Type 2 Diabetes Therapy must be early and comprehensive. The general objectives of the treatment are to obtain normoglycemia but also to take care of all the cardiovascular risk factors that are often associated with diabetes. Treatment also aims to reduce obesity and sedentary lifestyle.
- Be adapted to each patient by being modulated according to physiological age, comorbidity, severity and age of diabetes.
- To rely on the active participation of the patient in order to obtain a long-term modification of the habits of life in particular in the food plan and the physical activity
- Call upon the complementarity of different health professionals
A. Type 2 Diabetes Therapy Goals:
- The search for an optimal glycemic control defined by a target value of glycated hemoglobin
(HbA1c) adapted to the context (normal healthy subject ranging from 4 to 6%)
- Early and strict management of risk cofactors:
– Blood pressure: strict blood pressure control <130/80 mmHg
– Lipids: targets for LDL-cholesterol graded according to a growing level of cardiovascular risk:
- LDL-cholesterol <1.9 g / l is reserved for small numbers of patients without any additional risk factor, without microangiopathy and whose diabetes has been evolving for less than 5 years
- LDL-cholesterol <1.6 g / l in other patients with at most one additional risk factor
- LDL cholesterol <1.3 g / l in patients with at least two additional risk to diabetes that has been less than 10 years old.
- LDL cholesterol <1 g / l
- In patients with secondary prevention
- or equivalent risk: – with renal impairment (albuminuria> 300 mg / day or DFG <60ml / min),
- Diabetes that has been evolving for more than 10 years and at least two additional risk factors
- Stop smoking
Risk Factors =
- Family history of early coronary disease
- Myocardial infarction or sudden death before age 55 in the father or relative of the first degree male,
- Myocardial infarction or sudden death before the age of 65 in the mother or in a first-degree female parent
- Family history of stroke before age 45
Smoking current or stopped for less than 3 years
- Permanent high blood pressure treated or not
- HDL-cholesterol <0.40 g / l (1.0 mmol / l) irrespective of sex – Microalbuminuria (> 30 mg / 24 hours)
- man 50 years or older
- woman aged 60 or over
- HDL-cholesterol protective factor> 0.60 g / l (1.5 mmol / l): then subtract “a risk” from the level score of
B. The Means Of Treatment:
1) Non-drug management
The active fight against a sedentary lifestyle as well as food planning represent interventions
irreplaceable at all stages of the management of type 2 diabetes.
80% of type 2 diabetics are obese. In these conditions, dietetics, by allowing to lose weight, represents the basis of treatment. Obtaining a weight loss is often difficult, but essential, and may be enough to normalize blood glucose at the beginning of diabetes.
Obtaining a weight loss requires a change in eating habits, which must be assessed initially through a food survey.
The food survey
It allows to specify the caloric level, without forgetting the calories alcohol, the number of meals taken per day, and the distribution between different nutrients.
Reduction of caloric intake
The goal is to obtain a weight loss of 1 to 4 kg per month. Caloric intake is usually reduced by 20 to 30% compared to food survey data. Nevertheless a frankly low calorie diet is incompatible with a socioprofessional and family life
normal, and under these conditions it is rare for diabetics to prescribe a diet unless 1,600 calories in women and 1,800 calories in men. Of course the caloric level will be adapted to the rhythm of weight loss and tolerance.
Distribution of food intake
Caloric intake should be divided into at least 3 meals a day, breakfast being everything indeed, and, in fact, often absent in the obese. The splitting of the food into five meals (3 main meals and 2 snacks) allowing a better distribution of the intake caloric on the day is often interesting. Meals and snacks must be mixed the carbohydrate combination of proteins and lipids making the meal less hyperglycaemic.
Distribution between different nutrients
It should approach the normal distribution: 50-55% of carbohydrates, 30-35% of lipids and 15% of proteins.
The carbohydrate safety ration to maintain is at least 100g of carbohydrates per day. The minimum protein ration is 0.7g / kg / day.
Fast-absorbing sugars should be avoided because of their character hyperglycemic, but also because they bring a significant amount of calories under a small volume. Fruit consumption is allowed but limited. The fruits represent 5% of the carbohydrate ration , 5% milk, and 90% slow sugars.
The consumption of polyunsaturated and monounsaturated fatty acids is favored over that of saturated fatty acids.
