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Type 1 Diabetes Mellitus

Article By

T. Kamat

D. Ajgaonkar



Type 1 diabetes accounts for only about 5-10% of all cases of diabetes. There are two types; idiopathic and immune mediated. It has serious short-term and long-term complications. Cardinal clinical features and complications such as diabetic ketoacidosis, are discussed here. Management of type 1 diabetes requires continuing attention to many aspects, including insulin administration, blood glucose monitoring, meal planning, and screening for comorbid conditions and diabetes-related complications. These complications include microvascular and macrovascular disease, which account for the major morbidity and mortality associated with type 1 diabetes.



Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both.[1] Based on the pathogenic process that leads to hyperglycaemia, DM is classified into two broad categories, type 1 and type 2 DM.[2] Type 1 DM (T1DM) occurs more often in children and was earlier known as juvenile diabetes and thereafter as the insulin- dependent diabetes. It accounts for 5-10% of all cases of DM and occurs due to autoimmune mediated destruction of the pancreatic beta (β) cells resulting in complete or near-total insulin deficiency.[2,3]

It has now been established that not all cases of type 1 diabetes are autoimmune mediated. Approximately 10% of the type 1 DM cases in Caucasians did not have any evidence of autoimmunity  for  pancreatic  β-cells, while among  Indians,  Japanese, African-Americans and Hispanics, the percentage of such patients may be higher, ranging  between 2-40%.[2,3] Recognizing this fact, the American Diabetes Association (ADA) classifies type 1 diabetes into:[4]

  • Type 1A – Immune mediated
  • Type 1B – Idiopathic

T1DM can develop at any age, but it is rare in infants. The incidence begins to rise by the age of 5 years and peaks between 10 to 14 years, around puberty. The incidence remains relatively high up to the age of 18-20 years and declines thereafter, and is less commonly seen beyond the age of 35 years.[2,3]


Type 1 DM is the result of interactions of genetic, environmental,  and  immunologic  factors that ultimately  lead  to  the  destruction  of the pancreatic  beta  cells and  lead  to  insulin deficiency.[1] Most patients with Type 1 DM have evidence of islet-directed autoimmunity while the few who lack immunologic  markers  are thought  to  develop insulin  deficiency by unknown, nonimmune mechanisms.

Individuals with a genetic susceptibility have normal beta cell mass at birth but begin to lose beta cells secondary to autoimmune destruction that occurs over months to years.[1,5-7] This autoimmune process is thought to be triggered by an  infectious or  environmental  stimulus. Numerous environmental triggers have been proposed and include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds.[1] In the majority, immunologic markers appear after the triggering event but before diabetes becomes clinically overt. Beta cell mass then begins to decline, and insulin secretion becomes progressively impaired, although normal glucose tolerance is maintained.

The rate of decline in beta cell mass varies widely among individuals, with some patients progressing rapidly to clinical diabetes and others evolving more slowly. Features of diabetes do not become evident until majority of beta cells are destroyed (~80%). At this point, residual functional beta cells still exist but are insufficient in number to maintain glucose tolerance.

After the initial clinical presentation of type 1 DM, a “honeymoon” phase may ensue during which time glycaemic control is still achieved with modest doses of insulin, or rarely, insulin is still not needed.[1,5-7] However, this fleeting phase of endogenous insulin production from residual beta cells eventually disappears as the autoimmune process destroys the remaining beta cells, and finally the individual becomes completely insulin deficient.[1]

Clinical Features:

Typically, T1DM has an insidious onset with weight loss (1-2 kg/week), along with polyuria, polydipsia polyphagia. Weakness, overwhelming fatigue with cramps and pains in legs may supervene. When unnoticed and uncared for, symptoms of anorexia, nausea, abdominal pain and signs of dehydration appear which may progress to ketoacidosis.[2]

The cardinal clinical features of T1DM in children are:[2,8,9]

  • Polyuria
  • Nocturnal enuresis
  • Polydipsia
  • Weight loss and failure to thrive
  • Lethargy
  • Dehydration

The classic symptom of polyphagia is often absent in children. Polyuria and nocturnal enuresis are classical manifestations of diabetes in children. Diabetes is a very common cause of secondary enuresis in children. History of bed wetting at night, in a previously continent child should arouse suspicion of diabetes.

Other non-specific symptoms which may indicate the presence of childhood diabetes are given in Table 1. Type 1 diabetes may also present as poor weight gain and failure to thrive. In fact, every astute physician should consider diabetes in a child or adolescent, for failure to thrive without any obvious reason.[2,8,9]

TC-Oct 2017 - 014 - Table1 T1DM

Simple testing of urine and a sample of blood for glucose analysis reveals the diagnosis. High plasma glucose above 250-300 mg/dL along with heavy glucosuria and ketonuria establish the diagnosis beyond doubt.

