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LADA, the acronym for "Latent Autoimmune Diabetes of the Adult", stands for a hybrid form of diabetes first described in 1977 (Carlsson S 2019) which has characteristics of both type 1 and type 2 diabetes. Some authors prefer the term "Intermediary Diabetes Mellitus" instead of LADA (Ionescu-Tirgoviste C et al. 2018). In contrast to type 1 diabetes, the LADA type of diabetes mellitus develops a protracted insulin deficiency. LADA diabetics typically become clinically conspicuous in adulthood (>25 years) and are conspicuous by frequent hypoglycaemia when the diabetes is stopped. The C-peptide levels are usually slightly reduced in LADA and can hardly be stimulated.

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In relation to all type 2 diabetics, one reckons with about 10% (5% to 15%) LADA patients among the diagnosed type 2 diabetics in Germany. Overall, the prevalence of LADA diabetes is not known exactly. Regional accumulations and genetic differences between the ethnic groups, as is the case for type 1 diabetes, are also described for LADA. Asians are more likely to have antibodies than genuine Europeans.

Age-related prevalence of LADA (UKPDS 25 study):

• 25 to 34 years LADA prevalence: 34
• 35 to 44 years LADA prevalence:14
• 45 to 54 years LADA prevalence:9
• 55 to 64 years LADA prevalence:7

Genetics: The etiopathogenesis of LADA is not clear. Viral effects as well as factors such as obesity, physical inactivity, alcohol consumption and smoking (Carlsson S 2019) are accused. In contrast to type 1 diabetes, the destruction of islet cells is protracted. Thus, the diagnosis of LADA usually takes significantly longer than for type 1 diabetes.

In LADA patients, 4 different antibodies can be detected partly isolated, partly combined:

• Cytoplasmatic antibodies directly against the islet cells = islet cell antibodies (ICA)
• Antibodies against the enzyme glutamic acid decarboxylase (GADA or GAD65A)
• Antibodies against the enzyme tyrosine phosphatase IA-2 (IA-2A)
• Antibodies against insulin = Insulin autoantibodies (IAA)
• In a larger study (n=3,672) with type 2 diabetes, 6 % had ICA, 10 % had GADA and 4 % had both islet antibodies. With increasing age, both the proportion of patients with single antibodies and the proportion of patients with the combination of ICA and GAD decreased significantly. Phenotypically, older LADA patients are comparable to type 2 diabetics and younger LADA patients to type 1 diabetics. LADA patients who showed multiple autoantibodies are usually female and slimmer than patients with type 2 diabetes (Maddaloni E et al 2019).

HLA status: The majority of LADA patients show the same risk alleles as type 1 diabetics (e.g. HLA-DRB1/ HLA-DQB1 - Carlsson S 2019-). Family history of LADA diabetics is similar to that of type 1 diabetes.

LADA patients are often initially diagnosed with type 2 diabetes by mistake, since the LADA diabetic has similar clinical features to an "autoantibody-negative" type 2 diabetic. However, those affected are leaner than the type 2 diabetic. LADA diabetics, like type 2 diabetics, show evidence of metabolic syndrome such as dyslipidemia (hyperlipidemia, elevated triglycerides) and hypertension. However, unlike type 2 diabetics, adult LADA patients show cytoplasmic islet cell antibodies (ICA) and/or glutamic acid decarboxylase antibodies (GADA).

LADA can be diagnosed only in the synopsis of anamnestic, clinical and serological (antibody determinations) (Ionescu-Tirgoviste C et al. 2018):

• Age at diagnosis of type 2 diabetes > 25 years.
• Slim or low BMI (<25 kg/m²).
• Acute symptoms such as polyuria, polydipsia, or ketonuria at diagnosis (rare)
• Signs of other autoimmune reactions
• Family history of autoimmune disease
• Good response to insulin
• Rapid loss of effect of oral antidiabetics
• Low blood C-peptide and insulin levels

Evidence of LADA is the detection of antibodies in the serum. Antibodies against the enzyme glutamate decarboxylase(GAD-AK; note: GAD-AK are also found in other autoimmune endocrinopathies, e.g. Hashimoto's thyroiditis, Addison's disease and in various neurological diseases).

Important: Insulin autoantibodies (IAA) should only be determined in patients who have not yet been treated with insulin. These antibodies are also produced as an immune response to insulin therapy. The determination of IA-2 antibodies is less sensitive than the determination of GADA. The detection of antibodies does not have to be accompanied by symptoms of disease.

LADA patients often have more severe neuropathies, especially "small fibre neuropathy" compared to type 2 diabetics (Alam U et al. 2018).

The therapy of LADA (as with the other forms of diabetes) is individualized. A balanced diet and oral antidiabetic medications can often be sufficient to control blood glucose levels and long-term blood glucose (HbA1c) levels at the onset of the disease.

On average, 70% of LADA patients younger than 45 years start insulin therapy within 6 years of diagnosis. Only about 40% of patients > 45 years of age become insulin dependent. If the GAD antibody titer is low, and in the absence of other islet autoantibodies, it is reasonable to assume that the beta cell mass of the body is still sufficient to continue to produce sufficient insulin (Hals IK1 et al.). In these cases, it should be sufficient to monitor blood glucose levels closely and - if necessary - initiate antidiabetic therapy.

Metformin: To date, there are insufficient data on the efficacy of metformin and other diabetes medications in the treatment of LADA.

If insulin secretion is analyzed in LADA patients (glucagon test), a low initial insulin level is shown, which hardly increases at all even after stimulation with glucagon. In contrast, in type 2 diabetes, high insulin levels are always present at the beginning of the disease.

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