They are reduced because of the large caloric intake they represent. They should not not exceed a glass of wine per meal.
Their consumption has a double interest. On the one hand they reduce the hyperglycemic arrow post on the other hand they help to combat diet-induced constipation low calorie.
The consumption of non-caloric sweeteners (aspartame) is allowed.
Many products low in carbohydrates (containing sweeteners), but also in lipids are currently on the market and may be attractive under the scheme of a diabetic type 2.
1-2) Physical Activity
By facilitating the use of glucose and increasing the sensitivity to endogenous insulin, the activity Physicians participate in the control of blood glucose levels in type 2 diabetics. It also improves dyslipidemia by increasing HDL and decreasing triglycerides.
Physical activity consists of realistic changes to the daily lifestyle and as much as possible is based on three times 45 minutes per week of more intensive activity adapted to the profile of the patient. She maintains the osteo-articular apparatus and allows the maintenance of a satisfactory muscular mass, and contributes to the general hygiene of life.
Physical exercise should be regular, appropriate, prescribed after cardiovascular evaluation and represent some relaxation for the patient.
1-3) Monitoring the glycemic balance
a) Glycemic self-monitoring
The practice of glycemic self-monitoring (GAS) in type 2 diabetes allows a perception of the disease by the patient who is confronted with the values of his blood sugar. This awareness of the disease has brought about a drastic change in the patient’s participation in treatment and in taking in charge of his illness.
The ASG practice also allows the dosage of a sulphonylurea any other treatment that may alter insulin secretion.
Fasting blood glucose essentially reflects hepatic glucose production, while post prandial is rather dependent on the peripheral use of glucose. Mechanisms of hyperglycemia at these different times of the day are therefore different. It is therefore useful that the Type 2 Diabetes Monitor fasting blood glucose before and 2 hours after the 3 main meals, one to three times per week. The information obtained is recorded on a logbook on which can also be reported other parameters: variation of the diet, physical activity, monitoring of blood pressure and weight. This is a real health book.
b) Other means of surveillance
– glycated proteins: the measurement of glycated hemoglobin (HbA1c) gives information on the glycemic balance of the two to three months preceding the sampling, that of fructosamine provides information on the balance of the previous 15 days. Surveillance of type 2 diabetes requires a measurement of HbA1c every 3 months.
– Ketonuria: surveillance of ketonuria is useful in periods of imbalance of diabetes, to detect a transition to insulin-dependence or transient insulin-dependence will result in the association: strong hyperglycemia and strong ketonuria. By cons the secondary weight loss caloric restriction will result in an improvement in blood sugar and sometimes the appearance of a moderate ketonuria.
1-4) Therapeutic Education:
Therapeutic education is a fundamental part of the care of any patient diabetic. It must be implemented as soon as diabetes is discovered by medical professionals or paramedics trained in this activity. It is recommended to propose to the patient a therapeutic education in group (preferably) or individual by doctors and paramedics (dietician, nurse,
medico-educational educator, psychologist).
2) Drug Management (see table)
Until 2008, 5 types of oral hypoglycemic agents were available: sulfonylureas (or sulfonamides), glinides, biguanides, thiazolidinediones and alphaglucosidase inhibitors. The action hypoglycemic of these 5 classes of drugs is well established, their mechanisms of action different. These 5 classes were taken into account in the HAS 2006 recommendations. Two other therapeutic classes have recently been made available, these are glucagonlike analogues peptide 1 (GLP1) and inhibitors of the enzyme dipeptidyl peptidase 4 (DPP4).
2.1) The drugs of insulin resistance:
211) The biguanides:
Biguanides do not stimulate insulin secretion. Their main action is to reduce production hepatic glucose by slowing down gluconeogenesis. They also promote the peripheral action of insulin. Biguanides do not cause weight gain. They can even contribute to weight loss or weight balance when combined with other diabetes treatments that promote weight gain (including including insulin therapy). They do not induce hypoglycemia on their own.