Diabetic ketoacidosis (DKA) may be the presenting feature in more than half of children with T1DM.[1,2] If the initial manifestations are not promptly diagnosed, DKA develops due to accelerated catabolic process. The signs, symptoms and biochemical findings suggestive of DKA are summarized in Table 2.

TC-Oct 2017 - 015 - Table2 T1DM


  1. A) Microvascular Complications

Retinopathy rarely develops before 5 years from onset of T1DM. Incidence of retinopathy increases from 10 to 15 years and by 20 years of the disease approximately 90% of patients may have retinopathy.

Nephropathy develops slower with around 20% of patients developing nephropathy in course of 10-15 years following onset of T1DM and in up to a maximum of 45% of patients by 20 years of the disease. T1DM patients with micro albuminuria have a 20-fold higher risk for development of clinical nephropathy.

Neuropathy prevalence is lower in T1DM than in T2DM at the time of onset. While it is uncommon in children, its incidence starts increasing after 10 years following diagnosis and it is also related to degree of glycaemic control as in T2DM.

  1. B) Cardiovascular Complications

In young patient with T1DM those diagnosed before 20 years of age there is preponderance of renal deaths during the third decade after onset of diabetes, while beyond 30 years from diagnosis, cardiovascular death predominates. In those diagnosed after 35 years of age, renal deaths accounts for around 2% while CVD accounts for over 50% of mortality.


Insulin is the mainstay for treatment of virtually all type 1 diabetes patients. As individuals with type 1 DM partially or completely lack endogenous insulin production, the administration of basal, exogenous insulin is essential for regulating glycogen breakdown, gluconeogenesis, lipolysis, and ketogenesis. Likewise, insulin replacement for meals should be appropriate for the carbohydrate intake and promote normal glucose utilization and storage. The goal is to design and implement insulin regimens that mimic physiologic insulin secretion. Most type 1 patients require 0.4– to 0.8 U/kg/day.


The earliest commercial insulin preparations were produced from beef and pork pancreas. They contained ~1% (10,000 ppm) of other proteins (proinsulin) which were potentially antigenic. These have now been totally replaced by highly purified pork/beef insulins and recombinant human insulins/insulin analogues.

In the 1970s, superior purification techniques were applied to produce ‘highly purified insulins’ which contain <10 ppm impurities. These highly purified insulins were less antigenic and caused less insulin resistance or injection site lipodystrophy. In the 1980s, the ‘human insulins’ (having the amino acid sequence similar to human insulin) were produced by using genetic engineering techniques. Using genetic engineering technology in 1990s it became possible to produce ‘insulin analogues’ with modified absorption and pharmacokinetics on subcutaneous (s.c.) injection. In the western world, pork and beef insulins have largely been replaced by human insulins or insulin analogues. Except for considerations of cost, human insulins and analogues are now being commonly used in India as well.


1) Meal-time/prandial/bolus Insulin

Short Acting

Regular insulin: regular recombinant human insulin is like the endogenous insulin polypeptide. However, when in solution the regular insulin molecules tend to self-aggregate to form hexamers.[10] After s.c. injection, the hexamers are converted to dimers and  then further to monomers which are then absorbed.

This process of conversion from hexamer to monomer takes approximately 30 to 45 minutes, thus delaying the absorption.

The pharmacokinetic profile of regular insulin is given in Table 3. The  pharmacokinetics  of regular  insulin  do  not  match  that  of  meal stimulated endogenous insulin secretion. When injected subcutaneously just before a meal, the delayed peak and longer duration of action results in early postprandial hyperglycaemia and late postprandial hypoglycaemia. Therefore, it must be injected at least 30 minutes before a meal.[10-11] To overcome this drawback, insulin analogues were developed which have faster onset of action.

Rapid-acting analogues:

Insulin analogues are produced by modifying the insulin molecule in a manner to achieve insulin that can exist as a monomer in solution, resulting in a quick onset, more defined peak, as well as a shorter duration of action on s.c. injection.[10,11]

Currently 3 rapid acting analogues are available:

Insulin Lispro: Produced by transposition of proline and lysine at the B28 and B29 positions.

Insulin Aspart: The proline at B28 of human insulin is replaced by aspartic acid.

Insulin Glulisine:  produced by replacing asparagine at B23 with lysine and lysine at B29 with glutamic acid.

