Concept and Therapeutic Approach of Intermediate Hyperglycemia with Special Reference to Unani Medicine

Intermediate Hyperglycemia is a category of glucose tolerance representing an intermediate stage between normal glucose tolerance (NGT) and diabetes. Within this category are two subcategories: impaired fasting glucose (IFG; 100 –125 mg/dl) and impaired glucose tolerance (IGT; defined as a 2-h oral glucose tolerance test (OGTT) plasma glucose concentration of 140 –199 mg/dl). Intermediate Hyperglycemia is not specifically mentioned in Unani medicine, however some classical Unani physicians have described the initial symptoms and factors leading to the pathology. In Unani medicine the risk factors are described in terms of ‘ Su-e-mizaj ’ as per the concept of Tibb. So, it is considered in the context of Zeyabutus which is described as a disease which develops due to Su-e-mizaj haar (abnormal hot temperament) by the majority of scholars. The two major pathophysiologic defects responsible for losing glucose tolerance are insulin resistance and β-cell glucose insensitivity, both appearing in subjects of Intermediate Hyperglycemia. Symptoms mentioned in Unani medicine may be increased frequency of micturition (ants and flies are attracted to urine), increased thirst, nocturia, dryness of mouth and whole body, fatigue, loss of weight, malaise, cramps in lower extremities. The drug based approach for management of Intermediate Hyperglycemia is associated with inherent drawbacks, including toxicity, tolerability, cost and efficacy. Oral hypoglycemic drugs are also associated with various side effects as Biguanides cause gastrointestinal upsets, anorexia, nausea, diarrhea and lactic acidosis. There are a number of single Unani drugs like Jamun ( Syzigium cuimini ), Karela Bark or Bitter Gourd ( Momordica charantia Neem ( Azadirachta indica Methi ( Trigionella foenum ( Gymmema sylvestre ) and compound formulations like Qurs Ziyabetus, Qurs Tabasheer, Qurs Kafoor , Qurs Gulnar.


INTRODUCTION
The overall prevalence of Intermediate Hyperglycemia/prediabetes to be 10·3% (WHO criteria) or 24·7% (ADA criteria), depending on which definition was used. Intermediate Hyperglycemia and Prediabetes are the term used for each other, because it refers to an intermediate stage between normoglycemia and apparent Diabetes Mellitus. It is a type of metabolic disorder with slight increase in blood glucose level from normal but not reaching up to the level of Diabetes Mellitus [1] 16.1% (ADA definition) and in 7% and was more common among women, both men and women, the frequency of IGT increased by age categories [2].
The World Health Organization (WHO) in 2006 has recommended the term Intermediate Hyperglycemia to describe glycaemic levels between 'normal' glucose tolerance and diabetes. The term 'pre-diabetes' is discouraged to avoid any stigma associated with the word diabetes and the fact that many people do not progress to diabetes as the term implies [3].
Intermediate Hyperglycemia is a category of glucose tolerance representing an intermediate stage between normal glucose tolerance (NGT) and diabetes. Within this category are two subcategories: impaired fasting glucose (IFG; defined as a fasting plasma glucose concentration of 100 -125 mg/dl) and impaired glucose tolerance (IGT; defined as a 2-h oral glucose tolerance test (OGTT) plasma glucose concentration of 140-199 mg/dl) although both subcategories increase the risk for diabetes [4].
Intermediate Hyperglycemia is not specifically defined as a disease in Unani medicine, however some classical Unani physicians have described that initial symptoms and factors leading to the pathology.
In Unani medicine the risk factors are described in terms of 'Su-e-mizaj' as per the concept of Tibb. In this context diabetes is described as a disease which develops due to Su-e-mizaj haar (abnormal hot temperament) by the majority of scholars [5,6].
Public health programs focused on increasing personal awareness of risk, community support and education, and government resources are necessary to slow the progression of Intermediate Hyperglycemia to T2DM. Importantly, health care systems need to recognize "Intermediate Hyperglycemia" as a disease and to use this term to promote programs. Diet and exercise are first line intervention along with oral hypoglycemic drugs to achieve the goal of improving glycemic control and preventing both microvascular and macrovascular health risk factors. With above facts both dietary and lifestyle changes can improve blood sugar level in Intermediate Hyperglycemia. Its incidence is increasing day by day and to overcome the problem of Intermediate Hyperglycemia.
Several efforts have been introduced in the modern system of medicine. But most of these efforts are not effective and fail to prevent complications of Intermediate Hyperglycemia and diabetes.

