Monday, November 19, 2012

CLINICAL MANAGEMENT OF DIABETES MELLITUS

DIET

Dietary modifications includes,
  • Low intake of simple carbohydrates with increase uptake in complex carbohydrates which can be slowly absorbed and have high glycemic index. Carbohydrates (complex carbohydrates) should provide approximately 55% of total energy
  • Protein should provide 15% of total energy.
  • There should be no more than 30% energy intake from fat, with increase in uptake of unsaturated fatty and <7% saturated fatty acid uptake.
  • Sodium intake should not exceed 6g/day and plentiful fruits preferably less sugar containing and vegetables (five portions a day).
  • A total daily dietary fiber intake of 40g is ideal.

EXERCISE

Regular low-intensity exercise like brisk walking, swimming or cycling for 30 min 3-5 times/week. This improves glucose disposal (by increasing GLUT4 in skeletal muscle), prevents progression from IGT to type 2 diabetes (by about 50%), increases basal metabolic rate (BMR) and reduces cardiovascular events.

SMOKING CESSATION




PHARMACOLOGICAL MANAGEMENT

ASPIRIN

Aspirin (or clopidogrel if aspirin is contraindicated) should be given for all men and women with type 1 or 2 diabetes over the age of 40, and those over 30 who have additional risk factors (e.g. family history, hypertension, smoking, dyslipidaemia, albuminuria). In lower age aspirin is avoided due to risk of Reye’s syndrome.

LIPID LOWERING AGENT

Consumption of saturated fat, cholesterol and transunsaturated fat, inadequate exercise are the primary cause of dyslipidaemia whereas alcohol excess, hypothyroidism, liver disease are the secondary cause of dyslipidaemia.

Metformin, pioglitazone and insulin can be used as lipid lowering agent; they either increase insulin action or reduce the flux of NEFA to liver (pioglitazone).

HMG-CoA reductase inhibitors, statins: They lower LDL-C. The ADA currently recommends an LDL-C target of 2.6 mmol/L in all patients over 40 years with diabetes as primary prevention, and in younger people with risk factors. ADA also recommends targets for tirglycerides of 1.7 mmol/L and HDL above 1.1 mmol/L.

HYPERTENSION

The ADA adopted the target of 130/80 to start treatment of hypertension in diabetes. ACE inhibitors of angiotensin II blockers are first line agents in diabetes. Amlodipine is the second line of drug in combination with ACE inhibitor Angiotensin receptor blocker, ARB.

ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR ANTAGONIST

Angiotensin II (ATII) increases hepatic glucose production and decreases insulin sensitivity. Use of these agents increases insulin sensitivity. These are indicted for subjects with diabetes and hypertension, microalbuminuria, proteinuria, mild to moderate renal impairment, diabetic retinopathy, ischaemic heart disease and stroke.

HYPOGLYCAEMIC TREATMENT IN DIABETES

METFORMIN
This improves glycaemic control without weight gain. This is the first choice in treating type 2 diabetes especially overweight subjects. It reduces hepatic glucose output, improves peripheral glucose uptake and utilization in insulin-sensitive tissues (muscle, adipose tissue tissue) and reduces intestinal glucose transport. In type 2 diabetes, metformin can be used as monotherapy, or combined with insulin or with sulphonylureas and/or thiazolidinediones. In type 1 it is used with insulin for obese adults.

The main side effect of the use of biguanides (of which metformin is one) is lactic acidosis presented with lethargy nausea, vomiting, abdominal pain.
Biochemical features of lactic acidosis are elevated anion gap metabolic acidosis with high blood lactate.

