glycaemia makes the glucose go into the beta-cell throughout the GLUT 2 transporters. The effects are: the secretion of already produced insulin, and the production of neo-synthesis insulin.
Two elements are always present in diabetic pathology: hyper-glycaemia and a contemporary dysfunction of the activity of insulin, which is either reduced or altered.
There are various types of diabetes:
- diabetes type 1, in which the normal absorption of sugars in peripheral tissue based on the insulin stimulus is reduced, with consequent hyper-glycaemia, caused by a genetic deficit of insulin and ketoacidosis risk
- diabetes type 2, in which hyper-glycaemia characterizes a heterogeneous group of pathology, with different degrees of insulin-resistance, altered secretion of insulin, and excessive hepatic glucose production
- diabetes type 3, recently discovered [6] is the typically encephalic diabetes, linked in 65% of cases to Alzheimer pathology that it has also been defined “double diabetes” due to the coexistence at the same time of conditions characteristic of both diabetes type 1 and insulin-resistance. It has been observed that the brain produces insulin as pancreas does, and that in diabetes type 3 there is a central insulin-resistance and the deposition of proteic plaques similar to those typical of Alzheimer pathology at the same time.
In this situation the central nervous system has a key-role towards diabetic pathology:
- there are neurons producing insulin
- insulin is important in diabetes type 3 pathogenesis, and linked with Alzheimer pathology
- insulin acts on the encephalic structures (hypothalamus, mesencephalon, reward pathway) involved in the central regulation of diabetes itself.
The function of the central nervous system towards diabetes can consequently be hypothesized for all the three types of diabetes.
The risk factors for diabetes are:
- familiarity for diabetes
- obesity
- sedentary lifestyle
- ethnic origin
- hypertension
- hypercholesterolemia
- vasculopathies
Pathogenesis is distinguished by a progression:
- in the not still clinically manifested pathology phases, there is a normal tolerance to glucides, a good quantity of basal fast insulin continually secreted, and a post-prandial secretion of insulin (still produced and from a neo-synthesis)
- on the contrary, when a condition of altered equilibrium begins:
1. less basal fast insulin is secreted
2. less post-prandial insulin is secreted
3. there is an increase in the glycaemia level.
- the consequence is hyper-glycaemia caused by the little amount of insulin for less stimulation to the peripheral tissue using glucose which normally goes into the tissue thanks to the effect of insulin on them with an anabolic function
The toxicity is dual:
1. from glucides – high glucose acts on cells leading to an insulin-resistance condition that consists in two elements:
- a reduction of insulin receptors
- altered post-receptorial functioning of insulin itself
this takes place
a. in primis on the pancreatic beta-cell, which is less and less able to absume glucose, with consequent less synthesis and less secretion of insulin
b. on the retina: with a possible retinopathy
c. and on the kidney, from which nephropathy
2. from lipids – there is an elevation of free fatty acids (FFA) toxic particularly on beta-cell. The elevation of lipids is typical of metabolic syndrome, frequently associated to diabetic pathology; dysmetabolic patients have characteristics of: central obesity with augmented waist circumference, arterial hypertension, increased triglycerides, less HDL cholesterol, and insulin-resistance to diabetes.
In addition to the characteristics of an obesity condition above (diabetes type 2), diabetic patient has at exordium: polyuria (augmentation of the quantity of urine), polydipsia (increased thirstiness), polyphagia vs loss of weight (particularly in diabetes type 1), weakness, augmented frequency of superficial infections and low tendency of wound healing.
Complications may be: retinopathy, kidney failure, polyneuropathies, gastroenteric alterations, frequent infections of urinary system, erectile dysfunction, coronaropathy and cardiopathy, diabetic foot.
Diagnosis is based on parameters that measure fast glycaemia and after reaching an oral quantity of glucose [2,3]: we talk about a normal glycaemia if less than 110 mg/dL, classifying this as altered glycaemia that going until 125 mg/dL which is, which is useful in defining a diabetes mellitus condition. A similar classification may be made by measuring the glycaemia levels after the subministration of an oral quantity of glucose, in this way obtaining values that define situations of glucides intolerance or real diabetes mellitus.