CONCEPT OF INTERMEDIATE HYPERGLYCEMIA IN UNANI MEDICINE
According to Hakeem Azam khan 'Ziabetus haar' is the disease which is mentioned as diabetes mellitus type 2 in the present era [7]. In Al-akseer he described that the initial symptoms of diabetes are having polydipsia without dehydration, frequent micturition without burning along with watery urine having less viscosity [6]. Almost similar symptoms are mentioned by Ibn-e-Sina who also described polyuria as the first symptom of diabetes which later on progressed to Diq (Asthenia) [5]. The classical Unani scholars, (Razi 865AD, Ibn-e-Sina 980AD) have well recognised Ziabetus (diabetes) and were familiar with the manifestations of the diabetes. They described most of the symptoms of diabetes such as excessive thirst, frequency of urination, dribbling of urine, urine appearing white, losing its consistency to resemble water, excessive micturition without burning sensation, incontinence of urine [6,8,9]. Buroodat-e-Badan, Jigar wa Gurda, Su-e-Mizaj Haar Gurda (Hot derangement in temperament of kidney) and Su-e-Mizaj Barid Gurda (Cold derangement in temperament of kidney). It is a disease in which the patient feels excessive thirst without fever and dryness and consumed water is passed out through the kidneys immediately after intake by the patient without any metabolic change and patient still feels thirsty. Zakariya Razi in Kitab-ul-Hawi-fil-Tib says that the patient of diabetes complains of polydipsia, whereas, the consumed water is passed out as such. He further mentions other symptoms associated with this disease like polyuria, polydipsia, even nocturia and incontinence of urine [8].

PATHOPHYSIOLOGY OF INTERMEDIATE HYPERGLYCEMIA
Normally the glucose system is highly homeostatic, swinging in plasma glucose concentrations rarely exceeding mmol/L (54 mg/dl), Plasma glucose concentration represents a balance between entry of glucose into and exit from the circulation via excretion. Disturbances in the homeostasis (either excessive release or defective removal or combination of the two result in an increasing glucose level). Abnormality in glucose and insulin concentration and dynamics occurs constantly and insidiously with the development towards Type 2 diabetes [10]. The two major pathophysiologic 4 defects responsible for losing glucose tolerance are insulin resistance and β-cell glucose insensitivity, both appearing in subjects of Intermediate hyperglycemia/ Pre-diabetes [11]. Jalinoos (Galen) described it as a disease specific to kidneys because of weakness in their retentive ability. He attributed that the weakness of quwwat-e-mughayyarah may be a causative factor of diabetes. He mentioned that, when hot temperament is associated with moisture, then absorption (into the kidneys) is less, urine is dark in colour, viscous and, if cold temperament is predominant along with dryness, then the power of absorption is very strong and this is the most lethal form of diabetes [12,13].
Zakariya Razi in Al-Hawi-fil-Tib states that this disease is basically caused due to abnormal hot temperament of the kidneys. This hot temperament affects the bladder also. Due to the increased heat, the kidneys absorb a lot of fluids from the gastro-intestinal tract. And also, due to weakness of quwwat-e-masika, the kidneys are not able to retain these fluids and they are immediately diverted to the bladder, and excreted as such. The loss of fluids is again responsible for increasing the already abnormal hot temperament. This gives rise to a vicious cycle of intake and excretion [8]. According to Ibne Nafees in diabetes quwwate-masika of the kidneys is weakened due to the abnormal hot temperament, therefore, they are unable to retain the fluids in the body and the quwwat-e-dafi'a is stimulated and it expels the fluids immediately after intake. Thus the cycle of absorption (into the kidneys) and excretion continues. On this basis, it has been named dulaab (water-wheel) and dawwarah (whirling etc). Ibne Sina termed the disease "aldulab" (water wheel) and "Zalqul Kulliya" (diarrhea of the kidneys) also described the complications as mental troubles, impotence, gangrene.
Ibne Sina was the first who wrote a differentiating feature of Ziabetus (Diabetes) associated with emaciation from other causes of polyuria [12].

