In the UK, around 90% of people with diabetes have type 2 diabetes (T2D), around 8% have type 1 diabetes (T1D) and almost 2% have other forms of diabetes.
- T1D generally presents in young, thin patients, with marked symptoms of polyuria, polydipsia, weight loss, and diabetic ketoacidosis (DKA).
- T2D usually affects older, overweight people, and they are generally initially treated with oral medications .
- MODY: When the presentation is atypical, other forms of diabetes should be considered, for example, maturity-onset diabetes of the young (MODY) in a young, thin person with mild hyperglycemia and a strong family history. of diabetes diagnosed at an early age.
- LADA: In lean middle-aged adults with hyperglycemia, autoimmune diabetes (LADA) should be considered. If the patient is non-white and overweight, DKA-prone diabetes should be suspected.
| Etiological classification of diabetes mellitus | |
| Gestational diabetes | |
| Genetic defects in β-cell function | Transient neonatal diabetes Permanent neonatal diabetes Mitochondrial DNA mutations |
| Genetic defects in insulin action | Insulin resistance type A Leprechaunism Rabson-Mendenhall syndrome Lipoatrophic diabetes |
| Exocrine pancreas disease | Pancreatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy |
| Endocrinopathies | Acromegaly Cushing syndrome Glucagonoma Pheochromocytoma Hyperthyroidism Somatostatinoma |
| drug induced | Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Diazoxide Beta-adrenergic agonists Thiazides Gamma interferon Immunotherapy, etc. |
| Infections | Congenital rubella Cytomegalovirus |
| Rare forms of immune-mediated diabetes | Anti-insulin receptor antibodies |
| Other genetic syndromes associated with diabetes | Down syndrome Klinefelter syndrome Turner syndrome Wolfram syndrome Friedreich’s ataxia Huntington’s chorea Laurence-Moon-Biedl syndrome Myotonic dystrophy Porphyria Prader-Willi syndrome |
| Midlife diabetes in young people |
MODY is a group of monogenic β-cell disorders, also known as monogenic diabetes .
It is characterized by early age onset (usually <25 years), autosomal dominant transmission, absence of autoimmune markers, absence of insulin resistance, and insulin independence.
It is estimated to represent 1% to 2% of patients diagnosed with diabetes and, in the UK, the prevalence of MODY is estimated at 108 cases/million. However, this may be a significant underestimate and these figures are not considered accurate until screening studies are performed in the general population. The most common mutations are hepatocyte nuclear factor 1 alpha (HNF1α; 52%), glucokinase (GCK; 32%), and HNF4α (10%).
> Hepatocyte nuclear factor 1-alpha gene
Previously called MODY3, mutations in the HNF1α gene on chromosome 3 are associated with a progressive defect in insulin secretion. Those mutations also result in a low renal threshold for glucose and therefore carriers of these mutations have glycosuria.
People with MODY HNF-1 may develop micro- and macrovascular complications, as seen in T1D and T2D, and are at increased risk of cardiovascular mortality. They are exquisitely sensitive to sulfonylureas, with which they often maintain excellent glycemic control for years, although some patients eventually require insulin therapy.
> Glucokinase gene
Formerly called MODY2, the GCK gene is located on chromosome 7. This mutation results in a higher threshold for glucose stimulated by insulin secretion. Insulin secretion remains regulated and, therefore, hyperglycemia is usually mild and stable. Patients are asymptomatic and hyperglycemia is often found incidentally or during pregnancy. No diabetes-related microvascular complications are observed.
There are no large studies evaluating long-term macrovascular effects, but GCK mutation carriers appear to have cardiovascular risk profiles. No treatment is needed outside of pregnancy. During pregnancy, women are closely monitored and insulin is occasionally used, but if the fetus is macrosomic, the mainstay of treatment is early delivery.
> Hepatocyte nuclear factor 4 alpha gene
Previously known as MODY1, the HNF4α gene is located on chromosome 20 and is expressed in both the liver and pancreatic β cells. Its function is to positively regulate HNF1α activity and is therefore similarly associated with an abnormal response of insulin secretion to glucose. Unlike HNF1α, HNF4α mutation carriers have a normal renal glucose threshold. Similar to HNF1α, patients can develop micro- and macrovascular complications; and are also extremely sensitive to sulfonylureas.
| Research |
Clinicians should suspect MODY if patients are young, have a strong family history of diabetes diagnosed at a young age (<30 years), have no features suggestive of insulin resistance, and are not insulin dependent .
These investigations are useful to aid diagnosis, when there is clinical suspicion: negative autoantibody profile (islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GAD65), insulinoma-associated autoantibodies 2 (IA2), zinc-8 transporting autoantibodies [ZnT8]) and sufficient C-peptide levels, compared to paired blood glucose levels.
High-sensitivity C-Reactive Protein, which is under the transcriptional control of HNF1α, is lower in patients with HNF1α mutations. Given its modest cost and availability, it could be used as a biomarker to identify those with HNF1α MODY. The creatinine/urinary C peptide ratio is also important, as a practical tool for outpatients in whom it is necessary to differentiate between MODY HNF1α and MODY HNF4α and T1D of more than 5 years of evolution.
There is an online MODY probability calculator , which can help quantify clinical suspicion of MODY, and can be found at: www.diabetesgenes.org. Ultimately, the diagnosis is made through genetic testing. Doctors should refer to a diabetologist or clinical geneticist. The MODY genetic testing form can also be found on the corresponding website.
| Latent autoimmune diabetes in adults |
LADA is a heterogeneous condition that shares characteristics of T1D and T2D. Typically presents as T2D but is associated with progression to early insulin therapy. It is debated whether LADA is a distinct entity or simply part of the T1D spectrum.