After diabetes has been diagnosed, or even only of a pre-diabetic condition, it is necessary to develop the different grades of a therapeutic plan based on the pivots of the care of this pathology (variously combined; the aim is to reduce the HbA1c –glycated hemoglobin- under 7%):
1. diet and physical activity – improvement of the metabolic condition of the patient with the reduction of body mass index (BMI, corresponding at (weight –kg-) divided (height –meters-, volume)), and re-balancing of the ratio between fat-free-mass and fat-mass (balanced diabetic program and physical activity)
as regards the diet, it is made personalized according to age, sex, physical activity, actual weight and ideal weight (glucides 50-55%, proteins 10-20%, lipids <30%); glucides substituted are often preferred, like saccharin or other non glycidic sweeteners
as regards physical activity aerobic is preferred: 30 minutes 3-4 times a week (having a cardiac frequency corresponding to 220˗years), choosing the activities in an individualized way, according to the overall clinical situation
2. metformin, a pharmaceutical of the biguanides family, used for the treatment of diabetes mellitus type 2, which acts by increasing the use of glucose by peripheral tissues which permits arise in their insulin response in turn
there are many vantages of metformine:
o reduces the HbA1c by 1-2%
o leads to loss of weight
o improves the lipidic prophile
o does not cause hyper-glycaemia
3. insulin secretors (like glitazones, tiazolindiones), drugs indicated in diabetes type 2, amplifying the effects of insulin in adipose tissue and in skeletal muscle tissue
they are used mostly in patients who need more than 1 UI/kg/die of insulin
4. alfa glycosidase inhibitors (acarbose): these reduce glucides absorption
5. insulin – creation of insulinic draft associating long-acting molecules for a basal optimal insulinization with short-acting molecules in immediately post-prandial molecules (at mean dose 0,5-1 UI/kg/die). Usually the plans comprehend two injections per die of an intermediate insulin combined with a rapid-action insulin before breakfast and dinner, an injection of glargine before night or lispro o aspart before lunch.
6. the following are also useful: an auto-monitorized glycaemia control at an individualized frequency, flu vaccine, measurement of blood pressure, lipid profile, micro-albuminuria control, EKG at rest, complete cardiologic evaluation, oculist exam, foot exam.
Correct prevention is particularly based on the integration of new logic in the classical concept of diabetes, and all its implications.
Regarding diabetes, recent studies have shown that:
a- insulin is produced by neurons too, stem cells of central nervous system [7]
b- thanks to its embryological origin, common to which of central nervous system (neuro-ectoderm), beta cells present a particular characteristic: they have the dopa-decarbossilase, an enzyme able to convert L-dopa in dopamine. This suggests that pancreatic insulae are involved in a neuroendocrine system called apud which is involved in a real dopaminergic system with encephalic regulation [8]
c- insulin acts on the central nervous system, particularly at the reward pathway level, the encephalic system of reward liking emotional responses to the functions regulating superior hormonal systems; this pathway has as dopamine pathways neural circuitries, mostly mesencephalic neurotransmitter.
The center of this neural pathway is the VTA, ventral tegmental area, which is linked with the cortex (prefrontal and limbic), basal ganglia (amygdala and the nucleus accumbens) and other systems (bulbar, medullary, antinociceptives).
Dopamine is released after stimuli coming from different parts (neurons have phasic more than tonic, continuous, activity).
Reward pathway is a regulating center of instinctive mechanisms, automatic or unconscious behaviors, vegetative reactions and emotive responses. It is also the target place of much molecular stimuli, all included in the concept of “drugs”:
1. endogenous molecules produced in the CNS, neurotransmitters, hormones, and their exogenous analogues, whether chemicals or pharmaceuticals
2. endogenous peripheral molecules and other chemically obtained molecules
3. every natural or artificial molecule able to change the neuro-transmettitorial balance taking place in the VTA
The reward is activated (at a medial level) after certain stimuli and it feeds itself: it tends to establish and mantain the original input leading to the raise of dopamine (input associated to dopamine according to a pavlovian conditioning which is sought for the pleasure in itself).