The most common are digestive: anorexia, nausea, abdominal discomfort and diarrhea. These effects are less if the drug is taken during or at the end of a meal and if the dosage is increased gradually or limited in some patients. The most serious adverse effect of the biguanide class is lactic acidosis; its occurrence is very rare; his prognosis is very unfavorable. The lactic acidosis reported in patients receiving metformin are due either to inappropriate prescriptions or to non-compliance with contraindications or precautions of use: anesthesia or injection of iodized contrast medium, renal insufficiency, hypoxic state, insufficiency hepatocellular, cardiogenic shock, severe respiratory or hepatic insufficiency, acute limb ischemia or myocardial infarction in the acute or very recent phase
212) Glitazones (thiazolidinediones):
Thiazolidinediones (pioglitazone, rosiglitazone) act specifically on insulin resistance. These products reduce blood sugar, insulinemia and triglyceridemia, by improving insulin sensitivity especially at the muscular level.
Their mechanism of action goes through their binding to nuclear receptors, PPAR gamma which allows activation of certain genes involved in the metabolism of carbohydrates and lipids.
The average weight gain in patients treated with glitazones in clinical trials is 2-4 kg but can be more important.
Glitazones can cause edema by water-soluble retention and promote the decompensation of heart failure. As a result, heart failure and a history of heart failure (class I to IV) constitute a formal contraindication to the prescription of glitazones. Increased fracture risk (distal extremities of arms and legs) in patients treated with glitazones. In addition, a recent meta-analysis puts the doubt on a possible increase in the risk of infarction
myocardial death and cardio-vascular death in type 2 diabetic patients treated with rosiglitazones.
Due to the pharmacological mode of action of glitazones, optimal metabolic effects are not observed after 3 to 6 months of treatment for a given dosage. Likewise, these effects can persist weeks after stopping treatment. This will be taken into account in the adaptation of treatment especially for bi or triple therapies as well as for the monitoring and the evolution of the undesirable effects.
2.2.2 Hypoglycemic sulfonamides:
Mechanisms of action:
Hypoglycemic sulfonamides act primarily by stimulating the secretion of insulin by the β-cells islands of Langerhans. Sulfonylureas bind to a specific receptor on the cell membrane ß. They regulate the secretion of insulin by closing the potassium channels which causes a depolarization of the membrane and calcium entry into the ß cells. The increase in calcium concentration intracellular stimulates the release of insulin by exocytosis.
Hypoglycemia is the most common side effect associated with the use of sulphonylurea Elderly patients and patients with kidney failure are most at risk of accidents hypoglycemic. Other risk factors for hypoglycaemic hypoglycemic hypoglycemic events are; alcoholic beverages, meal suppression, unusual physical exercise, taking potentiating drugs (miconazole, dextropropoxyphene, fluconazole, phenylbutazone, and the conversion enzyme), the moderate nature of the hyperglycemia before treatment, a too rapid increase doses of sulfonamides hypoglycemic, malnutrition, liver disease. Hypoglycemic hypoglycemic hypoglycemic agents are often more serious and prolonged than those observed under insulin. They are contraindicated in patients with renal impairment, and in subjects at risk hypoglycaemia (hepatic cirrhosis, alcoholism, surgery) and in subjects over 75 years old.
Action mechanism :
They are insulin-secretagogues agents. They stimulate insulin secretion by acting on the potassium channel ATP-dependent, but their binding site on the beta cell is different from that of sulfonamides. They stimulate the early peak of insulin secretion and have a preferential action on postprandial glucose, Their combination with a sulphonylurea provides no benefit compared to the use of each separately at its maximum effective dose
Side effects :
Glinides are not contraindicated in patients with moderate renal impairment (creatinine clearance> 30 ml / min). However, they will be used with caution and progressivity in elderly or renally impaired subjects. They are eliminated by the bile duct and are contraindicated in cases of hepatic insufficiency.
2.3) Alphaglucosidase inhibitor
They slow down the intestinal absorption of complex dietary carbohydrates. They are mainly active on the postprandial glucose. Alphaglucosidase inhibitors can not induce hypoglycaemia by themselves.
Their side effects are digestive and frequent, minor, observed on average in 30% of patients (meteorism, flatulence, intestinal discomfort, diarrhea); they can decrease with time. increasing Gradual dose to the desired dose can prevent or reduce this symptomatology.