ETIOLOGY OF INTERMEDIATE HYPERGLYCEMIA
The etiology of disease is considered to be seated in the kidneys and the liver. Ziabetus is caused by one of more of the following factors:

a. Su-e-Mizaj Haar kulliya (Hot derangement in the temperament of kidneys)
Kidneys absorb water in an excess amount from circulation due to excessive hotness or derangement in temperament, so they cannot retain much amount of fluid and pass in the form of urine frequently (polyuria) and the patient drinks water frequently (polydipsia) to overcome his thirst [9].

b. Su-e-Mizaj Barid kulliya (Cold Derangement in Temperament of Kidney)
Sometimes, Ziabetus develops due to excessive exposure of cold to kidneys that may lead to Sue mizaj barid (cold derangement in temperament) [9,19].

c. Zoaf-ul-Kulliya (Weakness of Kidneys/ Renal insufficiency)
Water cannot be retained properly due to the weakness of kidneys and their Quwate masik [19].

d. Barudat-e-kabid wa kulliya (Cold Derangement in Temperament of Kidneys and liver).
It is due to the excessive exposure of the whole body or liver or kidneys to cold, which leads to sue mizaj barid (cold derangement in temperament [7, 19,20]

e. Ittisa-ul-kulliya wa Majrā-e-Bauwl (Dilatation of Kidneys and urinary tract)
Water cannot be retained for long or required time due to dilatation of kulliya wa Majrae Baul (Dilatation of Kidneys and Tubules) so it is passed out rapidly [7,19].

Symptoms in Intermediate Hyperglycemia
Intermediate Hyperglycemia/Prediabetes remains undiagnosed for several years because this disease develop without any appearance of symptoms and sign. But sometimes symptoms in Intermediate Hyperglycemia are frequent urination and excessive thirst same as of type 2 diabetes

DIAGNOSTIC CRITERIA FOR INTERMEDIATE HYPERGLYCEMIA (PRE-DIABETES)
The World Health Organization (WHO) has defined the state of intermediate hyperglycemia using two specific parameters: Impaired fasting glucose (IFG) defined as fasting plasma glucose (FPG) of 6.1-6.9 mmol/L (110 to 125 mg/dl). Impaired glucose tolerance (IGT) defined as 2 h plasma glucose of 7.8-11.0 mmol/L (140-200 mg/dl) after ingestion of 75 g of oral glucose load or a combination of the two based on a 2 h oral glucose tolerance test (OGTT) [26]. The American Diabetes Association (ADA), on the other hand has the same cut-off value for IGT (140-200 mg/dl) but has a lower cut-off value for IFG (100-125 mg/dl) and has additional hemoglobin A1c (HbA1c) based criteria of a level of 5.7% to 6.4% for the definition of Pre-diabetes [27].

Diagnosis through Unani medicine
Diagnosis of Ziabetus Shakari depends on the above mentioned clinical features.

HEALTH RISKS OF INTERMEDIATE HYPERGLYCEMIA
Likewise diabetes, Intermediate Hyperglycemia may have concomitant damage to organs and produce health risks like: nephropathies and chronic kidney diseases, retinopathy, neuropathies, macrovascular disorders [28,29,30]. Unani physicians were also aware about the complications related to diabetes (Ziabetsus). a. lbn-e-Sina mentioned that diabetic patients may develop due to loss of body fluids phthisis (Diq) and cachexia (Zooban-e-Aza) [5].
b. Azam Khan mentioned this disease as very perilous and said that this disease affects elderly people then it becomes almost untreatable [6].

Non-pharmacological Interventions or Life style modifications
Modification in lifestyle may serve as keystone of treatment focus on diet, 7% of weight loss and 150 minutes per week of moderate physical activity. Risk of developing diabetes is reduced by 90% in person who lost weight and who meet physical exercise/dietary targets. These results are consistent with Finnish Diabetes Prevention Study in which participants met four or five of their goals. In a study with IFG it has been reported that intensive weight loss is more effective in reducing the conversion of Type 2 diabetes from IFG as compared to less intensive intervention. [31] It has also been noted that sustained loss of 5-10% body weight in obese and overweight patients proven to be effective in preventing progression of Type 2 diabetes from Prediabetes. [32] A modest weight loss (5%-10%) and moderate intensity physical activity (30 minutes) daily) is the mainstay of treatment for subjects with prediabetes. When lifestyle modification is ineffective, it is advised in subjects who are at high risk due to high chance of progressive deterioration of glucose control. Also, in the patients who are unable or unwilling to engage in lifestyle modifications or those have inadequate response to lifestyle change, pharmacotherapy is advised [31].