The news in research about reward mechanisms is in the fact that it has been observed that insulin has effects on this circuitry: experimental data underline that insulin causes a rise in the dopamine precursor (mRNA).
Insulin stimulates the nucleus accumbens, the site of the elaboration of pleasure mechanisms (as a consequence there is an augmentation of the transit through reward circuitries) [4, 5]. It has been observed that in diabetic subjects, due to insulin-resistance (a lower effect of insulin) this mechanism is altered, due to the low response at a cellular and at an intracellular level to hormone (in a similar way as at peripheral level): this means that diabetic subject require more and more quantity of insulin for the same effect of gratification.
It has also been demonstrated that beta-cells express D2 receptors for dopamine, and the transduction of this dopaminergic signal gets to an inhibition to the secretion of insulin [9]: the more dopamine there is the less insulin is secreted, the more reward pathway is stimulated the less insulin will be in the blood.
This means that
- in diabetic patient an hypothetical opening hypo-dopaminemia gets to an hyper-insulinemic status leading to an addiction to protein that gets to an insulin-resistance condition typical of advanced diabetic pathology conditions;
- in every condition of hypo-dopaminemia there is the consequence of hyper-insulinemia, a risk due to insulin-resistance.
On the contrary, if a sufficient level of dopamine is maintained, thanks to correctly received rewards, insulin disequilibrium would not occur or would take place in a more controlled way.
The fact that insulin acts at a cerebral level reveals that the mind become a key element in its pathogenesis and in the therapy of diabetic pathology, mainly when associated with obesity. It is in fact verified that every treatment acting on molecular insulinic systems acts at the same time even on the same mechanisms of the central nervous system. [10]
Pharmacological therapy is fundamental: as already stated diabetic patient often gets different kinds of insulin combined between them, metformin, alfa-glycosidase inhibitors, and glitazones.
Other than this, it is possible to reassess the meaning of diet and physical activity, which must be seen not as a constrictive system functional to a therapy, but interpreted as two gratification methods leading to an improvement that is not only functional but also global for the individual.
The real news is in the use of psychotherapy of others similar as hypnosis-therapy. Particularly (in a study of University of Bologna [11]) it has been shown that behavioral-cognitive therapy in a group of patients affected by a liver disease typical of metabolic syndrome has lead to better effect other than diet and loss of weight, with a normalization of hepatic enzymes, and insulin-resistance and the parameters of dysmetabolic pathology. The conclusion was that subjects who followed psychotherapy had a general amelioration of their parameters with beneficial effect kept even at two-years follow-up.
Moreover in the USA it has been verified many times that diabetic patients could have a reduced subministration of their daily insulin unities thanks to hypnosis sessions finalized at a revaluation of their way of seeing food and more global mental well-being: there have been cases of juvenile diabetes healed thanks to hypnosis.
It is possible to think to integrated therapies, associating all these therapeutic methods (pharmacological, psychological, alternative) so to get better accomplishments. Stevia, a historically anti-diabetic plant, could be used as an alternative therapy, always associating its use as a sweetener with traditional therapies. [12]
Moreover we can hypothesize real reward therapy, particularly in those patients for whom weight and diet are a problem in diabetes pathogenesis: it could be possible to automatically associate renunciations of “bad” foods from the diet with auto-gratifications like more functional hobbies (a walk, a bike ride, physical activity in specialized centers, swimming at a pool) or simply with pleasant activities lived as alternative gratifications that are useful in reducing the interest in bad foods (cinema, theatre, conferences, social centers, society games, pets, wellness centers).
In diabetic pathology, as in many other metabolic alterations, it is always more important to relate the specifically conceived physiopathological situation to more global logic, while keeping in mind a vision that includes the most innovative (neuro)scientific researches, and an interest in the concrete improvement of health. This is fundamental not only to know metabolic pathologies in a more complete way, but mostly to integrate different kinds of drugs and therapies.
The relation between the functions of mesencephalic reward pathway and metabolic pathologies typical of the Western world permits improvements in the classic therapies (insulin, anti-obesity therapy) with new molecules (now only experimental) and other therapies able to positively act on mind (psychotherapy, hypnosis, alternative therapies), according to the need of every single patient.
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