SULPHONYLUREAS (AND RELATED INSULIN SECRETOGOGUES)
These drugs acts as insulin secretogogues, reducing glucose by augmenting the firs-phase insulin release.
In beta cells the APT dependent potassium channel has regulator domain of sulphonylurea receptor 1 (SUR-1). Sulphonylurea binds to this site and cause closure of KATP channels depolarizing the membrane, causing rapid influx of calcium ions via voltage dependent calcium channels. The resultant increase in free ionized calcium triggers cytoskeletal trafficking of secretory granules to plasma membrane and release of insulin by exocytosis. Other drugs like Glibenclamide, meglitinides nateglinide acts through same mechanism binding to SUR-1.
These drugs in contraindicated in type 1 diabetes, pregnancy, lactation and hepatic and renal insufficiency.

PPAR- γ ANALOGUES:
E.g. Thiazolidinediones; these are ligands for orphan nuclear peroxisome proliferator activator receptor family (PPARα, PPARγ, and PPARδ). These receptors are expressed in tissue that metabolizes fatty acids extensively like liver, kidneys, heart and muscle. They also increases HDL-C apolipoproteins, apo A-I, II decrease hepatic C-III production thus lowering TG vial reduced formation of VLDL. The nuclear PPAR receptors are endogenously activated by fatty acids and fatty acid-derived eicosanoids and the action of fibrate group of lipid lowering agents is mediated via PPARα receptors. Activation of PPARs leads to formation of heterodimers with the retinoid X receptor (RXR), bound to its own endogenous ligand, retinoic acid. These PPAR-RXR dimers bind to their response element (PPREs) modulating transcription of >40 target genes.

The insulin sensitizing effect of PPARγ agonist is due to fatty acid steal mechanism (i.e. changes in NEFA metabolism benefits for other tissues). These increases free fatty acid uptake in adipose tissue (by about 60%) and also increase fatty acid oxidation in liver, heart, kidneys and skeletal muscle. So, hepatic uptake of NEFA is reduced by 40%, rendering liver more insulin sensitive and giving these agents a potential role in treatment of hepatic steatosis. In adipose tissue they cause adipocyte differentiation and fat distribution from central to subcutaneous depots further reducing hepatic uptake of NEFA.

Thiazolidinediones are used in combination with both metformin and sulphonylurea as triple therapy. Other PPAR analogues are pioglitazone, rosiglitazones.
INSULINS 
In type 1 diabetes beta cell function, that falls to 10% of normal at disease presentation, doubles after initiation of insulin therapy and metabolic stabilization (honeymoon effect). This may be due to amelioration of glucotoxicity or lipotoxicity on the reduced numbers of and metabolically stressed beta cells.


All patients with type 1 diabetes are treated with exogenous insulin. Both long-acting or basal and short-acting or bolus insulin are used. Rapid acting insulin has rapid onset of action (<15 min), permitting injection immediately before or just after eating and has 3-5 hours of action which reduces the risk of hypoglycemia before next meal. It has sharper peak response resembling first-phase insulin release in normal persons. Some rapid acting insulins are Insulin aspart, it is homologous to human insulin with exception of single substitution of aspartate for proline in position B28. In Insulin lispro proline and lysine at B28 and 29 respectively are reversed.


Long acting insulins e.g. glargine and detemir, has 24h duration of action with minimum peak action. The regimen consists of twice daily insulin mixture of longer and shorter acting insulins in ratio typically between 75/25 and 60/40. Another compromise of single dose of long-acting insulin at night with doses of short-acting insulin immediately before meals during the day (basal-bolus regimen).

In type 2 diabetes patients require insulin treatment after a median of 7 years from diagnosis. Insulin treatment in overweight or obese has risk of further weight gain, which increase the need for escalating insulin does and spiraling obesity. Reasons for weight gain after starting insulin in type 2 diabetes include a reduction in energy wastage through glycosuria, anabolic effects of insulin, reduction in attention to diet and exercise in presence of an highly effective means of glycemic control and increased eating because of the need to avoid or treat hypoglycemia on insulin regimens. These patients do not require exogenous insulin throughout 24 hours. Most patients with type 2 diabetes especially those who are overweight, should remain on metformin when insulin is instituted in whatever form.  

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