Table: List of the main oral hypoglycemic agents
|Family||Trade name||Molecule||Dose / cp (mg)||Maximum dosage / day|
|Stagid||Metformin Embonate||700||850 mg and 1000 MG|
Diamicron LP 30
|4 cp in 2 or 3 shots
4 cp in 1 take
|Glibenclamide *|| 5
|20 mg or 4 cp|
|12 mg / d .1 taken per meal|
There are also combinations of oral antidiabetic drugs:
- Glucovance (glibenclamide 2.5 or 5mg / metformin 500 or 1000mg)
- Avandamet (rosiglitazone 2 or 4 mg / metformin 500 or 1000 mg)
- Competact (pioglitazone 15 mg / metformin 850 mg)
Glucose-dependent insulinotropic peptide (GIP) and glucagon-like-peptide-1 (GLP-1) two peptides secreted respectively by the K cells of the duodenum and the L cells of the ileum and the proximal colon in response to the meal are the main actors of the incretin effect, that is to say that they:
- Potentialising insulin secretion in a manner adapted to the glycemic level
- Preserve pancreatic beta cells
- Reduce circulating glucagon levels
- Train gastric emptying
The half-life of GLP-1 is very short due to its degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). During type 2 diabetes, there is a decrease in this incretin effect.
Analogues of GLP1: incretin mimetics
Incretinimetics are agonists of the GLP-1 receptor, resistant to degradation by the enzyme DPP-IV due to changes in their structure. The first representatives of this class are the exenatide (Byetta®) and liraglutide. They are administered subcutaneously in one (liraglutide) or two (exenatide) injections per day. A new form of exenatide is under development to consider a single injection weekly.
Their undesirable effects are mainly of a digestive nature with the occurrence of nausea and vomiting in the first weeks of treatment. They cause weight loss regardless of this effect secondary. They have a significant impact on postprandial blood glucose. The indication is: type 2 diabetes in combination with metformin and sulfonamide combination therapy hypoglycemic in patients who have not obtained adequate glycemic control with hypoglycemic agents Oral.
Inhibitors of the enzyme DPP4 prolong the half-life and therefore the effects of gluco-incretins endogenous agents (GLP-1 and GIP). The first representatives of this class are sitagliptin (Januvia®) and vildagliptin (Galvus®). They are administered in one or two daily doses per os. They have an impact significant effect on postprandial glucose. They have no impact on the weight. The indication is as follows: Type 2 diabetes mellitus in combination with metformin or a thiazolidinedione in patients who have not obtained adequate glycemic control.
2.5) Special case of Rimonabant (Acomplia®)
Rimonabant (Acomplia®) is the first molecule in the family of selective receptor antagonists cannabinoid type 1 (CB1). CB1 receptors belong to the endocannabinoid system. This is a physiological system present in the brain and peripheral tissues (especially adipocytes) which acts on energy balance, glucose and lipid metabolism, body weight and neurons of the mesolimbic system taking highly appetitive, sugary or fatty foods.
This is a treatment indicated in obese or overweight patients with associated risk factor. Reimbursement of Acomplia® is reserved for obese patients (BMI 30kg / m²) and diabetic patients type 2, insufficiently controlled by metformin or sulfonamide monotherapy and with HbA1c included between 6.5% and 10%. Treatment must be associated with diet and physical activity.
Rimonabant (Acomplia®) should not be prescribed in patients with severe depression, a history of depression or uncontrolled psychiatric pathology, or treated with anti-depressants.
Insulin is a useful therapeutic tool under certain circumstances in type 2 diabetics (see recommendations paragraph 3). General information about different types of insulins are given in the chapter on type 1 diabetes.
3) Recommendations for adapting treatment in type II diabetes: (recommendations AFSSAPS-HAS November 2006)
Dietary management and physical activity are the cornerstone of initial diabetes treatment and need to be strengthened at each step of the therapeutic management.
STEP 1 :
Hygiene and dietary measures (detailed above) must be implemented as soon as the diagnosis of Type 2 diabetes is confirmed and constantly pursued. It is recommended to seek out from the outset and sustainably maintain the near-normal glycemic standardization retaining a goal of HbA1c <6%
2ND STEP :
- HbA1c <6% after 6 months of hygienic and dietary measures: Continuation of hygienic and dietary rules alone.
- HbA1c between 6% and 6.5% after 6 months of hygienic and dietary measures: When HbA1C remains> 6% despite 6 months of well-managed lifestyle care and followed by In a satisfactory manner, the working group recommends the prescription of metformin and thus even before threshold value of 6.5%. Metformin will be chosen regardless of the level of BMI because of its excellent benefit / risk ratio. follows from the following data:
- The results of the UKPDS study showed that in overweight or obese type 2 diabetic patients, metformin is able to reduce the risk of micro and macroangiopathic complications
- This medicine does not expose to the risk of hypoglycemia
- Its good safety of use when the precautions of use and against indications are seen.