Pharmacological Interventions
There are numerous groups of pharmacological interventions include anti-hyperglycemic drugs, antiobesity medication and others like Renin-angiotensin blockers and Statins have been studied in context of management for Prediabetes [32]. The drug based approach for management of Intermediate Hyperglycemia (prediabetes) is associated with inherent drawbacks, including toxicity, tolerability, cost and efficacy. Oral hypoglycemic drugs are also associated with various side effects as Biguanides cause gastrointestinal upsets, anorexia, nausea, diarrhea and lactic acidosis. Similarly sulfonylureas cause weight gain, thiazolidinediones enhance the risk of myocardial infarction and ɑglucosidase inhibitors have side effects like flatulence, abdominal comfort, bloating, diarrhoea etc.

Line of Treatment (Usool-e-Ilaj) a. Correction of Su-e-Mizaj
Unani line of treatment may be effective for correction of kidney and correction of its temperament (Su-e-Mizaj) and could be preventive in progressing the disease further.

b. Removal of predisposing cause
Remove the predisposing factors which are responsible for this disease.   Avoid humid and cold environments.

Use of Mubarridat (Refrigerant) and Murattibat (Humectants)
According to Hippocrate it is a disease of hot and dry derangement of temperament (Sue-Mizaj haar yabis) As per the basic concept of Ilaj-bil-zid (Barid-ratab) is advised. For this purpose cold vegetables and cold fruits are used but these entities should not have the diuretic action etc. [5].

Use of Habisat wa Qabizat (Astringent and styptics)
Habis and Qabiz drugs have been used by Unani physicians to control polyuria by increasing the retention power of kidneys thereby decreasing excretion of urine. As far as diet is concerned use of astringent (Oabizat-wa-Habisat) foods are advised for diabetic patients. According to Sarabiyun, regimen like tarteeb badan, aghzia barida and use of zimad-e-barid over kidneys are beneficial [6].

Taskeen-e-Atash (Quenching of the thirst):
As the diabetic patient suffers from excessive thirst (polydipsia).There is a need to quench thirst in order to provide symptomatic relief to the diabetic patients and to save them from dryness. Taskeene-Atash (quenching of the thirst) is advised as an early management for diabetes. For quenching thirst, drinking cold water followed by vomiting is advised. Feeling of thirst will decrease. Uses of diuretics are contra-indicated [19].

Taqwiyat wa Tabreed-e-Kulya (strengthening and cooling of kidneys):
It is advised in order to overcome the hot derangement of temperament of the kidneys. For this purpose it is advised to apply cold liniment (Zimad-e-Barid) at the site of the kidneys. Along with this use diets and medicine which are nephro-protective (Muqawi-e-Gurda Advia-wa-Aghzia) are also preferred like Ma-ul-Shaeer and Ab-e-Anar. While according to Jalinoos use of alkaliser and Tabreede-Kulliya should be the way of treatment [5].

Use of Dafa-e-Ziyabetus Advia:
Several Unani physicians like Razi, Majoosi, Ibn-e-Sina and Mohammad Azam khan had prescribed several medicinal plants either single or as a constituent of compound formulations, for the treatment of Ziyabetus Shakari [5,6,8,9].
a. Jamun (Syzigium cumini) Jamun seeds control the level of sugar in urine and decrease the Diabetic symptoms. This is the main quality of Jamun seeds.

CONCLUSION
Intermediate Hyperglycemia is a new terminology used for the intermediate state between normal glycemic level and hyperglycemic level. In this condition every effort is taken against conversion of Intermediate Hyperglycemia into diabetes mellitus. A conventional method of treatment is effective but produces side effects. In Unani medicine there are a large number of single drugs as well as compound formulations which are very effective particularly in this stage. Some of the Unani drugs are validated but a lot are still required for scientific validation on a large scale.

NOTE:
The study highlights the efficacy of "Unani" which is an ancient tradition, used in some parts of India. This ancient concept should be carefully evaluated in the light of modern medical science and can be utilized partially if found suitable.