Studies suggest that LADA accounts for 2% to 12% of cases that appear in adulthood. Compared to T2D, people with LADA tend to be younger, thinner, and have a personal or family history of autoimmune diseases.
Features of metabolic syndrome tend to be present at a similar or higher frequency in LADA than in T1D.
It has considerable heterogeneity and sometimes its phenotype and characteristics are indistinguishable from T1D or T2D. LADA was believed to be a more insidious presentation of T1D but, unlike typical T1D, it does not present acutely with DKA or as a diabetic emergency with insulin requirement.
In general, it occurs after the age of 30, regardless of insulin at the time of diagnosis. for more than 6 months, and presence of positive autoantibodies for diabetes.
An analysis of patients enrolled in the UKPDS trial showed no significant differences in cardiovascular outcomes compared with patients with T2DM, after adjustment for confounders.
It was also observed that patients with LADA had a higher risk of microvascular complications compared to patients with T2D, secondary to worse glycemic control. Therefore, optimization of glycemic control and secondary prevention of diabetic complications should be an important aspect in the management of LADA.
| Research |
As mentioned, positivity for autoantibodies is a characteristic of LADA, of which the GAD65 antibody is the most sensitive. Up to 90% of patients with LADA have positive autoantibodies.
Therefore, the GAD65 antibody is a good screening antibody, and if there is still a strong suspicion of LADA in a GAD65-negative patient, other diabetes autoantibodies should be tested. C-peptide, as a marker of endogenous insulin production, is a useful management aid. With LADA, patients tend to present at a low but still detectable level.
| Treatment |
LADA treatment aims to preserve insulin secretion capacity, starting with insulin when appropriate and doing standard secondary prevention of diabetic complications.
Sulfonylureas may accelerate the decline in C-peptide levels and are not recommended for the treatment of LADA. A recent consensus statement from an international panel of experts suggests the use of C-peptide to guide the management of LADA.
C-peptide levels should be measured at the same time as blood glucose, and should be between 13.30 mg/ml and 130 mg/ml. If C-peptide levels are <900 mg/ml, a multiple insulin regimen is recommended and the patient should be treated as T1D. If C-peptide levels are between 900 mg/ml and 2,120 mg/ml, the patient should be treated as T2D, avoiding the use of sulfonylureas.
C-peptide levels should be repeated every 6 months. If levels are > 2,120 mg/ml, it will be treated as T2D and measurements will be repeated when deterioration in glucose control is noted.
| Diabetes prone to ketosis |
Ketosis-prone diabetes is characterized by DKA in patients who do not fit the typical characteristics of T1D. After initial insulin treatment and improvement in glycemic control, there is often a marked improvement in β-cell function, allowing discontinuation of insulin therapy within a few months. In these patients, there is an acute reduction in insulin secretion and action, due to glucose toxicity on β cells.
Insulin treatment can improve hyperglycemia and β-cell function and therefore cease the need for further insulin therapy within months.
This is most commonly seen in people of non-white ethnicity, particularly black or Afro-Caribbean people, with a strong male predominance, strong family history, older age and higher body mass index. There is also a link between glucose-6 phosphate dehydrogenase deficiency (a condition that is common in West African men) and ketosis-prone diabetes.
It is important to recognize this clinical entity since unnecessary continuation of insulin therapy could cause greater weight gain, hypoglycemia, and impact on quality of life. On the other hand, incorrect diagnosis of these patients with T2D could neglect the importance of controlling ketones when they are altered.
| Investigations and management |
DKA should be treated according to DKA protocols, and all patients should be discharged on insulin. After discharge, the diabetes team should follow patients, to reevaluate β-cell function with C-peptide measurements, and to evaluate autoimmunity. They must have a negative autoantibody profile.
Typically, C-peptide levels are low at the time of DKA and increase over a few weeks or months. In most patients with sufficient C-peptide compared to their glucose level, insulin can be safely discontinued. They can be well controlled with diet or metformin for a few years, but can relapse with DKA. Patients with insufficient C-peptide compared to their matched glucose level should continue insulin therapy.
| Secondary causes of diabetes |
There are many secondary causes. Although they are much less common, it is important to recognize them so that the primary disease can be diagnosed with computed tomography (CT) if there is new-onset T2D in older people, with marked weight loss, anorexia, abdominal pain, or features of exocrine insufficiency.
> Pancreatic cancer
Pancreatic cancer may rarely present with hyperglycemia due to pancreatic dysfunction caused by the cancer. Consider screening for pancreatic cancer by CT if it is a recent onset of T2D in an elderly patient with marked weight loss, anorexia, abdominal pain, or manifestations of exocrine pancreas.
> Hemochromatosis
Hemochromatosis can present with hyperglycemia due to iron deposited in the pancreas. There should be clinical suspicion if there is skin hyperpigmentation, arthralgia, hypogonadism or features of liver disease. Laboratory tests that may be associated with hemochromatosis include unexplained abnormal liver function, elevated serum ferritin, and elevated transferrin saturations. The diagnosis will be confirmed by HFE gene mutation testing. Diabetes treatment in hemochromatosis is similar to that of T2D and can sometimes also be improved with phlebotomy.
Conclusion Diabetes is a common condition and affects a large proportion of people we see in clinical practice. Although the general practitioner will be familiar with the presentations of T2D and T1D, it is important to consider other rare forms of diabetes and, if the presentation is atypical, other forms of diabetes should be suspected and the specialist team consulted at an early stage. |