Its very favorable cost-effectiveness ratio
In case of intestinal intolerance to metformin adequately prescribed or contraindication to this molecule, an alphaglucosidase inhibitor can be used. The other therapeutic classes are not recommended at this stage of diabetes (glitazones, insulin secretors, insulin).
- HbA1C> at 6.5% despite 6 months of health and dietary management: monotherapy of your choice:
If after 6 months of health and dietary management (after 3 months if the hyperglycemia is higher), the HbA1c remains higher than 6.5%, one has the choice between the different classes of hypoglycemic agents:
Regardless of the Body Mass Index, drug treatment can be started first by:
- In case of intolerance or contraindication, the inhibitors of alphaglucosidase. (especially if there is post-meal hyperglycemia)
- If the body mass index is less than 27, we can choose first intention for an insulin secretor (sulfonamide or glinide), mainly if hyperglycaemia is more marked and lower hypoglycemic risk.
-HbA1C <6.5% after 6 months of one of the monotherapies: Continuation of treatment idem
-HbA1C> 6.5% after 6 months of one of the monotherapies: If, despite maximal dose monotherapy, HbA1c is> 6.5%, then one of the two therapies following 7:
- Metformin + insulin secretor
- Metformin + glitazone
- Metformin + alphaglucosidase inhibitor
- Insulinosecretor + glitazone, in case of intolerance or contraindication to metformin
- Insulin secretor + alphaglucosidase inhibitors (if post-prandial hyperglycaemia less effective on HbA1c than other associations)
For some patients the desire to simplify the therapy may make use of fixed associations of dual therapy in one tablet: metformin + sulphonylurea or metformin + glitazone (cf. combinations of oral antidiabetic drugs).
The choice of the association must take into account the tolerance and contraindications of each class of the age of the subject, the hypoglycemic risk the importance of hyperglycemia, the clinical profile and
biological specific to each patient
The two main elements of the decision are:
Predominant insulinopenia and progressive elevation of HbA1c especially associated with BMI <27 kg / m² refer to a combination metformin + insulin secretor (sulfonamide or glinide), after have made sure of the absence of ketonuria which can testify to a transition to insulin type 2 diabetes.
Marked overweight in favor of predominant insulin resistance associated with BMI > 27 kg / m² lead to a metformin + glitazone combination. It should be borne in mind that the delay to obtain a hypoglycemic effect is longer to obtain with glitazone than with other ADOs.
The poor digestive tolerance of the metformin + alphaglucosidase inhibitor combination may a factor limiting its use.
- HbA1c is <6.5% after 6 months or more of dual therapy: Continuation of identical treatment
- Failure of dual therapy: HbA1c exceeds 7% after 6 months or more of dual therapy It is then recommended:
- or the trial of a triple oral therapy in the absence of obvious signs of insulinopenia (slimming, ketonuria, hbA1c> 9%): metformin + insulin secretor + glitazone although this association needs to be evaluated in the duration.
- If, after more than 6 months of maximal oral triple therapy, HbA1c remains above or equal to 8%, should be switched to insulin
- So opt for the addition of insulin right away: a single injection of an intermediate insulin (NPH) or a slow-acting analogue at bedtime
Insulin therapy of type 2 diabetes
First-line insulin therapy consisting of a single injection of an intermediate insulin or analogous slow, meets the following rules:
- Low initial dose, usually of the order of 10 to 12 units
- Self-monitoring blood glucose including in all cases a waking blood glucose plus a blood glucose in the end in the afternoon if a sulphonylurea is combined
- Definition of a glycemic target for waking glucose, usually 0.80 g / l to 1.20 g / l
- Inform the patient about the need to increase the insulin dose regularly and that the dose to achieve the goal often exceeds 40 units
- Dose increase every 2 or 3 days
- Accompaniment by a nurse for the increase of the dose whenever necessary
In case of failure (hbA1c> 8%), intensified insulin therapy (2 to 4 injections per day) should be implemented
for example, either:
- 2 to 3 mixtures: Intermediate + Analogue fast in pre-prandial or
- A slow basal + 1 to 3 Fast analogs in pre-prandial (basal-bolus scheme).