Table 3 gives the pharmacokinetics of rapid acting analogues. Their pharmacokinetic profile more closely resembles the physiologic meal stimulated insulin release. Unlike regular insulin, they can be injected immediately before or even after the meal, which allows the dose to be altered based on the quantity of food consumed. A better control of post-meal glycaemia and a lower risk of late post-prandial hypoglycaemia have been obtained.[11,12]

2) Basal Insulins

Another drawback on regular insulin is that it is not suitable for providing a low, constant basal level of action in the inter-digestive period. To overcome these problems, long acting ‘modified’ or ‘retard’ preparations of insulin have been developed by complexing it with protamine. Further, long-acting insulin analogues without a peak are now available.[12]

Intermediate acting insulin

Isophane (Neutral Protamine Hagedorn or NPH) insulin:  is a suspension of insulin complexes with protamine. On subcutaneous injection, the complex dissociates slowly leading to delayed onset, late peak and an intermediate duration of action (Table 3). It is mostly combined with regular insulin in the ratio 70:30 or 50:50 and is injected s.c. twice daily before breakfast and before dinner (split-mixed regimen). While the late peak provides a means to cover post lunch glucose excursions in a twice daily regimen, it makes NPH less satisfactory for overnight basal insulin replacement.[10-12]

Long acting insulin analogues: an ideal basal insulin should be without a peak, in contrast to NPH which exhibits a delayed peak. Basal insulin analogues have been developed by altering insulin structure in a way to achieve prolonged absorption following s.c. administration and a peak-less 24-hour duration of action.[11,12] Three such analogues are available:

Insulin Glargine: has a substitution of glycine for arginine at A21 and has 2 additional arginine residues at B30. It remains soluble in the acidic pH of the formulation, but precipitates at neutral pH encountered on s.c. injection.  In the subcutaneous tissue, an amorphous precipitate is formed from which monomeric insulin molecules dissociate slowly to enter the circulation.  Onset of action is delayed, but relatively low blood levels of insulin are maintained for upto 24 hours resulting in a ‘peak-less’ effect. Thus, it is suitable for once daily injection and is mostly injected at bed time. Lower incidence of night-time hypoglycaemia compared to isophane insulin has been reported. It effectively lowers fasting and inter-digestive blood glucose levels but does not control post- meal glycaemia.[12]

Insulin Detemir: Myristic acid (a fatty acid) is attached to the amino group of lysine at B29 of insulin chain. As a result, it binds to albumin after s.c. injection from which the free form becomes available slowly. A profile of action like glargine is obtained, however it may require twice daily dosing.[12,13]

Insulin Degludeg: is an ultra-long acting insulin analogue created by deletion of threonine in B30, attaching lysine at B29 with a spacer molecule glutamic acid and a fatty acid to spacer glutamic acid. These allows Degludeg to self-aggregate on s.c. injection and form large multi-hexamer complexes which slowly dissociate into monomers and are absorbed. It can be injected once in 24 hours with variable timings.[12,13]

TC-Oct 2017 - 016 - Table3 T1DM


Normal physiological release of insulin occurs at a constitutive basal rate and meal-related bursts that are precisely regulated to control the blood glucose levels. Type 1 diabetics lack both, basal as well as the post meal bursts. Any satisfactory insulin regimen should provide basal control by inhibiting hepatic glucose output, lipolysis and protein breakdown, as well as supply extra amount to meet postprandial needs for disposal of absorbed glucose and amino acids. Based on an individual’s requirement, many regimens of insulin replacement are employed. The two most commonly used regimens are discussed below:

Basal-bolus regimen: An intermediate or long- acting-insulin (glargine) is injected once daily either before breakfast or before bed-time for basal coverage with a regular or rapid acting analogue before each meal, as bolus insulin (Figure 1A). Such intensive regimens more completely meet the objective of achieving a round-the-clock euglycaemia, but are more demanding and expensive.

Premixed regimen: A frequently used regimen uses mixture of regular with isophane insulin or rapid acting analogue with protamine analogue insulin in various proportions. The total daily dose of a 30:70 or 50:50 mixture is usually divided into two doses and injected s.c. before breakfast and before dinner (Figure 1B). While it offers the convenience of only two daily injections, post-prandial glycaemia may not be adequately controlled and late hypoglycaemia may occur.

TC-Oct 2017 - 017 Insulin Regimens in T1DM


The incidence of Type 1 DM continues to increase globally and it has serious short and long-term implications.  The disorder has a strong genetic component, though the factors that trigger the onset of clinical disease remain largely unknown.  Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly regarding disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Newer insulins and treatment approaches have led to improved outcomes in terms of both glycaemic control and reduced risks for development of complications. Nevertheless, major challenges remain in the development of approaches to the prevention and management of type 1 diabetes and its complications.





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