At this stage, oral antidiabetic agents may be continued, in the absence of intolerance and contraindication.
At the stage of insulin therapy of type 2 diabetics, the use of the diabetologist’s expertise, resulting in a coordinated care general practitioner-diabetologist, should be considered in particular if difficulties are encountered.
At the stage of fractional insulin therapy (> 1 injection), this remedy becomes essential.
4) Place of new treatments for type 2 diabetes:
Rimonabant can be prescribed in obese patients (BMI 30kg / m²) and diabetic patients type 2, insufficiently controlled by metformin or sulfonamide monotherapy and with HbA1c included between 6.5% and 10%.
Inhibitors of the enzyme DPP4 are indicated in case of failure of monotherapy: in combination with metformin or a thiazolidinedione in patients who have not achieved adequate glycemic control.
GLP1 analogs are indicated in combination with the dual therapy metformin and sulphonylurea in patients who have not obtained adequate glycemic control.
5) transient insulin therapy:
In hospital, any type 2 diabetic hospitalized for a severe intercurrent pathology, must be subject to regular blood glucose monitoring and in case of infectious, traumatic or surgical stress important, the initiation of a transitional insulin therapy, a few weeks, is the most safe to prevent acid-keto decompensation and to control intercurrent pathology.
Regular monitoring of the glycemic balance by means of a glucose meter, in the patient’s bed, which will be carried out in a systematic way, before the 3 main meals and before bedtime, ie 4 controls to which additional post-prandial checks can be linked according to the special circumstances.
If it is a patient presenting an intercurrent pathology, not involving major functions vital, or to undergo a minor surgery, use a scheme combining 2 or 3 injections daily intermediate-acting insulin ± 3 injections of a fast-acting insulin analogue.
In patients with serious infectious or vascular disease, or who require important surgical intervention, an alternative to this type of scheme may be the establishment of a Continuous subcutaneous injection using a portable pump, see continuous continuous administration intravenous.
The proposed doses allow to start insulin therapy in a diabetic patient, hitherto untreated by insulin. These are minimum doses that will have to be adapted according to the surveillance glycemic. To determine these doses, the age, weight and importance of intercurrent pathology that motivates the initiation of insulin therapy.
6) Transient intensive insulin therapy:
In type 2 diabetic patients with treatment failure who, despite dual antidiabetic therapy with or without insulin therapy, are in chronic glycemic imbalance (blood glucose> 2g / l, HbA1C> 8%), intensive intensive subcutaneous or intravenous insulin therapy may be proposed. It is performed in a specialized environment for 5 days, after verifying the absence of contraindications Ophthalmologic (clichés of FO or angiography essential before). Its goal is to normalize blood glucose levels increasing insulin doses; this normoglycemia makes it possible to lift the glucotoxicity responsible for deterioration of insulin secretion and worsening of insulin resistance. At the end of this period of
normoglycemia, the standard treatment (oral antidiabetic agents +/- insulin therapy in 1 to 3 injections) is adapted and its effectiveness is partly restored.
Summary of therapeutic escalation in the treatment of type 2 diabetes
|Prescription threshold||Therapeutic strategy||Goal|
|HbA1c> 6%||Step 1
Hygieno-dietetic measures (MHD)
|If melgre step 1. HbA1c > 6% (at the early stage of diabetes). If despite step 1, HbA1c > 6.5%||2nd step
MONOTHERAPY + MHD: Metformine or IAGMONOTHERAPY at choice + MHD
Metformin or IAG or SU or Glinides
|If, despite stage 2, HbA1c > 6.5%||Step 3
BITHERAPIE + MHD
|If, despite stage 3, HbA1c> 7%||Step 4
TRITHERAPIE + MHD or INSULIN + ADO + MHD
|If, despite stage 4, HbA1c> 8%||Step 5
INSULIN + ADO + MHD INSULIN FRACTIONNEE + MHD
ADO = Oral antidiabetic
IAG = alpha-glucosidase inhibitors
SU = Hypoglycemic sulphonamides
Insulin + ADO = Insulin release: intermediate or slow at night: fractionated insulin: 1 injection / D or 2 to 4 / D
MHD = hygienodietetic measures